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Sample records for potential pathophysiological role

  1. Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide.

    PubMed

    Ozgocmen, Salih; Ozyurt, Huseyin; Sogut, Sadik; Akyol, Omer

    2006-05-01

    Fibromyalgia (FM) is a common chronic pain syndrome with an unknown etiology. Recent years added new information to our understanding of FM pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, hypothalamic-pituitary-adrenal axis hormones, oxidative stress, and mechanisms of pain modulation, central sensitization, and autonomic functions in FM revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of FM. Oxidative stress and nitric oxide may play an important role in FM pathophysiology, however it is still not clear whether oxidative stress abnormalities documented in FM are the cause or the effect. This should encourage further researches evaluating the potential role of oxidative stress and nitric oxide in the pathophysiology of FM and the efficacy of antioxidant treatments (omega-3 and -6 fatty acids, vitamins and others) in double blind and placebo controlled trials. These future researches will enhance our understanding of the complex pathophysiology of this disorder. PMID:16328420

  2. Pathophysiology of hypophosphatasia and the potential role of asfotase alfa

    PubMed Central

    Orimo, Hideo

    2016-01-01

    Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. PMID:27274262

  3. Pathophysiology of hypophosphatasia and the potential role of asfotase alfa.

    PubMed

    Orimo, Hideo

    2016-01-01

    Hypophosphatasia (HPP) is an inherited systemic bone disease that is characterized by bone hypomineralization. HPP is classified into six forms according to the age of onset and severity as perinatal (lethal), perinatal benign, infantile, childhood, adult, and odontohypophosphatasia. The causative gene of the disease is the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP). TNAP is expressed ubiquitously, and its physiological role is apparent in bone mineralization. A defect in bone mineralization can manifest in several ways, including rickets or osteomalacia in HPP patients. Patients with severe forms suffer from respiratory failure because of hypoplastic chest, which is the main cause of death. They sometimes present with seizures due to a defect in vitamin B6 metabolism resulting from the lack of alkaline phosphatase activity in neuronal cells, which is also lethal. Patients with a mild form of the disease exhibit rickets or osteomalacia and a functional defect of exercise. Odontohypophosphatasia shows only dental manifestations. To date, 302 mutations in the ALPL gene have been reported, mainly single-nucleotide substitutions, and the relationships between phenotype and genotype have been partially elucidated. An established treatment for HPP was not available until the recent development of enzyme replacement therapy. The first successful enzyme replacement therapy in model mice using a modified human TNAP protein (asfotase alfa) was reported in 2008, and subsequently success in patients with severe form of the disease was reported in 2012. In 2015, asfotase alfa was approved in Japan in July, followed by in the EU and Canada in August, and then by the US Food and Drug Administration in the USA in October. It is expected that therapy with asfotase alfa will drastically change treatments and prognosis of HPP. PMID:27274262

  4. Role of the Hemostatic System on SCD Pathophysiology and Potential Therapeutics

    PubMed Central

    Pakbaz, Zahra; Wun, Ted

    2014-01-01

    Synopsis Recent studies suggest that sickle cell disease is a hypercoagulable state contributing to the vaso-occlusive events in microcirculation resulting in acute and chronic sickle cell related organ damage. In this article, we will review the existing evidence for contribution of hemostatic system perturbation to sickle cell disease pathophysiology. We will also review the data showing increased risk of thromboembolic events, particularly newer information on the incidence of VTE. Finally, the potential role of platelet inhibitors and anticoagulants in SCD will be briefly reviewed. PMID:24589271

  5. The Role of Muscarinic Receptors in the Pathophysiology of Mood Disorders: A Potential Novel Treatment?

    PubMed Central

    Jeon, Won Je; Dean, Brian; Scarr, Elizabeth; Gibbons, Andrew

    2015-01-01

    The central cholinergic system has been implicated in the pathophysiology of mood disorders. An imbalance in central cholinergic neurotransmitter activity has been proposed to contribute to the manic and depressive episodes typical of these disorders. Neuropharmacological studies into the effects of cholinergic agonists and antagonists on mood state have provided considerable support for this hypothesis. Furthermore, recent clinical studies have shown that the pan-CHRM antagonist, scopolamine, produces rapid-acting antidepressant effects in individuals with either major depressive disorder (MDD) or bipolar disorder (BPD), such as bipolar depression, contrasting the delayed therapeutic response of conventional mood stabilisers and antidepressants. This review presents recent data from neuroimaging, post-mortem and genetic studies supporting the involvement of muscarinic cholinergic receptors (CHRMs), particularly CHRM2, in the pathophysiology of MDD and BPD. Thus, novel drugs that selectively target CHRMs with negligible effects in the peripheral nervous system might produce more rapid and robust clinical improvement in patients with BPD and MDD. PMID:26630954

  6. Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure

    PubMed Central

    Salles, Thiago A.; dos Santos, Leonardo; Barauna, Valério G.; Girardi, Adriana C. C.

    2015-01-01

    Dipeptidyl peptidase IV (DPPIV) is a widely expressed multifunctional serine peptidase that exists as a membrane-anchored cell surface protein or in a soluble form in the plasma and other body fluids. Numerous substrates are cleaved at the penultimate amino acid by DPPIV, including glucagon-like peptide-1 (GLP-1), brain natriuretic peptide (BNP) and stromal cell-derived factor-1 (SDF-α), all of which play important roles in the cardiovascular system. In this regard, recent reports have documented that circulating DPPIV activity correlates with poorer cardiovascular outcomes in human and experimental heart failure (HF). Moreover, emerging evidence indicates that DPPIV inhibitors exert cardioprotective and renoprotective actions in a variety of experimental models of cardiac dysfunction. On the other hand, conflicting results have been found when translating these promising findings from preclinical animal models to clinical therapy. In this review, we discuss how DPPIV might be involved in the cardio-renal axis in HF. In addition, the potential role for DPPIV inhibitors in ameliorating heart disease is revised, focusing on the effects of the main DPPIV substrates on cardiac remodeling and renal handling of salt and water. PMID:25690036

  7. Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential

    PubMed Central

    Belo, Hélio; Silva, Gabriela; Cardoso, Bruno A.; Porto, Beatriz; Minguillon, Jordi; Barbot, José; Coutinho, Jorge; Casado, Jose A.; Benedito, Manuela; Saturnino, Hema; Costa, Emília; Bueren, Juan A.; Surralles, Jordi; Almeida, Antonio

    2015-01-01

    Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population. PMID:26466379

  8. Cation channels of the transient receptor potential superfamily: their role in physiological and pathophysiological processes of smooth muscle cells.

    PubMed

    Dietrich, Alexander; Chubanov, Vladimir; Kalwa, Hermann; Rost, Benjamin R; Gudermann, Thomas

    2006-12-01

    Smooth muscle cells (SMC) are essential components of many tissues of the body. Ion channels regulate their membrane potential, the intracellular Ca(2+) concentration ([Ca(2+)](i)) and their contractility. Among the ion channels expressed in SMC cation channels of the transient receptor potential (TRP) superfamily allow the entry of Na(+), Ca(2+) and Mg(2+). Members of the TRP superfamily are essential constituents of tonically active channels (TAC), receptor-operated channels (ROC), store-operated channels (SOC) and stretch-activated channels (SAC). This review focusses on TRP channels (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7, TRPV2, TRPV4, TRPM4, TRPM7, TRPP2) whose physiological functions in SMC were dissected by downregulating channel activity in isolated tissues or by the analysis of gene-deficient mouse models. Their possible functional role and physiological regulation as homomeric or heteromeric channels in SMC are discussed. Moreover, TRP channels may also be responsible for pathophysiological processes involving SMC-like airway hyperresponsiveness and pulmonary hypertension. Therefore, they present important drug targets for future pharmacological interventions. PMID:16842858

  9. Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia

    PubMed Central

    Oliveira, Lucila H; Schiavinato, Josiane L; Fráguas, Mariane S; Lucena-Araujo, Antonio R; Haddad, Rodrigo; Araújo, Amélia G; Dalmazzo, Leandro F; Rego, Eduardo M; Covas, Dimas T; Zago, Marco A; Panepucci, Rodrigo A

    2015-01-01

    Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease. PMID:26251039

  10. Potential roles of microRNA-29a in the molecular pathophysiology of T-cell acute lymphoblastic leukemia.

    PubMed

    Oliveira, Lucila H; Schiavinato, Josiane L; Fráguas, Mariane S; Lucena-Araujo, Antonio R; Haddad, Rodrigo; Araújo, Amélia G; Dalmazzo, Leandro F; Rego, Eduardo M; Covas, Dimas T; Zago, Marco A; Panepucci, Rodrigo A

    2015-10-01

    Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease. PMID:26251039

  11. Role of TNFα in pulmonary pathophysiology

    PubMed Central

    Mukhopadhyay, Srirupa; Hoidal, John R; Mukherjee, Tapan K

    2006-01-01

    Tumor necrosis factor alpha (TNFα) is the most widely studied pleiotropic cytokine of the TNF superfamily. In pathophysiological conditions, generation of TNFα at high levels leads to the development of inflammatory responses that are hallmarks of many diseases. Of the various pulmonary diseases, TNFα is implicated in asthma, chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In addition to its underlying role in the inflammatory events, there is increasing evidence for involvement of TNFα in the cytotoxicity. Thus, pharmacological agents that can either suppress the production of TNFα or block its biological actions may have potential therapeutic value against a wide variety of diseases. Despite some immunological side effects, anti-TNFα therapeutic strategies represent an important breakthrough in the treatment of inflammatory diseases and may have a role in pulmonary diseases characterized by inflammation and cell death. PMID:17034639

  12. Sleep, Plasticity and the Pathophysiology of Neurodevelopmental Disorders: The Potential Roles of Protein Synthesis and Other Cellular Processes

    PubMed Central

    Picchioni, Dante; Reith, R. Michelle; Nadel, Jeffrey L.; Smith, Carolyn B.

    2014-01-01

    Sleep is important for neural plasticity, and plasticity underlies sleep-dependent memory consolidation. It is widely appreciated that protein synthesis plays an essential role in neural plasticity. Studies of sleep-dependent memory and sleep-dependent plasticity have begun to examine alterations in these functions in populations with neurological and psychiatric disorders. Such an approach acknowledges that disordered sleep may have functional consequences during wakefulness. Although neurodevelopmental disorders are not considered to be sleep disorders per se, recent data has revealed that sleep abnormalities are among the most prevalent and common symptoms and may contribute to the progression of these disorders. The main goal of this review is to highlight the role of disordered sleep in the pathology of neurodevelopmental disorders and to examine some potential mechanisms by which sleep-dependent plasticity may be altered. We will also briefly attempt to extend the same logic to the other end of the developmental spectrum and describe a potential role of disordered sleep in the pathology of neurodegenerative diseases. We conclude by discussing ongoing studies that might provide a more integrative approach to the study of sleep, plasticity, and neurodevelopmental disorders. PMID:24839550

  13. Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential

    PubMed Central

    Dawson, Kristin; Aflaki, Mona; Nattel, Stanley

    2013-01-01

    The Wnt-Frizzled (Fzd) G-protein-coupled receptor system, involving 19 distinct Wnt ligands and 10 Fzd receptors, plays key roles in the development and functioning of many organ systems. There is increasing evidence that Wnt-Fzd signalling is important in regulating cardiac function. Wnt-Fzd signalling primarily involves a canonical pathway, with dishevelled-1-dependent nuclear translocation of β-catenin that derepresses Wnt-sensitive gene transcription, but can also include non-canonical pathways via phospholipase-C/Ca2+ mobilization and dishevelled-protein activation of small GTPases. Wnt-Fzd effects vary with specific ligand/receptor interactions and associated downstream pathways. This paper reviews the biochemistry and physiology of the Wnt-Fzd complex, and presents current knowledge of Wnt signalling in cardiac remodelling processes such as hypertrophy and fibrosis, as well as disease states such as myocardial infarction (MI), heart failure and arrhythmias. Wnt signalling is activated during hypertrophy; inhibiting Wnt signalling by activating glycogen synthase kinase attenuates the hypertrophic response. Wnt signalling has complex and time-dependent actions post-MI, so that either beneficial or harmful effects might result from Wnt-directed interventions. Stem cell biology, a promising area for therapeutic intervention, is highly regulated by Wnt signalling. The Wnt system regulates fibroblast function, and is prominently altered in arrhythmogenic ventricular cardiomyopathy, a familial disease involving excess deposition of fibroadipose tissue. Wnt signalling controls connexin43 expression, thereby contributing to the regulation of cardiac electrical stability and arrhythmia generation. Although much has been learned about Wnt-Fzd signalling in hypertrophy and infarction, its role is poorly understood for a broad range of other heart disorders. Much more needs to be learned for its contributions to be fully appreciated, and to permit more effective

  14. Bitter taste receptors: Extraoral roles in pathophysiology.

    PubMed

    Shaik, Feroz Ahmed; Singh, Nisha; Arakawa, Makoto; Duan, Kangmin; Bhullar, Rajinder P; Chelikani, Prashen

    2016-08-01

    Over the past decade tremendous progress has been made in understanding the functional role of bitter taste receptors (T2Rs) and bitter taste perception. This review will cover the recent advances made in identifying the role of T2Rs in pathophysiological states. T2Rs are widely expressed in various parts of human anatomy and have been shown to be involved in physiology of respiratory system, gastrointestinal tract and endocrine system. Empirical evidence has shown T2Rs to be an integral component of antimicrobial immune responses in upper respiratory tract infections. The studies on human airway smooth muscle cells have shown that a potent bitter tastant induced bronchodilatory effects mediated by bitter taste receptors. Clinical data suggests a role for T2R38 polymorphism in predisposition of individuals to chronic rhinosinusitis. The role of genetic variation in T2Rs and its impact on disease susceptibility have been investigated in various other disease risk factors such as alcohol dependence, head and neck cancers. Preliminary reports have demonstrated differential expression of functional T2Rs in breast cancer cell lines. Studies on the role of T2Rs in pathophysiology of diseases including chronic rhinosinusitis, asthma, cystic fibrosis, and cancer have been promising. However, research in this field is in its nascent stages, and more confirmatory studies on animal models and in clinical settings are required. PMID:27032752

  15. Mitophagy: mechanisms, pathophysiological roles, and analysis

    PubMed Central

    Ding, Wen-Xing; Yin, Xiao-Ming

    2013-01-01

    Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy. PMID:22944659

  16. The Pathophysiologic Roles of TRPM7 Channel

    PubMed Central

    Park, Hyun Soo; Hong, Chansik

    2014-01-01

    Transient receptor potential melastatin 7 (TRPM7) is a member of the melastatin-related subfamily and contains a channel and a kinase domain. TRPM7 is known to be associated with cell proliferation, survival, and development. It is ubiquitously expressed, highly permeable to Mg2+ and Ca2+, and its channel activity is negatively regulated by free Mg2+ and Mg-complexed nucleotides. Recent studies have investigated the relationships between TRPM7 and a number of diseases. TRPM7 regulates cell proliferation in several cancers, and is associated with ischemic cell death and vascular smooth muscle cell (VSMC) function. This review discusses the physiologic and pathophysiologic functions and significance of TRPM7 in several diseases. PMID:24634592

  17. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets.

    PubMed

    Vasconcelos, Luiz H C; Souza, Iara L L; Pinheiro, Lílian S; Silva, Bagnólia A

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  18. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets

    PubMed Central

    Vasconcelos, Luiz H. C.; Souza, Iara L. L.; Pinheiro, Lílian S.; Silva, Bagnólia A.

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  19. [Gut microbiota: Description, role and pathophysiologic implications].

    PubMed

    Landman, C; Quévrain, E

    2016-06-01

    The human gut contains 10(14) bacteria and many other micro-organisms such as Archaea, viruses and fungi. Studying the gut microbiota showed how this entity participates to gut physiology and beyond this to human health, as a real "hidden organ". In this review, we aimed to bring information about gut microbiota, its structure, its roles and its implication in human pathology. After bacterial colonization in infant, intestinal microbial composition is unique for each individual although more than 95% can be assigned to four major phyla. The use of culture independent methods and more recently the development of high throughput sequencing allowed to depict precisely gut microbiota structure and diversity as well as its alteration in diseases. Gut microbiota is implicated in the maturation of the host immune system and in many fundamental metabolic pathways including sugars and proteins fermentation and metabolism of bile acids and xenobiotics. Imbalance of gut microbial populations or dysbiosis has important functional consequences and is implicated in many digestive diseases (inflammatory bowel diseases, colorectal cancer, etc.) but also in obesity and autism. These observations have led to a surge of studies exploring therapeutics which aims to restore gut microbiota equilibrium such as probiotics or fecal microbiota transplantation. But recent research also investigates biological activity of microbial products which could lead to interesting therapeutics leads. PMID:26749318

  20. Role of Sirtuins in Regulating Pathophysiology of the Heart.

    PubMed

    Bindu, Samik; Pillai, Vinodkumar B; Gupta, Mahesh P

    2016-08-01

    Cardiovascular diseases (CVDs) are expanding at an alarming rate and people's propensity to develop them increases with age. Growing evidence indicates that sirtuins play a pivotal role in regulating a multitude of age-related diseases. Sirtuins are versatile molecules conserved from archaea to mammals. They are regulated by various metabolic and environmental stimuli. Seven sirtuin homologs (SIRT1-7) are present in mammals, with diverse cellular locations. Recent studies have delineated roles of sirtuins in regulating cardiac pathophysiological conditions under various stressors. SIRT1 is the most extensively studied sirtuin, while the role of other sirtuins in maintaining cardiac growth and function is still emerging. In this review we discuss the present understanding of the role of sirtuins in regulating pathophysiological conditions of the heart. PMID:27210897

  1. Molecular structure and pathophysiological roles of the Mitochondrial Calcium Uniporter.

    PubMed

    Mammucari, Cristina; Raffaello, Anna; Vecellio Reane, Denis; Rizzuto, Rosario

    2016-10-01

    Mitochondrial Ca(2+) uptake regulates a wide array of cell functions, from stimulation of aerobic metabolism and ATP production in physiological settings, to induction of cell death in pathological conditions. The molecular identity of the Mitochondrial Calcium Uniporter (MCU), the highly selective channel responsible for Ca(2+) entry through the IMM, has been described less than five years ago. Since then, research has been conducted to clarify the modulation of its activity, which relies on the dynamic interaction with regulatory proteins, and its contribution to the pathophysiology of organs and tissues. Particular attention has been placed on characterizing the role of MCU in cardiac and skeletal muscles. In this review we summarize the molecular structure and regulation of the MCU complex in addition to its pathophysiological role, with particular attention to striated muscle tissues. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID:26968367

  2. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome

    PubMed Central

    Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

    2014-01-01

    Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting. PMID:24976697

  3. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome.

    PubMed

    Muscatello, Maria Rosaria A; Bruno, Antonio; Scimeca, Giuseppe; Pandolfo, Gianluca; Zoccali, Rocco A

    2014-06-28

    Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting. PMID:24976697

  4. Acute and Impaired Wound Healing: Pathophysiology and Current Methods for Drug Delivery, Part 2: Role of Growth Factors in Normal and Pathological Wound Healing: Therapeutic Potential and Methods of Delivery

    PubMed Central

    Demidova-Rice, Tatiana N.; Hamblin, Michael R.; Herman, Ira M.

    2012-01-01

    This is the second of 2 articles that discuss the biology and pathophysiology of wound healing, reviewing the role that growth factors play in this process and describing the current methods for growth factor delivery into the wound bed. PMID:22820962

  5. Hydrogen Sulfide Chemical Biology: Pathophysiological roles and detection

    PubMed Central

    Kolluru, Gopi K; Shen, Xinggui; Bir, Shyamal C.; Kevil, Christopher G.

    2014-01-01

    Hydrogen sulfide (H2S) is the most recent endogenous gasotransmitter that has been reported to serve many physiological and pathological functions in different tissues. Studies over the past decade have revealed that H2S can be synthesized through numerous pathways and its bioavailability regulated through its conversion into different biochemical forms. H2S exerts its biological effects in various manners including redox regulation of protein and small molecular weight thiols, polysulfides, thiosulfate/sulfite, iron-sulfur cluster proteins, and anti-oxidant properties that affect multiple cellular and molecular responses. However, precise measurement of H2S bioavailability and its associated biochemical and pathophysiological roles remains less well understood. In this review, we discuss recent understanding of H2S chemical biology, its relationship to tissue pathophysiological responses and possible therapeutic uses. PMID:23850632

  6. Potential Therapeutic Roles for Inhibition of the PI3K/Akt/mTOR Pathway in the Pathophysiology of Diabetic Retinopathy

    PubMed Central

    Jacot, Jorge L.; Sherris, David

    2011-01-01

    Novel therapeutics such as inhibitors of PI3K/Akt/mTOR pathway presents a unique opportunity for the management of diabetic retinopathy (DR). Second generation mTOR inhibitors have the prospect to be efficacious in managing various stages of disease progression in DR. During early stages, the mTOR inhibitors suppress HIF-1α, VEGF, leakage, and breakdown of the blood-retinal barrier. These mTOR inhibitors impart a pronounced inhibitory effect on inflammation, an early component with diverse ramifications influencing the progression of DR. These inhibitors suppress IKK and NF-κB along with downstream inflammatory cytokines, chemokines, and adhesion molecules. In proliferative DR, mTOR inhibitors suppress several growth factors that play pivotal roles in the induction of pathological angiogenesis. Lead mTOR inhibitors in clinical trials for ocular indications present an attractive treatment option for chronic use in DR with favorable safety profile and sustained ocular pharmacokinetics following single dose. Thereby, reducing dosing frequency and risk associated with chronic drug administration. PMID:22132311

  7. Potential serum biomarkers in the pathophysiological processes of stroke

    PubMed Central

    Miao, Yanying; Liao, James K

    2014-01-01

    Stroke is a leading cause of death and serious long-term disability. Ischemic stroke is the major subtype of stroke. Currently, its diagnosis is mainly dependent upon clinical symptoms and neuroimaging techniques. Despite these clinical and imaging modalities, often strokes are not recognized after initial onset. As early intervention of medical or surgical therapy is often associated with improved outcomes, there is an urgent need to improve the speed and accuracy of stroke diagnosis. Stroke is a complex pathophysiological process involving; energy failure, imbalance of ion homeostasis, acidosis, intracellular calcium overload, neuronal excitotoxicity, free radical-mediated lipid oxidation, inflammatory cell infiltration, and glial cell activation. These events ultimately lead to neuronal apoptotic cell death or necrosis. In this review, we have summarized the serum biomarkers according to the pathophysiological processes of stroke, which have been intensively studied in clinical trials of stroke over the past five years, and also used Medline’s ‘related article’ option to identify further articles. We focused on the potential biomarkers pertaining to vascular injury, metabolic changes, oxidative injury, and inflammation, and newly studied biomarkers, and discussed how these biomarkers could be used for the diagnosis or determining the prognosis of stroke. PMID:24417214

  8. Priapism: pathophysiology and the role of the radiologist

    PubMed Central

    Halls, J E; Patel, D V; Walkden, M; Patel, U

    2012-01-01

    Priapism is defined as a penile erection that persists for 4 h or longer and is unrelated to sexual activity. Its identification is important as lack of timely treatment (particularly of the low flow/ischaemic subgroup) can result in persisting erectile dysfunction as a consequence of irreversible corporal fibrosis. This review describes the physiology and anatomy of the normal erection, the aetiology and pathophysiology of the different types of priapism, and the role of the radiologist in the management of the condition. The treatment of iatrogenic priapism following intracavernosal injection of pharmacostimulant is discussed. PMID:22960245

  9. Cadmium induced testicular pathophysiology: prophylactic role of taurine.

    PubMed

    Manna, Prasenjit; Sinha, Mahua; Sil, Parames C

    2008-01-01

    The aim of the present study was to investigate the role of taurine against cadmium induced testicular pathophysiology. Cadmium (in the form of Cadmium chloride, CdCl(2)) administration at a dose of 4 mg/kg body weight for 6 days significantly decreased testicular Delta(5)-3beta-HSD and 17beta-HSD activities along with the reduction in the plasma testosterone level. In addition, reductions in testicular sperm count as well as loss in sperm motility were also observed in Cd-intoxication. Cd increased the intracellular concentration of reactive oxygen species and testicular Cd accumulation. Besides, increased levels of lipid peroxidation, protein carbonylation, glutathione disulfide and DNA fragmentation as well as decreased levels of the activities of the antioxidant enzymes, total thiols and reduced glutathione were also found to be associated with this toxicity. Taurine pretreatment at a dose of 100 mg/kg body weight for 5 days, on the other hand, could prevent all the Cd-induced testicular pathophysiology and oxidative insult related studied parameters. Taurine treatment, in addition also increased the in vivo ferric reducing antioxidant power linearly up to a dose of 100 mg/kg body weight. Histological examination of testicular sections from experimental animals supported these results. The effect of a well established antioxidant, vitamin C has been included in the study as a positive control. Combining all, data suggest that being an antioxidant, taurine plays a beneficial role against Cd-induced adverse effects on the male reproductive system. PMID:18926901

  10. The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

    PubMed Central

    Ozier, Annaïg; Allard, Benoit; Bara, Imane; Girodet, Pierre-Olivier; Trian, Thomas; Marthan, Roger; Berger, Patrick

    2011-01-01

    Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function. PMID:22220184

  11. Monocytes and their pathophysiological role in Crohn's disease.

    PubMed

    Zhou, L; Braat, H; Faber, K N; Dijkstra, G; Peppelenbosch, M P

    2009-01-01

    Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn's disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn's disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn's disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account. PMID:18791847

  12. Role of nuclear progesterone receptor isoforms in uterine pathophysiology

    PubMed Central

    Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

    2015-01-01

    cellular signaling pathways required for growth. In contrast, progesterone via PR activation appears to increase leiomyoma growth. The exact role of PRs in cervical cancer is unclear. PRs regulate implantation and therefore aberrant PR function may be implicated in recurrent pregnancy loss (RPL). PRs likely regulate key immunogenic factors involved in RPL. However, the exact role of PRs in the pathophysiology of RPL and the use of progesterone for therapeutic benefit remains uncertain. CONCLUSIONS PRs are key mediators of progesterone action in uterine tissues and are essential for normal uterine function. Aberrant PR function (due to abnormal expression and/or function) is a major cause of uterine pathophysiology. Further investigation of the underlying mechanisms of PR isoform action in the uterus is required, as this knowledge will afford the opportunity to create progestin/PR-based therapeutics to treat various uterine pathologies. PMID:25406186

  13. Role of Microglial Activation in the Pathophysiology of Bacterial Meningitis.

    PubMed

    Barichello, Tatiana; Generoso, Jaqueline S; Simões, Lutiana R; Goularte, Jessica A; Petronilho, Fabricia; Saigal, Priyanka; Badawy, Marwa; Quevedo, João

    2016-04-01

    Bacterial meningitis is a life-threatening infection associated with cognitive impairment in many survivors. The pathogen invades the central nervous system (CNS) by penetrating through the luminal side of the cerebral endothelium, which is an integral part of the blood-brain barrier. The replication of bacteria within the subarachnoid space occurs concomitantly with the release of their compounds that are highly immunogenic. These compounds known as pathogen-associated molecular patterns (PAMPs) may lead to both an increase in the inflammatory response in the host and also microglial activation. Microglia are the resident macrophages of the CNS which, when activated, can trigger a host of immunological pathways. Classical activation increases the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species, while alternative activation is implicated in the inhibition of inflammation and restoration of homeostasis. The inflammatory response from classical microglial activation can facilitate the elimination of invasive microorganisms; however, excessive or extended microglial activation can result in neuronal damage and eventually cell death. This review aims to discuss the role of microglia in the pathophysiology of bacterial meningitis as well as the process of microglial activation by PAMPs and by endogenous constituents that are normally released from damaged cells known as danger-associated molecular patterns (DAMPs). PMID:25744564

  14. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia.

    PubMed

    Heyman, S N; Reichman, J; Brezis, M

    1999-11-01

    Recent experimental data underlies the role of hypoxic tubular injury in the pathophysiology of radiocontrast nephropathy. Although systemic transient hypoxemia, increased blood viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, imbalance between oxygen demand and supply plays a major role in radiocontrast-induced outer medullary hypoxic damage. Low oxygen tension normally exists in this renal region, reflecting the precarious regional oxygen supply and a high local metabolic rate and oxygen requirement, resulting from active salt reabsorption by medullary thick ascending limbs of Henle's loop. Radiologic contrast agents markedly aggravate outer medullary physiologic hypoxia. This results from enhanced metabolic activity and oxygen consumption (as a result of osmotic diuresis and increased salt delivery to the distal nephron) because the regional blood flow and the oxygen supply actually increase. The latter effect may result in part from the activation of various regulatory mediators of outer medullary blood flow to ensure maximal regional oxygen supply. Low-osmolar radiocontrast agents may be less nephrotoxic because of the smaller osmotic load and vasomotor alterations. Experimental radiocontrast-induced renal failure requires preconditioning of animals with various insults (for example, congestive heart failure, reduced renal mass, salt depletion, or inhibition of nitric oxide and prostaglandin synthesis). In all these perturbations, which resemble clinical conditions that predispose to contrast nephropathy, outer medullary hypoxic injury results from insufficiency or inactivation of mechanisms designed to preserve regional oxygen balance. This underlines the importance of identifying and ameliorating predisposing factors in the prevention of this iatrogenic disease. PMID:10548380

  15. Hyponatraemia in imported malaria: the pathophysiological role of vasopressin

    PubMed Central

    2012-01-01

    Background In the pathophysiology of hyponatraemia in malaria, the relative contribution of appropriate and inappropriate arginine vasopressin (AVP) release is unknown; the trigger for inappropriate AVP release is also unknown. Methods Serum copeptin, a stable and sensitive marker for AVP release, was analysed in a large cohort of patients with imported malaria (204 patients) and in a small prospective substudy (23 patients) in which urine sodium and osmolality were also available. Hyponatraemia was classified as mild (serum sodium 131-134 mmol/l) and moderate-to-severe (< 131 mmol/l). Results Serum copeptin on admission was higher in patients with moderate-to-severe hyponatraemia (median 18.5 pmol/L) compared with normonatraemic patients (12.7 pmol/L, p < 0.05). Despite prompt fluid resuscitation, the time to normalization of serum sodium was longer in patients with moderate-to-severe hyponatraemia (median 2.9 days) than in patients with mild hyponatraemia (median 1.7 days, p < 0.001). A poor correlation was found between serum sodium and copeptin levels on admission (rs = -0.17, p = 0.017). Stronger correlations were identified between serum C-reactive protein and copeptin (rs = -0.36, p < 0.0001) and between serum C-reactive protein and sodium (rs = 0.33, p < 0.0001). Data from the sub-study suggested inappropriate AVP release in seven of 13 hyponatraemic malaria patients; these patients had significantly higher body temperatures on admission. Conclusions In hyponatraemic patients with imported malaria, AVP release was uniformly increased and was either appropriate or inappropriate. Although the exact trigger for inappropriate AVP release remains unknown, the higher body temperatures, correlations with C-reactive protein and long normalization times of serum sodium, suggest an important role of the host inflammatory response to the invading malaria parasite. PMID:22280539

  16. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

    PubMed Central

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  17. Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations.

    PubMed

    Schuck, Patrícia Fernanda; Malgarin, Fernanda; Cararo, José Henrique; Cardoso, Fabiola; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-09-01

    Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition. PMID:26425393

  18. Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation.

    PubMed

    Riva, Nicoletta; Donadini, Marco P; Ageno, Walter

    2015-06-01

    Venous thromboembolism (VTE) is a multifactorial disease. Major provoking factors (e. g. surgery, cancer, major trauma, and immobilisation) are identified in 50-60 % of patients, while the remaining cases are classified as unprovoked. However, minor predisposing conditions may be detectable in these patients, possibly concurring to the pathophysiology of the disease, especially when co-existing. In recent years, the role of chronic inflammatory disorders, infectious diseases and traditional cardiovascular risk factors has been extensively investigated. Inflammation, with its underlying prothrombotic state, could be the potential link between these risk factors, as well as the explanation for the reported association between arterial and venous thromboembolic events. PMID:25472800

  19. Pathophysiological Role of Extracellular Purinergic Mediators in the Control of Intestinal Inflammation

    PubMed Central

    Kurashima, Yosuke; Kiyono, Hiroshi

    2015-01-01

    Purinergic mediators such as adenosine 5′-triphosphate (ATP) are released into the extracellular compartment from damaged tissues and activated immune cells. They are then recognized by multiple purinergic P2X and P2Y receptors. Release and recognition of extracellular ATP are associated with both the development and the resolution of inflammation and infection. Accumulating evidence has recently suggested the potential of purinergic receptors as novel targets for drugs for treating intestinal disorders, including intestinal inflammation and irritable bowel syndrome. In this review, we highlight recent findings regarding the pathophysiological role of purinergic mediators in the development of intestinal inflammation. PMID:25944982

  20. The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

    PubMed Central

    Pagel-Langenickel, Ines; Bao, Jianjun; Pang, Liyan; Sack, Michael N.

    2010-01-01

    Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM. PMID:19861693

  1. Role of vitamin D in the pathophysiology and treatment of type 2 diabetes.

    PubMed

    Stivelman, Erica; Retnakaran, Ravi

    2012-01-01

    The secosteroid vitamin D is best known for its role in calcium regulation and bone metabolism. Recently, however, an emerging body of evidence has suggested that vitamin D may have previously-unrecognized effects on a variety of physiologic processes, including those relating to glucose homeostasis. Indeed, vitamin D insufficiency has been linked with type 2 diabetes (T2DM). In this review, the potential association between vitamin D and T2DM will be evaluated from both a pathophysiologic and clinical perspective. We consider the biologic evidence in support of a mechanistic contribution of vitamin D insufficiency to insulin resistance and beta-cell dysfunction, the two main pathophysiologic defects underlying T2DM. We also evaluate the clinical data linking vitamin D with these metabolic defects and dysglycemia. Finally, interventional studies addressing the effect of vitamin D supplementation on glucose homeostasis are considered. At present, this evolving literature is marked by many conflicting results and methodologic limitations, such that definitive conclusion on the role of vitamin D in T2DM remains elusive. Nevertheless, in light of the widespread prevalence of both vitamin D insufficiency and T2DM, this potential relationship could hold enormous public health implications and hence demands further study to address its unresolved questions. PMID:22414057

  2. Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

    PubMed Central

    Chistiakov, Dimitry A.; Nikiforov, Nikita G.

    2016-01-01

    Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances. PMID:27493969

  3. Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine.

    PubMed

    Brighina, Filippo; Palermo, Antonio; Fierro, Brigida

    2009-04-01

    Dysfunction of neuronal cortical excitability has been supposed to play an important role in etiopathogenesis of migraine. Neurophysiological techniques like evoked potentials (EP) and in the last years non-invasive brain stimulation techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation gave important contribution to understanding of such issue highlighting possible mechanisms of cortical dysfunctions in migraine. EP studies showed impaired habituation to repeated sensorial stimulation and this abnormality was confirmed across all sensorial modalities, making defective habituation a neurophysiological hallmark of the disease. TMS was employed to test more directly cortical excitability in visual cortex and then also in motor cortex. Contradictory results have been reported pointing towards hyperexcitability or on the contrary to reduced preactivation of sensory cortex in migraine. Other experimental evidence speaks in favour of impairment of inhibitory circuits and analogies have been proposed between migraine and conditions of sensory deafferentation in which down-regulation of GABA circuits is considered the more relevant pathophysiological mechanism. Whatever the mechanism involved, it has been found that repeated sessions of high-frequency rTMS trains that have been shown to up-regulate inhibitory circuits could persistently normalize habituation in migraine. This could give interesting insight into pathophysiology establishing a link between cortical inhibition and habituation and opening also new treatment strategies in migraine. PMID:19209386

  4. Role of ghrelin in the pathophysiology of gastrointestinal disease.

    PubMed

    Cheung, Cynthia K; Wu, Justin Che-Yuen

    2013-09-01

    Ghrelin is a 28-amino-acid peptide that plays multiple roles in humans and other mammals. The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and acid secretion by the GI tract. Many GI disorders involving infection, inflammation, and malignancy are also correlated with altered ghrelin production and secretion. Although suppressed ghrelin responses have already been observed in various GI disorders, such as chronic gastritis, Helicobacter pylori infection, irritable bowel syndrome, functional dyspepsia, and cachexia, elevated ghrelin responses have also been reported in celiac disease and inflammatory bowel disease. Moreover, we recently reported that decreased fasting and postprandial ghrelin levels were observed in female patients with functional dyspepsia compared with healthy subjects. These alterations of ghrelin responses were significantly correlated with meal-related symptoms (bloating and early satiation) in female functional dyspepsia patients. We therefore support the notion that abnormal ghrelin responses may play important roles in various GI disorders. Furthermore, human clinical trials and animal studies involving the administration of ghrelin or its receptor agonists have shown promising improvements in gastroparesis, anorexia, and cancer. This review summarizes the impact of ghrelin, its family of peptides, and its receptors on GI diseases and proposes ghrelin modulation as a potential therapy. PMID:24073306

  5. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy

    PubMed Central

    Luis-Rodríguez, Desirée; Martínez-Castelao, Alberto; Górriz, José Luis; De-Álvaro, Fernando; Navarro-González, Juan F

    2012-01-01

    Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication. PMID:22253941

  6. Key roles for the small leucine-rich proteoglycans in renal and pulmonary pathophysiology

    PubMed Central

    Nastase, Madalina V.; Iozzo, Renato V.; Schaefer, Liliana

    2014-01-01

    Background Small leucine-rich proteoglycans (SLRPs) are molecules that have signaling roles in a multitude of biological processes. In this respect, SLRPs play key roles in the evolution of a variety of diseases throughout the human body. Scope of Review We will critically review current developments in the roles of SLRPs in several types of disease of the kidney and lungs. Particular emphasis will be given to the roles of decorin and biglycan, the best characterized members of the SLRP gene family. Major Conclusions In both renal and pulmonary disorders, SLRPs are essential elements that regulate several pathophysiological processes including fibrosis, inflammation and tumor progression. Decorin has remarkable antifibrotic and antitumorigenic properties and is considered a valuable potential treatment of these diseases. Biglycan can modulate inflammatory processes in lung and renal inflammation and is a potential target in the treatment of inflammatory conditions. General significance SLRPs can serve as either treatment targets or as potential treatment in renal or lung disease. PMID:24508120

  7. Physiological and pathophysiological bone turnover - role of the immune system.

    PubMed

    Weitzmann, M Neale; Ofotokun, Ighovwerha

    2016-09-01

    Osteoporosis develops when the rate of osteoclastic bone breakdown (resorption) exceeds that of osteoblastic bone formation, which leads to loss of BMD and deterioration of bone structure and strength. Osteoporosis increases the risk of fragility fractures, a cause of substantial morbidity and mortality, especially in elderly patients. This imbalance between bone formation and bone resorption is brought about by natural ageing processes, but is frequently exacerbated by a number of pathological conditions. Of importance to the aetiology of osteoporosis are findings over the past two decades attesting to a deep integration of the skeletal system with the immune system (the immuno-skeletal interface (ISI)). Although protective of the skeleton under physiological conditions, the ISI might contribute to bone destruction in a growing number of pathophysiological states. Although numerous research groups have investigated how the immune system affects basal and pathological osteoclastic bone resorption, recent findings suggest that the reach of the adaptive immune response extends to the regulation of osteoblastic bone formation. This Review examines the evolution of the field of osteoimmunology and how advances in our understanding of the ISI might lead to novel approaches to prevent and treat bone loss, and avert fractures. PMID:27312863

  8. Pulmonary surfactants and their role in pathophysiology of lung disorders.

    PubMed

    Akella, Aparna; Deshpande, Shripad B

    2013-01-01

    Surfactant is an agent that decreases the surface tension between two media. The surface tension between gaseous-aqueous interphase in the lungs is decreased by the presence of a thin layer of fluid known as pulmonary surfactant. The pulmonary surfactant is produced by the alveolar type-II (AT-II) cells of the lungs. It is essential for efficient exchange of gases and for maintaining the structural integrity of alveoli. Surfactant is a secretory product, composed of lipids and proteins. Phosphatidylcholine and phosphatidylglycerol are the major lipid constituents and SP-A, SP-B, SP-C, SP-D are four types of surfactant associated proteins. The lipid and protein components are synthesized separately and are packaged into the lamellar bodies in the AT-II cells. Lamellar bodies are the main organelle for the synthesis and metabolism of surfactants. The synthesis, secretion and recycling of the surfactant lipids and proteins is regulated by complex genetic and metabolic mechanisms. The lipid-protein interaction is very important for the structural organization of surfactant monolayer and its functioning. Alterations in surfactant homeostasis or biophysical properties can result in surfactant insufficiency which may be responsible for diseases like respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases. The biochemical, physiological, developmental and clinical aspects of pulmonary surfactant are presented in this article to understand the pathophysiological mechanisms of these diseases. PMID:23441475

  9. Pathophysiology of polycystic ovary syndrome: the role of hyperandrogenism.

    PubMed

    Catteau-Jonard, Sophie; Dewailly, Didier

    2013-01-01

    The cardinal features of polycystic ovary syndrome (PCOS) are hyperandrogenism and oligoanovulation. The increase in ovarian androgen production is a fundamental characteristic of PCOS and, although enigmatic, it is at the heart of one of the major issues about the pathophysiology of PCOS, i.e. whether it has developmental origins or not. Intraovarian androgens are designated as primarily responsible for the follicle excess. The defective selection of a dominant follicle in anovulatory patients results from both an insufficient secretion of FSH and a local inhibition of FSH action. Anti-müllerian hormone (AMH) seems to be involved in the latter by repressing the FSH-dependent aromatase activity. AMH level is increased in PCOS because of the follicle excess and increased production per follicle. Therefore, in anovulatory patients, serum FSH, although at low to normal plasma concentrations, would not be able to induce a decrease in AMH sufficient to allow the expression of aromatase. In conclusion, the fundamental anomaly of PCOS is still unknown, but it can be hypothesized that any genetic, epigenetic or environmental factor leading to intraovarian hyperandrogenism can result in PCOS. PMID:24002402

  10. The pathophysiological role of bacterial biofilms in chronic sinusitis.

    PubMed

    Dlugaszewska, Jolanta; Leszczynska, Malgorzata; Lenkowski, Marcin; Tatarska, Agnieszka; Pastusiak, Tomasz; Szyfter, Witold

    2016-08-01

    Chronic rhinosinusitis (CRS) is a very common disorder that remains poorly understood from a pathogenic standpoint. Recent research on the pathogenesis of CRS has been focused on the potential role of biofilms in this chronic infection. The aim of this study was to assess the sinuses' microflora and biofilm formation on the sino-nasal mucosa in patients with CRS. Paranasal sinus mucosa specimens were harvested at the time of functional endoscopic sinus surgery (FESS). Classical microbiology techniques for the isolation and identification of sinus mucosa microbial flora were used. Scanning electron microscopy (SEM) was used to detect biofilm on the surface of mucosa. A microtiter plate assay for in vitro biofilm formation was employed, divided into three aliquots. One part was assessed for bacterial presence, utilizing an API manual system and the Vitek(®) 2 Compact system. The two remaining aliquots were tested by in vitro conventional microbiological assay with the use of the Infinite M200 (Tecan) microtiter plate reader, and also by scanning electron microscopy (SEM). A microbiological examination of mucosal specimens had taken during FESS operation revealed the presence of various types of bacteria in 29 out of 30 tested samples. Out of 62 different strains isolated from patients with CRS, 23 strains of coagulase-negative Staphylococcus epidermidis and 6 strains of Escherichia coli were the most frequently isolated microorganisms, accounting for 37.1 and 9.7 %, respectively. Among the 62 isolated strains, 58 were used to assess biofilm formation. From the total of 58 isolates, 8.6 % were strong biofilm producers, 20.7 % were moderate, and 70.7 % of isolates were considered to be non- or weak biofilm producers. SEM of the 30 nasal concha mucosal samples taken from patients with CRS revealed biofilm in 23 specimens. A marked destruction of the epithelium was observed, with variation in degrees of severity, from disarrayed cilia to complete absence of cilia

  11. Pathophysiology, prevention, and potential treatment of neural tube defects.

    PubMed

    Manning, S M; Jennings, R; Madsen, J R

    2000-01-01

    Neural tube defects (NTD) remain a major cause of morbidity in spite of the reduction in liveborn incidence with periconceptional folic acid. However, the etiology remains unknown. This article reviews studies that address causation and potential treatment of NTD in humans and in animal models that resemble aspects of the common human NTD. Studies of nutritional markers of vitamin B12 and folic acid support a defect in homocysteine metabolism; a thermolabile variant of methylene tetrahydrofolate reductase, an enzyme that remethylates homocysteine to methionine, correlates with a risk of NTD in some human populations. Numerous mouse mutant models of NTD exist, attesting to the ease of disruption of neurulation, and a genetic basis for this malformation. Of these models, the curly tail mouse mutant most closely resembles the common human NTD. Folic acid does not prevent NTD in this model; however inositol supplementation does result in a significant reduction in incidence. Recent advances in fetal surgery, and evidence from mechanically created myelomeningocele in large animals amenable to surgical intervention suggest that the handicaps associated with myelomeningocele and associated Chiari Type II malformation may be prevented by in utero NTD closure. Success will depend on preservation of neurological tissue until such intervention is possible. Further research in animal models at the genetic and cellular levels, together with technological surgical advances, provide hope that prevention of more NTD and the associated handicaps may be possible. MRDD Research Reviews 6:6-14, 2000. PMID:10899792

  12. Role of renal sensory nerves in physiological and pathophysiological conditions

    PubMed Central

    2014-01-01

    Whether activation of afferent renal nerves contributes to the regulation of arterial pressure and sodium balance has been long overlooked. In normotensive rats, activating renal mechanosensory nerves decrease efferent renal sympathetic nerve activity (ERSNA) and increase urinary sodium excretion, an inhibitory renorenal reflex. There is an interaction between efferent and afferent renal nerves, whereby increases in ERSNA increase afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes to maintain low ERSNA to minimize sodium retention. High-sodium diet enhances the responsiveness of the renal sensory nerves, while low dietary sodium reduces the responsiveness of the renal sensory nerves, thus producing physiologically appropriate responses to maintain sodium balance. Increased renal ANG II reduces the responsiveness of the renal sensory nerves in physiological and pathophysiological conditions, including hypertension, congestive heart failure, and ischemia-induced acute renal failure. Impairment of inhibitory renorenal reflexes in these pathological states would contribute to the hypertension and sodium retention. When the inhibitory renorenal reflexes are suppressed, excitatory reflexes may prevail. Renal denervation reduces arterial pressure in experimental hypertension and in treatment-resistant hypertensive patients. The fall in arterial pressure is associated with a fall in muscle sympathetic nerve activity, suggesting that increased ARNA contributes to increased arterial pressure in these patients. Although removal of both renal sympathetic and afferent renal sensory nerves most likely contributes to the arterial pressure reduction initially, additional mechanisms may be involved in long-term arterial pressure reduction since sympathetic and sensory nerves reinnervate renal tissue in a similar time-dependent fashion following renal denervation. PMID:25411364

  13. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

    SciTech Connect

    Cover, Cathleen; Liu Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P.; Bajt, Mary Lynn; Jaeschke, Hartmut . E-mail: jaeschke@email.arizona.edu

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.

  14. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity.

    PubMed

    Cover, Cathleen; Liu, Jie; Farhood, Anwar; Malle, Ernst; Waalkes, Michael P; Bajt, Mary Lynn; Jaeschke, Hartmut

    2006-10-01

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-alpha, interleukin-1beta and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose. PMID:16781746

  15. Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders

    PubMed Central

    2016-01-01

    Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration. PMID:27230456

  16. Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders.

    PubMed

    Hong, Heeok; Kim, Byung Sun; Im, Heh-In

    2016-05-01

    Brain diseases and disorders such as Alzheimer disease, Parkinson disease, depression, schizophrenia, autism, and addiction lead to reduced quality of daily life through abnormal thoughts, perceptions, emotional states, and behavior. While the underlying mechanisms remain poorly understood, human and animal studies have supported a role of neuroinflammation in the etiology of these diseases. In the central nervous system, an increased inflammatory response is capable of activating microglial cells, leading to the release of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In turn, the pro-inflammatory cytokines aggravate and propagate neuroinflammation, degenerating healthy neurons and impairing brain functions. Therefore, activated microglia may play a key role in neuroinflammatory processes contributing to the pathogenesis of psychiatric disorders and neurodegeneration. PMID:27230456

  17. Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy

    PubMed Central

    Chen, Peng-Sheng; Chen, Lan S.; Fishbein, Michael C.; Lin, Shien-Fong; Nattel, Stanley

    2014-01-01

    Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia (AT) and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review we focus on the relationship between the autonomic nervous system and the pathophysiology of AF, and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches and biological therapies. While the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future. PMID:24763467

  18. Physiological and pathophysiological roles of NAMPT and NAD metabolism.

    PubMed

    Garten, Antje; Schuster, Susanne; Penke, Melanie; Gorski, Theresa; de Giorgis, Tommaso; Kiess, Wieland

    2015-09-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing. PMID:26215259

  19. The role of VEGF165b in pathophysiology

    PubMed Central

    Peiris-Pagès, Maria

    2012-01-01

    Anti-angiogenic vascular endothelial growth factor A (VEGF)165b and pro-angiogenic VEGF165 are generated from the same transcript, and their relative amounts are dependent on alternative splicing. The role of VEGF165b has not been investigated in as much detail as VEGF165, although it appears to be highly expressed in non-angiogenic tissues and, in contrast with VEGF165, is downregulated in tumors and other pathologies associated with abnormal neovascularization such as diabetic retinopathy or Denys Drash syndrome. VEGF165b inhibits VEGFR2 signaling by inducing differential phosphorylation, and it can be used to block angiogenesis in in vivo models of tumorigenesis and angiogenesis-related eye disease. Recent reports have identified three serine/arginine-rich proteins, SRSF1, SRSF2 and SRSF6, and studied their role in regulating terminal splice-site selection. Since the balance of VEGF isoforms is lost in cancer and angiogenesis-related conditions, control of VEGF splicing could also be used as a basis for therapy in these diseases. PMID:23076130

  20. Pathophysiological and protective roles of mitochondrial ion channels

    PubMed Central

    O’Rourke, Brian

    2000-01-01

    Mitochondria possess a highly permeable outer membrane and an inner membrane that was originally thought to be relatively impermeable to ions to prevent dissipation of the electrochemical gradient for protons. Although recent evidence has revealed a rich diversity of ion channels in both membranes, the purpose of these channels remains incompletely determined. Pores in the outer membrane are fundamental participants in apoptotic cell death, and this process may also involve permeability transition pores on the inner membrane. Novel functions are now being assigned to other ion channels of the inner membrane. Examples include protection against ischaemic injury by mitochondrial KATP channels and the contribution of inner membrane anion channels to spontaneous mitochondrial oscillations in cardiac myocytes. The central role of mitochondria in both the normal function of the cell and in its demise makes these channels prime targets for future research and drug development. PMID:11080248

  1. Pathophysiology of Bronchoconstriction: Role of Oxidatively Damaged DNA Repair

    PubMed Central

    Bacsi, Attila; Pan, Lang; Ba, Xueqing; Boldogh, Istvan

    2016-01-01

    Purpose of review To provide an overview on the present understanding of roles of oxidative DNA damage repair in cell signaling underlying bronchoconstriction common to, but not restricted to various forms of asthma and chronic obstructive pulmonary disease Recent findings Bronchoconstriction is a tightening of smooth muscle surrounding the bronchi and bronchioles with consequent wheezing and shortness of breath. Key stimuli include air pollutants, viral infections, allergens, thermal and osmotic changes, and shear stress of mucosal epithelium, triggering a wide range of cellular, vascular and neural events. Although activation of nerve fibers, the role of G-proteins, protein kinases and Ca++, and molecular interaction within contracting filaments of muscle are well defined, the overarching mechanisms by which a wide range of stimuli initiate these events are not fully understood. Many, if not all, stimuli increase levels of reactive oxygen species (ROS), which are signaling and oxidatively modifying macromolecules, including DNA. The primary ROS target in DNA is guanine, and 8-oxoguanine is one of the most abundant base lesions. It is repaired by 8-oxoguanine DNA glycosylase1 (OGG1) during base excision repair processes. The product, free 8-oxoG base, is bound by OGG1 with high affinity, and the complex then functions as an activator of small GTPases, triggering pathways for inducing gene expression and contraction of intracellular filaments in mast and smooth muscle cells. Summary Oxidative DNA damage repair-mediated cell activation signaling result in gene expression that “primes” the mucosal epithelium and submucosal tissues to generate mediators of airway smooth muscle contractions. PMID:26694039

  2. Regulation and pathophysiological role of epithelial turnover in the gut.

    PubMed

    Günther, Claudia; Buchen, Barbara; Neurath, Markus F; Becker, Christoph

    2014-11-01

    Cell death in the intestinal epithelium has to be tightly controlled. Excessive or misplaced epithelial cell death can result in barrier dysfunction and, as a consequence thereof, uncontrolled translocation of components of the microbial flora from the lumen into the bowel wall. Susceptibility to gastrointestinal infections or chronic inflammation of the gut, as observed in patients with inflammatory bowel disease, can be the result of such dysregulation. Conversely, defects in cell death initiation might lead to an irregular accumulation of epithelial cells and cause intestinal cancer development. Until recently, activation of caspases in the intestinal epithelium was considered as a potential contributor to barrier dysfunction and as a pathogenic factor in the development of intestinal inflammation. Thus blocking of caspases appeared to be a potential therapeutic option for patients with inflammatory bowel disease. Recent studies on necroptosis however demonstrated that also inhibition of caspases can cause barrier dysfunction and intestinal inflammation. Caspase-8 on top of its functions in the extrinsic apoptosis pathway also controls necroptosis and turns out to be an essential molecule in regulating tissue homeostasis in the gut. Epithelial caspase-8 therefore emerges as a checkpoint not only of cell survival and cell death, but also as a regulator of the mode of cell death. According to this model, both excessive activity as well as a lack of activity of caspase-8 results in epithelial cell death and intestinal inflammation and caspase-8 needs to be tightly controlled to warrant tissue homeostasis in the gut. PMID:24973733

  3. Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases

    PubMed Central

    Britzen-Laurent, Nathalie; Herrmann, Christian; Naschberger, Elisabeth; Croner, Roland S; Stürzl, Michael

    2016-01-01

    Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton.

  4. Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases.

    PubMed

    Britzen-Laurent, Nathalie; Herrmann, Christian; Naschberger, Elisabeth; Croner, Roland S; Stürzl, Michael

    2016-07-28

    Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton. PMID:27605879

  5. Role of Liver X Receptor in AD Pathophysiology

    PubMed Central

    Sandoval-Hernández, Adrián G.; Buitrago, Luna; Moreno, Herman; Cardona-Gómez, Gloria Patricia; Arboleda, Gonzalo

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD. PMID:26720273

  6. Role of Liver X Receptor in AD Pathophysiology.

    PubMed

    Sandoval-Hernández, Adrián G; Buitrago, Luna; Moreno, Herman; Cardona-Gómez, Gloria Patricia; Arboleda, Gonzalo

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD. PMID:26720273

  7. The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders.

    PubMed

    Peterlik, Daniel; Flor, Peter J; Uschold-Schmidt, Nicole

    2016-01-01

    Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders. PMID:27296643

  8. Emerging Roles of Natriuretic Peptides and their Receptors in Pathophysiology of Hypertension and Cardiovascular Regulation

    PubMed Central

    Pandey, Kailash N.

    2009-01-01

    Thus far, three related natriuretic peptides (NPs) and three distinct receptors have been identified, which have advanced our knowledge towards understanding the control of high blood pressure, hypertension, and cardiovascular disorders to a great extent. Biochemical and molecular studies have been advanced to examine receptor function and signaling mechanisms and the role of second messenger cGMP in pathophysiology of hypertension, renal hemodynamics, and cardiovascular functions. The development of gene-knockout and gene-duplication mouse models along with transgenic mice have provided a framework for understanding the importance of the antagonistic actions of natriuretic peptides receptor in cardiovascular events at the molecular level. Now, NPs are considered as circulating markers of congestive heart failure, however, their therapeutic potential for the treatment of cardiovascular diseases such as hypertension, renal insufficiency, cardiac hypertrophy, congestive heart failure, and stroke has just begun to unfold. Indeed, the alternative avenues of investigations in this important are need to be undertaken, as we are at the initial stage of the molecular therapeutic and pharmacogenomic implications. PMID:19746200

  9. Role of Anticonvulsant and Antiepileptogenic Neurosteroids in the Pathophysiology and Treatment of Epilepsy

    PubMed Central

    Reddy, Doodipala Samba

    2011-01-01

    This review highlights the role of major endogenous neurosteroids in seizure disorders and the promise of neurosteroid replacement therapy in epilepsy. Neurosteroids are endogenous modulators of seizure susceptibility. Neurosteroids such as allopregnanolone (3α-hydroxy-5α-pregnane-20-one) and allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one) are positive modulators of GABA-A receptors. Aside from peripheral tissues, neurosteroids are synthesized within the brain, mostly in principal neurons. Neurosteroids potentiate synaptic GABA-A receptor function and also activate δ-subunit-containing extrasynaptic GABA-A receptors that mediate tonic currents and thus may play an important role in neuronal network excitability and seizure susceptibility. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. They protect against seizures induced by GABA-A receptor antagonists, 6-Hz model, pilocarpine-induced limbic seizures, and seizures in kindled animals. Unlike benzodiazepines, tolerance does not occur to their actions during chronic administration. Our recent studies provide compelling evidence that neurosteroids may have antiepileptogenic properties. There is emerging evidence that endogenous neurosteroids may play a key role in the pathophysiology of catamenial epilepsy, stress–sensitive seizure conditions, temporal lobe epilepsy, and alcohol-withdrawal seizures. It is suggested that neurosteroid replacement with natural or synthetic neurosteroids may be useful in the treatment of epilepsy. Synthetic analogs of neurosteroids that are devoid of hormonal side effects show promise in the treatment of diverse seizure disorders. Agents that stimulate endogenous production of neurosteroids may also be useful for treatment of epilepsy. PMID:22654805

  10. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology

    PubMed Central

    2014-01-01

    The physiological functions of the urinary bladder are to store and periodically expel urine. These tasks are facilitated by the contraction and relaxation of the urinary bladder smooth muscle (UBSM), also known as detrusor smooth muscle, which comprises the bladder wall. The large-conductance voltage- and Ca2+-activated K+ (BK, BKCa, MaxiK, Slo1, or KCa1.1) channel is highly expressed in UBSM and is arguably the most important physiologically relevant K+ channel that regulates UBSM function. Its significance arises from the fact that the BK channel is the only K+ channel that is activated by increases in both voltage and intracellular Ca2+. The BK channels control UBSM excitability and contractility by maintaining the resting membrane potential and shaping the repolarization phase of the spontaneous action potentials that determine UBSM spontaneous rhythmic contractility. In UBSM, these channels have complex regulatory mechanisms involving integrated intracellular Ca2+ signals, protein kinases, phosphodiesterases, and close functional interactions with muscarinic and β-adrenergic receptors. BK channel dysfunction is implicated in some forms of bladder pathologies, such as detrusor overactivity, and related overactive bladder. This review article summarizes the current state of knowledge of the functional role of UBSM BK channels under normal and pathophysiological conditions and provides new insight toward the BK channels as targets for pharmacological or genetic control of UBSM function. Modulation of UBSM BK channels can occur by directly or indirectly targeting their regulatory mechanisms, which has the potential to provide novel therapeutic approaches for bladder dysfunction, such as overactive bladder and detrusor underactivity. PMID:24990859

  11. The role of osmoregulation in the pathophysiology and management of severe ovarian hyperstimulation syndrome.

    PubMed

    Evbuomwan, Isaac

    2013-09-01

    Severe ovarian hyperstimulation syndrome (OHSS), with an incidence of 1-2% of superovulation cycles, remains one of the most important complications of gonadotrophin use in assisted reproductive technologies because of its associated morbidity and rarely, mortality. Despite the wealth of scientific and clinical interest that this iatrogenic complication has generated, its pathophysiology is still not adequately elucidated and its management has thus remained empirical. Disorders of salt and water balance are two very important features that have been reported during severe OHSS. Some of the clinical and biochemical changes resulting from this disorder of salt and water balance are similar to those previously reported in pregnancy and liver cirrhosis. The pathophysiology of these clinical changes has been explained in part in pregnancy and liver cirrhosis by changes in osmoregulation function. It is this similarity in the clinical and biochemical changes in OHSS, pregnancy and liver cirrhosis that has prompted the investigation of the role of osmoregulation function in the pathophysiology of OHSS. The current article has been written to provide further details in support of recent excellent articles and guidelines, highlighting the physiological basis and rationale governing some aspects of, and the role of osmoregulation in the management of the OHSS syndrome. PMID:24047195

  12. The Pathophysiology of Insomnia

    PubMed Central

    Levenson, Jessica C.; Kay, Daniel B.

