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Sample records for brain death induce

  1. Brain death.

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    Beresford, H R

    1999-05-01

    Current law in the United States authorizes physicians to diagnose brain death by applying generally accepted neurologic criteria for determining loss of function of the entire brain. This article offers a medical-legal perspective on problems that may arise with respect to the determination of brain death. These include the possibility of diagnostic error, conceptual disagreements that may constrain the use of neurologic criteria to diagnose death, and the conflation of brain death and loss of consciousness. This article also addresses legal aspects of the debate over whether to expand the definition of brain death to include permanent unconsciousness. Although existing laws draw a clear distinction between brain death and the persistent vegetative state, many courts have authorized removal of life support from individuals whose unconsciousness is believed to be permanent on proof that removal accords with preferences expressed before sentience was lost.

  2. Brain death.

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    Wijdicks, Eelco F M

    2013-01-01

    The diagnosis of brain death should be based on a simple premise. If every possible confounder has been excluded and all possible treatments have been tried or considered, irreversible loss of brain function is clinically recognized as the absence of brainstem reflexes, verified apnea, loss of vascular tone, invariant heart rate, and, eventually, cardiac standstill. This condition cannot be reversed - not even partly - by medical or surgical intervention, and thus is final. Many countries in the world have introduced laws that acknowledge that a patient can be declared brain-dead by neurologic standards. The U.S. law differs substantially from all other brain death legislation in the world because the U.S. law does not spell out details of the neurologic examination. Evidence-based practice guidelines serve as a standard. In this chapter, I discuss the history of development of the criteria, the current clinical examination, and some of the ethical and legal issues that have emerged. Generally, the concept of brain death has been accepted by all major religions. But patients' families may have different ideas and are mostly influenced by cultural attitudes, traditional customs, and personal beliefs. Suggestions are offered to support these families. © 2013 Elsevier B.V. All rights reserved.

  3. Brain death induces renal expression of heme oxygenase-1 and heat shock protein 70

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    van Dullemen Leon FA

    2013-01-01

    Full Text Available Abstract Background Kidneys derived from brain dead donors have lower graft survival and higher graft-function loss compared to their living donor counterpart. Heat Shock Proteins (HSP are a large family of stress proteins involved in maintaining cell homeostasis. We studied the role of stress-inducible genes Heme Oxygenase-1 (HO-1, HSP27, HSP40, and HSP70 in the kidney following a 4 hour period of brain death. Methods Brain death was induced in rats (n=6 by inflating a balloon catheter in the epidural space. Kidneys were analysed for HSPs using RT-PCR, Western blotting, and immunohistochemistry. Results RT-PCR data showed a significant increase in gene expression for HO-1 and HSP70 in kidneys of brain dead rats. Western blotting revealed a massive increase in HO-1 protein in brain dead rat kidneys. Immunohistochemistry confirmed these findings, showing extensive HO-1 protein expression in the renal cortical tubules of brain dead rats. HSP70 protein was predominantly increased in renal distal tubules of brain dead rats treated for hypotension. Conclusion Renal stress caused by brain death induces expression of the cytoprotective genes HO-1 and HSP70, but not of HSP27 and HSP40. The upregulation of these cytoprotective genes indicate that renal damage occurs during brain death, and could be part of a protective or recuperative mechanism induced by brain death-associated stress.

  4. Administration of Protocatechuic Acid Reduces Traumatic Brain Injury-Induced Neuronal Death

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    Sang Hwon Lee

    2017-11-01

    Full Text Available Protocatechuic acid (PCA was first purified from green tea and has shown numerous biological activities, including anti-apoptotic, anti-inflammatory, and anti-atherosclerotic effects. The effect of PCA on traumatic brain injury (TBI-induced neuronal death has not previously been evaluated. TBI is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. TBI causes neuronal death in the hippocampus and cerebral cortex. The present study aimed to evaluate the therapeutic potential of PCA on TBI-induced neuronal death. Here, TBI was induced by a controlled cortical impact model using rats. PCA (30 mg/kg was injected into the intraperitoneal (ip space immediately after TBI. Neuronal death was evaluated with Fluoro Jade-B (FJB staining at 24 h after TBI. Oxidative injury was detected by 4-hydroxy-2-nonenal (4HNE, glutathione (GSH concentration was analyzed by glutathione adduct with N-ethylmaleimide (GS-NEM staining at 24 h after TBI, and microglial activation in the hippocampus was detected by CD11b immunohistochemistry at one week after TBI. We found that the proportion of degenerating neurons, oxidative injury, GSH depletion, and microglia activation in the hippocampus and cortex were all reduced by PCA treatment following TBI. Therefore, our study suggests that PCA may have therapeutic potential in preventing TBI-induced neuronal death.

  5. Sumoylation of hypoxia-inducible factor-1α ameliorates failure of brain stem cardiovascular regulation in experimental brain death.

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    Julie Y H Chan

    2011-03-01

    Full Text Available One aspect of brain death is cardiovascular deregulation because asystole invariably occurs shortly after its diagnosis. A suitable neural substrate for mechanistic delineation of this aspect of brain death resides in the rostral ventrolateral medulla (RVLM. RVLM is the origin of a life-and-death signal that our laboratory detected from blood pressure of comatose patients that disappears before brain death ensues. At the same time, transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α plays a pro-life role in experimental brain death, and HIF-1α is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death.A clinically relevant animal model that employed mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical changes in RVLM during distinct phenotypes in systemic arterial pressure spectrum that reflect maintained or defunct brain stem cardiovascular regulation were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1, Ubc9 (the only known conjugating enzyme for the sumoylation pathway or HIF-1α, augmented sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional activity of HIF-1α in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. Furthermore, loss-of-function manipulations by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the upregulated nitric oxide synthase I/protein kinase G signaling cascade, which sustains the brain stem cardiovascular regulatory machinery during the pro-life phase.We conclude that sumoylation of HIF-1α in RVLM ameliorates brain stem

  6. Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling.

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    Sung, Pei-Hsun; Lee, Fan-Yen; Lin, Ling-Chun; Chen, Kuan-Hung; Lin, Hung-Sheng; Shao, Pei-Lin; Li, Yi-Chen; Chen, Yi-Ling; Lin, Kun-Chen; Yuen, Chun-Man; Chang, Hsueh-Wen; Lee, Mel S; Yip, Hon-Kan

    2018-01-09

    We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IκB, NF-κB, IL-1β, IFN-γ, TNF-α and IL-6) were higher in brain tissue from BD animals than controls. Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re-induced with luzindole (all P DAMP inflammatory axis.

  7. Brain Death and Islam

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    Ziad-Miller, Amna; Elamin, Elamin M.

    2014-01-01

    How one defines death may vary. It is important for clinicians to recognize those aspects of a patient’s religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only. PMID:25287999

  8. Diagnosis of brain death

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    Calixto Machado

    2010-06-01

    Full Text Available Brain death (BD should be understood as the ultimate clinical expression of a brain catastrophe characterized by a complete and irreversible neurological stoppage, recognized by irreversible coma, absent brainstem reflexes, and apnea. The most common pattern is manifested by an elevation of intracranial pressure to a point beyond the mean arterial pressure, and hence cerebral perfusion pressure falls and, as a result, no net cerebral blood flow is present, in due course leading to permanent cytotoxic injury of the intracranial neuronal tissue. A second mechanism is an intrinsic injury affecting the nervous tissue at a cellular level which, if extensive and unremitting, can also lead to BD. We review here the methodology of diagnosing death, based on finding any of the signs of death. The irreversible loss of cardio-circulatory and respiratory functions can cause death only when ischemia and anoxia are prolonged enough to produce an irreversible destruction of the brain. The sign of such loss of brain functions, that is to say BD diagnosis, is fully reviewed.

  9. Does liver ischemic preconditioning in brain death donors induce kidney preconditioning? A retrospective analysis.

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    Desai, Kunj K; Mora-Esteves, Cesar; Holland, Bart K; Dikdan, George; Fisher, Adrian; Wilson, Dorian J; Koneru, Baburao

    2014-02-15

    It is unclear whether ischemic preconditioning (IPC) of solid organs induces remote IPC (RIPC) in donors after brain death (DBD). Outcomes in kidney recipients from 163 DBD in two randomized trials of liver IPC (5 min=62 and 10 min=101) were obtained retrospectively from the Scientific Registry of Transplant Recipients. Controls were kidney recipients from donors without IPC. Mean cold ischemia times were less than 20 hr. Primary outcomes were delayed graft function, defined as dialysis during the first posttransplantation week, and death-censored graft survival. Secondary outcomes were duration of initial hospital stay, patient survival, and estimated glomerular filtration rate 6, 12, 36, and 60 months after transplantation. After exclusions (40 kidneys not recovered, 21 not transplanted, 8 en bloc, 23 with extrarenal organs, and 6 with missing records), 228 recipients were included. Delayed graft function occurred in 23% of No RIPC and 28% of RIPC kidneys (P=0.54). One- and 3-year graft survival rates were 92% and 90%, respectively, in the No RIPC and 90% and 81%, respectively, in the RIPC group (P=0.12), and mean hospital stay was 9.3±13.9 and 9.7±8.2 days, respectively (P=0.15). There were no significant between group differences in patient survival and estimated glomerular filtration rate at any time point. Despite design and power limitations, our results suggest that liver IPC in DBD is of no clinical benefit to kidney recipients. Inconsistent efficacy and impracticality severely limit the usefulness of IPC in DBD. Other modalities of preconditioning should be tested.

  10. Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain.

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    Kevin D Broad

    Full Text Available In a range of animal species, exposure of the brain to general anaesthesia without surgery during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex but include an increase in brain cell death. In humans, attempts to link adverse cognitive development to infantile anaesthesia exposure have yielded ambiguous results. One caveat that may influence the interpretation of human studies is that infants are not exposed to general anaesthesia without surgery, raising the possibility that surgery itself, may contribute to adverse cognitive development. Using piglets, we investigated whether a minor surgical procedure increases cell death and disrupts neuro-developmental and cognitively salient gene transcription in the neonatal brain. We randomly assigned neonatal male piglets to a group who received 6h of 2% isoflurane anaesthesia or a group who received an identical anaesthesia plus 15 mins of surgery designed to replicate an inguinal hernia repair. Compared to anesthesia alone, surgery-induced significant increases in cell death in eight areas of the brain. Using RNAseq data derived from all 12 piglets per group we also identified significant changes in the expression of 181 gene transcripts induced by surgery in the cingulate cortex, pathway analysis of these changes suggests that surgery influences the thrombin, aldosterone, axonal guidance, B cell, ERK-5, eNOS and GABAA signalling pathways. This suggests a number of novel mechanisms by which surgery may influence neural and cognitive development independently or synergistically with the effects of anaesthesia.

  11. Mitochondrial dysfunction: a crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain.

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    Kamat, Pradeep K; Tota, Santoshkumar; Shukla, Rakesh; Ali, Shakir; Najmi, Abul Kalam; Nath, Chandishwar

    2011-12-01

    Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca(2+) and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca(2+) and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Programmed Cell Death in the Honey Bee (Apis mellifera) (Hymenoptera: Apidae) Worker Brain Induced by Imidacloprid.

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    Wu, Yan-Yan; Zhou, Ting; Wang, Qiang; Dai, Ping-Li; Xu, Shu-Fa; Jia, Hui-Ru; Wang, Xing

    2015-08-01

    Honey bees are at an unavoidable risk of exposure to neonicotinoid pesticides, which are used worldwide. Compared with the well-studied roles of these pesticides in nontarget site (including midgut, ovary, or salivary glands), little has been reported in the target sites, the brain. In the current study, laboratory-reared adult worker honey bees (Apis mellifera L.) were treated with sublethal doses of imidacloprid. Neuronal apoptosis was detected using the TUNEL technique for DNA labeling. We observed significantly increased apoptotic markers in dose- and time-dependent manners in brains of bees exposed to imidacloprid. Neuronal activated caspase-3 and mRNA levels of caspase-1, as detected by immunofluorescence and real-time quantitative PCR, respectively, were significantly increased, suggesting that sublethal doses of imidacloprid may induce the caspase-dependent apoptotic pathway. Additionally, the overlap of apoptosis and autophagy in neurons was confirmed by transmission electron microscopy. It further suggests that a relationship exists between neurotoxicity and behavioral changes induced by sublethal doses of imidacloprid, and that there is a need to determine reasonable limits for imidacloprid application in the field to protect pollinators. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Cancer: brain-regulated biphasic stress response induces cell growth or cell death to adapt to psychological stressors.

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    Thomas, Charles; Bhatia, Shruti

    2014-01-01

    According to Indian Vedic philosophy, a human being contains 3 major bodies: (1) the matter body--brain, organs, and senses; (2) the mental body--mind, individual consciousness, intellect, and ego; and (3) the soul or causal body--universal consciousness. The third, which is located in the heart according to all spiritual traditions and recent scientific literature, can be seen as the information body that contains all memories. The mental body, which can interface with the matter and information bodies, can be seen as a field of immaterial energy that can carry, regulate, and strengthen all information (eg, thoughts or emotions) both positively and negatively. This body of information may store ancestral and/or autobiographical memories: unconscious memories from inner traumas--inner information (Ii) or samskaras in Vedic philosophy--and conscious memories from outer traumas--outer information (Io). These conscious and unconscious memories can be seen as potential psychological stressors. Resonance between Ii and Io may induce active conflicts if resistance occurs in the mental body; this conflict may cause specific metabolic activity in the brain and a stress response in the physical body, which permits adjustment to psychological stressors. The brainregulated stress response may be biphasic: cell death or growth induced by adrenergic molecular pathways during the conflict's unresolved phase and reversion to cell growth or death induced by cholinergic molecular pathways during the conflict's resolved phase. Case studies and data mining from PubMed suggest that this concept complies with the principles of holistic medicine and the scientific literature supporting its benefits. We suggest that the evolution of cancer can be seen as a biphasic stress response regulated by the brain to adapt to psychological stressors, which produce imbalance among the physical, mental, and information bodies.

  14. Inflammatory responses are not sufficient to cause delayed neuronal death in ATP-induced acute brain injury.

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    Hey-Kyeong Jeong

    Full Text Available BACKGROUND: Brain inflammation is accompanied by brain injury. However, it is controversial whether inflammatory responses are harmful or beneficial to neurons. Because many studies have been performed using cultured microglia and neurons, it has not been possible to assess the influence of multiple cell types and diverse factors that dynamically and continuously change in vivo. Furthermore, behavior of microglia and other inflammatory cells could have been overlooked since most studies have focused on neuronal death. Therefore, it is essential to analyze the precise roles of microglia and brain inflammation in the injured brain, and determine their contribution to neuronal damage in vivo from the onset of injury. METHODS AND FINDINGS: Acute neuronal damage was induced by stereotaxic injection of ATP into the substantia nigra pars compacta (SNpc and the cortex of the rat brain. Inflammatory responses and their effects on neuronal damage were investigated by immunohistochemistry, electron microscopy, quantitative RT-PCR, and stereological counting, etc. ATP acutely caused death of microglia as well as neurons in a similar area within 3 h. We defined as the core region the area where both TH(+ and Iba-1(+ cells acutely died, and as the penumbra the area surrounding the core where Iba-1(+ cells showed activated morphology. In the penumbra region, morphologically activated microglia arranged around the injury sites. Monocytes filled the damaged core after neurons and microglia died. Interestingly, neither activated microglia nor monocytes expressed iNOS, a major neurotoxic inflammatory mediator. Monocytes rather expressed CD68, a marker of phagocytic activity. Importantly, the total number of dopaminergic neurons in the SNpc at 3 h (∼80% of that in the contralateral side did not decrease further at 7 d. Similarly, in the cortex, ATP-induced neuron-damage area detected at 3 h did not increase for up to 7 d. CONCLUSIONS: Different cellular

  15. Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Verbeek, M.M.; Otte-Holler, I.; Donkelaar, H.J. ten; Waal, R.M.W. de; Kremer, H.P.H.

    2002-01-01

    Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of

  16. Isoflurane Exposure Induces Cell Death, Microglial Activation and Modifies the Expression of Genes Supporting Neurodevelopment and Cognitive Function in the Male Newborn Piglet Brain.

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    Broad, Kevin D; Hassell, Jane; Fleiss, Bobbi; Kawano, Go; Ezzati, Mojgan; Rocha-Ferreira, Eridan; Hristova, Mariya; Bennett, Kate; Fierens, Igor; Burnett, Ryan; Chaban, Badr; Alonso-Alconada, Daniel; Oliver-Taylor, Aaron; Tachsidis, Ilias; Rostami, Jamshid; Gressens, Pierre; Sanders, Robert D; Robertson, Nicola J

    2016-01-01

    Exposure of the brain to general anesthesia during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex, incompletely understood and may be sexually dimorphic, but include developmentally inappropriate apoptosis, inflammation and a disruption to cognitively salient gene expression. We investigated the effects of a 6h isoflurane exposure on cell death, microglial activation and gene expression in the male neonatal piglet brain. Piglets (n = 6) were randomised to: (i) naive controls or (ii) 6h isoflurane. Cell death (TUNEL and caspase-3) and microglial activation were recorded in 7 brain regions. Changes in gene expression (microarray and qPCR) were assessed in the cingulate cortex. Electroencephalography (EEG) was recorded throughout. Isoflurane anesthesia induced significant increases in cell death in the cingulate and insular cortices, caudate nucleus, thalamus, putamen, internal capsule, periventricular white matter and hippocampus. Dying cells included both neurons and oligodendrocytes. Significantly, microglial activation was observed in the insula, pyriform, hippocampus, internal capsule, caudate and thalamus. Isoflurane induced significant disruption to the expression of 79 gene transcripts, of these 26 are important for the control of transcription and 23 are important for the mediation of neural plasticity, memory formation and recall. Our observations confirm that isoflurane increases apoptosis and inflammatory responses in the neonatal piglet brain but also suggests novel additional mechanisms by which isoflurane may induce adverse neural and cognitive development by disrupting the expression of genes mediating activity dependent development of neural circuits, the predictive adaptive responses of the brain, memory formation and recall.

  17. Recovery from a possible cytomegalovirus meningoencephalitis-induced apparent brain stem death in an immunocompetent man: a case report.

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    Rahardjo, Theresia Monica; Maskoen, Tinni Trihartini; Redjeki, Ike Sri

    2016-08-26

    Recovery from cytomegalovirus meningoencephalitis with brain stem death in an immunocompetent patient is almost impossible. We present a remarkable recovery from a possible cytomegalovirus infection in an immunocompetent man who had severe neurological syndromes, suggesting brain stem death complicated by pneumonia and pleural effusion. A 19-year-old Asian man presented at our hospital's emergency department with reduced consciousness and seizures following high fever, headache, confusion, and vomitus within a week before arrival. He was intubated and sent to our intensive care unit. He had nuchal rigidity and tetraparesis with accentuated tendon reflexes. Electroencephalography findings suggested an acute structural lesion at his right temporal area or an epileptic state. A cerebral spinal fluid examination suggested viral infection. A computed tomography scan was normal at the early stage of disease. Immunoglobulin M, immunoglobulin G anti-herpes simplex virus, and immunoglobulin M anti-cytomegalovirus were negative. However, immunoglobulin G anti-cytomegalovirus was positive, which supported a diagnosis of cytomegalovirus meningoencephalitis. His clinical condition deteriorated, spontaneous respiration disappeared, cranial reflexes became negative, and brain stem death was suspected. Therapy included antivirals, corticosteroids, antibiotics, anticonvulsant, antipyretics, antifungal agents, and a vasopressor to maintain hemodynamic stability. After 1 month, he showed a vague response to painful stimuli at his supraorbital nerve and respiration started to appear the following week. After pneumonia and pleural effusion were resolved, he was weaned from the ventilator and moved from the intensive care unit on day 90. This case highlights several important issues that should be considered. First, the diagnosis of brain stem death must be confirmed with caution even if there are negative results of brain stem death test for a long period. Second, cytomegalovirus

  18. Donation after brain circulation determination of death.

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    Dalle Ave, Anne L; Bernat, James L

    2017-02-23

    The fundamental determinant of death in donation after circulatory determination of death is the cessation of brain circulation and function. We therefore propose the term donation after brain circulation determination of death [DBCDD]. In DBCDD, death is determined when the cessation of circulatory function is permanent but before it is irreversible, consistent with medical standards of death determination outside the context of organ donation. Safeguards to prevent error include that: 1] the possibility of auto-resuscitation has elapsed; 2] no brain circulation may resume after the determination of death; 3] complete circulatory cessation is verified; and 4] the cessation of brain function is permanent and complete. Death should be determined by the confirmation of the cessation of systemic circulation; the use of brain death tests is invalid and unnecessary. Because this concept differs from current standards, consensus should be sought among stakeholders. The patient or surrogate should provide informed consent for organ donation by understanding the basis of the declaration of death. In cases of circulatory cessation, such as occurs in DBCDD, death can be defined as the permanent cessation of brain functions, determined by the permanent cessation of brain circulation.

  19. Questionnaire on Brain Death and Organ Procurement.

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    Hammad, Saleh; Alnammourah, Manal; Almahmoud, Farah; Fawzi, Mais; Breizat, Abdel-Hadi

    2017-02-01

    The subject of organs for transplant after brain death raises many concerns, including definition and timing of death, how to permit human organ transplant, and the idea of paying for organs. Many ethical concerns are raised regarding regulations and procedures for organ transplant in developing countries. These include where and how to obtain organs and the concept of justice in organ distribution. We administered 2682 questionnaires to 628 men and 2054 women over 24 months (range, 18 to 70 years old). We included people from universities, colleges, and the general public and asked questions on the circumstances of death, the conditions of conversations around organ donation, and reasons for acceptance or refusal of donation. The identical questionnaire, consisting of 8 questions, was administered twice: before and after a teaching session on brain death and organ procurement. The study was approved by our Ethical Review Committee and in accordance with the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all participants. We found that 72.1% understood brain death in the prequestionnaire and 88% understood brain death in the postquestionnaire, with 63.8% versus 68% accepting the concept of brain death, 50.6% versus 58.3% thinking that their religion is against brain death, 11.3% versus 11.3% carrying a donor card, 50.7% versus 58.9% wanting to carry a donor card, 46.4% versus 56.4% agreeing to give consent for organ donation if a relative was diagnosed with brain death, 28.3% versus 50% aware of the laws and regulations concerning brain death and organ donation and transplant in Jordan, and 35.4% versus 40% in agreement with the Presumed Consent Law, respectively. In Jordan, along with legal requirements concerning brain death and organ donation and transplant, there is a lack of acceptance of organ donation after brain death, necessitating further work and activities to achieve self-sufficiency from donated organs.

  20. History of brain death as death: 1968 to the present.

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    De Georgia, Michael A

    2014-08-01

    The concept of brain death was formulated in 1968 in the landmark report A Definition of Irreversible Coma. While brain death has been widely accepted as a determination of death throughout the world, many of the controversies that surround it have not been settled. Some may be rooted in a misconstruction about the history of brain death. The concept evolved as a result of the convergence of several parallel developments in the second half of the 20th century including advances in resuscitation and critical care, research into the underlying physiology of consciousness, and growing concerns about technology, medical futility, and the ethics of end of life care. Organ transplantation also developed in parallel, and though it clearly benefited from a new definition of death, it was not a principal driving force in its creation. Since 1968, the concept of brain death has been extensively analyzed, debated, and reworked. Still there remains much misunderstanding and confusion, especially in the general public. In this comprehensive review, I will trace the evolution of the definition of brain death as death from 1968 to the present, providing background, history and context. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Brain death and organ donation of children.

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    Gündüz, Ramiz Coşkun; Şahin, Şanlıay; Uysal-Yazıcı, Mutlu; Ayar, Ganime; Yakut, Halil İbrahim; Akman, Alkım Öden; Hirfanoğlu, İbrahim Murat; Kalkan, Gökhan

    2014-01-01

    We aimed to define the demographic characteristics, clinical features and outcome of patients with brain death, and to emphasize the importance of organ donation from children. Data for the period from September 2009 to October 2012 were collected retrospectively. Twenty children who were diagnosed as brain death were included. Data including demographics, major cause leading to brain death, duration of brain death evaluation, ancillary tests used to confirm brain death, complications and outcome, duration of hospitalization and organ donation were collected for statistical evaluation. The mean age was 6.2 years, and the male/female ratio 1.85. The major cause leading to brain death was most often traumatic brain injury, seen in 11 patients (55%). The mean duration of brain death evaluation was 6.7 and 1.7 days in Centers I and II respectively. The mean duration of hospitalization was 12.5 days. Electroencephalography (EEG) was used in 18 patients (90%). Complications included hyperglycemia in 13 cases and diabetes incipitus in 7 cases (65% and 35%, respectively). Mean duration of survival was 9.8 days. In Center I, one of the patients' parents gave consent to organ donation, while four parents in Center II agreed to organ donation. The study demonstrated that the duration of brain death evaluation was longer in Center I than in Center II (porgan donation, survival after diagnosis of brain death and length of stay in the PICU (p>0.05). Early diagnosis of brain death and prompt evaluation of patients by ICU physicians once the diagnosis is taken into consideration will probably yield better organs and reduce costs. Training PICU physicians, nurses and organ donation coordinators, and increasing children's awareness of the need for organ donation via means of public communication may increase families' rate of agreement to organ donation in the future.

  2. Ginkgo biloba extract EGb761 attenuates brain death-induced renal injury by inhibiting pro-inflammatory cytokines and the SAPK and JAK-STAT signalings.

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    Li, Yifu; Xiong, Yunyi; Zhang, Huanxi; Li, Jun; Wang, Dong; Chen, Wenfang; Yuan, Xiaopeng; Su, Qiao; Li, Wenwen; Huang, Huiting; Bi, Zirong; Liu, Longshan; Wang, Changxi

    2017-03-23

    This study aimed to investigate the protective effects of EGb761, a Ginkgo Biloba extract, against brain death-induced kidney injury. Sixty male Sprague Dawley rats were randomly divided into six groups: sham, brain-death (BD), BD + EGb b48h (48 hours before BD), BD + EGb 2 h (2 hours after BD), BD + EGb 1 h, and BD + EGb 0.5 h. Six hours after BD, serum sample and kidney tissues were collected for analyses. The levels of blood urea nitrogen (BUN) and serum creatinine significantly elevated in the BD group than in sham group. In all the EGb761-treated BD animals except for the BD + Gb 2 h group, the levels of BUN and serum creatinine significantly reduced (all P < 0.01). EGb761 attenuated tubular injury and lowered the histological score. In addition, the longer duration of drug treatment was, the better protective efficacy could be observed. EGb761 significantly reduced IL-1β, IL-6, TNF-α, MCP-1, IP-10 mRNA expression and macrophage infiltration in the kidney. EGb761 treatment at 48 hour before brain death significantly attenuate the levels of p-JNK-MAPK, p-p38-MAPK, and p-STAT3 proteins (all P < 0.05, compared to BD group). In summary, our data showed that EGb761 treatment protected donor kidney from BD-induced damages by blocking SAPK and JAK-STAT signalings. Early administration of EGb761 can provide better protective efficacy.

  3. Medical and ethical dilemma in brain death.

    Science.gov (United States)

    Streba, Irina; Damian, Simona; Ioan, Beatrice

    2012-01-01

    For centuries, death has been defined, medically speaking, as the irreversible cessation of breathing and of nervous and cardiac activity. What radically changed this definition was the introduction of the concept "brain death" in 1968, by the "Ad Hoc Committee of the Harvard Medical School". According to it, the irreversible coma was associated with brain death and considered to be a criterion for the diagnosis of the deceased individual. The evergrowing need for transplant organs (provided this respects the dead honor rule, stipulating that organs can't be harvested unless someone is deceased) lead to making arbitrary decisions regarding the establishment of the exact time of death during the process of "losing life". What actually triggers the controversy related to the concept of brain death is the dilemma of associating this concept with that of biologic death or death of the person, the difference between the two being made by whether the mental characteristics are accepted or not in defining and individualizing the death of the human being. Given these circumstances, a dilemma appears--that of defining the death of the individual: we define death, as it has been for centuries, as the moment when the cardio-respiratory function no longer exists, which leads to the loss of tens of thousands of lives that might have been saved through transplant. Yet, this may lead to manipulating the border between life and death, with the risk of trespassing each individual's right to life.

  4. Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3β/Mitochondrial Fission Pathway.