    2015-01-01

    Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality that is associated with difficulty falling asleep, frequent nighttime awakenings with difficulty returning to sleep, and/or awakening earlier in the morning than desired. Although progress has been made in our understanding of the nature, etiology, and pathophysiology of insomnia, there is still no universally accepted model. Greater understanding of the pathophysiology of insomnia may provide important information regarding how, and under what conditions, the disorder develops and is maintained as well as potential targets for prevention and treatment. The aims of this report are (1) to summarize current knowledge on the pathophysiology of insomnia and (2) to present a model of the pathophysiology of insomnia that considers evidence from various domains of research. Working within several models of insomnia, evidence for the pathophysiology of the disorder is presented across levels of analysis, from genetic to molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and self-report. We discuss the role of hyperarousal as an overarching theme that guides our conceptualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that integrates the various types of evidence presented. PMID:25846534

  13. The pathophysiology of insomnia.

    PubMed

    Levenson, Jessica C; Kay, Daniel B; Buysse, Daniel J

    2015-04-01

    Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality that is associated with difficulty falling asleep, frequent nighttime awakenings with difficulty returning to sleep, and/or awakening earlier in the morning than desired. Although progress has been made in our understanding of the nature, etiology, and pathophysiology of insomnia, there is still no universally accepted model. Greater understanding of the pathophysiology of insomnia may provide important information regarding how, and under what conditions, the disorder develops and is maintained as well as potential targets for prevention and treatment. The aims of this report are (1) to summarize current knowledge on the pathophysiology of insomnia and (2) to present a model of the pathophysiology of insomnia that considers evidence from various domains of research. Working within several models of insomnia, evidence for the pathophysiology of the disorder is presented across levels of analysis, from genetic to molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and self-report. We discuss the role of hyperarousal as an overarching theme that guides our conceptualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that integrates the various types of evidence presented. PMID:25846534

  14. Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System.

    PubMed

    Yagami, Tatsurou; Koma, Hiromi; Yamamoto, Yasuhiro

    2016-09-01

    Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF2α, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF2α, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange via EP1, resulting in the excess Ca(2+) accumulation. Neither PGE2, PGF2α, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although

  15. The role of AMH in the pathophysiology of polycystic ovarian syndrome.

    PubMed

    Garg, Deepika; Tal, Reshef

    2016-07-01

    Polycystic ovarian syndrome (PCOS) affects 5 - 10% of reproductive age women, but its pathogenesis is still poorly understood. The aim of this review is to collate evidence and summarize our current knowledge of the role of anti-Müllerian hormone (AMH) in PCOS pathogenesis. AMH is increased and correlated with the various reproductive and metabolic/endocrine alterations in PCOS. AMH plays an inhibitory role in follicular development and recruitment, contributing to follicular arrest. AMH inhibitory action on FSH-induced aromatase production likely contributes to hyperandrogenism in PCOS, which further enhances insulin resistance in these women. Elevated serum AMH concentrations are predictive of poor response to various treatments of PCOS including weight loss, ovulation induction and laparoscopic ovarian drilling, while improvement in various clinical parameters following treatment is associated with serum AMH decline, further supporting an important role for AMH in the pathophysiology of this syndrome. This review emphasizes the need for understanding the exact mechanism of action of AMH in the pathophysiology of PCOS. This may lead to the development of new treatment modalities targeting AMH to treat PCOS, as well as help clinicians in prognostication and better tailoring existing treatments for this disease. PMID:27174394

  16. Understanding migraine: Potential role of neurogenic inflammation

    PubMed Central

    Malhotra, Rakesh

    2016-01-01

    . With this objective, the present review summarizes the evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology and pharmacology of migraine headache as well as its potential significance in better tailoring therapeutic interventions in migraine or other neurological disorders. In addition, we have briefly highlighted the pathophysiological role of neurogenic inflammation in various other neurological disorders. PMID:27293326

  17. Understanding migraine: Potential role of neurogenic inflammation.

    PubMed

    Malhotra, Rakesh

    2016-01-01

    . With this objective, the present review summarizes the evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology and pharmacology of migraine headache as well as its potential significance in better tailoring therapeutic interventions in migraine or other neurological disorders. In addition, we have briefly highlighted the pathophysiological role of neurogenic inflammation in various other neurological disorders. PMID:27293326

  18. The emerging role of autophagy in the pathophysiology of diabetes mellitus

    PubMed Central

    Gonzalez, Claudio D; Lee, Myung-Shik; Marchetti, Piero; Pietropaolo, Massimo; Towns, Roberto; Vaccaro, Maria I; Watada, Hirotaka

    2011-01-01

    An emerging body of evidence supports a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus. Persistent high concentrations of glucose lead to imbalances in the antioxidant capacity within the cell resulting in oxidative stress-mediated injury in both disorders. An anticipated consequence of impaired autophagy is the accumulation of dysfunctional organelles such as mitochondria within the cell. Mitochondria are the primary site of the production of reactive oxygen species (ROS), and an imbalance in ROS production relative to the cytoprotective action of autophagy may lead to the accumulation of ROS. Impaired mitochondrial function associated with increased ROS levels have been proposed as mechanisms contributing to insulin resistance. In this article we review and interpret the literature that implicates a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus as it applies to β-cell dysfunction, and more broadly to organ systems involved in complications of diabetes including the cardiovascular, renal and nervous systems. PMID:20935516

  19. The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease.

    PubMed

    Bonini, Matteo; Usmani, Omar S

    2015-12-01

    Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), represent a major social and economic burden for worldwide health systems. During recent years, increasing attention has been directed to the role of small airways in respiratory diseases, and their exact contribution to the pathophysiology of asthma and COPD continues to be clarified. Indeed, it has been suggested that small airways play a distinct role in specific disease phenotypes. Besides providing information on small airways structure and diagnostic procedures, this review therefore aims to present updated and evidence-based findings on the role of small airways in the pathophysiology of asthma and COPD. Most of the available information derives from either pathological studies or review articles and there are few data on the natural history of small airways disease in the onset or progression of asthma and COPD. Comparisons between studies on the role of small airways are hard to draw because both asthma and COPD are highly heterogeneous conditions. Most studies have been performed in small population samples, and different techniques to characterize aspects of small airways function have been employed in order to assess inflammation and remodelling. Most methods of assessing small airways dysfunction have been largely confined to research purposes, but some data are encouraging, supporting the utilization of certain techniques into daily clinical practice, particularly for early-stage diseases, when subjects are often asymptomatic and routine pulmonary function tests may be within normal ranges. In this context further clinical trials and real-life feedback on large populations are desirable. PMID:26037949

  20. The fetal circulation, pathophysiology of hypoxemic respiratory failure and pulmonary hypertension in neonates, and the role of oxygen therapy.

    PubMed

    Lakshminrusimha, S; Saugstad, O D

    2016-06-01

    Neonatal hypoxemic respiratory failure (HRF), a deficiency of oxygenation associated with insufficient ventilation, can occur due to a variety of etiologies. HRF can result when pulmonary vascular resistance (PVR) fails to decrease at birth, leading to persistent pulmonary hypertension of newborn (PPHN), or as a result of various lung disorders including congenital abnormalities such as diaphragmatic hernia, and disorders of transition such as respiratory distress syndrome, transient tachypnea of newborn and perinatal asphyxia. PVR changes throughout fetal life, evident by the dynamic changes in pulmonary blood flow at different gestational ages. Pulmonary vascular transition at birth requires an interplay between multiple vasoactive mediators such as nitric oxide, which can be potentially inactivated by superoxide anions. Superoxide anions have a key role in the pathophysiology of HRF. Oxygen (O2) therapy, used in newborns long before our knowledge of the complex nature of HRF and PPHN, has continued to evolve. Over time has come the discovery that too much O2 can be toxic. Recommendations on the optimal inspired O2 levels to initiate resuscitation in term newborns have ranged from 100% (pre 1998) to the currently recommended use of room air (21%). Questions remain about the most effective levels, particularly in preterm and low birth weight newborns. Attaining the appropriate balance between hypoxemia and hyperoxemia, and targeting treatments to the pathophysiology of HRF in each individual newborn are critical factors in the development of improved therapies to optimize outcomes. PMID:27225963

  1. The Role of CD44 in the Pathophysiology of Chronic Lymphocytic Leukemia

    PubMed Central

    Gutjahr, Julia Christine; Greil, Richard; Hartmann, Tanja Nicole

    2015-01-01

    CD44 interactions with hyaluronan (HA) play a key role in various malignancies, supporting tumor cell migration, adhesion, and survival. In contrast to solid tumors, the expression of CD44 standard and variant forms and their functional interplay with HA is less understood in hematological malignancies. Chronic lymphocytic leukemia (CLL) is a highly abundant B-cell malignancy with a well coordinated balance between cell cycle-arrest and proliferation of tumor subpopulations. The long-term survival and proliferation of CLL cells requires their dynamic interactions with stromal and immune cells in lymphoid organs. Interactions of HA with CD44 and HA-mediated motility receptor (RHAMM) contribute to CLL cell localization, and hence CLL pathophysiology, by shaping homing, interstitial migration, and adhesion of the tumor cells. CD44 can complex with key prognostic factors of CLL, particularly CD38 and CD49d, bridging the gap between prognosis and cellular function. Here, we review the current evidence for the individual and associated contributions of CD44 to CLL pathophysiology, the dynamic functional regulation of CD44 upon CLL cell activation, and possible therapeutic strategies targeting CD44 in CLL. PMID:25941526

  2. The role of neuropeptide Y in the pathophysiology of atherosclerotic cardiovascular disease.

    PubMed

    Zhu, Ping; Sun, Weiwei; Zhang, Chenliang; Song, Zhiyuan; Lin, Shu

    2016-10-01

    With average life expectancy rising greatly, the incidence rate of arteriosclerotic cardiovascular disease (ASCVD) has significantly increased. The heart disease has now become the number one killer that threatens the global population health, the second is stroke. It will be of great significance to investigate the underlying pathophysiological mechanisms of ASCVD in order to promote effective prevention and treatment. The neuropeptide Y (NPY) has now been discovered for more than thirty years and is widely distributed in the central nervous system (CNS) and peripheral tissues. By combining with certain receptors, NPY performs a variety of physiological functions, including the regulation of food intake, cardiovascular effects, development, hormonal secretion, sexual behavior, biological rhythms, temperature and emotion. In ASCVD, increased peripheral NPY was involved in the pathophysiological process of atherosclerosis through affecting the vascular endothelial dysfunction, the formation of foam cells, the proliferation of vascular smooth muscle cells, the local inflammatory response of plaques and the activation and aggregation of platelets. Via central and/or the peripheral nervous system, increased NPY was associated with dyslipidemia, hypertension, obesity, diabetes, impaired glucose tolerance, and smoking which are all risk factors for ASCVD. In this review, we summarize the role of neuropeptide Y in the development of atherosclerotic cardiovascular disease. PMID:27389447

  3. Heterotopic ossification: Pathophysiology, clinical features, and the role of radiotherapy for prophylaxis

    SciTech Connect

    Balboni, Tracy A.; Gobezie, Reuben; Mamon, Harvey J. . E-mail: hmamon@partners.org

    2006-08-01

    Heterotopic ossification (HO) is a benign condition of abnormal formation of bone in soft tissue. HO is frequently asymptomatic, though when it is more severe it typically manifests as decreased range of motion at a nearby joint. HO has been recognized to occur in three distinct contexts-trauma, neurologic injury, and genetic abnormalities. The etiology of HO is incompletely understood. A posited theory is that HO results from the presence of osteoprogenitor cells pathologically induced by an imbalance in local or systemic factors. Individuals at high risk for HO development frequently undergo prophylaxis to prevent HO formation. The two most commonly employed modalities for prophylaxis are nonsteroidal anti-inflammatory drugs and radiation therapy. This review discusses HO pathophysiology, clinical features, and the role of radiotherapy for prophylaxis.

  4. A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders

    PubMed Central

    Reinhard, Sarah M.; Razak, Khaleel; Ethell, Iryna M.

    2015-01-01

    The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called ‘critical periods.’ MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer’s disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders. PMID:26283917

  5. Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy

    PubMed Central

    Diness, Jonas G.; Bentzen, Bo H.; Sørensen, Ulrik S.

    2015-01-01

    Abstract: Small-conductance Ca2+-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti–atrial fibrillation principle. PMID:25830485

  6. Exercise pathophysiology and the role of oxygen therapy in idiopathic interstitial pneumonia.

    PubMed

    Troy, Lauren K; Young, Iven H; Lau, Edmund M T; Corte, Tamera J

    2016-08-01

    Exercise limitation is a common feature in idiopathic interstitial pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP. PMID:26416262

  7. Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy.

    PubMed

    Diness, Jonas G; Bentzen, Bo H; Sørensen, Ulrik S; Grunnet, Morten

    2015-11-01

    Small-conductance Ca(2+)-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle. PMID:25830485

  8. The Pathophysiological Role of the PKCδ Pathway in the Intervertebral Disc: In vitro, ex vivo and in vivo studies

    PubMed Central

    Ellman, Michael B; Kim, Jaesung; An, Howard S; Kroin, Jeffrey S.; Li, Xin; Chen, Di; Yan, Dongyao; Buechter, Doug D; Nakayama, Keiichi; Liu, Bo; Morganand, Stephanie; Im, Hee-Jeong

    2011-01-01

    Objective PKCδ activation was found to be a principal rate-limiting step in matrix-degrading enzyme production in human articular chondrocytes. However, the role of the PKC pathways, specifically PKCδ, has not yet been assessed in intervertebral disc tissue homeostasis. Methods Using in vitro, ex vivo, and in vivo techniques, we evaluated the pathophysiological role of the PKCδ pathway by examining (i) proteoglycan deposition; (ii) matrix-degrading enzyme production and activity; (iii) downstream signaling pathways regulated by PKCδ; and (iv) the effect on in vivo models of disc degeneration in genetically-engineered PKCδ knockout mice. Results Pathway-specific inhibitor studies reveal a vital role of PKCδ-MAPK (ERK, p38, JNK) axis and NFκB in disc homeostasis. Accordingly, PKCδ knockout mice are markedly resistant to disc degeneration in a disc injury model in vivo. Conclusion Suppression of the PKCδ pathway may be beneficial in the prevention and/or treatment of disc degeneration, and these findings provide evidence for the potential therapeutic role of pathway-specific inhibitors of the PKCδ cascade in the future. PMID:22161873

  9. Pathophysiologic changes due to TASER® devices versus excited delirium: potential relevance to deaths-in-custody?

    PubMed

    Jauchem, James R

    2011-05-01

    The syndrome of excited delirium has been implicated in some deaths-in-custody which also involved the use of electronic control devices (ECDs) (including those manufactured by TASER International) on subjects. This review is an update on recent studies of pathophysiologic changes related to these two separate but parallel topics: a) first, the use of ECDs during law-enforcement activities; and b) second, the occurrence of excited delirium during such activities. This is a narrative review of elements that may be of use in generating hypotheses relating to potential similarities or differences between the two topics. Differences between changes in most factors due to excited delirium versus those of ECD applications were not readily apparent in most cases. These factors include: direct and indirect effects on the cardiovascular system, respiration, rhabdomyolysis and muscle enzymes, hyperkalemia, acidosis, hyperglycemia, and increased hematocrit. One factor that may exhibit consistent differences, however, is increased body temperature, which is often evident during excited delirium (versus a lack of increase temperature during ECD exposures). Thus, on the basis of this review, a more detailed delineation of this factor could be a major focus for future forensic investigations of deaths-in-custody involving either excited delirium or ECD exposures. PMID:21550562

  10. The Role of Neurosteroids in the Pathophysiology and Treatment of Catamenial Epilepsy

    PubMed Central

    Reddy, Doodipala Samba

    2009-01-01

    SUMMARY Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Generally, a two-fold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy. Based on this criteria, recent clinical studies indicate that catamenial epilepsy affects 31 – 60% of the women with epilepsy. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. However, there is no specific drug available today for catamenial epilepsy, which has not been successfully treated with conventional antiepileptic drugs. Elucidation of the pathophysiology of catamenial epilepsy is a prerequisite to develop specific targeted approaches for treatment or prevention of the disorder. Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy. There is emerging evidence that endogenous neurosteroids with anticonvulsant or proconvulsant effects could play a critical role in catamenial epilepsy. It is thought that perimenstrual catamenial epilepsy is associated with the withdrawal of anticonvulsant neurosteroids. Progesterone and other hormonal agents have been shown in limited trials to be moderately effective in catamenial epilepsy, but may cause endocrine side effects. Synthetic neurosteroids, which enhance the tonic GABA-A receptor function, might provide an effective approach for the catamenial epilepsy therapy without producing hormonal side effects. PMID:19406620

  11. Role of neuro-immunological factors in the pathophysiology of mood disorders.

    PubMed

    Bhattacharya, Anindya; Derecki, Noel C; Lovenberg, Timothy W; Drevets, Wayne C

    2016-05-01

    Mood disorders, despite the widespread availability of monoamine-based antidepressant treatments, are associated with persistently high rates of disability, together with elevated rates of mortality due to suicide, cardiovascular disease, and other causes. The development of more effective treatments has been hindered by the lack of knowledge about the etiology and pathogenesis of mood disorders. An emerging area of science that promises novel pathways to antidepressant and mood stabilizing therapies surrounds evidence that immune cells and their signaling play a major role in the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). Here, we review evidence that the release of neuroactive cytokines, particularly interleukins such as IL-1β, IL-6, and TNF-α, is altered in these disorders and discuss mechanisms such as the ATP-gated ion channel P2X7, through which cytokine signaling can influence neuro-glial interactions. Brain P2X7, an emerging target and antagonism of P2X7 holds promise as a novel mechanism for targeting treatment-resistant depression. We further discuss the role of microglia and astroglia in central neuroinflammation and their interaction with the peripheral immune system We present extant clinical evidence that bolsters the role of neuroinflammation and neuroactive cytokines in mood disorders. To that end, the role of clinical imaging by probing neuroinflammatory markers is also discussed briefly. Finally, we present data using preclinical neuroinflammation models that produce depression-like behaviors in experimental animals to identify neuroinflammatory mechanisms which may aid in novel neuroimmune target identification for the development of exciting pharmacological interventions in mood disorders. PMID:26803500

  12. Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus

    PubMed Central

    Abell, Sally K.; De Courten, Barbora; Boyle, Jacqueline A.; Teede, Helena J.

    2015-01-01

    Understanding pathophysiology and identifying mothers at risk of major pregnancy complications is vital to effective prevention and optimal management. However, in current antenatal care, understanding of pathophysiology of complications is limited. In gestational diabetes mellitus (GDM), risk prediction is mostly based on maternal history and clinical risk factors and may not optimally identify high risk pregnancies. Hence, universal screening is widely recommended. Here, we will explore the literature on GDM and biomarkers including inflammatory markers, adipokines, endothelial function and lipids to advance understanding of pathophysiology and explore risk prediction, with a goal to guide prevention and treatment of GDM. PMID:26110385

  13. Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiology.

    PubMed

    Bolignano, Davide; Cabassi, Aderville; Fiaccadori, Enrico; Ghigo, Ezio; Pasquali, Renato; Peracino, Andrea; Peri, Alessandro; Plebani, Mario; Santoro, Antonio; Settanni, Fabio; Zoccali, Carmine

    2014-10-01

    Arginine vasopressin (AVP) plays a key role in many physiologic and pathologic processes. The most important stimulus for AVP release is a change in plasma osmolality. AVP is also involved in the response and adaptation to stress. Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps. Copeptin (CTproAVP), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of the AVP system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP represents AVP levels and its behavior represents changes in plasma osmolality, stress and various disease states, and shows some of the various physiologic and pathophysiologic conditions associated with increased or decreased AVP. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Autosomal polycystic kidney disease (ADPKD) patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance. A possibility raised by these clinical observations is that CTproAVP may serve to identify patients who could benefit from an intervention aimed at countering AVP. PMID:24940718

  14. Emerging roles of A-kinase anchoring proteins in cardiovascular pathophysiology.

    PubMed

    Diviani, Dario; Reggi, Erica; Arambasic, Miroslav; Caso, Stefania; Maric, Darko

    2016-07-01

    Heart and blood vessels ensure adequate perfusion of peripheral organs with blood and nutrients. Alteration of the homeostatic functions of the cardiovascular system can cause hypertension, atherosclerosis, and coronary artery disease leading to heart injury and failure. A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that are crucially involved in modulating the function of the cardiovascular system both under physiological and pathological conditions. AKAPs assemble multifunctional signaling complexes that ensure correct targeting of the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to precise subcellular compartments. This allows local regulation of specific effector proteins that control the function of vascular and cardiac cells. This review will focus on recent advances illustrating the role of AKAPs in cardiovascular pathophysiology. The accent will be mainly placed on the molecular events linked to the control of vascular integrity and blood pressure as well as on the cardiac remodeling process associated with heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID:26643253

  15. The Role of CD44 in Disease Pathophysiology and Targeted Treatment

    PubMed Central

    Jordan, Andre R.; Racine, Ronny R.; Hennig, Martin J. P.; Lokeshwar, Vinata B.

    2015-01-01

    The cell-surface glycoprotein CD44 is involved in a multitude of important physiological functions including cell proliferation, adhesion, migration, hematopoiesis, and lymphocyte activation. The diverse physiological activity of CD44 is manifested in the pathology of a number of diseases including cancer, arthritis, bacterial and viral infections, interstitial lung disease, vascular disease, and wound healing. This diversity in biological activity is conferred by both a variety of distinct CD44 isoforms generated through complex alternative splicing, posttranslational modifications (e.g., N- and O-glycosylation), interactions with a number of different ligands, and the abundance and spatial distribution of CD44 on the cell surface. The extracellular matrix glycosaminoglycan hyaluronic acid (HA) is the principle ligand of CD44. This review focuses both CD44-hyaluronan dependent and independent CD44 signaling and the role of CD44–HA interaction in various pathophysiologies. The review also discusses recent advances in novel treatment strategies that exploit the CD44–HA interaction either for direct targeting or for drug delivery. PMID:25954275

  16. ‘There and back again’: revisiting the pathophysiological roles of human endogenous retroviruses in the post-genomic era

    PubMed Central

    Magiorkinis, Gkikas; Belshaw, Robert; Katzourakis, Aris

    2013-01-01

    Almost 8% of the human genome comprises endogenous retroviruses (ERVs). While they have been shown to cause specific pathologies in animals, such as cancer, their association with disease in humans remains controversial. The limited evidence is partly due to the physical and bioethical restrictions surrounding the study of transposons in humans, coupled with the major experimental and bioinformatics challenges surrounding the association of ERVs with disease in general. Two biotechnological landmarks of the past decade provide us with unprecedented research artillery: (i) the ultra-fine sequencing of the human genome and (ii) the emergence of high-throughput sequencing technologies. Here, we critically assemble research about potential pathologies of ERVs in humans. We argue that the time is right to revisit the long-standing questions of human ERV pathogenesis within a robust and carefully structured framework that makes full use of genomic sequence data. We also pose two thought-provoking research questions on potential pathophysiological roles of ERVs with respect to immune escape and regulation. PMID:23938753

  17. GI stem cells – new insights into roles in physiology and pathophysiology

    PubMed Central

    von Furstenberg, Richard J.

    2016-01-01

    Abstract This overview gives a brief historical summary of key discoveries regarding stem cells of the small intestine. The current concept is that there are two pools of intestinal stem cells (ISCs): an actively cycling pool that is marked by Lgr5, is relatively homogeneous and is responsible for daily turnover of the epithelium; and a slowly cycling or quiescent pool that functions as reserve ISCs. The latter pool appears to be quite heterogeneous and may include partially differentiated epithelial lineages that can reacquire stem cell characteristics following injury to the intestine. Markers and methods of isolation for active and quiescent ISC populations are described as well as the numerous important advances that have been made in approaches to the in vitro culture of ISCs and crypts. Factors regulating ISC biology are briefly summarized and both known and unknown aspects of the ISC niche are discussed. Although most of our current knowledge regarding ISC physiology and pathophysiology has come from studies with mice, recent work with human tissue highlights the potential translational applications arising from this field of research. Many of these topics are further elaborated in the following articles. PMID:27107928

  18. The role of the mast cell in the pathophysiology of asthma.

    PubMed

    Bradding, Peter; Walls, Andrew F; Holgate, Stephen T

    2006-06-01

    There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma. PMID:16750987

  19. Role of the clathrin adaptor PICALM in normal hematopoiesis and polycythemia vera pathophysiology

    PubMed Central

    Ishikawa, Yuichi; Maeda, Manami; Pasham, Mithun; Aguet, Francois; Tacheva-Grigorova, Silvia K.; Masuda, Takeshi; Yi, Hai; Lee, Sung-Uk; Xu, Jian; Teruya-Feldstein, Julie; Ericsson, Maria; Mullally, Ann; Heuser, John; Kirchhausen, Tom; Maeda, Takahiro

    2015-01-01

    Clathrin-dependent endocytosis is an essential cellular process shared by all cell types. Despite this, precisely how endocytosis is regulated in a cell-type-specific manner and how this key pathway functions physiologically or pathophysiologically remain largely unknown. PICALM, which encodes the clathrin adaptor protein PICALM, was originally identified as a component of the CALM/AF10 leukemia oncogene. Here we show, by employing a series of conditional Picalm knockout mice, that PICALM critically regulates transferrin uptake in erythroid cells by functioning as a cell-type-specific regulator of transferrin receptor endocytosis. While transferrin receptor is essential for the development of all hematopoietic lineages, Picalm was dispensable for myeloid and B-lymphoid development. Furthermore, global Picalm inactivation in adult mice did not cause gross defects in mouse fitness, except for anemia and a coat color change. Freeze-etch electron microscopy of primary erythroblasts and live-cell imaging of murine embryonic fibroblasts revealed that Picalm function is required for efficient clathrin coat maturation. We showed that the PICALM PIP2 binding domain is necessary for transferrin receptor endocytosis in erythroblasts and absolutely essential for erythroid development from mouse hematopoietic stem/progenitor cells in an erythroid culture system. We further showed that Picalm deletion entirely abrogated the disease phenotype in a Jak2V617F knock-in murine model of polycythemia vera. Our findings provide new insights into the regulation of cell-type-specific transferrin receptor endocytosis in vivo. They also suggest a new strategy to block cellular uptake of transferrin-bound iron, with therapeutic potential for disorders characterized by inappropriate red blood cell production, such as polycythemia vera. PMID:25552701

  20. Revisiting the Role of the Prefrontal Cortex in the Pathophysiology of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Halperin, Jeffrey M.; Schulz, Kurt P.

    2006-01-01

    Most neural models for the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) have centered on the prefrontal cortex and its interconnections with the striatum and other subcortical structures. However, research only partially supports these models, and they do not correspond with the development of the prefrontal cortex and its…

  1. Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice.

    PubMed

    Cover, Cathleen; Fickert, Peter; Knight, Tamara R; Fuchsbichler, Andrea; Farhood, Anwar; Trauner, Michael; Jaeschke, Hartmut

    2005-03-01

    DNA fragmentation in hepatocytes occurs early after acetaminophen (AAP) overdose in mice. DNA strandbreaks can induce excessive activation of poly(ADP-ribose) polymerases (PARP), which may lead to oncotic necrosis. Based on controversial findings with chemical PARP inhibitors, the role of PARP-1 activation in AAP hepatotoxicity remains unclear. To investigate PARP-1 activation and evaluate a pathophysiological role of PARP-1, we used both PARP inhibitors (3-aminobenzamide; 5-aminoisoquinolinone) and PARP gene knockout mice (PARP-/-). Treatment of C3Heb/FeJ mice with 300 mg/kg AAP resulted in DNA fragmentation and alanine aminotransferase (ALT) release as early as 3 h, with further increase of these parameters up to 12 h. Few nuclei of hepatocytes stained positive for poly-ADP-ribosylated nuclear proteins (PAR) as indicator for PARP-1 activation at 4.5 h. However, the number of PAR-positive cells and staining intensity increased substantially at 6 and 12 h. Pretreatment with 500 mg/kg 3-aminobenzamide before AAP attenuated hepatic glutathione depletion and completely eliminated DNA fragmentation and liver injury. Delayed treatment several hours after AAP was still partially protective. On the other hand, liver injury was not attenuated in PARP-/- mice compared to wild-type animals. Similarly, the specific PARP-1 inhibitor 5-aminoisoquinolinone (5 mg/kg) was not protective. However, 3-aminobenzamide attenuated liver injury in WT and PARP-/- mice. In summary, PARP-1 activation is a consequence of DNA fragmentation after AAP overdose. However, PARP-1 activation is not a relevant event for AAP-induced oncotic necrosis. The protection of 3-aminobenzamide against AAP-induced liver injury was due to reduced metabolic activation and potentially its antioxidant effect but independent of PARP-1 inhibition. PMID:15601672

  2. Zinc-Permeable Ion Channels: Effects on Intracellular Zinc Dynamics and Potential Physiological/Pathophysiological Significance

    PubMed Central

    Inoue, Koichi; O'Bryant, Zaven; Xiong, Zhi-Gang

    2015-01-01

    Zinc (Zn2+) is one of the most important trace metals in the body. It is necessary for the normal function of a large number of proteins including enzymes and transcription factors. While extracellular fluid may contain up to micromolar Zn2+, intracellular Zn2+ concentration is generally maintained at a subnanomolar level; this steep gradient across the cell membrane is primarily attributable to Zn2+ extrusion by Zn2+ transporting systems. Interestingly, systematic investigation has revealed that activities, previously believed to be dependent on calcium (Ca2+), may be partially mediated by Zn2+. This is also supported by new findings that some Ca2+-permeable channels such as voltage-dependent calcium channels (VDCCs), N-methyl-D-aspartate receptors (NMDA), and amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA-Rs) are also permeable to Zn2+. Thus, the importance of Zn2+ in physiological and pathophysiological processes is now more widely appreciated. In this review, we describe Zn2+-permeable membrane molecules, especially Zn2+-permeable ion channels, in intracellular Zn2+dynamics and Zn2+ mediated physiology/pathophysiology. PMID:25666796

  3. PDGFRα in Liver Pathophysiology: Emerging Roles in Development, Regeneration, Fibrosis, and Cancer

    PubMed Central

    Kikuchi, Alexander; Monga, Satdarshan Pal

    2015-01-01

    Platelet-derived growth factor receptor α (PDGFRα) is an isoform of the PDGFR family of tyrosine kinase receptors involved in cell proliferation, survival, differentiation, and growth. In this review, we highlight the role of PDGFRα and the current evidence of its expression and activities in liver development, regeneration, and pathology—including fibrosis, cirrhosis, and liver cancer. Studies elucidating PDGFRα signaling in processes ranging from profibrotic signaling, angiogenesis, and oxidative stress to epithelial-to-mesenchymal transition point toward PDGFRα as a potential therapeutic target in various hepatic pathologies, including hepatic fibrosis and liver cancer. Furthermore, PDGFRα localization and modulation during liver development and regeneration may lend insight into its potential roles in various pathologic states. We will also briefly discuss some of the current targeted treatments for PDGFRα, including multireceptor tyrosine kinase inhibitors and PDGFRα-specific inhibitors. PMID:25700367

  4. [Micro RNA and its role in the pathophysiology of spinal cord injury - a further step towards neuroregenerative medicine].

    PubMed

    Quinzaños-Fresnedo, Jimena; Sahagún-Olmos, Roberto Carlos

    2015-01-01

    In the pathophysiology of spinal cord injury, the secondary biological processes involving changes in gene expression become more important day a day. Within these changes, the expression of different microRNAs has been involved in some of the pathophysiological processes of spinal cord injury. There are several studies that describe the transient expression of microRNA in spinal cord injury, some of them related to inflammation and apoptosis and others to functional recovery and regeneration. MicroRNA may be a potential target for the treatment of spinal cord injury, modifying the processes of inflammation, oxidation, apoptosis, functional recovery and regeneration. It is necessary to continue the study of microRNAs in spinal cord injury, as well as the identification of their target genes and signaling mechanisms involved in its neurological effects. With this, the ultimate goal is the development of effective and safe therapeutic and diagnostic strategies for patients with spinal cord injury. PMID:26162489

  5. The Role of the Nervous System in the Pathophysiology of Psoriasis: A Review of Cases of Psoriasis Remission or Improvement Following Denervation Injury.

    PubMed

    Zhu, Tian Hao; Nakamura, Mio; Farahnik, Benjamin; Abrouk, Michael; Lee, Kristina; Singh, Rasnik; Gevorgyan, Alexander; Koo, John; Bhutani, Tina

    2016-06-01

    As most efforts in the last decade have focused on the immunologic basis of inflammatory skin disease, there has been less emphasis on the role of the nervous system in the disease process of psoriasis. Evidence in support of the neurocutaneous pathway has come from observations of patients experiencing unilateral improvement and even complete remission following nerve damage in the affected dermatomal region. The aim of this review was to investigate the role of neuropeptides in the intricate pathophysiology of psoriasis. The PubMed database was searched for individual case reports or case series that reported clearance or significant improvement in psoriatic disease in patients following documented nerve injury. A total of 11 cases were found that reported improvement of psoriatic lesions in areas afflicted by central or peripheral nerve injury. The most common causes of denervation were inadvertent surgical interruption, cerebrovascular accident, and poliomyelitis. In four cases the patients eventually regained neurologic function, which was associated with a recurrence of skin lesions. In cases of permanent nerve damage, there was remission of psoriasis. The cases reported in the literature to date provide clinical evidence that absence of neural input leads to psoriasis improvement, suggesting a crucial role of the nervous system in the pathophysiology of psoriatic disease. In fact, neuropeptides such as nerve growth factor, substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide may be important contributors of psoriatic disease and potential targets for future therapies. PMID:26935938

  6. Minireview: Pathophysiological roles of the TR4 nuclear receptor: lessons learned from mice lacking TR4.

    PubMed

    Lin, Shin-Jen; Zhang, Yanqing; Liu, Ning-Chun; Yang, Dong-Rong; Li, Gonghui; Chang, Chawnshang

    2014-06-01

    Testicular nuclear receptor 4 (TR4), also known as NR2C2, belongs to the nuclear receptor superfamily and shares high homology with the testicular nuclear receptor 2. The natural ligands of TR4 remained unclear until the recent discoveries of several energy/lipid sensors including the polyunsaturated fatty acid metabolites, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, and their synthetic ligands, thiazolidinediones, used for treatment of diabetes. TR4 is widely expressed throughout the body and particularly concentrated in the testis, prostate, cerebellum, and hippocampus. It has been shown to play important roles in cerebellar development, forebrain myelination, folliculogenesis, gluconeogenesis, lipogenesis, muscle development, bone development, and prostate cancer progression. Here we provide a comprehensive summary of TR4 signaling including its upstream ligands/activators/suppressors, transcriptional coactivators/repressors, downstream targets, and their in vivo functions with potential impacts on TR4-related diseases. Importantly, TR4 shares similar ligands/activators with another key nuclear receptor, peroxisome proliferator-activated receptor γ, which raised several interesting questions about how these 2 nuclear receptors may collaborate with or counteract each other's function in their related diseases. Clear dissection of such molecular mechanisms and their differential roles in various diseases may help researchers to design new potential drugs with better efficacy and fewer side effects to battle TR4 and peroxisome proliferator-activated receptor γ involved diseases. PMID:24702179

  7. Pathophysiological role of microRNA-29 in pancreatic cancer stroma

    PubMed Central

    Kwon, Jason J.; Nabinger, Sarah C.; Vega, Zachary; Sahu, Smiti Snigdha; Alluri, Ravi K.; Abdul-Sater, Zahi; Yu, Zhangsheng; Gore, Jesse; Nalepa, Grzegorz; Saxena, Romil; Korc, Murray; Kota, Janaiah

    2015-01-01

    Dense fibrotic stroma associated with pancreatic ductal adenocarcinoma (PDAC) is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Current, anti-stromal therapies have failed to improve tumor response to chemotherapy and patient survival. Furthermore, recent studies show that stroma impedes tumor progression, and its complete ablation accelerates PDAC progression. In an effort to understand the molecular mechanisms associated with tumor-stromal interactions, using in vitro and in vivo models and PDAC patient biopsies, we show that the loss of miR-29 is a common phenomenon of activated pancreatic stellate cells (PSCs)/fibroblasts, the major stromal cells responsible for fibrotic stromal reaction. Loss of miR-29 is correlated with a significant increase in extracellular matrix (ECM) deposition, a major component in PDAC stroma. Our in vitro miR-29 gain/loss-of-function studies document the role of miR-29 in PSC-mediated ECM stromal protein accumulation. Overexpression of miR-29 in activated stellate cells reduced stromal deposition, cancer cell viability, and cancer growth in co-culture. Furthermore, the loss of miR-29 in TGF-β1 activated PSCs is SMAD3 dependent. These results provide insights into the mechanistic role of miR-29 in PDAC stroma and its potential use as a therapeutic agent to target PDAC. PMID:26095125

  8. The role of vitamin D in pathophysiology and treatment of fibromyalgia.

    PubMed

    Jesus, Carlos A S; Feder, David; Peres, Mario F P

    2013-08-01

    Recent studies showed that most cells have receptors and enzymes responsible for metabolism of vitamin D. Several diseases have been linked to vitamin D deficiency, such as hypertension, diabetes, depression, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and chronic pain syndromes such as fibromyalgia. The association between fibromyalgia and vitamin D deficiency is very controversial in the literature with conflicting studies and methodological problems, which leads to more questions than answers. The purpose of this article is to raise questions about the association of hypovitaminosis D with fibromyalgia considering causal relationships, treatment, and pathophysiological explanations. PMID:23801008

  9. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury

    PubMed Central

    Sancho-Martínez, Sandra M.; López-Novoa, José M.; López-Hernández, Francisco J.

    2015-01-01

    The histological substrate of many forms of intrinsic acute kidney injury (AKI) has been classically attributed to tubular necrosis. However, more recent studies indicate that necrosis is not the main form of cell death in AKI and that other forms such as apoptosis, regulated necrosis (i.e. necroptosis and parthanatos), autophagic cell death and mitotic catastrophe, also participate in AKI and that their contribution depends on the cause and stage of AKI. Herein, we briefly summarize the main characteristics of the major types of cell death and we also critically review the existing evidence on the occurrence of different types of cell death reported in the most common experimental models of AKI and human specimens. We also discuss the pathophysiological mechanisms linking tubule epithelial cell death with reduced glomerular filtration, azotaemia and hydroelectrolytic imbalance. For instance, special relevance is given to the analysis of the inflammatory component of some forms of cell death over that of others, as an important and differential pathophysiological determinant. Finally, known molecular mechanisms and signalling pathways involved in each cell death type pose appropriate targets to specifically prevent or reverse AKI, provided that further knowledge of their participation and repercussion in each AKI syndrome is progressively increased in the near future. PMID:26413280

  10. Targeting different pathophysiological events after traumatic brain injury in mice: Role of melatonin and memantine.

    PubMed

    Kelestemur, Taha; Yulug, Burak; Caglayan, Ahmet Burak; Beker, Mustafa Caglar; Kilic, Ulkan; Caglayan, Berrak; Yalcin, Esra; Gundogdu, Reyhan Zeynep; Kilic, Ertugrul

    2016-01-26

    The tissue damage that emerges during traumatic brain injury (TBI) is a consequence of a variety of pathophysiological events, including free radical generation and over-activation of N-methyl-d-aspartate-type glutamate receptors (NMDAR). Considering the complex pathophysiology of TBI, we hypothesized that combination of neuroprotective compounds, targeting different events which appear during injury, may be a more promising approach for patients. In this context, both NMDAR antagonist memantine and free radical scavenger melatonin are safe in humans and promising agents for the treatment of TBI. Herein, we examined the effects of melatonin administered alone or in combination with memantine on the activation of signaling pathways, injury development and DNA fragmentation. Both compounds reduced brain injury moderately and the density of DNA fragmentation significantly. Notably, melatonin/memantine combination decreased brain injury and DNA fragmentation significantly, which was associated with reduced p38 and ERK-1/2 phosphorylation. As compared with melatonin and memantine groups, SAPK/JNK-1/2 phosphorylation was also reduced in melatonin/memantine combined animals. In addition, melatonin, memantine and their combination decreased iNOS activity significantly. Here, we provide evidence that melatonin/memantine combination protects brain from traumatic injury, which was associated with decreased DNA fragmentation, p38 phosphorylation and iNOS activity. PMID:26639427

  11. CRTH2 plays an essential role in the pathophysiology of Cry j 1-induced pollinosis in mice.

    PubMed

    Nomiya, Rie; Okano, Mitsuhiro; Fujiwara, Tazuko; Maeda, Megumi; Kimura, Yoshinobu; Kino, Kosuke; Yokoyama, Minehiko; Hirai, Hiroyuki; Nagata, Kinya; Hara, Toshifumi; Nishizaki, Kazunori; Nakamura, Masataka

    2008-04-15

    PGD(2) is the major prostanoid produced during the acute phase of allergic reactions. Two PGD(2) receptors have been isolated, DP and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), but whether they participate in the pathophysiology of allergic diseases remains unclear. We investigated the role of CRTH2 in the initiation of allergic rhinitis in mice. First, we developed a novel murine model of pollinosis, a type of seasonal allergic rhinitis. Additionally, pathophysiological differences in the pollinosis were compared between wild-type and CRTH2 gene-deficient mice. An effect of treatment with ramatroban, a CRTH2/T-prostanoid receptor dual antagonist, was also determined. Repeated intranasal sensitization with Cry j 1, the major allergen of Cryptomeria japonica pollen, in the absence of adjuvants significantly exacerbated nasal hyperresponsive symptoms, Cry j 1-specific IgE and IgG1 production, nasal eosinophilia, and Cry j 1-induced in vitro production of IL-4 and IL-5 by submandibular lymph node cells. Additionally, CRTH2 mRNA in nasal mucosa was significantly elevated in Cry j 1-sensitized mice. Following repeated intranasal sensitization with Cry j 1, CRTH2 gene-deficient mice had significantly weaker Cry j 1-specific IgE/IgG1 production, nasal eosinophilia, and IL-4 production by submandibular lymph node cells than did wild-type mice. Similar results were found in mice treated with ramatroban. These results suggest that the PGD(2)-CRTH2 interaction is elevated following sensitization and plays a proinflammatory role in the pathophysiology of allergic rhinitis, especially pollinosis in mice. PMID:18390753

  12. Role of Anxiety in the Pathophysiology of Irritable Bowel Syndrome: Importance of the Amygdala

    PubMed Central

    Myers, Brent; Meerveld, Beverley Greenwood-Van

    2009-01-01

    A common characteristic of irritable bowel syndrome (IBS) is that symptoms, including abdominal pain and abnormal bowel habits, are often triggered or exacerbated during periods of stress and anxiety. However, the impact of anxiety and affective disorders on the gastrointestinal (GI) tract is poorly understood and may in part explain the lack of effective therapeutic approaches to treat IBS. The amygdala is an important structure for regulating anxiety with the central nucleus of the amygdala facilitating the activation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system in response to stress. Moreover, chronic stress enhances function of the amygdala and promotes neural plasticity throughout the amygdaloid complex. This review outlines the latest findings obtained from human studies and animal models related to the role of the emotional brain in the regulation of enteric function, specifically how increasing the gain of the amygdala to induce anxiety-like behavior using corticosterone or chronic stress increases responsiveness to both visceral and somatic stimuli in rodents. A focus of the review is the relative importance of mineralocorticoid receptor and glucocorticoid receptor-mediated mechanisms within the amygdala in the regulation of anxiety and nociceptive behaviors that are characteristic features of IBS. This review also discusses several outstanding questions important for future research on the role of the amygdala in the generation of abnormal GI function that may lead to potential targets for new therapies to treat functional bowel disorders such as IBS. PMID:20582274

  13. Role of protein phosphatase-1 inhibitor-1 in cardiac physiology and pathophysiology

    PubMed Central

    Nicolaou, Persoulla; Hajjar, Roger J.; Kranias, Evangelia G.

    2009-01-01

    The type 1 protein phosphatase (PP1) is a critical negative regulator of Ca2+ cycling and contractility in the cardiomyocyte. In particular, it mediates restoration of cardiac function to basal levels, after β-adrenergic stimulation, by dephosphorylating key phospho-proteins. PP1 is a holoenzyme comprised of its catalytic and auxiliary subunits. These regulatory proteins dictate PP1's subcellular localization, substrate specificity and activity. Amongst them, inhibitor-1 is of particular importance since it has been implicated as an integrator of multiple neurohormonal pathways, which finely regulate PP1 activity, at the level of the sarcoplasmic reticulum (SR). In fact, perturbations in the regulation of PP1 by inhibitor-1 have been implicated in the pathogenesis of heart failure, suggesting that inhibitor-1-based therapeutic interventions may ameliorate cardiac dysfunction and remodeling in the failing heart. This review will discuss the current views on the role of inhibitor-1 in cardiac physiology, its possible contribution to cardiac disease and its potential as a novel therapeutic strategy. PMID:19481088

  14. Activation of Peroxisome Proliferator-activated Receptor γ (PPARγ) and CD36 Protein Expression: THE DUAL PATHOPHYSIOLOGICAL ROLES OF PROGESTERONE.

    PubMed

    Yang, Xiaoxiao; Zhang, Wenwen; Chen, Yuanli; Li, Yan; Sun, Lei; Liu, Ying; Liu, Mengyang; Yu, Miao; Li, Xiaoju; Han, Jihong; Duan, Yajun

    2016-07-15

    Progesterone or its analog, one of components of hormone replacement therapy, may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized LDL (oxLDL) that enhances macrophage/foam cell formation, is activated by the transcription factor peroxisome proliferator-activated receptor γ (PPARγ). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and the pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression, which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPARγ expression and PPARγ promoter activity in a PR-dependent manner and the binding of PR with the progesterone response element in the PPARγ promoter. Specific deletion of macrophage PPARγ (MφPPARγ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. We also determined that, associated with gestation and increased serum progesterone levels, CD36 and PPARγ expression in mouse adipose tissue, skeletal muscle, and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play dual pathophysiological roles by activating PPARγ expression, in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis, and enhances the PPARγ-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy. PMID:27226602

  15. The role of cerebellar circuitry alterations in the pathophysiology of autism spectrum disorders

    PubMed Central

    Mosconi, Matthew W.; Wang, Zheng; Schmitt, Lauren M.; Tsai, Peter; Sweeney, John A.

    2015-01-01

    The cerebellum has been repeatedly implicated in gene expression, rodent model and post-mortem studies of autism spectrum disorder (ASD). How cellular and molecular anomalies of the cerebellum relate to clinical manifestations of ASD remains unclear. Separate circuits of the cerebellum control different sensorimotor behaviors, such as maintaining balance, walking, making eye movements, reaching, and grasping. Each of these behaviors has been found to be impaired in ASD, suggesting that multiple distinct circuits of the cerebellum may be involved in the pathogenesis of patients' sensorimotor impairments. We will review evidence that the development of these circuits is disrupted in individuals with ASD and that their study may help elucidate the pathophysiology of sensorimotor deficits and core symptoms of the disorder. Preclinical studies of monogenetic conditions associated with ASD also have identified selective defects of the cerebellum and documented behavioral rescues when the cerebellum is targeted. Based on these findings, we propose that cerebellar circuits may prove to be promising targets for therapeutic development aimed at rescuing sensorimotor and other clinical symptoms of different forms of ASD. PMID:26388713

  16. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology

    PubMed Central

    Browning, Kirsteen N.

    2015-01-01

    Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID:26578870

  17. Circulating MicroRNAs as Potential Molecular Biomarkers in Pathophysiological Evolution of Pregnancy.

    PubMed

    Cretoiu, Dragos; Xu, Jiahong; Xiao, Junjie; Suciu, Nicolae; Cretoiu, Sanda Maria

    2016-01-01

    MicroRNAs represent nonprotein coding small RNA molecules that are very stable to degradation and responsible for gene silencing in most eukaryotic cells. Increased evidence has been accumulating over the years about their potential value as biomarkers for several diseases. MicroRNAs were predicted to be involved in nearly all biological processes from development to oncogenesis. In this review, we address the importance of circulating microRNAs in different conditions associated with pregnancy starting with the implantation period to preeclampsia and we shortly describe the correlation between placental circulating miRNAs and pregnancy status. We also discuss the importance of microRNAs in recurrent abortion and ectopic pregnancy. PMID:27493447

  18. Circulating MicroRNAs as Potential Molecular Biomarkers in Pathophysiological Evolution of Pregnancy

    PubMed Central

    Xu, Jiahong; Xiao, Junjie; Suciu, Nicolae

    2016-01-01

    MicroRNAs represent nonprotein coding small RNA molecules that are very stable to degradation and responsible for gene silencing in most eukaryotic cells. Increased evidence has been accumulating over the years about their potential value as biomarkers for several diseases. MicroRNAs were predicted to be involved in nearly all biological processes from development to oncogenesis. In this review, we address the importance of circulating microRNAs in different conditions associated with pregnancy starting with the implantation period to preeclampsia and we shortly describe the correlation between placental circulating miRNAs and pregnancy status. We also discuss the importance of microRNAs in recurrent abortion and ectopic pregnancy. PMID:27493447

  19. Role of Anti-Müllerian Hormone in pathophysiology, diagnosis and treatment of Polycystic Ovary Syndrome: a review.

    PubMed

    Dumont, Agathe; Robin, Geoffroy; Catteau-Jonard, Sophie; Dewailly, Didier

    2015-01-01

    Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women. Excessive ovarian production of Anti-Müllerian Hormone, secreted by growing follicles in excess, is now considered as an important feature of PCOS. The aim of this review is first to update the current knowledge about the role of AMH in the pathophysiology of PCOS. Then, this review will discuss the improvement that serum AMH assay brings in the diagnosis of PCOS. Last, this review will explain the utility of serum AMH assay in the management of infertility in women with PCOS and its utility as a marker of treatment efficiency on PCOS symptoms. It must be emphasized however that the lack of an international standard for the serum AMH assay, mainly because of technical issues, makes it difficult to define consensual thresholds, and thus impairs the widespread use of this new ovarian marker. Hopefully, this should soon improve. PMID:26691645

  20. Role of microRNAs in gastrointestinal smooth muscle fibrosis and dysfunction: novel molecular perspectives on the pathophysiology and therapeutic targeting.

    PubMed

    Krishna, Chadalavada Vijay; Singh, Jagmohan; Thangavel, Chellappagounder; Rattan, Satish

    2016-04-01

    MicroRNAs (miRNAs) belong to a group of short noncoding RNA molecules with important roles in cellular biology. miRNAs regulate gene expression by repressing translation or degrading the target mRNA. Recently, a growing body of evidence suggests that miRNAs are implicated in many diseases and could be potential biomarkers. Fibrosis and/smooth muscle (SM) dysfunction contributes to the morbidity and mortality associated with several diseases of the gastrointestinal tract (GIT). Currently available therapeutic modalities are unsuccessful in efficiently blocking or reversing fibrosis and/or SM dysfunction. Recent understanding of the role of miRNAs in signaling pathway of fibrogenesis and SM phenotype switch has provided a new insight into translational research. However, much is still unknown about the molecular targets and therapeutic potential of miRNAs in the GIT. This review discusses miRNA biology, pathophysiology of fibrosis, and aging- associated SM dysfunction in relation to the deregulation of miRNAs in the GIT. We also highlight the role of selected miRNAs associated with fibrosis and SM dysfunction-related diseases of the GIT. PMID:26822916

  1. Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?

    PubMed Central

    Reuwer, Anne Q; Nowak-Sliwinska, Patrycja; Mans, Laurie A; van der Loos, Chris M; von der Thüsen, Jan H; Twickler, Marcel Th B; Spek, C Arnold; Goffin, Vincent; Griffioen, Arjan W; Borensztajn, Keren S

    2012-01-01

    Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention. PMID:22128761

  2. Mitophagy: Basic Mechanism and Potential Role in Kidney Diseases

    PubMed Central

    Tang, Chengyuan; He, Liyu; Liu, Jing; Dong, Zheng

    2015-01-01

    Background Mitochondria play fundamental roles in cellular metabolism, signaling, and viability. Disruption of mitochondria not only leads to dysfunction of the organelles but also activates mechanisms of cell injury and death, contributing to the pathogenesis of various diseases. Summary Removal of damaged mitochondria is therefore crucial for cellular homeostasis and survival. Mitophagy, the selective elimination of mitochondria via autophagy, is an important mechanism of mitochondrial quality control in physiological and pathological conditions. Defects in mitophagy have been implicated in a variety of human disorders, including both acute and chronic kidney diseases. However, the role and regulatory mechanisms of mitophagy in kidney cells and tissues remain largely unknown. Key Message This review provides updated information on mitophagy and suggests a potential role of mitophagy in renal pathophysiology.

  3. The Emerging Role of MitomiRs in the Pathophysiology of Human Disease.

    PubMed

    Duarte, Filipe V; Palmeira, Carlos M; Rolo, Anabela P

    2015-01-01

    that could be a target for several mitomiRs. However, perhaps a more challenging topic concerning mitomiRs is whether the mitochondrial DNA can harbor miRNA sequences, indicating an involvement of mitochondria in small RNA-generating pathways. The identification of populations of miRNAs in the mitochondria pushed scientists in the field to question its biological functions. It is established that miRNAs, originated in the nuclear genome, are exported to cytosol where they are processed and exert their function by inhibiting nuclear genome-derived mRNA. Actually it is also known that some miRNAs are imported into mitochondria where they interact with some mitochondrial genome-derived mRNA molecules. More strikingly, it has also come to light that mitochondrial genome (mtDNA) can originate some miRNA molecules that exert their function directly on mitochondrial transcripts. The links between miRNA deregulation and human disease have been reported in almost all medicine fields. Currently, great efforts are being invested in understanding the involvement of miRNA deregulation in disease and unlocking the mechanisms by which they act. This new field of investigation has revealed the tremendous potential of miRNAs as diagnostic or even as valuable therapeutic tools. miRNAs have recently emerged as key regulators of metabolism. Metabolic syndrome is a systemic disorder that includes a spectrum of abnormalities associated with obesity and type II diabetes. Defects in mitochondrial function, namely related to oxidation of fatty acids, have been linked to diet-induced obesity and the development of insulin resistance in adipose tissue and skeletal muscle. Consistently, obese individuals have mitochondria with compromised bioenergetic capacity. Therefore, increasing interest is being given to the role of miRNAs on metabolic regulation, with relevance on mitochondria and the mechanisms purported for miRNA actions, particularly acting in mitochondria or in mitochondria

  4. Role of Regulators of G Protein Signaling Proteins in Bone Physiology and Pathophysiology

    PubMed Central

    Jules, Joel; Yang, Shuying; Chen, Wei; Li, Yi-Ping

    2016-01-01

    Regulators of G protein signaling (RGS) proteins enhance the intrinsic GTPase activity of α subunits of the heterotrimeric G protein complex of G protein-coupled receptors (GPCRs) and thereby inactivate signal transduction initiated by GPCRs. The RGS family consists of nearly 37 members with a conserved RGS homology domain which is critical for their GTPase accelerating activity. RGS proteins are expressed in most tissues, including heart, lung, brain, kidney, and bone and play essential roles in many physiological and pathological processes. In skeletal development and bone homeostasis as well as in many bone disorders, RGS proteins control the functions of various GPCRs, including the parathyroid hormone receptor type 1 and calcium-sensing receptor and also regulate various critical signaling pathways, such as Wnt and calcium oscillations. This chapter will discuss the current findings on the roles of RGS proteins in regulating signaling of key GPCRs in skeletal development and bone homeostasis. We also will examine the current updates of RGS proteins’ regulation of calcium oscillations in bone physiology and highlight the roles of RGS proteins in selected bone pathological disorders. Despite the recent advances in bone and mineral research, RGS proteins remain understudied in the skeletal system. Further understanding of the roles of RGS proteins in bone should not only provide great insights into the molecular basis of various bone diseases but also generate great therapeutic drug targets for many bone diseases. PMID:26123302

  5. Pathophysiology of the Peritoneal Membrane during Peritoneal Dialysis: The Role of Hyaluronan

    PubMed Central

    Yung, Susan; Chan, Tak Mao

    2011-01-01

    During peritoneal dialysis (PD), constant exposure of mesothelial cells to bioincompatible PD solutions results in the denudation of the mesothelial monolayer and impairment of mesothelial cell function. Hyaluronan, a major component of extracellular matrices, is synthesized by mesothelial cells and contributes to remesothelialization, maintenance of cell phenotype, and tissue remodeling and provides structural support to the peritoneal membrane. Chronic peritoneal inflammation is observed in long-term PD patients and is associated with increased hyaluronan synthesis. During inflammation, depolymerization of hyaluronan may occur with the generation of hyaluronan fragments. In contrast to native hyaluronan which offers a protective role to the peritoneum, hyaluronan fragments exacerbate inflammatory and fibrotic processes and therefore assist in the destruction of the tissue. This paper will discuss the contribution of mesothelial cells to peritoneal membrane alterations that are induced by PD and the putative role of hyaluronan in these processes. PMID:22203782

  6. The Role of Stem Cells in the Etiology and Pathophysiology of Endometriosis.

    PubMed

    Hufnagel, Demetra; Li, Fei; Cosar, Emine; Krikun, Graciela; Taylor, Hugh S

    2015-09-01

    Human endometrium is a dynamic organ that normally undergoes repetitive cyclic regeneration. To enable this rapid regeneration, it is not surprising that the endometrium contains a reservoir of progenitor stem cells. However, this pool of cells that allows the growth of the endometrium also allows for unrestrained growth that can reach beyond the endometrium. In this review, we will address the role of stem cells in endometriosis. Recent characterization of stem cell populations within human endometrium has opened the possibility of understanding their physiologic as well as their pathologic roles. While stem cells are critical to the cyclic regeneration of a healthy endometrium, we have shown that both endometrium-derived and bone marrow-derived stem cells can migrate to ectopic sites and contribute to the development of endometriosis. Furthermore, endometriosis interferes with the normal stem cell trafficking to the uterus that is necessary for endometrial growth and repair. Altered stem cell mobility and engraftment characterize this disease. PMID:26375413

  7. Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses

    PubMed Central

    Yamaguchi, Akira; Katsuyama, Kayoko; Nagahama, Kiyotaka; Takai, Toshiyuki; Aoki, Ichiro; Yamanaka, Shoji

    2004-01-01

    Mice containing a disruption of the Hexb gene have provided a useful model system for the study of the human lysosomal storage disorder known as Sandhoff disease (SD). Hexb–/– mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. Our study revealed that the disease states in this model are associated with the appearance of antiganglioside autoantibodies. Both elevation of serum antiganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the disease in Hexb–/– mice; serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor γ gene (FcRγ) was additionally disrupted in Hexb–/– mice, as it plays a key role in immune complex–mediated autoimmune diseases. Clinical symptoms were improved and life spans were extended in the Hexb–/–FcRγ–/– mice; the number of apoptotic cells was also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in SD and therefore provides a target for novel therapies. PMID:14722612

  8. Pathophysiology of central sleep apneas.

    PubMed

    Hernandez, Adam B; Patil, Susheel P

    2016-05-01

    The transition from wake to sleep is accompanied by a host of physiologic changes, which result in major alterations in respiratory control and may result in sleep-related breathing disorders. The central sleep apneas are a group of sleep-related breathing disorders that are characterized by recurrent episodes of airflow reduction or cessation due to a temporary reduction or absence of central respiratory drive. The fundamental hallmark of central sleep apnea (CSA) disorders is the presence of ventilatory control instability; however, additional mechanisms play a role in one or more specific manifestations of CSA. CSA may manifest during conditions of eucapnia/hypocapnia or chronic hypercapnia, which is a useful clinical classification that lends understanding to the underlying pathophysiology and potential therapies. In this review, an overview of normal breathing physiology is provided, followed by a discussion of pathophysiologic mechanisms that promote CSA and the mechanisms that are specific to different manifestations of CSA. PMID:26782104

  9. Role of oxidative stress in the pathophysiology of Toxoplasma gondii infection.

    PubMed

    Dincel, Gungor Cagdas; Atmaca, Hasan Tarik

    2016-06-01

    Oxidative stress (OS) plays an essential role in the pathogenesis of common neurodegenerative diseases. We have previously shown that Toxoplasma gondii (T. gondii) induces high nitric oxide (NO) production, glial activation, and apoptosis that altogether cause severe neuropathology in toxoplasma encephalitis (TE). The objective of this study was to investigate the cytotoxic effect of OS and to identify a correlation between the causes of T. gondii induced neuropathology. Expression levels of glutathione reductase (GR), Cu/Zn superoxide dismutase (SOD1), neuron specific enolase (NSE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were investigated. Results of the study revealed that the levels of GR (P <0.005) and NSE (P <0.001) expression in the brain tissue markedly increased while SOD1 activity decreased (P <0.001) in the infected group compared to the non-infected group. In addition, intense staining for 8-OHdG (P <0.05) was observed both in the nucleus and the cytoplasm of neurons and glial cells that underwent OS. These results were reasonable to suggest that T. gondii-mediated OS might play a pivotal role and a different type of role in the mechanism of neurodegeneration/neuropathology in the process of TE. The results also clearly indicated that increased levels of NO and apoptosis might contribute to OS-related pathogenesis of TE. As a result, OS and expression of NSE might give an idea of the disease progress and may have a critical diagnostic significance for patients with T. gondii infection. PMID:26966143

  10. The Role of the Calcium-Sensing Receptor in Bone Biology and Pathophysiology

    PubMed Central

    Theman, TA; Collins, MT

    2009-01-01

    Bone cells, particularly osteoblasts and osteoclasts, exhibit functional responses to calcium (Ca2+). The identification of the calcium-sensing receptor (CaR) in parathyroid glands as the master regulator of parathyroid hormone (PTH) secretion proved that cells could specifically respond to changes in divalent cation concentration. Yet, after many years of study, it remains unclear whether this receptor, which has also been identified in bone, has functional import there. Various knockout and transgenic mouse models have been developed, but conclusions about skeletal phenotypes remain elusive. Complex endocrine feedback loops involving calcium, phosphorus, vitamin D, and PTH confound efforts to isolate the effects of a single mineral, hormone, or receptor and most models fail to account for other local factors such as parathyroid hormone related protein (PTHrP). We review the relevant mouse models and discuss the importance of CaR in chondrogenesis and osteogenesis. We present the evidence for a non-redundant role for CaR in skeletal mineralization, including our experience in patients with activating CaR mutations. Additionally, we review emerging research on the importance of the CaR to the regulation of serum calcium homeostasis independent of PTH, the role of the CaR in the hematopoietic stem cell niche with implications for bone marrow transplant, and early evidence that implies a role for the CaR as a factor in skeletal metastasis from breast and prostate cancer. We conclude with a discussion of drugs that target the CaR directly either as agonists (calcimimetics) or antagonists (calcilytics), and the consequences for bone physiology and pathology. PMID:19355939

  11. The central role of aquaporins in the pathophysiology of ischemic stroke

    PubMed Central

    Vella, Jasmine; Zammit, Christian; Di Giovanni, Giuseppe; Muscat, Richard; Valentino, Mario

    2015-01-01

    Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4-null mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K+-channels (Kir4.1) and glial K+ uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4-null mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke. PMID:25904843

  12. Considerations on the role of environmental toxins in idiopathic Parkinson’s disease pathophysiology

    PubMed Central

    2014-01-01

    Neurodegenerative diseases are characterized by a progressive dysfunction of the nervous system. Often associated with atrophy of the affected central or peripheral nervous structures, they include diseases such as Parkinson’s Disease (PD), Alzheimer’s Disease and other dementias, Genetic Brain Disorders, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s Disease), Huntington’s Disease, Prion Diseases, and others. The prevalence of neurodegenerative diseases has increased over the last years. This has had a major impact both on patients and their families and has exponentially increased the medical bill by hundreds of billions of Euros. Therefore, understanding the role of environmental and genetic factors in the pathogenesis of PD is crucial to develop preventive strategies. While some authors believe that PD is mainly genetic and that the aging of the society is the principal cause for this increase, different studies suggest that PD may be due to an increased exposure to environmental toxins. In this article we review epidemiological, sociological and experimental studies to determine which hypothesis is more plausible. Our conclusion is that, at least in idiopathic PD (iPD), the exposure to toxic environmental substances could play an important role in its aetiology. PMID:24826210

  13. α-Enolase, a Multifunctional Protein: Its Role on Pathophysiological Situations

    PubMed Central

    Díaz-Ramos, Àngels; Roig-Borrellas, Anna; García-Melero, Ana; López-Alemany, Roser

    2012-01-01

    α-Enolase is a key glycolytic enzyme in the cytoplasm of prokaryotic and eukaryotic cells and is considered a multifunctional protein. α-enolase is expressed on the surface of several cell types, where it acts as a plasminogen receptor, concentrating proteolytic plasmin activity on the cell surface. In addition to glycolytic enzyme and plasminogen receptor functions, α-Enolase appears to have other cellular functions and subcellular localizations that are distinct from its well-established function in glycolysis. Furthermore, differential expression of α-enolase has been related to several pathologies, such as cancer, Alzheimer's disease, and rheumatoid arthritis, among others. We have identified α-enolase as a plasminogen receptor in several cell types. In particular, we have analyzed its role in myogenesis, as an example of extracellular remodelling process. We have shown that α-enolase is expressed on the cell surface of differentiating myocytes, and that inhibitors of α-enolase/plasminogen binding block myogenic fusion in vitro and skeletal muscle regeneration in mice. α-Enolase could be considered as a marker of pathological stress in a high number of diseases, performing several of its multiple functions, mainly as plasminogen receptor. This paper is focused on the multiple roles of the α-enolase/plasminogen axis, related to several pathologies. PMID:23118496

  14. Atherosclerosis pathophysiology and the role of novel risk factors: a clinicobiochemical perspective.

    PubMed

    Mallika, V; Goswami, Binita; Rajappa, Medha

    2007-01-01

    Atherosclerosis is the root cause of the biggest killer of the 21st century. Mechanisms contributing to atherogenesis are multiple and complex. A number of theories-including the role of dyslipidemia, hypercoagulability, oxidative stress, endothelial dysfunction, and inflammation and infection by certain pathogens-have been propounded from time to time explain this complex phenomenon. Recently it has been suggested that atherosclerosis is a multifactorial, multistep disease that involves chronic inflammation at every step, from initiation to progression, and that all the risk factors contribute to pathogenesis by aggravating the underlying inflammatory process. A better understanding of the pathogenesis of atherosclerosis will aid in devising pharmaceutical and lifestyle modifications for reducing mortality resulting from coronary artery disease (CAD).A comprehensive literature search was conducted using the Web sites of the National Library of Medicine (http:// www.ncbl.nlm.nih.gov/) and PubMed Central, the US National Library of Medicine's digital archive of life sciences literature (http:// www.pubmedcentral.nih.gov/). The data were accessed from books and journals in which relevant articles in this field were published. The whole spectrum of coronary artery disease evolves through various events that lead to the formation and progression of atherosclerotic plaque and finally its complications. Atherosclerosis is the culprit behind coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The pathogenic mechanisms are varied and complex. Of late, the role of lipoprotein (a), homocysteine, and inflammation and infection as prime culprits in pathogenesis of CAD is the subject of intense research and debate. The appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework to understand the clinical benefits of newer therapeutic strategies, and a better understanding of pathogenesis aids in formulating

  15. The role of copper ions in pathophysiology and fluorescent sensors for the detection thereof.

    PubMed

    Verwilst, Peter; Sunwoo, Kyoung; Kim, Jong Seung

    2015-04-01

    Copper ions are indispensible to life and maintaining tight control over the homeostasis of copper ions in the body is a prerequisite to sustaining health. Aberrations in normal copper levels, both systemic as well as on a tissue or cellular scale, are implicated in a wide range of diseases, such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (prion diseases). The current understanding of how copper influences these diseases is described. The field of fluorescent copper sensors both functioning via a reaction based mechanism as well as by directly binding copper ions has known an inflation in recent years, and the importance of this field to elucidating the role of copper in cell biology is pointed out. Progress in these tightly interwoven fields has resulted in a better understanding of a number of diseases related to copper imbalances and current developments might open the path for novel and innovating therapies to address these diseases. PMID:25647245

  16. A Role for White Matter Abnormalities in the Pathophysiology of Bipolar Disorder

    PubMed Central

    Mahon, Katie; Burdick, Katherine E.; Szeszko, Philip R.

    2010-01-01

    Bipolar disorder is a chronically disabling psychiatric disorder characterized by manic states that is often interspersed with periods of depression whose neurobiology remains largely unknown. There is, however, increasing evidence that white matter (WM) abnormalities may play an important role in the neurobiology of the disorder. In this review we critically evaluate evidence for WM abnormalities in bipolar disorder obtained from neuroimaging, neuropathological, and genetic research. Increased rates of white matter hyperintensities, regional volumetric abnormalities, abnormal water diffusion along prefrontal-subcortical tracts, fewer oligodendrocytes in prefrontal WM, and alterations in the expression of myelin-and oligodendrocyte-related genes are among the most consistent findings. Abnormalities converge in the prefrontal WM and, in particular, tracts that connect prefrontal regions and subcortical gray matter structures known to be involved in emotion. Taken together, the evidence supports and clarifies a model of bipolar disorder that involves disconnectivity in regions implicated in emotion generation and regulation. PMID:19896972

  17. [Role of endocannabinoid 2-arachidonoylglycerol in the physiology and pathophysiology of the cardiovascular system].

    PubMed

    Karabowicz, Piotr; Grzęda, Emilia; Baranowska-Kuczko, Marta; Malinowska, Barbara

    2014-01-01

    Cannabinoids, the active ingredients of Cannabis sativa var. indica, have been used by humans as recreational and therapeutic agents for thousands of years. This group of substances also includes synthetic ligands and, synthesized in the body of humans and animals, endocannabinoids. The best known compound classified as an endogenous cannabinoid is anandamide. However, recent studies show that another compound of this group, 2-arachidonoylglycerol (2-AG), also performs many important functions in the organism. 2-Arachidonoylglycerol plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart. Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis. Thus, it may be a novel attractive therapeutic target. However, because of rapid metabolism and opposite effects dependent on the experimental model, the function of 2-AG still remains to be established. PMID:24934539

  18. The Oligomycin-Sensitivity Conferring Protein of Mitochondrial ATP Synthase: Emerging New Roles in Mitochondrial Pathophysiology

    PubMed Central

    Antoniel, Manuela; Giorgio, Valentina; Fogolari, Federico; Glick, Gary D.; Bernardi, Paolo; Lippe, Giovanna

    2014-01-01

    The oligomycin-sensitivity conferring protein (OSCP) of the mitochondrial FOF1 ATP synthase has long been recognized to be essential for the coupling of proton transport to ATP synthesis. Located on top of the catalytic F1 sector, it makes stable contacts with both F1 and the peripheral stalk, ensuring the structural and functional coupling between FO and F1, which is disrupted by the antibiotic, oligomycin. Recent data have established that OSCP is the binding target of cyclophilin (CyP) D, a well-characterized inducer of the mitochondrial permeability transition pore (PTP), whose opening can precipitate cell death. CyPD binding affects ATP synthase activity, and most importantly, it decreases the threshold matrix Ca2+ required for PTP opening, in striking analogy with benzodiazepine 423, an apoptosis-inducing agent that also binds OSCP. These findings are consistent with the demonstration that dimers of ATP synthase generate Ca2+-dependent currents with features indistinguishable from those of the PTP and suggest that ATP synthase is directly involved in PTP formation, although the underlying mechanism remains to be established. In this scenario, OSCP appears to play a fundamental role, sensing the signal(s) that switches the enzyme of life in a channel able to precipitate cell death. PMID:24786291

  19. Role of Inflammasome Activation in the Pathophysiology of Vascular Diseases of the Neurovascular Unit

    PubMed Central

    Mohamed, Islam N.; Ishrat, Tauheed; Fagan, Susan C.

    2015-01-01

    Abstract Significance: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases. Recent Advances: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome. Critical Issues: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke. Future Directions: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases. Antioxid. Redox Signal. 22, 1188–1206. PMID:25275222

  20. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification.

    PubMed

    Sheen, Campbell R; Kuss, Pia; Narisawa, Sonoko; Yadav, Manisha C; Nigro, Jessica; Wang, Wei; Chhea, T Nicole; Sergienko, Eduard A; Kapoor, Kapil; Jackson, Michael R; Hoylaerts, Marc F; Pinkerton, Anthony B; O'Neill, W Charles; Millán, José Luis

    2015-05-01

    Medial vascular calcification (MVC) is a pathological phenomenon that causes vascular stiffening and can lead to heart failure; it is common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases. These conditions share the common feature of tissue-nonspecific alkaline phosphatase (TNAP) upregulation in the vasculature. To evaluate the role of TNAP in MVC, we developed a mouse model that overexpresses human TNAP in vascular smooth muscle cells in an X-linked manner. Hemizygous overexpressor male mice (Tagln-Cre(+/-) ; Hprt(ALPL) (/Y) or TNAP-OE) show extensive vascular calcification, high blood pressure, and cardiac hypertrophy, and have a median age of death of 44 days, whereas the cardiovascular phenotype is much less pronounced and life expectancy is longer in heterozygous (Tagln-Cre(+/-) ; Hprt(ALPL) (/-) ) female TNAP-OE mice. Gene expression analysis showed upregulation of osteoblast and chondrocyte markers and decreased expression of vascular smooth muscle markers in the aortas of TNAP-OE mice. Through medicinal chemistry efforts, we developed inhibitors of TNAP with drug-like pharmacokinetic characteristics. TNAP-OE mice were treated with the prototypical TNAP inhibitor SBI-425 or vehicle to evaluate the feasibility of TNAP inhibition in vivo. Treatment with this inhibitor significantly reduced aortic calcification and cardiac hypertrophy, and extended lifespan over vehicle-treated controls, in the absence of secondary effects on the skeleton. This study shows that TNAP in the vasculature contributes to the pathology of MVC and that it is a druggable target. PMID:25428889

  1. Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression.

    PubMed

    Kim, Yong-Ku; Na, Kyoung-Sae

    2016-10-01

    Treatment-resistant depression (TRD) causes substantial socioeconomic burden. Although a consensus on the definition of TRD has not yet been reached, it is certain that classic monoaminergic antidepressants are ineffective for TRD. One decade ago, many researchers found ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, to be an alternative to classic monoaminergic antidepressants. The major mechanisms of action of ketamine rapidly induce synaptogenesis in the brain-derived neurotrophic factor (BDNF) pathway. Although excessive glutamatergic neurotransmission and consequent excitotoxicity were considered a major cause of TRD, recent evidence suggests that the extrasynaptic glutamatergic receptor signal pathway mainly contributes to the detrimental effects of TRD. Glial cells such as microglia and astrocytes, early life adversity, and glucocorticoid receptor dysfunction participate in complex cross-talk. An appropriate reuptake of glutamate at the astrocyte is crucial for preventing 'spill-over' of synaptic glutamate and binding to the extrasynaptic NMDA receptor. Excessive microglial activation and the inflammatory process cause astrocyte glutamatergic dysfunction, which in turn activates microglial function. Early life adversity and glucocorticoid receptor dysfunction result in vulnerability to stress in adulthood. A maladaptive response to stress leads to increased glutamatergic release and pro-inflammatory cytokines, which then activate microglia. However, since the role of inflammatory mediators such as pro-inflammatory cytokines is not specific for depression, more disease-specific mechanisms should be identified. Last, although much research has focused on ketamine as an alternative antidepressant for TRD, its long-lasting effectiveness and adverse events have not been rigorously demonstrated. Additionally, evidence suggests that substantial brain abnormalities develop in ketamine abusers. Thus, more investigations for ketamine and other novel

  2. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification†

    PubMed Central

    Sheen, Campbell R.; Kuss, Pia; Narisawa, Sonoko; Yadav, Manisha C.; Nigro, Jessica; Wang, Wei; Chhea, T. Nicole; Sergienko, Eduard A.; Kapoor, Kapil; Jackson, Michael R.; Hoylaerts, Marc. F.; Pinkerton, Anthony B.; O'Neill, W. Charles; Millán, Jose Luis

    2015-01-01

    Medial vascular calcification (MVC) is a pathological phenomenon common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases, that causes vascular stiffening and can lead to heart failure. These conditions share the common feature of tissue-nonspecific alkaline phosphatase (TNAP) upregulation in the vasculature. To evaluate the role of TNAP in MVC, we developed a mouse model that overexpresses human TNAP in vascular smooth muscle cells in an X-linked manner. Hemizygous overexpressor male mice (Tagln-Cre+/-; HprtALPL/Y, or TNAP-OE) show extensive vascular calcification, high blood pressure, cardiac hypertrophy and have a median age of death of 44 days, whereas the cardiovascular phenotype is much less pronounced and life expectancy is longer in heterozygous (Tagln-Cre+/-; HprtALPL/-) female TNAP-OE mice. Gene expression analysis showed upregulation of osteoblast and chondrocyte markers and decreased expression of vascular smooth muscle markers in the aortas of TNAP-OE mice. Through medicinal chemistry efforts, we developed inhibitors of TNAP with drug-like pharmacokinetic characteristics. TNAP-OE mice were treated with the prototypical TNAP inhibitor SBI-425 or vehicle to evaluate the feasibility of TNAP inhibition in vivo. Treatment with this inhibitor significantly reduced aortic calcification and cardiac hypertrophy, and extended lifespan over vehicle-treated controls, in the absence of secondary effects on the skeleton. This study shows that TNAP in the vasculature contributes to the pathology of MVC and that it is a druggable target. This article is protected by copyright. All rights reserved PMID:25428889

  3. [Respective roles of cortisol, aldosterone and angiotensin II during pathophysiology of atherosclerosis].

    PubMed

    Ayari, Hanène

    2013-01-01

    The involvement of angiotensin II, cortisol and aldosterone in increased cardiovascular risk is well known but their interactions within arterial wall and during atheroma formation are not established. In fact, mild cortisol excess is associated with a higher prevalence of cardiovascular events, increased intima media thickness, a higher frequency of atherosclerotic plaques and increased mortality. Conversely, remission from hypercortisolism is followed by improvement in cardiovascular risk markers as intima-media thickness or arterial distensibility, suggesting a strong link between cortisol excess and adverse vascular remodeling. On the other hand, implication of renin-angiotensin system (RAS) in atheromatous remodeling is well documented. The RAS also includes aldosterone, a mineralocorticoid which secretion is mainly and strongly stimulated by angiotensin II, and which receptor (MR) can also be activated by cortisol given that MR affinity is similar for both aldosterone and cortisol. The role of aldosterone in arterial remodeling is still very controversial. Aldosterone treatment associated with a high salt diet induced not only hypertension but also oxidative stress, collagen synthesis and vascular inflammation. However in models without salt loading or arterial hypertension, such as the treatment with deoxycorticosterone acetate in dogs, no alterations in aortic structure were observed and moreover, the MR blockade with eplerenone did not attenuate atherosclerosis in the aorta of diabetic Apo-E KO mice. It stems that among the different effects and mechanisms described in cell experiments, it is not known which are indeed operating in situ in human vessels and thus, if local cortisol is deleterious or beneficial and, if activation of MR by aldosterone or cortisol is important in vascular remodeling and atherogenesis. RAS blocker treatment would be particularly beneficial in essential hypertensive patients with low plasma renin, to attenuate both angiotensin

  4. Guanylyl Cyclase/Atrial Natriuretic Peptide Receptor-A: Role in the Pathophysiology of Cardiovascular Regulation

    PubMed Central

    Pandey, Kailash N.

    2012-01-01

    Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti-proliferative effects, which are important in the control of blood pressure and cardiovascular events. One principal locus involved in the regulatory action of ANP and brain natriuretic peptide (BNP) is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA). Studies on ANP, BNP, and their receptor, GC-A/NPRA, have greatly increased our knowledge of the control of hypertension and cardiovascular disorders. Cellular, biochemical, and molecular studies have helped to delineate the receptor function and signaling mechanisms of NPRA. Gene-targeted and transgenic mouse models have advanced our understanding of the importance of ANP, BNP, and GC-A/NPRA in disease states at the molecular level. Importantly, ANP and BNP are used as critical markers of cardiac events; however, their therapeutic potentials for the diagnosis and treatment of hypertension, heart failure, and stroke have just begun to be realized. We are now just at the initial stage of molecular therapeutics and pharmacogenomic advancement of the natriuretic peptides. More investigations should be undertaken and ongoing ones be extended in this important field. PMID:21815745

  5. Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation.

    PubMed

    Pandey, Kailash N

    2011-08-01

    Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti-proliferative effects, which are important in the control of blood pressure and cardiovascular events. One principal locus involved in the regulatory action of ANP and brain natriuretic peptide (BNP) is guanylyl cyclase / natriuretic peptide receptor-A (GC-A/NPRA). Studies on ANP, BNP, and their receptor, GC-A/NPRA, have greatly increased our knowledge of the control of hypertension and cardiovascular disorders. Cellular, biochemical, and molecular studies have helped to delineate the receptor function and signaling mechanisms of NPRA. Gene-targeted and transgenic mouse models have advanced our understanding of the importance of ANP, BNP, and GC-A/NPRA in disease states at the molecular level. Importantly, ANP and BNP are used as critical markers of cardiac events; however, their therapeutic potentials for the diagnosis and treatment of hypertension, heart failure, and stroke have just begun to be realized. We are now just at the initial stage of molecular therapeutics and pharmacogenomic advancement of the natriuretic peptides. More investigations should be undertaken and ongoing ones be extended in this important field. PMID:21815745

  6. Pathophysiological mechanism and therapeutic role of S100 proteins in cardiac failure: a systematic review.

    PubMed

    Imbalzano, Egidio; Mandraffino, Giuseppe; Casciaro, Marco; Quartuccio, Sebastiano; Saitta, Antonino; Gangemi, Sebastiano

    2016-09-01

    S100 proteins are a family of highly acidic calcium-binding proteins involved in calcium handling in many tissues and organs. Some of these proteins are highly expressed in cardiac tissue, and an impairment of some specific S100 proteins has been related to heart failure. To check this hypothesis, we decided to review the literature since 2008 until May 2015. According to the studies collected, recovering S100A1 levels may enhance contractile/relaxing performance in heart failure, reverse negative force-frequency relationship, improve contractile reserve, reverse diastolic dysfunction and protect against pro-arrhythmic reductions of sarcoplasmic reticulum calcium. The safety profile of gene therapy was also confirmed. Increased S100B protein levels were related to a worse outcome in chronic heart failure. S100A8/A9 complex plasma levels, as well as other inflammatory biomarkers, were significantly higher in chronic heart failure patients. S100A2 seems to increase both contractile and relaxation performance in animal cardiomyocytes. Otherwise, S100A6 cardiac expression seems to have no effects on contractility. S100A4 KO mice showed reduced cardiac interstitial fibrosis. Data collected encourage a potential prospective application in human. These proteins could be exploited as biomarkers in stadiation and prognosis of chronic heart failure, as well as therapeutic target to rescue failing heart. Registration details The study protocol has been registered in PROSPERO ( http://www.crd.york.ac.uk/PROSPERO/ ) under registration number CRD42015027932. PMID:26833319

  7. Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory.

    PubMed

    Pace-Schott, Edward F; Germain, Anne; Milad, Mohammed R

    2015-01-01

    Post-traumatic stress disorder (PTSD) is accompanied by disturbed sleep and an impaired ability to learn and remember extinction of conditioned fear. Following a traumatic event, the full spectrum of PTSD symptoms typically requires several months to develop. During this time, sleep disturbances such as insomnia, nightmares, and fragmented rapid eye movement sleep predict later development of PTSD symptoms. Only a minority of individuals exposed to trauma go on to develop PTSD. We hypothesize that sleep disturbance resulting from an acute trauma, or predating the traumatic experience, may contribute to the etiology of PTSD. Because symptoms can worsen over time, we suggest that continued sleep disturbances can also maintain and exacerbate PTSD. Sleep disturbance may result in failure of extinction memory to persist and generalize, and we suggest that this constitutes one, non-exclusive mechanism by which poor sleep contributes to the development and perpetuation of PTSD. Also reviewed are neuroendocrine systems that show abnormalities in PTSD, and in which stress responses and sleep disturbance potentially produce synergistic effects that interfere with extinction learning and memory. Preliminary evidence that insomnia alone can disrupt sleep-dependent emotional processes including consolidation of extinction memory is also discussed. We suggest that optimizing sleep quality following trauma, and even strategically timing sleep to strengthen extinction memories therapeutically instantiated during exposure therapy, may allow sleep itself to be recruited in the treatment of PTSD and other trauma and stress-related disorders. PMID:26034578

  8. [The role of MicroRNAs in the pathophysiology of neuroblastoma and their possible use in diagnosis, prognosis and therapy].

    PubMed

    Vinklárek, J; Novák, J; Bienertová-Vašků, J; Stěrba, J; Slabý, O

    2014-01-01

    Neuroblastoma (NBL) is a typical childhood tumor developing from the precursor cells of the sympathetic nervous tissue and accounting for approximately 7% of total malignancies in pediatrics and 15% of deaths associated with this malignancy. MicroRNAs (miRNAs) are small single-stranded RNA molecules that are involved in posttranscriptional regulation of gene expression, whereas the pathophysiology of neuroblastoma tumor growth involves both upregulation of the protooncogenic miRNAs as well as downregulation of the tumor-suppresor ones. Comparison of the expression profiles of miRNAs in specific subtypes of neuroblastoma seems to be a useful tool adding to the classification of the diseases, and the assessment of the levels of specific miRNAs may be useful for estimation of the individual treatment response as well as prognosis of the patient. This paper provides the basic review of the studies focused on the role of miRNAs in pathogenesis of neuroblastoma and provides a survey of current/ possible use of these miRNAs in diagnostics, therapy or prognosis estimation in the neuroblastoma patients. PMID:25312710

  9. Updates in the pathophysiological mechanisms of Parkinson’s disease: Emerging role of bone marrow mesenchymal stem cells

    PubMed Central

    Ahmed, Hanaa H; Salem, Ahmed M; Atta, Hazem M; Eskandar, Emad F; Farrag, Abdel Razik H; Ghazy, Mohamed A; Salem, Neveen A; Aglan, Hadeer A

    2016-01-01

    AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson’s disease (PD) pathophysiology. METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done. RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs. CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD

  10. The potential role of biomarkers in predicting gestational diabetes.

    PubMed

    Brink, Huguette S; van der Lely, Aart Jan; van der Linden, Joke

    2016-09-01

    Gestational diabetes (GD) is a frequent complication during pregnancy and is associated with maternal and neonatal complications. It is suggested that a disturbing environment for the foetus, such as impaired glucose metabolism during intrauterine life, may result in enduring epigenetic changes leading to increased disease risk in adult life. Hence, early prediction of GD is vital. Current risk prediction models are based on maternal and clinical parameters, lacking a strong predictive value. Adipokines are mainly produced by adipocytes and suggested to be a link between obesity and its cardiovascular complications. Various adipokines, including adiponectin, leptin and TNF&, have shown to be dysregulated in GD. This review aims to outline biomarkers potentially associated with the pathophysiology of GD and discuss the role of integrating predictive biomarkers in current clinical risk prediction models, in order to enhance the identification of those at risk. PMID:27492245

  11. [PATHOPHYSIOLOGY OF CARDIORENAL SYNDROME].

    PubMed

    Thervet, Éric

    2016-06-01

    The pathophysiology of cardiorenal syndromes (SCR) is becoming better understood. The traditional view was that the left ventricular systolic dysfunction leads to a decrease in renal blood flow. Although this mechanism still makes sense as a contributing factor to SCR, its role as the principal pathophysiological SCR component or even as essential hemodynamic underlying factor has been challenged by recent discoveries. Regarding hemodynamic, the role of increased venous pressure is more and more accepted as demonstrated by the increase in abdominal pressure. Moreover, the role of neurohormonal mechanisms is emphasized in particular through the autonomic nervous system, the renin angiotensin aldosterone system, arginine vasopressin, adenosine and inflammatory mediators. Abnormal endothelial function is also responsible for a worsening of lesions especially through the reduction of shear stress. Finally, atherosclerosis, proteinuria, anemia with iron metabolism modifications, the nutritional status and vitamin D deficiency as well as FGF23 changes may be important and could represent interesting new therapeutic approaches in patients with SCR. PMID:27538312

  12. Incretin hormones and maturity onset diabetes of the young--pathophysiological implications and anti-diabetic treatment potential.

    PubMed

    Østoft, Signe Harring

    2015-09-01

    Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity. Patients with MODY are effectively treated with sulphonylurea (SU) due to very high sensitivity to these drugs, but they are also prone to develop hypoglycaemia. The objectives of this thesis were to study the pathophysiology of GCK-diabetes and HNF1A-diabetes by investigating the incretin effect, the physiological response to food ingestion and to estimate the treatment potential of a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with HNF1A-diabetes. In Study I we investigated the incretin effect and the responses of islet hormones and incretin hormones to oral glucose tolerance test (OGTT) and isoglycaemic IV glucose infusion (IIGI) in patients with GCK-diabetes, in patients with HNF1A-diabetes, and in BMI and age matched healthy individuals (CTRLs). In Study II we investigated responses of islet hormones and incretin hormones to a more physiological stimulus consisting of a standardised meal test in patients with GCK-diabetes, in patients with HNF1A--diabetes, and in BMI and age matched CTRLs. In Study III we conducted a randomised, double-blind, crossover trial investigating the glucose lowering effect and risk of hypoglycaemia during 6 weeks of treatment with the GLP-1RA, liraglutide compared to the SU, glimepiride

  13. Telocyte morphologies and potential roles in diseases.

    PubMed

    Zheng, Yonghua; Bai, Chunxue; Wang, Xiangdong

    2012-06-01

    Telocytes (TCs) are a new type of interstitial cells, a small cellular body with the presence of 2-5 prolongations named as telopode (Tp)-very thin (less than 0.2 µm) and extremely long (10-1,000 µm), a moniliform aspect, and caveolae, containing a nucleus surrounded by a small amount of cytoplasm. The nucleus occupies about 25% of TC body volume and contains clusters of heterochromatin attached to the nuclear envelope. The perinuclear cytoplasm is rich in mitochondria and contains a small Golgi complex, rough and smooth endoplasmic reticulum and cytoskeletal elements. TCs have several immunophenotypes such as CD34, c-kit, and vimentin. TCs were found in many organs of mammals with potential biological functions, even though the exact function remains unclear. Recently, we identified and isolated TCs from the trachea for the first time and confirmed the existence of TC in lung tissues, which could have the potential significance in the pathogenesis of pulmonary diseases. Future efforts are required to clarify pathophysiological functions of TCs in the disease. PMID:21928344

  14. Potential Pathophysiological Mechanisms of the Beneficial Role of Endometrial Injury in In Vitro Fertilization Outcome.

    PubMed

    Siristatidis, Charalampos; Vrachnis, Nikos; Vogiatzi, Paraskevi; Chrelias, Charalampos; Retamar, Andrea Quinteiro; Bettocchi, Stefano; Glujovsky, Demián

    2014-03-01

    Successful embryo implantation is a complex process that involves multiple biological mechanisms and reciprocal interactions between the embryo and the proliferated endometrium. In this review, we provide an informative contribution on the pathways underlying the beneficial nature of endometrial injury toward improving implantation rates of embryos conceived and through in vitro fertilization. The evidence published to date are in favor of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained and recurrent implantation failure. Endometrial injury triggers a series of biological responses but the findings suggest that no particular pathway is solely adequate to explain the association between trauma and improved pregnancy rates rather than a cluster of events in response to trauma which benefits embryo implantation in ways both known and unknown to the scientific community. PMID:24604231

  15. Pathophysiology of inner ear decompression sickness: potential role of the persistent foramen ovale.

    PubMed

    Mitchell, Simon J; Doolette, David J

    2015-06-01

    Inner-ear decompression sickness (inner ear DCS) may occur in isolation ('pure' inner-ear DCS), or as part of a multisystem DCS presentation. Symptoms may develop during decompression from deep, mixed-gas dives or after surfacing from recreational air dives. Modelling of inner-ear inert gas kinetics suggests that onset during decompression results from supersaturation of the inner-ear tissue and in-situ bubble formation. This supersaturation may be augmented by inert gas counterdiffusion following helium to nitrogen gas switches, but such switches are unlikely, of themselves, to precipitate inner-ear DCS. Presentations after surfacing from air dives are frequently the 'pure' form of inner ear DCS with short symptom latency following dives to moderate depth, and the vestibular end organ appears more vulnerable than is the cochlea. A large right-to-left shunt (usually a persistent foramen ovale) is found in a disproportionate number of cases, suggesting that shunted venous gas emboli (VGE) cause injury to the inner-ear. However, this seems an incomplete explanation for the relationship between inner-ear DCS and right-to-left shunt. The brain must concomitantly be exposed to larger numbers of VGE, yet inner-ear DCS frequently occurs in the absence of cerebral symptoms. This may be explained by slower inert gas washout in the inner ear than in the brain. Thus, there is a window after surfacing within which VGE arriving in the inner-ear (but not the brain) would grow due to inward diffusion of supersaturated inert gas. A similar difference in gas kinetics may explain the different susceptibilities of cochlear and vestibular tissue within the inner-ear itself. The cochlea has greater perfusion and a smaller tissue volume, implying faster inert gas washout. It may be susceptible to injury by incoming arterial bubbles for a shorter time after surfacing than the vestibular organ. PMID:26165533

  16. P2X and P2Y Receptors—Role in the Pathophysiology of the Nervous System

    PubMed Central

    Puchałowicz, Kamila; Tarnowski, Maciej; Baranowska-Bosiacka, Irena; Chlubek, Dariusz; Dziedziejko, Violetta

    2014-01-01

    Purinergic signalling plays a crucial role in proper functioning of the nervous system. Mechanisms depending on extracellular nucleotides and their P2 receptors also underlie a number of nervous system dysfunctions. This review aims to present the role of purinergic signalling, with particular focus devoted to role of P2 family receptors, in epilepsy, depression, neuropathic pain, nervous system neoplasms, such as glioma and neuroblastoma, neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease and multiple sclerosis. The above-mentioned conditions are associated with changes in expression of extracellular ectonucleotidases, P2X and P2Y receptors in neurons and glial cells, as well as releasing considerable amounts of nucleotides from activated or damaged nervous tissue cells into the extracellular space, which contributes to disturbance in purinergic signalling. The numerous studies indicate a potential possibility of using synthetic agonists/antagonists of P2 receptors in treatment of selected nervous system diseases. This is of particular significance, since numerous available agents reveal a low effectiveness and often produce side effects. PMID:25530618

  17. Pharmacological and Physiological Characterization of the Tremulous Jaw Movement Model of Parkinsonian Tremor: Potential Insights into the Pathophysiology of Tremor

    PubMed Central

    Collins-Praino, Lyndsey E.; Paul, Nicholas E.; Rychalsky, Kristen L.; Hinman, James R.; Chrobak, James J.; Senatus, Patrick B.; Salamone, John D.

    2011-01-01

    Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3–7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A2A antagonists). TJMs occur in the same 3–7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1–2 Hz), and postural tremor (8–14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor. PMID:21772815

  18. The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals.

    PubMed

    Fox, Helen; Sinha, Rajita

    2014-01-01

    The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity and behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the upregulation of core adrenergic and corticotropin-releasing factor mechanisms that subserve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but also they may be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward, and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress- and cue-induced craving state not only in women but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug-seeking behavior also suggests that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine-dependent individuals are typically polydrug abusers and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications that target catecholaminergic frontostriatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence. PMID:24484979

  19. Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.

    PubMed

    Mayfield, Jody; Blednov, Yuri A; Harris, R Adron

    2015-01-01

    G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. PMID:26422988

  20. Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction

    PubMed Central

    Mayfield, Jody; Blednov, Yuri A.; Harris, R. Adron

    2016-01-01

    G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson’s disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. PMID:26422988

  1. “Soluble Tissue Factor” in the 21st Century: Definitions, Biochemistry, and Pathophysiological Role in Thrombus Formation

    PubMed Central

    Bogdanov, Vladimir Y.; Versteeg, Henri H.

    2016-01-01

    Tissue factor (TF), the main trigger of blood coagulation, is essential for normal hemostasis. Over the past 20 years, heightened intravascular levels and activity of TF have been increasingly perceived as an entity that significantly contributes to venous as well as arterial thrombosis. Various forms of the TF protein in the circulation have been described and proposed to be thrombogenic. Aside from cell and vessel wall-associated TF, several forms of non–cell-associated TF circulate in plasma and may serve as a causative factor in thrombosis. At the present time, no firm consensus exists regarding the extent, the vascular setting(s), and/or the mechanisms by which such TF forms contribute to thrombus initiation and propagation. Here, we summarize the existing paradigms and recent, sometimes paradigm-shifting findings elucidating the structural, mechanistic, and pathophysiological characteristics of plasma-borne TF. PMID:26408917

  2. The Nephrology Clinical Research Nurse Role: Potential Role Conflicts.

    PubMed

    Micklos, Lisa

    2016-01-01

    Clinical research nursing is becoming more visible to nephrology professionals. As more nephrology practices and units are participating in clinical trials, clinical research nursing is gaining interest as a career niche among nephrology nurses. This unique specialty requires that nephrology clinical nurse nurses (CRNs) reconcile the roles of nurse as caregiver and nurse as researcher, which may result in a role conflict. Nephrology nurses should be aware that they may experience this role conflict when transitioning from patient care to a position as a clinical research nurse. These nurses can rely on the American Nurses Association's Code of Ethics for Nurses and the Oncology Nursing Society's Oncology Clinical Trials Nurse Competencies to help reconcile the potential role conflict. PMID:27501633

  3. Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue.

    PubMed

    Aghamohammadzadeh, Reza; Heagerty, Anthony M

    2012-06-01

    The advent of the obesity epidemic has highlighted the need to re-assess more closely the pathophysiology of obesity-related hypertension with the aim of identifying new therapies. In this article, we review the role of the renin-angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of this condition. We also discuss the potential role of the perivascular adipose tissue in the context of obesity-related hypertension. PMID:22713152

  4. SIDS: a pathophysiologic solution?

    PubMed

    Lobban, C D R

    2003-05-01

    Recent massive reductions in SIDS cases, world-wide, since the introduction of parental advice to sleep infants in the supine position, has the epidemiologic value of eliminating some hypotheses and strengthening others. A pathophysiologic cause of death now seems likely rather than a pathologic one. Without the characteristic morbidity consistent in disease, epidemiologically identified risk factors may assume primary importance. However, this hypothesis suggests that in addition to such risks, there may be an unrecognised pathologic condition in some infants which potentiates susceptibility. PMID:12710901

  5. Potential roles of telocytes in lung diseases.

    PubMed

    Shi, Lin; Dong, Nian; Chen, Chengshui; Wang, Xiangdong

    2016-07-01

    Telocytes (TCs) are a unique type of interstitial cells with specific, extremely long prolongations named telopodes (Tps), as shown by immune-positive staining against CD34, c-kit and vimentin. They were found in many organs of mammals, with potential biological functions, including the trachea and lung, even though the exact function remains unclear. Here, we give a historical overview of the TCs research field and summarize the latest findings associated with TCs, with a special focus on the recent progress about TCs specific gene and protein profiles that has been made in understanding that TCs may play a potential, but important, role in the pathogenesis of lung diseases. PMID:26855021

  6. Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

    PubMed Central

    YOUNG, Jared W; GEYER, Mark A

    2013-01-01

    The group of schizophrenia disorders affects approximately 1% of the population and has both genetic and environmental etiologies. Sufferers report various behavioral abnormalities including hallucinations and delusions (positive symptoms), reduced joy and amotivation (negative symptoms), plus inattention and poor learning (cognitive deficits). Despite the heterogeneous symptoms experienced, most patients smoke. The self-medication hypothesis posits that patients smoke to alleviate symptoms, consistent with evidence for nicotine-induced enhancement of cognition. While nicotine acts on multiple nicotinic acetylcholine receptors (nAChRs), the primary target of research is often the homomeric α7 nAChR. Given genetic linkages between schizophrenia and this receptor, its association with P50 sensory gating deficits, and its reduced expression in post-mortem brains, many have attempted to develop α7 nAChR ligands for treating schizophrenia. Recent evidence that ligands can be orthosteric agonists or positive allosteric modulators (PAMs) has revitalized the hope for treatment discovery. Herein, we present evidence regarding: 1) Pathophysiological alterations of α7 nAChRs that might occur in patients; 2) Mechanistic evidence for the normal action of α7 nAChRs; 3) Preclinical studies using α7 nAChR orthosteric agonists and type I/II PAMs; and 4) Where successful translational testing has occurred for particular compounds, detailing what is still required. We report that the accumulating evidence is positive, but that greater work is required using positron emission tomography to understand current alterations in α7 nAChR expression and their relationship to symptoms. Finally, cross-species behavioral tasks should be used more regularly to determine the predictive efficacy of treatments. PMID:23856289

  7. The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD.

    PubMed

    Gentile, C L; Weir, T L; Cox-York, K A; Wei, Y; Wang, D; Reese, L; Moran, G; Estrada, A; Mulligan, C; Pagliassotti, M J; Foster, M T

    2015-01-01

    Visceral adiposity is associated with type-2-diabetes, inflammation, dyslipidemia and non-alcoholic fatty liver disease (NAFLD), whereas subcutaneous adiposity is not. We hypothesized that the link between visceral adiposity and liver pathophysiology involves inherent or diet-derived differences between visceral and subcutaneous adipose tissue to store and mobilize saturated fatty acids. The goal of the present study was to characterize the fatty acid composition of adipose tissue triglyceride and portal vein fatty acids in relation to indices of liver dysregulation. For 8 weeks rats had free access to control (CON; 12.9% corn/safflower oil; 3.6 Kcal/g), high saturated fat (SAT; 45.2% cocoa butter; 4.5 Kcal/g) or high polyunsaturated fat (PUFA; 45.2% safflower oil; 4.5 Kcal/g) diets. Outcome measures included glucose tolerance, visceral and subcutaneous adipose tissue triglyceride, liver phospholipids and plasma (portal and systemic) free fatty acid composition, indices of inflammation and endoplasmic reticulum stress in the liver and adipose tissue depots and circulating adipo/cytokines. Hepatic triglycerides were significantly increased in both high fat diet groups compared to control and were significantly higher in PUFA compared to SAT. Although glucose tolerance was not different among diet groups, SAT increased markers of inflammation and ER stress in the liver and both adipose tissue depots. Fatty acid composition did not differ among adipose depots or portal blood in any dietary group. Overall, these data suggest that diets enriched in saturated fatty acids are associated with liver inflammation, ER stress and injury, but that any link between visceral adipose tissue and these liver indices does not involve selective changes to fatty acid composition in this depot or the portal vein. PMID:26167414

  8. Meta-analysis is not enough: The critical role of pathophysiology in determining optimal care in clinical nutrition.

    PubMed

    Soeters, Peter; Bozzetti, Federico; Cynober, Luc; Elia, Marinos; Shenkin, Alan; Sobotka, Lubos

    2016-06-01

    Evidence based medicine has preferably been based on prospective randomized controlled trials (PRCT's) and subsequent meta-analyses in many fields including nutrition and metabolism. These meta-analyses often yield convincing, contradictory or no proof of effectiveness. Consequently recommendations and guidelines of varying validity and quality have been published, often failing to convince the medical, insurance and government worlds to support nutritional care. Causes for lack of adequate proof of effectiveness are manifold. Many studies and meta-analyses lacked pathophysiological depth in design and interpretation. Study populations were not homogenous and endpoints not always clearly defined. Patients were included not at nutritional risk, unlikely to benefit from nutritional intervention. Others received nutrients in excess of requirements or tolerance due to organ failure. To include all available studies in a meta-analysis, study quality and homogeneity were only assessed on the basis of formal study design and outcome rather than on patient characteristics. Consequently, some studies showed benefit but included patients suffering harm, other studies were negative but contained patients that benefited. Recommendations did not always emphasize these shortcomings, confusing the medical and nutritional community and creating the impression that nutritional support is not beneficial. Strong reliance on meta-analyses and guidelines shifts the focus of education from studying clinical and nutritional physiology to memorizing guidelines. To prevent or improve malnutrition more physiological knowledge should be acquired to personalize nutritional practices and to more correctly value and evaluate the evidence. This also applies to the design and interpretation of PRCT's and meta-analyses. PMID:26615913

  9. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia

    PubMed Central

    LaMarca, Babbette

    2012-01-01

    Summary Alterations in vascular function contributes to hypertension as well as multi-organ dysfunction in women with preeclampsia (1,4, 11–14). Preterm preeclampsia remains a leading cause of maternal death and perinatal morbidity and most recently it has been recognized that women whom endure preeclampsia are at a greater risk for cardiovascular disease later in life. The pathophysiologic processes that underlie preeclampsia has been proposed to occur in two stages: stage 1, reduced placental perfusion, and stage 2, the maternal clinical syndrome (1,4). Placental ischemia/hypoxia is believed to result in the release of a variety of placental factors that have profound effects on blood flow and arterial pressure regulation (Figure 1) (1, 4, 10, 11). These factors include a host of molecules such as the soluble VEGF receptor-1 (sFlt-1), the angiotensin II type-1 receptor autoantibody (AT1-AA), and cytokines such as TNF-α and Interleukin 6 which in turn generate widespread dysfunction of the maternal vascular endothelium (1–11). This dysfunction results in formation of factors such as endothelin, reactive oxygen species (ROS), and augmented vascular sensitivity to angiotensin II (1–11). In addition, preeclampsia is also associated with decreased formation of vasodilators such as nitric oxide and prostacyclin (1–11). These alterations in vascular function not only lead to hypertension but multi-organ dysfunction, especially in women with early onset preeclampsia (1,4, 11–14). Therefore, identifying the connection between placental ischemia and maternal cardiovascular abnormalities is an important area of investigation (1,10,11,21). In addition, the quantitative importance of the various endothelial and humoral factors that mediate vascular dysfunction and hypertension during preeclampsia remains to be elucidated. PMID:20502423

  10. The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD

    PubMed Central

    Gentile, CL; Weir, TL; Cox-York, KA; Wei, Y; Wang, D; Reese, L; Moran, G; Estrada, A; Mulligan, C; Pagliassotti, MJ; Foster, MT

    2015-01-01

    Visceral adiposity is associated with type-2-diabetes, inflammation, dyslipidemia and non-alcoholic fatty liver disease (NAFLD), whereas subcutaneous adiposity is not. We hypothesized that the link between visceral adiposity and liver pathophysiology involves inherent or diet-derived differences between visceral and subcutaneous adipose tissue to store and mobilize saturated fatty acids. The goal of the present study was to characterize the fatty acid composition of adipose tissue triglyceride and portal vein fatty acids in relation to indices of liver dysregulation. For 8 weeks rats had free access to control (CON; 12.9% corn/safflower oil; 3.6 Kcal/g), high saturated fat (SAT; 45.2% cocoa butter; 4.5 Kcal/g) or high polyunsaturated fat (PUFA; 45.2% safflower oil; 4.5 Kcal/g) diets. Outcome measures included glucose tolerance, visceral and subcutaneous adipose tissue triglyceride, liver phospholipids and plasma (portal and systemic) free fatty acid composition, indices of inflammation and endoplasmic reticulum stress in the liver and adipose tissue depots and circulating adipo/cytokines. Hepatic triglycerides were significantly increased in both high fat diet groups compared to control and were significantly higher in PUFA compared to SAT. Although glucose tolerance was not different among diet groups, SAT increased markers of inflammation and ER stress in the liver and both adipose tissue depots. Fatty acid composition did not differ among adipose depots or portal blood in any dietary group. Overall, these data suggest that diets enriched in saturated fatty acids are associated with liver inflammation, ER stress and injury, but that any link between visceral adipose tissue and these liver indices does not involve selective changes to fatty acid composition in this depot or the portal vein. PMID:26167414

  11. Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy

    PubMed Central

    Itoh, Nobuyuki; Ohta, Hiroya; Konishi, Morichika

    2015-01-01

    The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms. Paracrine and endocrine FGFs are secreted signaling molecules by acting via cell-surface FGF receptors (FGFRs). Paracrine FGFs require heparan sulfate as a cofactor for FGFRs. In contrast, endocrine FGFs, comprising FGF19, FGF21, and FGF23, require α-Klotho or β-Klotho as a cofactor for FGFRs. Endocrine FGFs, which are specific to vertebrates, lost heparan sulfate-binding affinity and acquired a systemic signaling system with α-Klotho or β-Klotho during early vertebrate evolution. The phenotypes of endocrine FGF knockout mice indicate that they play roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism. Accumulated evidence for the involvement of endocrine FGFs in human genetic and metabolic diseases also indicates their pathophysiological roles in metabolic diseases, potential risk factors for metabolic diseases, and useful biomarkers for metabolic diseases. The therapeutic utility of endocrine FGFs is currently being developed. These findings provide new insights into the physiological and pathophysiological roles of endocrine FGFs and potential diagnostic and therapeutic strategies for metabolic diseases. PMID:26483756

  12. Pathophysiology of Endometriosis: Role of High Mobility Group Box-1 and Toll-Like Receptor 4 Developing Inflammation in Endometrium.

    PubMed

    Yun, Bo Hyon; Chon, Seung Joo; Choi, Young Sik; Cho, SiHyun; Lee, Byung Seok; Seo, Seok Kyo

    2016-01-01

    Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P<0.05). HESCs showed significant proliferation following treatment with rHMGB-1 (P<0.05), and increased TLR4 expression was observed following rHMGB-1 treatment (P<0.05) in a concentration-dependent manner

  13. Neuromyelitis optica: potential roles for intravenous immunoglobulin.

    PubMed

    Wingerchuk, Dean M

    2013-01-01

    Neuromyelitis optica (NMO) is an idiopathic central nervous system inflammatory demyelinating disease that causes optic neuritis, transverse myelitis, and other CNS syndromes. It is distinct from multiple sclerosis and is associated with autoantibodies that target aquaporin-4 (AQP4), an astrocyte water channel. Evidence indicating antibody-mediated immune injury in NMO includes its association with other autoimmune diseases, lesional pathology that reveals prominent complement activation and immunoglobulin deposition, pathogenic potential of AQP4 autoantibodies based on in vitro studies, and reports of putative animal models of the disease. The rationale and potential role for intravenous immunoglobulin in NMO will be discussed in the context of both relapse treatment and relapse prevention. PMID:22976554

  14. Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease: Skin Innervation and Contact Heat Evoked Potential.

    PubMed

    Lin, Chin-Hsien; Chao, Chi-Chao; Wu, Shao-Wei; Hsieh, Paul-Chen; Feng, Fang-Ping; Lin, Yea-Huey; Chen, Ya-Mei; Wu, Ruey-Meei; Hsieh, Sung-Tsang

    2016-03-01

    Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 ± 10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 ± 9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 ± 3.2 (range 2-17 years) years and the UPDRS part III score was 25.6 ± 9.7 (range 10-48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 ± 1.65 vs 6.36 ± 3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 ± 10.23 vs 33.28 ± 10.48 μV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small-fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both

  15. The role of endothelin system in cardiovascular disease and the potential therapeutic perspectives of its inhibition.

    PubMed

    Kaoukis, Andreas; Deftereos, Spyridon; Raisakis, Konstantinos; Giannopoulos, Georgios; Bouras, Georgios; Panagopoulou, Vasiliki; Papoutsidakis, Nikolaos; Cleman, Michael W; Stefanadis, Christodoulos

    2013-01-01

    Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one. PMID:23470073

  16. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    PubMed Central

    Orihara, Kanami; Matsuda, Akio

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) and bronchial asthma are common respiratory diseases that are caused by chronic inflammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α) and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF) plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma. PMID:19281078

  17. Pathophysiology of Coronary Collaterals#

    PubMed Central

    Stoller, Michael; Seiler, Christian

    2014-01-01

    While the existence of structural adaptation of coronary anastomoses is undisputed, the potential of coronary collaterals to be capable of functional adaptation has been questioned. For many years, collateral vessels were thought to be rigid tubes allowing only limited blood flow governed by the pressure gradient across them. This concept was consistent with the notion that although collaterals could provide adequate blood flow to maintain resting levels, they would be unable to increase blood flow sufficiently in situations of increased myocardial oxygen demand. However, more recent studies have demonstrated the capability of the collateral circulation to deliver sufficient blood flow even during exertion or pharmacologic stress. Moreover, it has been shown that increases in collateral flow could be attributed directly to collateral vasomotion. This review summarizes the pathophysiology of the coronary collateral circulation, ie the functional adapation of coronary collaterals to acute alterations in the coronary circulation. PMID:23701025

  18. Neurosteroids; potential underpinning roles in maintaining homeostasis.

    PubMed

    Rahmani, Behrouz; Ghasemi, Rasoul; Dargahi, Leila; Ahmadiani, Abolhassan; Haeri, Ali

    2016-01-01

    The neuroactive steroids which are synthesized in the brain and nervous system are known as "Neurosteroids". These steroids have crucial functions such as contributing to the myelination and organization of the brain connectivity. Under the stressful circumstances, the concentrations of neurosteroid products such as allopregnanolone (ALLO) and allotetrahydrodeoxycorticosterone (THDOC) alter. It has been suggested that these stress-derived neurosteroids modulate the physiological response to stress. Moreover, it has been demonstrated that the hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological adaptation following stress in order to maintain homeostasis. Although several regulatory pathways have been introduced, the exact role of neurosteroids in controlling HPA axis is not clear to date. In this review, we intend to discern specific pathways associated with regulation of HPA axis in which neuroactive steroids have the main role. In this respect, we propose pathways that may be initiated after neurosteroidogenesis in different brain subregions following acute stress which are potentially capable of activating or inhibiting the HPA axis. PMID:26432100

  19. The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans.

    PubMed

    Ballestri, Stefano; Nascimbeni, Fabio; Romagnoli, Dante; Baldelli, Enrica; Lonardo, Amedeo

    2016-03-01

    Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined. PMID:26921205

  20. The Role of Oscillations and Synchrony in Cortical Networks and Their Putative Relevance for the Pathophysiology of Schizophrenia

    PubMed Central

    Uhlhaas, Peter J.; Haenschel, Corinna; Nikolić, Danko; Singer, Wolf

    2008-01-01

    Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. By now, there is extensive evidence to suggest that cognitive functions depending on coordination of distributed neural responses, such as perceptual grouping, attention-dependent stimulus selection, subsystem integration, working memory, and consciousness, are associated with synchronized oscillatory activity in the theta-, alpha-, beta-, and gamma-band, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia, that involve dysfunctional cognition and behavior. In the following article, we aim to summarize the evidence on the role of neural oscillations during normal brain functioning and their relationship to cognitive processes. In the second part, we review research that has examined oscillatory activity during cognitive and behavioral tasks in schizophrenia. These studies suggest that schizophrenia involves abnormal oscillations and synchrony that are related to cognitive dysfunctions and some of the symptoms of the disorder. Perspectives for future research will be discussed in relationship to methodological issues, the utility of neural oscillations as a biomarker, and the neurodevelopmental hypothesis of schizophrenia. PMID:18562344

  1. Extracellular Vesicles: Potential Roles in Regenerative Medicine

    PubMed Central

    De Jong, Olivier G.; Van Balkom, Bas W. M.; Schiffelers, Raymond M.; Bouten, Carlijn V. C.; Verhaar, Marianne C.

    2014-01-01

    Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell–cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering. PMID:25520717

  2. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-01-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID:25326836

  3. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    PubMed

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. PMID:25437458

  4. G protein-coupled receptor signalling in the cardiac nuclear membrane: evidence and possible roles in physiological and pathophysiological function

    PubMed Central

    Tadevosyan, Artavazd; Vaniotis, George; Allen, Bruce G; Hébert, Terence E; Nattel, Stanley

    2012-01-01

    G protein-coupled receptors (GPCRs) play key physiological roles in numerous tissues, including the heart, and their dysfunction influences a wide range of cardiovascular diseases. Recently, the notion of nuclear localization and action of GPCRs has become more widely accepted. Nuclear-localized receptors may regulate distinct signalling pathways, suggesting that the biological responses mediated by GPCRs are not solely initiated at the cell surface but may result from the integration of extracellular and intracellular signalling pathways. Many of the observed nuclear effects are not prevented by classical inhibitors that exclusively target cell surface receptors, presumably because of their structures, lipophilic properties, or affinity for nuclear receptors. In this topical review, we discuss specifically how angiotensin-II, endothelin, β-adrenergic and opioid receptors located on the nuclear envelope activate signalling pathways, which convert intracrine stimuli into acute responses such as generation of second messengers and direct genomic effects, and thereby participate in the development of cardiovascular disorders. PMID:22183719

  5. The Role of Plasma Kallikrein-Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches.

    PubMed

    Abdulaal, Marwan; Haddad, Nour Maya N; Sun, Jennifer K; Silva, Paolo S

    2016-01-01

    Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention. PMID:26959125

  6. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics

    PubMed Central

    Deiuliis, J A

    2016-01-01

    The prevalence of overweight and obesity in developed and developing countries has greatly increased the risk of insulin resistance and type 2 diabetes mellitus. It is evident from human and animal studies that obesity alters microRNA (miRNA) expression in metabolically important organs, and that miRNAs are involved in changes to normal physiology, acting as mediators of disease. miRNAs regulate multiple pathways including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and food intake regulation. Thus, miRNA-based therapeutics represent an innovative and attractive treatment modality, with non-human primate studies showing great promise. In addition, miRNA measures in plasma or bodily fluids may be used as disease biomarkers and predictors of metabolic disease in humans. This review analyzes the role of miRNAs in obesity and insulin resistance, focusing on the miR-17/92, miR-143-145, miR-130, let-7, miR-221/222, miR-200, miR-223, miR-29 and miR-375 families, as well as miRNA changes by relevant tissue (adipose, liver and skeletal muscle). Further, the current and future applications of miRNA-based therapeutics and diagnostics in metabolic disease are discussed. PMID:26311337

  7. The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease

    PubMed Central

    Ayyadurai, Saravanan; Charania, Moiz A.; Laroui, Hamed; Yan, Yutao; Merlin, Didier

    2012-01-01

    Intestinal inflammation is characterized by epithelial disruption, leading to loss of barrier function and the recruitment of immune cells, including neutrophils. Although the mechanisms are not yet completely understood, interactions between environmental and immunological factors are thought to be critical in the initiation and progression of intestinal inflammation. In recent years, it has become apparent that the di/tripeptide transporter PepT1 may play an important role in the pathogenesis of such inflammation. In healthy individuals, PepT1 is primarily expressed in the small intestine and transports di/tripeptides for metabolic purposes. However, during chronic inflammation such as that associated with inflammatory bowel disease, PepT1 expression is upregulated in the colon, wherein the protein is normally expressed either minimally or not at all. Several recent studies have shown that PepT1 binds to and transports various bacterial di/tripeptides into colon cells, leading to activation of downstream proinflammatory responses via peptide interactions with innate immune receptors. In the present review, we examine the relationship between colonic PepT1-mediated peptide transport in the colon and activation of innate immune responses during disease. It is important to understand the mechanisms of PepT1 action during chronic intestinal inflammation to develop future therapies addressing inappropriate immune activation in the colon. PMID:22194420

  8. Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease.

    PubMed

    Enomoto, Atsushi; Endou, Hitoshi

    2005-09-01

    Renal proximal and distal tubules are highly polarized epithelial cells that carry out the specialized directional transport of various solutes. This renal function, which is essential for homeostasis in the body, is achieved through the close pairing of apical and basolateral carriers expressed in the renal epithelial cells. The family of organic anion transporters (OATs), which belong to the major facilitator superfamily (SLC22A), are expressed in the renal epithelial cells to regulate the excretion and reabsorption of endogenous and exogenous organic anions. We now understand that these OATs are crucial components in the renal handling of drugs and their metabolites, and they are implicated in various clinically important drug interactions, and their adverse reactions. In recent years, the molecular entities of these transporters have been identified, and their function and regulatory mechanisms have been partially clarified. Workers in this field have identified URAT1 (urate transporter 1), a novel member of the OAT family that displays unique and selective substrate specificity compared with other multispecific OATs. In the OAT family, URAT1 is the main transporster responsible for human genetic diseases. In this review, we introduce and discuss some novel aspects of OATs, with special emphasis on URAT1, in the context of their biological significance, functional regulation, and roles in human disease. PMID:16189627

  9. Cadmium induced pathophysiology: prophylactic role of edible jute (Corchorus olitorius) leaves with special emphasis on oxidative stress and mitochondrial involvement.