    Science.gov (United States)

    Liu, Yanan; Yan, Yasheng; Inagaki, Yasuyoshi; Logan, Sarah; Bosnjak, Zeljko J; Bai, Xiaowen

    2017-07-01

    Growing animal evidence demonstrates that prolonged exposure to propofol during brain development induces widespread neuronal cell death, but there is little information on the role of astrocytes. Astrocytes can release neurotrophic growth factors such as brain-derived neurotrophic factor (BDNF), which can exert the protective effect on neurons in paracrine fashion. We hypothesize that during propofol anesthesia, BDNF released from developing astrocytes may not be sufficient to prevent propofol-induced neurotoxicity. Hippocampal astrocytes and neurons isolated from neonatal Sprague Dawley rats were exposed to propofol at a clinically relevant dose of 30 μM or dimethyl sulfoxide as control for 6 hours. Propofol-induced cell death was determined by propidium iodide (PI) staining in astrocyte-alone cultures, neuron-alone cultures, or cocultures containing either low or high density of astrocytes (1:9 or 1:1 ratio of astrocytes to neurons ratio [ANR], respectively). The astrocyte-conditioned medium was collected 12 hours after propofol exposure and measured by protein array assay. BDNF concentration in astrocyte-conditioned medium was quantified using enzyme-linked immunosorbent assay. Neuron-alone cultures were treated with BDNF, tyrosine receptor kinase B inhibitor cyclotraxin-B, glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1 before propofol exposure. Western blot was performed for quantification of the level of protein kinase B and GSK3β. Mitochondrial shape was visualized through translocase of the outer membrane 20 staining. Propofol increased cell death in neurons by 1.8-fold (% of PI-positive cells [PI%] = 18.6; 95% confidence interval [CI], 15.2-21.9, P .05]). Astrocytes secreted BDNF in a cell density-dependent way and propofol decreased BDNF secretion from astrocytes. Administration of BDNF, CHIR99021, or Mdivi-1 significantly attenuated the propofol-induced neuronal death and aberrant mitochondria in

  5. Notification of brain death in the hospital

    Directory of Open Access Journals (Sweden)

    Bruna Soares de Jesus Souza

    2015-05-01

    Full Text Available Objective: to identifying brain death in the hospital. Methods: it is a cross sectional and quantitative study which analyzed secondary data extracted from the notified brain death registers and from the medical records of the eligible patients. The data were processed and analyzed through descriptive statistics and comparisons. Results: of the 64 cases of notifications, the male gender predominated (67.2% within the age range from 40 to 59 years (64.1%. There was a greater proportion (71.8% of causes of death related to Hemorrhagic Cerebral Vascular Accident and Traumatic Brain Injury caused by motorcycle accident, showing statistically significant difference (p<0.05 regarding the gender, age and location. Conclusion: the Hemorrhagic Cerebral Vascular Accident was the most prevalent cause of notification of brain death and the Intensive Therapy Unit was the most notified venue.

  6. Brain death and disorders of consciousness

    National Research Council Canada - National Science Library

    Schiff, Nicholas D; Fins, Joseph J

    2016-01-01

    While often confused by non-medical specialists, brain death and disorders of consciousness such as coma, vegetative state, and minimally conscious state are clearly distinct and unambiguously distinguishable...

  7. Notification of brain death in the hospital

    OpenAIRE

    Bruna Soares de Jesus Souza; Gerlene Grudka Lira; Rachel Mola

    2015-01-01

    Objective: to identifying brain death in the hospital. Methods: it is a cross sectional and quantitative study which analyzed secondary data extracted from the notified brain death registers and from the medical records of the eligible patients. The data were processed and analyzed through descriptive statistics and comparisons. Results: of the 64 cases of notifications, the male gender predominated (67.2%) within the age range from 40 to 59 years (64.1%). There was a greater proportion (71.8...

  8. The influence of brain death on liver function

    NARCIS (Netherlands)

    Olinga, Peter; Hoeven, Joost Alexander Boreas van der; Merema, M.T.; Freund, R.L.; Ploeg, R.J; Groothuis, Geny

    Background: In this study, we investigated the influence of brain death on inflammatory response and the effects of brain death on liver function both directly after explantation and after reoxygenation. Methods: The influence of brain death on liver function was studied in rats using a brain death

  9. Cell Death in the Developing Brain after Hypoxia-Ischemia

    Science.gov (United States)

    Thornton, Claire; Leaw, Bryan; Mallard, Carina; Nair, Syam; Jinnai, Masako; Hagberg, Henrik

    2017-01-01

    Perinatal insults such as hypoxia–ischemia induces secondary brain injury. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. The cell death mechanisms have been shown to be quite different in the developing brain compared to that in the adult. The aim of this review is update on what cell death mechanisms that are operating particularly in the setting of the developing CNS. In response to mild stress stimuli a number of compensatory mechanisms will be activated, most often leading to cell survival. Moderate-to-severe insults trigger regulated cell death. Depending on several factors such as the metabolic situation, cell type, nature of the stress stimulus, and which intracellular organelle(s) are affected, the cell undergoes apoptosis (caspase activation) triggered by BAX dependent mitochondrial permeabilzation, necroptosis (mixed lineage kinase domain-like activation), necrosis (via opening of the mitochondrial permeability transition pore), autophagic cell death (autophagy/Na+, K+-ATPase), or parthanatos (poly(ADP-ribose) polymerase 1, apoptosis-inducing factor). Severe insults cause accidental cell death that cannot be modulated genetically or by pharmacologic means. However, accidental cell death leads to the release of factors (damage-associated molecular patterns) that initiate systemic effects, as well as inflammation and (regulated) secondary brain injury in neighboring tissue. Furthermore, if one mode of cell death is inhibited, another route may step in at least in a scenario when upstream damaging factors predominate over protective responses. The provision of alternative routes through which the cell undergoes death has to be taken into account in the hunt for novel brain protective strategies. PMID:28878624

  10. Approach of Complex Networks for the Determination of Brain Death

    Science.gov (United States)

    Sun, Wei-Gang; Cao, Jian-Ting; Wang, Ru-Bin

    2011-06-01

    In clinical practice, brain death is the irreversible end of all brain activity. Compared to current statistical methods for the determination of brain death, we focus on the approach of complex networks for real-world electroencephalography in its determination. Brain functional networks constructed by correlation analysis are derived, and statistical network quantities used for distinguishing the patients in coma or brain death state, such as average strength, clustering coefficient and average path length, are calculated. Numerical results show that the values of network quantities of patients in coma state are larger than those of patients in brain death state. Our findings might provide valuable insights on the determination of brain death.

  11. Effects of mood stabilizers on oxidative stress-induced cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania: Mood stabilizers exert protective effects against ouabain-induced activation of the cell death pathway.

    Science.gov (United States)

    Valvassori, Samira S; Resende, Wilson R; Lopes-Borges, Jéssica; Mariot, Edemilson; Dal-Pont, Gustavo C; Vitto, Marcelo F; Luz, Gabrielle; de Souza, Claudio T; Quevedo, João

    2015-06-01

    The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on mitochondrial superoxide, lipid peroxidation, and proteins involved in cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania. Wistar rats received Li, VPA, or saline twice a day for 13 days. On the 7th day of treatment, the animals received a single intracerebroventricular injection of ouabain or aCSF. After the ICV injection, the treatment with mood stabilizers continued for 6 additional days. The locomotor activity of rats was measured using the open-field test. In addition, we analyzed oxidative stress parameters, specifically levels of phosphorylated p53 (pp53), BAX and Bcl-2 in the brain of rats by immunoblot. Li and VPA reversed ouabain-related hyperactivity. Ouabain decreased Bcl-2 levels and increased the oxidative stress parameters BAX and pp53 in the brains of rats. Li and VPA improved these ouabain-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. These findings suggest that the Na(+)/K(+)-ATPase can be an important link between oxidative damage and the consequent reduction of neuronal and glial density, which are both observed in BD, and that Li and VPA exert protective effects against ouabain-induced activation of the apoptosis pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. A Response to the Legitimacy of Brain Death in Islam.

    Science.gov (United States)

    Rady, Mohamed Y; Verheijde, Joseph L

    2016-08-01

    Brain death is a novel construct of death for the procurement of transplantable organs. Many authoritative Islamic organizations and governments have endorsed brain death as true death for organ donation. Many commentators have reiterated the misconception that the Quranic text does not define death. We respond by clarifying: (1) the Quran does define death as biologic disintegration and clearly distinguishes it from the dying process, (2) brain death belongs scientifically within the spectrum of neurologic disorders of consciousness and should not be confused with death, and (3) religious and legal discord about brain death has grown in jurisdictions worldwide. We urge for public transparency and truthfulness about brain death and the accommodation and respect of religious objection to the determination of death by neurologic criteria.

  13. Family presence during brain death evaluation: a randomized controlled trial*.

    Science.gov (United States)

    Tawil, Isaac; Brown, Lawrence H; Comfort, David; Crandall, Cameron S; West, Sonlee D; Rollstin, Amber D; Dettmer, Todd S; Malkoff, Marc D; Marinaro, Jonathan

    2014-04-01

    To evaluate if a family presence educational intervention during brain death evaluation improves understanding of brain death without affecting psychological distress. Randomized controlled trial. Four ICUs at an academic tertiary care center. Immediate family members of patients suspected to have suffered brain death. Subjects were group randomized to presence or absence at bedside throughout the brain death evaluation with a trained chaperone. All randomized subjects were administered a validated "understanding brain death" survey before and after the intervention. Subjects were assessed for psychological well-being between 30 and 90 days after the intervention. Follow-up assessment of psychological well-being was performed using the Impact of Event Scale and General Health Questionnaire. Brain death understanding, Impact of Event Scale, and General Health Questionnaire scores were analyzed using Wilcoxon nonparametric tests. Analyses were adjusted for within family correlation. Fifty-eight family members of 17 patients undergoing brain death evaluation were enrolled: 38 family members were present for 11 brain death evaluations and 20 family members were absent for six brain death evaluations. Baseline understanding scores were similar between groups (median 3.0 [presence group] vs 2.5 [control], p = 0.482). Scores increased by a median of 2 (interquartile range, 1-2) if present versus 0 (interquartile range, 0-0) if absent (p Family presence during brain death evaluation improves understanding of brain death with no apparent adverse impact on psychological well-being. Family presence during brain death evaluation is feasible and safe.

  14. Brain death in neonates: a case report

    Directory of Open Access Journals (Sweden)

    Georgios Mitsiakos

    2014-06-01

    Full Text Available Brain death (BD is the permanent and complete loss of cerebral and brainstem function. It is relatively uncommon in newborns with its percentage among deaths being 1-6.3%. BD leads to debate for medical, ethical and philosophical issues. It is a challenging condition in neonatal intensive care units (NICUs since difficulties for BD diagnosis in neonates and ever more so in preterm neonates do arise. Revised guidelines for BD diagnosis definition include history with known etiology, clinical examination, apnea testing and neurological evaluation often assisted by ancillary tests. We present the case of a near term female baby that was born with brain death due to hypoxic ischemic encephalopathy. We conclude that BD in newborns is a challenge to NICUs and there is a need for establishing and implementing new guidelines and checklists on national basis. Proceedings of the 10th International Workshop on Neonatology · Cagliari (Italy · October 22nd-25th, 2014 · The last ten years, the next ten years in Neonatology Guest Editors: Vassilios Fanos, Michele Mussap, Gavino Faa, Apostolos Papageorgiou

  15. Quinazoline-based tricyclic compounds that regulate programmed cell death, induce neuronal differentiation, and are curative in animal models for excitotoxicity and hereditary brain disease

    OpenAIRE

    Vainshtein, A.; Veenman, L; Shterenberg, A; Singh, S; Masarwa, A; Dutta, B.; Island, B; Tsoglin, E; Levin, E.; Leschiner, S; Maniv, I; Pe?er, L; Otradnov, I; Zubedat, S; Aga-Mizrachi, S

    2015-01-01

    Expanding on a quinazoline scaffold, we developed tricyclic compounds with biological activity. These compounds bind to the 18?kDa translocator protein (TSPO) and protect U118MG (glioblastoma cell line of glial origin) cells from glutamate-induced cell death. Fascinating, they can induce neuronal differentiation of PC12 cells (cell line of pheochromocytoma origin with neuronal characteristics) known to display neuronal characteristics, including outgrowth of neurites, tubulin expression, and ...

  16. Death Associated Protein Kinases: Molecular Structure and Brain Injury

    Directory of Open Access Journals (Sweden)

    Claire Thornton

    2013-07-01

    Full Text Available Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1.

  17. Ethical aspects of the concept of brain death

    Directory of Open Access Journals (Sweden)

    A. V. Pinchuk

    2013-01-01

    Full Text Available The authors attempt to summarize views of leading russian experts in bioethics and medical deontology on the moral and ethical issues related to the development of the concept of brain death and its application in modern medicine. A variety of ethical issues associated with the use of the concept of "brain death" in organ donation and clinical transplantation is noted. The official attitude of representatives of the world's major faiths to the problems of brain death and organ transplantation is reflected. Authors express their own attitude to the issues discussed, as professionals facing daily with challenges of brain death in their own clinical practice.

  18. [Brain death in Ibero-America].

    Science.gov (United States)

    Escudero, D; Matesanz, R; Soratti, C A; Flores, José Ignacio

    2009-12-01

    To examine the diagnosis of brain death (BD) in Latin America. The term BD has long been used to define the death of an individual despite legal differences and variations in the diagnostic criteria applied in each country. A survey was conducted to gain information on the medical and legal diagnosis of BD in the 21 countries that make up the Latin American Network/Council of Donation and Transplant. All the Latin American countries except for Nicaragua legally recognize BD as the death of the person. To declare a person dead, 2 or 3 doctors are required in most countries. In all the countries, the requirements that must be fulfilled are unresponsive coma, lack of brainstem reflexes and of spontaneous breathing. Partial pressure of arterial carbon dioxide levels required in the apnea test vary from 50-60mm Hg. The minimum temperature required for a neurological examination ranges from 32 degrees -35 degrees C. The atropine test is mandatory in 7 (35%) countries. The most recommended observation period is 6h, but there is great variation and can be up to 24h. In 8 countries (40%), an instrumental test is obligatory, while in the remaining countries this is only undertaken under special circumstances. In some countries, when organs are not donated for transplant, support measures are not withdrawn, this being more frequent in children. There seems to be some uniformity in the main diagnostic criteria applied, with differences observed in clinical prerequisites, neurological exams, observation time, instrumental tests and the clinical decisions made following a declaration of BD. It is recommended that diagnostic criteria be standardized.

  19. Phagocytosis executes delayed neuronal death after focal brain ischemia

    OpenAIRE

    Neher, Jonas J.; Emmrich, Julius V.; Fricker, Michael; Mander, Palwinder K.; Théry, Clotilde; Brown, Guy C.

    2013-01-01

    Brain ischemia is a major cause of death and disability worldwide, but the cellular mechanisms of delayed neuronal loss and brain atrophy after cerebral ischemia are poorly understood and thus currently untreatable. Surprisingly, we find that after cerebral ischemia, brain macrophages phagocytose viable and functional neurons, causing brain atrophy and motor dysfunction. Our data show that delayed neuronal death and functional impairment after cerebral ischemia can be prevented by blocking sp...

  20. Variability of Brain Death Policies in the United States.

    Science.gov (United States)

    Greer, David M; Wang, Hilary H; Robinson, Jennifer D; Varelas, Panayiotis N; Henderson, Galen V; Wijdicks, Eelco F M

    2016-02-01

    Brain death is the irreversible cessation of function of the entire brain, and it is a medically and legally accepted mechanism of death in the United States and worldwide. Significant variability may exist in individual institutional policies regarding the determination of brain death. It is imperative that brain death be diagnosed accurately in every patient. The American Academy of Neurology (AAN) issued new guidelines in 2010 on the determination of brain death. To evaluate if institutions have adopted the new AAN guidelines on the determination of brain death, leading to policy changes. Fifty-two organ procurement organizations provided US hospital policies pertaining to the criteria for determining brain death. Organizations were instructed to procure protocols specific to brain death (ie, not cardiac death or organ donation procedures). Data analysis was conducted from June 26, 2012, to July 1, 2015. Policies were evaluated for summary statistics across the following 5 categories of data: who is qualified to perform the determination of brain death, what are the necessary prerequisites for testing, details of the clinical examination, details of apnea testing, and details of ancillary testing. We compared these data with the standards in the 2010 AAN update on practice parameters for brain death. A total of 508 unique hospital policies were obtained, representing the majority of hospitals in the United States that would be eligible and equipped to evaluate brain death in a patient. Of these, 492 provided adequate data for analysis. Although improvement with AAN practice parameters was readily apparent, there remained significant variability across all 5 categories of data, such as excluding the absence of hypotension (276 of 491 policies [56.2%]) and hypothermia (181 of 228 policies [79.4%]), specifying all aspects of the clinical examination and apnea testing, and specifying appropriate ancillary tests and how they were to be performed. Of the 492 policies

  1. Confounding factors in diagnosing brain death: a case report

    Directory of Open Access Journals (Sweden)

    Login Ivan S

    2002-06-01

    Full Text Available Abstract Background Brain death is strictly defined medically and legally. This diagnosis depends on three cardinal neurological features: coma, absent brainstem reflexes, and apnea. The diagnosis can only be made, however, in the absence of intoxication, hypothermia, or certain medical illnesses. Case presentation A patient with severe hypoxic-ischemic brain injury met the three cardinal neurological features of brain death but concurrent profound hypothyroidism precluded the diagnosis. Our clinical and ethical decisions were further challenged by another facet of this complex case. Although her brain damage indicated a hopeless prognosis, we could not discontinue care based on futility because the only known surrogate was mentally retarded and unable to participate in medical planning. Conclusion The presence of certain medical conditions prohibits a diagnosis of brain death, which is a medicolegal diagnosis of death, not a prediction or forecast of future outcome. While prognostication is important in deciding to withdraw care, it is not a component in diagnosing brain death.

  2. Total brain death: a reply to Alan Shewmon.

    Science.gov (United States)

    Lee, Patrick; GriseZ, Germain

    2012-06-01

    D. Alan Shewmon has advanced a well-documented challenge to the widely accepted total brain death criterion for death of the human being. We show that Shewmon’s argument against this criterion is unsound, though he does refute the standard argument for that criterion. We advance a distinct argument for the total brain death criterion and answer likely objections. Since human beings are rational animals--sentient organisms of a specific type--the loss of the radical capacity for sentience (the capacity to sense or to develop the capacity to sense) involves a substantial change, the passing away of the human organism. In human beings total brain death involves the complete loss of the radical capacity for sentience, and so in human beings total brain death is death.

  3. The presence of family during brain stem death testing.

    Science.gov (United States)

    Doran, Majella

    2004-02-01

    Prior to 1959, cardiac and respiratory cessation was universally and unambiguously accepted as confirming the death of a person [M. Morioka, J. Clin. Nurs. 10 (2001) 132; Reconsidering brain death: a lesson from Japan's fifteen years of experience, 2001, http://proquest.umi.com/pqdweb]. However, with the rapid pace of modern technology and resuscitation techniques, the boundaries between life and death have become blurred [J. Bothamley, Organ donation: brain stem death, 2000, http://proquest.umi.com/pqdweb; Re-examining death: against a higher brain criterion, 1999, http://proquest.umi.com/pqdweb]. As a result, a redefinition of death, "brain death" has emerged [M. Brazier, Medicine, Patients and the Law, New ed., Penquin Books, London, 1992]. Most families faced with the brain stem death of a relative find the concept difficult to understand and have trouble in accepting that their relative is actually dead. In Part One of this two part series, the needs of families who are facing the brain stem death of a family member will be examined and explanations offered as to why families find the concept difficult to grasp. In addition, it will also advocate that family members are given the choice to be or not to be present during brain stem death testing. It is suggested that the presence of family members during brain stem death testing not only helps families to accept this concept of death but also promotes the grieving process. In Part Two, the barriers that inhibit family involvement and presence will be explored and methods for involving family proposed.

  4. Radio-induced brain lesions

    Directory of Open Access Journals (Sweden)

    Gorgan Mircea Radu

    2014-03-01

    Full Text Available Introduction : Radiotherapy, an important tool in multimodal oncologic treatment, can cause radio-induced brain lesion development after a long period of time following irradiation.

  5. The death of whole-brain death: the plague of the disaggregators, somaticists, and mentalists.

    Science.gov (United States)

    Veatch, Robert M

    2005-08-01

    In its October 2001 issue, this journal published a series of articles questioning the Whole-Brain-based definition of death. Much of the concern focused on whether somatic integration-a commonly understood basis for the whole-brain death view-can survive the brain's death. The present article accepts that there are insurmountable problems with whole-brain death views, but challenges the assumption that loss of somatic integration is the proper basis for pronouncing death. It examines three major themes. First, it accepts the claim of the "disaggregators" that some behaviors traditionally associated with death can be unbundled, but argues that other behaviors (including organ procurement) must continue to be associated. Second, it rejects the claims of the "somaticists," that the integration of the body is critical, arguing instead for equating death with the irreversible loss of "embodied consciousness," that is, the loss of integration of bodily and mental function. Third, it defends higher-brain views against the charge that they are necessarily "mentalist," that is, that they equate death with losing some mental function such as consciousness or personhood. It argues, instead, for the integration of bodily and mental function as the critical feature of human life and that its irreversible loss constitutes death.

  6. A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells

    Directory of Open Access Journals (Sweden)

    Lei Joy X

    2011-01-01

    Full Text Available Abstract Background Molecular changes in multiple biological processes contribute to the development of chronic neurodegeneration such as late onset Alzheimer's disease (LOAD. To discover how these changes are reflected at the level of gene expression, we used a subtractive transcription-based amplification of mRNA procedure to identify novel genes that have altered expression levels in the brains of Alzheimer's disease (AD patients. Among the genes altered in expression level in AD brains was a transcript encoding a novel protein, SDIM1, that contains 146 amino acids, including a typical signal peptide and two transmembrane domains. Here we examined its biochemical properties and putative roles in neuroprotection/neurodegeneration. Results QRT-PCR analysis of additional AD and control post-mortem human brains showed that the SDIM1 transcript was indeed significantly down regulated in all AD brains. SDIM1 is more abundant in NT2 neurons than astrocytes and present throughout the cytoplasm and neural processes, but not in the nuclei. In NT2 neurons, it is highly responsive to stress conditions mimicking insults that may cause neurodegeneration in AD brains. For example, SDIM1 was significantly down regulated 2 h after oxygen-glucose deprivation (OGD, though had recovered 16 h later, and also appeared significantly up regulated compared to untreated NT2 neurons. Overexpression of SDIM1 in neuro-progenitor cells improved cells' ability to survive after injurious insults and its downregulation accelerated cell death induced by OGD. Yeast two-hybrid screening and co-immunoprecipitation approaches revealed, both in vitro and in vivo, an interaction between SDIM1 and DNAJB4, a heat shock protein hsp40 homolog, recently known as an enhancer of apoptosis that also interacts with the mu opioid receptor in human brain. Overexpression of DNAJB4 alone significantly reduced cell viability and SDIM1 co-overexpression was capable of attenuating the cell death

  7. Public education and misinformation on brain death in mainstream media.

    Science.gov (United States)

    Lewis, Ariane; Lord, Aaron S; Czeisler, Barry M; Caplan, Arthur

    2016-09-01

    We sought to evaluate the caliber of education mainstream media provides the public about brain death. We reviewed articles published prior to July 31, 2015, on the most shared/heavily trafficked mainstream media websites of 2014 using the names of patients from two highly publicized brain death cases, "Jahi McMath" and "Marlise Muñoz." We reviewed 208 unique articles. The subject was referred to as being "alive" or on "life support" in 72% (149) of the articles, 97% (144) of which also described the subject as being brain dead. A definition of brain death was provided in 4% (9) of the articles. Only 7% (14) of the articles noted that organ support should be discontinued after brain death declaration unless a family has agreed to organ donation. Reference was made to well-known cases of patients in persistent vegetative states in 16% (34) of articles and 47% (16) of these implied both patients were in the same clinical state. Mainstream media provides poor education to the public on brain death. Because public understanding of brain death impacts organ and tissue donation, it is important for physicians, organ procurement organizations, and transplant coordinators to improve public education on this topic. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. A survey of American neurologists about brain death: understanding the conceptual basis and diagnostic tests for brain death.

    Science.gov (United States)

    Joffe, Ari R; Anton, Natalie R; Duff, Jonathan P; Decaen, Allan

    2012-02-17

    Neurologists often diagnose brain death (BD) and explain BD to families in the intensive care unit. This study was designed to determine whether neurologists agree with the standard concept of death (irreversible loss of integrative unity of the organism) and understand the state of the brain when BD is diagnosed. A previously validated survey was mailed to a random sample of 500 board-certified neurologists in the United States. Main outcomes were: responses indicating the concept of death that BD fulfills and the empirical state of the brain that would rule out BD. After the second mailing, 218 (44%) surveys were returned. Few (n = 52, 27%; 95% confidence interval (CI), 21%, 34%) responded that BD is death because the organism has lost integrative unity. The most common justification was a higher brain concept (n = 93, 48%; 95% CI, 41%, 55%), suggesting that irreversible loss of consciousness is death. Contrary to the recent President's Council on Bioethics, few (n = 22, 12%; 95% CI, 8%, 17%) responded that the irreversible lack of vital work of an organism is a concept of death that the BD criterion may satisfy. Many responded that certain brain functions remaining are not compatible with a diagnosis of BD, including EEG activity, evoked potential activity, and hypothalamic neuroendocrine function. Many also responded that brain blood flow and lack of brainstem destruction are not compatible with a diagnosis of BD. American neurologists do not have a consistent rationale for accepting BD as death, nor a clear understanding of diagnostic tests for BD.

  9. Mechanisms of Ethanol-induced Death of Cerebellar Granule Cells

    Science.gov (United States)

    Luo, Jia

    2012-01-01

    Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system (CNS) underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that is most susceptible to ethanol during development. Ethanol exposure causes a loss of both cerebellar Purkinje cells and granule cells. This review focuses on the toxic effect of ethanol on cerebellar granule cells (CGC) and the underlying mechanisms. Both in vitro and in vivo studies indicate that ethanol induces apoptotic death of CGC. The vulnerability of CGC to ethanol-induced death diminishes over time as neurons mature. Several mechanisms for ethanol-induced apoptosis of CGC have been suggested. These include inhibition of NMDA receptors, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, disturbance of potassium channel currents, thiamine deficiency, and disruption of translational regulation. Cultures of CGC provide an excellent system to investigate cellular/molecular mechanisms of ethanol-induced neurodegeneration and to evaluate interventional strategies. This review will also discuss the approaches leading to neuroprotection against ethanol-induced neuroapoptosis. PMID:20927663

  10. The clinical diagnosis of brain death

    African Journals Online (AJOL)

    -~": 1 Deep coma without any kind of response. 2 Irreversible and irreparable brain injury. 3 Absence of brainstem and spinal integrated reflexes. 4 Negative atropine test. 5 Proved apnoea with an apnoea test. 6 Electroencephalogram results ...

  11. Hypercoagulation following brain death cannot be reversed by the neutralization of systemic tissue factor.

    Science.gov (United States)

    Hvas, Christine L; Fenger-Eriksen, Christian; Høyer, Søren; Sørensen, Benny; Tønnesen, Else

    2013-08-01

    Cerebral injury and brain death is associated with apparent hypercoagulation and poor organ outcome. This experimental study challenges the hypotheses that i) brain death causes hypercoagulation and microvascular thrombosis and that ii) neutralizing systemic tissue factor (TF) by in vitro addition of a TF inhibitor (recombinant active site-inhibited factor VIIa (ASIS)) can reverse the hypercoagulable profile. Using a validated pig model of intracranial hemorrhage and brain death, 20 pigs were randomized to either control or brain death. The primary endpoints were coagulation parameters measured with whole blood thromboelastometry (ROTEM), thrombin generation and a porcine TF-sensitive plasma clotting time assay. In vitro spiking experiments with ASIS were performed in parallel with the latter two assessments. The kidneys were examined histologically for microvascular thromboses. Brain death induced hypercoagulation, as demonstrated with ROTEM, thrombin generation, and reduced TF-sensitive plasma clotting time. In vitro inhibition of TF with ASIS did not reverse the hypercoagulation. No microvascular thromboses were found in the kidneys. Brain death causes hypercoagulation; however, inhibition of TF does not reverse the coagulopathy. Thus, TF release does not seem to be the primary cause of this hypercoagulation. Minor changes in the levels of protein C suggest that the protein C pathway may be linked to the observed coagulopathy. © 2013.

  12. Similar liver transplantation survival with selected cardiac death donors and brain death donors

    NARCIS (Netherlands)

    Dubbeld, J.; Hoekstra, H.; Farid, W.; Ringers, J.; Porte, R. J.; Metselaar, H. J.; Baranski, A. G.; Kazemier, G.; van den Bere, A. P.; van Hoek, B.