    PubMed

    Dewanjee, Saikat; Gangopadhyay, Moumita; Sahu, Ranabir; Karmakar, Sarmila

    2013-10-01

    The present study was undertaken to evaluate the protective effect of aqueous extract of Corchorus olitorius leaves (AECO) against CdCl₂ intoxication. In vitro bioassay on isolated mice hepatocytes confirmed dose dependent cytoprotective effect of AECO. The CdCl₂ (30 μM) exhibited a significantly increased levels of lipid peroxidation, protein carbonylation along with the reduction of antioxidant enzymes and reduced glutathione levels in hepatocytes. AECO (200 and 400 μg/ml) + CdCl₂ (30 μM) could significantly restore the aforementioned oxidation parameters in hepatocytes. Beside this, AECO could significantly reduce Cd-induced increase in Bad/Bcl-2 ratio and the over-expression of NF-κB, caspase 3 and caspase 9. In in vivo assay, CdCl₂ (4 mg/kg body weight, for 6 days) treated rats exhibited a significantly increased intracellular Cd accumulation, oxidative stress and DNA fragmentation in the organs. In addition, the haematological parameters were significantly altered in the CdCl₂ treated rats. Simultaneous administration of AECO (50 and 100 mg/kg body weight), could significantly restore the biochemical, antioxidant and haematological parameters near to the normal status. Histological studies of the organs supported the protective role of jute leaves. Presence of substantial quantity of phenolic compounds and flavonoids in extract may be responsible for overall protective effect. PMID:23891759

  10. Role of genetic polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease.

    PubMed

    Fedele, Francesco; Mancone, Massimo; Chilian, William M; Severino, Paolo; Canali, Emanuele; Logan, Suzanna; De Marchis, Maria Laura; Volterrani, Maurizio; Palmirotta, Raffaele; Guadagni, Fiorella

    2013-11-01

    Conventionally, ischemic heart disease (IHD) is equated with large vessel coronary disease. However, recent evidence has suggested a role of compromised microvascular regulation in the etiology of IHD. Because regulation of coronary blood flow likely involves activity of specific ion channels, and key factors involved in endothelium-dependent dilation, we proposed that genetic anomalies of ion channels or specific endothelial regulators may underlie coronary microvascular disease. We aimed to evaluate the clinical impact of single-nucleotide polymorphisms in genes encoding for ion channels expressed in the coronary vasculature and the possible correlation with IHD resulting from microvascular dysfunction. 242 consecutive patients who were candidates for coronary angiography were enrolled. A prospective, observational, single-center study was conducted, analyzing genetic polymorphisms relative to (1) NOS3 encoding for endothelial nitric oxide synthase (eNOS); (2) ATP2A2 encoding for the Ca²⁺/H⁺-ATPase pump (SERCA); (3) SCN5A encoding for the voltage-dependent Na⁺ channel (Nav1.5); (4) KCNJ8 and KCNJ11 encoding for the Kir6.1 and Kir6.2 subunits of K-ATP channels, respectively; and (5) KCN5A encoding for the voltage-gated K⁺ channel (Kv1.5). No significant associations between clinical IHD manifestations and polymorphisms for SERCA, Kir6.1, and Kv1.5 were observed (p > 0.05), whereas specific polymorphisms detected in eNOS, as well as in Kir6.2 and Nav1.5 were found to be correlated with IHD and microvascular dysfunction. Interestingly, genetic polymorphisms for ion channels seem to have an important clinical impact influencing the susceptibility for microvascular dysfunction and IHD, independent of the presence of classic cardiovascular risk factors. PMID:24068186

  11. Role of Oxidative and Nitrosative Stress in Pathophysiology of Toxic Epidermal Necrolysis and Stevens Johnson Syndrome—A Pilot Study

    PubMed Central

    Peter, Dincy; Amirtharaj, G Jayakumar; Mathew, Teena; Pulimood, Susanne; Ramachandran, Anup

    2015-01-01

    Background: Oxidative and nitrosative stress caused by drug metabolism may be a trigger for keratinocyte apoptosis in the epidermis seen in toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS). Aims: To estimate oxidative damage in the serum and to examine the role of nitric oxide in mediating epidermal damage in patients with TEN and SJS. Materials and Methods: A prospective study was conducted among TEN and SJS patients and controls in a tertiary care center between January 2006 and February 2010. Patients with a maculopapular drug rash without detachment of skin constituted the control group 1 (drug exposed). Patients without a drug rash constituted the control group 2 (drug unexposed). The serum values of protein carbonyls, malondialdehyde, conjugated diene and nitrates were measured. Two-group comparison with the non-parametric Mann–Whitney U test was used. Significance of differences if any was established using Pearson's Chi-square test. Results: Ten patients in the SJS-TEN group (study group), 8 patients in control group 1 and 7 patients in control group 2 were included. More than one drug was implicated in 4/10 patients in group 1 and 3/8 patients in group 2. SCORTEN of 0, 1 and 3 at admission were seen in 2, 6 and 2 patients, respectively. The serum values of protein carbonyls, malondialdehyde, conjugated diene and nitrates were not significantly increased in the study group when compared to the controls. Conclusions: There was no elevation of oxidative stress markers in patients with TEN and SJS as compared to the control population. PMID:26538686

  12. Molecular Pathophysiology of Priapism: Emerging Targets

    PubMed Central

    Anele, Uzoma A.; Morrison, Belinda F.; Burnett, Arthur L.

    2015-01-01

    Priapism is an erectile disorder involving uncontrolled, prolonged penile erection without sexual purpose, which can lead to erectile dysfunction. Ischemic priapism, the most common of the variants, occurs with high prevalence in patients with sickle cell disease. Despite the potentially devastating complications of this condition, management of recurrent priapism episodes historically has commonly involved reactive treatments rather than preventative strategies. Recently, increasing elucidation of the complex molecular mechanisms underlying this disorder, principally involving dysregulation of nitric oxide signaling, has allowed for greater insights and exploration into potential therapeutic targets. In this review, we discuss the multiple molecular regulatory pathways implicated in the pathophysiology of priapism. We also identify the roles and mechanisms of molecular effectors in providing the basis for potential future therapies. PMID:25392014

  13. The Role of Congestion in Cardiorenal Syndrome Type 2: New Pathophysiological Insights into an Experimental Model of Heart Failure

    PubMed Central

    Angelini, Annalisa; Castellani, Chiara; Virzì, Grazia Maria; Fedrigo, Marny; Thiene, Gaetano; Valente, Marialuisa; Ronco, Claudio; Vescovo, Giorgio

    2015-01-01

    Background In cardiorenal syndrome type 2 (CRS2), the role of systemic congestion in heart failure (HF) is still obscure. We studied a model of CRS2 [monocrotaline (MCT)-treated rats] secondary to pulmonary hypertension and right ventricular (RV) failure in order to evaluate the contribution of prevalent congestion to the development of kidney injury. Methods Ten animals were treated with MCT for 4 weeks until they developed HF. Eleven animals were taken as controls. Signs of hypertrophy and dilatation of the right ventricle demonstrated the occurrence of HF. Brain natriuretic peptide (BNP), serum creatinine (sCreatinine), both kidney and heart neutrophil gelatinase-associated lipocalin (NGAL), matrix metallopeptidase 9 (MMP9), serum cytokines as well as kidney and heart cell death, as assessed by TUNEL, were studied. Results Rats with HF showed higher BNP levels [chronic HF (CHF) 4.8 ± 0.5 ng/ml; controls 1.5 ± 0.2 ng/ml; p < 0.0001], marked RV hypertrophy and dilatation (RV mass/RV volume: CHF 1.46 ± 0.31, controls 2.41 ± 0.81; p < 0.01) as well as pleural and peritoneal effusions. A significant increase in proinflammatory cytokines and sCreatinine was observed (CHF 3.06 ± 1.3 pg/ml vs. controls 0.54 ± 0.23 pg/ml; p = 0.04). Serum (CHF 562.7 ± 93.34 ng/ml vs. controls 245.3 ± 58.19 ng/ml; p = 0.02) as well as renal and heart tissue NGAL levels [CHF 70,680 ± 4,337 arbitrary units (AU) vs. controls 32,120 ± 4,961 AU; p = 0.001] rose significantly, and they were found to be complexed with MMP9 in CHF rats. A higher number of kidney TUNEL-positive tubular cells was also detected (CHF 114.01 ± 45.93 vs. controls 16.36 ± 11.60 cells/mm2; p = 0.0004). Conclusion In this model of CHF with prevalent congestion, kidney injury is characterized by tubular damage and systemic inflammation. The upregulated NGAL complexed with MMP9 perpetuates the vicious circle of kidney/heart damage by enhancing the enzymatic activity of MMP9 with extracellular matrix degradation

  14. Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands.

    PubMed

    Jurutka, Peter W; Bartik, Leonid; Whitfield, G Kerr; Mathern, Douglas R; Barthel, Thomas K; Gurevich, Miriam; Hsieh, Jui-Cheng; Kaczmarska, Magdalena; Haussler, Carol A; Haussler, Mark R

    2007-12-01

    The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH)(2)D(3). Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)(2)D(3) induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)(2)D(3) synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)(2)D(3)-FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)(2)D(3)-PTH axis that regulates calcium. 1,25(OH)(2)D(3) also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH)(2)D(3) supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain omega3/omega6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric

  15. The pathophysiology of agitation.

    PubMed

    Lindenmayer, J P

    2000-01-01

    Agitation is a nonspecific constellation of relatively unrelated behaviors that can be seen in a number of different clinical conditions, usually presenting a fluctuating course. Multiple underlying pathophysiologic abnormalities are mediated by dysregulations of dopaminergic, serotonergic, noradrenergic, and GABAergic systems. Pathophysiologic mechanisms of agitation that operate in the different clinical disorders where agitation occurs are discussed. These pathophysiologic abnormalities are not associated with distinct clinical features. Although there may be a final common pathway, there is no unifying etiologic pathophysiology. The author suggests that the clinician address the underlying pathophysiology through a treatment intervention that addresses the overarching psychiatric disorder. Generally, agents that reduce dopaminergic or noradrenergic tone or increase serotonergic or GABAergic tone will attenuate agitation, often irrespective of etiology. PMID:11154018

  16. PPAR-δ in Vascular Pathophysiology

    PubMed Central

    Wang, Nanping

    2008-01-01

    Peroxisome proliferator-activated receptors belong to the superfamily of ligand-dependent nuclear receptor transcription factors, which include three subtypes: PPAR-α, β/δ, and γ. PPAR-δ, play important roles in the regulation of cell growth and differentiation as well as tissue wound and repair. Emerging evidence has also demonstrated that PPAR-δ is implicated in lipids and glucose metabolism. Most recently, the direct effects of PPAR-δ on cardiovascular processes such as endothelial function and angiogenesis have also been investigated. Therefore, it is suggested that PPAR-δ may have critical roles in cardiovascular pathophysiology and is a potential target for therapeutic intervention of cardiovascular disorders such as atherosclerosis. PMID:19132133

  17. [Sickle cell pathophysiology].

    PubMed

    Renaudier, P

    2014-11-01

    Sickle cell disease is associated with the inversion of one base pair (A = T → A = T). The sixth codon of the beta globin chain [GAA] becomes [GTA]. Accordingly, the sixth amino acid (glutamic acid, negatively charged) is replaced by valine, hydrophobic. A hydrophobic site is present on the outside of the HbS β chain. This incurs a hydrophobic bond with the phenylalanine in position 85 and leucine in position 88, in which outsource deoxy haemoglobin. Therefore, it creates a HbS polymer that deforms the red blood cell and causes vaso-occlusive crisis in the capillary venous pole. In this conventional design, the roles are added to the nitrogen monoxide and vascular tone, the increase in adhesion of red blood cells to the endothelium damage caused by red blood cells HbS: dehydration, senescence, formation of microvesicles. If these advances in our understanding of the pathophysiology have not yet had a clinical application, they will happen one day. It is therefore particularly important to pursue in France the network structure of sickle cell disease with a view to set up multicenter trials when the day comes. PMID:25282490

  18. Transcriptional activation of vascular cell adhesion molecule-1 gene in vivo and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock.

    PubMed

    Essani, N A; Bajt, M L; Farhood, A; Vonderfecht, S L; Jaeschke, H

    1997-06-15

    Polymorphonuclear leukocytes (neutrophils) can cause hepatic parenchymal cell injury during endotoxin (ET) shock. Because adhesion molecules are critical for inflammatory cell damage, the role of vascular cell adhesion molecule-1 (VCAM-1) was studied in the pathophysiology of ET shock. ET-sensitive mice (C3Heb/FeJ) were treated with 700 mg/kg galactosamine in combination with 100 microg/kg Salmonella abortus equi ET, 15 microg/kg TNF-alpha, or 13 to 23 microg/kg IL-1. VCAM-1 mRNA formation was strongly activated in animals treated with ET, TNF-alpha, or IL-1. In contrast, only TNF-alpha and IL-1, not ET, induced VCAM-1 gene transcription in livers of ET-resistant mice (C3H/HeJ). Immunohistochemistry and isolation of liver cells during endotoxemia indicated that VCAM-1 mRNA and protein were only formed in endothelial cells and Kupffer cells, not in hepatocytes. Galactosamine/ET induced neutrophil accumulation in sinusoids (515 +/- 30 neutrophils/50 high power fields) followed by transmigration at 7 h. At that time, severe liver injury was observed (necrosis, 53 +/- 5%). An anti-VCAM-1 Ab (3 mg/kg) attenuated the area of necrosis by 60%. The Ab reduced neutrophil transmigration by 84%, but had no effect on the total number of cells in the liver vasculature. Flow cytometric analysis identified the presence of very late Ag-4 on mouse peripheral neutrophils. Our data demonstrated cytokine-dependent VCAM-1 gene transcription and protein expression in the liver during endotoxemia. Neutrophils were able to use very late Ag-4/VCAM-1 interactions to transmigrate into liver parenchyma in vivo. Preventing transmigration by blocking VCAM-1 protected hepatocytes against neutrophil-induced injury. PMID:9190948

  19. Pathophysiology of burns.

    PubMed

    Keck, Maike; Herndon, David H; Kamolz, Lars P; Frey, Manfred; Jeschke, Marc G

    2009-01-01

    Burn injury represents a significant problem worldwide. Advances in therapy strategies, based on better understanding of the pathophysiologic responses after burn injury have improved the clinical outcome of patients with burn injuries over the past years. This article describes the present understanding of the pathophysiology of a burn injury including both the local and systemic responses, focusing on the many facets of organ and systemic effects directly resulting from hypovolemia and circulating mediators following burn trauma. PMID:19652939

  20. CHOLINERGIC CIRCUITS AND SIGNALING IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA

    PubMed Central

    Berman, Joshua A.; Talmage, David A.; Role, Lorna W.

    2008-01-01

    Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification—particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena—the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia. PMID:17349862

  1. On the potential role of glutamate transport in mental fatigue.

    PubMed

    Rönnbäck, Lars; Hansson, Elisabeth

    2004-11-01

    Mental fatigue, with decreased concentration capacity, is common in neuroinflammatory and neurodegenerative diseases, often appearing prior to other major mental or physical neurological symptoms. Mental fatigue also makes rehabilitation more difficult after a stroke, brain trauma, meningitis or encephalitis. As increased levels of proinflammatory cytokines are reported in these disorders, we wanted to explore whether or not proinflammatory cytokines could induce mental fatigue, and if so, by what mechanisms.It is well known that proinflammatory cytokines are increased in major depression, "sickness behavior" and sleep deprivation, which are all disorders associated with mental fatigue. Furthermore, an influence by specific proinflammatory cytokines, such as interleukin (IL)-1, on learning and memory capacities has been observed in several experimental systems. As glutamate signaling is crucial for information intake and processing within the brain, and due to the pivotal role for glutamate in brain metabolism, dynamic alterations in glutamate transmission could be of pathophysiological importance in mental fatigue. Based on this literature and observations from our own laboratory and others on the role of astroglial cells in the fine-tuning of glutamate neurotransmission we present the hypothesis that the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta and IL-6 could be involved in the pathophysiology of mental fatigue through their ability to attenuate the astroglial clearance of extracellular glutamate, their disintegration of the blood brain barrier, and effects on astroglial metabolism and metabolic supply for the neurons, thereby attenuating glutamate transmission. To test whether our hypothesis is valid or not, brain imaging techniques should be applied with the ability to register, over time and with increasing cognitive loading, the extracellular concentrations of glutamate and potassium (K+) in humans suffering from mental fatigue. At

  2. An update on oxidative stress-mediated organ pathophysiology.

    PubMed

    Rashid, Kahkashan; Sinha, Krishnendu; Sil, Parames C

    2013-12-01

    Exposure to environmental pollutants and drugs can result in pathophysiological situations in the body. Research in this area is essential as the knowledge on cellular survival and death would help in designing effective therapeutic strategies that are needed for the maintenance of the normal physiological functions of the body. In this regard, naturally occurring bio-molecules can be considered as potential therapeutic targets as they are normally available in commonly consumed foodstuffs and are thought to have minimum side effects. This review article describes the detailed mechanisms of oxidative stress-mediated organ pathophysiology and the ultimate fate of the cells either to survive or to undergo necrotic or apoptotic death. The mechanisms underlying the beneficial role of a number of naturally occurring bioactive molecules in oxidative stress-mediated organ pathophysiology have also been included in the review. The review provides useful information about the recent progress in understanding the mechanism(s) of various types of organ pathophysiology, the complex cross-talk between these pathways, as well as their modulation in stressed conditions. Additionally, it suggests possible therapeutic applications of a number of naturally occurring bioactive molecules in conditions involving oxidative stress. PMID:24084033

  3. Potential role of sirtuins in livestock production.

    PubMed

    Ghinis-Hozumi, Y; Antaramian, A; Villarroya, F; Piña, E; Mora, O

    2013-01-01

    Sirtuins are NAD(+)-dependent histone and protein deacetylases, which have been studied during the last decade with a focus on their role in lifespan extension and age-related diseases under normal and calorie-restricted or pathological conditions. However, sirtuins also have the ability to regulate energy homeostasis as they can sense the metabolic state of the cell through the NAD(+)/NADH ratio; hence, changes in the diet can modify the expression of these enzymes. Dietary manipulations are a common practice currently being used in livestock production with favorable results, probably due in part to the enhanced activity of sirtuins. Nevertheless, sirtuin expression in livestock species has not been a research target. For these reasons, the goal of this review is to awaken interest in these enzymes for future detailed characterization in livestock species by presenting a general introduction to what sirtuins are, how they work and what is known about their role in livestock. PMID:23031219

  4. Cannabinoids: is there a potential treatment role in epilepsy?

    PubMed Central

    Blair, Robert E; Deshpande, Laxmikant S; DeLorenzo, Robert J

    2016-01-01

    Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system’s regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy. PMID:26234319

  5. Cannabinoids: is there a potential treatment role in epilepsy?

    PubMed

    Blair, Robert E; Deshpande, Laxmikant S; DeLorenzo, Robert J

    2015-01-01

    Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system's regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy. PMID:26234319

  6. Potential role for metformin in urologic oncology

    PubMed Central

    Sayyid, Rashid Khalid

    2016-01-01

    Metformin is one of the most commonly used drugs worldwide. It is currently considered first-line pharmacological agent for management of diabetes mellitus type 2. Recent studies have suggested that metformin may have further benefits, especially in the field of urologic oncology. Use of metformin has been shown to be associated with decreased incidence and improved outcomes of prostate, bladder, and kidney cancer. These studies suggest that metformin does have a future role in the prevention and management of urologic malignancies. In this review, we will discuss the latest findings in this field and its implications on the management of urologic oncology patients. PMID:27195314

  7. Potential role of bicarbonate during pyrite oxidation

    SciTech Connect

    Evangelou, V.P.; Holt, A.; Seta, A.K.

    1998-07-15

    The need to prevent the development of acid mine drainage (AMD) by oxidation of pyrite has triggered numerous investigations into the mechanisms of its oxidation. According to Frontier molecular orbital (FMO) theory, the surface-exposed sulfur atom of pyrite possesses an unshared electron pair which produces a slightly negatively charged pyrite surface that can attract cations such as Fe{sup 2+}. Because of surface electroneutrality and pH considerations, however, the pyrite surface Fe{sup 2+} coordinates OH. The authors proposed that this surface Fe{sup 2+} OH when in the presence of CO{sub 2} is converted to {minus}FeCO{sub 3} or {minus}FeHCO{sub 3}, depending on pH. In this study, using Fourier transform infrared spectroscopy (FT-IR) they demonstrated that such complexes form on the surface of pyrite and continue to persist even after a significant fraction of the surface Fe{sup 2+} was oxidized to Fe{sup 3+}. FT-IR spectra also showed the presence of two carbonyl absorption bands (1,682 and 1,653 cm{sup {minus}1}) on the surface of pyrite upon exposure to CO{sub 2} which suggested that pyrite surface carbon complexes existed in two different surface chemical environments, pointing out two potential mechanisms of pyrite surface-CO{sub 2} interactions. One potential mechanism involved formation of a pyrite surface-Fe(II)HCO{sub 3} complex, whereas a second potential mechanism involved formation of a pyrite surface-carboxylic acid group complex [{minus}Fe(II)SSCOOFe-(II)].

  8. Potential roles of the prokineticins in reproduction

    PubMed Central

    Maldonado-Pérez, David; Evans, Jemma; Denison, Fiona; Millar, Robert P.; Jabbour, Henry N.

    2007-01-01

    Prokineticins are multifunctional secreted proteins that were originally identified as regulators of intestinal contraction but subsequently shown to affect vascular function, hyperalgesia, spermatogenesis, neuronal survival, circadian rhythm, nociception, feeding behaviour, immune responses, haematopoiesis and the development of the olfactory and gonadotropin-releasing hormone systems. Their role in the reproductive tract is still not fully elucidated, although they are reputed to increase microvascular permeability. Expression of prokineticins and their receptors has been reported in the ovary, uterus, placenta, testis and prostate. Their expression has also been reported in various pathologies of the reproductive tract, and future studies will highlight whether inhibition of prokineticin function in these pathologies would be a useful therapeutic target. PMID:17208447

  9. Surgical inflammation: a pathophysiological rainbow

    PubMed Central

    Arias, Jose-Ignacio; Aller, María-Angeles; Arias, Jaime

    2009-01-01

    Tetrapyrrole molecules are distributed in virtually all living organisms on Earth. In mammals, tetrapyrrole end products are closely linked to oxygen metabolism. Since increasingly complex trophic functional systems for using oxygen are considered in the post-traumatic inflammatory response, it can be suggested that tetrapyrrole molecules and, particularly their derived pigments, play a key role in modulating inflammation. In this way, the diverse colorfulness that the inflammatory response triggers during its evolution would reflect the major pathophysiological importance of these pigments in each one of its phases. Therefore, the need of exploiting this color resource could be considered for both the diagnosis and treatment of the inflammation. PMID:19309494

  10. The role of potential barrier formation in spacecraft charging

    NASA Technical Reports Server (NTRS)

    Purvis, C. K.

    1983-01-01

    The role of potential barrier formation in spacecraft charging at geosynchronous orbit is discussed. The evidence for, and understanding of, spacecraft charging and its hazards to spacecraft operation in the early 1970's are summarized. Theoretical and experimental advances which have changed the basic understanding of the role of barrier formation in charging phenomenology are described. Potential barriers are found to play a fundamental role in the dynamics of spacecraft charging. The consequences for structural and differential charging and for discharging are described.

  11. NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology

    PubMed Central

    Cave, Alison; Grieve, David; Johar, Sofian; Zhang, Min; Shah, Ajay M

    2005-01-01

    Chronic heart failure, secondary to left ventricular hypertrophy or myocardial infarction, is a condition with increasing morbidity and mortality. Although the mechanisms underlying the development and progression of this condition remain a subject of intense interest, there is now growing evidence that redox-sensitive pathways play an important role. This article focuses on the involvement of reactive oxygen species derived from a family of superoxide-generating enzymes, termed NADPH oxidases (NOXs), in the pathophysiology of ventricular hypertrophy, the accompanying interstitial fibrosis and subsequent heart failure. In particular, the apparent ability of the different NADPH oxidase isoforms to define the response of a cell to a range of physiological and pathophysiological stimuli is reviewed. If confirmed, these data would suggest that independently targeting different members of the NOX family may hold the potential for therapeutic intervention in the treatment of cardiac disease. PMID:16321803

  12. Pathophysiology of tic disorders.

    PubMed

    Yael, Dorin; Vinner, Esther; Bar-Gad, Izhar

    2015-08-01

    Tics are the defining symptom of Tourette syndrome and other tic disorders (TDs); however, they form only a part of their overall symptoms. The recent surge of studies addressing the underlying pathophysiology of tics has revealed an intricate picture involving multiple brain areas and complex pathways. The myriad of pathophysiological findings stem, at least partially, from the multifaceted properties of tics and the disorders that express them. Distinct brain pathways mediate the expression of tics, whereas others are involved in the generation of the premonitory urge, associated comorbidities, and other changes in brain state. Expression of these symptoms is controlled by additional networks underlying voluntary suppression by the patient or those reflecting overall behavioral state. This review aims to simplify the complex picture of tic pathophysiology by dividing it into these key components based on converging data from human and animal model studies. Thus, involvement of the corticobasal ganglia pathway and its interaction with motor, sensory, limbic, and executive networks in each of the components as well as their control by different neuromodulators is described. This division enables a focused definition of the neuronal systems involved in each of these processes and allows a better understanding of the pathophysiology of TDs as a whole. PMID:26179434

  13. Pathophysiology of migraine

    PubMed Central

    Goadsby, Peter J.

    2012-01-01

    Migraine is a common disabling brain disorder whose pathophysiology is now being better understood. The study of anatomy and physiology of pain producing structures in the cranium and the central nervous system modulation of the input have led to the conclusion that migraine involves alterations in the sub-cortical aminergic sensory modulatory systems that influence the brain widely. PMID:23024559

  14. Abdominal bloating: pathophysiology and treatment.

    PubMed

    Seo, A Young; Kim, Nayoung; Oh, Dong Hyun

    2013-10-01

    Abdominal bloating is a very common and troublesome symptom of all ages, but it has not been fully understood to date. Bloating is usually associated with functional gastrointestinal disorders or organic diseases, but it may also appear alone. The pathophysiology of bloating remains ambiguous, although some evidences support the potential mechanisms, including gut hypersensitivity, impaired gas handling, altered gut microbiota, and abnormal abdominal-phrenic reflexes. Owing to the insufficient understanding of these mechanisms, the available therapeutic options are limited. However, medical treatment with some prokinetics, rifaximin, lubiprostone and linaclotide could be considered in the treatment of bloating. In addition, dietary intervention is important in relieving symptom in patients with bloating. PMID:24199004

  15. Pathophysiology of the Belgrade rat

    PubMed Central

    Veuthey, Tania; Wessling-Resnick, Marianne

    2014-01-01

    The Belgrade rat is an animal model of divalent metal transporter 1 (DMT1) deficiency. This strain originates from an X-irradiation experiment first reported in 1966. Since then, the Belgrade rat’s pathophysiology has helped to reveal the importance of iron balance and the role of DMT1. This review discusses our current understanding of iron transport homeostasis and summarizes molecular details of DMT1 function. We describe how studies of the Belgrade rat have revealed key roles for DMT1 in iron distribution to red blood cells as well as duodenal iron absorption. The Belgrade rat’s pathology has extended our knowledge of hepatic iron handling, pulmonary and olfactory iron transport as well as brain iron uptake and renal iron handling. For example, relationships between iron and manganese metabolism have been discerned since both are essential metals transported by DMT1. Pathophysiologic features of the Belgrade rat provide us with a unique and interesting animal model to understand iron homeostasis. PMID:24795636

  16. Potential roles for tumour necrosis factor alpha during embryonic development.

    PubMed

    Wride, M A; Sanders, E J

    1995-01-01

    This paper reviews the evidence indicating possible roles for tumour necrosis factor-alpha (TNF alpha) in development. It is proposed that TNF alpha may have essentially three major roles during embryonic development, which may be analogous to its roles in the immune system and during inflammation: a role in programmed cell death; a role as a cellular growth and differentiation factor; and also a role in the remodelling of extracellular matrix, and the regulation of cell adhesion molecules and integrins. The concept of the existence of a cytokine array during embryogenesis, analogous to that occurring in inflammation, is discussed, as well as potential roles for TNF alpha in the induction of ubiquitin; protective mechanisms embryonic cells may employ against TNF alpha-mediated cytotoxicity; and a consideration of the role TNF alpha may play in a "free radical theory of development". PMID:7717528

  17. Pathophysiology of Manganese-Associated Neurotoxicity

    PubMed Central

    Racette, Brad A.; Aschner, Michael; Guilarte, Tomas R.; Dydak, Ulrike; Criswell, Susan R.; Zheng, Wei

    2012-01-01

    to humans. Dr. Aschner’s presentation discussed mechanisms of dopaminergic neuronal toxicity in C. elegans and demonstrates a compelling potential role of Mn in dopaminergic degeneration. Dr. Guilarte’s experimental, non-human primate model of Mn neurotoxicity suggests that Mn decreases dopamine release in the brain without loss of neuronal integrity markers, including dopamine. Dr. Racette’s presentation demonstrates a unique pattern of dopaminergic dysfunction in active welders with chronic exposure to Mn containing welding fumes. Finally, Dr. Dydak presented novel magnetic resonance (MR) spectroscopy data in Mn exposed smelter workers and demonstrated abnormalities in the thalamus and frontal cortex for those workers. This symposium provided some converging evidence of the potential neurotoxic impact of Mn on the dopaminergic system and challenged existing paradigms on the pathophysiology of Mn in the central nervous system. PMID:22202748

  18. Obesity: Pathophysiology and Intervention

    PubMed Central

    Zhang, Yi; Liu, Ju; Yao, Jianliang; Ji, Gang; Qian, Long; Wang, Jing; Zhang, Guansheng; Tian, Jie; Nie, Yongzhan; Zhang, Yi Edi.; Gold, Mark S.; Liu, Yijun

    2014-01-01

    Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity. PMID:25412152

  19. Obesity: pathophysiology and intervention.

    PubMed

    Zhang, Yi; Liu, Ju; Yao, Jianliang; Ji, Gang; Qian, Long; Wang, Jing; Zhang, Guansheng; Tian, Jie; Nie, Yongzhan; Zhang, Yi Edi; Gold, Mark S; Liu, Yijun

    2014-11-01

    Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity. PMID:25412152

  20. Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression.

    PubMed

    Dutta, Suman; Reamtong, Onrapak; Panvongsa, Wittaya; Kitdumrongthum, Sarunya; Janpipatkul, Keatdamrong; Sangvanich, Polkit; Piyachaturawat, Pawinee; Chairoungdua, Arthit

    2015-09-01

    Cholangiocarcinoma (CCA), a common primary malignant tumor of bile duct epithelia, is highly prevalent in Asian countries and unresponsive to chemotherapeutic drugs. Thus, a newly recognized biological entity for early diagnosis and treatment is highly needed. Exosomes are small membrane bound vesicles found in body fluids and released by most cell types including cancer cells. The vesicles contain specific subset of proteins and nucleic acids corresponding to cell types and play essential roles in pathophysiological processes. The present study aimed to assess the protein profiles of CCA-derived exosomes and their potential roles. We have isolated exosomes from CCA cells namely KKU-M213 and KKU-100 derived from Thai patients and their roles were investigated by incubation with normal human cholangiocyte (H69) cells. Exosomes were internalized into H69 cells and had no effects on viability or proliferation of the host cells. Interestingly, the exosomes from KKU-M213 cells only induced migration and invasion of H69 cells. Proteomic analysis of the exosomes from KKU-M213 cells disclosed multiple cancer related proteins that are not present in H69 exosomes. Consistent with the protein profile, treatment with KKU-M213 exosomes induced β-catenin and reduced E-cadherin expressions in H69 cells. Collectively, our results suggest that a direct cell-to-cell transfer of oncogenic proteins via exosomal pathway may be a novel mechanism for CCA progression and metastasis. PMID:26148937

  1. Reform in Teaching Preclinical Pathophysiology

    ERIC Educational Resources Information Center

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-01-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff…

  2. An Overlook to the Characteristics and Roles Played by Eotaxin Network in the Pathophysiology of Food Allergies: Allergic Asthma and Atopic Dermatitis.

    PubMed

    Ahmadi, Zahra; Hassanshahi, Gholamhossein; Khorramdelazad, Hossein; Zainodini, Nahid; Koochakzadeh, Leila

    2016-06-01

    Investigations revealed substantial parts accomplished by chemokines specifically eotaxins and their specific receptors. They are functionally involved in the modulation of the pathologic state of tissue inflammation which is as a result of allergic reactions. Chemokines as small proteins with approximately 8-10 kDa molecular weight are considered and fit in the bigger family of cytokines, containing basic heparin-binding polypeptide mediators. Chemokines actively interfere in the processes of selective, oriented leukocyte (including eosinophil) recruitment. As eminent from their name, more specifically, eotaxins are specialized for eosinophils' oriented locomotion toward allergic inflamed regions. To date, three members are defined for eotaxin subfamily as follows: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26), all of them bind to and activate CCR3 but have a low level of homology and appear to exhibit different physiological potentials. Allergy is described as a clinical state in which a pathologic hypersensitivity reaction is always initiated throughout an immunologic mechanism; similar to other immunologic reactions, an allergic reaction could also either be antibody or cell mediated. This type of allergic reactions occurs in all age groups and damages several different organs, having a significant impact on the emotional and social health of patients and their families and relatives. Concerning introductory comments introduced above, the authors of the present review attempted to collect and provide the latest evidences and information regarding the correlation between expression of eotaxin family members and allergy, in a wider extent, in two important allergic disorders: atopic asthma (AA) and atopic dermatitis (AD). Overall, concerning the most recent articles published within the database in the life sciences literature regarding the fundamental role(s) played by eotaxins in the pathogenesis of AA and AD, the authors of the current article

  3. Brain Amyloid-β Plays an Initiating Role in the Pathophysiological Process of the PS1V97L-Tg Mouse Model of Alzheimer's Disease.

    PubMed

    Wang, Wei; Lu, Lu; Wu, Qiao-Qi; Jia, Jian-Ping

    2016-04-12

    Amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation are major pathophysiological events in Alzheimer's disease (AD). However, the relationships among these processes and which first exerts an effect are unknown. In the present study, we investigated age-dependent behavioral changes and the sequential pathological progression from the brain to the periphery in AD transgenic (PS1V97L-Tg) mice and their wild-type littermates. We discovered that the brain Aβ significantly increased at 6 months old, the increased brain Aβ caused memory dysfunction, and the ability of Aβ to induce tau hyperphosphorylation might be due to oxidative stress and neuroinflammatory reactions. The levels of Aβ42, total tau (t-tau), oxidative stress parameters, and proinflammatory cytokines in plasma can be used to differentiate between PS1V97L-Tg mice and their wild-type littermates at different time points. Collectively, our findings support the hypothesis that Aβ is a trigger among these pathophysiological processions and show that plasma biomarkers can reflect the condition of the AD brain. PMID:27079718

  4. The pathophysiology of eosinophilic esophagitis.

    PubMed

    Raheem, Mayumi; Leach, Steven T; Day, Andrew S; Lemberg, Daniel A

    2014-01-01

    Eosinophilic esophagitis (EoE) is an emerging disease characterized by esophageal eosinophilia (>15eos/hpf), lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast-cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with transforming growth factor-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE. PMID:24910846

  5. The Pathophysiology of Eosinophilic Esophagitis

    PubMed Central

    Raheem, Mayumi; Leach, Steven T.; Day, Andrew S.; Lemberg, Daniel A.

    2014-01-01

    Eosinophilic esophagitis (EoE) is an emerging disease characterized by esophageal eosinophilia (>15eos/hpf), lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast-cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with transforming growth factor-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE. PMID:24910846

  6. Brief Report: Pathophysiology of Autism: Neurochemistry.

    ERIC Educational Resources Information Center

    Cook, Edwin H., Jr.

    1996-01-01

    This paper reviews what is known about the role of neurochemicals in controlling the development of the brain and in the pathophysiology of autism. Suggested approaches to further research involve using animal models, examining effects of drugs on neurochemicals, and using such technologies as positron emission tomography and magnetic resonance…

  7. [Cardiac potassium channels: molecular structure, physiology, pathophysiology and therapeutic implications].

    PubMed

    Mironov, N Iu; Golitsyn, S P

    2013-01-01

    Potassium channels and currents play essential roles in cardiac repolarization. Potassium channel blockade by class III antiarrhythmic drugs prolongs cardiac repolarization and results in termination and prevention of cardiac arrhythmias. Excessive inhomogeneous repolarization prolongation may lead to electrical instability and proarrhythmia (Torsade de Pointes tachycardia). This review focuses on molecular structure, physiology, pathophysiology and therapeutic potential of potassium channels of cardiac conduction system and myocardium providing information on recent findings in pathogenesis of cardiac arrhythmias, including inherited genetic abnormalities, and future perspectives. PMID:24654438

  8. Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment

    PubMed Central

    Azevedo, Paula S.; Polegato, Bertha F.; Minicucci, Marcos F.; Paiva, Sergio A. R.; Zornoff, Leonardo A. M.

    2016-01-01

    Cardiac remodeling is defined as a group of molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury. The process results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. Here, we discuss the concepts and clinical implications of cardiac remodeling, and the pathophysiological role of different factors, including cell death, energy metabolism, oxidative stress, inflammation, collagen, contractile proteins, calcium transport, geometry and neurohormonal activation. Finally, the article describes the pharmacological treatment of cardiac remodeling, which can be divided into three different stages of strategies: consolidated, promising and potential strategies. PMID:26647721

  9. Calcium signalling in pancreatic stellate cells: Mechanisms and potential roles.

    PubMed

    Gryshchenko, Oleksiy; Gerasimenko, Julia V; Gerasimenko, Oleg V; Petersen, Ole H

    2016-03-01

    Hepatic and pancreatic stellate cells may or may not be regarded as stem cells, but they are capable of remarkable transformations. There is less information about stellate cells in the pancreas than in the liver, where they were discovered much earlier and therefore have been studied longer and more intensively than in the pancreas. Most of the work on pancreatic stellate cells has been carried out in studies on cell cultures, but in this review we focus attention on Ca(2+) signalling in stellate cells in their real pancreatic environment. We review current knowledge on patho-physiologically relevant Ca(2+) signalling events and their underlying mechanisms. We focus on the effects of bradykinin in the initial stages of acute pancreatitis, an often fatal disease in which the pancreas digests itself and its surroundings. Ca(2+) signals, elicited in the stellate cells by the action of bradykinin, may have a negative effect on the outcome of the acute disease process and promote the development of chronic pancreatitis. The bradykinin-elicited Ca(2+) signals can be inhibited by blockade of type 2 receptors and also by blockade of Ca(2+)-release activated Ca(2+) channels. The potential benefits of such pharmacological inhibition for the treatment of pancreatitis are reviewed. PMID:26960936

  10. Potential role of gut microbiota and tissue barriers in Parkinson's disease and amyotrophic lateral sclerosis.

    PubMed

    Fang, Xin

    2016-09-01

    Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with pathophysiology that may be related to the gastrointestinal tract. It is well established that tissue barriers maintain homeostasis and health. Furthermore, gut microbiota may have an impact on brain activity through the gut-microbiota-brain axis under both physiological and pathological conditions. In this review, we highlight the current knowledge regarding the role of gut microbiota and tissue barriers in PD and ALS. To our knowledge, this is the first review of the key issues involving both the altered gut microbiota and impaired tissue barriers in the pathophysiology of PD and ALS. PMID:26381230

  11. The role of 5-alpha reductase inhibitors in prostate pathophysiology: Is there an additional advantage to inhibition of type 1 isoenzyme?

    PubMed

    Goldenberg, Larry; So, Alan; Fleshner, Neil; Rendon, Ricardo; Drachenberg, Darrel; Elhilali, Mostafa

    2009-06-01

    Normal growth and function of the prostate are contingent on the reduction of testosterone to dihydrotestosterone (DHT) by 5-alpha reductase (5-AR) enzymes types 1 and 2. It has been theorized that an overabundance of DHT may be implicated in the pathogenesis of both benign prostatic hyperplasia (BPH) and prostate cancer. Inhibitors of 5-AR such as dutasteride and finasteride may therefore have an important role in the prevention and treatment of BPH and prostate cancer. Dutasteride provides greater suppression of DHT than finasteride, thereby underlying the hypothesis that inhibition of both type 1 and type 2 would provide correspondingly greater protection than inhibition of type 2 alone. We review the potential significance of the 5-AR inhibitors in reducing the risk of prostate cancer according to the basic biology of prostate disease. PMID:19543428

  12. The role of angiogenic factors in fibroid pathogenesis: potential implications for future therapy

    PubMed Central

    Tal, Reshef; Segars, James H.

    2014-01-01

    Background It is well established that tumors are dependent on angiogenesis for their growth and survival. Although uterine fibroids are known to be benign tumors with reduced vascularization, recent work demonstrates that the vasculature of fibroids is grossly and microscopically abnormal. Accumulating evidence suggests that angiogenic growth factor dysregulation may be implicated in these vascular and other features of fibroid pathophysiology. Methods Literature searches were performed in PubMed and Google Scholar for articles with content related to angiogenic growth factors and myometrium/leiomyoma. The findings are hereby reviewed and discussed. Results Multiple growth factors involved in angiogenesis are differentially expressed in leiomyoma compared with myometrium. These include epidermal growth factor (EGF), heparin-binding-EGF, vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β and adrenomedullin. An important paradox is that although leiomyoma tissues are hypoxic, leiomyoma feature down-regulation of key molecular regulators of the hypoxia response. Furthermore, the hypoxic milieu of leiomyoma may contribute to fibroid development and growth. Notably, common treatments for fibroids such as GnRH agonists and uterine artery embolization (UAE) are shown to work at least partly via anti-angiogenic mechanisms. Conclusions Angiogenic growth factors play an important role in mechanisms of fibroid pathophysiology, including abnormal vasculature and fibroid growth and survival. Moreover, the fibroid's abnormal vasculature together with its aberrant hypoxic and angiogenic response may make it especially vulnerable to disruption of its vascular supply, a feature which could be exploited for treatment. Further experimental studies are required in order to gain a better understanding of the growth factors that are involved in normal and pathological myometrial angiogenesis, and to assess

  13. Critical role of canonical transient receptor potential channel 7 in initiation of seizures.

    PubMed

    Phelan, Kevin D; Shwe, U Thaung; Abramowitz, Joel; Birnbaumer, Lutz; Zheng, Fang

    2014-08-01

    Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel. PMID:25049394

  14. Critical role of canonical transient receptor potential channel 7 in initiation of seizures

    PubMed Central

    Phelan, Kevin D.; Shwe, U Thaung; Abramowitz, Joel; Birnbaumer, Lutz; Zheng, Fang

    2014-01-01

    Status epilepticus (SE) is a life-threatening disease that has been recognized since antiquity but still causes over 50,000 deaths annually in the United States. The prevailing view on the pathophysiology of SE is that it is sustained by a loss of normal inhibitory mechanisms of neuronal activity. However, the early process leading to the initiation of SE is not well understood. Here, we show that, as seen in electroencephalograms, SE induced by the muscarinic agonist pilocarpine in mice is preceded by a specific increase in the gamma wave, and genetic ablation of canonical transient receptor potential channel (TRPC) 7 significantly reduces this pilocarpine-induced increase of gamma wave activity, preventing the occurrence of SE. At the cellular level, TRPC7 plays a critical role in the generation of spontaneous epileptiform burst firing in cornu ammonis (CA) 3 pyramidal neurons in brain slices. At the synaptic level, TRPC7 plays a significant role in the long-term potentiation at the CA3 recurrent collateral synapses and Schaffer collateral-CA1 synapses, but not at the mossy fiber-CA3 synapses. Taken together, our data suggest that epileptiform burst firing generated in the CA3 region by activity-dependent enhancement of recurrent collateral synapses may be an early event in the initiation process of SE and that TRPC7 plays a critical role in this cellular event. Our findings reveal that TRPC7 is intimately involved in the initiation of seizures both in vitro and in vivo. To our knowledge, this contribution to initiation of seizures is the first identified functional role for the TRPC7 ion channel. PMID:25049394

  15. Current concepts in the pathophysiology of glaucoma

    PubMed Central

    Agarwal, Renu; Gupta, Suresh K; Agarwal, Puneet; Saxena, Rohit; Agrawal, Shyam S

    2009-01-01

    Glaucoma, the second leading cause of blindness, is characterized by changes in the optic disc and visual field defects. The elevated intraocular pressure was considered the prime factor responsible for the glaucomatous optic neuropathy involving death of retinal ganglion cells and their axons. Extensive investigations into the pathophysiology of glaucoma now reveal the role of multiple factors in the development of retinal ganglion cell death. A better understanding of the pathophysiological mechanisms involved in the onset and progression of glaucomatous optic neuropathy is crucial in the development of better therapeutic options. This review is an effort to summarize the current concepts in the pathophysiology of glaucoma so that newer therapeutic targets can be recognized. The literature available in the National Medical Library and online Pubmed search engine was used for literature review. PMID:19574692

  16. Pathophysiology of Birth Asphyxia.

    PubMed

    Rainaldi, Matthew A; Perlman, Jeffrey M

    2016-09-01

    The pathophysiology of asphyxia generally results from interruption of placental blood flow with resultant fetal hypoxia, hypercarbia, and acidosis. Circulatory and noncirculatory adaptive mechanisms exist that allow the fetus to cope with asphyxia and preserve vital organ function. With severe and/or prolonged insults, these compensatory mechanisms fail, resulting in hypoxic ischemic injury, leading to cell death via necrosis and apoptosis. Permanent brain injury is the most severe long-term consequence of perinatal asphyxia. The severity and location of injury is influenced by the mechanisms of injury, including degree and duration, as well as the developmental maturity of the brain. PMID:27524444

  17. Pathophysiology of hypertension in obese children: a systematic review.

    PubMed

    Wirix, A J G; Kaspers, P J; Nauta, J; Chinapaw, M J M; Kist-van Holthe, J E

    2015-10-01

    Hypertension is increasingly common in overweight and obese children. The mechanisms behind the development of hypertension in obesity are complex, and evidence is limited. In order to effectively treat obese children for hypertension, it is important to have a deeper understanding of the pathophysiology of hypertension in obese children. The present review summarizes the main factors associated with hypertension in obese children and discusses their potential role in its pathophysiology. Systematic searches were conducted in PubMed and EMBASE for articles published up to October 2014. In total, 60 relevant studies were included. The methodological quality of the included studies ranged from weak to strong. Several factors important in the development of hypertension in obese children have been suggested, including endocrine determinants, such as corticosteroids and adipokines, sympathetic nervous system activity, disturbed sodium homeostasis, as well as oxidative stress, inflammation and endothelial dysfunction. Understanding the pathophysiology of hypertension in overweight and obese children is important and could have implications for its screening and treatment. Based on solely cross-sectional observational studies, it is impossible to infer causality. Longitudinal studies of high methodological quality are needed to gain more insight into the complex mechanisms behind the development of hypertension in obese children. PMID:26098701

  18. The pathophysiology of concussions in youth.

    PubMed

    Shrey, Daniel W; Griesbach, Grace S; Giza, Christopher C

    2011-11-01

    Mild traumatic brain injury, especially sport-related concussion, is common among young persons. Consequences of transient pathophysiologic dysfunction must be considered in the context of a developing or immature brain, as must the potential for an accumulation of damage with repeated exposure. This review summarizes the underlying neurometabolic cascade of concussion, with emphasis on the young brain in terms of acute pathophysiology, vulnerability, alterations in plasticity and activation, axonal injury, and cumulative risk from chronic, repetitive damage, and discusses their implications in the context of clinical care for the concussed youth, highlighting areas for future investigation. PMID:22050937

  19. Drug Disposition in Pathophysiological Conditions

    PubMed Central

    Gandhi, Adarsh; Moorthy, Bhagavatula; Ghose, Romi

    2014-01-01

    Expression and activity of several key drug metabolizing enzymes (DMEs) and transporters are altered in various pathophysiological conditions, leading to altered drug metabolism and disposition. This can have profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy by causing inter-individual variabilities in drug responses. This review article highlights altered drug disposition in inflammation and infectious diseases, and commonly encountered disorders such as cancer, obesity/diabetes, fatty liver diseases, cardiovascular diseases and rheumatoid arthritis. Many of the clinically relevant drugs have a narrow therapeutic index. Thus any changes in the disposition of these drugs may lead to reduced efficacy and increased toxicity. The implications of changes in DMEs and transporters on the pharmacokinetics/pharmacodynamics of clinically-relevant medications are also discussed. Inflammation-mediated release of pro-inflammatory cytokines and activation of toll-like receptors (TLRs) are known to play a major role in down-regulation of DMEs and transporters. Although the mechanism by which this occurs is unclear, several studies have shown that inflammation-associated cell-signaling pathway and its interaction with basal transcription factors and nuclear receptors in regulation of DMEs and transporters play a significant role in altered drug metabolism. Altered regulation of DMEs and transporters in a multitude of disease states will contribute towards future development of powerful in vitro and in vivo tools in predicting the drug response and opt for better drug design and development. The goal is to facilitate a better understanding of the mechanistic details underlying the regulation of DMEs and transporters in pathophysiological conditions. PMID:22746301

  20. Drug disposition in pathophysiological conditions.

    PubMed

    Gandhi, Adarsh; Moorthy, Bhagavatula; Ghose, Romi

    2012-11-01

    Expression and activity of several key drug metabolizing enzymes (DMEs) and transporters are altered in various pathophysiological conditions, leading to altered drug metabolism and disposition. This can have profound impact on the pharmacotherapy of widely used clinically relevant medications in terms of safety and efficacy by causing inter-individual variabilities in drug responses. This review article highlights altered drug disposition in inflammation and infectious diseases, and commonly encountered disorders such as cancer, obesity/diabetes, fatty liver diseases, cardiovascular diseases and rheumatoid arthritis. Many of the clinically relevant drugs have a narrow therapeutic index. Thus any changes in the disposition of these drugs may lead to reduced efficacy and increased toxicity. The implications of changes in DMEs and transporters on the pharmacokinetics/pharmacodynamics of clinically-relevant medications are also discussed. Inflammation-mediated release of pro-inflammatory cytokines and activation of toll-like receptors (TLRs) are known to play a major role in down-regulation of DMEs and transporters. Although the mechanism by which this occurs is unclear, several studies have shown that inflammation-associated cell-signaling pathway and its interaction with basal transcription factors and nuclear receptors in regulation of DMEs and transporters play a significant role in altered drug metabolism. Altered regulation of DMEs and transporters in a multitude of disease states will contribute towards future development of powerful in vitro and in vivo tools in predicting the drug response and opt for better drug design and development. The goal is to facilitate a better understanding of the mechanistic details underlying the regulation of DMEs and transporters in pathophysiological conditions. PMID:22746301

  1. Menstrual dysfunction in pathophysiologic states.

    PubMed

    Neinstein, L S

    1985-10-01

    The menstrual cycle is a complex entity involving many interactions of the central nervous system, hypothalamus, pituitary and ovaries. Normal menstrual function depends on a pulsatile gonadotropin-releasing hormone secretion leading to a pulsatile luteinizing hormone and follicle-stimulating hormone secretion that stimulates the ovaries. A cyclic burst of luteinizing hormone is also required for ovulation. Certain pathophysiologic states, such as those produced by stress, exercise and drugs, have the potential to affect the cycle at many levels. Chronic illness may have effects on beta-endorphins and hypothalamic functioning. Alternatively, the weight loss associated with chronic illness may alter estrogen metabolism, thus altering hypothalamic or pituitary function. Anorexia nervosa and simple weight loss may have effects at the hypothalamic level or through altering estrogen metabolism, as well. PMID:3911586

  2. Tachykinin receptors and airway pathophysiology.

    PubMed

    Maggi, C A

    1993-05-01

    The mammalian tachykinins (TKs), substance P and neurokinin A, are present in sensory nerve fibres in the upper and lower airways of various mammalian species, including humans. TKs are released from these afferent nerves in an "efferent" mode at peripheral level, especially in response to irritant stimuli. TKs exert a variety of biological effects (bronchoconstriction, plasma protein extravasation, stimulation of mucus secretion), collectively known as "neurogenic inflammation", and this process is thought to be of potential pathogenic relevance for various airway diseases. The recent development of potent and selective TK receptor antagonists on the one hand provides important new tools for the understanding of basic airway physiology and pathophysiology and, on the other, opens new possibilities for therapy of airway diseases. PMID:8390944

  3. Reform in teaching preclinical pathophysiology.

    PubMed

    Li, Yong-Yu; Li, Kun; Yao, Hong; Xu, Xiao-Juan; Cai, Qiao-Lin

    2015-12-01

    Pathophysiology is a scientific discipline that studies the onset and progression of pathological conditions and diseases, and pathophysiology is one of the core courses in most preclinical medical curricula. In China, most medical schools house a Department of Pathophysiology, in contrast to medical schools in many developed countries. The staff in Chinese Departments of Pathophysiology generally consists of full-time instructors or lecturers who teach medical students. These lecturers are sometimes lacking in clinic knowledge and experiences. To overcome this, in recent years, we have been trying to bring new trends in teaching pathophysiology into our curriculum. Our purpose in writing this article was to share our experiences with our colleagues and peers worldwide in the hope that the insights we have gained in pathophysiology teaching will be of some value to educators who advocate teaching reform in medical schools. PMID:26628645

  4. The Potential Role of Artificial Intelligence Technology in Education.

    ERIC Educational Resources Information Center

    Salem, Abdel-Badeeh M.

    The field of Artificial Intelligence (AI) and Education has traditionally a technology-based focus, looking at the ways in which AI can be used in building intelligent educational software. In addition AI can also provide an excellent methodology for learning and reasoning from the human experiences. This paper presents the potential role of AI in…

  5. Conceptualising the Potential Role of L1 in CLIL

    ERIC Educational Resources Information Center

    Lin, Angel M. Y.

    2015-01-01

    Content and language integrated learning (CLIL) is a rapidly growing area of both research and practice in all parts of the world, especially in Europe and Asia. As a young discipline, CLIL has a good potential of distinguishing itself from monolingual L2 immersion education models by becoming more flexible and balanced about the role of L1 in…

  6. Pathophysiology of venous thrombosis.

    PubMed

    Myers, D D

    2015-03-01

    In this chapter, an overview of some of the prominent risk factors that contribute to the pathophysiology of venous thrombosis will be discussed. In 1856, Dr Rudolf Virchow developed the concept outlining the genesis of intravascular thrombosis. Dr Virchow hypothesized that circulatory stasis due to interrupted blood flow, changes in the blood leading to blood coagulation, and irritation or damage to the vascular endothelium would initiate acute venous thrombus generation. Presently, it is known that these above-mentioned risk factors are influenced by increasing age, gender, and obesity. The current chapter will focus on recent preclinical and clinical investigations that will give the reader insight into the prothrombotic mechanisms that lead to acute venous thrombosis. PMID:25729062

  7. Secondary osteoporosis: pathophysiology & diagnosis.

    PubMed

    Emkey, Gregory R; Epstein, Sol

    2014-12-01

    Osteoporosis is a skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue that increase the susceptibility to fracture. Secondary osteoporosis is loosely defined as low bone mineral density or increased risk of fragility fracture caused by any factor other than aging or postmenopausal status. The purpose of this review is to discuss the current understanding of the pathophysiology and contribution to fracture risk of many of the more common causes of secondary osteoporosis, as well as diagnostic considerations, outlined by organ system. While not comprehensive, included are a wide array of diseases, conditions, and medications that have been associated with bone loss and susceptibility to fractures. The hope is to highlight the importance to the general clinician of screening for and treating the osteoporosis in these patients, so to limit the resultant increased morbidity associated with fractures. PMID:25432361

  8. Aquaporin 1, a potential therapeutic target for migraine with aura

    PubMed Central

    2010-01-01

    The pathophysiology of migraine remains largely unknown. However, evidence regarding the molecules participating in the pathophysiology of migraine has been accumulating. Water channel proteins, known as aquaporins (AQPs), notably AQP-1 and AQP-4, appears to be involved in the pathophysiology of several neurological diseases. This review outlines newly emerging evidence indicating that AQP-1 plays an important role in pain signal transduction and migraine and could therefore serve as a potential therapeutic target for these diseases. PMID:20969805

  9. Nicotinic Acetylcholine Receptors in the Pathophysiology of Al zheimer's Disease: The Role of Protein-Protein Interactions in Current and Future Treatment.

    PubMed

    Thomsen, Morten Skøtt; Andreasen, Jesper Tobias; Arvaniti, Maria; Kohlmeier, Kristi Anne

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus, and their demonstrated role in processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine, and more recently nAChR selective ligands have undergone clinical trials. Here we discuss recent findings suggesting that the expression and function of nAChRs in AD may be regulated by direct interactions with specific proteins, including Lynx proteins, NMDA-receptors and the Wnt/β-catenin pathway, as well as β-amyloid. The ability of protein interactions to modify nAChR function adds a new level of complexity to cholinergic signaling in the brain that may be specifically altered in AD. It is currently not known to what degree current nAChR ligands affect these interactions, and it is possible that the difference in the clinical effect of nAChR ligands in AD is related to differences in their ability to modulate nAChR protein interactions, rather than their effects on ion flow through the receptors. Drugs designed to target these interactions may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD. Notably, the development of experimental drugs that specifically modulate these interactions may provide the opportunity to selectively affect those aspects of nAChR function that are affected in AD. PMID:26818866

  10. Role of paf-acether in the mediation of pathophysiological responses to aggregated immunoglobulins. Studies with the platelet-activating factor receptor antagonist BN 52021.

    PubMed

    Fernandez-Gallardo, S; Cano, E; Braquet, P; Sanchez Crespo, M

    1988-01-01

    Sprague-Dawley rats were challenged with an intravenous (i.v.) infusion of soluble aggregates of immunoglobulin G. Animals receiving a dose of aggregates of 40 mg/kg showed a significantly reduced time of lysis of diluted blood clot, which paralleled the appearance in plasma of tissue-type plasminogen activator. These changes occurred about 5-10 min after the challenge, which is a more protracted time-course than that observed in response to paf-acether. A significant increase in serum levels of N-acetylglucosaminidase was also observed in the animals several minutes after challenge. Blood neutrophil count showed a 50% reduction that reached its maximum at 10 min and was followed by an overshoot after 30 min. In experiments in rats previously depleted of circulating PMN by treatment with vinblastine, no significant differences were observed in N-acetylglucosaminidase release as compared to non-treated animals. Since prior evidence indicated that endogenously generated paf-acether could be a mediator responsible for these changes, at least to some extent, the compound BN 52021, a specific antagonist of the paf-acether receptor was given to these animals prior to the challenge with the complexes. All the above mentioned responses were significantly reduced by BN 52021, which is in keeping with the hypothesis involving endogenous paf-acether release in the mediation of these changes. By contrast, BN 52021 did not interfere with the clearance of the aggregates from the circulation, which seems to be a beneficial mechanism to reduce immune-mediated tissue injury. These data extend the number of paf-acether mediated pathophysiological changes that can be observed in response to immune aggregates. PMID:3139574

  11. Potential ecological roles of flavonoids from Stellera chamaejasme

    PubMed Central

    Yan, Zhiqiang; Zeng, Liming; Jin, Hui; Qin, Bo

    2015-01-01

    Stellera chamaejasme L. (Thymelaeaceae), a perennial weed, distributes widely in the grasslands of Russia, Mongolia and China. The plant synthesizes various secondary metabolites including a group of flavonoids. To our knowledge, flavonoids play important roles in the interactions between plants and the environment. So, what are the benefits to S. chamaejasme from producing these flavonoids? Here, we discuss the potential ecological role of flavonoids from S. chamaejasme in protecting the plant from insects and other herbivores, as well as pathogens and competing plant species, and new data are provided on the phytotoxicity of flavonoids from S. chamaejasme toward Poa annua L. PMID:25848835

  12. Potential ecological roles of flavonoids from Stellera chamaejasme.

    PubMed

    Yan, Zhiqiang; Zeng, Liming; Jin, Hui; Qin, Bo

    2015-01-01

    Stellera chamaejasme L. (Thymelaeaceae), a perennial weed, distributes widely in the grasslands of Russia, Mongolia and China. The plant synthesizes various secondary metabolites including a group of flavonoids. To our knowledge, flavonoids play important roles in the interactions between plants and the environment. So, what are the benefits to S. chamaejasme from producing these flavonoids? Here, we discuss the potential ecological role of flavonoids from S. chamaejasme in protecting the plant from insects and other herbivores, as well as pathogens and competing plant species, and new data are provided on the phytotoxicity of flavonoids from S. chamaejasme toward Poa annua L. PMID:25848835

  13. Leptin in human physiology and pathophysiology

    PubMed Central

    Magkos, Faidon; Brinkoetter, Mary; Sienkiewicz, Elizabeth; Dardeno, Tina A.; Kim, Sang-Yong; Hamnvik, Ole-Petter R.; Koniaris, Anastasia

    2011-01-01

    Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical

  14. The chronobiology, etiology and pathophysiology of obesity

    PubMed Central

    Garaulet, M; Ordovás, JM; Madrid, JA

    2015-01-01

    The effect of CD on human health is an emerging issue. Many records link CD with diseases such as cancer, cardiovascular, cognitive impairment and obesity, all of them conducive to premature aging. The amount of sleep has declined by 1.5 h over the past century, accompanied by an important increase in obesity. Shift work, sleep deprivation and exposure to bright light at night increase the prevalence of adiposity. Animal models have shown that mice with Clock gene disruption are prone to developing obesity and MetS. This review summarizes the latest developments with regard to chronobiology and obesity, considering (1) how molecular clocks coordinate metabolism and the specific role of the adipocyte; (2) CD and its causes and pathological consequences; (3) the epidemiological evidence of obesity as a chronobiological illness; and (4) theories of circadian disruption and obesity. Energy intake and expenditure, relevance of sleep, fat intake from a circadian perspective and psychological and genetic aspects of obesity are examined. Finally, ideas about the use of chronobiology in the treatment of obesity are discussed. Such knowledge has the potential to become a valuable tool in the understanding of the relationship between the chronobiology, etiology and pathophysiology of obesity. PMID:20567242

  15. Pathophysiology of diabetic dyslipidaemia: where are we?

    PubMed

    Vergès, Bruno

    2015-05-01

    Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus, with a two- to fourfold increase in cardiovascular disease risk compared with non-diabetic individuals. Abnormalities in lipid metabolism that are observed in the context of type 2 diabetes are among the major factors contributing to an increased cardiovascular risk. Diabetic dyslipidaemia includes not only quantitative lipoprotein abnormalities, but also qualitative and kinetic abnormalities that, together, result in a shift towards a more atherogenic lipid profile. The primary quantitative lipoprotein abnormalities are increased triacylglycerol (triglyceride) levels and decreased HDL-cholesterol levels. Qualitative lipoprotein abnormalities include an increase in large, very low-density lipoprotein subfraction 1 (VLDL1) and small, dense LDLs, as well as increased triacylglycerol content of LDL and HDL, glycation of apolipoproteins and increased susceptibility of LDL to oxidation. The main kinetic abnormalities are increased VLDL1 production, decreased VLDL catabolism and increased HDL catabolism. In addition, even though LDL-cholesterol levels are typically normal in patients with type 2 diabetes, LDL particles show reduced turnover, which is potentially atherogenic. Although the pathophysiology of diabetic dyslipidaemia is not fully understood, the insulin resistance and relative insulin deficiency observed in patients with type 2 diabetes are likely to contribute to these lipid changes, as insulin plays an important role in regulating lipid metabolism. In addition, some adipocytokines, such as adiponectin or retinol-binding protein 4, may also contribute to the development of dyslipidaemia in patients with type 2 diabetes. PMID:25725623

  16. LPA receptor signaling: pharmacology, physiology, and pathophysiology

    PubMed Central

    Yung, Yun C.; Stoddard, Nicole C.; Chun, Jerold

    2014-01-01

    Lysophosphatidic acid (LPA) is a small ubiquitous lipid found in vertebrate and nonvertebrate organisms that mediates diverse biological actions and demonstrates medicinal relevance. LPA’s functional roles are driven by extracellular signaling through at least six 7-transmembrane G protein-coupled receptors. These receptors are named LPA1–6 and signal through numerous effector pathways activated by heterotrimeric G proteins, including Gi/o, G12/13, Gq, and Gs. LPA receptor-mediated effects have been described in numerous cell types and model systems, both in vitro and in vivo, through gain- and loss-of-function studies. These studies have revealed physiological and pathophysiological influences on virtually every organ system and developmental stage of an organism. These include the nervous, cardiovascular, reproductive, and pulmonary systems. Disturbances in normal LPA signaling may contribute to a range of diseases, including neurodevelopmental and neuropsychiatric disorders, pain, cardiovascular disease, bone disorders, fibrosis, cancer, infertility, and obesity. These studies underscore the potential of LPA receptor subtypes and related signaling mechanisms to provide novel therapeutic targets. PMID:24643338

  17. Understanding the pathophysiology of itch

    PubMed Central

    Garibyan, Lilit; Rheingold, Curtis G.; Lerner, Ethan A.

    2013-01-01

    Itch is the most common symptom described by our patients. Treating this symptom can be challenging. A revolution is ongoing in understanding the pathophysiology of itch and will allow this challenge to be met. The present authors review and update the current understanding of the pathophysiology of itch. PMID:23551365

  18. Potential roles of optical interconnections within broadband switching modules

    NASA Astrophysics Data System (ADS)

    Lalk, Gail R.; Habiby, Sarry F.; Hartman, Davis H.; Krchnavek, Robert R.; Wilson, Donald K.; Young, Kenneth C., Jr.

    1991-04-01

    An investigation of potential physical design bottlenecks in future broadband telecommunication switches has led to the identification of several areas where optical interconnections may play a role in the practical realization of required system performance. In the model used the speed and interconnection densities as well as requirements for ease-of-access and efficient power utilization challenge conventional partitioning and packaging strategies. Potential areas where optical interconnections may relieve some of the physical design bottlenecks include fiber management at the customer interface to the switch routing and distribution of high-density interconnections within the fabric of the switch and backplane interconnections to increase system throughput.

  19. Pathophysiology of Heart Failure.

    PubMed

    Tanai, Edit; Frantz, Stefan

    2015-01-01

    Heart failure is considered an epidemic disease in the modern world affecting approximately 1% to 2% of adult population. It presents a multifactorial, systemic disease, in which--after cardiac injury--structural, neurohumoral, cellular, and molecular mechanisms are activated and act as a network to maintain physiological functioning. These coordinated, complex processes lead to excessive volume overload, increased sympathetic activity, circulation redistribution, and result in different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an accurate diagnosis and to specify the underlying cause. The most important, outcome determining factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical regimes, novel targets, and fine regulation of these processes try to keep these compensatory mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgical therapy options give new chances in the management of heart failure. For the optimization and establishment of these and novel therapeutical approaches, complete and comprehensive understanding of the underlying mechanisms is essentially needed. Besides diagnosis and treatment, efforts should be made for better prevention in heart failure by treatment of risk factors, or identifying and following risk groups. This summary of the pathophysiology of heart failure tries to give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of heart failure to contribute to a more comprehensive knowledge of the disease. PMID:26756631

  20. The Pathophysiology of Concussion.

    PubMed

    Choe, Meeryo C

    2016-06-01

    Concussion is a significant issue in medicine and the media today. With growing interest on the long-term effects of sports participation, it is important to understand what occurs in the brain after an impact of any degree. While some of the basic pathophysiology has been elucidated, much is still unknown about what happens in the brain after traumatic brain injury, particularly with milder injuries where no damage can be seen at the structural level on standard neuroimaging. Understanding the chain of events from a cellular level using studies investigating more severe injuries can help to drive research efforts in understanding the symptomatology that is seen in the acute phase after concussion, as well as point to mechanisms that may underlie persistent post-concussive symptoms. This review discusses the basic neuropathology that occurs after traumatic brain injury at the cellular level. We also present the pathology of chronic traumatic encephalopathy and its similarities to other neurodegenerative diseases. We conclude with recent imaging and biomarker findings looking at changes that may occur after repeated subconcussive blows, which may help to guide efforts in understanding if cumulative subconcussive mechanical forces upon the brain are detrimental in the long term or if concussive symptoms mark the threshold for brain injury. PMID:27184060

  1. Pathophysiology of anemia and erythrocytosis.

    PubMed

    Hodges, Vivien M; Rainey, Susan; Lappin, Terence R; Maxwell, A Peter

    2007-11-01

    An increasing understanding of the process of erythropoiesis raises some interesting questions about the pathophysiology, diagnosis and treatment of anemia and erythrocytosis. The mechanisms underlying the development of many of the erythrocytoses, previously characterised as idiopathic, have been elucidated leading to an increased understanding of oxygen homeostasis. Characterisation of anemia and erythrocytosis in relation to serum erythropoietin levels can be a useful addition to clinical diagnostic criteria and provide a rationale for treatment with erythropoiesis stimulating agents (ESAs). Recombinant human erythropoietin as well as other ESAs are now widely used to treat anemias associated with a range of conditions, including chronic kidney disease, chronic inflammatory disorders and cancer. There is also heightened awareness of the potential abuse of ESAs to boost athletic performance in competitive sport. The discovery of erythropoietin receptors outside of the erythropoietic compartment may herald future applications for ESAs in the management of neurological and cardiac diseases. The current controversy concerning optimal hemoglobin levels in chronic kidney disease patients treated with ESAs and the potential negative clinical outcomes of ESA treatment in cancer reinforces the need for cautious evaluation of the pleiotropic effects of ESAs in non-erythroid tissues. PMID:17656101

  2. Benign prostatic hyperplasia - progress in pathophysiology and management.

    PubMed

    Dobrek, Łukasz; Thor, Piotr Jan

    2015-11-01

    Benign prostatic hyperplasia (BPH) is a common disease of the aging male population, in affected individuals often accompanied by metabolic syndrome. BPH is manifested by a complex range of symptoms originating from the lower urinary tract (LUTS - lower urinary tract symptoms), including disturbances resulting from impaired bladder compliance and bladder overactivity (e.g. frequency, nocturia, urinary incontinence, dysuria) and symptoms associated with the bladder outlet obstruction (e.g. the difficulty in voiding initiating, intermittency, involuntary interruption of voiding, weak urinary stream, straining to void). Despite numerous studies, the pathogenesis of BPH remains not completely understood, and the condition awaits a comprehensive description. The current pathophysiological view emphasizes the role of hormonal dysregulation, locally released in the prostate growth factors action and a complex inflammatory, BPH-associated process with the release of a number of pro-proliferative mediators. The current BPH pharmacotherapy involves administration of α-1-blockers, 5-α-reductase inhibitors, antimuscarinic drugs (cholinolytics) and phosphodiesterase- 5-inhibitors. Progress in the BPH pathophysiology allows the disclosure of additional, potential targets of pharmacological intervention, such as β-3 adrenoreceptor or CB1 cannabinoid receptor agonists, P2X1 purinergic or ETA endothelin receptors antagonists, RhoA/Rho kinase system inhibitors, nitric oxide donors, drugs indirectly (luteinizing hormone - releasing hormone antagonists) or directly (antiandrogens) abolishing the effect of testosterone and its derivatives or agents blocking the action of proinflammatory cytokines. The article briefly discusses the pathophysiology of the aforementioned issues and the current BPH management along with the future, potential opportunities for pharmacotherapy of the. PMID:26637089

  3. Etiology and pathophysiology of inflammatory bowel disease--environmental factors.

    PubMed

    Andus, T; Gross, V

    2000-01-01

    Environmental factors play an important role in the pathophysiology of inflammatory bowel disease. There is a strong and consistent association between smoking and Crohn's disease, and between nonsmoking and ulcerative colitis. Despite extensive research, the exact pathophysiological mechanisms for these associations remain unclear. In spite of this, some clinical trials with nicotine-patches showed beneficial effects for the treatment of ulcerative colitis. Associations of Crohn's disease and ulcerative colitis with other environmental factors are weaker like the association with use of oral contraceptives or those less well investigated such as the association with childhood hygiene. Most studies suggesting a potential pathogenetic role of Mycobacterium paratuberculosis or an effect of tuberculostatic therapy in Crohn's disease could not be reproduced by others. Perinatal or childhood infections by viruses like measles are heavily debated, but not proven to be causal for inflammatory bowel disease. Coagulation disorders have been described as protecting from inflammatory bowel disease, suggesting hypercoagulability to be a pathogenetic factor. Some studies described that appendectomy may prevent the onset of ulcerative colitis in man and mice. Other environmental factors such as hydrogen sulfide, tonsillectomy, diet, blood transfusions, and Listeria also require confirmation. There are, however, convincing data from genetic animal models and twin studies that environmental factors as the intestinal bacterial flora interact with susceptible hosts to cause inflammatory bowel disease. Inflammatory bowel diseases have multifactorial etiologies, which require a differentiated approach for treatment and prevention. PMID:10690583

  4. Pathophysiology of Sleep Apnea

    PubMed Central

    Veasey, Sigrid C.; Morgan, Barbara J.; O'Donnell, Christopher P.

    2010-01-01

    hypoxic-induced “neural injury.” We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae. PMID:20086074

  5. Mast cells: potential positive and negative roles in tumor biology.

    PubMed

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. PMID:24777963

  6. Heart Failure: Pathophysiology, Diagnosis, Medical Treatment Guidelines, and Nursing Management.

    PubMed

    Rogers, Chad; Bush, Nathania

    2015-12-01

    Heart failure (HF) is a debilitating chronic disease and is expected to increase in upcoming years due to demographic changes. Nurses in all settings have an essential role in supporting patients in managing this disease. This article describes the pathophysiology of HF, diagnosis, medical management, and nursing interventions. It is crucial for nurses to understand the pathophysiology of HF and the importance that nursing actions have on enhancing medical management to alleviate symptoms and to deter the advancement of the pathophysiologic state. Such an understanding can ultimately reduce morbidity and mortality and optimize quality of life in patients with HF. PMID:26596665

  7. Potential Roles of Fungal Extracellular Vesicles during Infection.

    PubMed

    Joffe, Luna S; Nimrichter, Leonardo; Rodrigues, Marcio L; Del Poeta, Maurizio

    2016-01-01

    Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Additionally, recent studies have demonstrated that fungal EVs stimulate the host immune system. In this review, putative roles of fungal EVs are discussed, including their potential as vaccination tools and their possible contribution to pathogenesis in invasive fungal diseases. PMID:27390779

  8. Potential Roles of Fungal Extracellular Vesicles during Infection

    PubMed Central

    Joffe, Luna S.; Nimrichter, Leonardo

    2016-01-01

    ABSTRACT Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Additionally, recent studies have demonstrated that fungal EVs stimulate the host immune system. In this review, putative roles of fungal EVs are discussed, including their potential as vaccination tools and their possible contribution to pathogenesis in invasive fungal diseases. PMID:27390779

  9. Conventional progesterone receptors (PR) B and PRA are expressed in human spermatozoa and may be involved in the pathophysiology of varicocoele: a role for progesterone in metabolism.

    PubMed

    De Amicis, F; Guido, C; Perrotta, I; Avena, P; Panza, S; Andò, S; Aquila, S

    2011-10-01

    The physiological roles of intracellular progesterone (PRG) receptors (PRs) have been studied intensively in female mammals, while their functions in male are scarce. Conventional PRs were evidenced in our study by Western blotting, concomitantly in healthy spermatozoa and in oligoasthenoteratozoospermic samples without and with varicocoele. Transmission electron microscopy revealed the presence of the PRs on the membrane as well as in the nucleus, mitochondria and flagellum. A reduced expression of the PRs was observed only in varicocoele spermatozoa. Responses to PRG treatment on cholesterol efflux, tyrosine phosphorylation, src and Akt activities, acrosin activity and acrosome reaction in varicocoele spermatozoa were reduced or absent. To further investigate PRG significance in human male gamete, we focused its action on lipid and glucose metabolism. The evaluation of the triglycerides content, lipase and acyl-CoA dehydrogenase activities suggests that PRG through the PRs exerts a lipolytic effect on human spermatozoa. An increase in glucose-6-phosphate dehydrogenase activity was also obtained, evidencing a role for PRG on glucose metabolism. In 'varicocoele' spermatozoa, the PRG did not induce energy consumption. The action of PRs on sperm metabolism is a novel finding that renews the importance of PRG in male fertility. Our results showed that varicocoele may lead to male factor infertility by a mechanism involving a decreased PR expression in human spermatozoa that evidences a detrimental effect on spermatozoa at the molecular level, going beyond the abnormal sperm morphology described to date. PMID:20946440

  10. Current and potential roles of ghrelin in clinical practice.

    PubMed

    Angelidis, G; Valotassiou, V; Georgoulias, P

    2010-12-01

    Ghrelin is a novel GH-releasing peptide, which has been identified as an endogenous ligand for GH-secretagogue receptor. Ghrelin is mainly secreted by the stomach and plays a critical role in a variety of physiological processes including endocrine, metabolic, cardiovascular, immunological, and other actions. Ghrelin stimulates food intake via hypothalamic neurons and causes a positive energy balance and body weight gain by decreasing fat utilization and promoting adiposity. Given the multiple effects of ghrelin, its potential clinical applications have been evaluated in various conditions. Preliminary trials have shown that it may prove valuable in the management of disease-induced cachexia. Ghrelin may improve the wasting syndrome through GH-dependent or GH-independent effects. Moreover, ghrelin may play a role in the management of disorders of gut motility and obesity. Finally, other potential clinical applications of ghrelin include the treatment of patients with diabetes mellitus, infections, rheumatological diseases or GH deficiency and the diagnosis of this hormonal disorder. PMID:21293171

  11. Realising their potential? Exploring interprofessional perceptions and potential of the advanced practitioner role: a qualitative analysis

    PubMed Central

    Powell, Tom; Watkins, Dianne; Kelly, Daniel

    2015-01-01

    Objectives To explore perceptions of the current practice and future potential of advanced practitioners (APs) from the perspectives of different professional groups in Wales UK. Design A qualitative study consisting of nine focus group interviews. Methods Initially verbatim transcriptions of each focus group interviews were analysed thematically before themes were merged to represent perceptions for the whole data set. Participants Data were gathered from a total of 67 stakeholders—including APs from a variety of professional groups (eg, nursing, physiotherapy, paramedics) as well as managers, workforce developers, educators and medical staff who have a role developing and supporting APs in practice. Results The results are presented in four themes: (1) demand, policy context and future priorities, (2) role clarity and standardisation, (3) agreement and understanding of the role and (4) interprofessional working. The context within which current and future AP roles were considered was influenced by inexorable demands for healthcare and the requirements to meet health policy priorities. Developing AP roles were hampered currently by a lack of shared understanding and ‘joined-up’ working between different groups such as medical practitioners, managers, commissioners and educators. Conclusions For the AP role to flourish more ‘joined-up’ thinking, support and development opportunities are required between APs, managers, senior clinicians, commissioners and educators. Working together to plan and deliver education, innovation and service delivery is of prime importance to meeting ever increasing complex health needs. This will ensure that future APs are adequately prepared and supported to reach their full potential and help deliver necessary innovations in current models of care delivery. PMID:26656024

  12. [Functional pathophysiology of consciousness].

    PubMed

    Jellinger, Kurt A

    2009-01-01

    from important somatic and sensory pathways and acts as a control system of neuronal activities of the cerebral cortex. The principal function of the ARAS is to focus our alertness on specific stimuli or internal processes, which run via complex neuronal cell groups and numerous neurotransmitters that influence various aspects of consciousness and wakefulness. Stimulation of the ARAS produces an arousal reaction as the electric correlate of consciousness; its destruction causes coma and related states. The highest level are cortical (prefrontal and association) networks for recognition, motor activity, longterm memory and attention, the left hemisphere being considered as the dominant one. Different levels of consciousness are distinguished: 1. hyperalertness, 2. alertness (normal state of wakefulness), 3. somnolence or lethargy, 4. obtundation with tendency to fall asleep, 5. stupor, 6. coma and its subtypes, like akinetic mutism, apallic syndrome or persistent vegative state, locked-in syndrome, delirium, and catatonia. They are caused by damages in various functional levels of the brain, by psychogenic factors or experimentally, and are accompanied by characteristic neurological and psychiatric disorders. The relevant morphological lesions can be detected by electrophysiological and imaging studies. The bases of functional anatomy and pathophysiology of consciousness, its cognitive aspects and its major disorders, their causes and functional substrates with reference to sleep and both spontaneous and iatrogenic disorders of consciousness are critically summarized. PMID:19573504

  13. Potential role of viruses in white plague coral disease

    PubMed Central

    Soffer, Nitzan; Brandt, Marilyn E; Correa, Adrienne MS; Smith, Tyler B; Thurber, Rebecca Vega

    2014-01-01

    White plague (WP)-like diseases of tropical corals are implicated in reef decline worldwide, although their etiological cause is generally unknown. Studies thus far have focused on bacterial or eukaryotic pathogens as the source of these diseases; no studies have examined the role of viruses. Using a combination of transmission electron microscopy (TEM) and 454 pyrosequencing, we compared 24 viral metagenomes generated from Montastraea annularis corals showing signs of WP-like disease and/or bleaching, control conspecific corals, and adjacent seawater. TEM was used for visual inspection of diseased coral tissue. No bacteria were visually identified within diseased coral tissues, but viral particles and sequence similarities to eukaryotic circular Rep-encoding single-stranded DNA viruses and their associated satellites (SCSDVs) were abundant in WP diseased tissues. In contrast, sequence similarities to SCSDVs were not found in any healthy coral tissues, suggesting SCSDVs might have a role in WP disease. Furthermore, Herpesviridae gene signatures dominated healthy tissues, corroborating reports that herpes-like viruses infect all corals. Nucleocytoplasmic large DNA virus (NCLDV) sequences, similar to those recently identified in cultures of Symbiodinium (the algal symbionts of corals), were most common in bleached corals. This finding further implicates that these NCLDV viruses may have a role in bleaching, as suggested in previous studies. This study determined that a specific group of viruses is associated with diseased Caribbean corals and highlights the potential for viral disease in regional coral reef decline. PMID:23949663

  14. Potential role of viruses in white plague coral disease.

    PubMed

    Soffer, Nitzan; Brandt, Marilyn E; Correa, Adrienne M S; Smith, Tyler B; Thurber, Rebecca Vega

    2014-02-01

    White plague (WP)-like diseases of tropical corals are implicated in reef decline worldwide, although their etiological cause is generally unknown. Studies thus far have focused on bacterial or eukaryotic pathogens as the source of these diseases; no studies have examined the role of viruses. Using a combination of transmission electron microscopy (TEM) and 454 pyrosequencing, we compared 24 viral metagenomes generated from Montastraea annularis corals showing signs of WP-like disease and/or bleaching, control conspecific corals, and adjacent seawater. TEM was used for visual inspection of diseased coral tissue. No bacteria were visually identified within diseased coral tissues, but viral particles and sequence similarities to eukaryotic circular Rep-encoding single-stranded DNA viruses and their associated satellites (SCSDVs) were abundant in WP diseased tissues. In contrast, sequence similarities to SCSDVs were not found in any healthy coral tissues, suggesting SCSDVs might have a role in WP disease. Furthermore, Herpesviridae gene signatures dominated healthy tissues, corroborating reports that herpes-like viruses infect all corals. Nucleocytoplasmic large DNA virus (NCLDV) sequences, similar to those recently identified in cultures of Symbiodinium (the algal symbionts of corals), were most common in bleached corals. This finding further implicates that these NCLDV viruses may have a role in bleaching, as suggested in previous studies. This study determined that a specific group of viruses is associated with diseased Caribbean corals and highlights the potential for viral disease in regional coral reef decline. PMID:23949663

  15. Bacteriophage and their potential roles in the human oral cavity

    PubMed Central

    Edlund, Anna; Santiago-Rodriguez, Tasha M.; Boehm, Tobias K.; Pride, David T.

    2015-01-01

    The human oral cavity provides the perfect portal of entry for viruses and bacteria in the environment to access new hosts. Hence, the oral cavity is one of the most densely populated habitats of the human body containing some 6 billion bacteria and potentially 35 times that many viruses. The role of these viral communities remains unclear; however, many are bacteriophage that may have active roles in shaping the ecology of oral bacterial communities. Other implications for the presence of such vast oral phage communities include accelerating the molecular diversity of their bacterial hosts as both host and phage mutate to gain evolutionary advantages. Additional roles include the acquisitions of new gene functions through lysogenic conversions that may provide selective advantages to host bacteria in response to antibiotics or other types of disturbances, and protection of the human host from invading pathogens by binding to and preventing pathogens from crossing oral mucosal barriers. Recent evidence suggests that phage may be more involved in periodontal diseases than were previously thought, as their compositions in the subgingival crevice in moderate to severe periodontitis are known to be significantly altered. However, it is unclear to what extent they contribute to dysbiosis or the transition of the microbial community into a state promoting oral disease. Bacteriophage communities are distinct in saliva compared to sub- and supragingival areas, suggesting that different oral biogeographic niches have unique phage ecology shaping their bacterial biota. In this review, we summarize what is known about phage communities in the oral cavity, the possible contributions of phage in shaping oral bacterial ecology, and the risks to public health oral phage may pose through their potential to spread antibiotic resistance gene functions to close contacts. PMID:25861745

  16. Bacteriophage and their potential roles in the human oral cavity.

    PubMed

    Edlund, Anna; Santiago-Rodriguez, Tasha M; Boehm, Tobias K; Pride, David T

    2015-01-01

    The human oral cavity provides the perfect portal of entry for viruses and bacteria in the environment to access new hosts. Hence, the oral cavity is one of the most densely populated habitats of the human body containing some 6 billion bacteria and potentially 35 times that many viruses. The role of these viral communities remains unclear; however, many are bacteriophage that may have active roles in shaping the ecology of oral bacterial communities. Other implications for the presence of such vast oral phage communities include accelerating the molecular diversity of their bacterial hosts as both host and phage mutate to gain evolutionary advantages. Additional roles include the acquisitions of new gene functions through lysogenic conversions that may provide selective advantages to host bacteria in response to antibiotics or other types of disturbances, and protection of the human host from invading pathogens by binding to and preventing pathogens from crossing oral mucosal barriers. Recent evidence suggests that phage may be more involved in periodontal diseases than were previously thought, as their compositions in the subgingival crevice in moderate to severe periodontitis are known to be significantly altered. However, it is unclear to what extent they contribute to dysbiosis or the transition of the microbial community into a state promoting oral disease. Bacteriophage communities are distinct in saliva compared to sub- and supragingival areas, suggesting that different oral biogeographic niches have unique phage ecology shaping their bacterial biota. In this review, we summarize what is known about phage communities in the oral cavity, the possible contributions of phage in shaping oral bacterial ecology, and the risks to public health oral phage may pose through their potential to spread antibiotic resistance gene functions to close contacts. PMID:25861745

  17. On the potential role of SSS observations on ENSO prediction

    NASA Astrophysics Data System (ADS)

    Ballabrera, J.; Murtugudde, R.; Busalacchi, A. J.

    2003-04-01

    Multiple regression analysis is used here to construct statistical prediction models for the El Niño/Southern Oscillation (ENSO) to explore the potential impact of monitoring Pacific Ocean sea surface salinity (SSS) on prediction of equatorial Pacific sea surface temperature. This study, one of the first focusing on the direct role of SSS in ENSO predictions, is motivated by proposed missions for remote sensing of SSS. A forward stepwise method is used to extract significant predictors of the Niño-3 sea surface temperature (SST) index from observed monthly anomalies of tropical SST, SSS, sea level, freshwater flux, and components of the wind stress. The results indicate that sea surface salinity monitoring would have small impact on the statistical nowcast (reconstruction) of ENSO, but a potential role in the 6-12 month forecasts. Correlation maps show two regions of high correlation: an equatorial region (between 170E-160W), and an off-equatorial region (between 170E-140W and 5S-20S). Short lag correlations display the negative relationship between the warm phase of ENSO with negative equatorial SSS anomalies related with the increase of local rainfall. Such an equatorial negative correlation coexists with an area of positive correlations off-the equator. The region with positive correlations moves eastward as the lag increases, reaching the geographical limit of the SSS observations at six months lag. The region of negative correlation moves northward and becomes weaker as the lag increases (it is non-significant for 9-months lag). For lags longer than 9 months, significant positive correlations are found south of the equator (5S-10S). At these lags, positive salinity anomalies have the potential to modify the subsurface stratification of the western Pacific as they are subducted westward. Thus, the availability of continuous remotely sensed SSS data might add considerably to ENSO predictions at longer lead-time, as a result of SSS induced changes in the

  18. The role of d-dimer as first marker of thrombophilia in women affected by sterility: implications in pathophysiology and diagnosis of thrombophilia induced sterility

    PubMed Central

    Di Micco, Pierpaolo; D'Uva, Maristella; Strina, Ida; Mollo, Antonio; Amato, Valeria; Niglio, Alferio; De Placido, Giuseppe

    2004-01-01

    Background D-dimer is considered a marker of hypercoagulable state and of endogenous fibrinolysis, so increased d-dimer is detectable in patients affected by thrombosis. Yet, several studies showed that also infertility, in particular secondary infertility due to recurrent fetal losses, has been often related to thrombotic events, in particular in women carrying thrombotic risk factors such as inherited thrombophilia (MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms and/or inhAfter this screening we selected 39erited protein C, protein S, AT III deficiency) or acquired thrombophilia (primary antiphospholipid syndrome, acquired protein C, protein S, AT III deficiency, drugs induced thrombophilia). However, because its high predictive negative value in case of suspected thrombosis, increased d-dimer has been often associated to subclinical thrombophilia. The aim of this study is to investigate the role of d-dimer as first marker of thrombophilia in women affected by unexplained infertility and subsequently to search the cause of increased d-dimer, such as inherited and/or acquired thrombophilia. Patients and Methods We selected 79 patients with unexplained primary or secondary infertility. We excluded 40 patients affected by hydrosalpinx, uterine fibroids, uterine malformations, endocrinological and immunological diseases, luteal insufficiency, cytogenetical alterations. All remaining 39 patients were tested for d-dimer and divided in two groups: the patients of group A (25 patients) showed increased plasma d-dimer, in group B were included 14 patients with normal plasma level of d-dimer. After this step all 39 patients were screened for MTHFRC677T, PTHRA20210G, Factor V Leiden polimorphisms, protein C, protein S, AT III, anticardiolipin IgM and IgG, lupus anticoagulant. In the control group were included 15 age matched women without sterility problems referred to our outpatient's section of vascular medicine for suspected deep venous thrombosis. Statistical

  19. Ceramide Signaling and Metabolism in Pathophysiological States of the Lung.

    PubMed

    Petrache, Irina; Berdyshev, Evgeny V

    2016-01-01

    Following the discovery of ceramide as the central signaling and metabolic relay among sphingolipids, studies of its involvement in lung health and pathophysiology have exponentially increased. In this review, we highlight key studies in the context of recent progress in metabolomics and translational research methodologies. Evidence points toward an important role for the ceramide/sphingosine-1-phosphate rheostat in maintaining lung cell survival, vascular barrier function, and proper host response to airway microbial infections. Sphingosine kinase 1 has emerged as an important determinant of sphingosine-1-phosphate lung levels, which, when aberrantly high, contribute to lung fibrosis, maladaptive vascular remodeling, and allergic asthma. New sphingolipid metabolites have been discovered as potential biomarkers of several lung diseases. Although multiple acute and chronic lung pathological conditions involve perturbations in sphingolipid signaling and metabolism, there are specific patterns, unique sphingolipid species, enzymes, metabolites, and receptors, which have emerged that deepen our understanding of lung pathophysiology and inform the development of new therapies for lung diseases. PMID:26667073

  20. Jaundice associated pruritis: a review of pathophysiology and treatment.

    PubMed

    Bassari, Ramez; Koea, Jonathan B

    2015-02-01

    To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective. PMID:25663760

  1. Jaundice associated pruritis: A review of pathophysiology and treatment

    PubMed Central

    Bassari, Ramez; Koea, Jonathan B

    2015-01-01

    To review the underlying pathophysiology and currently available treatments for pruritis associated with jaundice. English language literature was reviewed using MEDLINE, PubMed, EMBASE and clinicaltrials.gov for papers and trails addressing the pathophysiology and potential treatments for pruritis associated with jaundice. Recent advances in the understanding of the peripheral anatomy of itch transmission have defined a histamine stimulated pathway and a cowhage stimulated pathway with sensation conveyed centrally via the contralateral spinothalamic tract. Centrally, cowhage and histamine stimulated neurons terminate widely within the thalamus and sensorimotor cortex. The causative factors for itch in jaundice have not been clarified although endogenous opioids, serotonin, steroid and lysophosphatidic acid all play a role. Current guidelines for the treatment of itching in jaundice recommend initial management with biliary drainage where possible and medical management with ursodeoxycholic acid, followed by cholestyramine, rifampicin, naltrexone and sertraline. Other than biliary drainage no single treatment has proved universally effective. Pruritis associated with jaundice is a common but poorly understood condition for which biliary drainage is the most effective therapy. Pharmacological therapy has advanced but remains variably effective. PMID:25663760

  2. Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock.

    PubMed

    Essani, N A; Fisher, M A; Simmons, C A; Hoover, J L; Farhood, A; Jaeschke, H

    1998-03-01

    We studied the role of P-selectin, an adhesion molecule known to be important for neutrophil localization to sites of inflammation, in a model of inflammatory liver injury. Male C3Heb/FeJ (ET-sensitive) mice treated with 700 mg/kg galactosamine and 100 microg/kg Salmonella abortus equi endotoxin (Gal/ET), murine tumor necrosis factor alpha (TNF-alpha, 15 microg/kg), or interleukin-1 (IL-1, 13-23 microg/kg), showed increased P-selectin mRNA levels in the liver. In contrast, C3H/HeJ (ET-resistant) mice responded only to cytokines with P-selectin mRNA formation. Whereas no P-selectin expression was detectable in control livers, there was temporary staining of endothelium in large blood vessels but not in sinusoids between 3 and 5 h after ET, TNF-alpha, or IL-1 treatment. Severe liver injury induced by Gal/ET at 7 h was not inhibited by an anti-P-selectin antibody in C3Heb/FeJ mice or in P-selectin-deficient animals. Sequestration of neutrophils in sinusoids, i.e. those neutrophils that have been identified as critical for the injury, was not affected by the antibody or in P-selectin-deficient mice. However, the temporary margination in portal and post-sinusoidal venules was reduced by 75% in anti-P-selectin antibody-treated animals and by 51% in P-selectin-deficient mice. We conclude that hepatic P-selectin gene transcription in vivo involves cytokines. However, blocking P-selectin neither attenuated sinusoidal neutrophil sequestration nor prevented neutrophil-induced liver injury during endotoxin shock but attenuated neutrophil margination in larger vessels. Thus, our data demonstrate similarities and fundamental differences in the requirement for adhesion molecules to localize neutrophils in the liver vasculature compared to other organs during an inflammatory response. PMID:9500515

  3. Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.

    PubMed

    Yin, Jun; Michalick, Laura; Tang, Christine; Tabuchi, Arata; Goldenberg, Neil; Dan, Qinghong; Awwad, Khader; Wang, Liming; Erfinanda, Lasti; Nouailles, Geraldine; Witzenrath, Martin; Vogelzang, Alexis; Lv, Lu; Lee, Warren L; Zhang, Haibo; Rotstein, Ori; Kapus, Andras; Szaszi, Katalin; Fleming, Ingrid; Liedtke, Wolfgang B; Kuppe, Hermann; Kuebler, Wolfgang M

    2016-03-01

    The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI. PMID:26222277

  4. Potential Role of Atomic Force Microscopy in Systems Biology

    PubMed Central

    Ramachandran, Srinivasan; Arce, Fernando Teran; Lal, Ratnesh

    2011-01-01

    Systems biology is a quantitative approach for understanding a biological system at its global level through systematic perturbation and integrated analysis of all its components. Simultaneous acquisition of information datasets pertaining to the system components (e.g., genome, proteome) is essential to implement this approach. There are limitations to such an approach in measuring gene expression levels and accounting for all proteins in the system. The success of genomic studies is critically dependent on PCR for its amplification, but PCR is very uneven in amplifying the samples, ineffective in scarce samples and unreliable in low copy number transcripts. On the other hand, lack of amplifying techniques for proteins critically limits their identification to only a small fraction of high concentration proteins. Atomic force microscopy (AFM), AFM cantilever sensors and AFM force spectroscopy in particular, could address these issues directly. In this article, we reviewed and assessed their potential role in systems biology. PMID:21766465

  5. Potential role of NADPH oxidase in pathogenesis of pancreatitis

    PubMed Central

    Cao, Wei-Li; Xiang, Xiao-Hui; Chen, Kai; Xu, Wei; Xia, Shi-Hai

    2014-01-01

    Studies have demonstrated that reactive oxygen species (ROS) are closely related to inflammatory disorders. Nicotinamide adenine dinucleotide phosphate oxidase (NOX), originally found in phagocytes, is the main source of ROS in nonphagocytic cells. Besides directly producing the detrimental highly reactive ROS to act on biomolecules (lipids, proteins, and nucleic acids), NOX can also activate multiple signal transduction pathways, which regulate cell growth, proliferation, differentiation and apoptosis by producing ROS. Recently, research on pancreatic NOX is no longer limited to inflammatory cells, but extends to the aspect of pancreatic acinar cells and pancreatic stellate cells, which are considered to be potentially associated with pancreatitis. In this review, we summarize the literature on NOX protein structure, activation, function and its role in the pathogenesis of pancreatitis. PMID:25133019

  6. Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review

    PubMed Central

    Rom, Slava; Persidsky, Yuri

    2013-01-01

    An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer’s disease to name a few), mainly mediated by CB2 activation. Development of CB2 agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB2 activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection. PMID:23471521

  7. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation.

    PubMed

    Rom, Slava; Persidsky, Yuri

    2013-06-01

    An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB(1), CB(2)) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB(2) activation. Development of CB(2) agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB(2) activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection. PMID:23471521

  8. Potential Roles for New Communication Technologies in Treatment of Addiction

    PubMed Central

    Johnson, Kimberly; Isham, Andrew; Shah, Dhavan V.; Gustafson, David H.

    2011-01-01

    Information and communication technologies offer clinicians the opportunity to work with patients to manage chronic conditions, including addiction. The early research on the efficacy of electronic treatment and support tools is promising. Sensors have recently received increased attention as key components of electronic treatment and recovery management systems. Although results of the research are very promising, concerns at the clinical and policy level must be addressed before widespread adoption of these technologies can become practical. First, clinicians must adapt their practices to incorporate a continuing flow of patient information. Second, payment and regulatory systems must make adjustments far beyond what telemedicine and electronic medical records have required. This paper examines potential roles of information and communication technologies as well as process and regulatory challenges. PMID:21739171

  9. Potential role of atomic force microscopy in systems biology.

    PubMed

    Ramachandran, Srinivasan; Teran Arce, Fernando; Lal, Ratnesh

    2011-01-01

    Systems biology is a quantitative approach for understanding a biological system at its global level through systematic perturbation and integrated analysis of all its components. Simultaneous acquisition of information data sets pertaining to the system components (e.g., genome, proteome) is essential to implement this approach. There are limitations to such an approach in measuring gene expression levels and accounting for all proteins in the system. The success of genomic studies is critically dependent on polymerase chain reaction (PCR) for its amplification, but PCR is very uneven in amplifying the samples, ineffective in scarce samples and unreliable in low copy number transcripts. On the other hand, lack of amplifying techniques for proteins critically limits their identification to only a small fraction of high concentration proteins. Atomic force microscopy (AFM), AFM cantilever sensors, and AFM force spectroscopy in particular, could address these issues directly. In this article, we reviewed and assessed their potential role in systems biology. PMID:21766465

  10. Elobixibat and its potential role in chronic idiopathic constipation

    PubMed Central

    Acosta, Andres

    2014-01-01

    Chronic idiopathic constipation is highly prevalent among adults. Bile acids (BAs) and the enterohepatic BA circulation modulate colonic secretion and motility that affect transit. BAs in the colon have a dual action as osmotic and stimulant agents. Newer agents, such as elobixibat (A3309), an inhibitor of the ileal BA transporter, have the potential to improve significantly the management of chronic constipation, with minimal adverse effects. Elobixibat modulates the enterohepatic BA circulation, enhancing the delivery of BAs to the colon where they induce secretory and motor effects. Secondary effects of the inhibition of BA absorption are reduced activation of the farnesoid X receptor, decreased secretion of fibroblast growth factor-19 into the portal circulation, and increased BA synthesis. This review focuses on the role of BAs, the enterohepatic BA circulation, and an ileal BA transporter inhibitor (elobixibat) in chronic constipation. PMID:25057297

  11. Current pathophysiological concepts in cerebral small vessel disease

    PubMed Central

    Rincon, Fred; Wright, Clinton B.

    2014-01-01

    The association between cerebral small vessel disease (SVD) – in the form of white matter lesions, infarctions, and hemorrhages – with vascular cognitive impairment (VCI), has mostly been deduced from observational studies. Pathological conditions affecting the small vessels of the brain and leading to SVD have suggested plausible molecular mechanisms involved in vascular damage and their impact on brain function. However, much still needs to be clarified in understanding the pathophysiology of VCI, the role of neurodegenerative processes such as Alzheimer’s disease, and the impact of aging itself. In addition, both genetic predispositions and environmental exposures may potentiate the development of SVD and interact with normal aging to impact cognitive function and require further study. Advances in technology, in the analysis of genetic and epigenetic data, neuroimaging such as magnetic resonance imaging, and new biomarkers will help to clarify the complex factors leading to SVD and the expression of VCI. PMID:24715862

  12. Mitochondrial dysfunction in bipolar disorder: Evidence, pathophysiology and translational implications.

    PubMed

    Scaini, Giselli; Rezin, Gislaine T; Carvalho, Andre F; Streck, Emilio L; Berk, Michael; Quevedo, João

    2016-09-01

    Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD. PMID:27377693

  13. Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management

    PubMed Central

    Mollan, Susan P; Ali, Fizzah; Hassan-Smith, Ghaniah; Botfield, Hannah; Friedman, Deborah I; Sinclair, Alexandra J

    2016-01-01

    Idiopathic intracranial hypertension (IIH) is a rare but important disease associated with significant morbidity. There is an expected rise in prevalence in line with the escalating global burden of obesity. Modern revisions in the terminology and diagnostic criteria for IIH help guide clinicians in investigations and researchers in standardising recruitment criteria for clinical trials. The pathophysiology of IIH is incompletely characterised; suggested underpinning mechanisms include the role of cerebrospinal fluid regulation as well as metabolic and endocrinological perspectives. Recent treatment trials are providing insights into the management but debate still surrounds key areas in treatment. This review will provide an up-to-date discussion on the potential pathogenic mechanisms and management of IIH. PMID:26888960

  14. Potential role of folate in pre-eclampsia.

    PubMed

    Singh, Mansi Dass; Thomas, Philip; Owens, Julie; Hague, William; Fenech, Michael

    2015-10-01

    Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review was to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia. PMID:26359215

  15. Potential Role of Activating Transcription Factor 5 during Osteogenesis.

    PubMed

    Vicari, Luisa; Calabrese, Giovanna; Forte, Stefano; Giuffrida, Raffaella; Colarossi, Cristina; Parrinello, Nunziatina Laura; Memeo, Lorenzo

    2016-01-01

    Human adipose-derived stem cells are an abundant population of stem cells readily isolated from human adipose tissue that can differentiate into connective tissue lineages including bone, cartilage, fat, and muscle. Activating transcription factor 5 is a transcription factor of the ATF/cAMP response element-binding protein (CREB) family. It is transcribed in two types of mRNAs (activating transcription factor 5 isoform 1 and activating transcription factor 5 isoform 2), encoding the same single 30-kDa protein. Although it is well demonstrated that it regulates the proliferation, differentiation, and apoptosis, little is known about its potential role in osteogenic differentiation. The aim of this study was to evaluate the expression levels of the two isoforms and protein during osteogenic differentiation of human adipose-derived stem cells. Our data indicate that activating transcription factor 5 is differentially expressed reaching a peak of expression at the stage of bone mineralization. These findings suggest that activating transcription factor 5 could play an interesting regulatory role during osteogenesis, which would provide a powerful tool to study bone physiology. PMID:26770207

  16. Potential role of Thiobacillus caldus in arsenopyrite bioleaching

    SciTech Connect

    Dopson, M.; Lindstroem, E.B.

    1999-01-01

    The authors investigated the potential role of the three strains of Thiobacillus caldus (KU, BC13, and C-SH12) in arsenopyrite leaching in combination with a moderately thermophilic iron oxidizer, Sulfobacillus thermosulfidooxidans. Pure cultures of T. caldus and S. thermosulfidooxidans were used as well as defined mixed cultures. By measuring released iron, tetrathionate, and sulfur concentrations, the authors found that the presence of T. caldus KU and BC13 in the defined mixed culture lowered the concentration of sulfur, and levels of tetrathionate were comparable to or lower than those in the presence of S. thermosulfidooxidans. This suggests that T. caldus grows on the sulfur compounds that build up during leaching, increasing the arsenopyrite-leaching efficiency. This result was similar to leaching arsenopyrite with a pure culture of S. thermosulfidooxidans in the presence of yeast extract. Therefore, three possible roles of T. caldus in the leaching environment can be hypothesized: to remove the buildup of solid sulfur that can cause an inhibitory layer on the surface of the mineral, to aid heterotrophic and mixotrophic growth by the release of organic chemicals, and to solubilize solid sulfur by the production of surface-active agents. The results showed that T. caldus KU was the most efficient at leaching arsenopyrite under the conditions tested, followed by BC13, and finally C-SH12.

  17. Potential Roles of BMP9 in Liver Fibrosis

    PubMed Central

    Bi, Jianjun; Ge, Shengfang

    2014-01-01

    Liver fibrosis is a common phenomenon that is associated with several pathologies and is characterized by excessive extracellular matrix deposition that leads to progressive liver dysfunction. Bone morphogenetic protein 9 (BMP9) is the most recently discovered member of the BMP family. BMP9 bound with high affinity to activin receptor-like kinase 1 (ALK1) and endoglin in non-parenchymal liver cells. In addition, BMP9 activated Smad1/Smad5/Smad8 and induced the expression of the target genes inhibitor of differentiation 1 (Id1), hepcidin, Snail and the co-receptor endoglin in liver cells. Although the role of BMP9 in liver fibrosis is currently poorly understood, the presence of BMP9-activated proteins and its target genes have been reported to be associated with liver fibrosis development. This review summarizes the indirect connection between BMP9 and liver fibrosis, with a focus on the BMP9 signaling pathway members ALK1, endoglin, Id1, hepcidin and Snail. The observations on the role of BMP9 in regulating liver fibrosis may help in understanding the pathology mechanisms of liver disease. Furthermore, BMP9 could be served as a potent biomarker and the target of potential therapeutic drugs to treat hepatocytes fibrosis. PMID:25393508

  18. Expression Patterns and Potential Biological Roles of Dip2a

    PubMed Central

    Palange, Norberto J.; Jia, Ruirui; Ma, Jun; Bah, Fatoumata Binta; Sah, Rajiv Kumar; Li, Dan; Wang, Daji; Bah, Fatoumata Binta Maci; Togo, Jacques; Jin, Honghong; Ban, Luying; Feng, Xuechao; Zheng, Yaowu

    2015-01-01

    Disconnected (disco)-interacting protein 2 homolog A is a member of the DIP2 protein family encoded by Dip2a gene. Dip2a expression pattern has never been systematically studied. Functions of Dip2a in embryonic development and adult are not known. To investigate Dip2a gene expression and function in embryo and adult, a Dip2a-LacZ mouse model was generated by insertion of β-Gal cDNA after Dip2a promoter using CRISPR/Cas9 technology. Dip2a-LacZ mouse was designed to be a lacZ reporter mouse as well as a Dip2a knockout mouse. Heterozygous mice were used to study endogenous Dip2a expression and homozygotes to study DIP2A-associated structure and function. LacZ staining indicated that Dip2a is broadly expressed in neuronal, reproductive and vascular tissues, as well as in heart, kidney, liver and lung. Results demonstrate that Dip2a is expressed in ectoderm-derived tissues in developing embryos. Adult tissues showed rich staining in neurons, mesenchymal, endothelial, smooth muscle cells and cardiomyocytes by cell types. The expression pattern highly overlaps with FSTL1 and supports previous report that DIP2A to be potential receptor of FSTL1 and its protective roles of cardiomyocytes. Broad and intense embryonic and adult expression of Dip2a has implied their multiple structural and physiological roles. PMID:26605542

  19. Expression Patterns and Potential Biological Roles of Dip2a.

    PubMed

    Zhang, Luqing; Mabwi, Humphrey A; Palange, Norberto J; Jia, Ruirui; Ma, Jun; Bah, Fatoumata Binta; Sah, Rajiv Kumar; Li, Dan; Wang, Daji; Bah, Fatoumata Binta Maci; Togo, Jacques; Jin, Honghong; Ban, Luying; Feng, Xuechao; Zheng, Yaowu

    2015-01-01

    Disconnected (disco)-interacting protein 2 homolog A is a member of the DIP2 protein family encoded by Dip2a gene. Dip2a expression pattern has never been systematically studied. Functions of Dip2a in embryonic development and adult are not known. To investigate Dip2a gene expression and function in embryo and adult, a Dip2a-LacZ mouse model was generated by insertion of β-Gal cDNA after Dip2a promoter using CRISPR/Cas9 technology. Dip2a-LacZ mouse was designed to be a lacZ reporter mouse as well as a Dip2a knockout mouse. Heterozygous mice were used to study endogenous Dip2a expression and homozygotes to study DIP2A-associated structure and function. LacZ staining indicated that Dip2a is broadly expressed in neuronal, reproductive and vascular tissues, as well as in heart, kidney, liver and lung. Results demonstrate that Dip2a is expressed in ectoderm-derived tissues in developing embryos. Adult tissues showed rich staining in neurons, mesenchymal, endothelial, smooth muscle cells and cardiomyocytes by cell types. The expression pattern highly overlaps with FSTL1 and supports previous report that DIP2A to be potential receptor of FSTL1 and its protective roles of cardiomyocytes. Broad and intense embryonic and adult expression of Dip2a has implied their multiple structural and physiological roles. PMID:26605542

  20. OCT monitoring of pathophysiological processes

    NASA Astrophysics Data System (ADS)

    Gladkova, Natalia D.; Shakhova, Natalia M.; Shakhov, Andrei; Petrova, Galina P.; Zagainova, Elena; Snopova, Ludmila; Kuznetzova, Irina N.; Chumakov, Yuri; Feldchtein, Felix I.; Gelikonov, Valentin M.; Gelikonov, Grigory V.; Kamensky, Vladislav A.; Kuranov, Roman V.; Sergeev, Alexander M.

    1999-04-01

    Based on results of clinical examination of about 200 patients we discuss capabilities of the optical coherence tomography (OCT) in monitoring and diagnosing of various pathophysiological processes. Performed in several clinical areas including dermatology, urology, laryngology, gynecology, and dentistry, our study shows the existence of common optical features in manifestation of a pathophysiological process in different organs. In this paper we focus at such universal tomographic optical signs for processes of inflammation, necrosis and tumor growth. We also present data on dynamical OCT monitoring of evolution of pathophysiological processes, both at the stage of disease development and following-up results of different treatments such as drug application, radiation therapy, cryodestruction, and laser vaporization. The discovered peculiarities of OCT images for structural and functional imaging of biological tissues can be put as a basis for application of this method for diagnosing of pathology, guidance of treatment, estimation of its adequacy and assessing of the healing process.

  1. A Potential Role for smallsats and Cubesats in Lunar Exploration

    NASA Astrophysics Data System (ADS)

    Carpenter, James; Fisackerly, Richard; Houdou, Bérengère; De Rosa, Diego; Schiemann, Jens D.; Walker, Roger; Zeppenfeldt, Frank

    2015-04-01

    The Moon is an important exploration destination for ESA, which is currently engaged in activities to access and exploit the Moon through developments in future human exploration systems and precursor robotic surface missions. However, recent major advancements in Smallsat and Cubesat technologies, and their application to fields such as Earth imaging and atmospheric science, has opened the possibility of utilising these smaller, lower cost platforms beyond LEO and potentially at the Moon. ESA is interested in understanding how emerging Smallsat & Cubesat instrument and platform technology could be applied to Lunar Exploration, particularly in the fields of technology demonstration and investigations which can be precursors to longer term l exploration activies. Lunar Cubesats can offer an means of access to the Moon, which complements larger ESA-led opportunities on international surface missions and via future human exploration systems. In this talk ESA will outline its current objectives in Lunar Exploration and highlight potential future opportunities for Smallsat and Cubesat platforms to play a role.

  2. Porifera Lectins: Diversity, Physiological Roles and Biotechnological Potential

    PubMed Central

    Gardères, Johan; Bourguet-Kondracki, Marie-Lise; Hamer, Bojan; Batel, Renato; Schröder, Heinz C.; Müller, Werner E. G.

    2015-01-01

    An overview on the diversity of 39 lectins from the phylum Porifera is presented, including 38 lectins, which were identified from the class of demosponges, and one lectin from the class of hexactinellida. Their purification from crude extracts was mainly performed by using affinity chromatography and gel filtration techniques. Other protocols were also developed in order to collect and study sponge lectins, including screening of sponge genomes and expression in heterologous bacterial systems. The characterization of the lectins was performed by Edman degradation or mass spectrometry. Regarding their physiological roles, sponge lectins showed to be involved in morphogenesis and cell interaction, biomineralization and spiculogenesis, as well as host defense mechanisms and potentially in the association between the sponge and its microorganisms. In addition, these lectins exhibited a broad range of bioactivities, including modulation of inflammatory response, antimicrobial and cytotoxic activities, as well as anticancer and neuromodulatory activity. In view of their potential pharmacological applications, sponge lectins constitute promising molecules of biotechnological interest. PMID:26262628

  3. Porifera Lectins: Diversity, Physiological Roles and Biotechnological Potential.

    PubMed

    Gardères, Johan; Bourguet-Kondracki, Marie-Lise; Hamer, Bojan; Batel, Renato; Schröder, Heinz C; Müller, Werner E G

    2015-08-01

    An overview on the diversity of 39 lectins from the phylum Porifera is presented, including 38 lectins, which were identified from the class of demosponges, and one lectin from the class of hexactinellida. Their purification from crude extracts was mainly performed by using affinity chromatography and gel filtration techniques. Other protocols were also developed in order to collect and study sponge lectins, including screening of sponge genomes and expression in heterologous bacterial systems. The characterization of the lectins was performed by Edman degradation or mass spectrometry. Regarding their physiological roles, sponge lectins showed to be involved in morphogenesis and cell interaction, biomineralization and spiculogenesis, as well as host defense mechanisms and potentially in the association between the sponge and its microorganisms. In addition, these lectins exhibited a broad range of bioactivities, including modulation of inflammatory response, antimicrobial and cytotoxic activities, as well as anticancer and neuromodulatory activity. In view of their potential pharmacological applications, sponge lectins constitute promising molecules of biotechnological interest. PMID:26262628

  4. Pathophysiology of carpal tunnel syndrome

    PubMed Central

    Aboonq, Moutasem S.

    2015-01-01

    Carpal tunnel syndrome (CTS) is the most common median nerve neuropathy, accounting for 90% of all neuropathies. Carpal tunnel syndrome presents in 3.8% of the general population, with a higher prevalence among women. There are several risk factors associated with CTS, including both medical and non medical factors. The pathophysiologic mechanisms involved in the median nerve compression and traction are thought to be complex, and as yet are not fully understood. The present review aimed to provide an overview of the pathophysiology of median nerve neuropathy in the carpal tunnel, and subsequent development of CTS. PMID:25630774

  5. Pathophysiology of glaucoma in uveitis.

    PubMed

    Ritch, R

    1981-09-01

    Glaucoma secondary to uveitis may occur by any one or by a combination of several different pathophysiological mechanisms. These include acute angle-closure due to iris bombé caused by posterior synechiae; chronic angle-closure due to peripheral anterior synechiae; and open angle glaucoma due to obstruction and/or inflammation of the trabecular meshwork. Secretory hypotony may mask impairment of outflow, while steroids used to treat the uveitis may further complicate the situation by causing a rise in intraocular pressure. Careful delineation of the pathophysiology involved is the cornerstone of successful management. PMID:6963820

  6. Pathophysiology of Atherosclerotic Plaque Development.

    PubMed

    Rognoni, Andrea; Cavallino, Chiara; Veia, Alessia; Bacchini, Sara; Rosso, Roberta; Facchini, Manuela; Secco, Gioel G; Lupi, Alessandro; Nardi, Federico; Rametta, Francesco; Bongo, Angelo S

    2015-01-01

    Cardiovascular diseases and in particular coronary atherosclerotic disease are the leading cause of mortality and morbidity in the industrialized countries. Coronary atherosclerosis has been recognized for over a century and it was the subject of various studies. Pathophysiological studies have unravelled the interactions of molecular and cellular elements involved in atherogenesis; during the last decades the basic research has focused on the study of the instability of atherosclerotic plaque. Plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes including ST - segment elevation myocardial infarction and non ST - segment elevation myocardial infarction. This is a brief review of the pathophysiology of atherosclerotic plaque development. PMID:25544119

  7. Coagulation disorders and their cutaneous presentations: Pathophysiology.

    PubMed

    Chang, Yunyoung; Dabiri, Ganary; Damstetter, Elizabeth; Baiyee Ebot, Emily; Powers, Jennifer Gloeckner; Phillips, Tania

    2016-05-01

    Hypercoagulable states are inherited or acquired predispositions to venous or arterial thromboses that are best understood in the context of the coagulation cascade. Dermatologists can play a critical role in diagnosing and treating patients with hypercoagulable states because cutaneous symptoms may be a presenting manifestation, thereby reducing morbidity and mortality related to these conditions. This review focuses on the epidemiology and pathophysiology of hypercoagulable states, while the accompanying article iterates the basic clinical features, diagnostic testing, and management of patients who have these conditions. PMID:27085225

  8. Diagnosis, pathophysiology, and treatment of photophobia.

    PubMed

    Katz, Bradley J; Digre, Kathleen B

    2016-01-01

    Photophobia, an abnormal intolerance to light, is associated with a number of ophthalmic and neurologic conditions. In the presence of normal neurologic and ophthalmologic examinations, the most common conditions associated with photophobia are migraine, blepharospasm, and traumatic brain injury. Recent evidence indicates that the intrinsically photosensitive retinal ganglion cells play a key role in the pathophysiology of photophobia. Although pharmacologic manipulation of intrinsically photosensitive retinal ganglion cells and the neural pathways that mediate photophobia may be possible in the future, current therapies are directed at the underlying cause of the photophobia and optical modulation of these cells and pathways. PMID:26875996

  9. Pathophysiology of anthracycline cardiotoxicity.

    PubMed

    Mele, Donato; Tocchetti, Carlo G; Pagliaro, Pasquale; Madonna, Rosalinda; Novo, Giuseppina; Pepe, Alessia; Zito, Concetta; Maurea, Nicola; Spallarossa, Paolo

    2016-05-01

    Anthracyclines (ANTs) are powerful drugs that have reduced the mortality of cancer patients. However, their use is limited by the development of cardiotoxicity (CTX), which is dose dependent and may lead to left ventricular dysfunction and heart failure. Although various strategies have been suggested to reduce the negative effects of ANTs, CTX is still an important unresolved clinical issue. This may be due at least partly to the incomplete characterization of the molecular and cellular mechanisms of ANT-induced CTX. In addition, although various forms of cardiac damage have been demonstrated with the use of these drugs in experimental studies, it is not yet clear how these translate to the clinical setting. Appropriate characterization of potential candidates for ANT-based therapies is essential to decide whether to administer these drugs. Hopefully, new information from genetic profiling will help to identify patients who are at high risk of developing CTX. PMID:27183523

  10. Alcoholic cardiomyopathy: Pathophysiologic insights

    PubMed Central

    Piano, Mariann R.; Phillips, Shane A.