    Background: The outcome of orthotopic liver transplantation (OLT) with controlled graft donation after cardiac death (DCD) is usually inferior to that with graft donation after brain death (DBD). This study compared outcomes from OLT with DBD versus controlled DCD donors with predefined restrictive

  13. Prevention of hypoglycemia-induced neuronal death by minocycline

    Science.gov (United States)

    2012-01-01

    Diabetic patients who attempt strict management of blood glucose levels frequently experience hypoglycemia. Severe and prolonged hypoglycemia causes neuronal death and cognitive impairment. There is no effective tool for prevention of these unwanted clinical sequelae. Minocycline, a second-generation tetracycline derivative, has been recognized as an anti-inflammatory and neuroprotective agent in several animal models such as stroke and traumatic brain injury. In the present study, we tested whether minocycline also has protective effects on hypoglycemia-induced neuronal death and cognitive impairment. To test our hypothesis we used an animal model of insulin-induced acute hypoglycemia. Minocycline was injected intraperitoneally at 6 hours after hypoglycemia/glucose reperfusion and injected once per day for the following 1 week. Histological evaluation for neuronal death and microglial activation was performed from 1 day to 1 week after hypoglycemia. Cognitive evaluation was conducted 6 weeks after hypoglycemia. Microglial activation began to be evident in the hippocampal area at 1 day after hypoglycemia and persisted for 1 week. Minocycline injection significantly reduced hypoglycemia-induced microglial activation and myeloperoxidase (MPO) immunoreactivity. Neuronal death was significantly reduced by minocycline treatment when evaluated at 1 week after hypoglycemia. Hypoglycemia-induced cognitive impairment is also significantly prevented by the same minocycline regimen when subjects were evaluated at 6 weeks after hypoglycemia. Therefore, these results suggest that delayed treatment (6 hours post-insult) with minocycline protects against microglial activation, neuronal death and cognitive impairment caused by severe hypoglycemia. The present study suggests that minocycline has therapeutic potential to prevent hypoglycemia-induced brain injury in diabetic patients. PMID:22998689

  14. Brain death: recent ethical and religious considerations in Iran.

    Science.gov (United States)

    Akrami, S M; Osati, Z; Zahedi, F; Raza, M

    2004-12-01

    The Islamic Republic of Iran has a long history of medicine. The principles derived from core Islamic teachings provide a comprehensive moral, ethical, and legal framework for the practice of medicine. The issue of brain death has significant impact on the procurement of organs from cadavers. It is a major subject of debate and interest to bioscientists, legal experts, religious scholars, and the general public. Laws related to the ethical and legal aspects of cadaver organ donation from the brain dead have not been defined in many Muslim countries. This report presents recent advances in Iranian law with regard to the ethics of organ transplantation and the definition of brain death.

  15. Portrayal of Brain Death in Film and Television.

    Science.gov (United States)

    Lewis, A; Weaver, J; Caplan, A

    2017-03-01

    We sought to evaluate whether television and cinematic coverage of brain death is educational or misleading. We identified 24 accessible productions that addressed brain death using the archives of the Paley Center for Media (160 000 titles) and the Internet Movie Database (3.7 million titles). Productions were reviewed by two board-certified neurologists. Although 19 characters were pronounced brain dead, no productions demonstrated a complete examination to assess for brain death (6 included an assessment for coma, 9 included an evaluation of at least 1 brainstem reflex, but none included an assessment of every brainstem reflex, and 2 included an apnea test). Subjectively, both authors believed only a small fraction of productions (13% A.L., 13% J.W.) provided the public a complete and accurate understanding of brain death. Organ donation was addressed in 17 productions (71%), but both reviewers felt that the discussions about organ donation were professional in a paucity of productions (9% for A.L., 27% for J.W.). Because television and movies serve as a key source for public education, the quality of productions that feature brain death must be improved. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  16. Do not resuscitate, brain death, and organ transplantation: Islamic perspective

    Science.gov (United States)

    Chamsi-Pasha, Hassan; Albar, Mohammed Ali

    2017-01-01

    Muslim patients and families are often reluctant to discuss and accept fatal diagnoses and prognoses. In many instances, aggressive therapy is requested by a patient's family, prolonging the life of the patient at all costs. Islamic law permits the withdrawal of futile treatment, including life support, from terminally ill patients allowing death to take its natural course. “Do not resuscitate” is permitted in Islamic law in certain situations. Debate continues about the certainty of brain death criteria within Islamic scholars. Although brain death is accepted as true death by the majority of Muslim scholars and medical organizations, the consensus in the Muslim world is not unanimous, and some scholars still accept death only by cardiopulmonary criteria. Organ transplantation has been accepted in Islamic countries (with some resistance from some jurists). Many fatwas (decrees) of Islamic Jurisprudence Councils have been issued and allowed organs to be donated from living competent adult donor; and from deceased (cadavers), provided that they have agreed to donate or their families have agreed to donate after their death (usually these are brain-dead cases). A clear and well-defined policy from the ministry of health regarding do not resuscitate, brain death, and other end-of-life issues is urgently needed for all hospitals and health providers in most (if not all) Muslim and Arab countries. PMID:28469984

  17. Teaching the concept of brain death in undergraduate medical education.

    Science.gov (United States)

    Holling, Markus; Stummer, Walter; Friederichs, Hendrik

    2015-01-01

    To establish and evaluate a new approach to teach medical students how to assess brain death in patients. A total of 120 fourth-year medical students at Münster Medical School (Germany) participated in a 1-hour lecture on how to assess brain death in patients. After this lecture, students were assigned to 2 groups. One group attended an additional practical course on the evaluation of brain death and received training using a new high-fidelity simulation device. The other group did not participate in any additional training session. All students completed a questionnaire before the lecture and a second questionnaire at the conclusion of the study. For the group undergoing the additional training, the second questionnaire was completed after the additional training session. The additional practical training session significantly improved the students' performance in assessing brain death and promoted the self-assessment and motivation of the medical students. The establishment of a new practical teaching concept led to significant improvements in medical students' assessments of brain death in a practical session. These improvements in medical education could have significant implications for the clinical assessment of patients in the future. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

  18. Inducible cell death in plant immunity

    DEFF Research Database (Denmark)

    Hofius, Daniel; Tsitsigiannis, Dimitrios I; Jones, Jonathan D G

    2006-01-01

    Programmed cell death (PCD) occurs during vegetative and reproductive plant growth, as typified by autumnal leaf senescence and the terminal differentiation of the endosperm of cereals which provide our major source of food. PCD also occurs in response to environmental stress and pathogen attack......, and these inducible PCD forms are intensively studied due their experimental tractability. In general, evidence exists for plant cell death pathways which have similarities to the apoptotic, autophagic and necrotic forms described in yeast and metazoans. Recent research aiming to understand these pathways...

  19. Nitric oxide synthase expression and apoptotic cell death in brains of AIDS and AIDS dementia patients

    NARCIS (Netherlands)

    Vincent, V. A.; de Groot, C. J.; Lucassen, P. J.; Portegies, P.; Troost, D.; Tilders, F. J.; van Dam, A. M.

    1999-01-01

    To determine the occurrence and cellular localization of inducible nitric oxide synthase (iNOS), NOS activity and its association with cell death in brains of AIDS and AIDS dementia complex (ADC) patients. Post-mortem cerebral cortex tissue of eight AIDS patients, eight ADC patients and eight

  20. Brain dead or not? CT angiogram yielding false-negative result on brain death confirmation.

    Science.gov (United States)

    Johnston, Robyn; Kaliaperumal, Chandrasekaran; Wyse, Gerald; Kaar, George

    2013-01-08

    We describe a case of severe traumatic brain injury with multiple facial and skull fractures where CT angiogram (CTA) failed to yield a definite result of brain death as an ancillary test. A 28-year-old man was admitted following a road traffic accident with a Glasgow Coma Score (GCS) of 3/15 and fixed pupils. CT brain revealed uncal herniation and diffuse cerebral oedema with associated multiple facial and skull fractures. 72 h later, his clinical condition remained the same with high intracranial pressure refractory to medical management. Clinical confirmation on brain death was not feasible owing to facial injuries. A CTA, performed to determine brain perfusion, yielded a 'false-negative' result. Skull fractures have possibly led to venous prominence in the cortical and deep venous drainage system. This point needs to be borne in mind while considering CTA as an ancillary test to confirm brain death.

  1. Do Spanish Medical Students Understand the Concept of Brain Death?

    Science.gov (United States)

    Ríos, Antonio; López-Navas, A; López-López, A; Gómez, F J; Iriarte, J; Herruzo, R; Blanco, G; Llorca, F J; Asunsolo, A; Sánchez, P; Gutiérrez, P R; Fernández, A; de Jesús, M T; Alarcón, L Martínez; Del Olivo, M; Fuentes, L; Hernández, J R; Virseda, J; Yelamos, J; Bondía, J A; Hernández, A M; Ayala, M A; Ramírez, P; Parrilla, P

    2018-01-01

    To analyze the level of understanding of the brain death concept among medical students in universities in Spain. This cross-sectional sociological, interdisciplinary, and multicenter study was performed on 9598 medical students in Spain. The sample was stratified by geographical area and academic year. A previously validated self-reported measure of brain death knowledge (questionnaire Proyecto Colaborativo Internacional Donante sobre la Donación y Transplante de Organos) was completed anonymously by students. Respondents completed 9275 surveys for a completion rate of 95.7%. Of those, 67% (n = 6190) of the respondents understood the brain death concept. Of the rest, 28% (n = 2652) did not know what it meant, and the remaining 5% (n = 433) believed that it did not mean that the patient was dead. The variables related to a correct understanding of the concept were: (1) being older ( P < .001), (2) studying at a public university ( P < .001), (3) year of medical school ( P < .001), (4) studying at one of the universities in the south of Spain ( P = .003), (5) having discussed donation and transplantation with the family ( P < .001), (6) having spoken to friends about the matter ( P < .001), (7) a partner's favorable attitude toward donation and transplantation ( P < .001), and (8) religious beliefs ( P < .001). Sixty-seven percent of medical students know the concept of brain death, and knowledge improved as they advanced in their degree.

  2. Local exposure of 849 MHz and 1763 MHz radiofrequency radiation to mouse heads does not induce cell death or cell proliferation in brain

    OpenAIRE

    Kim, Tae-Hyoung; Huang, Tai-Qin; Jang, Ja-June; Kim, Man Ho; Kim, Hyun-Jeong; Lee, Jae-Seon; Pack, Jeong Ki; Seo, Jeong-Sun; Park, Woong-Yang

    2008-01-01

    Even though there is no direct evidence to prove the cellular and molecular changes induced by radiofrequency (RF) radiation itself, we cannot completely exclude the possibility of any biological effect of mobile phone frequency radiation. We established a carousel-type exposure chamber for 849 MHz or 1763 MHz of mobile phone RF radiation to expose RF to the heads of C57BL mice. In this chamber, animals were irradiated intermittently at 7.8 W/kg for a maximum of 12 months. During this period,...

  3. Gadolinium-enhanced magnetic resonance angiography in brain death

    Science.gov (United States)

    Luchtmann, M.; Beuing, O.; Skalej, M.; Kohl, J.; Serowy, S.; Bernarding, J.; Firsching, R.

    2014-01-01

    Confirmatory tests for the diagnosis of brain death in addition to clinical findings may shorten observation time required in some countries and may add certainty to the diagnosis under specific circumstances. The practicability of Gadolinium-enhanced magnetic resonance angiography to confirm cerebral circulatory arrest was assessed after the diagnosis of brain death in 15 patients using a 1.5 Tesla MRI scanner. In all 15 patients extracranial blood flow distal to the external carotid arteries was undisturbed. In 14 patients no contrast medium was noted within intracerebral vessels above the proximal level of the intracerebral arteries. In one patient more distal segments of the anterior and middle cerebral arteries (A3 and M3) were filled with contrast medium. Gadolinium-enhanced MRA may be considered conclusive evidence of cerebral circulatory arrest, when major intracranial vessels fail to fill with contrast medium while extracranial vessels show normal blood flow.

  4. Ethical aspects of brain death and end-of-life

    Directory of Open Access Journals (Sweden)

    Gabriel Oselka

    Full Text Available Abstract Ethical issues surrounding brain death and end-of-life have not been afforded in Brazil the same attention as in many developed countries. There appears to be reluctance on the part of Brazilian doctors to limit or suspend procedures or treatment which prolongs life of patients in terminal phases of severe incurable illness, or to suspend the artificial means of supporting vegetative functions in cases of brain death outside the context of organ and tissue donation for transplant. Fears grounded in possible administrative (Regional Medical Councils or legal repercussions, as well as ambiguous interpretations of religious precepts, partially explain this reluctance which often results in unnecessary prolonging of patient suffering. A recent resolution by the Federal Medical Council on end-of-life may offer doctors some guidance and confidence in dealing with highly complex ethical situations.

  5. A Donation After Circulatory Death Program Has the Potential to Increase the Number of Donors After Brain Death.

    Science.gov (United States)

    Broderick, Andrew R; Manara, Alex; Bramhall, Simon; Cartmill, Maria; Gardiner, Dale; Neuberger, James

    2016-02-01

    Donation after circulatory death has been responsible for 75% of the increase in the numbers of deceased organ donors in the United Kingdom. There has been concern that the success of the donation after circulatory death program has been at the expense of donation after brain death. The objective of the study was to ascertain the impact of the donation after circulatory death program on donation after brain death in the United Kingdom. Retrospective cohort study. A national organ procurement organization. Patients referred and assessed as donation after circulatory death donors in the United Kingdom between October and December 2013. None. A total of 257 patients were assessed for donation after circulatory death. Of these, 193 were eligible donors. Three patients were deemed medically unsuitable following surgical inspection, 56 patients did not proceed due to asystole, and 134 proceeded to donation. Four donors had insufficient data available for analysis. Therefore, 186 cases were analyzed in total. Organ donation would not have been possible in 79 of the 130 actual donors if donation after circulatory death was not available. Thirty-six donation after circulatory death donors (28% of actual donors) were judged to have the potential to progress to brain death if withdrawal of life-sustaining treatment had been delayed by up to a further 36 hours. A further 15 donation after circulatory death donors had brain death confirmed or had clinical indications of brain death with clear mitigating circumstances in all but three cases. We determined that the maximum potential donation after brain death to donation after circulatory death substitution rate observed was 8%; however due to mitigating circumstances, only three patients (2%) could have undergone brain death testing. The development of a national donation after circulatory death program has had minimal impact on the number of donation after brain death donors. The number of donation after brain death donors

  6. Some questions about brain death: a case report.

    Science.gov (United States)

    Joffe, Ari R; Anton, Natalie R

    2007-10-01

    A 13-year-old girl had an anaphylactic cardiac arrest with 45 minutes of resuscitation. After rewarming on day 3, a first examination was compatible with brain death, including an apnea test. Shortly thereafter, a stimulus to the trapezius muscle above the clavicles resulted in bilateral lower-limb withdrawal. A subsequent examination by another intensivist found, during vestibulo-ocular testing, bilateral lower-limb withdrawal. A radionuclide cerebral blood-flow test indicated no intracranial flow, and a computed tomography scan indicated diffuse severe cerebral edema. After these tests, stimulus to the trapezius muscle resulted in bilateral lower-limb extensor posturing. The next day, on repeated examination, the patient no longer had any response to stimulus, and was declared brain dead. This case raised two questions. Why should an intermittent lower-limb withdrawal response to supraclavicular stimulus be a more critical brain function, precluding a diagnosis of brain death (indicating that the patient has not lost integrative unity of the organism), than all other clinical and radiological findings? Was the withdrawal response of spinal origin or brainstem origin? How one chooses to interpret the withdrawal of lower limbs elicited by supraclavicular stimulus directly determines whether the patient in this case was dead.

  7. Arsenic-induced suicidal erythrocyte death

    Energy Technology Data Exchange (ETDEWEB)

    Mahmud, Hasan; Foeller, Michael; Lang, Florian [University of Tuebingen (Germany). Department of Physiology

    2009-02-15

    Environmental exposure to arsenic has been associated with anemia, which could result from suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by increase in cytosolic Ca{sup 2+} concentration, ceramide and energy depletion. The present experiments explored, whether arsenic stimulates eryptosis. According to annexin V-binding, arsenic trioxide (7{mu}M) within 48 h significantly increased phosphatidylserine exposure of human erythrocytes without inducing hemolysis. According to forward scatter, arsenic trioxide (7{mu}M) significantly decreased cell volume. Moreover, Fluo3-fluorescence showed that arsenic (10 {mu}M) significantly increased cytosolic Ca{sup 2+} concentration. According to binding of respective fluorescent antibodies, arsenic trioxide (10{mu}M) significantly increased ceramide formation. Arsenic (10{mu}M) further lowered the intracellular ATP concentration. Removal of extracellular Ca{sup 2+} or inhibition of the Ca{sup 2+}-permeable cation channels with amiloride blunted the effects of arsenic on annexin V-binding and cell shrinkage. In conclusion, arsenic triggers suicidal erythrocyte death by increasing cytosolic Ca{sup 2+} concentration, by stimulating the formation of ceramide and by decreasing ATP availability. (orig.)

  8. Bile Acid-Induced Suicidal Erythrocyte Death

    Directory of Open Access Journals (Sweden)

    Elisabeth Lang

    2016-04-01

    Full Text Available Background/Aims: In nucleated cells, bile acids may activate cation channels subsequently leading to entry of Ca2+. In erythrocytes, increase of cytosolic Ca2+ activity triggers eryptosis, the suicidal death of erythrocytes characterized by phosphatidylserine exposure at the cell surface and cell shrinkage. Eryptosis is triggered by bile duct ligation, an effect partially attributed to conjugated bilirubin. The present study explored, whether bile acids may stimulate eryptosis. Methods: Phosphatidylserine exposing erythrocytes have been identified utilizing annexin V binding, cell volume estimated from forward scatter, cytosolic Ca2+ activity determined using Fluo-3 fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Results: The exposure of human erythrocytes to glycochenodesoxycholic (GCDC and taurochenodesoxycholic (TCDC acid was followed by a significant decrease of forward scatter and significant increase of Fluo-3 fluorescence, ceramide abundance as well as annexin V binding. The effect on annexin V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusion: Bile acids stimulate suicidal cell death, an effect paralleled by and in part due to Ca2+ entry and ceramide. The bile acid induced eryptosis may in turn lead to accelerated clearance of circulating erythrocytes and, thus, may contribute to anemia in cholestatic patients.

  9. Patulin-Induced Suicidal Erythrocyte Death

    Directory of Open Access Journals (Sweden)

    Adrian Lupescu

    2013-07-01

    Full Text Available Background: Patulin, the most common mycotoxin in apples and apple-derived products, triggers apoptosis and has thus been considered for the treatment of cancer. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling leading to phosphatidylserine-exposure at the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i. The present study explored, whether exposure of human erythrocytes to patulin is followed by eryptosis. Methods: Forward scatter was measured to estimate cell volume, annexin V binding to detect phosphatidylserine-exposure, hemoglobin release to quantify hemolysis, and Fluo3-fuorescence to determine [Ca2+]i. Results: A 48 h exposure to patulin significantly increased [Ca2+]I (5 µM, significantly decreased forward scatter (5 µM and significantly increased annexin-V-binding (2.5 µM. Patulin (10 µM induced annexin-V-binding was virtually abrogated by removal of extracellular Ca2+. Conclusion: Patulin stimulates Ca2+ entry into erythrocytes, an effect triggering suicidal erythrocyte death or eryptosis.

  10. Patulin-induced suicidal erythrocyte death.

    Science.gov (United States)

    Lupescu, Adrian; Jilani, Kashif; Zbidah, Mohanad; Lang, Florian

    2013-01-01

    Patulin, the most common mycotoxin in apples and apple-derived products, triggers apoptosis and has thus been considered for the treatment of cancer. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling leading to phosphatidylserine-exposure at the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)]i). The present study explored, whether exposure of human erythrocytes to patulin is followed by eryptosis. Forward scatter was measured to estimate cell volume, annexin V binding to detect phosphatidylserine-exposure, hemoglobin release to quantify hemolysis, and Fluo3-fuorescence to determine [Ca(2+)]i. A 48 h exposure to patulin significantly increased [Ca(2+)]I (5 µM), significantly decreased forward scatter (5 µM) and significantly increased annexin-V-binding (2.5 µM). Patulin (10 µM) induced annexin-V-binding was virtually abrogated by removal of extracellular Ca(2+). Patulin stimulates Ca(2+) entry into erythrocytes, an effect triggering suicidal erythrocyte death or eryptosis. Copyright © 2013 S. Karger AG, Basel.

  11. [Brain death and organ transplantation: ethical dilemmas for nursing?].

    Science.gov (United States)

    Windels-Buhr, D

    1997-06-01

    According to the WHO Program, nurses should be active in public health care as equal members of a multiprofessional team. This position requires competent professional action, which also implies moral competence, especially necessitated by the coming paradigmatic changes caused by shifts in the previous and current boundaries of the paradigm human being. One reason for this shift are the greater medical technical possibilities. The medical definition of brain death as the death of a human being per se is one example of the altered boundary and its consequences. Must future components of the nursing metaparadigm be changed because of this? To what extent is nursing ethically obligated to integrate changes in social values into its metaparadigm, ethics and objectives? The nursing metaparadigm, Henderson's definition of nursing, the ICN's Basic Code of Ethics, and the nursing model according to Roper, Logan & Tierney were used as the basis in the analysis of the subject matter and problems. Furthermore, philosophical viewpoints of Jonas & Harris will be included to clarify the deontological and teleological aspects of standard ethics. Finally, conclusions are drawn about the intra- and interprofessional ethical discourse about brain death and organ transplantation among nursing professionals.

  12. Cell death induced by endoplasmic reticulum stress.

    Science.gov (United States)

    Iurlaro, Raffaella; Muñoz-Pinedo, Cristina

    2016-07-01

    The endoplasmic reticulum is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occurs in this organelle. Many conditions that impose stress on cells, including hypoxia, starvation, infections and changes in secretory needs, challenge the folding capacity of the cell and promote endoplasmic reticulum stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim of restoring homeostasis. This is known as the unfolded protein response, which also intersects with the integrated stress response that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the unfolded protein response are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as c-Jun N-terminal kinase 1 (JNK) and the downstream transcription factors XBP1, ATF4 and CHOP. These proteins aim to restore homeostasis, but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. In addition, endoplasmic reticulum stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of caspase-8. Endoplasmic reticulum stress is a common feature in the pathology of numerous diseases because it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to endoplasmic reticulum stress can accelerate discovery of drugs against these diseases. © 2015 FEBS.

  13. Modulation of Brain Dead Induced Inflammation by Vagus Nerve Stimulation

    NARCIS (Netherlands)

    Hoeger, S.; Bergstraesser, C.; Selhorst, J.; Fontana, J.; Birck, R.; Waldherr, R.; Beck, G.; Sticht, C.; Seelen, M. A.; van Son, W. J.; Leuvenink, H.; Ploeg, R.; Schnuelle, P.; Yard, B. A.

    Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability

  14. Saquinavir Induced Suicidal Death of Human Erythrocytes

    Directory of Open Access Journals (Sweden)

    Sabrina Waibel

    2015-11-01

    Full Text Available Background/Aims: The antiretroviral protease inhibitor saquinavir is used for the treatment of HIV infections. Effects of saquinavir include induction of apoptosis, the suicidal death of nucleated cells. Saquinavir treatment may further lead to anemia. In theory, anemia could result from accelerated erythrocyte loss by enhanced suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i, oxidative stress with increase of reactive oxygen species (ROS and ceramide. The present study explored, whether and how saquinavir induces eryptosis. Methods: To this end, flow cytometry was employed to estimate erythrocyte volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin-V-binding, [Ca2+]i from Fluo3-fluorescence, ROS abundance from DCFDA fluorescence and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to saquinavir significantly decreased forward scatter (≥ 5 µg/ml, significantly increased the percentage of annexin-V-binding cells (≥ 10 µg/ml, significantly increased Fluo3-fluorescence (15 µg/ml, significantly increased DCFDA fluorescence (15 µg/ml, but did not significantly modify ceramide abundance. The effect of saquinavir on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusions: Saquinavir triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of ROS formation and Ca2+ entry.

  15. Lapatinib Induced Suicidal Death of Human Erythrocytes

    Directory of Open Access Journals (Sweden)

    Jens Zierle

    2015-12-01

    Full Text Available Background/Aims: The human epidermal growth factor receptors tyrosine kinase inhibitor lapatinib has been shown to trigger suicidal death or apoptosis of tumor cells and is thus used for the treatment of malignancy. Side effects of lapatinib include anemia, which could, at least in theory, result from stimulation of eryptosis, the suicidal death of erythrocytes which is characterized by cell shrinkage and phospholipid scrambling of the cell membrane leading to phosphatidylserine translocation to the erythrocyte surface. Mechanisms involved in the triggering of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i, and ceramide. The present study explored, whether lapatinib induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS from DCFDA dependent fluorescence, and ceramide abundance utilizing labelled specific antibodies. Results: A 48 hours exposure of human erythrocytes to lapatinib (≥ 1 µg/ml significantly increased the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Lapatinib (7.5 µg/ml did not significantly modify DCFDA fluorescence and ceramide abundance. Lapatinib slightly, but significantly decreased Fluo3-fluorescence (≥ 5 µg/ml. Lapatinib (7.5 µg/ml enhanced the annexin-V-binding in the presence of the Ca2+ ionophore ionomycin (1 µM without significantly modifying Fluo3 fluorescence in the presence of ionomycin. The effect of lapatinib on forward scatter but not on annexin-V-binding was significantly blunted by removal of extracellular Ca2+. Conclusion: Lapatinib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect occurring despite decrease of cytosolic Ca2+ activity.

  16. Dose-dependent regional brain acetylcholinesterase and acylpeptide hydrolase inhibition without cell death after chlorpyrifos administration.

    Science.gov (United States)

    Cardona, Diana; López-Granero, Caridad; Cañadas, Fernando; Llorens, Jordi; Flores, Pilar; Pancetti, Floria; Sánchez-Santed, Fernando

    2013-01-01

    Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry and household settings. It has been well established that the main mechanism of acute toxic action of OP is the inhibition of acetylcholinesterase (AChE). However, we observed long term deficit after acute subcutaneous exposure to Chlorpyrifos (CPF) even when AChE activity is restored. In fact, besides AChE inhibition, non-AChE targets have also been proposed as an alternative mechanism involved in the acute lethal action and side effects of short or long-term exposure. In this context, our main aim in this research was to establish a dose-response curve of Acylpeptide hydrolase (APH) and AChE regional brain activity after acute CPF administration that could explain these long term effects observed in the literature. Moreover, since available data suggest that long term effects of OPs exposure could involve neuronal cell death, our second aim was to evaluate, assessing by Fluoro-Jade B (FJB) staining, whether CPF produces induced cell death. Our results show that an acute exposure to 250 mg/kg CPF does not induce neuronal death as measured by FJB but produces highest AChE regional brain inhibition after administration. In addition, APH seems to be more sensitive than AChE to CPF exposure because after 31 days of exposure, complete recovery was seen only for APH activity at Frontal Cortex, Cerebellum and Brain Stem.

  17. Considering ethical dilemmas related to brain death in newborns

    Directory of Open Access Journals (Sweden)

    Ilias Chatziioannidis

    2014-01-01

    Full Text Available Brain death (BD, as the irreversible and permanent loss of cerebral and brainstem function, is relatively uncommon among newborns who need life support. It is considered the result of an acute and irreversible central nervous system insult. Asphyxia, severe intracranial hemorrhage and infection are the most common causes of  BD in children. BD diagnosis is usually based on clinical criteria. Dilemmas about life prolonging treatment for severely compromised infants – as brain dead infants are – has become challenging since neonatal intensive care unit (NICU care has developed, quality of life and resource issues are nowadays continuously underlined. Caring for premature babies is expensive and costs have risen especially since an increased number of infants with handicaps survives. Intensivists’ main duty is first to save lives and then to interrupt treatment in certain conditions like detrimental brain damage. The objective of this article is to present ethical decisions regarding brain dead newborns in order to balance between organ donation necessities and withholding/withdrawing treatment, with respect to the important role of infants’ parents in the process.