    2014-01-01

    Alcoholic cardiomyopathy is a specific heart muscle disease found in individuals with a history of long-term heavy alcohol consumption. Alcoholic cardiomyopathy is associated with a number of adverse histological, cellular, and structural changes within the myocardium. Several mechanisms are implicated in mediating the adverse effects of ethanol, including the generation of oxidative stress, apoptotic cell death, impaired mitochondrial bioenergetics/stress, derangements in fatty acid metabolism and transport, and accelerated protein catabolism. In this review, we discuss the evidence for such mechanisms and present the potential importance of drinking patterns, genetic susceptibility, nutritional factors, race, and sex. The purpose of this review is to provide a mechanistic paradigm for future research in the area of alcoholic cardiomyopathy. PMID:24671642

  11. Maillard reaction, mitochondria and oxidative stress: potential role of antioxidants.

    PubMed

    Edeas, M; Attaf, D; Mailfert, A-S; Nasu, M; Joubet, R

    2010-06-01

    Glycation and oxidative stress are two important processes known to play a key role in complications of many disease processes. Oxidative stress, either via increasing reactive oxygen species (ROS), or by depleting the antioxidants may modulate the genesis of early glycated proteins in vivo. Maillard Reactions, occur in vivo as well as in vitro and are associated with the chronic complications of diabetes, aging and age-related diseases. Hyperglycaemia causes the autoxidation of glucose, glycation of proteins, and the activation of polyol metabolism. These changes facilitate the generation of reactive oxygen species and decrease the activity of antioxidant enzymes such as Cu,Zn-superoxide dismutase, resulting in a remarkable increase of oxidative stress. A large body of evidence indicates that mitochondria alteration is involved and plays a central role in various oxidative stress-related diseases. The damaged mitochondria produce more ROS (increase oxidative stress) and less ATP (cellular energy) than normal mitochondria. As they are damaged, they cannot burn or use glucose or lipid and cannot provide cell with ATP. Further, glucose, amino acids and lipid will not be correctly used and will accumulate outside the mitochondria; they will undergo more glycation (as observed in diabetes, obesity, HIV infection and lipodystrophia). The objective of this paper is to discuss how to stop the vicious circle established between oxidative stress, Maillard Reaction and mitochondria. The potential application of some antioxidants to reduce glycation phenomenon and to increase the antioxidant defence system by targeting mitochondria will be discussed. Food and pharmaceutical companies share the same challenge, they must act now, urgently and energetically. PMID:20031340

  12. Chorangiosis: the potential role of smoking and air pollution.

    PubMed

    Akbulut, Metin; Sorkun, Hulya Cetin; Bir, Ferda; Eralp, Ayhan; Duzcan, Ender

    2009-01-01

    Chorangiosis is considered to be strongly associated with various fetal, maternal, and placental disorders, including pre-eclampsia, diabetes, hypertension, and major congenital anomalies, and has been found to correlate with increased fetal morbidity and mortality. In this study, we investigated the pathologic effects of maternal smoking and air pollution on the pathogenesis of chorangiosis. We investigated 92 placentas macroscopically and microscopically over a 3-month period (March 2006-May 2006) at Denizli State Hospital to identify the frequency of chorangiosis and the potential role of maternal smoking and air pollution. Placental changes were examined by light microscopy after hematoxylin and eosin (H&E) staining and immunohistochemical evaluation of CD 34 and CD 68; muscle-specific actin was used to confirm the diagnosis. Among the 92 mothers included in the study, 33 were smokers (group I), 31 were thought to have been exposed to air pollution (group II), and 28 were living in rural areas free of air pollution and maternal smoking (group III). Chorangiosis was found in 14% (13/92) of all placentas: 7 (53.8%) cases were assigned to group I, 5 (38.5%) to group II, and 1 (7.7%) to group III. Vascular changes were found mainly in the smoking and air pollution groups. There appeared to be no correlation of these vascular changes with placental weight, parity, gestational age, major congenital anomalies, and maternal factors, including diabetes and pre-eclampsia. We presume that smoking and air pollution may contribute to the development of chorangiosis. We suggest that chorangiosis may be an adaptive response to maternal hypoxia, and studies addressing the role of smoking and air pollution in chorangiosis may provide new insights into the pathogenesis of this condition. PMID:18635319

  13. Role of oxidants in microbial pathophysiology.

    PubMed Central

    Miller, R A; Britigan, B E

    1997-01-01

    Reactive oxidant species (superoxide, hydrogen peroxide, hydroxyl radical, hypohalous acid, and nitric oxide) are involved in many of the complex interactions between the invading microorganism and its host. Regardless of the source of these compounds or whether they are produced under normal conditions or those of oxidative stress, these oxidants exhibit a broad range of toxic effects to biomolecules that are essential for cell survival. Production of these oxidants by microorganisms enables them to have a survival advantage in their environment. Host oxidant production, especially by phagocytes, is a counteractive mechanism aimed at microbial killing. However, this mechanism may be contribute to a deleterious consequence of oxidant exposure, i.e., inflammatory tissue injury. Both the host and the microorganism have evolved complex adaptive mechanisms to deflect oxidant-mediated damage, including enzymatic and nonenzymatic oxidant-scavenging systems. This review discusses the formation of reactive oxidant species in vivo and how they mediate many of the processes involved in the complex interplay between microbial invasion and host defense. PMID:8993856

  14. The role of transient receptor potential channels in metabolic syndrome.

    PubMed

    Liu, Daoyan; Zhu, Zhiming; Tepel, Martin

    2008-11-01

    Metabolic syndrome is correlated with increased cardiovascular risk and characterized by several factors, including visceral obesity, hypertension, insulin resistance, and dyslipidemia. Several members of a large family of nonselective cation entry channels, e.g., transient receptor potential (TRP) canonical (TRPC), vanilloid (TRPV), and melastatin (TRPM) channels, have been associated with the development of cardiovascular diseases. Thus, disruption of TRP channel expression or function may account for the observed increased cardiovascular risk in metabolic syndrome patients. TRPV1 regulates adipogenesis and inflammation in adipose tissues, whereas TRPC3, TRPC5, TRPC6, TRPV1, and TRPM7 are involved in vasoconstriction and regulation of blood pressure. Other members of the TRP family are involved in regulation of insulin secretion, lipid composition, and atherosclerosis. Although there is no evidence that a single TRP channelopathy may be the cause of all metabolic syndrome characteristics, further studies will help to clarify the role of specific TRP channels involved in the metabolic syndrome. (Hypertens Res 2008; 31: 1989-1995). PMID:19098369

  15. Potential Antidepressant Role of Neurotransmitter CART: Implications for Mental Disorders

    PubMed Central

    Mao, Peizhong

    2011-01-01

    Depression is one of the most prevalent and debilitating public health concerns. Although no single cause of depression has been identified, it appears that interaction among genetic, epigenetic, biochemical, environmental, and psychosocial factors may explain its etiology. Further, only a fraction of depressed patients show full remission while using current antidepressants. Therefore, identifying common pathways of the disorder and using that knowledge to develop more effective pharmacological treatments are two primary targets of research in this field. Brain-enriched neurotransmitter CART (cocaine- and amphetamine-regulated transcript) has multiple functions related to emotions. It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system, which is considered to have an important role in regulating mood. Notably, adolescents carrying a missense mutation in the CART gene exhibit increased depression and anxiety. Hence, CART peptide may be a novel promising antidepressant agent. In this paper, we summarize recent progress in depression and CART. In particular, we emphasize a new antidepressant function for CART. PMID:21785720

  16. The potential roles of science centers in climate change adaptation

    NASA Astrophysics Data System (ADS)

    Hamilton, P.

    2012-12-01

    The overwhelming consensus amongst climatologists is that anthropogenic climate change is underway, but leading climate scientists also anticipate that over the next 20 years research may only modestly reduce the uncertainty about where, when and by how much climate will change. Uncertainty presents not only scientific challenges but social, political and economic quandaries as well. Both scientific and educational communities understand that climate change will test the resilience of societies especially because of the uncertainties regarding the timing, nature and severity of climate change. Thus the need is great for civic conversations regarding climate change adaptation. What roles might science centers play in helping their audiences and communities make decisions about climate change adaptation despite less-than-perfect knowledge? And how might informal and formal education work together on this task? This session will begin with a review of some initial efforts by selected science centers and their partners to engage their audiences in and help their communities grapple with climate change adaptation. It then will conclude with an audience discussion about potential future efforts by science centers both individually and in collaboration with formal education institutions to elevate public and policymaker awareness and appreciation of the need for climate change adaptation.

  17. Role of the Transmembrane Potential in the Membrane Proton Leak

    PubMed Central

    Rupprecht, Anne; Sokolenko, Elena A.; Beck, Valeri; Ninnemann, Olaf; Jaburek, Martin; Trimbuch, Thorsten; Klishin, Sergey S.; Jezek, Petr; Skulachev, Vladimir P.; Pohl, Elena E.

    2010-01-01

    Abstract The molecular mechanism responsible for the regulation of the mitochondrial membrane proton conductance (G) is not clearly understood. This study investigates the role of the transmembrane potential (ΔΨm) using planar membranes, reconstituted with purified uncoupling proteins (UCP1 and UCP2) and/or unsaturated FA. We show that high ΔΨm (similar to ΔΨm in mitochondrial State IV) significantly activates the protonophoric function of UCPs in the presence of FA. The proton conductance increases nonlinearly with ΔΨm. The application of ΔΨm up to 220 mV leads to the overriding of the protein inhibition at a constant ATP concentration. Both, the exposure of FA-containing bilayers to high ΔΨm and the increase of FA membrane concentration bring about the significant exponential Gm increase, implying the contribution of FA in proton leak. Quantitative analysis of the energy barrier for the transport of FA anions in the presence and absence of protein suggests that FA− remain exposed to membrane lipids while crossing the UCP-containing membrane. We believe this study shows that UCPs and FA decrease ΔΨm more effectively if it is sufficiently high. Thus, the tight regulation of proton conductance and/or FA concentration by ΔΨm may be key in mitochondrial respiration and metabolism. PMID:20409469

  18. A Potential Role for Bat Tail Membranes in Flight Control

    PubMed Central

    Gardiner, James D.; Dimitriadis, Grigorios; Codd, Jonathan R.; Nudds, Robert L.

    2011-01-01

    Wind tunnel tests conducted on a model based on the long-eared bat Plecotus auritus indicated that the positioning of the tail membrane (uropatagium) can significantly influence flight control. Adjusting tail position by increasing the angle of the legs ventrally relative to the body has a two-fold effect; increasing leg-induced wing camber (i.e., locally increased camber of the inner wing surface) and increasing the angle of attack of the tail membrane. We also used our model to examine the effects of flying with and without a tail membrane. For the bat model with a tail membrane increasing leg angle increased the lift, drag and pitching moment (nose-down) produced. However, removing the tail membrane significantly reduced the change in pitching moment with increasing leg angle, but it had no significant effect on the level of lift produced. The drag on the model also significantly increased with the removal of the tail membrane. The tail membrane, therefore, is potentially important for controlling the level of pitching moment produced by bats and an aid to flight control, specifically improving agility and manoeuvrability. Although the tail of bats is different from that of birds, in that it is only divided from the wings by the legs, it nonetheless, may, in addition to its prey capturing function, fulfil a similar role in aiding flight control. PMID:21479137

  19. Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

    PubMed Central

    Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan

    2016-01-01

    Manganese is a vital nutrient and is maintained at an optimal level (2.5–5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012

  20. Nanodevices for studying nano-pathophysiology.

    PubMed

    Cabral, Horacio; Miyata, Kanjiro; Kishimura, Akihiro

    2014-07-01

    Nano-scaled devices are a promising platform for specific detection of pathological targets, facilitating the analysis of biological tissues in real-time, while improving the diagnostic approaches and the efficacy of therapies. Herein, we review nanodevice approaches, including liposomes, nanoparticles and polymeric nanoassemblies, such as polymeric micelles and vesicles, which can precisely control their structure and functions for specifically interacting with cells and tissues. These systems have been successfully used for the selective delivery of reporter and therapeutic agents to specific tissues with controlled cellular and subcellular targeting of biomolecules and programmed operation inside the body, suggesting a high potential for developing the analysis for nano-pathophysiology. PMID:24993612

  1. Memory recuperative potential of rifampicin in aluminum chloride-induced dementia: role of pregnane X receptors.

    PubMed

    Kaur, P; Sodhi, R K

    2015-03-12

    The present study has been designed to investigate the potential of rifampicin [Pregnane X receptors (PXR) agonist] in experimental dementia. Aluminum chloride (AlCl3) [100mg/kg, p.o. for 42days] was administered to Wistar rats (n=6) to induce dementia. Morris water maze (MWM) test was used to assess learning and memory and rota rod test was used to assess locomotor activity of the animals. A battery of biochemical tests and histopathological evaluation using hematoxylin and eosin (H&E) and Congo Red stains were performed at the end of the study. AlCl3-treated rats demonstrated impaired cognition and locomotor activity on MWM apparatus and rota rod test, respectively. These animals exhibited a significant rise in acetylcholinesterase (AChE) activity (138±3.6), thiobarbituric acid reactive species (TBARS) level (15±1.6), nitrite (56±2.4) level and myeloperoxidase (MPO) activity (4.1±0.9) along with decline in reduced glutathione (GSH) level (22±1.3) in comparison to the control group (p<0.05). Further the H&E and Congo Red-stained cerebral cortex sections of AlCl3-treated rats indicated severe neutrophilic infiltration and amyloid deposition. Rifampicin-treated AlCl3-rats exhibited significant attenuation in memory deficits, biochemical parameters like AChE activity (33±1.4), TBARS level (4.1±1.0), nitrite level (64±2.6), MPO activity (3.6±1.0) and GSH level (53±2.4) along with improved histopathological alterations and locomotor activity when compared with AlCl3-treated rats (p<0.05). Combined administration of ketoconazole (a PXR antagonist) and rifampicin to AlCl3-treated animals reversed the rifampicin-induced protective effects. Therefore the results obtained from the study indicate a defensive role of rifampicin in memory dysfunction which may probably be due to its anti-cholinesterase, anti-oxidative, anti-inflammatory and amyloid lowering effects. Moreover the study speculates the potential of PXR in the pathophysiology of dementia which is subject

  2. Saturation diving; physiology and pathophysiology.

    PubMed

    Brubakk, Alf O; Ross, John A S; Thom, Stephen R

    2014-07-01

    In saturation diving, divers stay under pressure until most of their tissues are saturated with breathing gas. Divers spend a long time in isolation exposed to increased partial pressure of oxygen, potentially toxic gases, bacteria, and bubble formation during decompression combined with shift work and long periods of relative inactivity. Hyperoxia may lead to the production of reactive oxygen species (ROS) that interact with cell structures, causing damage to proteins, lipids, and nucleic acid. Vascular gas-bubble formation and hyperoxia may lead to dysfunction of the endothelium. The antioxidant status of the diver is an important mechanism in the protection against injury and is influenced both by diet and genetic factors. The factors mentioned above may lead to production of heat shock proteins (HSP) that also may have a negative effect on endothelial function. On the other hand, there is a great deal of evidence that HSPs may also have a "conditioning" effect, thus protecting against injury. As people age, their ability to produce antioxidants decreases. We do not currently know the capacity for antioxidant defense, but it is reasonable to assume that it has a limit. Many studies have linked ROS to disease states such as cancer, insulin resistance, diabetes mellitus, cardiovascular diseases, and atherosclerosis as well as to old age. However, ROS are also involved in a number of protective mechanisms, for instance immune defense, antibacterial action, vascular tone, and signal transduction. Low-grade oxidative stress can increase antioxidant production. While under pressure, divers change depth frequently. After such changes and at the end of the dive, divers must follow procedures to decompress safely. Decompression sickness (DCS) used to be one of the major causes of injury in saturation diving. Improved decompression procedures have significantly reduced the number of reported incidents; however, data indicate considerable underreporting of injuries

  3. Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis

    PubMed Central

    Chana, Gursharan; Bousman, Chad A.; Money, Tammie T.; Gibbons, Andrew; Gillett, Piers; Dean, Brian; Everall, Ian P.

    2013-01-01

    Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and protein. However, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA (miRNA) dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations. PMID

  4. Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision-like Proteins?

    PubMed

    Talman, Virpi; Pascale, Alessia; Jäntti, Maria; Amadio, Marialaura; Tuominen, Raimo K

    2016-08-01

    Alzheimer's disease (AD), the most common cause of dementia, is an irreversible and progressive neurodegenerative disorder. It affects predominantly brain areas that are critical for memory and learning and is characterized by two main pathological hallmarks: extracellular amyloid plaques and intracellular neurofibrillary tangles. Protein kinase C (PKC) has been classified as one of the cognitive kinases controlling memory and learning. By regulating several signalling pathways involved in amyloid and tau pathologies, it also plays an inhibitory role in AD pathophysiology. Among downstream targets of PKC are the embryonic lethal abnormal vision (ELAV)-like RNA-binding proteins that modulate the stability and the translation of specific target mRNAs involved in synaptic remodelling linked to cognitive processes. This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology. This last aspect emphasizes the potential of pharmacological activation of PKC as a promising therapeutic strategy for the treatment of AD. PMID:27001133

  5. Insulin-like growth factors and their potential role in cardiac epigenetics.

    PubMed

    Iosef Husted, Cristiana; Valencik, Maria

    2016-08-01

    Cardiovascular disease (CVD) constitutes a major public health threat worldwide, accounting for 17.3 million deaths annually. Heart disease and stroke account for the majority of healthcare costs in the developed world. While much has been accomplished in understanding the pathophysiology, molecular biology and genetics underlying the diagnosis and treatment of CVD, we know less about the role of epigenetics and their molecular determinants. The impact of environmental changes and epigenetics in CVD is now emerging as critically important in understanding the origin of disease and the development of new therapeutic approaches to prevention and treatment. This review focuses on the emerging role of epigenetics mediated by insulin like-growth factors-I and -II in major CVDs such as heart failure, cardiac hypertrophy and diabetes. PMID:27061217

  6. Pathogenesis and Pathophysiology of Endometriosis

    PubMed Central

    Burney, Richard O.; Giudice, Linda C.

    2013-01-01

    Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential toward the development of novel diagnostic and treatment approaches for this debilitating condition. PMID:22819144

  7. The pathophysiology of chronic constipation

    PubMed Central

    Andrews, Christopher N; Storr, Martin

    2011-01-01

    Constipation is broadly defined as an unsatisfactory defecation characterized by infrequent stools, difficult stool passage or both. The common approach to the pathophysiology of constipation groups the disorder into primary and secondary causes. Primary causes are intrinsic problems of colonic or anorectal function, whereas secondary causes are related to organic disease, systemic disease or medications. The normal process of colonic transit and defecation is discussed, and the etiology of constipation is reviewed. PMID:22114753

  8. Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy.

    PubMed

    Lasheras, Jaime; Vilà, Maria; Zamora, Mònica; Riu, Efrén; Pardo, Rosario; Poncelas, Marcos; Cases, Ildefonso; Ruiz-Meana, Marisol; Hernández, Cristina; Feliu, Juan E; Simó, Rafael; García-Dorado, David; Villena, Josep A

    2016-07-15

    Diabetic cardiomyopathy is characterized by an abnormal oxidative metabolism, but the underlying mechanisms remain to be defined. To uncover potential mechanisms involved in the pathophysiology of diabetic cardiomyopathy, we performed a gene expression profiling study in hearts of diabetic db/db mice. Diabetic hearts showed a gene expression pattern characterized by the up-regulation of genes involved in lipid oxidation, together with an abnormal expression of genes related to the cardiac contractile function. A screening for potential regulators of the genes differentially expressed in diabetic mice found that estrogen-related receptor γ (ERRγ) was increased in heart of db/db mice. Overexpression of ERRγ in cultured cardiomyocytes was sufficient to promote the expression of genes involved in lipid oxidation, increase palmitate oxidation and induce cardiomyocyte hypertrophy. Our findings strongly support a role for ERRγ in the metabolic alterations that underlie the development of diabetic cardiomyopathy. PMID:27062900

  9. Gut microbiota and its pathophysiology in disease paradigms.

    PubMed

    Festi, Davide; Schiumerini, Ramona; Birtolo, Chiara; Marzi, Luca; Montrone, Lucia; Scaioli, Eleonora; Di Biase, Anna Rita; Colecchia, Antonio

    2011-01-01

    The gut flora carries out important functions for human health, although most of them are still unknown, and an alteration of any of them, due to a condition of dysbiosis, can lead to relevant pathological implications. Commensal bacteria in the gut are essential for the preservation of the integrity of the mucosal barrier function and an alteration in the anatomic functional integrity of this barrier has been implicated in the pathophysiologic process of different diseases. The gut microflora plays a role in modulating the intestinal immune system; in fact, it is essential for the maturation of gut-associated lymphatic tissue, the secretion of IgA and the production of antimicrobial peptides. The enteric flora represents a potent bioreactor which controls several metabolic functions, even if most of them are still unknown. The main metabolic functions are represented by the fermentation of indigestible food substances into simple sugars, absorbable nutrients, and short-chain fatty acids. Furthermore, the gut microbiota exerts important trophic and developmental functions on the intestinal mucosa. This overview focuses briefly on the physiological role of the gut microbiota in maintaining a healthy state and the potential role played by disturbances of both the function and composition of the gut microbiota in determining important pathological conditions, such as irritable bowel syndrome, inflammatory bowel disease, metabolic syndrome, obesity, and cancer. PMID:22179206

  10. Effect of alpha1-adrenergic receptors in cardiac pathophysiology.

    PubMed

    Shannon, Richard; Chaudhry, Mohammad

    2006-11-01

    Compelling evidence now exists that proves adrenergic blockade is at the center of neurohormonal antagonism in heart failure (HF). Catecholamines are well known to act through both beta- and alpha-adrenergic receptors (ARs), which mediate their effects through distinct receptor pathways. Beta-AR blockers are commonly used in the treatment of HF and have distinct receptor affinity profiles. The recent COMET trial comparing 2 important beta-blocking drugs showed a distinct advantage for carvedilol in decreasing the risk of mortality from HF. The mechanism of action for carvedilol differs from metoprolol tartrate in its ability to block both alpha- and beta-ARs, leading to renewed interest in the potential role of alpha-ARs in the progression of HF. In contrast, however, the ALLHAT study discontinued use of doxazosin, an alpha1-receptor blocker because of an increase in cardiovascular events among patients using this drug. The results of these studies appear to be in contrast with respect to the role of alpha-ARs in regards to cardiovascular pathophysiology. Further study of the alpha-receptor and understanding the role of alpha-ARs in HF is necessary to understand the therapeutic effect of alpha-blockade. This article reviews our understanding of the alpha-AR in HF. PMID:17070143

  11. Renin-angiotensin system in ventilator-induced diaphragmatic dysfunction: Potential protective role of Angiotensin (1-7).

    PubMed

    Sigurta', Anna; Zambelli, Vanessa; Bellani, Giacomo

    2016-09-01

    Ventilator-induced diaphragmatic dysfunction is a feared complication of mechanical ventilation that adversely affects the outcome of intensive care patients. Human and animal studies demonstrate atrophy and ultrastructural alteration of diaphragmatic muscular fibers attributable to increased oxidative stress, depression of the anabolic pathway regulated by Insulin-like growing factor 1 and increased proteolysis. The renin-angiotensin system, through its main peptide Angiotensin II, plays a major role in skeletal muscle diseases, mainly increasing oxidative stress and inducing insulin resistance, atrophy and fibrosis. Conversely, its counter-regulatory peptide Angiotensin (1-7) has a protective role in these processes. Recent data on rodent models show that renin-angiotensin system is activated after mechanical ventilation and that infusion of Angiotensin II induces diaphragmatic skeletal muscle atrophy. Given: (A) common pathways shared by ventilator-induced diaphragmatic dysfunction and skeletal muscle pathology induced by renin-angiotensin system, (B) evidences of an involvement of renin-angiotensin system in diaphragm atrophy and dysfunction, we hypothesize that renin-angiotensin system plays an important role in ventilator-induced diaphragmatic dysfunction, while Angiotensin (1-7) can have a protective effect on this pathological process. The activation of renin-angiotensin system in ventilator-induced diaphragmatic dysfunction can be demonstrated by quantification of its main components in the diaphragm of ventilated humans or animals. The infusion of Angiotensin (1-7) in an established rodent model of ventilator-induced diaphragmatic dysfunction can be used to test its potential protective role, that can be further confirmed with the infusion of Angiotensin (1-7) antagonists like A-779. Verifying this hypothesis can help in understanding the processes involved in ventilator-induced diaphragmatic dysfunction pathophysiology and open new possibilities for its

  12. Quantitative Phase Imaging Techniques for the Study of Cell Pathophysiology: From Principles to Applications

    PubMed Central

    Lee, KyeoReh; Kim, Kyoohyun; Jung, Jaehwang; Heo, JiHan; Cho, Sangyeon; Lee, Sangyun; Chang, Gyuyoung; Jo, YoungJu; Park, Hyunjoo; Park, YongKeun

    2013-01-01

    A cellular-level study of the pathophysiology is crucial for understanding the mechanisms behind human diseases. Recent advances in quantitative phase imaging (QPI) techniques show promises for the cellular-level understanding of the pathophysiology of diseases. To provide important insight on how the QPI techniques potentially improve the study of cell pathophysiology, here we present the principles of QPI and highlight some of the recent applications of QPI ranging from cell homeostasis to infectious diseases and cancer. PMID:23539026

  13. Potential role of district heating in the US

    SciTech Connect

    Powell, J.R.; Karkheck, J.

    1981-01-01

    The potential market penetration of district heating in the US is discussed. Estimates of optimal service levels, capital investment, and energy conservation potential are discussed. The technological concept of modern district heating and specific assessments of district heating in the US are briefly described. (MCW)

  14. Pathogenesis and Pathophysiology of Pneumococcal Meningitis

    PubMed Central

    Mook-Kanamori, Barry B.; Geldhoff, Madelijn; van der Poll, Tom; van de Beek, Diederik

    2011-01-01

    Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy. PMID:21734248

  15. Pathogenesis and pathophysiology of pneumococcal meningitis.

    PubMed

    Mook-Kanamori, Barry B; Geldhoff, Madelijn; van der Poll, Tom; van de Beek, Diederik

    2011-07-01

    Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy. PMID:21734248

  16. Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain

    PubMed Central

    MIYATAKE, Shin-Ichi; NONOGUCHI, Noasuke; FURUSE, Motomasa; YORITSUNE, Erina; MIYATA, Tomo; KAWABATA, Shinji; KUROIWA, Toshihiko

    2015-01-01

    New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient’s quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain. PMID:25744350

  17. The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma

    PubMed Central

    Belanger, KarryAnne K.; Ameredes, Bill T.; Boldogh, Istvan

    2016-01-01

    Asthma is characterized by reversible airway narrowing, shortness of breath, wheezing, coughing, and other symptoms driven by chronic inflammatory processes, commonly triggered by allergens. In 90% of asthmatics, most of these symptoms can also be triggered by intense physical activities and severely exacerbated by environmental factors. This condition is known as exercise-induced asthma (EIA). Current theories explaining EIA pathogenesis involve osmotic and/or thermal alterations in the airways caused by changes in respiratory airflow during exercise. These changes, along with existing airway inflammatory conditions, are associated with increased cellular levels of reactive oxygen species (ROS) affecting important biomolecules including DNA, although the underlying molecular mechanisms have not been completely elucidated. One of the most abundant oxidative DNA lesions is 8-oxoguanine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) during the base excision repair (BER) pathway. Whole-genome expression analyses suggest a cellular response to OGG1-BER, involving genes that may have a role in the pathophysiology of EIA leading to mast cell degranulation, airway hyperresponsiveness, and bronchoconstriction. Accordingly, this review discusses a potential new hypothesis in which OGG1-BER-induced gene expression is associated with EIA symptoms. PMID:27524866

  18. Risk assessment and predicting outcomes in patients with depressive symptoms: a review of potential role of peripheral blood based biomarkers.

    PubMed

    Jani, Bhautesh D; McLean, Gary; Nicholl, Barbara I; Barry, Sarah J E; Sattar, Naveed; Mair, Frances S; Cavanagh, Jonathan

    2015-01-01

    Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area. PMID:25698954

  19. Molecular pathophysiology of cerebral edema.

    PubMed

    Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc

    2016-03-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  20. Molecular pathophysiology of cerebral edema

    PubMed Central

    Gerzanich, Volodymyr; Simard, J Marc

    2015-01-01

    Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

  1. Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models

    PubMed Central

    Manganozzi, Lucilla; Moretti, Raffaella; Vexler, Zinaida S.; Gressens, Pierre

    2016-01-01

    BACKGROUND Arterial ischemic stroke occurs most frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared to childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. The understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many aspects remain still unclear. METHODS In this review, we will focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment. RESULTS Studies in neonatal rodent models of cerebral ischemia have shown a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort has been made and is still in act to try neuroprotective molecules based on the new physiopatological acquisition. CONCLUSION In this review we aim to give a comprehensive view of new insights concerning pathophysiological mechanism of focal and global perinatal brain injury and its new therapeutic approaches. PMID:26002050

  2. Potential role of lampalizumab for treatment of geographic atrophy

    PubMed Central

    Rhoades, William; Dickson, Drew; Do, Diana V

    2015-01-01

    The purpose of this article is to review the pathways underlying age-related macular degeneration and potential therapeutic targets, focusing on the complement pathway and the recent MAHALO Phase II trial of the investigational drug lampalizumab. This trial was the first to have shown positive results for the treatment of geographic atrophy in age-related macular degeneration. It has potential as a future treatment, and is currently undergoing a Phase III trial. PMID:26089637

  3. An Examination of Potential Change Roles in Education.

    ERIC Educational Resources Information Center

    Clark, David L.; Guba, Egon G.

    Change roles in educational innovation have either not been taken at all or have been inappropriately or inadequately taken. By dividing the innovation process into four parts--research, development, diffusion, and adoption--phases within each division can be identified, criteria set up, and evaluations made. Also, with attention to this four-part…

  4. Redox signaling in pathophysiology of hypertension

    PubMed Central

    2013-01-01

    Reactive oxygen species (ROS) are products of normal cellular metabolism and derive from various sources in different cellular compartments. Oxidative stress resultant from imbalance between ROS generation and antioxidant defense mechanisms is important in pathogenesis of cardiovascular diseases, such as hypertension, heart failure, atherosclerosis, diabetes, and cardiac hypertrophy. In this review we focus on hypertension and address sources of cellular ROS generation, mechanisms involved in regulation of radical homeostasis, superoxide dismutase isoforms in pathophysiology of hypertension; as well as radical intracellular signaling and phosphorylation processes in proteins of the affected cardiovascular tissues. Finally, we discuss the transcriptional factors involved in redox-sensitive gene transcription and antioxidant response, as well as their roles in hypertension. PMID:24047403

  5. Central Pattern Generator for Locomotion: Anatomical, Physiological, and Pathophysiological Considerations

    PubMed Central

    Guertin, Pierre A.

    2013-01-01

    This article provides a perspective on major innovations over the past century in research on the spinal cord and, specifically, on specialized spinal circuits involved in the control of rhythmic locomotor pattern generation and modulation. Pioneers such as Charles Sherrington and Thomas Graham Brown have conducted experiments in the early twentieth century that changed our views of the neural control of locomotion. Their seminal work supported subsequently by several decades of evidence has led to the conclusion that walking, flying, and swimming are largely controlled by a network of spinal neurons generally referred to as the central pattern generator (CPG) for locomotion. It has been subsequently demonstrated across all vertebrate species examined, from lampreys to humans, that this CPG is capable, under some conditions, to self-produce, even in absence of descending or peripheral inputs, basic rhythmic, and coordinated locomotor movements. Recent evidence suggests, in turn, that plasticity changes of some CPG elements may contribute to the development of specific pathophysiological conditions associated with impaired locomotion or spontaneous locomotor-like movements. This article constitutes a comprehensive review summarizing key findings on the CPG as well as on its potential role in Restless Leg Syndrome, Periodic Leg Movement, and Alternating Leg Muscle Activation. Special attention will be paid to the role of the CPG in a recently identified, and uniquely different neurological disorder, called the Uner Tan Syndrome. PMID:23403923

  6. Airway smooth muscle in the pathophysiology and treatment of asthma

    PubMed Central

    Solway, Julian

    2013-01-01

    Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma. PMID:23305987

  7. Pathophysiological basis of migraine prophylaxis.

    PubMed

    Galletti, Francesca; Cupini, Letizia Maria; Corbelli, Ilenia; Calabresi, Paolo; Sarchielli, Paola

    2009-10-01

    Several cellular and molecular mechanisms have been implicated in migraine pathophysiology including abnormal neuronal excitability and vascular events. Drugs from different pharmacological classes are used for migraine prophylaxis. These agents may normalize neuronal excitability by modulating distinct ionic channels and various neurotransmitter systems. They can also block cortical spreading depression, prevent peripheral and/or central pain sensitization, and normalize brainstem function. Most of the drugs recently used in migraine prophylaxis have been identified by serendipidy and they have been originally approved for other indications. Subsequently, their use has been extended to migraine prevention, according to their putative mechanisms of action. More recently, trials on adequate samples of migraine patients have been conducted for several drugs. In the present review, we will present and discuss the pathophysiological bases for the use of antidepressants, beta-adrenergic blockers, calcium channel blockers and antiepileptic drugs in migraine prevention. Currently, the major classes of conventional migraine preventive drugs include the antidepressant amitriptyline, the beta-adrenergic blocker propranolol, and the antiepileptic drugs topiramate and valproic acid. Promising results have recently been obtained for angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers. Some limited clinical findings have also been reported for atypical antipsychotic agents, nutritional supplements and also botulinum toxin. Targets of migraine preventive treatment are to reduce frequency and intensity of attacks and to decrease disability related to chronic headache. PMID:19654035

  8. Central role of the observable electric potential in transport equations.

    PubMed

    Garrido, J; Compañ, V; López, M L

    2001-07-01

    Nonequilibrium systems are usually studied in the framework of transport equations that involve the true electric potential (TEP), a nonobservable variable. Nevertheless another electric potential, the observable electric potential (OEP), may be defined to construct a useful set of transport equations. In this paper several basic characteristics of the OEP are deduced and emphasized: (i) the OEP distribution depends on thermodynamic state of the solution, (ii) the observable equations have a reference value for all other transport equations, (iii) the bridge that connects the OEP with a certain TEP is usually defined by the ion activity coefficient, (iv) the electric charge density is a nonobservable variable, and (v) the OEP formulation constitutes a natural model for studying the fluxes in membrane systems. PMID:11461346

  9. The role of fullerene shell upon stuffed atom polarization potential

    NASA Astrophysics Data System (ADS)

    Amusia, Miron; Chernysheva, Larissa

    2016-05-01

    We have demonstrated that the polarization of the fullerene shell considerably alters the polarization potential of an atom, stuffed inside a fullerene. This essentially affects the electron elastic scattering phases as well as corresponding cross-sections. We illustrate the general trend by concrete examples of electron scattering upon endohedrals that are formed when Ne and Ar atom are stuffed inside fullerene C60. To obtain the presented results, we have suggested a simplified approach that permits to incorporate the effect of fullerenes polarizability into the endohedrals polarization potential. By applying this approach, we obtained numeric results that show strong variations in shape and magnitudes of scattering phases and cross-sections due to effect of fullerene polarization upon the endohedral polarization potential. Using concrete examples we have demonstrated that the elastic scattering of electrons upon endohedrals is an entirely quantum mechanical process, where addition of even a single atom can qualitatively alter the multi-particle cross-section.

  10. Role of a fullerene shell upon stuffed atom polarization potential

    NASA Astrophysics Data System (ADS)

    Amusia, M. Ya.; Chernysheva, L. V.

    2016-02-01

    We have demonstrated that the polarization of the fullerene shell considerably alters the polarization potential of an atom, stuffed inside a fullerene. This essentially affects the electron elastic scattering phases as well as corresponding cross sections. We illustrate the general trend by particular examples of electron scattering upon endohedrals Ne@C60 and Ar@C60. To obtain the presented results, we have suggested a simplified approach that permits to incorporate the effect of fullerenes polarizability into the Ne@C60 and Ar@C60 polarization potential. By applying this approach, we obtained numeric results that show strong variations in shape and magnitudes of scattering phases and cross sections due to effect of fullerene polarization upon the endohedral polarization potential.

  11. Potential Role of Garcinol as an Anticancer Agent

    PubMed Central

    Saadat, Nadia; Gupta, Smiti V.

    2012-01-01

    Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis. In vitro as well as some in vivo studies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential. PMID:22745638

  12. The Potential Roles of Actin in The Nucleus

    PubMed Central

    Falahzadeh, Khadijeh; Banaei-Esfahani, Amir; Shahhoseini, Maryam

    2015-01-01

    Over the past few decades, actin’s presence in the nucleus has been demonstrated. Actin is a key protein necessary for different nuclear processes. Although actin is well known for its functional role in dynamic behavior of the cytoskeleton, emerging studies are now highlighting new roles for actin. At the present time there is no doubt about the presence of actin in the nucleus. A number of studies have uncovered the functional involvement of actin in nuclear processes. Actin as one of the nuclear components has its own structured and functional rules, such as nuclear matrix association, chromatin remodeling, transcription by RNA polymerases I, II, III and mRNA processing. In this historical review, we attempt to provide an overview of our current understanding of the functions of actin in the nucleus. PMID:25870830

  13. Incidence, diagnosis and pathophysiology of amniotic fluid embolism.

    PubMed

    Ito, F; Akasaka, J; Koike, N; Uekuri, C; Shigemitsu, A; Kobayashi, H

    2014-10-01

    Amniotic fluid embolism (AFE) is a rare clinical entity, sometimes fatal. A review was conducted to describe the frequency, diagnosis and pathophysiology of AFE. The reported incidences ranged from 1.9 cases per 100,000 maternities (UK) to 6.1 per 100,000 maternities (Australia), which can vary considerably, depending on the period, region of study and the definition. Although the development of amniotic fluid-specific markers would have an impact on early diagnosis, definition of AFE based on these markers is not widely accepted. To date, immunological mechanisms, amniotic fluid-dependent anaphylactic reaction and complement activation, have been proposed as potential pathogenetic and pathophysiological mechanisms. Immune cell activation induced through complement activation may be associated with the mechanism that immediately initiates maternal death, only in susceptible individuals. This review will focus on advances in the field of AFE biology and discuss the prevalence, diagnosis and pathophysiology of AFE. PMID:24865116

  14. Sirtuins in vascular diseases: Emerging roles and therapeutic potential.

    PubMed

    D'Onofrio, Nunzia; Vitiello, Milena; Casale, Rosario; Servillo, Luigi; Giovane, Alfonso; Balestrieri, Maria Luisa

    2015-07-01

    Silent information regulator-2 (Sir-2) proteins, or sirtuins, are a highly conserved protein family of histone deacetylases that promote longevity by mediating many of the beneficial effects of calorie restriction which extends life span and reduces the incidence of cancer, cardiovascular disease (CVD), and diabetes. Here, we review the role of sirtuins (SIRT1-7) in vascular homeostasis and diseases by providing an update on the latest knowledge about their roles in endothelial damage and vascular repair mechanisms. Among all sirtuins, in the light of the numerous functions reported on SIRT1 in the vascular system, herein we discuss its roles not only in the control of endothelial cells (EC) functionality but also in other cell types beyond EC, including endothelial progenitor cells (EPC), smooth muscle cells (SMC), and immune cells. Furthermore, we also provide an update on the growing field of compounds under clinical evaluation for the modulation of SIRT1 which, at the state of the art, represents the most promising target for the development of novel drugs against CVD, especially when concomitant with type 2 diabetes. PMID:25766107

  15. Nuclear Tau and Its Potential Role in Alzheimer's Disease.

    PubMed

    Bukar Maina, Mahmoud; Al-Hilaly, Youssra K; Serpell, Louise C

    2016-01-01

    Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer's disease (AD). For nearly four decades, research efforts have focused more on tau's role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau's localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration. PMID:26751496

  16. Homogeneous Dislocation Nucleation - role of geometrical parameters and interatomic potentials

    NASA Astrophysics Data System (ADS)

    Garg, Akanksha; Hasan, Asad; Maloney, Craig

    2014-03-01

    We perform atomistic simulations of dislocation nucleation in defect free crystals in 2D and 3D during indentation with circular (2D) or spherical (3D) indenters of radius R. We study realistic interatomic potentials such as embedded atom method (EAM) potentials for Al in addition to simple pair-wise interactions such as linear springs. The dislocation embryo is localized along a line (or plane in 3D) of atoms with a lateral extent, ξ, at some depth, D, below the surface. For all potentials, in 2D, the scaled critical - load, Fc / R , and contact length, Cc / R , decrease to R independent values in the limit of large R. However, despite the R independence of Fc / R and Cc / R , ξ / R and D / R display non-trivial scaling with R. Although both the interaction potential and the orientation of lattice affect the prefactors in the scaling relations (e.g. crystal with springs is much harder than EAM Aluminum), all the scaling laws are robust. Furthermore, we show that, despite the excellent prediction for the relation between F and C, Hertzian contact theory fails to correctly predict the strain underneath the indenter. This observation gives us hope that local nucleation criteria based on appropriate local strain may capture the nontrivial scaling laws. NSF-CMMI-1100245.

  17. The Potential Role of Cable Television in Wideband Distribution Systems.

    ERIC Educational Resources Information Center

    Feldman, N. E.

    Community antenna television (CATV) is particularly important because of its potential for economically supplying a large number of channels, for providing viewer feedback, and for at least partially shifting the basis of programing support from the advertiser to the viewer. This study examines these aspects of CATV in order to accomplish the…

  18. Pathophysiology and prevention of sudden cardiac death.

    PubMed

    Goyal, Vineet; Jassal, Davinder S; Dhalla, Naranjan S

    2016-03-01

    Sudden cardiac death (SCD) is known to occur in individuals with diverse diseases. Each disease state has a specific etiology and pathophysiology, and is diagnosed and treated differently. Etiologies for SCD include cardiac arrhythmias, coronary artery disease, congenital coronary artery anomalies, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, and aortic valve stenosis. A potential unifying mechanism of SCD in these diseases involves a massive stimulation of the sympathetic nervous system's stress response and the subsequent elevation of circulating catecholamines. The diagnosis of cardiac diseases that contribute to an increased risk for SCD is accomplished by a combination of different techniques including electrocardiography, echocardiography, magnetic resonance imaging, and invasive cardiac catheterization. Several therapies including anti-arrhythmic drugs, β-blockers, and antiplatelet agents may be used as medical treatment in patients for the prevention of SCD. Invasive therapies including percutaneous angioplasty, coronary artery bypass surgery, and implantable cardioverter-defibrillators are also used in the clinical management of SCD. PMID:26651385

  19. Pathophysiological and disease constraints on aerosol delivery

    SciTech Connect

    Gerrity, T.R.

    1989-01-01

    The dose of inhaled particles to the respiratory tract depends upon many factors. These factors include the size of the particles, the pattern of breathing (flow and tidal volume), the physical properties of the articles (hygroscopic or non-hygroscopic), anatomy of the respiratory tract, and the pathophysiologic status of the respiratory tract. In addition to these factors, which are primarily related to the deposition of particles, the rate of particle clearance from the respiratory tract also influences the dose of particles. The paper is a review of the various factors influencing dose of inhaled particles to the respiratory tract. The emphasis of the paper is on therapeutic aerosol particles, though the principals discussed also apply to toxic particles as well. An important area of consideration is the influence of disease on the delivery of particle dose. From the point of view of toxic particles this is important when considering potential susceptible populations.

  20. Nausea: a review of pathophysiology and therapeutics

    PubMed Central

    Singh, Prashant; Yoon, Sonia S.; Kuo, Braden

    2016-01-01

    The sensation of nausea is a common occurrence with diverse causes and a significant disease burden. Nausea is considered to function as a protective mechanism, warning the organism to avoid potential toxic ingestion. Less adaptive circumstances are also associated with nausea, including post-operative nausea, chemotherapy-induced nausea, and motion sickness. A common definition of nausea identifies the symptom as a precursor to the act of vomiting. The interaction, though present, does not appear to be a simple relationship. Nausea is unfortunately the ‘neglected symptom’, with current accepted therapy generally directed at improving gastrointestinal motility or acting to relieve emesis. Improved understanding of the pathophysiological basis of nausea has important implications for exploiting novel mechanisms or developing novel therapies for nausea relief. PMID:26770271

  1. Potential role of remote sensing in disaster relief management

    NASA Technical Reports Server (NTRS)

    Rush, M.; Holguin, A.; Vernon, S.

    1976-01-01

    Baseline or predisaster data which would be useful to decision making in the immediate postdisaster period were suggested for the six areas of public health concern along with guidelines for organizing these data. Potential sources of these data are identified. In order to fully assess the impact of a disaster on an area, information about its predisaster status must be known. Aerial photography is one way of acquiring and recording such data.

  2. Potential role of S-adenosylmethionine in osteosarcoma development

    PubMed Central

    Shi, Hui; Mu, Wei-dong; Zhang, Bing; Meng, Tao; Zhang, Shou-tao; Zhou, Dong-sheng

    2016-01-01

    The metastatic form of osteosarcoma is a life threatening one since it metastasizes to the lungs. The major cause of metastatic osteosarcoma is hypomethylation of numerous genes that undergo overexpression to enable the progression of the disease. In the present study, S-adenosylmethionine (SAM), a predominant methyl donor, was administered to find out its effects on osteosarcoma progression. As evidence of tumor suppression, the SAM-treated mouse tissue was analyzed histologically, which exemplifies the control that SAM has over abnormal cell proliferation, especially on primary osteosarcoma, but it lacks positive effects on metastatic osteosarcoma. At the molecular level, the successful inhibition of primary osteosarcoma was found to be associated with a lower expression of Sox2, a protein highly expressed in osteosarcoma stem cells, along with an upregulated expression of TCTP. The data suggest that the administration of SAM has a positive role in treating primary osteosarcoma, but it has no role in suppressing metastatic osteosarcoma. The decreased expression of Sox2 together with upregulation of TCTP following SAM administration indicates that SAM has a control over primary osteosarcoma. PMID:27382303

  3. A potential role for transmissible spongiform encephalopathies in Neanderthal extinction.

    PubMed

    Underdown, Simon

    2008-01-01

    The Neanderthals were a Eurasian human species of the genus Homo that disappeared approximately 30,000 years ago. The cause or causes of their extinction continues to intrigue specialists and non-specialists alike. Here a contributory role for Transmissible Spongiform Encephalopathies (TSEs) is suggested. TSEs could have infected Neanderthal groups as a result of general cannibalistic activity and brain tissue consumption in particular. Further infection could then have taken place through continued cannibalistic activity or via shared used of infected stone tools. A modern human hunter-gatherer proxy has been developed and applied as a hypothetical model to the Neanderthals. This hypothesis suggests that the impact of TSEs on the Neanderthals could have been dramatic and have played a large part in contributing to the processes of Neanderthal extinction. PMID:18280671

  4. Antibodies and Their Receptors: Different Potential Roles in Mucosal Defense

    PubMed Central

    Horton, Rachel E.; Vidarsson, Gestur

    2013-01-01

    Over recent years it has become increasingly apparent that mucosal antibodies are not only restricted to the IgM and IgA isotypes, but that also other isotypes and particularly IgG can be found in significant quantities at some mucosal surfaces, such as in the genital tract. Their role is more complex than traditionally believed with, among other things, the discovery of novel function of mucosal immunoglobulin receptors. A thorough knowledge in the source and function and mucosal immunoglobulins is particularly important in development of vaccines providing mucosal immunity, and also in the current climate of microbicide development, to combat major world health issues such as HIV. We present here a comprehensive review of human antibody mediated mucosal immunity. PMID:23882268

  5. Maternal syphilis: pathophysiology and treatment.

    PubMed Central

    Berman, Stuart M.

    2004-01-01

    Despite the long history of medical interest in syphilis and its effects on pregnancy outcome, many fundamental questions about the pathophysiology and treatment of syphilis during pregnancy remain unanswered. However, understanding has been advanced by recent scientific reports such as those which delineate the complete sequence of the genome of the syphilis spirochaete, provide a more precise description of fetal and neonate infection by use of rabbit infectivity tests and describe the gestational age distribution of fetal death secondary to syphilis. It appears that fetal syphilitic involvement progresses in a rather predictable fashion, and although there is disagreement about the optimal prenatal treatment regimen, programmatic efforts to prevent fetal death must provide seropositive pregnant women with a recommended treatment early in pregnancy, and certainly before the third trimester. PMID:15356936

  6. Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

    SciTech Connect

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-05-15

    Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1{sup -/-} mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1{sup -/-} mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1beta, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1{sup -/-} mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1{sup -/-} mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

  7. Potential Role of Caveolin-1 in Acetaminophen-Induced Hepatotoxicity

    PubMed Central

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-01-01

    Caveolin-1 (Cav-1) is a membrane scaffolding protein which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1−/−) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1−/− mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1−/− mice is not due to alterations in anti-oxidant defense. In wild type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1−/− mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1−/− mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury. PMID:20100502

  8. The Potential Role of Oral Fluid in Antidoping Testing

    PubMed Central

    Anizan, Sebastien; Huestis, Marilyn A.

    2015-01-01

    BACKGROUND Currently, urine and blood are the only matrices authorized for antidoping testing by the World Anti-Doping Agency (WADA). Although the usefulness of urine and blood is proven, issues remain for monitoring some drug classes and for drugs prohibited only in competition. The alternative matrix oral fluid (OF) may offer solutions to some of these issues. OF collection is easy, noninvasive, and sex neutral and is directly observed, limiting potential adulteration, a major problem for urine testing. OF is used to monitor drug intake in workplace, clinical toxicology, criminal justice, and driving under the influence of drugs programs and potentially could complement urine and blood for antidoping testing in sports. CONTENT This review outlines the present state of knowledge and the advantages and limitations of OF testing for each of the WADA drug classes and the research needed to advance OF testing as a viable alternative for antidoping testing. SUMMARY Doping agents are either prohibited at all times or prohibited in competition only. Few OF data from controlled drug administration studies are available for substances banned at all times, whereas for some agents prohibited only in competition, sufficient data may be available to suggest appropriate analytes and cutoffs (analytical threshold concentrations) to identify recent drug use. Additional research is needed to characterize the disposition of many banned substances into OF; OF collection methods and doping agent stability in OF also require investigation to allow the accurate interpretation of OF tests for antidoping monitoring. PMID:24153253

  9. Potential in vivo roles of nucleic acid triple-helices

    PubMed Central

    Buske, Fabian A

    2011-01-01

    The ability of double-stranded DNA to form a triple-helical structure by hydrogen bonding with a third strand is well established, but the biological functions of these structures remain largely unknown. There is considerable albeit circumstantial evidence for the existence of nucleic triplexes in vivo and their potential participation in a variety of biological processes including chromatin organization, DNA repair, transcriptional regulation and RNA processing has been investigated in a number of studies to date. There is also a range of possible mechanisms to regulate triplex formation through differential expression of triplex-forming RNAs, alteration of chromatin accessibility, sequence unwinding and nucleotide modifications. With the advent of next generation sequencing technology combined with targeted approaches to isolate triplexes, it is now possible to survey triplex formation with respect to their genomic context, abundance and dynamical changes during differentiation and development, which may open up new vistas in understanding genome biology and gene regulation. PMID:21525785

  10. The Anticancer Activity of Organotelluranes: Potential Role in Integrin Inactivation.

    PubMed

    Silberman, Alon; Kalechman, Yona; Hirsch, Shira; Erlich, Ziv; Sredni, Benjamin; Albeck, Amnon

    2016-05-17

    Organic Te(IV) compounds (organotelluranes) differing in their labile ligands exhibited anti-integrin activities in vitro and anti-metastatic properties in vivo. They underwent ligand substitution with l-cysteine, as a thiol model compound. Unlike inorganic Te(IV) compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the Te(IV) atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential. PMID:26991356

  11. Potential role of probiotics on colorectal cancer prevention

    PubMed Central

    2012-01-01

    Background Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. Discussion Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention. Summary Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways. PMID:23173670

  12. Potential role of human growth hormone in melanoma growth promotion.

    PubMed

    Handler, Marc Z; Ross, Andrew L; Shiman, Michael I; Elgart, George W; Grichnik, James M

    2012-10-01

    BACKGROUND Human growth hormone (HGH) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the malignant transformation and progression of a variety of cancers. HGH is also known to upregulate molecular signaling pathways implicated in the pathogenesis of melanoma. Although HGH has previously been implicated in promoting the clinical growth of both benign and malignant melanocytic neoplasms, to our knowledge there are no conclusive studies demonstrating an increased risk of melanoma following HGH therapy. Nevertheless, there are reports of melanoma developing subsequent to HGH coadministered with either other hormones or following irradiation. OBSERVATION A 49-year-old white man presented with a new pigmented papule that was diagnosed as melanoma. The patient reported using HGH for 3 months prior to the diagnosis. His 51-year-old wife, who also was white, had also been using exogenous HGH for 3 months and had been diagnosed as having a melanoma 2 weeks prior. CONCLUSIONS Given the unlikelihood of 2 unrelated people developing melanoma within a short time span, it is reasonable to assume that a common environmental component (HGH or other shared exposure) contributed to the development of both melanomas. Because of the increased use of exogenous HGH as an antiaging agent, it is important to be aware of the growth-promoting effects of this hormone. Until better data are available that determines the true risk of exogenous HGH, its use as an antiaging agent merits increased surveillance. PMID:23069955

  13. The Potential Role of DNA Methylation in Abdominal Aortic Aneurysms

    PubMed Central

    Ryer, Evan J.; Ronning, Kaitryn E.; Erdman, Robert; Schworer, Charles M.; Elmore, James R.; Peeler, Thomas C.; Nevius, Christopher D.; Lillvis, John H.; Garvin, Robert P.; Franklin, David P.; Kuivaniemi, Helena; Tromp, Gerard

    2015-01-01

    Abdominal aortic aneurysm (AAA) is a complex disorder that has a significant impact on the aging population. While both genetic and environmental risk factors have been implicated in AAA formation, the precise genetic markers involved and the factors influencing their expression remain an area of ongoing investigation. DNA methylation has been previously used to study gene silencing in other inflammatory disorders and since AAA has an extensive inflammatory component, we sought to examine the genome-wide DNA methylation profiles in mononuclear blood cells of AAA cases and matched non-AAA controls. To this end, we collected blood samples and isolated mononuclear cells for DNA and RNA extraction from four all male groups: AAA smokers (n = 11), AAA non-smokers (n = 9), control smokers (n = 10) and control non-smokers (n = 11). Methylation data were obtained using the Illumina 450k Human Methylation Bead Chip and analyzed using the R language and multiple Bioconductor packages. Principal component analysis and linear analysis of CpG island subsets identified four regions with significant differences in methylation with respect to AAA: kelch-like family member 35 (KLHL35), calponin 2 (CNN2), serpin peptidase inhibitor clade B (ovalbumin) member 9 (SERPINB9), and adenylate cyclase 10 pseudogene 1 (ADCY10P1). Follow-up studies included RT-PCR and immunostaining for CNN2 and SERPINB9. These findings are novel and suggest DNA methylation may play a role in AAA pathobiology. PMID:25993294

  14. The Potential Role of Probiotics in Cancer Prevention and Treatment.

    PubMed

    Yu, Ai-Qun; Li, Lianqin

    2016-01-01

    The human gut microbiota has a significant effect on many aspects of human physiology such as metabolism, nutrient absorption, and immune function. Imbalance of the microbiota has been implicated in many disorders including inflammatory bowel disease, obesity, asthma, psychiatric illnesses, and cancers. As a kind of functional foods, probiotics have been shown to play a protective role against cancer development in animal models. Clinical application of probiotics indicated that some probiotic strains could diminish the incidence of postoperative inflammation in cancer patients. Chemotherapy or radiotherapy-related diarrhea was relieved in patients who were administered oral probiotics. The present review summarizes the up-to-date studies on probiotic effects and the underlying mechanisms related to cancer. At present, it is commonly accepted that most commercial probiotic products are generally safe and can improve the health of the host. By modulating intestinal microbiota and immune response, some strains of probiotics can be used as an adjuvant for cancer prevention or/and treatment. PMID:27144297

  15. The Potential Role of Aurora Kinase Inhibitors in Haematological Malignancies

    PubMed Central

    Farag, Sherif S.

    2011-01-01

    Summary Aurora kinases play an important role in the control of the cell cycle and have been implicated in tumourigenesis in a number of cancers. Among the haematological malignancies, overexpression of Aurora kinases has been reported in acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, multiple myeloma, aggressive non-Hodgkin lymphoma and Hodgkin lymphoma. A large number of Aurora kinase inhibitors are currently in different stages of clinical development. In addition to varying in their selectivity for the different Aurora kinases, some also have activity directed at other cellular kinases involved in important molecular pathways in cancer cells. This review summarizes the biology of Aurora kinases and discusses why they may be good therapeutic targets in different haematological cancers. We describe preclinical data that has served as the rationale for investigating Aurora kinase inhibitors in different haematological malignancies, and summarize published results from early phase clinical trials. While the anti-tumour effects of Aurora kinase inhibitors appear promising, we highlight important issues for future clinical research and suggest that the optimal use of these inhibitors is likely to be in combination with cytotoxic agents already in use for the treatment of various haematological cancers. PMID:21980926

  16. Sustainable life support on Mars - the potential roles of cyanobacteria

    NASA Astrophysics Data System (ADS)

    Verseux, Cyprien; Baqué, Mickael; Lehto, Kirsi; de Vera, Jean-Pierre P.; Rothschild, Lynn J.; Billi, Daniela

    2016-01-01

    Even though technological advances could allow humans to reach Mars in the coming decades, launch costs prohibit the establishment of permanent manned outposts for which most consumables would be sent from Earth. This issue can be addressed by in situ resource utilization: producing part or all of these consumables on Mars, from local resources. Biological components are needed, among other reasons because various resources could be efficiently produced only by the use of biological systems. But most plants and microorganisms are unable to exploit Martian resources, and sending substrates from Earth to support their metabolism would strongly limit the cost-effectiveness and sustainability of their cultivation. However, resources needed to grow specific cyanobacteria are available on Mars due to their photosynthetic abilities, nitrogen-fixing activities and lithotrophic lifestyles. They could be used directly for various applications, including the production of food, fuel and oxygen, but also indirectly: products from their culture could support the growth of other organisms, opening the way to a wide range of life-support biological processes based on Martian resources. Here we give insights into how and why cyanobacteria could play a role in the development of self-sustainable manned outposts on Mars.

  17. Melioidosis: Epidemiology, Pathophysiology, and Management

    PubMed Central

    Cheng, Allen C.; Currie, Bart J.

    2005-01-01

    Melioidosis, caused by the gram-negative saprophyte Burkholderia pseudomallei, is a disease of public health importance in southeast Asia and northern Australia that is associated with high case-fatality rates in animals and humans. It has the potential for epidemic spread to areas where it is not endemic, and sporadic case reports elsewhere in the world suggest that as-yet-unrecognized foci of infection may exist. Environmental determinants of this infection, apart from a close association with rainfall, are yet to be elucidated. The sequencing of the genome of a strain of B. pseudomallei has recently been completed and will help in the further identification of virulence factors. The presence of specific risk factors for infection, such as diabetes, suggests that functional neutrophil defects are important in the pathogenesis of melioidosis; other studies have defined virulence factors (including a type III secretion system) that allow evasion of killing mechanisms by phagocytes. There is a possible role for cell-mediated immunity, but repeated environmental exposure does not elicit protective humoral or cellular immunity. A vaccine is under development, but economic constraints may make vaccination an unrealistic option for many regions of endemicity. Disease manifestations are protean, and no inexpensive, practical, and accurate rapid diagnostic tests are commercially available; diagnosis relies on culture of the organism. Despite the introduction of ceftazidime- and carbapenem-based intravenous treatments, melioidosis is still associated with a significant mortality attributable to severe sepsis and its complications. A long course of oral eradication therapy is required to prevent relapse. Studies exploring the role of preventative measures, earlier clinical identification, and better management of severe sepsis are required to reduce the burden of this disease. PMID:15831829

  18. The Potential Role(s) of Writing in Second Language Development

    ERIC Educational Resources Information Center

    Williams, Jessica

    2012-01-01

    Writing is often seen as having a minor role in second language learning. This article explores recent research that suggests that writing can have a facilitative role in language development. In particular, it focuses on three features of writing: (1) its slower pace, and (2) the enduring record that it leaves, both of which can encourage…

  19. A Potential Role for Allostatic Load in Preeclampsia

    PubMed Central

    Hux, Vanessa J.; Roberts, James M.

    2014-01-01

    Objective Preeclampsia is a multisystemic disorder of pregnancy associated with maternal and fetal complications as well as later-life cardiovascular disease. Its exact cause is not known. We developed a pregnancy-specific multisystem index score of physiologic risk and chronic stress, allostatic load (AL), early in pregnancy. Our objective was to determine whether AL measured early in pregnancy was associated with increased odds of developing preeclampsia. Methods Data were from a single-center, prospectively collected database in a 1:2 individual-matched case control of women enrolled at <15 weeks gestation. We matched 38 preeclamptic cases to 75 uncomplicated, term deliveries on age, parity, and lifetime smoking status. AL was determined using 9 measures of cardiovascular, metabolic, and inflammatory function. Cases and matched controls were compared using conditional logistic regression. We compared the model's association with preeclampsia to that of obesity, a well-known risk factor for preeclampsia, by assessing goodness-of-fit by Akaike information criterion (AIC), where a difference >1-2 suggests better fit. Results Early pregnancy AL was higher in women with preeclampsia (1.25 +/- 0.68 vs. 0.83 +/- 0.62, p=0.002); women with higher AL had increasing odds of developing preeclampsia (OR 2.91, 95% CI 1.50-5.65). The difference between AIC for AL and obesity was >2 (AIC 74.4 vs. 84.4), indicating AL had a stronger association with preeclampsia. Conclusion Higher allostatic load in early pregnancy is associated with increasing odds of preeclampsia. This work supports a possible role of multiple maternal systems and chronic stress early in pregnancy in the development of preeclampsia. PMID:24939173

  20. Circadian molecular clock in lung pathophysiology.

    PubMed

    Sundar, Isaac K; Yao, Hongwei; Sellix, Michael T; Rahman, Irfan

    2015-11-15

    Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

  1. Schizophrenia relapse, patient considerations, and potential role of lurasidone

    PubMed Central

    Citrome, Leslie

    2016-01-01

    When treating persons with schizophrenia, delaying time to relapse is a main goal. Antipsychotic medication has been the primary treatment approach, and there are a variety of different choices available. Lurasidone is a second-generation (atypical) antipsychotic agent that is approved for the treatment of schizophrenia and bipolar depression. Three long-term studies of lurasidone have examined time to relapse in persons with schizophrenia, including a classic placebo-controlled randomized withdrawal study and two 12-month active comparator studies (vs risperidone and vs quetiapine extended-release). Lurasidone 40–80 mg/d evidenced superiority over placebo (number needed to treat [NNT] vs placebo for relapse, 9). Lurasidone 40–160 mg/d was noninferior to quetiapine extended-release 200–800 mg/d on the outcome of relapse, and was superior on the outcome of avoidance of hospitalization (NNT 8) and the outcome of remission (NNT 7). Lurasidone demonstrated a lower risk for long-term weight gain than the active comparators. Demonstrated differences in tolerability profiles among the different choices of antipsychotics make it possible to attempt to match up an individual patient to the best choice for such patient based on past history of tolerability, comorbidities, and personal preferences, potentially improving adherence. PMID:27563237

  2. The Potential Role of Exercise in Neuro-Oncology

    PubMed Central

    Cormie, Prue; Nowak, Anna K.; Chambers, Suzanne K.; Galvão, Daniel A.; Newton, Robert U.

    2015-01-01

    Patients with brain and other central nervous system cancers experience debilitating physical, cognitive, and emotional effects, which significantly compromise quality of life. Few efficacious pharmacological strategies or supportive care interventions exist to ameliorate these sequelae and patients report high levels of unmet needs in these areas. There is strong theoretical rationale to suggest exercise may be an effective intervention to aid in the management of neuro-oncological disorders. Clinical research has established the efficacy of appropriate exercise in counteracting physical impairments such as fatigue and functional decline, cognitive impairment, as well as psychological effects including depression and anxiety. While there is promise for exercise to enhance physical and psychosocial wellbeing of patients diagnosed with neurologic malignancies, these patients have unique needs and research is urgently required to explore optimal exercise prescription specific to these patients to maximize safety and efficacy. This perspective article is a discussion of potential rehabilitative effects of targeted exercise programs for patients with brain and other central nervous system cancers and highlights future research directions. PMID:25905043

  3. Potential role of punicalagin against oxidative stress induced testicular damage

    PubMed Central

    Rao, Faiza; Tian, Hui; Li, Wenqing; Hung, Helong; Sun, Fei

    2016-01-01

    Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity ≥98%) on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS) induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU) against oxidative stress-induced infertility. Results demonstrated that 9 mg kg−1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility. PMID:26763544

  4. Preliminary thoughts concerning potential US Army threats/roles

    SciTech Connect

    Greene, R.A.; Solomon, K.A.; Miles, J.T.