  18. Edelfosine Induced Suicidal Death of Human Erythrocytes

    Directory of Open Access Journals (Sweden)

    Marilena Briglia

    2015-11-01

    Full Text Available Background/Aims: The anti-inflammatory, anti-autoimmune, antiparasitic, and anti-viral ether phospholipid edelfosine (1-O-octadecyl-2-O-methylglycero-3-phosphocholine stimulates apoptosis of tumor cells and is thus considered for the treatment of malignancy. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and phospholipid scrambling of the cell membrane with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i and oxidative stress. The present study explored, whether and how edelfosine induces eryptosis. Methods: Flow cytometry and photometry, respectively, were employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence, and abundance of reactive oxygen species (ROS from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA fluorescence. Results: A 6 hours exposure of human erythrocytes to edelfosine (5 µM significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, and significantly increased Fluo3-fluorescence, but did not significantly modify DCFDA fluorescence. The effect of edelfosine on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusions: Edelfosine triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of Ca2+ entry.

  19. Clofazimine Induced Suicidal Death of Human Erythrocytes

    National Research Council Canada - National Science Library

    Officioso, Arbace; Alzoubi, Kousi; Manna, Caterina; Lang, Florian

    2015-01-01

    .... In erythrocytes phospholipase A2 stimulates eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface...

  20. Patulin-induced suicidal erythrocyte death

    National Research Council Canada - National Science Library

    Lupescu, Adrian; Jilani, Kashif; Zbidah, Mohanad; Lang, Florian

    2013-01-01

    .... Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling leading to phosphatidylserine...

  1. Conditional Processes Induced by Birth and Death Processes

    OpenAIRE

    Masaru Iizuka; Matsuyo Tomisaki

    2010-01-01

    For birth and death processes with finite state space, we consider stochastic processes induced by conditioning on hitting the right boundary point before hitting the left boundary point. We call the induced stochastic processes the conditional processes. We show that the conditional processes are again birth and death processes when the right boundary point is absorbing. On the other hand, it is shown that the conditional processes do not have Markov property and they are not birth and death...

  2. Using the brain criterion in organ donation after the circulatory determination of death.

    Science.gov (United States)

    Dalle Ave, Anne L; Bernat, James L

    2016-06-01

    The UK, France, and Switzerland determine death using the brain criterion even in organ donation after the circulatory determination of death (DCDD), in which the United States and Canada use the circulatory-respiratory criterion. In our analysis of the scientific validity of the brain criterion in DCDD, we concluded that although it may be attractive in theory because it conceptualizes death as a unitary phenomenon, its use in practice is invalid. The preconditions (ie, the absence of reversible causes, such as toxic or metabolic disorders) for determining brain death cannot be met in DCDD. Thus, although brain death tests prove the cessation of tested brain functions, they do not prove that their cessation is irreversible. A stand-off period of 5 to 10 minutes is insufficient to achieve the irreversibility requirement of brain death. Because circulatory cessation inevitably leads to cessation of brain functions, first permanently and then irreversibly, the use of brain criterion is unnecessary to determine death in DCDD. Expanding brain death to permit it to be satisfied by permanent cessation of brain functions is controversial but has been considered as a possible means to declare death in uncontrolled DCDD. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.

    Science.gov (United States)

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid

    2015-06-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. © The Author (2015). Published by Oxford University Press on

  4. Artesunate induces necrotic cell death in schwannoma cells.

    Science.gov (United States)

    Button, R W; Lin, F; Ercolano, E; Vincent, J H; Hu, B; Hanemann, C O; Luo, S

    2014-10-16

    Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity.

  5. How Kidney Cell Death Induces Renal Necroinflammation.

    Science.gov (United States)

    Mulay, Shrikant R; Kumar, Santhosh V; Lech, Maciej; Desai, Jyaysi; Anders, Hans-Joachim

    2016-05-01

    The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs), mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. The clinical diagnosis of brain death | Hodelin-Tablada | East and ...

    African Journals Online (AJOL)

    Currently, the ability to maintain cerebral function with mechanical support, in the absence of spontaneous breathing and heart beat, and the power to ensure circulation and respiration, despite the complete destruction of the brain, demand a redefinition of death. There is now the concept of brain death. In this paper we ...

  7. Time for determining the diagnosis of brain death and its relation to organ donation

    Directory of Open Access Journals (Sweden)

    Ingrid Gurgel Amorim

    2017-04-01

    Full Text Available This study aimed to identify the time needed for confirmation of brain death and its relation to organ donation. Quantitative, descriptive and retrospective study with 175 patients who had diagnosis of brain death completed between January and December 2013. The time from 11 to 20 hours (38.9% prevailed, with average of 17.91 hours (SD 17.53. There was significant association between the finding of brain death diagnosis in less than 20 hours and the number of donated livers (P = 0.041. We stress the importance of speeding up the diagnosis of brain death as an important step of the donation process, in order to contribute to realization of transplants. Key words: Brain Death; Time; Directed Tissue Donation; Nursing.

  8. "Brain Death" and dead donor rule. Discussion and proposals on the thesis of Truog.

    Science.gov (United States)

    Bruzzone, Paolo

    2015-01-01

    The introduction in 1968 by the "ad hoc" Harvard committee of the concept of "Brain Death" gave birth to the worldwide diffusion of organ transplantation. Recently "Total Brain Failure" has been proposed as preferred term, instead of "Brain Death", by the President's Council on Bioethics. The concepts of "brain death" and of "dead donor rule" remain the ethical and moral support of organ transplantation. However both criteria has been questioned , either separately or all together , by many authors and particularly by Dr. Robert D. Truog.

  9. Extracorporeal Membrane Oxygenation for the Support of a Potential Organ Donor with a Fatal Brain Injury before Brain Death Determination

    Directory of Open Access Journals (Sweden)

    Sung Wook Chang

    2016-05-01

    Full Text Available The shortage of available organ donors is a significant problem and various efforts have been made to avoid the loss of organ donors. Among these, extracorporeal membrane oxygenation (ECMO has been introduced to help support and manage potential donors. Many traumatic brain injury patients have healthy organs that might be eligible for donation for transplantation. However, the condition of a donor with a fatal brain injury may rapidly deteriorate prior to brain death determination; this frequently results in the loss of eligible donors. Here, we report the use of venoarterial ECMO to support a potential donor with a fatal brain injury before brain death determination, and thereby preserve donor organs. The patient successfully donated his liver and kidneys after brain death determination.

  10. Spinal Decerebrate-Like Posturing After Brain Death: A Case Report and Review of the Literature.

    Science.gov (United States)

    Kumar, Abhay; Tummala, Pavan; Feen, Eliahu S; Dhar, Rajat

    2016-10-01

    Criteria for establishing brain death (BD) require absence of all brainstem-mediated reflexes including motor (ie, decerebrate or decorticate) posturing. A number of spinal cord automatisms may emerge after BD, but occurrence of decerebrate-like spinal reflexes may be particularly problematic; confusion of such stereotypic extension-pronation movements with brain stem reflexes may confound or delay definitive diagnosis of BD. We present a case in which we verified the noncerebral (ie, likely spinal) origin of such decerebrate-like reflexes. Case report and systematic review of literature. A 63-year-old woman presented with large pontine hemorrhage and complete loss of cerebral function, including no motor response to pain. Apnea testing confirmed death by neurologic criteria. Thirty-six hours after BD declaration, during assessment for organ donation, she began to exhibit spontaneous and stimulus-induced stereotypic extension-pronation of the upper extremities. The similarity of these movements to decerebrate posturing prompted concern for retained brain stem function, but repeat neurological examination of cranial nerves and apnea testing did not reveal any cerebral responses. Electrocerebral silence on electroencephalogram and absent perfusion on nuclear medicine brain imaging further confirmed BD. Review of PubMed yielded 5 additional case reports and 4 cohorts describing cases of decerebrate-like extension-pronation movements presenting in a delayed fashion after BD. Extension-pronation movements that mimic decerebrate posturing may be seen in a delayed fashion after BD. Verification of lack of any brain activity (by both examination and multiple ancillary tests) in this case and others prompts us to attribute these movements as spinal cord reflexes and propose they be recognized within the rubric of accepted post-BD automatisms that should not delay diagnosis or necessitate confirmatory testing. © The Author(s) 2016.

  11. Future doctors and brain death: what is the prognosis?

    Science.gov (United States)

    Afonso, R C; Buttros, D A B; Sakabe, D; Paranhos, G C; Garcia, L M C; Resende, M B; Ferraz-Neto, B H

    2004-05-01

    To evaluate the knowledge and the opinion of medical students at the Pontifical Catholic University of São Paulo related to the general aspects of donation, organ and tissue procurement, and basic concepts of brain death (BD). Questionnaires of 24 items were distributed among all students related to the concept and diagnosis of BD, personal aspects of tissue and organ donation, and general question concerning organ donation. The answers classified students as good versus bad experts of the concept and the diagnosis of BD. Of a total of 580 students, 361 (62.24%) answered the questionnaire. Although the concept of BD was known to 70%, only 35% had a good knowledge of the diagnosis. One percent of the students were opposed to the organ donation and 76% of them were donors. Approximately 90% would authorize organ retrieval from their family members but 27% had never discussed organ donation with their families. Most students were interested in the general aspects of donation and organ procurement (88.36%). The majority of the students know the concept of BD. General aspects regarding tissue and organ donation and diagnosis of BD might be improved with the continued education on the subject.

  12. Brain death after decompressive craniectomy: Incidence and pathophysiological mechanisms.

    Science.gov (United States)

    Salih, Farid; Finger, Tobias; Vajkoczy, Peter; Wolf, Stefan

    2017-06-01

    Patients who received decompressive craniectomy (DC) are usually not regarded to qualify for brain death (BD) as intracranial pressure (ICP) is not assumed to reach levels critical enough to cause cerebral perfusion failure. Here we investigated the incidence of BD after DC and analyzed the pathophysiological mechanisms. We searched our chart records of patients with DC for individuals who developed BD (2010-2016). We then analyzed the course of ICP and cerebral perfusion pressure (CPP) prior to BD and results from radiological tests that aim at demonstrating loss of cerebral perfusion in BD. BD was diagnosed in 12 of 164 (incidence 7.3%) patients (age=16-70years; male=7; mean longitudinal diameter: 136.2mm). Mean latency between DC and BD was 69.4h. Immediately after DC, mean ICP was 30.0mmHg (standard deviation±24.7mmHg), CPP was 56.8mmHg (±28.1). In the course to BD, ICP increased to 95.8mmHg (±16.1), CPP decreased to -9.9mmHg (±11.2). In patients in whom radiological methods were performed (n=5) loss of cerebral perfusion was demonstrated. Our study evidences that DC does not exclude BD. Even after DC, BD is preceded by a severely reduced CPP, supporting loss of cerebral perfusion as a critical step in BD pathophysiology. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Mechanisms of Ethanol-induced Death of Cerebellar Granule Cells

    OpenAIRE

    Luo, Jia

    2012-01-01

    Maternal ethanol exposure during pregnancy may cause fetal alcohol spectrum disorders (FASD). FASD is the leading cause of mental retardation. The most deleterious effect of fetal alcohol exposure is inducing neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system (CNS) underlies many of the behavioral deficits observed in FASD. The cerebellum is one of the brain areas that is most susceptible to ethanol during development. Ethanol exposure causes...

  14. Brain death: the challenges of translating medical science into Islamic bioethical discourse.

    Science.gov (United States)

    Padela, Aasim I; Basser, Taha A

    2012-09-01

    Islamic ethico-legal assessments of brain death are varied and controversial. Some Islamic ethico-legal bodies have concluded that brain death is equivalent to cardiopulmonary death; others regard it as an intermediate state between life and death, and a few opine that it does not meet the standards for legal death according to Islamic law. Yet this translation of the concept of brain death into the Islamic ethico-legal domain has generated multiple ethical complexities that receive insufficient attention within the extant medical and fiqh literature. How do Islamic legists understand brain death as a clinical phenomenon? How does the Islamic ethico-legal system treat medical uncertainty? What Islamic ethico-legal principles should apply to bioethical questions about life and death? In this paper, we analyze the arguments for, and against, the acceptance of brain death within the context of the deliberation of a representative juridical council. In our discussion we focus on areas in which the legists' ethico-legal reasoning hinges upon clinical conceptions of the state of the individual when diagnosed as brain dead. As Islamic ethics continues to engage scientific and technological advancements in these areas, such exploration of internal workings is necessary if we wish to better understand how Islamic ethical principles can contribute to bioethical deliberation.

  15. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Dae-Hee, E-mail: leedneo@gmail.com [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Kim, Dong-Wook [Department of Microbiology, Immunology, and Cancer Biology, University of VA (United States); Jung, Chang-Hwa [Division of Metabolism and Functionality Research, Korea Food Research Institute (Korea, Republic of); Lee, Yong J. [Departments of Surgery and Pharmacology and Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Park, Daeho, E-mail: daehopark@gist.ac.kr [School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712 (Korea, Republic of)

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. - Highlights: • Most GBM cells have been reported to be resistant to TRAIL-induced apoptosis. • Gingerol enhances the expression level of anti-apoptotic proteins by ROS. • Gingerol enhances TRAIL-induced apoptosis through actions on the ROS–Bcl2 pathway.

  16. Transcranial Doppler ultransonography as a confirmative diagnostic test in brain death: a review

    Directory of Open Access Journals (Sweden)

    Ali Ünal

    2012-11-01

    Full Text Available Before the invention of modern technologies death was defined as the cessation of cardiac and respiratoty functions. After the advances in mechanical ventilation and cardiopulmonary resucitation techniques the term “brain death” has been used instead and with the worldwide increase in cadaveric organ transplantation this term has increasingly gained importance. Brain death is a state which is diagnosed by neurological examination in patients who fulfill some specific criteria. In patients who cannot be examined thoroughly or in whom an apnoea test cannot be performed a confirmatory test is mandatory. Diagnostic tests for brain death can either be those who show neural activity or those who evaluate cerebral circulation. The cause that leads to the development of brain death is cessation of cerebral blood flow therefore diagnostic tests which evaluate the cerebral circulation are preferred in brain death. Transcranial Doppler ultrasonography steps forward among diagnostic tests that evaluate cerebral circulation because it is non-invasive, repeatable and can be performed at bedside. In order to use transcranial Doppler ultrasonography in the diagnosis of brain death one has to have very good knowledge about the effects of increasing intracranial pressure on the Doppler spectra and the various spectral forms of cerebral circulatory arrest. In this review the utility of transcranial Doppler ultrasonography in the diagnosis of brain death will be discussed.

  17. Knowledge of critical care nurses about the process of brain death diagnosis

    Directory of Open Access Journals (Sweden)

    Agnes Claudine Fontes de la Longuiniere

    2016-01-01

    Full Text Available Objectives: to understand the knowledge of critical care nurses about the process of brain death diagnosis. Methods: qualitative study conducted with nurses who work in the Intensive Care Unit. Data were collected through interviews and analyzed based on the Discourse of the Collective Subject technique. Results: as regards the concept of brain death, there was predominance of lack of brain activity. Regarding the procedures to confirm the diagnosis of brain death, the speeches brought up two stages composed of clinical tests and follow-up protocol. As for the nurses’ role in this process, the statements highlight the importance of informing the Intra-Hospital Committee of Organ and Tissue Donation and assisting the donor. Conclusion: participant nurses presented knowledge on the diagnosis of brain death and the role of nurses as part of the multidisciplinary team, revealing the importance of the performance of these professionals for achieving the organ donation and the need for constant improvement.

  18. Mitoxantrone-Induced Suicidal Erythrocyte Death

    Directory of Open Access Journals (Sweden)

    Markus Arnold

    2014-11-01

    Full Text Available Background/Aims: Mitoxantrone, a cytotoxic drug used for the treatment of malignancy and multiple sclerosis, is at least in part effective by triggering apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a type of suicidal cell death. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signalling involved in eryptosis include Ca2+-entry, ceramide formation and oxidative stress. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, formation of reactive oxidant species (ROS from 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. Results: A 48 hours exposure to mitoxantrone was followed by significant decrease of forward scatter (≥ 5 μg/ml mitoxantrone and increase of annexin-V-binding (≥ 10 μg/ml mitoxantrone, effects paralleled by significant increases of ROS formation (25 μg/ml mitoxantrone and ceramide abundance (25 μg/ml mitoxantrone. The effect of mitoxantrone was not significantly modified by nominal absence of extracellular Ca2+ but significantly blunted by the antioxidant N-acetylcysteine (1 mM. Conclusions: Mitoxantrone triggers cell membrane scrambling, an effect not requiring entry of extracellular Ca2+ but at least partially due to formation of ROS and ceramide.

  19. Informed consent for the diagnosis of brain death: a conceptual argument

    OpenAIRE

    Muramoto, Osamu

    2016-01-01

    Background This essay provides an ethical and conceptual argument for the use of informed consent prior to the diagnosis of brain death. It is meant to enable the family to make critical end-of-life decisions, particularly withdrawal of life support system and organ donation, before brain death is diagnosed, as opposed to the current practice of making such decisions after the diagnosis of death. The recent tragic case of a 13-year-old brain-dead patient in California who was maintained on a ...

  20. Programming stress-induced altruistic death in engineered bacteria

    Science.gov (United States)

    Tanouchi, Yu; Pai, Anand; Buchler, Nicolas E; You, Lingchong

    2012-01-01

    Programmed death is often associated with a bacterial stress response. This behavior appears paradoxical, as it offers no benefit to the individual. This paradox can be explained if the death is ‘altruistic': the killing of some cells can benefit the survivors through release of ‘public goods'. However, the conditions where bacterial programmed death becomes advantageous have not been unambiguously demonstrated experimentally. Here, we determined such conditions by engineering tunable, stress-induced altruistic death in the bacterium Escherichia coli. Using a mathematical model, we predicted the existence of an optimal programmed death rate that maximizes population growth under stress. We further predicted that altruistic death could generate the ‘Eagle effect', a counter-intuitive phenomenon where bacteria appear to grow better when treated with higher antibiotic concentrations. In support of these modeling insights, we experimentally demonstrated both the optimality in programmed death rate and the Eagle effect using our engineered system. Our findings fill a critical conceptual gap in the analysis of the evolution of bacterial programmed death, and have implications for a design of antibiotic treatment. PMID:23169002

  1. Minocycline Attenuates Iron-Induced Brain Injury.

    Science.gov (United States)

    Zhao, Fan; Xi, Guohua; Liu, Wenqaun; Keep, Richard F; Hua, Ya

    2016-01-01

    Iron plays an important role in brain injury after intracerebral hemorrhage (ICH). Our previous study found minocycline reduces iron overload after ICH. The present study examined the effects of minocycline on the subacute brain injury induced by iron. Rats had an intracaudate injection of 50 μl of saline, iron, or iron + minocycline. All the animals were euthanized at day 3. Rat brains were used for immunohistochemistry (n = 5-6 per each group) and Western blotting assay (n = 4). Brain swelling, blood-brain barrier (BBB) disruption, and iron-handling proteins were measured. We found that intracerebral injection of iron resulted in brain swelling, BBB disruption, and brain iron-handling protein upregulation (p minocycline with iron significantly reduced iron-induced brain swelling (n = 5, p Minocycline significantly decreased albumin protein levels in the ipsilateral basal ganglia (p minocycline co-injected animals. In conclusion, the present study suggests that minocycline attenuates brain swelling and BBB disruption via an iron-chelation mechanism.

  2. Brain death in Islamic ethico-legal deliberation: challenges for applied Islamic bioethics.

    Science.gov (United States)

    Padela, Aasim I; Arozullah, Ahsan; Moosa, Ebrahim

    2013-03-01

    Since the 1980s, Islamic scholars and medical experts have used the tools of Islamic law to formulate ethico-legal opinions on brain death. These assessments have varied in their determinations and remain controversial. Some juridical councils such as the Organization of Islamic Conferences' Islamic Fiqh Academy (OIC-IFA) equate brain death with cardiopulmonary death, while others such as the Islamic Organization of Medical Sciences (IOMS) analogize brain death to an intermediate state between life and death. Still other councils have repudiated the notion entirely. Similarly, the ethico-legal assessments are not uniform in their acceptance of brain-stem or whole-brain criteria for death, and consequently their conceptualizations of, brain death. Within the medical literature, and in the statements of Muslim medical professional societies, brain death has been viewed as sanctioned by Islamic law with experts citing the aforementioned rulings. Furthermore, health policies around organ transplantation and end-of-life care within the Muslim world have been crafted with consideration of these representative religious determinations made by transnational, legally-inclusive, and multidisciplinary councils. The determinations of these councils also have bearing upon Muslim clinicians and patients who encounter the challenges of brain death at the bedside. For those searching for 'Islamically-sanctioned' responses that can inform their practice, both the OIC-IFA and IOMS verdicts have palpable gaps in their assessments and remain clinically ambiguous. In this paper we analyze these verdicts from the perspective of applied Islamic bioethics and raise several questions that, if answered by future juridical councils, will better meet the needs of clinicians and bioethicists. © 2011 Blackwell Publishing Ltd.

  3. Evaluation and diagnosis of brain death by functional near-infrared spectroscopy

    Science.gov (United States)

    Pan, Boan; Zhong, Fulin; Huang, Xiaobo; Pan, Lingai; Lu, Sen; Li, Ting

    2017-02-01

    Brain death, the irreversible and permanent loss of the brain and brainstem functions, is hard to be judged precisely for some clinical reasons. The traditional diagnostic methods are time consuming, expensive and some are even dangerous. Functional near infrared spectroscopy (FNIRS), using the good scattering properties of major component of blood to NIR, is capable of noninvasive monitoring cerebral hemodynamic responses. Here, we attempt to use portable FNIRS under patients' natural state for brain death diagnosis. Ten brain death patients and seven normal subjects participated in FNIRS measurements. All of them were provided different fractional concentration of inspired oxygen (FIO2) in different time periods. We found that the concentration variation of deoxyhemoglobin concentration (Δ[Hb]) presents the trend of decrease in the both brain death patients and normal subjects with the raise of the FIO2, however, the data in the normal subjects is more significant. And the concentration variation of oxyhemoglobins concentration (Δ[HbO2]) emerges the opposite trends. Thus Δ[HbO2]/Δ[Hb] in brain death patients is significantly higher than normal subjects, and emerges the rising trend as time went on. The findings indicated the potential of FNIRS-measured hemodynamic index in diagnosing brain death.

  4. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells.

    Science.gov (United States)

    Lee, Dae-Hee; Kim, Dong-Wook; Jung, Chang-Hwa; Lee, Yong J; Park, Daeho

    2014-09-15

    Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    Science.gov (United States)

    Riad, Sandra; Bougherara, Habiba

    2015-01-01

    Cisplatin (CisPt) is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2) cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death). Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death). PMID:25685789

  6. Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

    Directory of Open Access Journals (Sweden)

    Laila Ziko

    2015-01-01

    Full Text Available Cisplatin (CisPt is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2 cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death. Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death.

  7. Informed consent for the diagnosis of brain death: a conceptual argument

    National Research Council Canada - National Science Library

    Osamu Muramoto

    2016-01-01

    .... It is meant to enable the family to make critical end-of-life decisions, particularly withdrawal of life support system and organ donation, before brain death is diagnosed, as opposed to the current...

  8. Use of Ancillary Tests When Determining Brain Death in Pediatric Patients in the United States.

    Science.gov (United States)

    Lewis, Ariane; Adams, Nellie; Chopra, Arun; Kirschen, Matthew P

    2017-10-01

    Although pediatric brain death guidelines stipulate when ancillary testing should be used during brain death determination, little is known about the way these recommendations are implemented in clinical practice. We conducted a survey of pediatric intensivists and neurologists in the United States on the use of ancillary testing. Although most respondents noted they only performed an ancillary test if the clinical examination and apnea test could not be completed, 20% of 195 respondents performed an ancillary test for other reasons, including (1) to convince a family that objected to the brain death determination that a patient is truly dead (n = 21), (2) personal preference (n = 14), and (3) institutional requirement (n = 5). Our findings suggest that pediatricians use ancillary tests for a variety of reasons during brain death determination. Medical societies and governmental regulatory bodies must reinforce the need for homogeneity in practice.

  9. Heat stress induces ferroptosis-like cell death in plants.

    Science.gov (United States)

    Distéfano, Ayelén Mariana; Martin, María Victoria; Córdoba, Juan Pablo; Bellido, Andrés Martín; D'Ippólito, Sebastián; Colman, Silvana Lorena; Soto, Débora; Roldán, Juan Alfredo; Bartoli, Carlos Guillermo; Zabaleta, Eduardo Julián; Fiol, Diego Fernando; Stockwell, Brent R; Dixon, Scott J; Pagnussat, Gabriela Carolina

    2017-02-01

    In plants, regulated cell death (RCD) plays critical roles during development and is essential for plant-specific responses to abiotic and biotic stresses. Ferroptosis is an iron-dependent, oxidative, nonapoptotic form of cell death recently described in animal cells. In animal cells, this process can be triggered by depletion of glutathione (GSH) and accumulation of lipid reactive oxygen species (ROS). We investigated whether a similar process could be relevant to cell death in plants. Remarkably, heat shock (HS)-induced RCD, but not reproductive or vascular development, was found to involve a ferroptosis-like cell death process. In root cells, HS triggered an iron-dependent cell death pathway that was characterized by depletion of GSH and ascorbic acid and accumulation of cytosolic and lipid ROS. These results suggest a physiological role for this lethal pathway in response to heat stress in Arabidopsis thaliana The similarity of ferroptosis in animal cells and ferroptosis-like death in plants suggests that oxidative, iron-dependent cell death programs may be evolutionarily ancient. © 2017 Distéfano et al.

  10. One or two types of death? Attitudes of health professionals towards brain death and donation after circulatory death in three countries.

    Science.gov (United States)

    Rodríguez-Arias, D; Tortosa, J C; Burant, C J; Aubert, P; Aulisio, M P; Youngner, S J

    2013-08-01

    This study examined health professionals' (HPs) experience, beliefs and attitudes towards brain death (BD) and two types of donation after circulatory death (DCD)--controlled and uncontrolled DCD. Five hundred and eighty-seven HPs likely to be involved in the process of organ procurement were interviewed in 14 hospitals with transplant programs in France, Spain and the US. Three potential donation scenarios--BD, uncontrolled DCD and controlled DCD--were presented to study subjects during individual face-to-face interviews. Our study has two main findings: (1) In the context of organ procurement, HPs believe that BD is a more reliable standard for determining death than circulatory death, and (2) While the vast majority of HPs consider it morally acceptable to retrieve organs from brain-dead donors, retrieving organs from DCD patients is much more controversial. We offer the following possible explanations. DCD introduces new conditions that deviate from standard medical practice, allow procurement of organs when donors' loss of circulatory function could be reversed, and raises questions about "death" as a unified concept. Our results suggest that, for many HPs, these concerns seem related in part to the fact that a rigorous brain examination is neither clinically performed nor legally required in DCD. Their discomfort could also come from a belief that irreversible loss of circulatory function has not been adequately demonstrated. If DCD protocols are to achieve their full potential for increasing organ supply, the sources of HPs' discomfort must be further identified and addressed.

  11. Determination of Death and the Dead Donor Rule: A Survey of the Current Law on Brain Death.

    Science.gov (United States)

    Nikas, Nikolas T; Bordlee, Dorinda C; Moreira, Madeline

    2016-06-01

    Despite seeming uniformity in the law, end-of-life controversies have highlighted variations among state brain death laws and their interpretation by courts. This article provides a survey of the current legal landscape regarding brain death in the United States, for the purpose of assisting professionals who seek to formulate or assess proposals for changes in current law and hospital policy. As we note, the public is increasingly wary of the role of organ transplantation in determinations of death, and of the variability of brain death diagnosing criteria. We urge that any attempt to alter current state statutes or to adopt a national standard must balance the need for medical accuracy with sound ethical principles which reject the utilitarian use of human beings and are consistent with the dignity of the human person. Only in this way can public trust be rebuilt. © The Author 2016. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Green tea polyphenol induces significant cell death in human lung ...

    African Journals Online (AJOL)

    Green tea polyphenol induces significant cell death in human lung cancer cells. Jie Huang, Fa-jiu Li, Shi Chen, Yi Shi, Xiao-jiang Wang, Chuan-hai Wang, Qing- ..... method for the determination of green and black tea polyphenols in biomatrices by high-performance liquid chromatography with coulometric array detection.

  13. Palladium induced oxidative stress and cell death in normal ...

    African Journals Online (AJOL)

    Pretreatment of hepatocytes with ROS scavengers and MPT pore sealing agents reduced cell death which explains the role of oxidative stress and mitochondrial pathway of ROS formation in Pd hepatocytes cell toxicity. Overall, the results have distinctly determined the mechanism by which Pd-induced toxicity in the ...

  14. Green tea polyphenol induces significant cell death in human lung ...

    African Journals Online (AJOL)

    Green tea polyphenol induces significant cell death in human lung cancer cells. ... Tropical Journal of Pharmaceutical Research ... (8-OHdG), and apoptosis based on 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were evaluated in non-small cell lung cancer (NSCLC) cell lines, namely, H1155, ...

  15. Radiation-induced brain injury: A review

    Directory of Open Access Journals (Sweden)

    Michael eRobbins

    2012-07-01

    Full Text Available Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (> 6 months to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses > 30 Gy; white matter necrosis occurs at fractionated doses > 60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain

  16. Informed consent for the diagnosis of brain death: a conceptual argument.

    Science.gov (United States)

    Muramoto, Osamu

    2016-10-13

    This essay provides an ethical and conceptual argument for the use of informed consent prior to the diagnosis of brain death. It is meant to enable the family to make critical end-of-life decisions, particularly withdrawal of life support system and organ donation, before brain death is diagnosed, as opposed to the current practice of making such decisions after the diagnosis of death. The recent tragic case of a 13-year-old brain-dead patient in California who was maintained on a ventilator for over 2 years illustrates how such a consent would have made a crucial difference. Conceptual, philosophical, and ethical analysis. I first consider a conceptual justification for the use of consent for certain non-beneficial and unwanted medical diagnoses. I suggest that the diagnosis of brain death falls into this category for some patients. Because the diagnostic process of brain death lacks the transparency of traditional death determination, has a unique epistemic structure and a complex risk-benefit profile which differs markedly from case to case, and presents conflicts of interest for physicians and society, I argue that pre-diagnostic counseling and informed consent should be part of the diagnostic process. This approach can be termed as "allow cardiac death", whose parallel logic with "allow natural death" is discussed. I also discuss potential negative impacts on organ donation and health care cost from this proposal and offer possible mitigation. I show that the pre-diagnostic counseling can improve the possibility for well-thought-out decisions regarding organ donation and terminating life-support system in cases of hopeless prognosis. This approach differs conceptually from the pluralism of the definition of death, such as those in New Jersey and Japan, and it upholds the Uniform Determination of Death Act. My intention is not to provide an instant panacea for the ongoing impasse of the brain death debate, but to point to a novel conceptual ground for a more

  17. Diverse Effects of an Acetylcholinesterase Inhibitor, Donepezil, on Hippocampal Neuronal Death after Pilocarpine-Induced Seizure.

    Science.gov (United States)

    Jeong, Jeong Hyun; Choi, Bo Young; Kho, A Ra; Lee, Song Hee; Hong, Dae Ki; Lee, Sang Hwon; Lee, Sang Yup; Song, Hong Ki; Choi, Hui Chul; Suh, Sang Won

    2017-11-02

    Epileptic seizures are short episodes of abnormal brain electrical activity. Many survivors of severe epilepsy display delayed neuronal death and permanent cognitive impairment. Donepezil is an acetylcholinesterase inhibitor and is an effective treatment agent for Alzheimer's disease. However, the role of donepezil in seizure-induced hippocampal injury remains untested. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25 mg/kg). Donepezil (2.5 mg/kg/day) was administered by gavage in three different settings: (1) pretreatment for three days before the seizure; (2) for one week immediately after the seizure; and (3) for three weeks from three weeks after the seizure. We found that donepezil showed mixed effects on seizure-induced brain injury, which were dependent on the treatment schedule. Pretreatment with donepezil aggravated neuronal death, oxidative injury, and microglia activation. Early treatment with donepezil for one week showed neither adverse nor beneficial effects; however, a treatment duration of three weeks starting three weeks after the seizure showed a significant reduction in neuronal death, oxidative injury, and microglia activation. In conclusion, donepezil has therapeutic effects when injected for three weeks after seizure activity subsides. Therefore, the present study suggests that the therapeutic use of donepezil for epilepsy patients requires a well-conceived strategy for administration.

  18. Medical Training and the Brain Death Exam: A Single Institution's Experience.

    Science.gov (United States)

    Kashkoush, Ahmed; Weisgerber, Amy; Dharaneeswaran, Kiruba; Agarwal, Nitin; Shutter, Lori

    2017-12-01

    Clinicians may have limited opportunities to perform neurological determination of death (NDD, or brain death) certification during their training. This study aimed to evaluate the level of resident exposure to the brain death exam at a large-volume donor hospital. In March 2014, we adapted a dual-physician model for NDD certification at our institution to improve resident education regarding NDD. To evaluate the incidence of resident exposure, we collected examiner information from all brain death exams conducted between January 2014 and July 2015. Organ procurement, family authorization, and brain death intervals were also collected to evaluate the impact of NDD timeliness on organ donation. A total of 68 patients who met NDD criteria were included in this study. For these patients, 127 brain death exams were performed, 108 (85%) by a critical care attending physician or fellow, 9 (7%) by a neurology resident, and 7 (6%) by a neurosurgery resident. Exposure rates for neurology and neurosurgery residents were approximately 0.22 and 0.20 exams/resident/year, respectively. The median brain death interval between exams was 1.0 hours (interquartile range, 0.0-2.5) hours. Resident involvement, time between exams, and dual exams were all found to be nonsignificant correlates of organ authorization and family refusal. Neurology and neurosurgery residents may be limited in their exposure to the brain death exam during training. High-volume donor hospitals may be able to complete 2 exams for NDD certification in a timely manner without detrimentally influencing organ authorization or family refusal rates. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Mitochondrial impairment induces excitotoxic death in cerebellar granule cells.

    Science.gov (United States)

    Bobba, Antonella; Atlante, Anna; Azzariti, Amalia; Sgaramella, Giuseppe; Calissano, Pietro; Marra, Ersilia

    2004-06-01

    A close relationship links mitochondria to cell death with mitochondrial function-impairment considered a major biochemical event in the process of both apoptosis and necrosis. We have used different inhibitors of oxidative phosphorylation, i.e. mitochondrial respiratory chain and ATP synthesis inhibitors, and an uncoupler to investigate the mode of cell death caused by these compounds in cerebellar granule cells. This study shows that in cultured cerebellar granule cells either oxidative phosphorylation inhibitors or uncoupler induce an excitotoxic-like reaction which is mediated by activation of NMDA receptors and is likely due to the release of glutamate. Consistently, survival may occur if the toxic action of glutamate is prevented.

  20. Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death.

    Science.gov (United States)

    Lee, Hyun Jung; Bach, Jae-Hyung; Chae, Hee-Sun; Lee, Sang Hyung; Joo, Wan Seok; Choi, Se Hoon; Kim, Kyung Yong; Lee, Won Bok; Kim, Sung Su

    2004-02-01

    3-Hydroxykynurenine (3-HK), an endogenous tryptophan metabolite, is known to have toxic effects in brain. However, the molecular mechanism of the toxicity has not been well identified. In this study, we investigated the involvement of MAPK/extracellular signal-regulated kinase (ERK) in the 3-HK-induced neuronal cell damage. Our results showed that 3-HK induced apoptotic neuronal cell death and ERK phosphorylation occurred during cell death. Inhibition of ERK activation using PD98059 considerably increased cell death. Furthermore, cell death was preceded by mitochondrial malfunction including collapse of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release from mitochondria to the cytosol. Interestingly, inhibition of ERK dramatically increased mitochondrial malfunction, and enhanced caspase activation, resulting in enhanced neuronal cell death. Thus, our results show that ERK plays a protective role by maintaining mitochondrial function and regulating caspase activity under conditions of cellular stress.

  1. The degree of certainty in brain death: probability in clinical and Islamic legal discourse.

    Science.gov (United States)

    Qazi, Faisal; Ewell, Joshua C; Munawar, Ayla; Asrar, Usman; Khan, Nadir

    2013-04-01

    The University of Michigan conference "Where Religion, Policy, and Bioethics Meet: An Interdisciplinary Conference on Islamic Bioethics and End-of-Life Care" in April 2011 addressed the issue of brain death as the prototype for a discourse that would reflect the emergence of Islamic bioethics as a formal field of study. In considering the issue of brain death, various Muslim legal experts have raised concerns over the lack of certainty in the scientific criteria as applied to the definition and diagnosis of brain death by the medical community. In contrast, the medical community at large has not required absolute certainty in its process, but has sought to eliminate doubt through cumulative diagnostic modalities and supportive scientific evidence. This has recently become a principal model, with increased interest in data analysis and evidence-based medicine with the intent to analyze and ultimately improve outcomes. Islamic law has also long employed a systematic methodology with the goal of eliminating doubt from rulings regarding the question of certainty. While ample criticism of the scientific criteria of brain death (Harvard criteria) by traditional legal sources now exists, an analysis of the legal process in assessing brain death, geared toward informing the clinician's perspective on the issue, is lacking. In this article, we explore the role of certainty in the diagnostic modalities used to establish diagnoses of brain death in current medical practice. We further examine the Islamic jurisprudential approach vis-à-vis the concept of certainty (yaqīn). Finally, we contrast the two at times divergent philosophies and consider what each perspective may contribute to the global discourse on brain death, understanding that the interdependence that exists between the theological, juridical, ethical, and medical/scientific fields necessitates an open discussion and active collaboration between all parties. We hope that this article serves to continue the

  2. Tunicamycin-induced unfolded protein response in the developing mouse brain

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Haiping; Wang, Xin [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Ke, Zun-Ji [Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203 (China); Comer, Ashley L.; Xu, Mei; Frank, Jacqueline A. [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Zhang, Zhuo; Shi, Xianglin [Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536 (United States); Luo, Jia, E-mail: jialuo888@uky.edu [Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536 (United States)

    2015-03-15

    Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident by the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1–CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress. - Highlights: • Tunicamycin caused a development-dependent UPR in the mouse brain. • Immature brain was more susceptible to tunicamycin-induced endoplasmic reticulum stress. • Tunicamycin caused more neuronal death in immature brain than mature brain. • Tunicamycin-induced neuronal death is region-specific.

  3. Conjugated Bilirubin Triggers Anemia by Inducing Erythrocyte Death

    Science.gov (United States)

    Lang, Elisabeth; Gatidis, Sergios; Freise, Noemi F; Bock, Hans; Kubitz, Ralf; Lauermann, Christian; Orth, Hans Martin; Klindt, Caroline; Schuier, Maximilian; Keitel, Verena; Reich, Maria; Liu, Guilai; Schmidt, Sebastian; Xu, Haifeng C; Qadri, Syed M; Herebian, Diran; Pandyra, Aleksandra A; Mayatepek, Ertan; Gulbins, Erich; Lang, Florian; Häussinger, Dieter; Lang, Karl S; Föller, Michael; Lang, Philipp A

    2015-01-01

    Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver-damaging diseases, such as infection and alcohol intoxication. At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca2+ influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, patients with hyperbilirubinemia had significantly lower erythrocyte and significantly higher reticulocyte counts compared to patients with low bilirubin levels. Conclusion: Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease. (Hepatology 2015;61:275–284) PMID:25065608

  4. Brain death and Islam: the interface of religion, culture, history, law, and modern medicine.

    Science.gov (United States)

    Miller, Andrew C; Ziad-Miller, Amna; Elamin, Elamin M

    2014-10-01

    How one defines death may vary. It is important for clinicians to recognize those aspects of a patient's religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only.

  5. The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia.

    Science.gov (United States)

    Boehme, S A; Lio, F M; Maciejewski-Lenoir, D; Bacon, K B; Conlon, P J

    2000-07-01

    Fractalkine is a CX3C-family chemokine, highly and constitutively expressed on the neuronal cell surface, for which a clear CNS physiological function has yet to be determined. Its cognate receptor, CX3CR-1, is constitutively expressed on microglia, the brain-resident macrophages; however, these cells do not express fractalkine. We now show that treatment of microglia with fractalkine maintains cell survival and inhibits Fas ligand-induced cell death in vitro. Biochemical characterization indicates that this occurs via mechanisms that may include 1) activation of the phosphatidylinositol-3 kinase/protein kinase B pathway, resulting in phosphorylation and blockade of the proapoptotic functions of BAD; 2) up-regulation of the antiapoptotic protein Bcl-xL; and 3) inhibition of the cleavage of BH3-interacting domain death agonist (BID). The observation that fractalkine serves as a survival factor for primary microglia in part by modulating the protein levels and the phosphorylation status of Bcl-2 family proteins reveals a novel physiological role for chemokines. These results, therefore, suggest that the interaction between fractalkine and CX3CR-1 may play an important role in promoting and preserving microglial cell survival in the CNS.

  6. Bortezomib induces autophagic death in proliferating human endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Belloni, Daniela; Veschini, Lorenzo [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Foglieni, Chiara [Department of Cardiology, IRCCS H San Raffaele, Milan (Italy); Dell' Antonio, Giacomo [Department of Pathology, IRCCS H San Raffaele, Milan (Italy); Caligaris-Cappio, Federico [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Universita Vita-Salute IRCCS H San Raffaele, Milan (Italy); Ferrarini, Marina [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy); Ferrero, Elisabetta, E-mail: elisabetta.ferrero@hsr.it [Myeloma Unit, Department of Oncology, IRCCS H San Raffaele, Milan (Italy)

    2010-04-01

    The proteasome inhibitor Bortezomib has been approved for the treatment of relapsed/refractory multiple myeloma (MM), thanks to its ability to induce MM cell apoptosis. Moreover, Bortezomib has antiangiogenic properties. We report that endothelial cells (EC) exposed to Bortezomib undergo death to an extent that depends strictly on their activation state. Indeed, while quiescent EC are resistant to Bortezomib, the drug results maximally toxic in EC switched toward angiogenesis with FGF, and exerts a moderate effect on subconfluent HUVEC. Moreover, EC activation state deeply influences the death pathway elicited by Bortezomib: after treatment, angiogenesis-triggered EC display typical features of apoptosis. Conversely, death of subconfluent EC is preceded by ROS generation and signs typical of autophagy, including intense cytoplasmic vacuolization with evidence of autophagosomes at electron microscopy, and conversion of the cytosolic MAP LC3 I form toward the autophagosome-associated LC3 II form. Treatment with the specific autophagy inhibitor 3-MA prevents both LC3 I/LC3 II conversion and HUVEC cell death. Finally, early removal of Bortezomib is accompanied by the recovery of cell shape and viability. These findings strongly suggest that Bortezomib induces either apoptosis or autophagy in EC; interfering with the autophagic response may potentiate the antiangiogenic effect of the drug.

  7. Death Induced by CD95 or CD95 Ligand Elimination

    Directory of Open Access Journals (Sweden)

    Abbas Hadji

    2014-04-01

    Full Text Available CD95 (Fas/APO-1, when bound by its cognate ligand CD95L, induces cells to die by apoptosis. We now show that elimination of CD95 or CD95L results in a form of cell death that is independent of caspase-8, RIPK1/MLKL, and p53, is not inhibited by Bcl-xL expression, and preferentially affects cancer cells. All tumors that formed in mouse models of low-grade serous ovarian cancer or chemically induced liver cancer with tissue-specific deletion of CD95 still expressed CD95, suggesting that cancer cannot form in the absence of CD95. Death induced by CD95R/L elimination (DICE is characterized by an increase in cell size, production of mitochondrial ROS, and DNA damage. It resembles a necrotic form of mitotic catastrophe. No single drug was found to completely block this form of cell death, and it could also not be blocked by the knockdown of a single gene, making it a promising way to kill cancer cells.

  8. Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury

    Directory of Open Access Journals (Sweden)

    Raul Chavez-Valdez

    2012-01-01

    Full Text Available Despite the introduction of therapeutic hypothermia, neonatal hypoxic ischemic (HI brain injury remains a common cause of developmental disability. Development of rational adjuvant therapies to hypothermia requires understanding of the pathways of cell death and survival modulated by HI. The conceptualization of the apoptosis-necrosis “continuum” in neonatal brain injury predicts mechanistic interactions between cell death and hydrid forms of cell death such as programmed or regulated necrosis. Many of the components of the signaling pathway regulating programmed necrosis have been studied previously in models of neonatal HI. In some of these investigations, they participate as part of the apoptotic pathways demonstrating clear overlap of programmed death pathways. Receptor interacting protein (RIP-1 is at the crossroads between types of cellular death and survival and RIP-1 kinase activity triggers formation of the necrosome (in complex with RIP-3 leading to programmed necrosis. Neuroprotection afforded by the blockade of RIP-1 kinase following neonatal HI suggests a role for programmed necrosis in the HI injury to the developing brain. Here, we briefly review the state of the knowledge about the mechanisms behind programmed necrosis in neonatal brain injury recognizing that a significant proportion of these data derive from experiments in cultured cell and some from in vivo adult animal models. There are still more questions than answers, yet the fascinating new perspectives provided by the understanding of programmed necrosis in the developing brain may lay the foundation for new therapies for neonatal HI.

  9. Care pathways for organ donation after brain death: guidance from available literature?

    Science.gov (United States)

    Hoste, Pieter; Vanhaecht, Kris; Ferdinande, Patrick; Rogiers, Xavier; Eeckloo, Kristof; Blot, Stijn; Hoste, Eric; Vogelaers, Dirk; Vandewoude, Koenraad

    2016-10-01

    A discussion of the literature concerning the impact of care pathways in the complex and by definition multidisciplinary process of organ donation following brain death. Enhancing the quality and safety of organs for transplantation has become a central concern for governmental and professional organizations. At the local hospital level, a donor coordinator can use a range of interventions to improve the donation and procurement process. Care pathways have been proven to represent an effective intervention in several settings for optimizing processes and outcomes. A discussion paper. A systematic review of the Medline, CINAHL, EMBASE and The Cochrane Library databases was conducted for articles published until June 2015, using the keywords donation after brain death and care pathways. Each paper was reviewed to investigate the effects of existing care pathways for donation after brain death. An additional search for unpublished information was conducted. Although literature supports care pathways as an effective intervention in several settings, few studies have explored its use and effectiveness for complex care processes such as donation after brain death. Nurses should be aware of their role in the donation process. Care pathways have the potential to support them, but their effectiveness has been insufficiently explored. Further research should focus on the development and standardization of the clinical content of a care pathway for donation after brain death and the identification of quality indicators. These should be used in a prospective effectiveness assessment of the proposed pathway. © 2016 John Wiley & Sons Ltd.

  10. Orientation of university students about brain-death and organ donation: A cross-sectional study.

    Science.gov (United States)

    Al Bshabshe, Ali A; Wani, Javed Iqbal; Rangreze, Imran; Asiry, Mohammed Ali M; Mansour, Haitham; Ahmed, Alhassan Gaba'n; Assiri, Jabber Madi

    2016-01-01

    The gap between demand and supply of organs continues. No country has found a concrete solution for tackling this problem. We attempted to evaluate the general information and attitude of university students in their primary basic science stage, when they did not receive special education regarding brain death and organ donation in Saudi Arabia. Since they were from different cities with different cultures and values, we believe that we could assess the educational needs of future doctors and paramedical staff, to help them gain enough competence for solving the concerns of the population at large. The present study is a secondary analysis of a survey conducted at the King Khalid University, Abha, Saudi Arabia, from March to May 2014, about the knowledge of and attitudes toward brain death, organ donation, and transplantation in a sample of university students. A total of 873 university students participated in the survey and 93% from the cohort had heard about brain death. Eighty-five percent got their information about brain death from the media. Seventy-three percent of the cohort had the impression that there is no difference between brain death and natural death. An organized educational program about all aspects of organ donation, particularly from deceased donors, seems necessary in the curriculum, which can be started at an early level and built up gradually to impart a gradual comprehensive knowledge on beliefs and practices about brain death, organ donation, and transplantation. The Saudi Center for Organ Transplantation in collaboration with other regional societies and regional professional organizations has to work together to achieve this long-term goal to save the precious lives of people, awaiting transplantation.

  11. Orientation of university students about brain-death and organ donation: A cross-sectional study

    Directory of Open Access Journals (Sweden)

    Ali A Al Bshabshe

    2016-01-01

    Full Text Available The gap between demand and supply of organs continues. No country has found a concrete solution for tackling this problem. We attempted to evaluate the general information and attitude of university students in their primary basic science stage, when they did not receive special education regarding brain death and organ donation in Saudi Arabia. Since they were from different cities with different cultures and values, we believe that we could assess the educational needs of future doctors and paramedical staff, to help them gain enough competence for solving the concerns of the population at large. The present study is a secondary analysis of a survey conducted at the King Khalid University, Abha, Saudi Arabia, from March to May 2014, about the knowledge of and attitudes toward brain death, organ donation, and transplantation in a sample of university students. A total of 873 university students participated in the survey and 93% from the cohort had heard about brain death. Eighty-five percent got their information about brain death from the media. Seventy-three percent of the cohort had the impression that there is no difference between brain death and natural death. An organized educational program about all aspects of organ donation, particularly from deceased donors, seems necessary in the curriculum, which can be started at an early level and built up gradually to impart a gradual comprehensive knowledge on beliefs and practices about brain death, organ donation, and transplantation. The Saudi Center for Organ Transplantation in collaboration with other regional societies and regional professional organizations has to work together to achieve this long-term goal to save the precious lives of people, awaiting transplantation.

  12. Cell death in the injured brain: roles of metallothioneins

    DEFF Research Database (Denmark)

    Pedersen, Mie Ø; Larsen, Agnete; Stoltenberg, Meredin

    2009-01-01

    oxygen species (ROS). ROS promote oxidative stress, which leads to neurodegeneration and ultimately results in programmed cell death (secondary injury). Since this delayed, secondary tissue loss occurs days to months following the primary injury it provides a therapeutic window where potential...... neuroprotective treatment could alleviate ongoing neurodegeneration, cell death and neurological impairment following TBI. Various neuroprotective drug candidates have been described, tested and proven effective in pre-clinical studies, including glutamate receptor antagonists, calcium-channel blockers......, and caspase inhibitors. However, most of the scientific efforts have failed in translating the experimental results into clinical trials. Despite intensive research, effective neuroprotective therapies are lacking in the clinic, and TBI continues to be a major cause of morbidity and mortality. This paper...

  13. Harvesting the living?: separating "brain death" and organ transplantation.

    Science.gov (United States)

    Campbell, Courtney S

    2004-09-01

    The chronic shortage of transplantable organs has reached critical proportions. In the wake of this crisis, some bioethicists have argued that there is sufficient public support to expand organ recovery through use of neocortical criteria of death or even pre-mortem organ retrieval. I present a typology of ways in which data gathered from the public can be misread or selectively used by bioethicists in service of an ideological or policy agenda, resulting in bad policy and bad ethics. Such risks should lead us to look at alternatives for increasing organ supplies short of expanding or abandoning the dead donor rule. The chronic problem of organ scarcity should prompt bioethicists to engage in constructive dialogue about the relation of the social sciences and bioethics, to examine the social malleability of the definition of death, and to revisit the question of the priority of organ transplants in the overall package of healthcare benefits provided to most, but not all, citizens.

  14. Up-regulation of K{sub ir}2.1 by ER stress facilitates cell death of brain capillary endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Kito, Hiroaki [Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan); Yamazaki, Daiju [Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan); Department of Biological Chemistry, Kyoto University, Graduate School of Pharmaceutical Sciences, Kyoto (Japan); Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya (Japan); Ohya, Susumu; Yamamura, Hisao [Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan); Asai, Kiyofumi [Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya (Japan); Imaizumi, Yuji, E-mail: yimaizum@phar.nagoya-cu.ac.jp [Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan)

    2011-07-29

    Highlights: {yields} We found that application of endoplasmic reticulum (ER) stress with tunicamycin to brain capillary endothelial cells (BCECs) induced cell death. {yields} The ER stress facilitated the expression of inward rectifier K{sup +} channel (K{sub ir}2.1) and induced sustained membrane hyperpolarization. {yields} The membrane hyperpolarization induced sustained Ca{sup 2+} entry through voltage-independent nonspecific cation channels and consequently facilitated cell death. {yields} The K{sub ir}2.1 up-regulation by ER stress is, at least in part, responsible for cell death of BCECs under pathological conditions. -- Abstract: Brain capillary endothelial cells (BCECs) form blood brain barrier (BBB) to maintain brain homeostasis. Cell turnover of BCECs by the balance of cell proliferation and cell death is critical for maintaining the integrity of BBB. Here we found that stimuli with tunicamycin, endoplasmic reticulum (ER) stress inducer, up-regulated inward rectifier K{sup +} channel (K{sub ir}2.1) and facilitated cell death in t-BBEC117, a cell line derived from bovine BCECs. The activation of K{sub ir} channels contributed to the establishment of deeply negative resting membrane potential in t-BBEC117. The deep resting membrane potential increased the resting intracellular Ca{sup 2+} concentration due to Ca{sup 2+} influx through non-selective cation channels and thereby partly but significantly regulated cell death in t-BBEC117. The present results suggest that the up-regulation of K{sub ir}2.1 is, at least in part, responsible for cell death/cell turnover of BCECs induced by a variety of cellular stresses, particularly ER stress, under pathological conditions.

  15. D. Alan Shewmon and the PCBE's White Paper on Brain Death: are brain-dead patients dead?

    Science.gov (United States)

    Brugger, E Christian

    2013-04-01

    The December 2008 White Paper (WP) on "Brain Death" published by the President's Council on Bioethics (PCBE) reaffirmed its support for the traditional neurological criteria for human death. It spends considerable time explaining and critiquing what it takes to be the most challenging recent argument opposing the neurological criteria formulated by D. Alan Shewmon, a leading critic of the "whole brain death" standard. The purpose of this essay is to evaluate and critique the PCBE's argument. The essay begins with a brief background on the history of the neurological criteria in the United States and on the preparation of the 2008 WP. After introducing the WP's contents, the essay sets forth Shewmon's challenge to the traditional neurological criteria and the PCBE's reply to Shewmon. The essay concludes by critiquing the WP's novel justification for reaffirming the traditional conclusion, a justification the essay finds wanting.

  16. Mechanisms of palmitate-induced cell death in human osteoblasts

    Directory of Open Access Journals (Sweden)

    Krishanthi Gunaratnam

    2013-11-01

    Lipotoxicity is an overload of lipids in non-adipose tissues that affects function and induces cell death. Lipotoxicity has been demonstrated in bone cells in vitro using osteoblasts and adipocytes in coculture. In this condition, lipotoxicity was induced by high levels of saturated fatty acids (mostly palmitate secreted by cultured adipocytes acting in a paracrine manner. In the present study, we aimed to identify the underlying mechanisms of lipotoxicity in human osteoblasts. Palmitate induced autophagy in cultured osteoblasts, which was preceded by the activation of autophagosomes that surround palmitate droplets. Palmitate also induced apoptosis though the activation of the Fas/Jun kinase (JNK apoptotic pathway. In addition, osteoblasts could be protected from lipotoxicity by inhibiting autophagy with the phosphoinositide kinase inhibitor 3-methyladenine or by inhibiting apoptosis with the JNK inhibitor SP600125. In summary, we have identified two major molecular mechanisms of lipotoxicity in osteoblasts and in doing so we have identified a new potential therapeutic approach to prevent osteoblast dysfunction and death, which are common features of age-related bone loss and osteoporosis.

  17. A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus.

    Science.gov (United States)

    Tajiri, Naoki; De La Peña, Ike; Acosta, Sandra A; Kaneko, Yuji; Tamir, Sharon; Landesman, Yosef; Carlson, Robert; Shacham, Sharon; Borlongan, Cesar V

    2016-04-01

    Exportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug-like inhibitors of XPO1, with potent anti-cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors. Here, we report that the SINE compounds (KPT-350 or KPT-335) sequestered TBI-induced neuroinflammation-related proteins (NF-(k)B, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF-α (20 ng/mL)-induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non-treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague-Dawley rats treated post-injury with SINE compounds exhibited significant reductions in TBI-induced behavioral and histological deficits. Animals that received KPT-350 orally starting at 2 h post-TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100-200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT-350 dosing, and throughout the 18-day post-TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT-350 reduced cortical core impact area and peri-impact cell death compared to vehicle treatment (P's < 0.05). Both in vitro and in vivo experiments revealed that KPT-350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF-(k)B expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious

  18. Hydrogen peroxide produced by oral Streptococci induces macrophage cell death.

    Directory of Open Access Journals (Sweden)

    Nobuo Okahashi

    Full Text Available Hydrogen peroxide (H2O2 produced by members of the mitis group of oral streptococci plays important roles in microbial communities such as oral biofilms. Although the cytotoxicity of H2O2 has been widely recognized, the effects of H2O2 produced by oral streptococci on host defense systems remain unknown. In the present study, we investigated the effect of H2O2 produced by Streptococcus oralis on human macrophage cell death. Infection by S. oralis was found to stimulate cell death of a THP-1 human macrophage cell line at multiplicities of infection greater than 100. Catalase, an enzyme that catalyzes the decomposition of H2O2, inhibited the cytotoxic effect of S. oralis. S. oralis deletion mutants lacking the spxB gene, which encodes pyruvate oxidase, and are therefore deficient in H2O2 production, showed reduced cytotoxicity toward THP-1 macrophages. Furthermore, H2O2 alone was capable of inducing cell death. The cytotoxic effect seemed to be independent of inflammatory responses, because H2O2 was not a potent stimulator of tumor necrosis factor-α production in macrophages. These results indicate that streptococcal H2O2 plays a role as a cytotoxin, and is implicated in the cell death of infected human macrophages.