    1991-06-01

    The rate at which the current world military/political perspective is changing demands consideration of a broader spectrum of potential threats then has been the case for the past few decades--during which the Soviet Union was the preeminent threat. Seemingly overnight, the cold war ceased, the requirement for massive U.S. military counters to the Soviet Union forces faded, and an era of constant (obvious) military threat disappeared. This situation has in turn been revolutionized by the Iraq invasion of Kuwait and the U.S. response. The paper addresses part of the problem facing military planners by defining a spectrum of threats that typify those the U.S. Army might face over the next decade or two. The purpose of the threat set is to support the evaluation of the effectiveness and usefulness, to the U.S. Army, of advanced technologies. The set of threats is intended to provide a complete set of characteristics rather then to be a complete list of the possibilities; it is illustrative rather than exhaustive. Although largely completed before the war with Iraq started, its content is still valid in that its purpose is to provide a framework for thinking about future U.S. Army technology needs.

  5. The potential role of biofuels within the built environment

    NASA Astrophysics Data System (ADS)

    Lewis, C.

    1980-04-01

    The potential contribution of biofuels within both developed and developing nations is examined, particularly with respect to their utilization within the built environment. It is stressed that biomass, mainly in the forms of wood, animal dung and agricultural residues, is essentially a renewable resource and today accounts for approximately one-sixth of global fuel supplies. Examples of fuelwood consumption in European countries and in Africa are presented and the future of the bioenergy is considered, taking into account such main estimates as national energy density (energy consumed/ha of land area) and biomass productivity (net energy output/ha/year). Bioenergy production in low and high latitude countries, is also examined. The results of work on the blue-green Spirulina, an alga which contains 65-70% protein, and may yield about 200 cu m of biogas, containing 65-68% of CH4 at an energy content of 5.25 GI from 410 kg of its biomass are discussed.

  6. Active axial spondyloarthritis: potential role of certolizumab pegol

    PubMed Central

    Ranatunga, Sriya; Miller, Anne V

    2014-01-01

    The axial spondyloarthropathies are a group of chronic inflammatory diseases that predominantly affect the axial joints. This group includes ankylosing spondylitis and nonradiographic axial spondyloarthropathy. While the pathogenesis of axial spondyloarthropathies is not clear, immunologically active tissues primarily include the entheses, ie, the areas where ligaments, tendons, and joint capsules attach to bone and to the annulus fibrosis at the vertebrae. One of the major mediators of the immune response in this group of diseases is tumor necrosis factor-alpha (TNFα). Blockade of TNFα results in reduced vascularity and inflammatory cell infiltration in the synovial tissues of affected joints. Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-TNFα monoclonal antibody. CZP has unique properties that differ from other available TNFα inhibitors by virtue of its lack of an Fc region, which minimizes potential Fc-mediated effects, and its PEGylation, which improves drug pharmacokinetics and bioavailability. It has been shown in clinical trials that CZP improves patient outcomes and reduces inflammation in the sacroiliac joints and spine in both ankylosing spondylitis and nonradiographic axial spondyloarthropathies. These data support CZP as a treatment option for axial spondyloarthropathies. PMID:24611014

  7. Evapotranspiration Cycles in a High Latitude Agroecosystem: Potential Warming Role.

    PubMed

    Ruairuen, Watcharee; Fochesatto, Gilberto J; Sparrow, Elena B; Schnabel, William; Zhang, Mingchu; Kim, Yongwon

    2015-01-01

    As the acreages of agricultural lands increase, changes in surface energetics and evapotranspiration (ET) rates may arise consequently affecting regional climate regimes. The objective of this study was to evaluate summertime ET dynamics and surface energy processes in a subarctic agricultural farm in Interior Alaska. The study includes micrometeorological and hydrological data. Results covering the period from June to September 2012 and 2013 indicated consistent energy fractions: LE/Rnet (67%), G/Rnet (6%), H/Rnet (27%) where LE is latent heat flux, Rnet is the surface net radiation, G is ground heat flux and H is the sensible heat flux. Additionally actual surface evapotranspiration from potential evaporation was found to be in the range of 59 to 66%. After comparing these rates with those of most prominent high latitude ecosystems it is argued here that if agroecosystem in high latitudes become an emerging feature in the land-use, the regional surface energy balance will significantly shift in comparison to existing Arctic natural ecosystems. PMID:26368123

  8. Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

    PubMed Central

    Basavarajappa, Balapal S.

    2015-01-01

    One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS), which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD). Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD. PMID:26529026

  9. Raxibacumab: potential role in the treatment of inhalational anthrax

    PubMed Central

    Kummerfeldt, Carlos E

    2014-01-01

    Anthrax is a highly contagious and potentially fatal human disease caused by Bacillus anthracis, an aerobic, Gram-positive, spore-forming rod-shaped bacterium with worldwide distribution as a zoonotic infection in herbivore animals. Bioterrorist attacks with inhalational anthrax have prompted the development of more effective treatments. Antibodies against anthrax toxin have been shown to decrease mortality in animal studies. Raxibacumab is a recombinant human monoclonal antibody developed against inhalational anthrax. The drug received approval after human studies showed its safety and animal studies demonstrated its efficacy for treatment as well as prophylaxis against inhalational anthrax. It works by preventing binding of the protective antigen component of the anthrax toxin to its receptors in host cells, thereby blocking the toxin’s deleterious effects. Recently updated therapy guidelines for Bacillus anthracis recommend the use of antitoxin treatment. Raxibacumab is the first monoclonal antitoxin antibody made available that can be used with the antibiotics recommended for treatment of the disease. When exposure is suspected, raxibacumab should be given with anthrax vaccination to augment immunity. Raxibacumab provides additional protection against inhalational anthrax via a mechanism different from that of either antibiotics or active immunization. In combination with currently available and recommended therapies, raxibacumab should reduce the morbidity and mortality of inhalational anthrax. PMID:24812521

  10. Potential role of punicalagin against oxidative stress induced testicular damage.

    PubMed

    Rao, Faiza; Tian, Hui; Li, Wenqing; Hung, Helong; Sun, Fei

    2016-01-01

    Punicalagin is isolated from pomegranate and widely used for the treatment of different diseases in Chinese traditional medicine. This study aimed to evaluate the effect of Punicalagin (purity ≥98%) on oxidative stress induced testicular damage and its effect on fertility. We detected the antioxidant potential of punicalagin in lipopolysaccharide (LPS) induced oxidative stress damage in testes, also tried to uncover the boosting fertility effect of Punicalagin (PU) against oxidative stress-induced infertility. Results demonstrated that 9 mg kg-1 for 7 days treatment significantly decreases LPS induced oxidative damage in testes and nitric oxide production. The administration of oxidative stress resulted in a significant reduction in testes antioxidants GSH, T-SOD, and CAT raised LPO, but treatment with punicalagin for 7 days increased antioxidant defense GSH, T-SOD, and CAT by the end of the experiment and reduced LPO level as well. PU also significantly activates Nrf2, which is involved in regulation of antioxidant defense systems. Hence, the present research categorically elucidates the protective effect of punicalagin against LPS induced oxidative stress induced perturbation in the process of spermatogenesis and significantly increased sperm health and number. Moreover, fertility success significantly decreased in LPS-injected mice compared to controls. Mice injected with LPS had fertility indices of 12.5%, while others treated with a combination of PU + LPS exhibited 75% indices. By promoting fertility and eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of infertility. PMID:26763544

  11. Evapotranspiration Cycles in a High Latitude Agroecosystem: Potential Warming Role

    PubMed Central

    Ruairuen, Watcharee

    2015-01-01

    As the acreages of agricultural lands increase, changes in surface energetics and evapotranspiration (ET) rates may arise consequently affecting regional climate regimes. The objective of this study was to evaluate summertime ET dynamics and surface energy processes in a subarctic agricultural farm in Interior Alaska. The study includes micrometeorological and hydrological data. Results covering the period from June to September 2012 and 2013 indicated consistent energy fractions: LE/Rnet (67%), G/Rnet (6%), H/Rnet (27%) where LE is latent heat flux, Rnet is the surface net radiation, G is ground heat flux and H is the sensible heat flux. Additionally actual surface evapotranspiration from potential evaporation was found to be in the range of 59 to 66%. After comparing these rates with those of most prominent high latitude ecosystems it is argued here that if agroecosystem in high latitudes become an emerging feature in the land-use, the regional surface energy balance will significantly shift in comparison to existing Arctic natural ecosystems. PMID:26368123

  12. Schizophrenia relapse, patient considerations, and potential role of lurasidone.

    PubMed

    Citrome, Leslie

    2016-01-01

    When treating persons with schizophrenia, delaying time to relapse is a main goal. Antipsychotic medication has been the primary treatment approach, and there are a variety of different choices available. Lurasidone is a second-generation (atypical) antipsychotic agent that is approved for the treatment of schizophrenia and bipolar depression. Three long-term studies of lurasidone have examined time to relapse in persons with schizophrenia, including a classic placebo-controlled randomized withdrawal study and two 12-month active comparator studies (vs risperidone and vs quetiapine extended-release). Lurasidone 40-80 mg/d evidenced superiority over placebo (number needed to treat [NNT] vs placebo for relapse, 9). Lurasidone 40-160 mg/d was noninferior to quetiapine extended-release 200-800 mg/d on the outcome of relapse, and was superior on the outcome of avoidance of hospitalization (NNT 8) and the outcome of remission (NNT 7). Lurasidone demonstrated a lower risk for long-term weight gain than the active comparators. Demonstrated differences in tolerability profiles among the different choices of antipsychotics make it possible to attempt to match up an individual patient to the best choice for such patient based on past history of tolerability, comorbidities, and personal preferences, potentially improving adherence. PMID:27563237

  13. Potential role of gastrointestinal microbiota composition in prostate cancer risk

    PubMed Central

    2013-01-01

    Background Among men in the U.S., prostate cancer is the most common cancer and the second leading cause of cancer death. Despite its prevalence, there are few established risk factors for prostate cancer. Some studies have found that intake of certain foods/nutrients may be associated with prostate cancer risk, but few have accounted for how intake and metabolic factors may interact to influence bioavailable nutrient levels and subsequent disease risk. Presentation of the hypothesis The composition of the gastrointestinal (GI) microbiome may influence metabolism of dietary compounds and nutrients (e.g., plant phenols, calcium, choline) that may be relevant to prostate cancer risk. We, therefore, propose the hypothesis that GI microbiota may have a markedly different composition among individuals with higher prostate cancer risk. These individuals could have microbial profiles that are conducive to intestinal inflammation and/or are less favorable for the metabolism and uptake of chemopreventive agents. Testing the hypothesis Because very little preliminary data exist on this potential association, a case–control study may provide valuable information on this topic. Such a study could evaluate whether the GI microbial profile is markedly different between three groups of individuals: healthy men, those with latent prostate cancer, and those with invasive prostate cancer. Any findings could then be validated in a larger study, designed to collect a series of specimens over time. Implications of the hypothesis Given the plethora of information emerging from the Human Microbiome Project, this is an opportune time to explore associations between the microbiome and complex human diseases. Identification of profiles that alter the host’s risk for disease may clarify inconsistencies in the literature on dietary factors and cancer risk, and could provide valuable targets for novel cancer prevention strategies. PMID:24180596

  14. Potential renovascular hypertension, space missions, and the role of magnesium

    PubMed Central

    Rowe, William J

    2009-01-01

    Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin’s apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now. PMID:21694921

  15. Potential renovascular hypertension, space missions, and the role of magnesium.

    PubMed

    Rowe, William J

    2009-01-01

    Space flight (SF) and dust inhalation in habitats cause hypertension whereas in SF (alone) there is no consistent hypertension but reduced diurnal blood pressure (BP) variation instead. Current pharmaceutical subcutaneous delivery systems are inadequate and there is impairment in the absorption, metabolism, excretion, and deterioration of some pharmaceuticals. Data obtained from the National Aeronautics and Space Administration through the Freedom of Information Act shows that Irwin returned from his 12-day Apollo 15 mission in 1971 and was administered a bicycle stress test. With just three minutes of exercise, his BP was >275/125 mm Hg (heart rate of only 130 beats per minute). There was no acute renal insult. Irwin's apparent spontaneous remission is suggested to be related to the increase of a protective vasodilator, and his atrial natriuretic peptide (ANP) reduced with SF because of reduced plasma volume. With invariable malabsorption and loss of bone/muscle storage sites, there are significant (P < 0.0001) reductions of magnesium (Mg) required for ANP synthesis and release. Reductions of Mg and ANP can trigger pronounced angiotensin (200%), endothelin, and catecholamine elevations (clearly shown in recent years) and vicious cycles between the latter and Mg deficits. There is proteinuria, elevated creatinine, and reduced renal concentrating ability with the potential for progressive inflammatory and oxidative stress-induced renal disease and hypertension with vicious cycles. After SF, animals show myocardial endothelial injuries and increased vascular resistance of extremities in humans. Even without dust, hypertension might eventually develop from renovascular hypertension during very long missions. Without sufficient endothelial protection from pharmaceuticals, a comprehensive gene research program should begin now. PMID:21694921

  16. Involvement of the Kynurenine Pathway in Human Glioma Pathophysiology

    PubMed Central

    Adams, Seray; Teo, Charles; McDonald, Kerrie L.; Zinger, Anna; Bustamante, Sonia; Lim, Chai K.; Sundaram, Gayathri; Braidy, Nady; Brew, Bruce J.; Guillemin, Gilles J.

    2014-01-01

    The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-γ) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD+, which is necessary for energy production and DNA repair. PMID:25415278

  17. Involvement of the kynurenine pathway in human glioma pathophysiology.

    PubMed

    Adams, Seray; Teo, Charles; McDonald, Kerrie L; Zinger, Anna; Bustamante, Sonia; Lim, Chai K; Sundaram, Gayathri; Braidy, Nady; Brew, Bruce J; Guillemin, Gilles J

    2014-01-01

    The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-γ) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+), which is necessary for energy production and DNA repair. PMID:25415278

  18. Role of sodium tungstate as a potential antiplatelet agent

    PubMed Central

    Fernández-Ruiz, Rebeca; Pino, Marc; Hurtado, Begoña; García de Frutos, Pablo; Caballo, Carolina; Escolar, Ginés; Gomis, Ramón; Diaz-Ricart, Maribel

    2015-01-01

    Purpose Platelet inhibition is a key strategy in the management of atherothrombosis. However, the large variability in response to current strategies leads to the search for alternative inhibitors. The antiplatelet effect of the inorganic salt sodium tungstate (Na2O4W), a protein tyrosine phosphatase 1B (PTP1B) inhibitor, has been investigated in this study. Methods Wild-type (WT) and PTP1B knockout (PTP1B−/−) mice were treated for 1 week with Na2O4W to study platelet function with the platelet function analyzer PFA-100, a cone-and-plate analyzer, a flat perfusion chamber, and thrombus formation in vivo. Human blood aliquots were incubated with Na2O4W for 1 hour to measure platelet function using the PFA-100 and the annular perfusion chamber. Aggregometry and thromboelastometry were also performed. Results In WT mice, Na2O4W treatment prolonged closure times in the PFA-100 and decreased the surface covered (%SC) by platelets on collagen. Thrombi formed in a thrombosis mice model were smaller in animals treated with Na2O4W (4.6±0.7 mg vs 8.9±0.7 mg; P<0.001). Results with Na2O4W were similar to those in untreated PTP1B−/− mice (5.0±0.3 mg). Treatment of the PTP1B−/− mice with Na2O4W modified only slightly this response. In human blood, a dose-dependent effect was observed. At 200 μM, closure times in the PFA-100 were prolonged. On denuded vessels, %SC and thrombi formation (%T) decreased with Na2O4W. Neither the aggregating response nor the viscoelastic clot properties were affected. Conclusion Na2O4W decreases consistently the hemostatic capacity of platelets, inhibiting their adhesive and cohesive properties under flow conditions in mice and in human blood, resulting in smaller thrombi. Although Na2O4W may be acting on platelet PTP1B, other potential targets should not be disregarded. PMID:26060394

  19. Pathophysiology of cardiotoxicity from target therapy and angiogenesis inhibitors.

    PubMed

    Maurea, Nicola; Coppola, Carmela; Piscopo, Giovanna; Galletta, Francesca; Riccio, Gennaro; Esposito, Emanuela; De Lorenzo, Claudia; De Laurentiis, Michelino; Spallarossa, Paolo; Mercuro, Giuseppe

    2016-05-01

    The progress in cancer therapy and the increase in number of long-term survivors reveal the issue of cardiovascular side-effects of anticancer drugs. Cardiotoxicity has become a significant problem, and the risks of adverse cardiac events induced by systemic drugs need to be seriously considered. Potential cardiovascular toxicities linked to anticancer agents include arrhythmias, myocardial ischemia and infarction, hypertension, thromboembolism, left ventricular dysfunction, and heart failure. It has been shown that several anticancer drugs seriously affect the cardiovascular system, such as ErbB2 inhibitors, vascular endothelial growth factor (VEGF) inhibitors, multitargeted kinase inhibitors, Abelson murine leukemia viral oncogene homolog inhibitors, and others. Each of these agents has a different mechanism through which it affects the cardiovascular system. ErbB2 inhibitors block the ErbB4/ErbB2 heterodimerization pathway triggered by Neuregulin-1, which is essential for cardiomyocyte survival. VEGF signaling is crucial for vascular growth, but it also has a major impact on myocardial function, and the VEGF pathway is also essential for maintenance of cardiovascular homeostasis. Drugs that inhibit the VEGF signaling pathway lead to a net reduction in capillary density and loss of contractile function. Here, we review the mechanisms and pathophysiology of the most significant cardiotoxic effects of ErbB2 inhibitors and antiangiogenic drugs. Moreover, we highlight the role of cardioncology in recognizing these toxicities, developing strategies to prevent or minimize cardiovascular toxicity, and reducing long-term cardiotoxic effects. PMID:27183521

  20. Pathophysiology and management of primary immune thrombocytopenia.

    PubMed

    Kashiwagi, Hirokazu; Tomiyama, Yoshiaki

    2013-07-01

    Primary immune thrombocytopenia, or idiopathic thrombocytopenic purpura (ITP), is an autoimmune disorder characterized by isolated thrombocytopenia due to accelerated platelet destruction and impaired platelet production. Autoantibodies against platelet surface glycoproteins, such as GPIIb/IIIa and GPIb/IX complexes, play major roles in both platelet destruction and impaired platelet production, although autoantibody-independent mechanisms, such as T cell-mediated cytotoxicity, may also be involved in its pathogenesis. Recent advances in the localization of autoantigenic epitopes and the characterization of T cell functional abnormalities in ITP patients have improved our understanding of the pathophysiology of this disease. Although corticosteroids and splenectomy remain central to the treatment of ITP, a new class of drugs, i.e., thrombopoietin receptor agonists (TPO-RAs) and rituximab, have substantially broadened the therapeutic options for refractory ITP patients. Moreover, the success of TPO-RAs in ITP patients shows that reduced platelet production caused by impaired megakaryocytopoiesis plays a greater role in ITP than previously recognized. PMID:23702914

  1. Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management

    PubMed Central

    Pappachan, Joseph M; Varughese, George I; Sriraman, Rajagopalan; Arunagirinathan, Ganesan

    2013-01-01

    Diabetes affects every organ in the body and cardiovascular disease accounts for two-thirds of the mortality in the diabetic population. Diabetes-related heart disease occurs in the form of coronary artery disease (CAD), cardiac autonomic neuropathy or diabetic cardiomyopathy (DbCM). The prevalence of cardiac failure is high in the diabetic population and DbCM is a common but underestimated cause of heart failure in diabetes. The pathogenesis of diabetic cardiomyopathy is yet to be clearly defined. Hyperglycemia, dyslipidemia and inflammation are thought to play key roles in the generation of reactive oxygen or nitrogen species which are in turn implicated. The myocardial interstitium undergoes alterations resulting in abnormal contractile function noted in DbCM. In the early stages of the disease diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes in the later stages with impaired left ventricular ejection fraction. Transmitral Doppler echocardiography is usually used to assess diastolic dysfunction, but tissue Doppler Imaging and Cardiac Magnetic Resonance Imaging are being increasingly used recently for early detection of DbCM. The management of DbCM involves improvement in lifestyle, control of glucose and lipid abnormalities, and treatment of hypertension and CAD, if present. The role of vasoactive drugs and antioxidants is being explored. This review discusses the pathophysiology, diagnostic evaluation and management options of DbCM. PMID:24147202

  2. Ascites fluid in severe acute pancreatitis: from pathophysiology to therapy.

    PubMed

    Dugernier, T; Laterre, P F; Reynaert, M S

    2000-01-01

    Several pathophysiological mechanisms are involved in the development of the inflammatory necrotizing process that takes place in the retroperitoneal area during the early phase of acute pancreatitis. They include premature intraglandular activation of pancreatic proenzymes (zymogens) and in particular trypsin, early microcirculatory impairment with subsequent ischaemia/reperfusion and overstimulation of immune effector cells. Although intra-acinar or interstitial activation of trypsinogen is most probably the trigger of acute pancreatitis, in recent years much emphasis has been put on the role of leukocytes. Based on numerous experimental and human data several pro-inflammatory mediators including cytokines, arachidonic acid derivatives, activated oxygen species and proteases are released locally by overactivated neutrophils and monocytes/macrophages among other cells. They are now believed to play a central role in the development of pancreatic necrosis and, once they gain access to the systemic circulation, in the emergence of early multisystem organ failure. However the sequential and relative contribution of each of these 3 pathophysiological mechanisms remain controversial and the precise identification of the mediators incriminated in local and remote tissue injury is still awaited. Severe acute pancreatitis still carries a mortality of 20% to 30%. With advances in intensive care management 80% of the deaths occur somewhat late in the attack due to infected pancreatic necrosis. Nevertheless early remote organ failures still remain a lifethreatening condition for most of these patients. A peritoneal exudate rich in activated lipolytic and proteolytic enzymes, vasoactive substances and several other pro-inflammatory mediators collect in over 60% of the patients with severe acute pancreatitis. On the basis of favourable animal experiments early percutaneous or surgical peritoneal lavage with or without the addition of antiproteases has been carried out in human

  3. Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative, and neurobehavioral disorders: A review.

    PubMed

    Saeedi Saravi, Seyed Soheil; Dehpour, Ahmad Reza

    2016-01-15

    Organochlorine pesticides (OCPs) are persistent and bioaccumulative environmental contaminants with potential neurotoxic effects. The growing body of evidence has demonstrated that prenatal exposure to organochlorines (OCs) is associated with impairment of neuropsychological development. The hypothesis is consistent with recent studies emphasizing the correlation of environmental as well as genetic factors to the pathophysiology of neurodevelopmental and neurobehavioral defects. It has been suggested that maternal exposure to OCPs results in impaired motor and cognitive development in newborns and infants. Moreover, in utero exposure to these compounds contributes to the etiology of autism. Although impaired neurodevelopment occurs through prenatal exposure to OCs, breastfeeding causes postnatal toxicity in the infants. Parkinson's disease (PD) is another neurological disorder, which has been associated with exposure to OCs, leading to α-synuclein accumulation and depletion of dopaminergic neurons. The study aimed to review the potential association between pre- and post-natal exposure to OCs and impaired neurodevelopmental processes during pregnancy and neuropsychological diseases such as PD, behavioral alterations, seizures and autism. PMID:26549647

  4. Potential Role of Concentrating Solar Power in Enabling High Renewables Scenarios in the United States

    SciTech Connect

    Denholm, P.; Hand, M.; Mai, T.; Margolis, R.; Brinkman, G.; Drury, E.; Mowers, M.; Turchi, C.

    2012-10-01

    This work describes the analysis of concentrating solar power (CSP) in two studies -- The SunShot Vision Study and the Renewable Electricity Futures Study -- and the potential role of CSP in a future energy mix.

  5. The pathophysiology of heart failure.

    PubMed

    Kemp, Clinton D; Conte, John V

    2012-01-01

    Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10-38 billion per year. Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common. There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality. PMID:22227365

  6. Media Impact on Fright Reactions and Belief in UFOs: The Potential Role of Mental Imagery.

    ERIC Educational Resources Information Center

    Sparks, Glenn G.; And Others

    1995-01-01

    Explores the potential role of mental imagery for media effects in emotional responses to frightening mass media, and in the effects of the media on beliefs in UFOs. Finds that individual differences in vividness of mental imagery may play a crucial role in moderating both types of media impact. (SR)

  7. Pathophysiology of seasonal affective disorder: a review

    PubMed Central

    Lam, RW; Levitan, RD

    2000-01-01

    The study of the pathophysiology of seasonal affective disorder (SAD, also known as winter depression) has historically been intimately linked to investigations into the mechanisms of action of light therapy. This paper reviews the studies on the pathophysiology of SAD with emphasis on circadian, neurotransmitter, and genetic hypotheses. There is substantial evidence for circadian phase shift and serotonergic hypotheses, but conflicting results may indicate that SAD is a biologically heterogeneous condition. Recent progress in defining the molecular mechanisms of the human circadian clock and retinal phototransduction of light will provide important new directions for future studies of the etiology and pathophysiology of SAD. PMID:11109298

  8. Chemokines and the pathophysiology of neuropathic pain

    PubMed Central

    White, Fletcher A.; Jung, Hosung; Miller, Richard J.

    2007-01-01

    Chemokines and chemokine receptors are widely expressed by cells of the immune and nervous systems. This review focuses on our current knowledge concerning the role of chemokines in the pathophysiology of chronic pain syndromes. Injury- or disease-induced changes in the expression of diverse chemokines and their receptors have been demonstrated in the neural and nonneural elements of pain pathways. Under these circumstances, chemokines have been shown to modulate the electrical activity of neurons by multiple regulatory pathways including increases in neurotransmitter release through Ca-dependent mechanisms and transactivation of transient receptor channels. Either of these mechanisms alone, or in combination, may contribute to sustained excitability of primary afferent and secondary neurons within spinal pain pathways. Another manner in which chemokines may influence sustained neuronal excitability may be their ability to function as excitatory neurotransmitters within the peripheral and central nervous system. As is the case for traditional neurotransmitters, injury-induced up-regulated chemokines are found within synaptic vesicles. Chemokines released after depolarization of the cell membrane can then act on other chemokine receptor-bearing neurons, glia, or immune cells. Because up-regulation of chemokines and their receptors may be one of the mechanisms that directly or indirectly contribute to the development and maintenance of chronic pain, these molecules may then represent novel targets for therapeutic intervention in chronic pain states. PMID:18083844

  9. Sickle cell disease: selected aspects of pathophysiology.

    PubMed

    Alexy, T; Sangkatumvong, S; Connes, P; Pais, E; Tripette, J; Barthelemy, J C; Fisher, T C; Meiselman, H J; Khoo, M C; Coates, T D

    2010-01-01

    Sickle cell disease (SCD), a genetically-determined pathology due to an amino acid substitution (i.e., valine for glutamic acid) on the beta-chain of hemoglobin, is characterized by abnormal blood rheology and periods of painful vascular occlusive crises. Sickle cell trait (SCT) is a typically benign variant in which only one beta chain is affected by the mutation. Although both SCD and SCT have been the subject of numerous studies, information related to neurological function and transfusion therapy is still incomplete: an overview of these areas is presented. An initial section provides pertinent background information on the pathology and clinical significance of these diseases. The roles of three factors in the clinical manifestations of the diseases are then discussed: hypoxia, autonomic nervous system regulation and blood rheology. The possibility of a causal relationship between these three factors and sudden death is also examined. It is concluded that further studies in these specific areas are warranted. It is anticipated that the outcome of such research is likely to provide valuable insights into the pathophysiology of SCD and SCT and will lead to improved clinical management and enhanced quality of life. PMID:20364061

  10. Perimenstrual asthma: from pathophysiology to treatment strategies.

    PubMed

    Graziottin, Alessandra; Serafini, Audrey

    2016-01-01

    The prevalence of asthma is about 9,7 % in women and 5,5 % in men. Asthma can deteriorate during the perimenstrual period, a phenomenon known as perimenstrual asthma (PMA), which represents a unique, highly symptomatic asthma phenotype. It is distinguished from traditional allergic asthma by aspirin sensitivity, less atopy, and lower lung capacity. PMA incidence is reported to vary between 19 and 40 % of asthmatic women. The presence of PMA has been related to increases in asthma-related emergency department visits, hospitalizations and emergency treatment including intubations. It is hypothesized that hormonal status may influence asthma in women, focusing on the role of sex hormones, and specifically on the impact of estrogens' fluctuations at ovulation and before periods. This paper will focus on the pathophysiology of hormone triggered cycle related inflammatory/allergic events and their relation with asthma. We reviewed the scientific literature on Pubmed database for studies on PMA. Key word were PMA, mastcells, estrogens, inflammation, oral contraception, hormonal replacement therapy (HRT), and hormone free interval (HFI). Special attention will be devoted to the possibility of reducing the perimenstrual worsening of asthma and associated symptoms by reducing estrogens fluctuations, with appropriate hormonal contraception and reduced HFI. This novel therapeutical approach will be finally discussed. PMID:27482380

  11. Pathophysiological basis of systemic treatments in psoriasis.

    PubMed

    Volc, Sebastian; Ghoreschi, Kamran

    2016-06-01

    Over the past 15 years, the spectrum of systemic antipsoriatic treatments has dramatically expanded. Until the end of the last millennium, systemic therapy had been restricted to four oral agents: methotrexate, cyclosporine, acitretin, and fumaric acid esters. Today, there are additionally seven biologics and one new oral antipsoriatic drug, as well as the first available biosimilars. Six more biologics with novel target structures and at least four biosimilars are currently being developed (phase III). This progress has been based on new insights into the pathogenesis of psoriasis, in which tumor necrosis factor and especially Th17 immune responses with their associated cytokines interleukin 23 and 17 play a key role. The development of new-generation biologics as well as immunomodulatory small molecules can be attributed to these pathophysiological findings. Phosphodiesterase 4 inhibitors, dimethyl fumarate, and Janus kinase inhibitors all interact with Th17 immune responses. Some of these drugs are in advanced clinical development and are also beneficial in psoriatic arthritis. Today, psoriasis and psoriatic arthritis therefore rank among the most readily treatable inflammatory autoimmune disorders. Dermatology is increasingly becoming a specialty of modern targeted immunotherapies. PMID:27240060

  12. Extracellular Vesicles: Role in Inflammatory Responses and Potential Uses in Vaccination in Cancer and Infectious Diseases

    PubMed Central

    Campos, João Henrique; Soares, Rodrigo Pedro; Ribeiro, Kleber; Cronemberger Andrade, André; Batista, Wagner Luiz; Torrecilhas, Ana Claudia

    2015-01-01

    Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases. PMID:26380326

  13. Retinal vein occlusion: pathophysiology and treatment options

    PubMed Central

    Karia, Niral

    2010-01-01

    This paper reviews the current thinking about retinal vein occlusion. It gives an overview of its pathophysiology and discusses the evidence behind the various established and emerging treatment paradigms. PMID:20689798

  14. Pathophysiological Progression Model for Selected Toxicological Endpoints

    EPA Science Inventory

    The existing continuum paradigms are effective models to organize toxicological data associated with endpoints used in human health assessments. A compendium of endpoints characterized along a pathophysiological continuum would serve to: weigh the relative importance of effects o...

  15. Pathophysiological Consequences of Calcium-Conducting Viroporins.

    PubMed

    Hyser, Joseph M; Estes, Mary K

    2015-11-01

    Eukaryotic cells have evolved a myriad of ion channels, transporters, and pumps to maintain and regulate transmembrane ion gradients. As intracellular parasites, viruses also have evolved ion channel proteins, called viroporins, which disrupt normal ionic homeostasis to promote viral replication and pathogenesis. The first viral ion channel (influenza M2 protein) was confirmed only 23 years ago, and since then studies on M2 and many other viroporins have shown they serve critical functions in virus entry, replication, morphogenesis, and immune evasion. As new candidate viroporins and viroporin-mediated functions are being discovered, we review the experimental criteria for viroporin identification and characterization to facilitate consistency within this field of research. Then we review recent studies on how the few Ca(2+)-conducting viroporins exploit host signaling pathways, including store-operated Ca(2+) entry, autophagy, and inflammasome activation. These viroporin-induced aberrant Ca(2+) signals cause pathophysiological changes resulting in diarrhea, vomiting, and proinflammatory diseases, making both the viroporin and host Ca(2+) signaling pathways potential therapeutic targets for antiviral drugs. PMID:26958925

  16. Renal ischemia/reperfusion injury; from pathophysiology to treatment

    PubMed Central

    Malek, Maryam; Nematbakhsh, Mehdi

    2015-01-01

    Ischemia/reperfusion injury (IRI) is caused by a sudden temporary impairment of the blood flow to the particular organ. IRI usually is associated with a robust inflammatory and oxidative stress response to hypoxia and reperfusion which disturbs the organ function. Renal IR induced acute kidney injury (AKI) contributes to high morbidity and mortality rate in a wide range of injuries. Although the pathophysiology of IRI is not completely understood, several important mechanisms resulting in kidney failure have been mentioned. In ischemic kidney and subsequent of re-oxygenation, generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure. Better understanding of the cellular pathophysiological mechanisms underlying kidney injury will hopefully result in the design of more targeted therapies to prevent and treatment the injury. In this review, we summarize some important potential mechanisms and therapeutic approaches in renal IRI. PMID:26060833

  17. Facial Erythema of Rosacea - Aetiology, Different Pathophysiologies and Treatment Options.

    PubMed

    Steinhoff, Martin; Schmelz, Martin; Schauber, Jürgen

    2016-06-15

    Rosacea is a common chronic skin condition that displays a broad diversity of clinical manifestations. Although the pathophysiological mechanisms of the four subtypes are not completely elucidated, the key elements often present are augmented immune responses of the innate and adaptive immune system, and neurovascular dysregulation. The most common primary feature of all cutaneous subtypes of rosacea is transient or persistent facial erythema. Perilesional erythema of papules or pustules is based on the sustained vasodilation and plasma extravasation induced by the inflammatory infiltrates. In contrast, transient erythema has rapid kinetics induced by trigger factors independent of papules or pustules. Amongst the current treatments for facial erythema of rosacea, only the selective α2-adrenergic receptor agonist brimonidine 0.33% topical gel (Mirvaso®) is approved. This review aims to discuss the potential causes, different pathophysiologies and current treatment options to address the unmet medical needs of patients with facial erythema of rosacea. PMID:26714888

  18. Pathophysiology and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathies.

    PubMed

    Svahn, J; Antoine, J-C; Camdessanché, J-P

    2014-12-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired dysimmune disorder characterized by strong heterogeneity in terms of clinical manifestations, prognostic and response to treatment. To date, its pathophysiology and potential target antigens are not totally identified despite substantial progress in the understanding of the involved molecular mechanisms. Recent researches in the field have underlined the importance of cell-mediated immunity (lymphocytesT CD4+, CD8+ and macrophages), the breakdown of blood-nerve barrier, a failure of T-cell regulation, and the disruption of nodal and paranodal organization at the node of Ranvier. This last point is possibly mediated by autoantibodies towards axoglial adhesion molecules which may disrupt sodium and potassium voltage-gated channels clustering leading to a failure of saltatory conduction and the apparition of conduction blocks. The purpose of this article is to overview the main pathophysiologic mechanisms and biomarkers identified in CIDP. PMID:25459126

  19. Glial Na(+) -dependent ion transporters in pathophysiological conditions.

    PubMed

    Boscia, Francesca; Begum, Gulnaz; Pignataro, Giuseppe; Sirabella, Rossana; Cuomo, Ornella; Casamassa, Antonella; Sun, Dandan; Annunziato, Lucio

    2016-10-01

    Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na(+) signaling influences and regulates important glial activities, and plays a role in neuron-glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na(+) pumps and Na(+) -dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na(+) homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer's disease, epilepsy, Parkinson's disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na(+) -dependent ion transporters, including Na(+) /K(+) ATPase, Na(+) /Ca(2+) exchangers, Na(+) /H(+) exchangers, Na(+) -K(+) -Cl(-) cotransporters, and Na(+) - HCO3- cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na(+) -dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na(+) dynamics in different neurological disorders. GLIA 2016;64:1677-1697. PMID:27458821

  20. The role of piRNA and its potential clinical implications in cancer

    PubMed Central

    Assumpção, Carolina Baraúna; Calcagno, Danielle Queiroz; Araújo, Taíssa Maíra Thomaz; dos Santos, Sidney Emmanuel Batista; dos Santos, Ândrea Kely Campos Ribeiro; Riggins, Gregory Joseph; Burbano, Rommel Rodriguez; Assumpção, Paulo Pimentel

    2016-01-01

    Epigenetic mechanisms work in an orchestrated fashion to control gene expression in both homeostasis and diseases. Among small noncoding RNAs, piRNAs seem to meet the necessary requirements to be included in this epigenetic network due to their role in both transcriptional and post-transcriptional regulation. piRNAs and PIWI proteins might play important roles in cancer occurrence, prognosis and treatment as reported previously. Nevertheless, the potential clinical relevance of these molecules has yet been elucidated. A brief overview of piRNA biogenesis and their potential roles as part of an epigenetic network that is possibly involved in cancer is provided. Moreover, potential strategies based on the use of piRNAs and PIWI proteins as diagnostic and prognostic biomarkers as well as for cancer therapeutics are discussed. PMID:25929784

  1. The role of piRNA and its potential clinical implications in cancer.

    PubMed

    Assumpção, Carolina Baraúna; Calcagno, Danielle Queiroz; Araújo, Taíssa Maíra Thomaz; Santos, Sidney Emmanuel Batista dos; Santos, Ândrea Kely Campos Ribeiro dos; Riggins, Gregory Joseph; Burbano, Rommel Rodriguez; Assumpção, Paulo Pimentel

    2015-01-01

    Epigenetic mechanisms work in an orchestrated fashion to control gene expression in both homeostasis and diseases. Among small noncoding RNAs, piRNAs seem to meet the necessary requirements to be included in this epigenetic network due to their role in both transcriptional and post-transcriptional regulation. piRNAs and PIWI proteins might play important roles in cancer occurrence, prognosis and treatment as reported previously. Nevertheless, the potential clinical relevance of these molecules has yet been elucidated. A brief overview of piRNA biogenesis and their potential roles as part of an epigenetic network that is possibly involved in cancer is provided. Moreover, potential strategies based on the use of piRNAs and PIWI proteins as diagnostic and prognostic biomarkers as well as for cancer therapeutics are discussed. PMID:25929784

  2. Intermittent hypoxia from obstructive sleep apnea may cause neuronal impairment and dysfunction in central nervous system: the potential roles played by microglia

    PubMed Central

    Yang, Qingchan; Wang, Yan; Feng, Jing; Cao, Jie; Chen, Baoyuan

    2013-01-01

    Obstructive sleep apnea (OSA) is a common condition characterized by repetitive episodes of complete (apnea) or partial (hypopnea) obstruction of the upper airway during sleep, resulting in oxygen desaturation and arousal from sleep. Intermittent hypoxia (IH) resulting from OSA may cause structural neuron damage and dysfunction in the central nervous system (CNS). Clinically, it manifests as neurocognitive and behavioral deficits with oxidative stress and inflammatory impairment as its pathophysiological basis, which are mediated by microglia at the cellular level. Microglia are dominant proinflammatory cells in the CNS. They induce CNS oxidative stress and inflammation, mainly through mitochondria, reduced nicotinamide adenine dinucleotide phosphate oxidase, and the release of excitatory toxic neurotransmitters. The balance between neurotoxic versus protective and anti- versus proinflammatory microglial factors might determine the final roles of microglia after IH exposure from OSA. Microglia inflammatory impairments will continue and cascade persistently upon activation, ultimately resulting in clinically significant neuron damage and dysfunction in the CNS. In this review article, we summarize the mechanisms of structural neuron damage in the CNS and its concomitant dysfunction due to IH from OSA, and the potential roles played by microglia in this process. PMID:23950649

  3. Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success

    PubMed Central

    Fengler, Karl; Rommel, Karl Philipp; Okon, Thomas; Schuler, Gerhard; Lurz, Philipp

    2016-01-01

    Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success. PMID:27621771

  4. Relaxin: new pathophysiological aspects and pharmacological perspectives for an old protein.

    PubMed

    Cernaro, Valeria; Lacquaniti, Antonio; Lupica, Rosaria; Buemi, Antoine; Trimboli, Domenico; Giorgianni, Grazia; Bolignano, Davide; Buemi, Michele

    2014-01-01

    Human relaxin-2 (hereafter simply defined as "relaxin") is a 6-kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in-depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future. PMID:23401142

  5. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues.

    PubMed

    Pellegrinelli, Vanessa; Carobbio, Stefania; Vidal-Puig, Antonio

    2016-06-01

    White adipose tissue (WAT) has key metabolic and endocrine functions and plays a role in regulating energy homeostasis and insulin sensitivity. WAT is characterised by its capacity to adapt and expand in response to surplus energy through processes of adipocyte hypertrophy and/or recruitment and proliferation of precursor cells in combination with vascular and extracellular matrix remodelling. However, in the context of sustained obesity, WAT undergoes fibro-inflammation, which compromises its functionality, contributing to increased risk of type 2 diabetes and cardiovascular diseases. Conversely, brown adipose tissue (BAT) and browning of WAT represent potential therapeutic approaches, since dysfunctional white adipocyte-induced lipid overspill can be halted by BAT/browning-mediated oxidative anti-lipotoxic effects. Better understanding of the cellular and molecular pathophysiological mechanisms regulating adipocyte size, number and depot-dependent expansion has become a focus of interest over recent decades. Here, we summarise the mechanisms contributing to adipose tissue (AT) plasticity and function including characteristics and cellular complexity of the various adipose depots and we discuss recent insights into AT origins, identification of adipose precursors, pathophysiological regulation of adipogenesis and its relation to WAT/BAT expandability in obesity and its associated comorbidities. PMID:27039901

  6. Renal sympathetic denervation in therapy resistant hypertension - pathophysiological aspects and predictors for treatment success.

    PubMed

    Fengler, Karl; Rommel, Karl Philipp; Okon, Thomas; Schuler, Gerhard; Lurz, Philipp

    2016-08-26

    Many forms of human hypertension are associated with an increased systemic sympathetic activity. Especially the renal sympathetic nervous system has been found to play a prominent role in this context. Therefore, catheter-interventional renal sympathetic denervation (RDN) has been established as a treatment for patients suffering from therapy resistant hypertension in the past decade. The initial enthusiasm for this treatment was markedly dampened by the results of the Symplicity-HTN-3 trial, although the transferability of the results into clinical practice to date appears to be questionable. In contrast to the extensive use of RDN in treating hypertensive patients within or without clinical trial settings over the past years, its effects on the complex pathophysiological mechanisms underlying therapy resistant hypertension are only partly understood and are part of ongoing research. Effects of RDN have been described on many levels in human trials: From altered systemic sympathetic activity across cardiac and metabolic alterations down to changes in renal function. Most of these changes could sustainably change long-term morbidity and mortality of the treated patients, even if blood pressure remains unchanged. Furthermore, a number of promising predictors for a successful treatment with RDN have been identified recently and further trials are ongoing. This will certainly help to improve the preselection of potential candidates for RDN and thereby optimize treatment outcomes. This review summarizes important pathophysiologic effects of renal denervation and illustrates the currently known predictors for therapy success. PMID:27621771

  7. The Usual Suspects: Comparison of the Relative Roles of Potential Urban Chikungunya Virus Vectors in Australia

    PubMed Central

    Jansen, Cassie C.; Williams, Craig R.; van den Hurk, Andrew F.

    2015-01-01

    The global re-emergence of chikungunya virus (CHIKV) over the last decade presents a serious public health risk to Australia. An increasing number of imported cases further underline the potential for local transmission to occur if local mosquitoes bite an infected traveller. Laboratory experiments have identified a number of competent Australian mosquito species, including the primary vectors of CHIKV abroad, Aedes aegypti and Aedes albopictus, and local endemic species Aedes vigilax and Aedes notoscriptus. The implication of these additional endemic species as potential vectors has generated much uncertainty amongst public health professionals regarding their actual role in CHIKV transmission in the field. Using data estimated from or documented in the literature, we parameterise a simple vectorial capacity model to evaluate the relative roles of Australian mosquito species in potential CHIKV transmission. The model takes into account a number of key biological and ecological variables which influence the role of a species in field transmission, including population density, human feeding rates, mosquito survival rates and vector competence. We confirm the relative importance of Ae. aegypti and Ae. albopictus in sustaining potential CHIKV transmission in Australia. Even at maximum estimated densities and human feeding rates, Ae. vigilax and Ae. notoscriptus are likely to play a relatively minor role in CHIKV transmission, when compared with either Ae. aegypti or Ae. albopictus. This relatively straightforward analysis has application for any region where mosquito species have been incriminated in vector competence experiments, but where their actual role in CHIKV transmission has not been established. PMID:26247366

  8. MicroRNA profiling of antler stem cells in potentiated and dormant states and their potential roles in antler regeneration.

    PubMed

    Ba, Hengxing; Wang, Datao; Li, Chunyi

    2016-04-01

    MicroRNAs (miRNAs) can effectively regulate gene expression at the post-transcriptional level and play a critical role in tissue growth, development and regeneration. Our previous studies showed that antler regeneration is a stem cell-based process and antler stem cells reside in the periosteum of a pedicle, the permanent bony protuberance, from which antler regeneration takes place. Antlers are the only mammalian organ that can fully regenerate and hence provide a unique opportunity to identify miRNAs that are involved in organ regeneration. In the present study, we used next generation sequencing technology sequenced miRNAs of the stem cells derived from either the potentiated or the dormant pedicle periosteum. A population of both conserved and 20 deer-specific miRNAs was identified. These conserved miRNAs were derived from 453 homologous hairpin precursors across 88 animal species, and were further grouped into 167 miRNA families. Among them, the miR-296 is embryonic stem cell-specific. The potentiation process resulted in the significant regulation (>±2 Fold, q value <0.05) of conserved miRNAs; 8 miRNA transcripts were down- and 6 up-regulated. Several GO biology processes and the Wnt, MAPK and TGF-beta signaling pathways were found to be up-regulated as part of antlerogenic stem cell potentiation process. This research has identified miRNAs that are associated either with the dormant or the potentiated antler stem cells and identified some target miRNAs for further research into their role played in mammalian organ regeneration. PMID:26738876

  9. Altered Mitochondrial Dynamics and TBI Pathophysiology.

    PubMed

    Fischer, Tara D; Hylin, Michael J; Zhao, Jing; Moore, Anthony N; Waxham, M Neal; Dash, Pramod K

    2016-01-01

    Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS), and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI) reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1), which translocates to the mitochondrial outer membrane (MOM) to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 h post-injury, followed by a significant decrease in length at 72 h. Post-TBI administration of Mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the

  10. Altered Mitochondrial Dynamics and TBI Pathophysiology

    PubMed Central

    Fischer, Tara D.; Hylin, Michael J.; Zhao, Jing; Moore, Anthony N.; Waxham, M. Neal; Dash, Pramod K.

    2016-01-01

    Mitochondrial function is intimately linked to cellular survival, growth, and death. Mitochondria not only generate ATP from oxidative phosphorylation, but also mediate intracellular calcium buffering, generation of reactive oxygen species (ROS), and apoptosis. Electron leakage from the electron transport chain, especially from damaged or depolarized mitochondria, can generate excess free radicals that damage cellular proteins, DNA, and lipids. Furthermore, mitochondrial damage releases pro-apoptotic factors to initiate cell death. Previous studies have reported that traumatic brain injury (TBI) reduces mitochondrial respiration, enhances production of ROS, and triggers apoptotic cell death, suggesting a prominent role of mitochondria in TBI pathophysiology. Mitochondria maintain cellular energy homeostasis and health via balanced processes of fusion and fission, continuously dividing and fusing to form an interconnected network throughout the cell. An imbalance of these processes, particularly an excess of fission, can be detrimental to mitochondrial function, causing decreased respiration, ROS production, and apoptosis. Mitochondrial fission is regulated by the cytosolic GTPase, dynamin-related protein 1 (Drp1), which translocates to the mitochondrial outer membrane (MOM) to initiate fission. Aberrant Drp1 activity has been linked to excessive mitochondrial fission and neurodegeneration. Measurement of Drp1 levels in purified hippocampal mitochondria showed an increase in TBI animals as compared to sham controls. Analysis of cryo-electron micrographs of these mitochondria also showed that TBI caused an initial increase in the length of hippocampal mitochondria at 24 h post-injury, followed by a significant decrease in length at 72 h. Post-TBI administration of Mitochondrial division inhibitor-1 (Mdivi-1), a pharmacological inhibitor of Drp1, prevented this decrease in mitochondria length. Mdivi-1 treatment also reduced the loss of newborn neurons in the

  11. Pathophysiology of Acute Kidney Injury

    PubMed Central

    Basile, David P.; Anderson, Melissa D.; Sutton, Timothy A.

    2014-01-01

    Acute kidney injury (AKI) is the leading cause of nephrology consultation and is associated with high mortality rates. The primary causes of AKI include ischemia, hypoxia or nephrotoxicity. An underlying feature is a rapid decline in GFR usually associated with decreases in renal blood flow. Inflammation represents an important additional component of AKI leading to the extension phase of injury, which may be associated with insensitivity to vasodilator therapy. It is suggested that targeting the extension phase represents an area potential of treatment with the greatest possible impact. The underlying basis of renal injury appears to be impaired energetics of the highly metabolically active nephron segments (i.e., proximal tubules and thick ascending limb) in the renal outer medulla, which can trigger conversion from transient hypoxia to intrinsic renal failure. Injury to kidney cells can be lethal or sublethal. Sublethal injury represents an important component in AKI, as it may profoundly influence GFR and renal blood flow. The nature of the recovery response is mediated by the degree to which sublethal cells can restore normal function and promote regeneration. The successful recovery from AKI depends on the degree to which these repair processes ensue and these may be compromised in elderly or CKD patients. Recent data suggest that AKI represents a potential link to CKD in surviving patients. Finally, earlier diagnosis of AKI represents an important area in treating patients with AKI that has spawned increased awareness of the potential that biomarkers of AKI may play in the future. PMID:23798302

  12. Autophagy in Plasma Cell Pathophysiology

    PubMed Central

    Oliva, Laura; Cenci, Simone

    2014-01-01

    Plasma cells (PCs) are the effectors responsible for antibody (Ab)-mediated immunity. They differentiate from B lymphocytes through a complete remodeling of their original structure and function. Stress is a constitutive element of PC differentiation. Macroautophagy, conventionally referred to as autophagy, is a conserved lysosomal recycling strategy that integrates cellular metabolism and enables adaptation to stress. In metazoa, autophagy plays diverse roles in cell differentiation. Recently, a number of autophagic functions have been recognized in innate and adaptive immunity, including clearance of intracellular pathogens, inflammasome regulation, lymphocyte ontogenesis, and antigen presentation. We identified a previously unrecognized role played by autophagy in PC differentiation and activity. Following B cell activation, autophagy moderates the expression of the transcriptional repressor Blimp-1 and immunoglobulins through a selective negative control exerted on the size of the endoplasmic reticulum and its stress signaling response, including the essential PC transcription factor, XBP-1. This containment of PC differentiation and function, i.e., Ab production, is essential to optimize energy metabolism and viability. As a result, autophagy sustains Ab responses in vivo. Moreover, autophagy is an essential intrinsic determinant of long-lived PCs in their as yet poorly understood bone marrow niche. In this essay, we discuss these findings in the context of the established biological functions of autophagy, and their manifold implications for adaptive immunity and PC diseases, in primis multiple myeloma. PMID:24659989

  13. The pathophysiology of jet lag.

    PubMed

    Sack, Robert L

    2009-03-01

    Jet Lag Disorder (JLD) is a recognized circadian rhythm sleep disorder characterized by insomnia or excessive daytime sleepiness (and sometimes general malaise and somatic symptoms) associated with transmeridian jet travel. It is a consequence of circadian misalignment that occurs after crossing time zones too rapidly for the circadian system to keep pace. The thesis of this review is that a rational treatment approach for jet lag can be grounded in an understanding of the biology of the human circadian timekeeping system. An overview of circadian rhythm physiology is presented with special emphasis on the role of light exposure and melatonin secretion in the regulation of circadian timing. Both timed light exposure (or avoidance) and exogenous melatonin administration have been recruited as treatment modalities to accelerate circadian realignment, based on an understanding of their role in circadian physiology. In addition to circadian misalignment, other contributing causes to jet lag are considered including travel-related sleep deprivation and fatigue. Clinical field trials that have tested the application of circadian rhythm based interventions are then reviewed. PMID:19237143

  14. Graph theory findings in the pathophysiology of temporal lobe epilepsy

    PubMed Central

    Chiang, Sharon; Haneef, Zulfi

    2014-01-01

    Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. PMID:24831083

  15. Graph theory findings in the pathophysiology of temporal lobe epilepsy.

    PubMed

    Chiang, Sharon; Haneef, Zulfi

    2014-07-01

    Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE. PMID:24831083

  16. Deep brain stimulation for severe autism: from pathophysiology to procedure.

    PubMed

    Sinha, Saurabh; McGovern, Robert A; Sheth, Sameer A

    2015-06-01

    Autism is a heterogeneous neurodevelopmental disorder characterized by early-onset impairment in social interaction and communication and by repetitive, restricted behaviors and interests. Because the degree of impairment may vary, a spectrum of clinical manifestations exists. Severe autism is characterized by complete lack of language development and potentially life-threatening self-injurious behavior, the latter of which may be refractory to medical therapy and devastating for affected individuals and their caretakers. New treatment strategies are therefore needed. Here, the authors propose deep brain stimulation (DBS) of the basolateral nucleus of the amygdala (BLA) as a therapeutic intervention to treat severe autism. The authors review recent developments in the understanding of the pathophysiology of autism. Specifically, they describe the genetic and environmental alterations that affect neurodevelopment. The authors also highlight the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development, which create a pattern of dysfunctional neural networks involved in socioemotional processing. They then discuss how these findings implicate the BLA as a key node in the pathophysiology of autism and review a reported case of BLA DBS for treatment of severe autism. Much progress has been made in recent years in understanding the pathophysiology of autism. The BLA represents a logical neurosurgical target for treating severe autism. Further study is needed that considers mechanistic and operative challenges. PMID:26030703

  17. Diabetic macular oedema: pathophysiology, management challenges and treatment resistance.

    PubMed

    Bahrami, Bobak; Zhu, Meidong; Hong, Thomas; Chang, Andrew

    2016-08-01

    Diabetic macular oedema (DMO) is the leading cause of vision loss in patients living with diabetes. DMO results from hyperglycaemia-induced activation of pathways that lead to oxidative stress and release of cytokines, impairing the inner and outer blood-retinal barriers. Improved understanding of the pathophysiological mechanisms leading to DMO have led to the development of effective therapies, including vitreoretinal surgery, laser photocoagulation, intravitreal anti-vascular endothelial growth factor drugs and corticosteroids. Advances in imaging, including fluorescein angiography and optical coherence tomography, have also enhanced diagnosis and management of the condition. Despite these advances, there remain patients who do not respond completely to therapy, reflecting the complex pathophysiology of DMO. These patients may be considered treatment-resistant. In this review, we summarise the pathophysiology of DMO, as well as the available treatments and their mechanism of action. Additionally, we focus on treatment-resistant disease and review the literature on potential options for managing this complication of diabetes. PMID:27179659

  18. The potential role of stem cells in the treatment of urinary incontinence

    PubMed Central

    Tran, Christine

    2015-01-01

    Voiding dysfunction encompasses a wide range of urologic disorders including stress urinary incontinence and overactive bladder that have a detrimental impact on the quality of life of millions of men and women worldwide. In recent years, we have greatly expanded our understanding of the pathophysiology of these clinical conditions. However, current gold standard therapies often provide symptomatic relief without targeting the underlying etiology of disease development. Recently, the use of stem cells to halt disease progression and reverse underlying pathology has emerged as a promising method to restore normal voiding function. Stem cells are classically thought to aid in tissue repair via their ability for multilineage differentiation and self-renewal. They may also exert a therapeutic effect via the secretion of bioactive factors that direct other stem and progenitor cells to the area of injury, and that also possess antiapoptotic, antiscarring, neovascularization, and immunomodulatory properties. Local injections of mesenchymal, muscle-derived, and adipose-derived stem cells have all yielded successful outcomes in animal models of mechanical, nerve, or external urethral sphincter injury in stress urinary incontinence. Similarly, direct injection of mesenchymal and adipose-derived stem cells into the bladder in animal models of bladder overactivity have demonstrated efficacy. Early clinical trials using stem cells for the treatment of stress urinary incontinence in both male and female patients have also achieved promising functional results with minimal adverse effects. Although many challenges remain to be addressed prior to the clinical implementation of this technology, novel stem-cell-based therapies are an exciting potential therapy for voiding dysfunction. PMID:25642292

  19. Epidemiology, pathophysiology, and the future of ocular toxoplasmosis.

    PubMed

    Kijlstra, Aize; Petersen, Eskild

    2014-04-01

    Despite large advances in the field of ocular toxoplasmosis, large gaps still exist in our knowledge concerning the epidemiology and pathophysiology of this potentially blinding infectious disease. Although ocular toxoplasmosis is considered to have a high health burden, still little is known about its exact prevalence and how it affects the quality of life. The epidemiology of toxoplasmosis depends on local habits throughout the globe, and changes are likely in view of increased meat consumption in developing countries and demands for higher animal welfare in the Western world. Water is increasingly seen as an important risk factor and more studies are needed to quantitate and control the role of water exposure (drinking, swimming). Tools are now becoming available to study both the human host as well as parasite genetic factors in the development of ocular toxoplasmosis. Further research on the role of Toxoplasma strains as well as basic studies on parasite virulence is needed to explain why Toxoplasma associated eye disease is so severe in some countries, such as Brazil. Although genetic analysis of the parasite represents the gold standard, further developments in serotyping using peptide arrays may offer practical solutions to study the role of parasite strains in the pathogenesis of Toxoplasma retinochoroiditis. More research is needed concerning the pathways whereby the parasite can infect the retina. Once in the retina further tissue damage may be due to parasite virulence factors or could be caused by an aberrant host immune response. Local intraocular immune responses are nowadays used for diagnostic procedures. Future developments may include the use of Raman technology or the direct visualization of a Toxoplasma cyst by optical coherence tomography (OCT). With the availability of ocular fluid specimens obtained for diagnostic purposes and the development of advanced proteomic techniques, a biomarker fingerprint that is unique for an eye with

  20. Futurism: Its Potential and Actual Role in Master of Business Administration (MBA) Education

    ERIC Educational Resources Information Center

    Peterson, Robin T.

    2006-01-01

    In this article, the author highlights the potential role of "futurism" in master of business administration (MBA) curricula and the conceivable offerings of futurism to business planners. This article serves as a corollary to educators in MBA business education and concerns to the nature of futurism, the benefits of futurism to managerial…

  1. Developing Effective Earthquake Risk Reduction Strategies: The Potential Role of Academic Institutions in Lebanon

    ERIC Educational Resources Information Center

    Baytiyeh, Hoda

    2015-01-01

    Lebanon faces the risk of powerful earthquakes with potentially devastating effects. However, the Lebanese people in general have not yet recognized this risk, as current educational programs and government officials have failed to inform them about it. This article discusses the essential role that Lebanese institutions of higher education should…

  2. CARDIOVASCULAR INJURY FROM ACUTE AND REPEATED EXPOSURE TO PARTICULATE MATTER (PM): POTENTIAL ROLE OF ZINC

    EPA Science Inventory

    CARDIOVASCULAR INJURY FROM ACUTE AND REPEATED EXPOSURE TO PARTICULATE MATTER (PM): POTENTIAL ROLE OF ZINC. UP Kodavanti, MC Schladweiler, AD Ledbetter, RH Jaskot, PS Gilmour, DC Christiani, WP Watkinson, DL Costa, JK McGee, A Nyska. NHEERL, USEPA, RTP, NC; CEMALB, UNC, Chapel Hil...