  19. Different Types of Cell Death Induced by Enterotoxins

    Directory of Open Access Journals (Sweden)

    Ming-Yuan Hong

    2010-08-01

    Full Text Available The infection of bacterial organisms generally causes cell death to facilitate microbial invasion and immune escape, both of which are involved in the pathogenesis of infectious diseases. In addition to the intercellular infectious processes, pathogen-produced/secreted enterotoxins (mostly exotoxins are the major weapons that kill host cells and cause diseases by inducing different types of cell death, particularly apoptosis and necrosis. Blocking these enterotoxins with synthetic drugs and vaccines is important for treating patients with infectious diseases. Studies of enterotoxin-induced apoptotic and necrotic mechanisms have helped us to create efficient strategies to use against these well-characterized cytopathic toxins. In this article, we review the induction of the different types of cell death from various bacterial enterotoxins, such as staphylococcal enterotoxin B, staphylococcal alpha-toxin, Panton-Valentine leukocidin, alpha-hemolysin of Escherichia coli, Shiga toxins, cytotoxic necrotizing factor 1, heat-labile enterotoxins, and the cholera toxin, Vibrio cholerae. In addition, necrosis caused by pore-forming toxins, apoptotic signaling through cross-talk pathways involving mitochondrial damage, endoplasmic reticulum stress, and lysosomal injury is discussed.

  20. Psychological symptoms in family members of brain death patients in intensive care unit in Kerman, Iran.

    Science.gov (United States)

    Hosseinrezaei, Hakimeh; Pilevarzadeh, Motahareh; Amiri, Masoud; Rafiei, Hossin; Taghati, Sedigheh; Naderi, Mosadegheh; Moradalizadeh, Mohammad; Askarpoor, Milad

    2014-02-08

    Having patients in Intensive Care Unit (ICU) remains an extremely stressful live event for family members, especially for those having to confront with brain death patients. The aim of present study was to determine the prevalence of depression, anxiety and stress among relatives of brain dead patients in ICU in Kerman, Iran. In a cross-sectional study, using DASS- 42 questionnaire, the symptoms of depression, anxiety and stress of family members of brain death patients were explored in Kerman, Iran. Of 244 eligible family members, 224 participated in this study (response rate of 91%). Generally, 76.8%, 75% and 70.1% of family members reported some levels of anxiety, depression and stress, respectively. More specifically, the rate of severe levels of anxiety, depression and stress among the participants were 48.7%, 33%, and 20.1% respectively. Prevalence of depression, anxiety and stress in family members of brain death patients in ICU remains high. Health care team members, especially nurses, should be aware and could consider this issue in the caring of family members of brain death patients.

  1. Control of adult neurogenesis by programmed cell death in the mammalian brain.

    Science.gov (United States)

    Ryu, Jae Ryun; Hong, Caroline Jeeyeon; Kim, Joo Yeon; Kim, Eun-Kyoung; Sun, Woong; Yu, Seong-Woon

    2016-04-21

    The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.

  2. Obesity-Induced Hypertension: Brain Signaling Pathways

    Science.gov (United States)

    da Silva, Alexandre A.; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E. P.; Hall, John E.

    2017-01-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

  3. Obesity-Induced Hypertension: Brain Signaling Pathways.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E P; Hall, John E

    2016-07-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension.

  4. Chemical -induced apoptotic cell death in tomato cells : involvement of caspase-like proteases

    NARCIS (Netherlands)

    Jong, de A.J.; Hoeberichts, F.A.; Yakimova, E.T.; Maximova, E.; Woltering, E.J.

    2000-01-01

    A new system to study programmed cell death in plants is described. Tomato (Lycopersicon esculentum Mill.) suspension cells were induced to undergo programmed cell death by treatment with known inducers of apoptosis in mammalian cells. This chemical-induced cell death was accompanied by the

  5. Cardiac Glycoside Glucoevatromonoside Induces Cancer Type-Specific Cell Death

    Directory of Open Access Journals (Sweden)

    Naira F. Z. Schneider

    2018-03-01

    Full Text Available Cardiac glycosides (CGs are natural compounds used traditionally to treat congestive heart diseases. Recent investigations repositioned CGs as potential anticancer agents. To discover novel cytotoxic CG scaffolds, we selected the cardenolide glucoevatromonoside (GEV out of 46 CGs for its low nanomolar anti-lung cancer activity. GEV presented reduced toxicity toward non-cancerous cell types (lung MRC-5 and PBMC and high-affinity binding to the Na+/K+-ATPase α subunit, assessed by computational docking. GEV-induced cell death was caspase-independent, as investigated by a multiparametric approach, and culminates in severe morphological alterations in A549 cells, monitored by transmission electron microscopy, live cell imaging and flow cytometry. This non-canonical cell death was not preceded or accompanied by exacerbation of autophagy. In the presence of GEV, markers of autophagic flux (e.g. LC3I-II conversion were impacted, even in presence of bafilomycin A1. Cell death induction remained unaffected by calpain, cathepsin, parthanatos, or necroptosis inhibitors. Interestingly, GEV triggered caspase-dependent apoptosis in U937 acute myeloid leukemia cells, witnessing cancer-type specific cell death induction. Differential cell cycle modulation by this CG led to a G2/M arrest, cyclin B1 and p53 downregulation in A549, but not in U937 cells. We further extended the anti-cancer potential of GEV to 3D cell culture using clonogenic and spheroid formation assays and validated our findings in vivo by zebrafish xenografts. Altogether, GEV shows an interesting anticancer profile with the ability to exert cytotoxic effects via induction of different cell death modalities.

  6. A long-term trend of drug-induced deaths in European countries

    Directory of Open Access Journals (Sweden)

    WenJun Zhang

    2017-12-01

    Full Text Available In present study, data of drug-induced deaths in 29 European countries were used to analyze the profile and trend of drug-induced deaths recorded for total population, males and females in order to provide some basic information on adverse effects and misuse of drugs. The results showed that Germany (28501 deaths and United Kindom (22537 deaths have the greatest accumalted number (1995-2014 of drug-induced deaths, followed by Italy (14134 deaths and Spain (11133 deaths. Germany (23% and United Kingdom (18% held the highest percentage of drug-induced deaths in Europe, followed by Italy (12%, Spain (9%, Sweden (4%, and Norway (4%, etc. For males, United Kindom (24% and Germany (20% held the highest percentage, followed by Poland (8%, Italy (6%, etc. Similarly, Germany (25% and United Kingdom (18% are the highest in death percentage of males, followed by Italy (13%, etc. Not less than 1 death/yr, the European countries with the highest linear growth of drug-induced deaths for total population (p<0.05 are Turkey (33.2 deaths/yr and Sweden (21.6 deaths/yr, followed by Ireland (8.9 deaths/yr, Estonia (7.3 deaths/yr, Finland (6.5 deaths/yr, Lithuania (2.6 deaths/yr, and Romania (2.3 deaths/yr. Not less than 1 death/yr, the European countries with the highest linear decline of drug-induced deaths for total population (p<0.05 are Italy (-53.9 deaths/yr and Germany (-42.1 deaths/yr, followed by Spain (-21.6 deaths/yr, Portugal (-9.8 deaths/yr, Czech Republic (-2.9 deaths/yr, and Hungry (-1.5 deaths/yr. In average, the number of drug-induced deaths for both total population and males in Europe declined at the annual rate of 2 deaths, and that for females grew at the annual rate of 0.1 death. Generally the continuous growth of drug-induced deaths was mostly attributed to the growth of drug uses, the deteriorated medical service, or the promotion of diagnostic levels, etc. However, the continuous decline of drug-induced deaths was mostly attributed to the

  7. Obesity-Induced Hypertension: Brain Signaling Pathways

    OpenAIRE

    do Carmo, Jussara M.; da Silva, Alexandre A.; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E. P.; Hall, John E.

    2016-01-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocorti...

  8. Neuroprotective profile of pyruvate against ethanol-induced neurodegeneration in developing mice brain.

    Science.gov (United States)

    Ullah, Najeeb; Naseer, Muhammad Imran; Ullah, Ikram; Kim, Tae Hyun; Lee, Hae Young; Kim, Myeong Ok

    2013-12-01

    Exposure to ethanol during developmental stages leads to several types of neurological disorders. Apoptotic neurodegeneration due to ethanol exposure is a main feature in alcoholism. Exposure of developing animals to alcohol induces apoptotic neuronal death and causes fetal alcohol syndrome. In the present study, we observed the possible protective effect of pyruvate against ethanol-induced neurodegeneration. Exposure of developing mice to ethanol (2.5 g/kg) induces apoptotic neurodegeneration and widespread neuronal cell death in the cortex and thalamus. Co-treatment of pyruvate (500 mg/kg) protects neuronal cell against ethanol by the reduced expression of caspase-3 in these brain regions. Immunohistochemical analysis and TUNNEL at 24 h showed that apoptotic cell death induced by ethanol in the cortex and thalamus is reduced by pyruvate. Histomorphological analysis at 24 h with cresyl violet staining also proved that pyruvate reduced the number of neuronal cell loss in the cortex and thalamus. The results showed that ethanol increased the expression of caspase-3 and thus induced apoptotic neurodegeneration in the developing mice cortex and thalamus, while co-treatment of pyruvate inhibits the induction of caspase-3 and reduced the cell death in these brain regions. These findings, therefore, showed that treatment of pyruvate inhibits ethanol-induced neuronal cell loss in the postnatal seven (P7) developing mice brain and may appear as a safe neuroprotectant for treating neurodegenerative disorders in newborns and infants.

  9. Beacon signal in transcranial color coded ultrasound: A sign for brain death

    Directory of Open Access Journals (Sweden)

    Mehmet Akif Topçuoğlu

    2014-04-01

    Full Text Available A widely under-recognized brain-death confirming transcranial ultrasonography pattern resembling the red-blue beacon signal was demonstrated. Familiarity to this distinct and characteristic ultrasonic pattern seems to be important in the perspective of point-of-care neurological ultrasound use and knobology.

  10. Slow induction of brain death leads to decreased renal function and increased hepatic apoptosis in rats

    NARCIS (Netherlands)

    Rebolledo, Rolando A.; Hoeksma, Dane; Hottenrott, Christina M. V.; Bodar, Yves J. L.; Ottens, Petra J.; Wiersema-Buist, Janneka; Leuvenink, Henri G. D.

    2016-01-01

    Background: Donor brain death (BD) is an independent risk factor for graft survival in recipients. While in some patients BD results from a fast increase in intracranial pressure, usually associated with trauma, in others, intracranial pressure increases more slowly. The speed of intracranial

  11. Cardiotocographic and Doppler Ultrasonographic Findings in a Fetus with Brain Death Syndrome

    Directory of Open Access Journals (Sweden)

    Yi-Ting Chen

    2006-09-01

    Conclusion: The possibility of intrauterine brain death should be considered in all cases of prolonged fixed FHR pattern, accompanied by absence of neuromuscular parameters of BPP, polyhydramnios and demonstrated cessation of cerebral blood flow by Doppler US. Increased awareness of this event may prevent unnecessary emergency cesarean section.

  12. [Structural Equation Modeling on Living and Brain Death Organ Donation Intention in Nursing Students].

    Science.gov (United States)

    Kim, Eun A; Choi, So Eun

    2015-12-01

    The purpose of this study was to test and validate a model to predict living and brain death organ donation intention in nursing students. The conceptual model was based on the theory planned behavior. Quota sampling methodology was used to recruit 921 nursing students from all over the country and data collection was done from October 1 to December 20, 2013. The model fit indices for the hypothetical model were suitable for the recommended level. Knowledge, attitude, subjective norm and perceived behavioral control explained 40.2% and 40.1% respectively for both living and brain death organ donation intention. Subjective norm was the most direct influential factor for organ donation intention. Knowledge had significant direct effect on attitude and indirect effect on subjective norm and perceived behavioral control. These effects were higher in brain death organ donation intention than in living donation intention. The overall findings of this study suggest the need to develop systematic education programs to increases knowledge about brain death organ donation. The development, application, and evaluation of intervention programs are required to improve subjective norm.

  13. Advantages of analyzing postmortem brain samples in routine forensic drug screening—case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD)

    DEFF Research Database (Denmark)

    Mardal, Marie; Johansen, Sys Stybe; Thomsen, Ragnar

    2017-01-01

    Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma...... levels. The cause of death in case 1 was collision-induced brain injury, while it was drowning in case 2 and 3 and thus not drug intoxication. However, the toxicological findings could help explain the decedent’s inability to cope with brain injury or drowning incidents. The presented findings could help...... establish reference concentrations in brain samples and assist in interpretation of results from forensic drug screening in brain tissue. This is to the author’s knowledge the first report of LSD, iso-LSD, and oxo-HO-LSD measured in brain tissue samples....

  14. Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death[S

    Science.gov (United States)

    Takabe, Wakako; Urano, Yasuomi; Vo, Diep-Khanh Ho; Shibuya, Kimiyuki; Tanno, Masaki; Kitagishi, Hiroaki; Fujimoto, Toyoshi; Noguchi, Noriko

    2016-01-01

    The 24(S)-hydroxycholesterol (24S-OHC), which plays an important role in maintaining brain cholesterol homeostasis, has been shown to possess neurotoxicity. We have previously reported that 24S-OHC esterification by ACAT1 and the resulting lipid droplet (LD) formation are responsible for 24S-OHC-induced cell death. In the present study, we investigate the functional roles of 24S-OHC esters and LD formation in 24S-OHC-induced cell death, and we identify four long-chain unsaturated fatty acids (oleic acid, linoleic acid, arachidonic acid, and DHA) with which 24S-OHC is esterified in human neuroblastoma SH-SY5Y cells treated with 24S-OHC. Here, we find that cotreatment of cells with 24S-OHC and each of these four unsaturated fatty acids increases prevalence of the corresponding 24S-OHC ester and exacerbates induction of cell death as compared with cell death induced by treatment with 24S-OHC alone. Using electron microscopy, we find in the present study that 24S-OHC induces formation of LD-like structures coupled with enlarged endoplasmic reticulum (ER) lumina, and that these effects are suppressed by treatment with ACAT inhibitor. Collectively, these results illustrate that ACAT1-catalyzed esterification of 24S-OHC with long-chain unsaturated fatty acid followed by formation of atypical LD-like structures at the ER membrane is a critical requirement for 24S-OHC-induced cell death. PMID:27647838

  15. N-Methyl-d-Aspartate (NMDA Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection

    Directory of Open Access Journals (Sweden)

    Vivian V. Costa

    2017-04-01

    Full Text Available Zika virus (ZIKV infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801, agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.

  16. Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats.

    Science.gov (United States)

    Fiordaliso, Fabio; Bianchi, Roberto; Staszewsky, Lidia; Cuccovillo, Ivan; Doni, Mirko; Laragione, Teresa; Salio, Monica; Savino, Costanza; Melucci, Silvia; Santangelo, Francesco; Scanziani, Eugenio; Masson, Serge; Ghezzi, Pietro; Latini, Roberto

    2004-11-01

    Diabetes and oxidative stress concur to cardiac myocyte death in various experimental settings. We assessed whether N-acetyl-L-cysteine (NAC), an antioxidant and glutathione precursor, has a protective role in a rat model of streptozotocin (STZ)-induced diabetes and in isolated myocytes exposed to high glucose (HG). Diabetic rats were treated with NAC (0.5 g/kg per day) or vehicle for 3 months. At sacrifice left ventricle (LV) myocyte number and size, collagen deposition and reactive oxygen species (ROS) were measured by quantitative histological methods. Diabetes reduced LV myocyte number by 29% and increased myocyte volume by 20% compared to non-diabetic controls. NAC protected from myocyte loss (+25% vs. untreated diabetics, P < 0.05) and reduced reactive hypertrophy (-16% vs. untreated diabetics, P < 0.05). Perivascular fibrosis was high in diabetic rats (+88% vs. control, P < 0.001) but prevented by NAC. ROS production and fraction of ROS-positive cardiomyocyte nuclei were drastically raised in diabetic rats (2.4- and 5.1-fold vs. control, P < 0.001) and normalized by NAC. In separate experiments, isolated adult rat ventricular myocytes were incubated in a medium containing high concentrations of glucose (HG, 25 mM) +/- 0.01 mM NAC; myocyte survival (Trypan blue exclusion and apoptosis by TUNEL) and glutathione content were evaluated. The number of dead and apoptotic myocytes increased five and 6.7-fold in HG and glutathione decreased by 48% (P < 0.05). NAC normalized cell death and apoptosis and prevented glutathione loss. NAC effectively protects from hyperglycemia-induced myocyte cell death and compensatory hypertrophy through direct scavenging of ROS and replenishment of the intracellular glutathione content.

  17. Heme oxygenase-1 plays a pro-life role in experimental brain stem death via nitric oxide synthase I/protein kinase G signaling at rostral ventrolateral medulla

    Directory of Open Access Journals (Sweden)

    Dai Kuang-Yu

    2010-09-01

    Full Text Available Abstract Background Despite its clinical importance, a dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death. A suitable neural substrate for mechanistic delineation on brain stem death resides in the rostral ventrolateral medulla (RVLM because it is the origin of a life-and-death signal that sequentially increases (pro-life and decreases (pro-death to reflect the advancing central cardiovascular regulatory dysfunction during the progression towards brain stem death in critically ill patients. The present study evaluated the hypothesis that heme oxygnase-1 (HO-1 may play a pro-life role as an interposing signal between hypoxia-inducible factor-1 (HIF-1 and nitric oxide synthase I (NOS I/protein kinase G (PKG cascade in RVLM, which sustains central cardiovascular regulatory functions during brain stem death. Methods We performed cardiovascular, pharmacological, biochemical and confocal microscopy experiments in conjunction with an experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol bilaterally into RVLM of adult male Sprague-Dawley rats. Results Western blot analysis coupled with laser scanning confocal microscopy revealed that augmented HO-1 expression that was confined to the cytoplasm of RVLM neurons occurred preferentially during the pro-life phase of experimental brain stem death and was antagonized by immunoneutralization of HIF-1α or HIF-1β in RVLM. On the other hand, the cytoplasmic presence of HO-2 in RVLM neurons manifested insignificant changes during both phases. Furthermore, immunoneutralization of HO-1 or knockdown of ho-1 gene in RVLM blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated pro-life NOS I/PKG signaling without affecting the pro-death NOS II/peroxynitrite cascade in RVLM. Conclusions We conclude that transcriptional

  18. The Last Word: A Comparison of Younger and Older Adults' Brain Responses to Reminders of Death.

    Science.gov (United States)

    Bluntschli, John R; Maxfield, Molly; Grasso, Robin L; Kisley, Michael A

    2015-12-29

    Terror management theory (TMT) suggests increased death awareness motivates various human behaviors and defenses. Recent research reveals age differences in response to increased awareness of death, and older adults' proximity to death may contribute to these differences. In the first known investigation of attention's role in these age differences, we examined brain response associated with attention allocation for death-related stimuli. Younger (ages 18-28) and older (ages 61-78) adults viewed emotionally neutral, death-related negative, general negative, and positive words while recording event-related potentials (ERPs). Younger adults exhibited greater amplitudes in the late positive potential component of the ERP in response to death-related than negative words, whereas older adults showed the opposite pattern. Findings provide neurophysiological support for the shift in older adults' responses to death-related stimuli found in other TMT research as well as studies reporting reduced explicit death anxiety in older adults. Results also highlight the importance of considering stimuli content in studies of attention and emotion. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Tat-HSP22 inhibits oxidative stress-induced hippocampal neuronal cell death by regulation of the mitochondrial pathway.

    Science.gov (United States)

    Jo, Hyo Sang; Kim, Dae Won; Shin, Min Jea; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Yeo, Eun Ji; Choi, Yeon Joo; Yeo, Hyeon Ji; Sohn, Eun Jeong; Son, Ora; Cho, Sung-Woo; Kim, Duk-Soo; Yu, Yeon Hee; Lee, Keun Wook; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2017-01-04

    Oxidative stress plays an important role in the progression of various neuronal diseases including ischemia. Heat shock protein 22 (HSP22) is known to protect cells against oxidative stress. However, the protective effects and mechanisms of HSP22 in hippocampal neuronal cells under oxidative stress remain unknown. In this study, we determined whether HSP22 protects against hydrogen peroxide (H2O2)-induced oxidative stress in HT-22 using Tat-HSP22 fusion protein. We found that Tat-HSP22 transduced into HT-22 cells and that H2O2-induced cell death, oxidative stress, and DNA damage were significantly reduced by Tat-HSP22. In addition, Tat-HSP22 markedly inhibited H2O2-induced mitochondrial membrane potential, cytochrome c release, cleaved caspase-3, and Bax expression levels, while Bcl-2 expression levels were increased in HT-22 cells. Further, we showed that Tat-HSP22 transduced into animal brain and inhibited cleaved-caspase-3 expression levels as well as significantly inhibited hippocampal neuronal cell death in the CA1 region of animals in the ischemic animal model. In the present study, we demonstrated that transduced Tat-HSP22 attenuates oxidative stress-induced hippocampal neuronal cell death through the mitochondrial signaling pathway and plays a crucial role in inhibiting neuronal cell death, suggesting that Tat-HSP22 protein may be used to prevent oxidative stress-related brain diseases including ischemia.

  20. Nitro-Oxidative Stress after Neuronal Ischemia Induces Protein Nitrotyrosination and Cell Death

    Directory of Open Access Journals (Sweden)

    Marta Tajes

    2013-01-01

    Full Text Available Ischemic stroke is an acute vascular event that obstructs blood supply to the brain, producing irreversible damage that affects neurons but also glial and brain vessel cells. Immediately after the stroke, the ischemic tissue produces nitric oxide (NO to recover blood perfusion but also produces superoxide anion. These compounds interact, producing peroxynitrite, which irreversibly nitrates protein tyrosines. The present study measured NO production in a human neuroblastoma (SH-SY5Y, a murine glial (BV2, a human endothelial cell line (HUVEC, and in primary cultures of human cerebral myocytes (HC-VSMCs after experimental ischemia in vitro. Neuronal, endothelial, and inducible NO synthase (NOS expression was also studied up to 24 h after ischemia, showing a different time course depending on the NOS type and the cells studied. Finally, we carried out cell viability experiments on SH-SY5Y cells with H2O2, a prooxidant agent, and with a NO donor to mimic ischemic conditions. We found that both compounds were highly toxic when they interacted, producing peroxynitrite. We obtained similar results when all cells were challenged with peroxynitrite. Our data suggest that peroxynitrite induces cell death and is a very harmful agent in brain ischemia.

  1. Nitro-Oxidative Stress after Neuronal Ischemia Induces Protein Nitrotyrosination and Cell Death

    Science.gov (United States)

    Tajes, Marta; ILL-Raga, Gerard; Palomer, Ernest; Ramos-Fernández, Eva; Guix, Francesc X.; Bosch-Morató, Mònica; Guivernau, Biuse; Jiménez-Conde, Jordi; Ois, Angel; Pérez-Asensio, Fernando; Reyes-Navarro, Mario; Galán, Ana M.; Alameda, Francesc; Escolar, Ginés; Opazo, Carlos; Planas, Anna; Roquer, Jaume; Valverde, Miguel A.; Muñoz, Francisco J.

    2013-01-01

    Ischemic stroke is an acute vascular event that obstructs blood supply to the brain, producing irreversible damage that affects neurons but also glial and brain vessel cells. Immediately after the stroke, the ischemic tissue produces nitric oxide (NO) to recover blood perfusion but also produces superoxide anion. These compounds interact, producing peroxynitrite, which irreversibly nitrates protein tyrosines. The present study measured NO production in a human neuroblastoma (SH-SY5Y), a murine glial (BV2), a human endothelial cell line (HUVEC), and in primary cultures of human cerebral myocytes (HC-VSMCs) after experimental ischemia in vitro. Neuronal, endothelial, and inducible NO synthase (NOS) expression was also studied up to 24 h after ischemia, showing a different time course depending on the NOS type and the cells studied. Finally, we carried out cell viability experiments on SH-SY5Y cells with H2O2, a prooxidant agent, and with a NO donor to mimic ischemic conditions. We found that both compounds were highly toxic when they interacted, producing peroxynitrite. We obtained similar results when all cells were challenged with peroxynitrite. Our data suggest that peroxynitrite induces cell death and is a very harmful agent in brain ischemia. PMID:23983901

  2. Blockade of maitotoxin-induced oncotic cell death reveals zeiosis

    Directory of Open Access Journals (Sweden)

    Schilling William P

    2002-01-01

    Full Text Available Abstract Background Maitotoxin (MTX initiates cell death by sequentially activating 1 Ca2+ influx via non-selective cation channels, 2 uptake of vital dyes via formation of large pores, and 3 release of lactate dehydrogenase, an indication of cell lysis. MTX also causes formation of membrane blebs, which dramatically dilate during the cytolysis phase. To determine the role of phospholipase C (PLC in the cell death cascade, U73122, a specific inhibitor of PLC, and U73343, an inactive analog, were examined on MTX-induced responses in bovine aortic endothelial cells. Results Addition of either U73122 or U73343, prior to MTX, produced a concentration-dependent inhibition of the cell death cascade (IC50 ≈ 1.9 and 0.66 μM, respectively suggesting that the effect of these agents was independent of PLC. Addition of U73343 shortly after MTX, prevented or attenuated the effects of the toxin, but addition at later times had little or no effect. Time-lapse videomicroscopy showed that U73343 dramatically altered the blebbing profile of MTX-treated cells. Specifically, U73343 blocked bleb dilation and converted the initial blebbing event into "zeiosis", a type of membrane blebbing commonly associated with apoptosis. Cells challenged with MTX and rescued by subsequent addition of U73343, showed enhanced caspase-3 activity 48 hr after the initial insult, consistent with activation of the apoptotic program. Conclusions Within minutes of MTX addition, endothelial cells die by oncosis. Rescue by addition of U73343 shortly after MTX showed that a small percentage of cells are destined to die by oncosis, but that a larger percentage survive; cells that survive the initial insult exhibit zeiosis and may ultimately die by apoptotic mechanisms.

  3. miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition.

    Science.gov (United States)

    Song, Juhyun; Yoon, So Ra; Kim, Oh Yoen

    2017-01-01

    Hyperglycemia-induced stress in the brain of patients with diabetes triggers the disruption of blood-brain barrier (BBB), leading to diverse neurological diseases including stroke and dementia. Recently, the role of microRNA becomes an interest in the research for deciphering the mechanism of brain endothelial cell damage under hyperglycemia. Therefore, we investigated whether mircoRNA Let7A (miR-Let7A) controls the damage of brain endothelial (bEnd.3) cells against high glucose condition. Cell viability, cell death marker expressions (p-53, Bax, and cleaved poly ADP-ribose polymerase), the loss of tight junction proteins (ZO-1 and claudin-5), proinflammatory response (interleukin-6, tumor necrosis factor-α), inducible nitric oxide synthase, and nitrite production were confirmed using MTT, reverse transcription-PCR, quantitative-PCR, Western blotting, immunofluorescence, and Griess reagent assay. miR-Let7A overexpression significantly prevented cell death and loss of tight junction proteins and attenuated proinflammatory response and nitrite production in the bEnd.3 cells under high glucose condition. Taken together, we suggest that miR-Let7A may attenuate brain endothelial cell damage by controlling cell death signaling, loss of tight junction proteins, and proinflammatory response against high glucose stress. In the future, the manipulation of miR-Let7A may be a novel solution in controlling BBB disruption which leads to the central nervous system diseases.

  4. Targeted cancer cell death induced by biofunctionalized magnetic nanowires

    KAUST Repository

    Contreras, Maria F.

    2014-02-01

    Magnetic micro and nanomaterials are increasingly interesting for biomedical applications since they possess many advantageous properties: they can become biocompatible, they can be functionalized to target specific cells and they can be remotely manipulated by magnetic fields. The goal of this study is to use antibody-functionalized nickel nanowires (Ab-NWs) as an alternative method in cancer therapy overcoming the limitations of current treatments that lack specificity and are highly cytotoxic. Ab-NWs have been incubated with cancer cells and a 12% drop on cell viability was observed for a treatment of only 10 minutes and an alternating magnetic field of low intensity and low frequency. It is believed that the Ab-NWs vibrate transmitting a mechanical force to the targeted cells inducing cell death. © 2014 IEEE.

  5. Legal Standards for Brain Death and Undue Influence in Euthanasia Laws.

    Science.gov (United States)

    Pope, Thaddeus Mason; Okninski, Michaela E

    2016-06-01

    A major appellate court decision from the United States seriously questions the legal sufficiency of prevailing medical criteria for the determination of death by neurological criteria. There may be a mismatch between legal and medical standards for brain death, requiring the amendment of either or both. In South Australia, a Bill seeks to establish a legal right for a defined category of persons suffering unbearably to request voluntary euthanasia. However, an essential criterion of a voluntary decision is that it is not tainted by undue influence, and this Bill falls short of providing adequate guidance to assess for undue influence.

  6. alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling

    NARCIS (Netherlands)

    Bantel, H; Sinha, B; Domschke, W; Peters, Georg; Schulze-Osthoff, K; Jänicke, R U

    2001-01-01

    Infections with Staphylococcus aureus, a common inducer of septic and toxic shock, often result in tissue damage and death of various cell types. Although S. aureus was suggested to induce apoptosis, the underlying signal transduction pathways remained elusive. We show that caspase activation and

  7. Process and barriers to organ donation and causes of brain death in northeast of Iran.

    Science.gov (United States)

    Bahrami, Abdollah; Khaleghi, Ebrahim; Vakilzadeh, Ali Khorsand; Afzalaghaee, Monavar

    2017-02-01

    Organ transplantation is the treatment of choice for some diseases. However, the need for cadaveric organ donation has either plateaued or is on a decreasing trend in some countries, especially in developed ones. In this study, we aimed to identify the barriers to organ donation in brain dead patients, who were referred to the organ procurement organizations (OPO) in northeast Iran. In this cross-sectional study during 2006 to 2013, data were collected from medical records of brain dead patients. Demographic information, cause of brain death, the process of obtaining informed consent, and the reasons for declining organ donation were obtained from the OPO records. The data were analyzed using chi-square test by SPSS 13 software. Of 1034 brain dead patients, 751 cases (72.6%) were eligible for organ donation, and, ultimately, 344 cases underwent organ donation. The rate of organ donation increased during the course of the study; medical and legal reasons as well as family refusal to authorize donation were the main barriers to the process. Based on the pattern of mortality, the need for living donors in developing countries, such as Iran and other countries in the Mediterranean region, can be reduced by improving the quality of healthcare, efficient identification of brain death, and obtaining consent with appropriate strategies.

  8. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production

    OpenAIRE

    Houlden, A.; Goldrick, M.; Brough, D; Vizi, E. S.; Lénárt, N.; Martinecz, B.; Roberts, I. S.; A.; Denes

    2016-01-01

    Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis tha...

  9. Mechanisms of blast induced brain injuries, experimental studies in rats.

    Science.gov (United States)

    Risling, M; Plantman, S; Angeria, M; Rostami, E; Bellander, B-M; Kirkegaard, M; Arborelius, U; Davidsson, J

    2011-01-01

    Traumatic brain injuries (TBI) potentially induced by blast waves from detonations result in significant diagnostic problems. It may be assumed that several mechanisms contribute to the injury. This study is an attempt to characterize the presumed components of the blast induced TBI. Our experimental models include a blast tube in which an anesthetized rat can be exposed to controlled detonations of explosives that result in a pressure wave with a magnitude between 130 and 260 kPa. In this model, the animal is fixed with a metal net to avoid head acceleration forces. The second model is a controlled penetration of a 2mm thick needle. In the third model the animal is subjected to a high-speed sagittal rotation angular acceleration. Immunohistochemical labeling for amyloid precursor protein revealed signs of diffuse axonal injury (DAI) in the penetration and rotation models. Signs of punctuate inflammation were observed after focal and rotation injury. Exposure in the blast tube did not induce DAI or detectable cell death, but functional changes. Affymetrix Gene arrays showed changes in the expression in a large number of gene families including cell death, inflammation and neurotransmitters in the hippocampus after both acceleration and penetration injuries. Exposure to the primary blast wave induced limited shifts in gene expression in the hippocampus. The most interesting findings were a downregulation of genes involved in neurogenesis and synaptic transmission. These experiments indicate that rotational acceleration may be a critical factor for DAI and other acute changes after blast TBI. The further exploration of the mechanisms of blast TBI will have to include a search for long-term effects. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability.

    Science.gov (United States)

    Kinney, Hannah C; Cryan, Jane B; Haynes, Robin L; Paterson, David S; Haas, Elisabeth A; Mena, Othon J; Minter, Megan; Journey, Kelley W; Trachtenberg, Felicia L; Goldstein, Richard D; Armstrong, Dawna D

    2015-01-01

    Sudden unexplained death in infants, including the sudden infant death syndrome, is likely due to heterogeneous causes that involve different intrinsic vulnerabilities and/or environmental factors. Neuropathologic research focuses upon the role of brain regions, particularly the brainstem, that regulate or modulate autonomic and respiratory control during sleep or transitions to waking. The hippocampus is a key component of the forebrain-limbic network that modulates autonomic/respiratory control via brainstem connections, but its role in sudden infant death has received little attention. We tested the hypothesis that a well-established marker of hippocampal pathology in temporal lobe epilepsy-focal granule cell bilamination in the dentate, a variant of granule cell dispersion-is associated with sudden unexplained death in infants. In a blinded study of hippocampal morphology in 153 infants with sudden and unexpected death autopsied in the San Diego County medical examiner's office, deaths were classified as unexplained or explained based upon autopsy and scene investigation. Focal granule cell bilamination was present in 41.2% (47/114) of the unexplained group compared to 7.7% (3/39) of the explained (control) group (p infants with sudden unexplained death may represent a developmental vulnerability that leads to autonomic/respiratory instability or autonomic seizures, and sleep-related death when the infants are challenged with homeostatic stressors. Importantly, these lesions can be recognized in microscopic sections prepared in current forensic practice. Future research is needed to determine the relationship between hippocampal and previously reported brainstem pathology in sudden infant death.

  11. Programmed Cell Death in Procyclic Form Trypanosoma brucei rhodesiense - Identification of Differentially Expressed Genes during Con A Induced Death

    Directory of Open Access Journals (Sweden)

    Welburn Susan C

    1999-01-01

    Full Text Available Trypanosoma brucei rhodesiense can be induced to undergo apoptosis after stimulation with Con A. As cell death in these parasites is associated with de novo gene expression we have applied a differential display technique, Randomly Amplified Differential Expressed Sequence-Polymerase Chain Reaction (RADES-PCR to the study of gene expression during Con A induced cell death in these organisms. Twenty-two differentially displayed products have been cloned and sequenced. These represent the first endogenous genes to be identified as implicated in cellular death in trypanosomatids (the most primitive eukaryote in which apoptosis has been described. Evidence for an ancestral death machinery, `proto-apoptosis' in single celled organisms is discussed.

  12. SWCNTs induced autophagic cell death in human bronchial epithelial cells.

    Science.gov (United States)

    Park, Eun-Jung; Zahari, Nur Elida M; Lee, Eun-Woo; Song, Jaewhan; Lee, Jae-Hyeok; Cho, Myung-Haing; Kim, Jae-Ho

    2014-04-01

    Carbon nanotubes are being actively introduced in electronics, computer science, aerospace, and other industries. Thus, the urgent need for toxicological studies on CNTs is mounting. In this study, we investigated the alterations in cellular response with morphological changes induced by single-walled carbon nanotubes (SWCNTs) in BEAS-2B cells, a human bronchial epithelial cell line. At 24h after exposure, SWCNTs rapidly decreased ATP production and cell viability as well a slight increase in the number of cells in the subG1 and G1 phases. In addition, SWCNTs increased the expression of superoxide dismutase (SOD)-1, but not SOD-2, and the number of cells generating ROS. The concentration of Cu and Zn ions also increased in a dose-dependent manner in cells exposed to SWCNTs. SWCNTs significantly enhanced the release of nitric oxide, interleukin (IL)-6, and IL-8 and up-regulated the expression of chemokine- and cytokine-related genes. Furthermore, the levels of autophagy-related genes, especially the DRAM1 gene, and the autophagosome formation-related proteins, were clearly up-regulated together with an increase of autophagosome-like vacuoles. Based on these results, we suggest that SWCNTs induce autophagic cell death through mitochondrial dysfunction and cytosolic damage in human bronchial epithelial cells. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. GAS1 induces cell death through an intrinsic apoptotic pathway.

    Science.gov (United States)

    Zarco, Natanael; González-Ramírez, Ricardo; González, Rosa O; Segovia, José

    2012-06-01

    Growth Arrest Specific 1 (GAS1) is a protein expressed when cells are arrested and during development. When ectopically expressed, GAS1 induces cell arrest and apoptosis of different cell lines, and we have previously demonstrated that the apoptotic process set off by GAS1 is caused by its capacity inhibiting the GDNF-mediated intracellular survival signaling. In the present work, we have dissected the molecular pathway leading to cell death. We employed the SH-SY5Y human neuroblastoma cell line that expresses GAS1 when deprived of serum. We observed, as we have previously described, that the presence of GAS1 reduces RET phosphorylation and inhibits the activation of AKT. We have now determined that the presence of GAS1 also triggers the dephosphorylation of BAD, which, in turn, provokes the release of Cytochrome-c from the mitochondria to the cytosol activating caspase-9, prompting the activity of caspase-3 and resulting in apoptosis of the cells. The apoptotic process is intrinsic, because there is no activation of caspase-8, thus this is consistent with apoptosis induced by the lack of trophic support. Interestingly, in cells where GAS1 has been silenced there is a significant delay in the onset of apoptosis.

  14. Boosting Focally-Induced Brain Plasticity by Dopamine

    National Research Council Canada - National Science Library

    Kuo, Min-Fang; Paulus, Walter; Nitsche, Michael A

    2008-01-01

    .... Transcranial direct current stimulation (tDCS) induces cortical excitability enhancement by anodal and depression by cathodal brain polarization, which is not restricted to specific subgroups of synapses...

  15. Neurotoxin envenomation mimicking brain death in a child: A case report and review of literature

    OpenAIRE

    Dayal, Madhu; Prakash, Smita; Verma, Pradeep K; Pawar, Mridula

    2014-01-01

    The spectrum of presentation of a victim of neurotoxic snake bite can range from mild ptosis to complete paralysis and ophthalmoplegia. We report a case of snake bite in a 10-year-old child who was comatosed with bilateral fixed dilated pupils and absent doll′s eye movement that was interpreted as brain death. Physicians need to be aware of the likelihood of snakebite presenting as locked in syndrome.

  16. Neurotoxin envenomation mimicking brain death in a child: A case report and review of literature.

    Science.gov (United States)

    Dayal, Madhu; Prakash, Smita; Verma, Pradeep K; Pawar, Mridula

    2014-07-01

    The spectrum of presentation of a victim of neurotoxic snake bite can range from mild ptosis to complete paralysis and ophthalmoplegia. We report a case of snake bite in a 10-year-old child who was comatosed with bilateral fixed dilated pupils and absent doll's eye movement that was interpreted as brain death. Physicians need to be aware of the likelihood of snakebite presenting as locked in syndrome.

  17. Neurotoxin envenomation mimicking brain death in a child: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Madhu Dayal

    2014-01-01

    Full Text Available The spectrum of presentation of a victim of neurotoxic snake bite can range from mild ptosis to complete paralysis and ophthalmoplegia. We report a case of snake bite in a 10-year-old child who was comatosed with bilateral fixed dilated pupils and absent doll′s eye movement that was interpreted as brain death. Physicians need to be aware of the likelihood of snakebite presenting as locked in syndrome.

  18. The concept of brain death did not evolve to benefit organ transplants.

    Science.gov (United States)

    Machado, Calixto; Kerein, Julius; Ferrer, Yazmina; Portela, Liana; de la C García, Maria; Manero, José M

    2007-04-01

    Although it is commonly believed that the concept of brain death (BD) was developed to benefit organ transplants, it evolved independently. Transplantation owed its development to advances in surgery and immunosuppressive treatment; BD owed its origin to the development of intensive care. The first autotransplant was achieved in the early 1900s, when studies of increased intracranial pressure causing respiratory arrest with preserved heartbeat were reported. Between 1902 and 1950, the BD concept was supported by the discovery of EEG, Crile's definition of death, the use of EEG to demonstrate abolition of brain potentials after ischaemia, and Crafoord's statement that death was due to cessation of blood flow. Transplantation saw the first xenotransplant in humans and the first unsuccessful kidney transplant from a cadaver. In the 1950s, circulatory arrest in coma was identified by angiography, and the death of the nervous system and coma dépassé were described. Murray performed the first successful kidney transplant. In the 1960s, the BD concept and organ transplants were instantly linked when the first kidney transplant using a brain-dead donor was performed; Schwab proposed to use EEG in BD; the Harvard Committee report and the Sydney Declaration appeared; the first successful kidney, lung and pancreas transplants using cadaveric (not brain-dead) donors were achieved; Barnard performed the first human heart transplant. This historical review demonstrates that the BD concept and organ transplantation arose separately and advanced in parallel, and only began to progress together in the late 1960s. Therefore, the BD concept did not evolve to benefit transplantation.

  19. Cardiotocographic and Doppler Ultrasonographic Findings in a Fetus with Brain Death Syndrome

    OpenAIRE

    Chen, Yi-Ting; Hsu, Shih-Tien; Tseng, Jenn-Jhy; Chen, Wei-Chih; Ho, Esther Shih-Chu; Chou, Min-Min

    2006-01-01

    Objective: The diagnosis of brain death syndrome by cardiotocography (CTG) and Doppler ultrasonography (US) is reported in a fetus at 35 weeks of gestation. Case Report: A 23-year-old, gravida 2, para 0, woman was referred to our hospital because of the absence of fetal movements. CTG showed fixed fetal heart rate (FHR) pattern. A detailed Doppler US examination of the fetus showed extensive cystic lesions of both cerebral hemispheres, polyhydramnios, total absence of neuromuscular paramet...

  20. Blood pressure and heart rate variability and baroreflex sensitivity before and after brain death

    OpenAIRE

    Conci, F.; Di, R; Castiglioni, P.

    2001-01-01

    OBJECTIVES—To evaluate spontaneous blood pressure and heart rate variability and spontaneous baroreflex sensitivity before and after brain death.
METHODS—Spontaneous variability of arterial blood pressure and heart rate—estimated by power spectra of systolic (SBP) and diastolic blood pressure (DBP) and pulse interval (PI)—and spontaneous baroreflex sensitivity (BRS)—estimated by the alpha index and the sequence technique—were evaluated in 11 patients twice: shortly before...

  1. CELECOXIB ATTENUATES SYSTEMIC LIPOPOLYSACCHARIDE-INDUCED BRAIN INFLAMMATION AND WHITE MATTER INJURY IN THE NEONATAL RATS

    Science.gov (United States)

    FAN, L.-W.; KAIZAKI, A.; TIEN, L.-T.; PANG, Y.; TANAKA, S.; NUMAZAWA, S.; BHATT, A. J.; CAI, Z.

    2013-01-01

    Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. Cyclooxygenase-2 (COX-2) can be induced by inflammatory stimuli, such as cytokines and pro-inflammatory molecules, suggesting that COX-2 may be considered as the target for anti-inflammation. The objective of the present study was to examine whether celecoxib, a selective COX-2 inhibitor, can reduce systemic LPS-induced brain inflammation and brain damage. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in postnatal day 5 (P5) of Sprague-Dawley rat pups and celecoxib (20 mg/kg) or vehicle was administered i.p. 5 min after LPS injection. The body weight and wire hanging maneuver test were performed 24 hr after the LPS exposure, and brain injury was examined after these tests. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury, as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes, concentrations of IL-1β and TNFα, and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure, and the protective effects are associated with its anti-inflammatory properties. PMID:23485816

  2. Apnea test in the determination of brain death in patients treated with extracorporeal membrane oxygenation (ECMO).

    Science.gov (United States)

    Saucha, Wojciech; Sołek-Pastuszka, Joanna; Bohatyrewicz, Romuald; Knapik, Piotr

    2015-01-01

    Extracorporeal Membrane Oxygenation (ECMO) is a well-established method of support in patients with severe respiratory and/or circulatory failure. Unfortunately, this invasive method of treatment is associated with a high risk of neurological complications including brain death. Proper diagnosis of brain death is crucial for the termination of futile medical care. Currently, the legal system in Poland does not provide an accepted protocol for apnea tests for patients on ECMO support. Veno-arterial ECMO is particularly problematic in this regard because it provides both gas exchange and circulatory support. CO₂ elimination by ECMO prevents hypercapnia, which is required to perform an apnea test. Several authors have described a safe apnea test procedure in patients on ECMO. Maximal reduction of the sweep gas flow to the oxygenator should maintain an acceptable haemoglobin oxygenation level and reduce elimination of carbon dioxide. Hypercapnia achieved via this method should allow an apnea test to be conducted in the typical manner. In the case of profound desaturation and an inadequate increase in the arterial CO₂ concentration, the sweep gas flow rate may be increased to obtain the desired oxygenation level, and exogenous carbon dioxide may be added to achieve a target carbon dioxide level. Incorporation of an apnea test for ECMO patients is planned in the next edition of the Polish guidelines on the determination of brain death.

  3. Interleukin-3 prevents neuronal death induced by amyloid peptide

    Directory of Open Access Journals (Sweden)

    Otth Carola

    2007-10-01

    Full Text Available Abstract Background Interleukin-3 (IL-3 is an important glycoprotein involved in regulating biological responses such as cell proliferation, survival and differentiation. Its effects are mediated via interaction with cell surface receptors. Several studies have demonstrated the expression of IL-3 in neurons and astrocytes of the hippocampus and cortices in normal mouse brain, suggesting a physiological role of IL-3 in the central nervous system. Although there is evidence indicating that IL-3 is expressed in some neuronal populations, its physiological role in these cells is poorly known. Results In this study, we demonstrated the expression of IL-3 receptor in cortical neurons, and analyzed its influence on amyloid β (Aβ-treated cells. In these cells, IL-3 can activate at least three classical signalling pathways, Jak/STAT, Ras/MAP kinase and the PI 3-kinase. Viability assays indicated that IL-3 might play a neuroprotective role in cells treated with Aβ fibrils. It is of interest to note that our results suggest that cell survival induced by IL-3 required PI 3-kinase and Jak/STAT pathway activation, but not MAP kinase. In addition, IL-3 induced an increase of the anti-apoptotic protein Bcl-2. Conclusion Altogether these data strongly suggest that IL-3 neuroprotects neuronal cells against neurodegenerative agents like Aβ.

  4. Curcumin induces apoptosis-independent death in oesophageal cancer cells.

    LENUS (Irish Health Repository)

    O'Sullivan-Coyne, G

    2009-10-06

    Background:Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines.Methods:MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting.Results:Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5-50 muM range. Cytotoxicity is associated with accumulation in G2\\/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin-proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug.Conclusion:Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.British Journal of Cancer advance online publication, 6 October 2009; doi:10.1038\\/sj.bjc.6605308 www.bjcancer.com.

  5. Curcumin induces apoptosis-independent death in oesophageal cancer cells.

    LENUS (Irish Health Repository)

    O'Sullivan-Coyne, G

    2012-01-31

    BACKGROUND: Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines. METHODS: MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting. RESULTS: Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5-50 muM range. Cytotoxicity is associated with accumulation in G2\\/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin-proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug. CONCLUSION: Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.

  6. Improving incidence of referrals for psychosocial and spiritual transdisciplinary care in a palliative care service: focus on brain death.

    Science.gov (United States)

    Markham, Kelly C

    2013-01-01

    The goal of this project was to examine the uniformity of the hospital's delivery of psychosocial and spiritual care for the families of patients being evaluated for brain death. A retrospective chart review encompassing one calendar year was conducted. After conferring with physicians and staff, a strategy was developed to capture information on patients who were diagnosed with brain death. Following evaluation of the information gathered, a proposal was introduced and hospital procedure revised. Triggers were put in place to ensure consistent offering of psycho-spiritual transdisciplinary services to the families of patients who are undergoing evaluation for brain death.

  7. Hypotonic hyponatremia by primary polydipsia caused brain death in a 10-year-old boy.

    Science.gov (United States)

    Ko, A Ra; Kim, Soo Jung; Jung, Mo Kyung; Kim, Ki Eun; Chae, Hyun Wook; Kim, Duk Hee; Kim, Ho-Seong; Kwon, Ah Reum

    2015-09-01

    Hypotonic hyponatremia by primary polydipsia can cause severe neurologic complications due to cerebral edema. A 10-year-and-4-month-old boy with a psychiatric history of intellectual disability and behavioral disorders who presented with chief complaints of seizure and mental change showed severe hypotonic hyponatremia with low urine osmolality (serum sodium, 101 mmol/L; serum osmolality, 215 mOsm/kg; urine osmolality, 108 mOsm/kg). The patient had been polydipsic for a few months prior, and this had been worse in the previous few days. A diagnosis of hypotonic hyponatremia caused by primary polydipsia was made. The patient was in a coma, and developed respiratory arrest and became brain death shortly after admission, despite the treatment. The initial brain magnetic resonance imaging showed severe brain swelling with tonsillar and uncal herniation, and the patient was declared as brain death. It has been reported that antidiuretic hormone suppression is inadequate in patients with chronic polydipsia, and that this inadequate suppression of antidiuretic hormone is aggravated in patients with acute psychosis. Therefore, hyponatremia by primary polydipsia, although it is rare, can cause serious and life-threatening neurologic complications.

  8. Cardiotocographic and Doppler ultrasonographic findings in a fetus with brain death syndrome.

    Science.gov (United States)

    Chen, Yi-Ting; Hsu, Shih-Tien; Tseng, Jenn-Jhy; Chen, Wei-Chih; Ho, Esther Shih-Chu; Chou, Min-Min

    2006-09-01

    The diagnosis of brain death syndrome by cardiotocography (CTG) and Doppler ultrasonography (US) is reported in a fetus at 35 weeks of gestation. A 23-year-old, gravida 2, para 0, woman was referred to our hospital because of the absence of fetal movements. CTG showed fixed fetal heart rate (FHR) pattern. A detailed Doppler US examination of the fetus showed extensive cystic lesions of both cerebral hemispheres, polyhydramnios, total absence of neuromuscular parameters of biophysical profile (BPP) and the cessation of cerebral blood flow. Umbilical cord artery blood gas analysis showed pH 7.3, PaO2 30 mmHg and PaCO2 35 mmHg. A floppy male infant weighing 2,450 g was delivered vaginally at 36 weeks of gestation and the Apgar scores were 1 and 1 at 5 and 10 minutes, respectively. The neonate died 2 days after delivery. Postmortem examination of the brain showed diffuse, anoxic changes with multicystic encephalomalacia in both hemispheres and the brain stem. No other maternal or placental abnormalities were seen. The possibility of intrauterine brain death should be considered in all cases of prolonged fixed FHR pattern, accompanied by absence of neuromuscular parameters of BPP, polyhydramnios and demonstrated cessation of cerebral blood flow by Doppler US. Increased awareness of this event may prevent unnecessary emergency cesarean section.

  9. Motricidade reflexa na morte cerebral The reflex activity in the brain death

    Directory of Open Access Journals (Sweden)

    Wilson L. Sanvito

    1972-03-01

    Full Text Available O diagnóstico de morte cerebral está baseado em critérios clínicos, eletrencefalográficos e angiográficos. Do ponto de vista clínico deve ser evidenciado o seguinte quadro: coma profundo, midríase paralítica bilateral, ausência de reação a qualquer estímulo externo, apnéia, arreflexia superficial e profunda. Do ponto de vista eletrencefalográfico são necessários dois registros, separados por um intervalo de 24 horas, evidenciando traçados iselétricos. No presente trabalho são estudados 15 pacientes com morte cerebral comprovada do ponto de vista clínico e eletrencefalográfico. Em 8 pacientes havia persistência de atividade reflexa durante a fase de morte cerebral (reflexos profundos e/ou superficiais. Fenômenos de automatismos medulares também foram verificados em 3 pacientes.The diagnosis of brain death is based in clinical, electroencephalographic and angiographic data. The criteria for diagnosis of brain death are: deep coma with unreceptivity and unresponsiveness, no movements or breathing (the patient's respiration must be maintained artificially, bilateral dilated and fixed pupils, absence of corneal reflexes, no response to caloric test, absence of deep tendon reflexes and of the superficial abdominal and plantar reflexes, isoelectric EEG maintained for twenty-four hours. The purpose of this study was to observe the natural clinical courses of 15 patients with brain death, specially the data concerning the deep and superficial reflexes. From 15 patients fulfilling the criteria of brain death, 8 maintained spinal reflexes up to the time of cardiac arrest; in five of these patients the superficial abdominal reflexes were present and the reflexes of spinal automatism could be elicited. These results show that the absence of deep and superficial reflexes can't be considered as essencial for the diagnosis of brain death.

  10. EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury.

    Science.gov (United States)

    Theus, M H; Ricard, J; Glass, S J; Travieso, L G; Liebl, D J

    2014-05-08

    Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, have a variety of roles in the developing and adult central nervous system that require direct cell-cell interactions; including regulating axon path finding, cell proliferation, migration and synaptic plasticity. Recently, we identified a novel pro-survival role for ephrins in the adult subventricular zone, where ephrinB3 blocks Eph-mediated cell death during adult neurogenesis. Here, we examined whether EphB3 mediates cell death in the adult forebrain following traumatic brain injury and whether ephrinB3 infusion could limit this effect. We show that EphB3 co-labels with microtubule-associated protein 2-positive neurons in the adult cortex and is closely associated with ephrinB3 ligand, which is reduced following controlled cortical impact (CCI) injury. In the complete absence of EphB3 (EphB3(-/-)), we observed reduced terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL), and functional improvements in motor deficits after CCI injury as compared with wild-type and ephrinB3(-/-) mice. We also demonstrated that EphB3 exhibits dependence receptor characteristics as it is cleaved by caspases and induces cell death, which is not observed in the presence of ephrinB3. Following trauma, infusion of pre-clustered ephrinB3-Fc molecules (eB3-Fc) into the contralateral ventricle reduced cortical infarct volume and TUNEL staining in the cortex, dentate gyrus and CA3 hippocampus of wild-type and ephrinB3(-/-) mice, but not EphB3(-/-) mice. Similarly, application of eB3-Fc improved motor functions after CCI injury. We conclude that EphB3 mediates cell death in the adult cortex through a novel dependence receptor-mediated cell death mechanism in the injured adult cortex and is attenuated following ephrinB3 stimulation.

  11. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Hengwen [Department of Radiation, Cancer Center of Guangdong General Hospital (Guangdong Academy of Medical Science), Guangzhou, 510080, Guangdong (China); Yang, Shana; Li, Jianhua [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Zhang, Yajie [Department of Pathology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Gao, Dongsheng [Department of Oncology, Guangdong Medical College Affiliated Pengpai Memorial Hospital, Hai Feng, 516400, Gungdong (China); Zhao, Shenting, E-mail: zhaoshenting@126.com [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China)

    2016-03-25

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.

  12. Entamoeba histolytica induces cell death of HT29 colonic epithelial cells via NOX1-derived ROS.

    Science.gov (United States)

    Kim, Kyeong Ah; Kim, Ju Young; Lee, Young Ah; Min, Arim; Bahk, Young Yil; Shin, Myeong Heon

    2013-02-01

    Entamoeba histolytica, which causes amoebic colitis and occasionally liver abscess in humans, is able to induce host cell death. However, signaling mechanisms of colon cell death induced by E. histolytica are not fully elucidated. In this study, we investigated the signaling role of NOX in cell death of HT29 colonic epithelial cells induced by E. histolytica. Incubation of HT29 cells with amoebic trophozoites resulted in DNA fragmentation that is a hallmark of apoptotic cell death. In addition, E. histolytica generate intracellular reactive oxygen species (ROS) in a contact-dependent manner. Inhibition of intracellular ROS level with treatment with DPI, an inhibitor of NADPH oxidases (NOXs), decreased Entamoeba-induced ROS generation and cell death in HT29 cells. However, pan-caspase inhibitor did not affect E. histolytica-induced HT29 cell death. In HT29 cells, catalytic subunit NOX1 and regulatory subunit Rac1 for NOX1 activation were highly expressed. We next investigated whether NADPH oxidase 1 (NOX1)-derived ROS is closely associated with HT29 cell death induced by E. histolytica. Suppression of Rac1 by siRNA significantly inhibited Entamoeba-induced cell death. Moreover, knockdown of NOX1 by siRNA, effectively inhibited E. histolytica-triggered DNA fragmentation in HT29 cells. These results suggest that NOX1-derived ROS is required for apoptotic cell death in HT29 colon epithelial cells induced by E. histolytica.