  3. Etiology, pathophysiology, and staging of hallux rigidus.

    PubMed

    Botek, Georgeanne; Anderson, Martha A

    2011-04-01

    The condition of hallux limitus is well understood and agreed on as visualized histologically and radiographically. But the historically described pathophysiology and anatomy that predisposes to hallux limitus has been challenged. Numerous investigators have proposed anatomic abnormalities of the foot as a primary cause of this condition, but perhaps trauma is the only unanimously agreed on cause. However, this accounts for only a small percentage of cases. To strive for better treatment outcomes, understanding the pathophysiology, assessing patient risk factors, and recognizing causative agents can better equip the foot and ankle surgeon in managing this condition. PMID:21669337

  4. Pathophysiological insights from studies of retrieved coronary atherectomy tissue.

    PubMed

    Glover, C; O'Brien, E R

    2000-12-01

    Coronary atherectomy offers the intuitive advantage of removing tissue mass in order to improve blood flow. A second major benefit of atherectomy is the opportunity to study lesion tissue and make pathophysiological insights. The value of the latter cannot be over emphasized, as current animal models for the study of atherosclerosis and restenosis are fraught with limitations. In this review, we outline some of the key descriptive findings that have emerged from the study of atherectomy specimens. Specifically, we will focus on the role of smooth muscle cell proliferation, thrombus organization and matrix formation in primary atherosclerotic lesions, as well as restenotic lesions after balloon angioplasty and stenting. PMID:11176010

  5. Pathophysiology of venous leg ulceration--an update.

    PubMed

    Dormandy, J A

    1997-01-01

    The microcirculatory component of the pathophysiology of venous ulceration is now attracting considerable research interests, but is still far from fully elucidated. Currently, the central role is filled by the inappropriately activated white cell and its interaction with the endothelium. Interstitial oedema, pericapillary fibrin cuff and capillary microthromboses could all fit in with this hypothesis. However, there are other demonstrated changes, for instance in lymphatic drainage, intrinsic fibrinolysis and hemorheological changes which also need to be taken into account. The interaction between the microcirculatory changes is an obvious target for the systemic pharmacotherapy of venous ulceration. PMID:8995347

  6. Links between genetics and pathophysiology in the autism spectrum disorders

    PubMed Central

    Holt, Richard; Monaco, Anthony P

    2011-01-01

    Autism spectrum disorders (ASD) are important neuropsychiatric disorders, currently estimated to affect approximately 1% of children, with considerable emotional and financial costs. Significant collaborative effort has been made over the last 15 years in an attempt to unravel the genetic mechanisms underlying these conditions. This has led to important discoveries, both of the roles of specific genes, as well as larger scale chromosomal copy number changes. Here, we summarize some of the latest genetic findings in the field of ASD and attempt to link them with the results of pathophysiological studies to provide an overall picture of at least one of the mechanisms by which ASD may develop. PMID:21805639

  7. Platelet activity in the pathophysiology of inflammatory bowel diseases.

    PubMed

    Chen, Chunqiu; Li, Yongyu; Yu, Zhen; Liu, Zhanju; Shi, Yanhong; Lewandowska, Urszula; Sobczak, Marta; Fichna, Jakub; Kreis, Martin

    2015-01-01

    Platelets play a crucial role in immune responses. Impaired platelet activation may cause persistent mucosal inflammation through P-selectin, CD40-CD40L and other systems influencing granulocytes, macrophages or endothelial cells. Pharmacological regulation of platelet activation may reduce thromboembolism and limit the interaction of platelets with endothelial and inflammatory cells, in turn weakening the inflammatory responses. In this review we focus on pathophysiological activities of platelets in inflammatory bowel diseases and discuss the studies on currently available anti-platelet therapies in the treatment of gastrointestinal inflammation. Finally, we provide a prospective view to new anti-platelet agents currently under development. PMID:25585124

  8. Stereospecific potentiation of opiate analgesia by cocaine: predominant role of noradrenaline.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1987-01-01

    Cocaine hydrochloride (50 mg) pellets implanted subcutaneously in male Wistar rats potentiated the analgesia of morphine, levorphanol, methadone and buprenorphine as measured by the tail-withdrawal test. Potentiated opiate analgesia was abolished by naloxone and further enhanced by desipramine and phenoxybenzamine. Yohimbine, alpha-methyl p-tyrosine, haloperidol, zimelidine, methysergide, p-chlorophenylalanine produced no significant effect on potentiated opiate analgesia. Pseudo-cocaine (dextro-cocaine), which is several-fold less potent than cocaine as an inhibitor of noradrenaline and dopamine reuptake in the CNS, had no significant effect on opiate analgesia. Analgesia produced by low doses of baclofen, a GABA agonist, was also not potentiated by cocaine. This study suggests a predominant role for noradrenaline in the stereospecific potentiation of opiate analgesia by cocaine. PMID:3822492

  9. Pathophysiology and treatment of psychosis in Parkinson's disease: a review.

    PubMed

    Zahodne, Laura B; Fernandez, Hubert H

    2008-01-01

    Psychotic symptoms in Parkinson's disease (PD) are relatively common and, in addition to creating a disturbance in patients' daily lives, have consistently been shown to be associated with poor outcome. Our understanding of the pathophysiology of psychosis in PD has expanded dramatically over the past 15 years, from an initial interpretation of symptoms as dopaminergic drug adverse effects to the current view of a complex interplay of extrinsic and disease-related factors.PD psychosis has unique clinical features, namely that it arises within a context of a clear sensorium and retained insight, there is relative prominence of visual hallucinations and progression occurs over time. PD psychosis tends to emerge later in the disease course, and disease duration represents one risk factor for its development. The use of anti-PD medications (particularly dopamine receptor agonists) has been the most widely identified risk factor for PD psychosis. Other risk factors discussed in the literature include older age, disease severity, sleep disturbance, cognitive impairment, dementia and/or depression.Recent efforts have aimed to explore the complex pathophysiology of PD psychosis, which is now known to involve an interaction between extrinsic, drug-related and intrinsic, disease-related components. The most important extrinsic factor is use of dopaminergic medication, which plays a prominent role in PD psychosis. Intrinsic factors include visual processing deficits (e.g. lower visual acuity, colour and contrast recognition deficits, ocular pathology and functional brain abnormalities identified amongst hallucinating PD patients); sleep dysregulation (e.g. sleep fragmentation and altered dream phenomena); neurochemical (dopamine, serotonin, acetylcholine, etc.) and structural abnormalities involving site-specific Lewy body deposition; and genetics (e.g. apolipoprotein E epsilon4 allele and tau H1H1 genotype). Preliminary reports have also shown a potential relationship

  10. Carbohydrates in plant immunity and plant protection: roles and potential application as foliar sprays.

    PubMed

    Trouvelot, Sophie; Héloir, Marie-Claire; Poinssot, Benoît; Gauthier, Adrien; Paris, Franck; Guillier, Christelle; Combier, Maud; Trdá, Lucie; Daire, Xavier; Adrian, Marielle

    2014-01-01

    Increasing interest is devoted to carbohydrates for their roles in plant immunity. Some of them are elicitors of plant defenses whereas other ones act as signaling molecules in a manner similar to phytohormones. This review first describes the main classes of carbohydrates associated to plant immunity, their role and mode of action. More precisely, the state of the art about perception of "PAMP, MAMP, and DAMP (Pathogen-, Microbe-, Damage-Associated Molecular Patterns) type" oligosaccharides is presented and examples of induced defense events are provided. A particular attention is paid to the structure/activity relationships of these compounds. The role of sugars as signaling molecules, especially in plant microbe interactions, is also presented. Secondly, the potentialities and limits of foliar sprays of carbohydrates to stimulate plant immunity for crop protection against diseases are discussed, with focus on the roles of the leaf cuticle and phyllosphere microflora. PMID:25408694

  11. Transient receptor potential (TRP) channels in the airway: role in airway disease

    PubMed Central

    Grace, M S; Baxter, M; Dubuis, E; Birrell, M A; Belvisi, M G

    2014-01-01

    Over the last few decades, there has been an explosion of scientific publications reporting the many and varied roles of transient receptor potential (TRP) ion channels in physiological and pathological systems throughout the body. The aim of this review is to summarize the existing literature on the role of TRP channels in the lungs and discuss what is known about their function under normal and diseased conditions. The review will focus mainly on the pathogenesis and symptoms of asthma and chronic obstructive pulmonary disease and the role of four members of the TRP family: TRPA1, TRPV1, TRPV4 and TRPM8. We hope that the article will help the reader understand the role of TRP channels in the normal airway and how their function may be changed in the context of respiratory disease. PMID:24286227

  12. Carbohydrates in plant immunity and plant protection: roles and potential application as foliar sprays

    PubMed Central

    Trouvelot, Sophie; Héloir, Marie-Claire; Poinssot, Benoît; Gauthier, Adrien; Paris, Franck; Guillier, Christelle; Combier, Maud; Trdá, Lucie; Daire, Xavier; Adrian, Marielle

    2014-01-01

    Increasing interest is devoted to carbohydrates for their roles in plant immunity. Some of them are elicitors of plant defenses whereas other ones act as signaling molecules in a manner similar to phytohormones. This review first describes the main classes of carbohydrates associated to plant immunity, their role and mode of action. More precisely, the state of the art about perception of “PAMP, MAMP, and DAMP (Pathogen-, Microbe-, Damage-Associated Molecular Patterns) type” oligosaccharides is presented and examples of induced defense events are provided. A particular attention is paid to the structure/activity relationships of these compounds. The role of sugars as signaling molecules, especially in plant microbe interactions, is also presented. Secondly, the potentialities and limits of foliar sprays of carbohydrates to stimulate plant immunity for crop protection against diseases are discussed, with focus on the roles of the leaf cuticle and phyllosphere microflora. PMID:25408694

  13. Connecting biodiversity and potential functional role in modern euxinic environments by microbial metagenomics.

    PubMed

    Llorens-Marès, Tomàs; Yooseph, Shibu; Goll, Johannes; Hoffman, Jeff; Vila-Costa, Maria; Borrego, Carles M; Dupont, Chris L; Casamayor, Emilio O

    2015-07-01

    Stratified sulfurous lakes are appropriate environments for studying the links between composition and functionality in microbial communities and are potentially modern analogs of anoxic conditions prevailing in the ancient ocean. We explored these aspects in the Lake Banyoles karstic area (NE Spain) through metagenomics and in silico reconstruction of carbon, nitrogen and sulfur metabolic pathways that were tightly coupled through a few bacterial groups. The potential for nitrogen fixation and denitrification was detected in both autotrophs and heterotrophs, with a major role for nitrogen and carbon fixations in Chlorobiaceae. Campylobacterales accounted for a large percentage of denitrification genes, while Gallionellales were putatively involved in denitrification, iron oxidation and carbon fixation and may have a major role in the biogeochemistry of the iron cycle. Bacteroidales were also abundant and showed potential for dissimilatory nitrate reduction to ammonium. The very low abundance of genes for nitrification, the minor presence of anammox genes, the high potential for nitrogen fixation and mineralization and the potential for chemotrophic CO2 fixation and CO oxidation all provide potential clues on the anoxic zones functioning. We observed higher gene abundance of ammonia-oxidizing bacteria than ammonia-oxidizing archaea that may have a geochemical and evolutionary link related to the dominance of Fe in these environments. Overall, these results offer a more detailed perspective on the microbial ecology of anoxic environments and may help to develop new geochemical proxies to infer biology and chemistry interactions in ancient ecosystems. PMID:25575307

  14. Connecting biodiversity and potential functional role in modern euxinic environments by microbial metagenomics

    PubMed Central

    Llorens-Marès, Tomàs; Yooseph, Shibu; Goll, Johannes; Hoffman, Jeff; Vila-Costa, Maria; Borrego, Carles M; Dupont, Chris L; Casamayor, Emilio O

    2015-01-01

    Stratified sulfurous lakes are appropriate environments for studying the links between composition and functionality in microbial communities and are potentially modern analogs of anoxic conditions prevailing in the ancient ocean. We explored these aspects in the Lake Banyoles karstic area (NE Spain) through metagenomics and in silico reconstruction of carbon, nitrogen and sulfur metabolic pathways that were tightly coupled through a few bacterial groups. The potential for nitrogen fixation and denitrification was detected in both autotrophs and heterotrophs, with a major role for nitrogen and carbon fixations in Chlorobiaceae. Campylobacterales accounted for a large percentage of denitrification genes, while Gallionellales were putatively involved in denitrification, iron oxidation and carbon fixation and may have a major role in the biogeochemistry of the iron cycle. Bacteroidales were also abundant and showed potential for dissimilatory nitrate reduction to ammonium. The very low abundance of genes for nitrification, the minor presence of anammox genes, the high potential for nitrogen fixation and mineralization and the potential for chemotrophic CO2 fixation and CO oxidation all provide potential clues on the anoxic zones functioning. We observed higher gene abundance of ammonia-oxidizing bacteria than ammonia-oxidizing archaea that may have a geochemical and evolutionary link related to the dominance of Fe in these environments. Overall, these results offer a more detailed perspective on the microbial ecology of anoxic environments and may help to develop new geochemical proxies to infer biology and chemistry interactions in ancient ecosystems. PMID:25575307

  15. Membrane Repair: Mechanisms and Pathophysiology.

    PubMed

    Cooper, Sandra T; McNeil, Paul L

    2015-10-01

    Eukaryotic cells have been confronted throughout their evolution with potentially lethal plasma membrane injuries, including those caused by osmotic stress, by infection from bacterial toxins and parasites, and by mechanical and ischemic stress. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Calcium has been identified as the key trigger to activate an effective membrane repair response that utilizes exocytosis and endocytosis to repair a membrane tear, or remove a membrane pore. We here review what is known about the cellular and molecular mechanisms of membrane repair, with particular emphasis on the relevance of repair as it relates to disease pathologies. Collective evidence reveals membrane repair employs primitive yet robust molecular machinery, such as vesicle fusion and contractile rings, processes evolutionarily honed for simplicity and success. Yet to be fully understood is whether core membrane repair machinery exists in all cells, or whether evolutionary adaptation has resulted in multiple compensatory repair pathways that specialize in different tissues and cells within our body. PMID:26336031

  16. Potential role of transient receptor potential channel M5 in sensing putative pheromones in mouse olfactory sensory neurons.

    PubMed

    Oshimoto, Arisa; Wakabayashi, Yoshihiro; Garske, Anna; Lopez, Roberto; Rolen, Shane; Flowers, Michael; Arevalo, Nicole; Restrepo, Diego

    2013-01-01

    Based on pharmacological studies of chemosensory transduction in transient receptor potential channel M5 (TRPM5) knockout mice it was hypothesized that this channel is involved in transduction for a subset of putative pheromones in mouse olfactory sensory neurons (OSNs). Yet, in the same study an electroolfactogram (EOG) in the mouse olfactory epithelium showed no significant difference in the responses to pheromones (and odors) between wild type and TRPM5 knockout mice. Here we show that the number of OSNs expressing TRPM5 is increased by unilateral naris occlusion. Importantly, EOG experiments show that mice lacking TRPM5 show a decreased response in the occluded epithelia to putative pheromones as opposed to wild type mice that show no change upon unilateral naris occlusion. This evidence indicates that under decreased olfactory sensory input TRPM5 plays a role in mediating putative pheromone transduction. Furthermore, we demonstrate that cyclic nucleotide gated channel A2 knockout (CNGA2-KO) mice that show substantially decreased or absent responses to odors and pheromones also have elevated levels of TRPM5 compared to wild type mice. Taken together, our evidence suggests that TRPM5 plays a role in mediating transduction for putative pheromones under conditions of reduced chemosensory input. PMID:23613997

  17. Potential Role of Transient Receptor Potential Channel M5 in Sensing Putative Pheromones in Mouse Olfactory Sensory Neurons

    PubMed Central

    Oshimoto, Arisa; Wakabayashi, Yoshihiro; Garske, Anna; Lopez, Roberto; Rolen, Shane; Flowers, Michael; Arevalo, Nicole; Restrepo, Diego

    2013-01-01

    Based on pharmacological studies of chemosensory transduction in transient receptor potential channel M5 (TRPM5) knockout mice it was hypothesized that this channel is involved in transduction for a subset of putative pheromones in mouse olfactory sensory neurons (OSNs). Yet, in the same study an electroolfactogram (EOG) in the mouse olfactory epithelium showed no significant difference in the responses to pheromones (and odors) between wild type and TRPM5 knockout mice. Here we show that the number of OSNs expressing TRPM5 is increased by unilateral naris occlusion. Importantly, EOG experiments show that mice lacking TRPM5 show a decreased response in the occluded epithelia to putative pheromones as opposed to wild type mice that show no change upon unilateral naris occlusion. This evidence indicates that under decreased olfactory sensory input TRPM5 plays a role in mediating putative pheromone transduction. Furthermore, we demonstrate that cyclic nucleotide gated channel A2 knockout (CNGA2-KO) mice that show substantially decreased or absent responses to odors and pheromones also have elevated levels of TRPM5 compared to wild type mice. Taken together, our evidence suggests that TRPM5 plays a role in mediating transduction for putative pheromones under conditions of reduced chemosensory input. PMID:23613997

  18. Orthostatic hypotension: epidemiology, pathophysiology and management

    NASA Technical Reports Server (NTRS)

    Jacob, G.; Robertson, D.

    1995-01-01

    Orthostatic hypotension is characterized by low upright blood pressure levels and symptoms of cerebral hypoperfusion. Whereas orthostatic hypotension is heterogeneous, correct pathophysiologic diagnosis is important because of therapeutic and prognostic considerations. Although therapy is not usually curative, it can be extraordinarily beneficial if it is individually tailored. Management of the Shy-Drager syndrome (multiple-system atrophy) remains a formidable challenge.

  19. A research update on the potential roles of aquaporin 4 in neuroinflammation.

    PubMed

    Lan, Yu-Long; Fang, Deng-Yang; Zhao, Jie; Ma, Tong-Hui; Li, Shao

    2016-06-01

    The presence of aquaporins (AQPs) in the brain has led to intense research on the underlying roles of this family of proteins under both normal and pathological conditions. Aquaporin 4 (AQP4) is the major water-channel membrane protein expressed in the central nervous system (CNS), primarily in astrocytes. Emerging evidence suggests that AQP4 could play an important role in water and ion homeostasis in the brain, and it has been studied in various brain pathological conditions. However, far less is known about the potential for AQP4 to influence neuroinflammation and, furthermore, its potential role in neurodegenerative disorders such as Alzheimer's disease (AD). It has been suggested that the pathogenesis of many clinical diseases, such as neuromyelitis optica (NMO), multiple sclerosis (MS) and brain injuries, is related to the regulation of AQP4 expression. Investigating the effects of AQP4 on microglia and astrocytes could be important to understand its role in the pathogenesis of neuroinflammation. Although the exact roles of non-steroidal anti-inflammatory drugs (NSAIDs) in protection against the detrimental effects of neuroinflammation remain unclear, research into the possible neuroprotective effects of AQP4 against neuroinflammation regulation seems to be important for future investigations. PMID:26259614

  20. A potential role for tissue kallikrein-related peptidases in human cervico-vaginal physiology.

    PubMed

    Shaw, Julie L V; Diamandis, Eleftherios P

    2008-06-01

    Human tissue kallikrein-related peptidases (KLK) are a family of 15 genes located on chromosome 19q13.4 that encode secreted serine proteases with trypsin- and/or chymotrypsin-like activity. Relatively large levels of many KLKs are present in human cervico-vaginal fluid (CVF) and in the supernatant of cultured human vaginal epithelial cells. Many KLKs are also hormonally regulated in vaginal epithelial cells, particularly by glucocorticoids and estrogens. The physiological role of KLK in the vagina is currently unknown; however, analysis of the CVF proteome has revealed clues for potential KLK functions in this environment. Here, we detail potential roles for KLKs in cervico-vaginal physiology. First, we suggest that KLKs play a role in the vagina similar to their role in skin physiology: (1) in the desquamation of vaginal epithelial cells, similar to their activity in the desquamation of skin corneocytes; and (2) in their ability to activate antimicrobial proteins in CVF as they do in sweat. Consequently, we hypothesize that dysregulated KLK expression in the vagina could lead to the development of pathological conditions such as desquamative inflammatory vaginitis. Second, we propose that KLKs may play a role in premature rupture of membranes and pre-term birth through their cleavage of fetal membrane extracellular matrix proteins. PMID:18627298

  1. Assessing Fundamental Drivers of the Global Electric Circuit and the Potential Role of Earthquakes (Invited)

    NASA Astrophysics Data System (ADS)

    Golkowski, M.; Kubicki, M.; Brady, B.

    2013-12-01

    The relationship between atmospheric currents and ionospheric potentials on a planetary scale, known as the Global Electric Circuit (GEC), has been the subject of investigation for almost 100 years. Lightning and thundercloud activity have long been suspected to be the fundamental drivers of the GEC. While these atmospheric activities play a role in the GEC, there is still some uncertainty whether they are the only driving mechanism of the observed DC global ionospheric potential. We reassess the role of lightning and thunderclouds as the main driver of the GEC using the newly deployed Vaisala Global Lightning Dataset (GLD360), which offers global and accurate real-time lightning coverage. Diurnal and geographic variation of lightning activity are averaged over the two year dataset and compared to previous results. Lightning activity for individual days is also compared with atmospheric electric field measurements made on the European continent. Our investigations suggest that atmospheric activity associated with lightning as the only primary driver of the GEC has difficulties. Several investigators have raised the possibility of the potential role of electromagnetic effects associated with fracturing of rock materials in the source region of crustal earthquakes on exciting the GEC. Unfortunately, the physical processes associated with crustal fracture in the source zone are poorly understood. We examine several mechanisms including the role that fluids present in the hypocentral region of pending earthquakes play in generating streaming potentials that may be associated with generating electromagnetic effects. Changes during the earthquake preparation process can produce observed changes in the GEC. We believe this mechanism provides a process that can generate electromagnetic effects that are crucially dependent on the focal mechanism, magnitude and rupture process of the pending earthquake. We highlight cases of anomalies in atmospheric electric field

  2. The pathophysiology of primary hyperparathyroidism.

    PubMed

    Brown, Edward M

    2002-11-01

    The parathyroid glands play a key role in maintaining near constancy of the extracellular calcium concentration ( Ca(o)2+) through their capacity to sense even minute changes in the level of blood calcium from its normal level. The G protein-coupled, Ca(o)(2+)-sensing receptor (CaSR) is the mechanism through which the parathyroid chief cells senses changes in Ca(o)2+. In primary hyperparathyroidism (PHPT), Ca(o)2+ is reset upward from its normal level. This defect likely arises from increases in both the mass of pathological parathyroid tissue as well as the set point for Ca(o)(2+)-regulated parathyroid hormone (PTH) release. The former likely arises from somatic mutations that enhance parathyroid cellular proliferation, although our understanding of the mechanism(s) underlying the latter is incomplete. However, substantial insights have been achieved through the study of inherited disorders caused by mutations in CaSR gene. In familial hypocalciuric hypercalcemia (FHH), heterozygous inactivating mutations in the CaSR gene produce mild, generally asymptomatic hypercalcemia, whereas in neonatal severe hyperparathyroidism (NSHPT), homozygous inactivating mutations cause severe hypercalcemia and hyperparathyroidism. Thus, the body's "calciostat" is reset upward in FHH and NSHPT because of resistance of CaSR-expressing cells, including the parathyroid cells, to Ca(o)2+. In FHH, there is a reduced complement of normal CaSRs (e.g., haploinsufficiency) that likely provides an explanation for the Ca(o)(2+)-resistance in this condition, whereas in NSHPT, there are no normally functioning CaSRs, thereby engendering more severe Ca(o)2+ resistance. Although somatic mutations in the CaSR gene could provide an explanation for the Ca(o)(2+)-resistance in PHPT, no such mutations have been found. Instead, in PHPT, the resistance of pathological parathyroid glands to Ca(o)2+ results, at least in part, from a reduced expression of otherwise apparently structurally normal CaSRs. Thus

  3. The potential role of telocytes in Tissue Engineering and Regenerative Medicine.

    PubMed

    Boos, Anja M; Weigand, Annika; Brodbeck, Rebekka; Beier, Justus P; Arkudas, Andreas; Horch, Raymund E

    2016-07-01

    Research and ideas for potential applications in the field of Tissue Engineering (TE) and Regenerative Medicine (RM) have been constantly increasing over recent years, basically driven by the fundamental human dream of repairing and regenerating lost tissue and organ functions. The basic idea of TE is to combine cells with putative stem cell properties with extracellular matrix components, growth factors and supporting matrices to achieve independently growing tissue. As a side effect, in the past years, more insights have been gained into cell-cell interaction and how to manipulate cell behavior. However, to date the ideal cell source has still to be found. Apart from commonly known various stem cell sources, telocytes (TC) have recently attracted increasing attention because they might play a potential role for TE and RM. It becomes increasingly evident that TC provide a regenerative potential and act in cellular communication through their network-forming telopodes. While TE in vitro experiments can be the first step, the key for elucidating their regenerative role will be the investigation of the interaction of TC with the surrounding tissue. For later clinical applications further steps have to include an upscaling process of vascularization of engineered tissue. Arteriovenous loop models to vascularize such constructs provide an ideal platform for preclinical testing of future therapeutic concepts in RM. The following review article should give an overview of what is known so far about the potential role of TC in TE and RM. PMID:26805441

  4. Multivariate analysis of pathophysiological factors in reflux oesophagitis.

    PubMed Central

    Cadiot, G; Bruhat, A; Rigaud, D; Coste, T; Vuagnat, A; Benyedder, Y; Vallot, T; Le Guludec, D; Mignon, M

    1997-01-01

    BACKGROUND: Reflux oesophagitis is considered a multifactorial disease, but the respective roles of the main factors involved in its pathophysiology have not been clearly established. AIMS: To attempt to assign these roles by means of a multivariate logistic regression analysis of the main parameters associated with reflux oesophagitis. PATIENTS: Eighty seven patients with gastro-oesophageal reflux disease were studied: 41 without oesophagitis and 46 with reflux oesophagitis grade 1 to 3. METHODS: (1) Monovariate comparison of patients' characteristics and of parameters derived from in hospital 24 hour oesophageal pH monitoring, oesophageal manometry, double isotope gastric emptying studies, and basal and pentagastrin stimulated gastric acid and pepsin output determinations, between patients with and without oesophagitis. (2) Multivariate logistic regression analysis including the parameters significant in the monovariate analysis. RESULTS: Among the 16 significant parameters from monovariate analysis, three significant independent parameters were identified by multivariate logistic regression analysis: number of refluxes lasting more than five minutes, reflecting oesophageal acid clearance (p = 0.002); basal lower oesophageal sphincter pressure (p = 0.008); and peak acid output (p = 0.012). These three parameters were not correlated with each other. The multivariate model was highly discriminant (correct classification of 81.3% of the cases (95% confidence intervals 0.723, 0.903). Risk for oesophagitis increased as a function of the tercile threshold values of the three parameters. Odds ratios of the three parameters for oesophagitis risk were similar, regardless of whether they were calculated when the patients were compared as a function of oesophagitis grade or the presence or absence of oesophagitis. CONCLUSIONS: This multivariate approach adds evidence that impaired oesophageal acid clearance and hypotonic lower oesophageal sphincter are the two major

  5. In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: a potential pathophysiological mechanism of striatal damage in this disorder.

    PubMed

    Fernandes, Carolina Gonçalves; da Rosa, Mateus Struecker; Seminotti, Bianca; Pierozan, Paula; Martell, Rafael Wolter; Lagranha, Valeska Lizzi; Busanello, Estela Natacha Brandt; Leipnitz, Guilhian; Wajner, Moacir

    2013-06-01

    3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a genetic disorder biochemically characterized by predominant accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Clinically, the patients present neurological symptoms and basal ganglia injury, whose pathomechanisms are partially understood. In the present study, we investigated the ex vivo effects of intrastriatal administration of HMG and MGA on important parameters of oxidative stress in striatum of developing rats. Our results demonstrate that HMG and MGA induce lipid and protein oxidative damage. HMG and MGA also increased 2',7'-dichlorofluorescein oxidation, whereas only HMG elicited nitric oxide production, indicating a role for reactive oxygen (HMG and MGA) and nitrogen (HMG) species in these effects. Regarding the enzymatic antioxidant defenses, both organic acids decreased reduced glutathione concentrations and the activities of superoxide dismutase and glutathione reductase and increased glutathione peroxidase activity. HMG also provoked an increase of catalase activity and a diminution of glucose-6-phosphate dehydrogenase activity. We finally observed that antioxidants fully prevented or attenuated HMG-induced alterations of the oxidative stress parameters, further indicating the participation of reactive species in these effects. We also observed that MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, prevented some of these effects, indicating the involvement of the NMDA receptor in HMG effects. The present data provide solid evidence that oxidative stress is induced in vivo by HMG and MGA in rat striatum and it is presumed that this pathomechanism may explain, at least in part, the cerebral alterations observed in HL deficiency. PMID:23611578

  6. Cardiovascular Simulation of Heart Failure Pathophysiology and Therapeutics.

    PubMed

    Doshi, Darshan; Burkhoff, Daniel

    2016-04-01

    Mathematical modeling and simulation allows for an in-depth examination of the cardiovascular system and provides the opportunity to develop deeper understanding. This review summarizes recent efforts at modeling the cardiovascular system and how these models have been useful in providing greater comprehension of the pathophysiology of heart failure, explaining the hemodynamic impact of various heart failure devices, predicting the hemodynamic effects and clinical outcomes of certain heart failure clinical trials, and perhaps aiding in patient selection for new therapies. The potential future use of these models in clinical research and clinical practice are also discussed. PMID:26703246

  7. Obesity and Pulmonary Hypertension: A Review of Pathophysiologic Mechanisms

    PubMed Central

    Friedman, Scott E.; Andrus, Bruce W.

    2012-01-01

    Pulmonary hypertension (PH) is a potentially life-threatening condition arising from a wide variety of pathophysiologic mechanisms. Effective treatment requires a systematic diagnostic approach to identify all reversible mechanisms. Many of these mechanisms are relevant to those afflicted with obesity. The unique mechanisms of PH in the obese include obstructive sleep apnea, obesity hypoventilation syndrome, anorexigen use, cardiomyopathy of obesity, and pulmonary thromboembolic disease. Novel mechanisms of PH in the obese include endothelial dysfunction and hyperuricemia. A wide range of effective therapies exist to mitigate the disability of PH in the obese. PMID:22988490

  8. The FGF family: biology, pathophysiology and therapy

    PubMed Central

    Beenken, Andrew; Mohammadi, Moosa

    2013-01-01

    The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases. PMID:19247306

  9. MicroRNAs take part in pathophysiology and pathogenesis of Male Pattern Baldness.

    PubMed

    Goodarzi, Hamed R; Abbasi, Ali; Saffari, Mojtaba; Tabei, Mohammad B; Noori Daloii, Mohammad R

    2010-07-01

    Male Pattern Baldness (MPB) or androgenetic alopecia is a common form of hair loss with androgens and genetics having etiological significance. Androgens are thought to pathophysiologically power on cascades of chronically dramatic alterations in genetically susceptible scalp dermal papillas, specialized cells in hair follicles in which androgens react, and finally resulting in a patterned alopecia. However, the exact mechanisms through which androgens, positive regulators of growth and anabolism in most body sites, paradoxically exert their effects on balding hair follicles, are not yet known. The role of microRNAs, a recently discovered class of non-coding RNAs, with a wide range of regulatory functions, has been documented in hair follicle formation and their deregulation in cancer of prostate, a target organ of androgens has also been delineated. Yet, there is a lack of knowledge in agreement with microRNAs' contribution in pathophysiology of MPB. To investigate the role of microRNAs in pathogenesis of MPB, we selected seven microRNAs, predicted bioinformatically on a reverse engineering basis, from previously published microarray gene expression data and analyzed their expression in balding relative to non-balding dermal papillas. We found for the first time upregulation of four microRNAs (miR-221, miR-125b, miR-106b and miR-410) that could participate in pathogenesis of MPB. Regarding microRNAs' therapeutic potential and accessibility of hair follicles for gene therapy, these microRNAs can be considered as good candidates for a new revolutionized generation of treatments. PMID:19821055

  10. Potential role of dietary lipids in the prophylaxis of some clinical conditions

    PubMed Central

    2015-01-01

    An imbalance of dietary lipids may potentially have a significant role in the pathobiology of some chronic diseases. Public health dietary fat recommendations have emphasized that low saturated fat, high monounsaturated fat, and high polyunsaturated fat with a lower ω-6 to ω-3 fatty acid ratio intake are necessary for normal health. However, such universal recommendations are likely to be hazardous, since the outcome of recommended lipid intake may depend on the consumption of other important dietary constituents that have an important role in the metabolism of lipids. In addition, consumption of fatty acids as per the individually tailored specific requirements in the context of other nutritional factors may have the potential to stabilize hormones, mood and sleep, and minimize adverse events. In support of this proposal, we review various factors that influence fatty acid metabolism, which need to be taken into consideration for appropriate utilization and consequently prevention of various diseases. PMID:26322094

  11. Poly(ADP-Ribose) Polymerase in Cervical Cancer Pathogenesis: Mechanism and Potential Role for PARP Inhibitors.

    PubMed

    Kotsopoulos, Ioannis C; Kucukmetin, Ali; Mukhopadhyay, Asima; Lunec, John; Curtin, Nicola J

    2016-05-01

    Treatment options for disease recurrence of women treated for locally advanced and advanced cervical cancer are very limited-largely palliative chemotherapy. The low efficacy of the currently available drugs raises the need for new targeted agents. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutic agents in cancers associated with defects in DNA repair. Their therapeutic potential in cervical cancer is currently being evaluated in 3 ongoing clinical trials. Here we review the available information regarding all the aspects of PARP in cervical intraepithelial neoplasia and invasive cervical cancer, from expression and the mechanism of action to the role of the polymorphisms in the pathogenesis of the disease, as well as the potential of the inhibitors. We finally propose a new unifying theory regarding the role of PARPs in the development of cervical carcinomas. PMID:26905326

  12. The Role of Bacterial Spores in Metal Cycling and Their Potential Application in Metal Contaminant Bioremediation.

    PubMed

    Butterfield, Cristina N; Lee, Sung-Woo; Tebo, Bradley M

    2016-04-01

    Bacteria are one of the premier biological forces that, in combination with chemical and physical forces, drive metal availability in the environment. Bacterial spores, when found in the environment, are often considered to be dormant and metabolically inactive, in a resting state waiting for favorable conditions for them to germinate. However, this is a highly oversimplified view of spores in the environment. The surface of bacterial spores represents a potential site for chemical reactions to occur. Additionally, proteins in the outer layers (spore coats or exosporium) may also have more specific catalytic activity. As a consequence, bacterial spores can play a role in geochemical processes and may indeed find uses in various biotechnological applications. The aim of this review is to introduce the role of bacteria and bacterial spores in biogeochemical cycles and their potential use as toxic metal bioremediation agents. PMID:27227313

  13. On the potential roles of ticks and migrating birds in the ecology of West Nile virus

    PubMed Central

    Hagman, Karl; Barboutis, Christos; Ehrenborg, Christian; Fransson, Thord; Jaenson, Thomas G. T.; Lindgren, Per-Eric; Lundkvist, Åke; Nyström, Fredrik; Waldenström, Jonas; Salaneck, Erik

    2014-01-01

    Background Mosquitoes are the primary vectors of West Nile virus (WNV). Ticks have, however, been suggested to be potential reservoirs of WNV. In order to investigate their role in the spread of the virus, ticks, which had been collected from birds migrating northwards from Africa to Europe, were analyzed for the potential presence of WNV-RNA. Methods On the Mediterranean islands Capri and Antikythira a total of 14,824 birds were captured and investigated from which 747 ticks were collected. Results and conclusion Most of the identified ticks (93%) were nymphs and larvae of Hyalomma marginatum sensu lato, most of which were or appear to be Hyalomma rufipes. Of these ticks 729 were individually screened for WNV-RNA. None of the ticks was found to be WNV positive. Thus, there was no evidence that Hyalomma marginatum s.l. ticks play a role in the spread of WNV from Africa to Europe. PMID:24455105

  14. The role of the computer in science fair projects: Current status and potential

    SciTech Connect

    Trainor, M.S.

    1991-01-01

    The need for more students to enter the field of science is acute in the nation, and science fair projects provide a motivational mechanism to entice students into pursuing scientific careers. Computers play a major role in science today. Because computers are a major source of entertainment for our children, one would expect them to play a significant role in many science fair projects. This study investigated current and potential uses of computers in science fair projects and incorporated an informal case study of scientists, teachers, and students involved in science fair projects from a highly scientific community. Interviews, a survey, and observations were conducted. Results indicated that most projects either do not use or inadequately use computers and that a significant potential for more effective use of computers for science fair projects exists.

  15. RNAi Screen Reveals Potentially Novel Roles of Cytokines in Myoblast Differentiation

    PubMed Central

    Ge, Yejing; Waldemer, Rachel J.; Nalluri, Ramakrishna; Nuzzi, Paul D.; Chen, Jie

    2013-01-01

    Cytokines are cell-secreted signaling molecules that modulate various cellular functions, with the best-characterized roles in immune responses. The expression of numerous cytokines in skeletal muscle tissues and muscle cells has been reported, but their function in skeletal myogenesis, the formation of skeletal muscle, has been largely underexplored. To systematically examine the potential roles of cytokines in skeletal myogenesis, we undertook an RNAi screen of 134 mouse cytokine genes for their involvement in the differentiation of C2C12 myoblasts. Our results have uncovered 29 cytokines as strong candidates for novel myogenic regulators, potentially conferring positive and negative regulation at distinct stages of myogenesis. These candidates represent a diverse collection of cytokine families, including interleukins, TNF-related factors, and chemokines. Our findings suggest the fundamental importance of cytokines in the cell-autonomous regulation of myoblast differentiation, and may facilitate future identification of novel therapeutic targets for improving muscle regeneration and growth in health and diseases. PMID:23844157

  16. Recent developments in the pathophysiology of irritable bowel syndrome

    PubMed Central

    El-Salhy, Magdy

    2015-01-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients. PMID:26167065

  17. Recent developments in the pathophysiology of irritable bowel syndrome.

    PubMed

    El-Salhy, Magdy

    2015-07-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder, the pathophysiology of which is not completely known, although it has been shown that genetic/social learning factors, diet, intestinal microbiota, intestinal low-grade inflammation, and abnormal gastrointestinal endocrine cells play a major role. Studies of familial aggregation and on twins have confirmed the heritability of IBS. However, the proposed IBS risk genes are thus far nonvalidated hits rather than true predisposing factors. There is no convincing evidence that IBS patients suffer from food allergy/intolerance, with the effect exerted by diet seemingly caused by intake of poorly absorbed carbohydrates and fiber. Obesity is a possible comorbidity of IBS. Differences in the microbiota between IBS patients and healthy controls have been reported, but the association between IBS symptoms and specific bacterial species is uncertain. Low-grade inflammation appears to play a role in the pathophysiology of a major subset of IBS, namely postinfectious IBS. The density of intestinal endocrine cells is reduced in patients with IBS, possibly as a result of genetic factors, diet, intestinal microbiota, and low-grade inflammation interfering with the regulatory signals controlling the intestinal stem-cell clonogenic and differentiation activities. Furthermore, there is speculation that this decreased number of endocrine cells is responsible for the visceral hypersensitivity, disturbed gastrointestinal motility, and abnormal gut secretion seen in IBS patients. PMID:26167065

  18. Heat Shock Proteins: Pathogenic Role in Atherosclerosis and Potential Therapeutic Implications

    PubMed Central

    Kilic, Arman; Mandal, Kaushik

    2012-01-01

    Heat shock proteins (HSPs) are a highly conserved group of proteins that are constitutively expressed and function as molecular chaperones, aiding in protein folding and preventing the accumulation of misfolded proteins. In the arterial wall, HSPs have a protective role under normal physiologic conditions. In disease states, however, HSPs expressed on the vascular endothelial cell surface can act as targets for detrimental autoimmunity due to their highly conserved sequences. Developing therapeutic strategies for atherosclerosis based on HSPs is challenged by the need to balance such physiologic and pathologic roles of these proteins. This paper summarizes the role of HSPs in normal vascular wall processes as well as in the development and progression of atherosclerosis. The potential implications of HSPs in clinical therapies for atherosclerosis are also discussed. PMID:23304456

  19. Amniotic Fluid Embolism Pathophysiology Suggests the New Diagnostic Armamentarium: β-Tryptase and Complement Fractions C3-C4 Are the Indispensable Working Tools

    PubMed Central

    Busardò, Francesco Paolo; Frati, Paola; Zaami, Simona; Fineschi, Vittorio

    2015-01-01

    Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word “AFE” was searched singularly and associated individually to each of the other keywords. Of the 146 sources found, only 19 were considered appropriate for the purpose of this paper. The clinical course is characterized by a rapid onset of symptoms, which include: acute hypotension and/or cardiac arrest, acute hypoxia (with dyspnoea, cyanosis and/or respiratory arrest), coagulopathies (disseminated intravascular coagulation and/or severe hemorrhage), coma and seizures. The pathology still determines a significant morbidity and mortality and potential permanent neurological sequelae for surviving patients. At this moment, numerous aspects involving the pathophysiology and clinical development are still not understood and several hypotheses have been formulated, in particular the possible role of anaphylaxis and complement. Moreover, the detection of serum tryptase and complement components and the evaluation of fetal antigens can explain several aspects of immune response. PMID:25807263

  20. Amniotic fluid embolism pathophysiology suggests the new diagnostic armamentarium: β-tryptase and complement fractions C3-C4 are the indispensable working tools.

    PubMed

    Busardò, Francesco Paolo; Frati, Paola; Zaami, Simona; Fineschi, Vittorio

    2015-01-01

    Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word "AFE" was searched singularly and associated individually to each of the other keywords. Of the 146 sources found, only 19 were considered appropriate for the purpose of this paper. The clinical course is characterized by a rapid onset of symptoms, which include: acute hypotension and/or cardiac arrest, acute hypoxia (with dyspnoea, cyanosis and/or respiratory arrest), coagulopathies (disseminated intravascular coagulation and/or severe hemorrhage), coma and seizures. The pathology still determines a significant morbidity and mortality and potential permanent neurological sequelae for surviving patients. At this moment, numerous aspects involving the pathophysiology and clinical development are still not understood and several hypotheses have been formulated, in particular the possible role of anaphylaxis and complement. Moreover, the detection of serum tryptase and complement components and the evaluation of fetal antigens can explain several aspects of immune response. PMID:25807263

  1. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology.

    PubMed

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  2. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    PubMed Central

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G.; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P.

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  3. Role of transient receptor potential and acid-sensing ion channels in peripheral inflammatory pain.

    PubMed

    White, John P M; Cibelli, Mario; Rei Fidalgo, Antonio; Paule, Cleoper C; Noormohamed, Faruq; Urban, Laszlo; Maze, Mervyn; Nagy, Istvan

    2010-03-01

    Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the context of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body's response to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions-as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation. PMID:20179512

  4. Mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs): potential role in healing cutaneous chronic wounds.

    PubMed

    Zou, Ji-Ping; Huang, Sha; Peng, Yan; Liu, Hong-Wei; Cheng, Biao; Fu, Xiao-Bing; Xiang, Xiao-Fei

    2012-12-01

    Chronic wounds remain a major challenge in modern medicine and represent a significant health care burden. Several treatments have been suggested, but without a full understanding of the exact mechanism by which chronic wound occurs. Numerous studies have shown that mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs) may have therapeutic potential in healing cutaneous chronic wounds through various mechanisms. So far, a series of hypotheses have been proposed, but a holistic image of them is lacking. This review provides a systematic analysis of recent research in animal models and preclinical or clinic trails to evaluate the potential role of MSCs in chronic cutaneous wound healing. Most important, we highlight how mesenchymal stem cells could potentially revolutionize our approach to treating cutaneous chronic wounds. Special attention should be focused on ongoing research regarding the challenges in using and prospects of MSCs in clinical settings. PMID:23222159

  5. Pathophysiology of the thalassemias. The Albion Walter Hewlett Award presentation.

    PubMed Central

    Schrier, S L

    1997-01-01

    The Albion Walter Hewlett Award (named for Professor of Medicine and Chair of the Stanford Department of Medicine 1916-1925) recognizes a role model, accomplished in discovery of the biological sciences and at the same time a consummate and compassionate physician. In introductory remarks, Dr. Stanley L. Schrier, Professor of Medicine (Hematology), the tenth recipient of the Award, indicated that the person so identified is no longer a viable model in academic medicine. The loss of this sort of person is serious because this appropriately trained physician-investigator was uniquely positioned to study pathophysiology, defined as the processes by which disordered biology produces disease. He used his own studies on the clinical manifestations of the thalassemias to clarify what he meant by pathophysiology. Thus he and his colleagues first defined membrane material properties of alpha and beta thalassemic RBC membranes and the states of hydration of alpha and beta thalassemic RBC and found them to be strikingly divergent. The biochemical counterparts of these alterations proved to be the accumulation of the excess unmatched partially oxidized globin chains on the membrane skeleton. In vitro studies with chemical oxidants selectively oxidized alpha and beta globin chains which then attached to the RBC membrane skeleton and reproduced the membrane material properties characteristic of beta and alpha thalassemia respectively. Many of these alterations had occurred prior to the reticulocyte stage so that pursuit of pathophysiology shifted to studies of marrow erythroid precursors, and it was shown that in beta thalassemia major there was accelerated programmed cell death as well as defective assembly of the membrane skeleton. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. PMID:9291745

  6. CTO Pathophysiology: How Does this Affect Management?

    PubMed Central

    Irving, John

    2014-01-01

    Chronic total occlusion (CTO) pathophysiology has been described in a few, small studies using post mortem histology, and more recently, in vivo intravascular ultrasound (IVUS) to analyse the constituents of occluded segments. Recent improvements in equipment and techniques have revealed new insights into physical characteristics of occluded coronaries, which in turn enable predictable procedural success. The purpose of this review is to consider the published evidence describing CTO pathophysiology from the perspective of the hybrid algorithm approach to CTO PCI. Methods: Literature searches using “Chronic Occlusion”, “angioplasty”, and” pathology” as keywords. Further searches on “coronary” “collateral”, “Viability”. Bibliographies were scrutinised for further key publications in an iterative process. Papers describing animal models were excluded. PMID:24694103

  7. Deficient Glutathione in the Pathophysiology of Mycotoxin-Related Illness

    PubMed Central

    Guilford, Frederick T.; Hope, Janette

    2014-01-01

    Evidence for the role of oxidative stress in the pathophysiology of mycotoxin-related illness is increasing. The glutathione antioxidant and detoxification systems play a major role in the antioxidant function of cells. Exposure to mycotoxins in humans requires the production of glutathione on an “as needed” basis. Research suggests that mycotoxins can decrease the formation of glutathione due to decreased gene expression of the enzymes needed to form glutathione. Mycotoxin-related compromise of glutathione production can result in an excess of oxidative stress that leads to tissue damage and systemic illness. The review discusses the mechanisms by which mycotoxin-related deficiency of glutathione may lead to both acute and chronic illnesses. PMID:24517907

  8. Deficient glutathione in the pathophysiology of mycotoxin-related illness.

    PubMed

    Guilford, Frederick T; Hope, Janette

    2014-02-01

    Evidence for the role of oxidative stress in the pathophysiology of mycotoxin-related illness is increasing. The glutathione antioxidant and detoxification systems play a major role in the antioxidant function of cells. Exposure to mycotoxins in humans requires the production of glutathione on an "as needed" basis. Research suggests that mycotoxins can decrease the formation of glutathione due to decreased gene expression of the enzymes needed to form glutathione. Mycotoxin-related compromise of glutathione production can result in an excess of oxidative stress that leads to tissue damage and systemic illness. The review discusses the mechanisms by which mycotoxin-related deficiency of glutathione may lead to both acute and chronic illnesses. PMID:24517907

  9. Pathophysiology of spontaneous venous gas embolism

    NASA Technical Reports Server (NTRS)

    Lambertsen, C. J.; Albertine, K. H.; Pisarello, J. B.; Flores, N. D.

    1991-01-01

    The use of controllable degrees and durations of continuous isobaric counterdiffusion venous gas embolism to investigate effects of venous gas embolism upon blood, cardiovascular, and respiratory gas exchange function, as well as pathological effects upon the lung and its microcirculation is discussed. Use of N2O/He counterdiffusion permitted performance of the pathophysiologic and pulmonary microstructural effects at one ATA without hyperbaric or hypobaric exposures.

  10. Pathophysiology and Classification of Respiratory Failure.

    PubMed

    Lamba, Tejpreet Singh; Sharara, Rihab Saeed; Singh, Anil C; Balaan, Marvin

    2016-01-01

    Respiratory failure is a condition in which the respiratory system fails in one or both of its gas exchange functions. It is a major cause of morbidity and mortality in patients admitted to intensive care units. It is a result of either lung failure, resulting in hypoxemia, or pump failure, resulting in alveolar hypoventilation and hypercapnia. This article covers the basic lung anatomy, pathophysiology, and classification of respiratory failure. PMID:26919670

  11. Pathophysiology and Treatment of Bacterial Meningitis

    PubMed Central

    Hoffman, Olaf

    2009-01-01

    Bacterial meningitis is a medical emergency requiring immediate diagnosis and immediate treatment. Streptococcus pneumoniae and Neisseria meningitidis are the most common and most aggressive pathogens of meningitis. Emerging antibiotic resistance is an upcoming challenge. Clinical and experimental studies have established a more detailed understanding of the mechanisms resulting in brain damage, sequelae and neuropsychological deficits. We summarize the current pathophysiological concept of acute bacterial meningitis and present current treatment strategies. PMID:21180625

  12. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights

    PubMed Central

    Vucic, Steve; Ziemann, Ulf; Eisen, Andrew; Hallett, Mark; Kiernan, Matthew C

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS. PMID:23264687

  13. [Electrophysiological evaluation of pathophysiological and pharmacological characteristics of chronic pain].

    PubMed

    Tanabe, Mitsuo

    2014-01-01

    Recent studies have revealed considerable evidence for our understanding of the mechanisms underlying the development and maintenance of chronic pain including neuropathic and inflammatory pain. It is considered that plastic changes in the spinal dorsal horn contribute to the amplification of pain signaling. Moreover, persistent pain affects brain function and also the endogenous descending pain regulatory system. To characterize these pathophysiological changes and pharmacological properties in chronic pain conditions at the synaptic level, we have employed in vitro electrophysiology in slices of the spinal cord and supraspinal regions such as brainstem and hippocampus of adult mice and in vivo electrophysiology in anesthetized rats. In particular, we have successfully prepared spinal slices with an attached dorsal root, where A-fiber- or C-fiber-evoked monosynaptic excitatory postsynaptic currents or miniature excitatory postsynaptic currents were recorded from voltage-clamped dorsal horn neurons. In anesthetized rats, C-fiber-evoked field potentials were recorded from the spinal dorsal horn in response to electrical stimulation of the sciatic nerve fibers, and their long-term potentiation was elicited to mimic increased synaptic efficacy after peripheral nerve injury. Of interest is the finding that some drugs exerted the injury-specific effects on synaptic transmission, thus strongly suggesting the importance of pharmacological analysis at the synaptic level combined with electrophysiological techniques to obtain pathophysiological information and new insights into drug research in this field. PMID:24584022

  14. The functional role of all postsynaptic potentials examined from a first-person frame of reference.

    PubMed

    Vadakkan, Kunjumon I

    2016-02-01

    When assigning a central role to the neuronal firing, a large number of incoming postsynaptic potentials not utilized during both supra- and subthreshold neuronal activations are not given any functional significance. Local synaptic potentials at the apical dendrites get attenuated as they arrive at the soma to nearly a twentieth of what a synapse proximal to the soma produces. Conservation of these functions necessitates searching for their functional roles. Potentials induced at the postsynapses of neurons of all the neuronal orders activated by sensory inputs carry small bits of sensory information. The activation of these postsynapses by any means other than the activation from their corresponding presynaptic terminals, that also contribute to oscillating potentials, induce the semblance of the arrival of activity from their presynaptic terminals. This is a candidate mechanism for inducing the first-person internal sensory elements of various higher brain functions as a systems property. They also contribute to the firing of subthreshold-activated neurons, including motor neurons. Operational mechanism of inter-postsynaptic functional LINKs can provide necessary structural requirements for these functions. The functional independence of the distal dendritic compartment and recent evidence for in vivo dendritic spikes indicate their independent role in the formation of internal sensory elements. In these contexts, a neuronal soma is flanked by a large number of quasi-functional internal sensory processing units operated using very little energy, even when a neuron is not firing. A large number of possible combinations of internal sensory units explains the corresponding number of specific memory retrievals by the system in response to various cue stimuli. PMID:26540219

  15. Pathogenesis and pathophysiology of bacterial meningitis.

    PubMed Central

    Tunkel, A R; Scheld, W M

    1993-01-01

    Bacterial meningitis remains a disease with associated unacceptable morbidity and mortality rates despite the availability of effective bactericidal antimicrobial therapy. Through the use of experimental animal models of infection, a great deal of information has been gleaned concerning the pathogenic and pathophysiologic mechanisms operable in bacterial meningitis. Most cases of bacterial meningitis begin with host acquisition of a new organism by nasopharyngeal colonization followed by systemic invasion and development of a high-grade bacteremia. Bacterial encapsulation contributes to this bacteremia by inhibiting neutrophil phagocytosis and resisting classic complement-mediated bactericidal activity. Central nervous system invasion then occurs, although the exact site of bacterial traversal into the central nervous system is unknown. By production and/or release of virulence factors into and stimulation of formation of inflammatory cytokines within the central nervous system, meningeal pathogens increase permeability of the blood-brain barrier, thus allowing protein and neutrophils to move into the subarachnoid space. There is then an intense subarachnoid space inflammatory response, which leads to many of the pathophysiologic consequences of bacterial meningitis, including cerebral edema and increased intracranial pressure. Attenuation of this inflammatory response with adjunctive dexamethasone therapy is associated with reduced concentrations of tumor necrosis factor in the cerebrospinal fluid, with diminished cerebrospinal fluid leukocytosis, and perhaps with improvement of morbidity, as demonstrated in recent clinical trials. Further information on the pathogenesis and pathophysiology of bacterial meningitis should lead to the development of more innovative treatment and/or preventive strategies for this disorder. Images PMID:8472245

  16. Potential role of estrogen in maintaining the imbalanced sympathetic and sensory innervation in endometriosis.

    PubMed

    Liang, Yanchun; Yao, Shuzhong

    2016-03-15

    Endometriosis, one of the most common benign gynecological diseases, affects millions of women of childbearing age. Endometriosis-associated pain is a major cause of disability and compromised quality of life in women. Neuropathic mechanisms are believed to play an important role. An imbalanced sympathetic and sensory innervation (reduced sympathetic innervation, with unchanged or increased sensory innervation in endometriotic lesions) has been demonstrated in endometriosis in recent studies. And it is believed to contribute to the pathogenesis of endometriosis-associated pain. It is primarily considered to be a natural adaptive program to endometriosis-associated inflammation. However, it is important to further clarify whether other potential modulating factors are involved in this dysregulation. It is generally accepted that endometriosis is an estrogen dependent disease. Higher estrogen biosynthesis and lower estrogen inactivation in endometriosis can lead to an excess of local estrogen in endometriotic lesions. In addition to its proliferative and anti-inflammatory actions, local estrogen in endometriosis also exerts potential neuromodulatory effects on the innervation in endometriosis. The aim of this review is to highlight the role of estrogen in mediating this imbalanced sympathetic and sensory innervation in endometriosis, through direct and indirect mechanisms on sympathetic and sensory nerves. Theoretical elaboration of the underlying mechanisms provides new insights in supporting the therapeutic role of estrogen in endometriosis-associated pain. PMID:26777300

  17. Potential Role of Epigenetic Mechanisms in the Regulation of Drug Metabolism and Transport

    PubMed Central

    Ingelman-Sundberg, Magnus; Zhong, Xiao-Bo; Hankinson, Oliver; Beedanagari, Sudheer; Yu, Ai-Ming; Peng, Lai

    2013-01-01

    This is a report of a symposium on the potential role of epigenetic mechanisms in the control of drug disposition sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2013 meeting in Boston, MA, April 21, 2013. Epigenetics is a rapidly evolving area, and recent studies have revealed that expression of drug-metabolizing enzymes and transporters is regulated by epigenetic factors, including histone modification, DNA methylation, and noncoding RNAs. The symposium speakers provided an overview of genetic and epigenetic mechanisms underlying variable drug metabolism and drug response, as well as the implications for personalized medicine. Considerable insight into the epigenetic mechanisms in differential regulation of the dioxin-inducible drug and carcinogen-metabolizing enzymes CYP1A1 and 1B1 was provided. The role of noncoding microRNAs in the control of drug metabolism and disposition through targeting of cytochrome P450 (P450) enzymes and ATP-binding cassette membrane transporters was discussed. In addition, potential effects of xenobiotics on chromatin interactions and epigenomics, as well as the possible role of long noncoding RNAs in regulation of P450s during liver maturation were presented. PMID:23918665

  18. Roles of plant metal tolerance proteins (MTP) in metal storage and potential use in biofortification strategies

    PubMed Central

    Ricachenevsky, Felipe K.; Menguer, Paloma K.; Sperotto, Raul A.; Williams, Lorraine E.; Fett, Janette P.

    2013-01-01

    Zinc (Zn) is an essential micronutrient for plants, playing catalytic or structural roles in enzymes, transcription factors, ribosomes, and membranes. In humans, Zn deficiency is the second most common mineral nutritional disorder, affecting around 30% of the world's population. People living in poverty usually have diets based on milled cereals, which contain low Zn concentrations. Biofortification of crops is an attractive cost-effective solution for low mineral dietary intake. In order to increase the amounts of bioavailable Zn in crop edible portions, it is necessary to understand how plants take up, distribute, and store Zn within their tissues, as well as to characterize potential candidate genes for biotechnological manipulation. The metal tolerance proteins (MTP) were described as metal efflux transporters from the cytoplasm, transporting mainly Zn2+ but also Mn2+, Fe2+, Cd2+, Co2+, and Ni2+. Substrate specificity appears to be conserved in phylogenetically related proteins. MTPs characterized so far in plants have a role in general Zn homeostasis and tolerance to Zn excess; in tolerance to excess Mn and also in the response to iron (Fe) deficiency. More recently, the first MTPs in crop species have been functionally characterized. In Zn hyperaccumulator plants, the MTP1 protein is related to hypertolerance to elevated Zn concentrations. Here, we review the current knowledge on this protein family, as well as biochemical functions and physiological roles of MTP transporters in Zn hyperaccumulators and non-accumulators. The potential applications of MTP transporters in biofortification efforts are discussed. PMID:23717323

  19. GHG Mitigation potential and cost in tropical forestry - Relative role for agroforestry

    SciTech Connect

    Makundi, Willy R.; Sathaye, Jayant A.

    2004-01-01

    This paper summarizes studies of carbon mitigation potential (MP) and costs of forestry options in seven developing countries with a focus on the role of agroforestry. A common methodological approach known as comprehensive mitigation assessment process (COMAP) was used in each study to estimate the potential and costs between 2000 and 2030. The approach requires the projection of baseline and mitigation land-use scenarios derived from the demand for forest products and forestland for other uses such as agriculture and pasture. By using data on estimated carbon sequestration, emission avoidance, costs and benefits, the model enables one to estimate cost effectiveness indicators based on monetary benefit per t C, as well as estimates of total mitigation costs and potential when the activities are implemented at equilibrium level. The results show that about half the MP of 6.9 Gt C (an average of 223 Mt C per year) between 2000 and 2030 in the seven countries could be achieved at a negative cost, and the other half at costs not exceeding $100 per t C. Negative cost indicates that non-carbon revenue is sufficient to offset direct costs of about half of the options. The agroforestry options analyzed bear a significant proportion of the potential at medium to low cost per t C when compared to other options. The role of agroforestry in these countries varied between 6% and 21% of the MP, though the options are much more cost effective than most due to the low wage or opportunity cost of rural labor. Agroforestry options are attractive due to the large number of people and potential area currently engaged in agriculture, but they pose unique challenges for carbon and cost accounting due to the dispersed nature of agricultural activities in the tropics, as well as specific difficulties arising from requirements for monitoring, verification, leakage assessment and the establishment of credible baselines.

  20. Mitigation potential and cost in tropical forestry - relative role for agroforestry

    SciTech Connect

    Makundi, Willy R.; Sathaye, Jayant A.

    2004-01-01

    This paper summarizes studies of carbon mitigation potential (MP) and costs of forestry options in seven developing countries with a focus on the role of agroforestry. A common methodological approach known as comprehensive mitigation assessment process (COMAP) was used in each study to estimate the potential and costs between 2000 and 2030. The approach requires the projection of baseline and mitigation land-use scenarios derived from the demand for forest products and forestland for other uses such as agriculture and pasture. By using data on estimated carbon sequestration, emission avoidance, costs and benefits, the model enables one to estimate cost effectiveness indicators based on monetary benefit per t C, as well as estimates of total mitigation costs and potential when the activities are implemented at equilibrium level. The results show that about half the MP of 6.9 Gt C (an average of 223 Mt C per year) between 2000 and 2030 in the seven countries could be achieved at a negative cost, and the other half at costs not exceeding $100 per t C. Negative cost indicates that non-carbon revenue is sufficient to offset direct costs of about half of the options. The agroforestry options analyzed bear a significant proportion of the potential at medium to low cost per t C when compared to other options. The role of agroforestry in these countries varied between 6% and 21% of the MP, though the options are much more cost effective than most due to the low wage or opportunity cost of rural labor. Agroforestry options are attractive due to the large number of people and potential area currently engaged in agriculture, but they pose unique challenges for carbon and cost accounting due to the dispersed nature of agricultural activities in the tropics, as well as specific difficulties arising from requirements for monitoring, verification, leakage assessment and the establishment of credible baselines.