  13. Legislative Enforcement of Nonconsensual Determination of Neurological (Brain) Death in Muslim Patients: A Violation of Religious Rights.

    Science.gov (United States)

    Rady, Mohamed Y; Verheijde, Joseph L

    2017-10-24

    Death is defined in the Quran with a single criterion of irreversible separation of the ruh (soul) from the body. The Quran is a revelation from God to man, and the primary source of Islamic knowledge. The secular concept of death by neurological criteria, or brain death, is at odds with the Quranic definition of death. The validity of this secular concept has been contested scientifically and philosophically. To legitimize brain death for the purpose of organ donation and transplantation in Muslim communities, Chamsi-Pasha and Albar (concurring with the US President's Council on Bioethics) have argued that irreversible loss of capacity for consciousness and breathing (apneic coma) in brain death defines true death in accordance with Islamic sources. They have postulated that the absence of nafs (personhood) and nafas (breath) in apneic coma constitutes true death because of departure of the soul (ruh) from the body. They have also asserted that general anesthesia is routine in brain death before surgical procurement. Their argument is open to criticism because: (1) the ruh is described as the essence of life, whereas the nafs and nafas are merely human attributes; (2) unlike true death, the ruh is still present even with absent nafs and nafas in apneic coma; and (3) the routine use of general anesthesia indicates the potential harm to brain-dead donors from surgical procurement. Postmortem general anesthesia is not required for autopsy. Therefore, the conclusion must be that legislative enforcement of nonconsensual determination of neurological (brain) death and termination of life-support and medical treatment violates the religious rights of observant Muslims.

  14. How Heme Oxygenase-1 Prevents Heme-Induced Cell Death.

    Directory of Open Access Journals (Sweden)

    Lilibeth Lanceta

    Full Text Available Earlier observations indicate that free heme is selectively toxic to cells lacking heme oxygenase-1 (HO-1 but how this enzyme prevents heme toxicity remains unexplained. Here, using A549 (human lung cancer and immortalized human bronchial epithelial cells incubated with exogenous heme, we find knock-down of HO-1 using siRNA does promote the accumulation of cell-associated heme and heme-induced cell death. However, it appears that the toxic effects of heme are exerted by "loose" (probably intralysosomal iron because cytotoxic effects of heme are lessened by pre-incubation of HO-1 deficient cells with desferrioxamine (which localizes preferentially in the lysosomal compartment. Desferrioxamine also decreases lysosomal rupture promoted by intracellularly generated hydrogen peroxide. Supporting the importance of endogenous oxidant production, both chemical and siRNA inhibition of catalase activity predisposes HO-1 deficient cells to heme-mediated killing. Importantly, it appears that HO-1 deficiency somehow blocks the induction of ferritin; control cells exposed to heme show ~10-fold increases in ferritin heavy chain expression whereas in heme-exposed HO-1 deficient cells ferritin expression is unchanged. Finally, overexpression of ferritin H chain in HO-1 deficient cells completely prevents heme-induced cytotoxicity. Although two other products of HO-1 activity--CO and bilirubin--have been invoked to explain HO-1-mediated cytoprotection, we conclude that, at least in this experimental system, HO-1 activity triggers the induction of ferritin and the latter is actually responsible for the cytoprotective effects of HO-1 activity.

  15. [Two cases in which the presence of ciliospinal response led to indecisiveness in the evaluation of brain death].

    Science.gov (United States)

    Ikeda, H; Aruga, T; Hayashi, M; Miyake, Y; Sugimoto, K; Mastumoto, K

    1999-02-01

    The ciliospinal reflex was first described by Budge in 1852. This reflex is used as an indicator of brain stem and autonomic nervous system functioning. In the Japanese guideline for determining brain death, the absence of this reflex is considered essential. We reported two cases in which the ciliospinal responses judged to be present resulted in the authors' indecision in determining brain death. They were the cases of a 74-year-old woman who suffered a right putaminal hemorrhage and that of a 28 year-old male with severe head and cervical cord injury. Although brain death was suspected in both cases from its clinical courses, the fact that the ciliospinal reflex was present in each case kept us from declaring that these patients were in the state of brain death. The center of the ciliospinal reflex lies in the first three segments of the thoracic spinal segments and two pathways are involved in this reflex. A noxious stimulation to the face will be registered through the brain stem, but if stimulation is in the neck or upper trunk, it may go directly to the spinal center. Because of the latter pathway to the spinal center, this reflex might remain in patients in whom the brain stem is completely nonfunctioning. Therefore, the presence of this reflex dose not always preclude a state of brain death.

  16. Dialysis Disequilibrium Syndrome: Brain death following hemodialysis for metabolic acidosis and acute renal failure – A case report

    Directory of Open Access Journals (Sweden)

    Bagshaw Sean M

    2004-08-01

    Full Text Available Abstract Background Dialysis disequilibrium syndrome (DDS is the clinical phenomenon of acute neurologic symptoms attributed to cerebral edema that occurs during or following intermittent hemodialysis (HD. We describe a case of DDS-induced cerebral edema that resulted in irreversible brain injury and death following acute HD and review the relevant literature of the association of DDS and HD. Case Presentation A 22-year-old male with obstructive uropathy presented to hospital with severe sepsis syndrome secondary to pneumonia. Laboratory investigations included a pH of 6.95, PaCO2 10 mmHg, HCO3 2 mmol/L, serum sodium 132 mmol/L, serum osmolality 330 mosmol/kg, and urea 130 mg/dL (46.7 mmol/L. Diagnostic imaging demonstrated multifocal pneumonia, bilateral hydronephrosis and bladder wall thickening. During HD the patient became progressively obtunded. Repeat laboratory investigations showed pH 7.36, HCO3 19 mmol/L, potassium 1.8 mmol/L, and urea 38.4 mg/dL (13.7 mmol/L (urea-reduction-ratio 71%. Following HD, spontaneous movements were absent with no pupillary or brainstem reflexes. Head CT-scan showed diffuse cerebral edema with effacement of basal cisterns and generalized loss of gray-white differentiation. Brain death was declared. Conclusions Death is a rare consequence of DDS in adults following HD. Several features may have predisposed this patient to DDS including: central nervous system adaptations from chronic kidney disease with efficient serum urea removal and correction of serum hyperosmolality; severe cerebral intracellular acidosis; relative hypercapnea; and post-HD hemodynamic instability with compounded cerebral ischemia.

  17. Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ming-Ju Tsai

    2017-06-01

    Full Text Available Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p < 0.0001. Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2, up-regulation of Bcl-2 homologous antagonist/killer (Bak, and nuclear translocation of apoptosis-inducing factor (AIF in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1, protein kinase B (Akt, extracellular signal-regulated kinase 1/2 (Erk1/2, MAPK/Erk kinase (MEK, and proline-rich Akt substrate of 40-kDa (PRAS40, which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.

  18. Montelukast Induces Apoptosis-Inducing Factor-Mediated Cell Death of Lung Cancer Cells.

    Science.gov (United States)

    Tsai, Ming-Ju; Chang, Wei-An; Tsai, Pei-Hsun; Wu, Cheng-Ying; Ho, Ya-Wen; Yen, Meng-Chi; Lin, Yi-Shiuan; Kuo, Po-Lin; Hsu, Ya-Ling

    2017-06-24

    Developing novel chemo-prevention techniques and advancing treatment are key elements to beating lung cancer, the most common cause of cancer mortality worldwide. Our previous cohort study showed that cysteinyl leukotriene receptor antagonists, mainly montelukast, decreased the lung cancer risk in asthma patients. In the current study, we conducted in vivo and in vitro experiments to demonstrate the inhibiting effect of montelukast on lung cancer and to investigate the underlying mechanisms. Using Lewis lung carcinoma-bearing mice, we showed that feeding montelukast significantly delayed the tumor growth in mice (p Montelukast inhibited cell proliferation and colony formation and induced the cell death of lung cancer cells. Further investigation showed the down-regulation of B-cell lymphoma 2 (Bcl-2), up-regulation of Bcl-2 homologous antagonist/killer (Bak), and nuclear translocation of apoptosis-inducing factor (AIF) in montelukast-treated lung cancer cells. Montelukast also markedly decreased the phosphorylation of several proteins, such as with no lysine 1 (WNK1), protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (Erk1/2), MAPK/Erk kinase (MEK), and proline-rich Akt substrate of 40-kDa (PRAS40), which might contribute to cell death. In conclusion, montelukast induced lung cancer cell death via the nuclear translocation of AIF. This study confirmed the chemo-preventive effect of montelukast shown in our previous cohort study. The utility of montelukast in cancer prevention and treatment thus deserves further studies.

  19. Xylanse-Induced cell death events in detached tobacco leaves

    NARCIS (Netherlands)

    Yordanova, Z.P.; Kapchina-Toteva, V.M.; Woltering, E.J.; Batchvarova, R.B.; Yakimova, E.T.

    2009-01-01

    Plant-pathogen interactions are associated with plant defense mechanism known as hypersensitive response (HR), which is a form of programmed cell death (PCD). In the present work we have tested the potency of chemicals, proven as PCD inhibitors in other systems, to prevent the spread of cell death

  20. N-acetylcysteine effectively mitigates cadmium-induced oxidative damage and cell death in Leydig cells in vitro.

    Science.gov (United States)

    Khanna, Smita; Mitra, Sumonto; Lakhera, Pramesh C; Khandelwal, Shashi

    2016-01-01

    Cadmium (Cd) is known to cause severe damage to various organs including lung, liver, kidney, brain and reproductive system. Several studies have reported the induction of oxidative stress pathways following Cd exposure. Since oxidative stress is also deemed responsible for inducing male infertility, a growing worldwide concern, we tried to understand whether the antioxidant N-acetylcysteine (NAC) can be a potential therapeutic agent to counter Cd toxicity using primary Leydig cells. This study highlights the initial cellular alterations which culminate in cell death induction. Primary Leydig cells were isolated from 28-day-old male Wistar rats, exposed to various concentrations of Cd in vitro and biochemical and cell death parameters were evaluated to understand the effect of Cd. NAC pre-treatment was done to understand its protective efficacy. Following Cd exposure to Leydig cells in vitro, we found simultaneous intracellular calcium (Ca(2+)) increase and reduction in mitochondrial membrane polarization at 30 min, followed by significant induction of reactive oxygen species and MAPK-extracellular-regulated kinases with concurrent glutathione depletion at 1 h, and significant cell death (both necrotic and apoptotic) at 6 and 18 h, respectively. Pre-treatment with NAC abrogated all these toxic manifestations and showed significantly reduced cell death. NAC also rescued the expression of 3-βHSD, a major steroidogenic protein. Taken together, these data illustrated that NAC can be used as a potential protective agent against Cd-induced testicular toxicity, especially with regards to oxidative stress-induced Leydig cell toxicity.

  1. Advantages of analyzing postmortem brain samples in routine forensic drug screening-Case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD).

    Science.gov (United States)

    Mardal, Marie; Johansen, Sys Stybe; Thomsen, Ragnar; Linnet, Kristian

    2017-09-01

    Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma and urine when available. LSD, its main metabolite 2-oxo-3-hydroxy-LSD (oxo-HO-LSD), and iso-LSD were quantified in biological samples according to a previously published procedure involving liquid-liquid extraction and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). LSD was measured in the brain tissue of all presented cases at a concentration level from 0.34-10.8μg/kg. The concentration level in the target organ was higher than in peripheral blood. Additional psychoactive compounds were quantified in blood and brain tissue, though all below toxic concentration levels. The cause of death in case 1 was collision-induced brain injury, while it was drowning in case 2 and 3 and thus not drug intoxication. However, the toxicological findings could help explain the decedent's inability to cope with brain injury or drowning incidents. The presented findings could help establish reference concentrations in brain samples and assist in interpretation of results from forensic drug screening in brain tissue. This is to the author's knowledge the first report of LSD, iso-LSD, and oxo-HO-LSD measured in brain tissue samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. β-Amyloid precursor protein staining of the brain in sudden infant and early childhood death.

    Science.gov (United States)

    Jensen, Lisbeth Lund; Banner, Jytte; Ulhøi, Benedicte Parm; Byard, Roger W

    2014-06-01

    To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children. Archival cerebral tissue was examined from a total of 176 cases (0 to 3 years of age). Each of the APP-stained sections was graded according to a simple scoring system based on the number and type of changes in eight anatomical regions. Examination of the sections revealed some degree of APP staining in 95% of the cases. The highest mean APP scores were found in cases of head trauma, and the lowest scores were found in the cases of drowning. APP staining, although sometimes minimal, was found in all 48 cases of and sudden infant death syndrome (SIDS). Patterns of APP staining (the amount and distribution) were different in cases of head trauma, infection and SIDS but were similar in the SIDS and asphyxia groups. This study demonstrates the use of an integrated scoring system that was developed to assess APP staining in the brain. APP staining was seen in a high proportion of cases, including relatively sudden deaths. The amount of APP was significantly higher in cases of trauma than in nontraumatic deaths. However, APP was detected within all groups. The pattern of APP staining was similar in infants who had died of SIDS and from mechanical asphyxia. © 2013 British Neuropathological Society.

  3. Experiences of the families concerning organ donation of a family member with brain death

    Science.gov (United States)

    Yousefi, Hojatollah; Roshani, Asieh; Nazari, Fatemeh

    2014-01-01

    Background: In recent years, the lack of organ for transplantation has resulted in health planners and authorities in all countries, including Iran, paying serious attention to the issue. Despite the above-mentioned fact, families with a member affected by brain death are not interested in organ donation. Objective: This study is aimed at making an investigation into the decision-making process of organ donation in families with brain death. Also, the research is aimed at investigating how the deterrent and facilitating factors in the process of organ donation can be made. Materials and Methods: The current research is a qualitative study with descriptive exploratory approach. Data were collected through unstructured interviews with 10 family members who gave consent to organ donation of their family members in 2012. Purposeful sampling processes began in March 2012 and lasted up to June 2012. Simultaneously, thematic approach was used in analyzing the data. Results: Data analysis led to finding 24 categories and 11 themes, which fell into two categories: facilitating and deterrent factors. The five main deterrent themes included the five themes of prohibiting factors that were shock, hope for recovery, unknown process, and conflict of opinions, and worrying association. The six main facilitating themes included humanistic desires, immortality, culture making, satisfaction of the deceased, assurance, and eternal honor. Conclusion: The findings indicated that there is ambiguity and different interpretations on brain death. The research also showed that using the experiences of donator families can provide practical and applied solutions to facilitate the process of organ donation and solve the problems faced by the health care system. PMID:24949074

  4. Experiences of the families concerning organ donation of a family member with brain death.

    Science.gov (United States)

    Yousefi, Hojatollah; Roshani, Asieh; Nazari, Fatemeh

    2014-05-01

    In recent years, the lack of organ for transplantation has resulted in health planners and authorities in all countries, including Iran, paying serious attention to the issue. Despite the above-mentioned fact, families with a member affected by brain death are not interested in organ donation. This study is aimed at making an investigation into the decision-making process of organ donation in families with brain death. Also, the research is aimed at investigating how the deterrent and facilitating factors in the process of organ donation can be made. The current research is a qualitative study with descriptive exploratory approach. Data were collected through unstructured interviews with 10 family members who gave consent to organ donation of their family members in 2012. Purposeful sampling processes began in March 2012 and lasted up to June 2012. Simultaneously, thematic approach was used in analyzing the data. Data analysis led to finding 24 categories and 11 themes, which fell into two categories: facilitating and deterrent factors. The five main deterrent themes included the five themes of prohibiting factors that were shock, hope for recovery, unknown process, and conflict of opinions, and worrying association. The six main facilitating themes included humanistic desires, immortality, culture making, satisfaction of the deceased, assurance, and eternal honor. The findings indicated that there is ambiguity and different interpretations on brain death. The research also showed that using the experiences of donator families can provide practical and applied solutions to facilitate the process of organ donation and solve the problems faced by the health care system.

  5. Inhibition of telomerase causes vulnerability to endoplasmic reticulum stress-induced neuronal cell death.

    Science.gov (United States)

    Hosoi, Toru; Nakatsu, Kanako; Shimamoto, Akira; Tahara, Hidetoshi; Ozawa, Koichiro

    2016-08-26

    Endoplasmic reticulum (ER) stress is implicated in several diseases, such as cancer and neurodegenerative diseases. In the present study, we investigated the possible involvement of telomerase in ER stress-induced cell death. ER stress-induced cell death was ameliorated in telomerase reverse transcriptase (TERT) over-expressing MCF7 cells (MCF7-TERT cell). Telomerase specific inhibitor, BIBR1532, reversed the inhibitory effect of TERT on ER stress-induced cell death in MCF7-TERT cells. These findings suggest that BIBR1532 may specifically inhibit telomerase activity, thereby inducing cell death in ER stress-exposed cells. TERT was expressed in the SH-SY5Y neuroblastoma cell line. To analyze the possible involvement of telomerase in ER stress-induced neuronal cell death, we treated SH-SY5Y neuroblastoma cells with BIBR1532 and analyzed ER stress-induced cell death. We found that BIBR1532 significantly enhanced the ER stress-induced neuronal cell death. These findings suggest that inhibition of telomerase activity may enhance vulnerability to neuronal cell death caused by ER stress. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death.

    Science.gov (United States)

    Takabe, Wakako; Urano, Yasuomi; Vo, Diep-Khanh Ho; Shibuya, Kimiyuki; Tanno, Masaki; Kitagishi, Hiroaki; Fujimoto, Toyoshi; Noguchi, Noriko

    2016-11-01

    The 24(S)-hydroxycholesterol (24S-OHC), which plays an important role in maintaining brain cholesterol homeostasis, has been shown to possess neurotoxicity. We have previously reported that 24S-OHC esterification by ACAT1 and the resulting lipid droplet (LD) formation are responsible for 24S-OHC-induced cell death. In the present study, we investigate the functional roles of 24S-OHC esters and LD formation in 24S-OHC-induced cell death, and we identify four long-chain unsaturated fatty acids (oleic acid, linoleic acid, arachidonic acid, and DHA) with which 24S-OHC is esterified in human neuroblastoma SH-SY5Y cells treated with 24S-OHC. Here, we find that cotreatment of cells with 24S-OHC and each of these four unsaturated fatty acids increases prevalence of the corresponding 24S-OHC ester and exacerbates induction of cell death as compared with cell death induced by treatment with 24S-OHC alone. Using electron microscopy, we find in the present study that 24S-OHC induces formation of LD-like structures coupled with enlarged endoplasmic reticulum (ER) lumina, and that these effects are suppressed by treatment with ACAT inhibitor. Collectively, these results illustrate that ACAT1-catalyzed esterification of 24S-OHC with long-chain unsaturated fatty acid followed by formation of atypical LD-like structures at the ER membrane is a critical requirement for 24S-OHC-induced cell death. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  7. Vasopressina e morte encefálica Vasopressin and brain death

    Directory of Open Access Journals (Sweden)

    ELIANE DE ARAUJO CINTRA

    2000-03-01

    Full Text Available A morte encefálica (ME resulta numa perda completa dos mecanismos centrais de regulação da estabilidade hemodinâmica mesmo em pacientes com suporte adequado da ventilação, correção hidroeletrolítica e ácido-básica e suporte farmacológico convencional máximo da circulação. Acredita-se que a diminuição da vasopressina circulante influencia de maneira preponderante a estabilidade cardiocirculatória de pacientes com ME, sendo a sua administração exógena defendida por alguns autores no manuseio do potencial doador de órgãos. O artigo analisa e discute alguns estudos experimentais e clínicos relevantes em relação ao comportamento da vasopressina na ME e seu papel na manutenção da estabilidade cardiocirculatória, bem como sua potencial utilidade no manuseio destes pacientes. Desta análise concluímos que o comportamento da vasopressina na ME e o seu real valor na manutenção do potencial doador ainda não estão totalmente esclarecidos, necessitando de investigações futuras.Brain death results in the breakdown of effective central regulatory mechanisms of cardiocirculatory stability, even in patients with artificial mechanical ventilation, correction of electrolytic and acid-basic disorders and maximal conventional pharmacological support of the circulation. Recent evidences have shown that the fall of vasopressin levels in the blood circulation significantly influences the cardiocirculatory stability of patients with brain death, and its exogenous administration is defended by many authors for the management of multiorgan donor patients. In this brief review we analyse and discuss some experimental and clinical relevant studies about the role of vasopressin in the control of cardiocirculatory stability in brain death, and its potential usefulness in the management of multiorgan donor. We conclude that the role of vasopressin in the pathophysiology of brain death and its usefulness as a pharmacological agent in the

  8. Anencefalia e morte cerebral (neurológica Anencephaly and brain death

    Directory of Open Access Journals (Sweden)

    Maria Lúcia Fernandes Penna

    2005-06-01

    Full Text Available Vem-se discutindo no país a ética da interrupção da gravidez no caso de fetos anencéfalos. Os opositores ao aborto nesses casos apontam, entre outros argumentos, que não se trata de morte cerebral devido à presença de tronco encefálico. Neste artigo discutimos o conceito de morte cerebral e sua aplicação no que tange à anencefalia. Apontamos alguns aspectos históricos do desenvolvimento desse conceito e a importância de ser considerada a diferença entre conceito e critérios. A morte neurológica é a perda definitiva e total da consciência, enquanto a presença do tronco cerebral é apenas um critério a ser usado nos casos de lesão encefálica em encéfalos antes perfeitos. O conceito de morte cerebral se aplica completamente à ausência de córtex dos anencéfalos, o que sem dúvida permite sua retirada do útero materno. Manter juridicamente a criminalização desse procedimento é uma interferência religiosa no Estado laico e democrático, que impede o exercício de escolha pelos indivíduos segundo seu credo.Brazilian society has recently discussed the ethics of interrupting pregnancy in the case of an anencephalic fetus. In such cases, anti-abortionists contend that anencephaly is not the same as brain death, since a brainstem is present. This article discusses the concept of brain death and its application to the issue of anencephaly. We point to key historical aspects in the development of this concept and the importance of considering the difference between concept and criteria. Neurological death is the definitive and complete loss of consciousness, while the presence of a brainstem is merely a criterion to be used in cases of head injury in previously intact brains. The concept of brain death is totally applicable to the absence of cortex in a fetus with anencephaly, which without a doubt allows such a fetus to be removed from the uterus. To maintain the criminalization of this procedure by legal means represents

  9. miR-134 regulates ischemia/reperfusion injury-induced neuronal cell death by regulating CREB signaling.

    Science.gov (United States)

    Huang, Weidong; Liu, Xiaobin; Cao, Jie; Meng, Facai; Li, Min; Chen, Bo; Zhang, Jie

    2015-04-01

    microRNA-134 (miR-134) has been reported to be a brain-specific miRNA and is differently expressed in brain tissues subjected to ischemic injury. However, the underlying mechanism of miR-134 in regulating cerebral ischemic injury remains poorly understood. The current study was designed to delineate the molecular basis of miR-134 in regulating cerebral ischemic injury. Using the oxygen-glucose deprivation (OGD) model of hippocampal neuron ischemia in vitro, we found that the overexpression of miR-134 mediated by recombinant adeno-associated virus (AAV) vector infection significantly promoted neuron death induced by OGD/reoxygenation, whereas the inhibition of miR-134 provided protective effects against OGD/reoxygenation-induced cell death. Moreover, cyclic AMP (cAMP) response element-binding protein (CREB) as a putative target of miR-134 was downregulated and upregulated by miR-134 overexpression or inhibition, respectively. The direct interaction between miR-134 and the 3'-untranslated region (UTR) of CREB mRNA was further confirmed by dual-luciferase reporter assay. Overexpression of miR-134 also inhibited the expression of the downstream gene of CREB, including brain-derived neurotrophic factor (BDNF) and the anti-apoptotic gene Bcl-2, whereas the inhibition of miR-134 upregulated the expression of BDNF and Bcl-2 in neurons after OGD/reoxygenation. Notably, the knockdown of CREB by CREB siRNA apparently abrogated the protective effect of anti-miR-134 on OGD/reoxygenation-induced cell death. Taken together, our study suggests that downregulation of miR-134 alleviates ischemic injury through enhancing CREB expression and downstream genes, providing a promising and potential therapeutic target for cerebral ischemic injury.

  10. Survey Regarding Attitude of Family About Organ Donation After Brain Death in Korea.

    Science.gov (United States)

    Lee, Hyun Ji; Jin, Myung Jae; Han, Sang Youb; Han, Kum Hyun; Oh, Se Won; Jang, Hye-Yeon; Park, Ui Jun; Kim, Hyoung Tae; Roh, Young-Nam

    2017-10-27

    BACKGROUND This study examined the attitude of patients' relatives in South Korea toward organ donation after brain death. MATERIAL AND METHODS A structured questionnaire was used to obtain the information on the attitude toward organ donation for relatives of patients who were admitted to the surgical intensive care unit (SICU) between March 1, 2014 and September 30, 2016. In total, 92 persons participated voluntarily. The investigation included general opinion about organ donation; and additional categorical analysis was performed. RESULTS In this study, 75% of participants agreed that they had positive thoughts on organ donation; however, fewer participants (60.9%) showed a positive attitude towards donating their own body, while only a third of participants (38.1%) agreed that they would donate relatives' body. We could confirm specifically concerns about excessive physical damage during organ recovery (34.7%) and ignorance or disrespect by hospital staff (15.2%), as well as consideration of being sacrificed for the benefit of others (26.0%). The participants who agreed to donate relatives' body showed significantly different responses in each categories of the questionnaire compared to the participants who disagreed or were undecided. CONCLUSIONS Despite positive perceptions concerning organ donation after brain death, there were nonetheless several prejudices and misunderstandings to overcome. The findings of this study can be used to establish evidence-based strategies.

  11. Knowledge and attitudes toward brain death and organ donation in Bojnurd.

    Science.gov (United States)

    Hejazi, Sima Sadat; Nikbakht, Shima; Jouybari, Leila; Abadi, Mehdi Hares; Davoodi, Davood; Azizi, Tooba Hoseini; Yahyaei, Sepideh

    2017-07-01

    Organ donation in Iran is common. Bojnurd (North Khorasan, Iran) is a multi-ethnic city, and people with different religions and cultures live together and that could be associated with their behavior and attitude towards health-related issues. So far, no study has taken place on brain death and organ donation in the province of North Khorasan. The aim of this study was to determine the knowledge and attitudes of citizens of Bojnurd toward brain death and organ donation. This cross-sectional study was conducted from March to September 2014, on 380 Bojnurd citizens who were selected through multi-stage sampling. The tool was a researcher-made questionnaire in three parts (demographic information, awareness and attitude surveys), containing 10 questions on awareness and 18 questions on attitude. The questionnaire validity and reliability were confirmed by content validity and Cronbach's alpha (0.76). The data were analyzed by using SPSS version 16, using Chi-square, independent-samples t-test, and Spearman correlation coefficient. Significance level was set at porgan donation was moderate and the attitude toward organ donation in the majority (74.1%) was poor. In people with poor attitudes, awareness was also lower, and this was statistically significant (p=0.047). the attitude towards organ donation was negative in the majority of the citizens. In order to correct the beliefs, develop positive attitude and increase citizens' knowledge, public education is essential.

  12. Xenon protects against blast-induced traumatic brain injury in an in vitro model.

    Science.gov (United States)

    Campos-Pires, Rita; Koziakova, Mariia; Yonis, Amina; Pau, Ashni; Macdonald, Warren; Harris, Katie; Edge, Christopher; Franks, Nicholas P; Mahoney, Peter; Dickinson, Robert

    2017-12-29

    The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (pBlast-induced propidium iodide fluorescence overlapped with cleaved caspase 3 immunofluorescence, indicating that shockwave-induced cell death involves apoptosis. Xenon (50% atm) applied 1 hour following blast exposure reduced injury 24 hours (pblast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for blast-induced traumatic brain injury.

  13. Infrequent near death experiences in severe brain injury survivors - A quantitative and qualitative study.

    Science.gov (United States)

    Hou, Yongmei; Huang, Qin; Prakash, Ravi; Chaudhury, Suprakash

    2013-01-01

    Near death experiences (NDE) are receiving increasing attention by the scientific community because not only do they provide a glimpse of the complexity of the mind-brain interactions in 'near-death' circumstances but also because they have significant and long lasting effects on various psychological aspects of the survivors. The over-all incidence-reports of NDEs in literature have varied widely from a modest Figure of 10% to around 35%, even up to an incredible Figure of 72% in persons who have faced close brush with death. Somewhat similar to this range of difference in incidences are the differences prevalent in the opinions that theorists and researchers harbor around the world for explaining this phenomena. None the less, objective evidences have supported physiological theories the most. A wide range of physiological processes have been targeted for explaining NDEs. These include cerebral anoxia, chemical alterations like hypercapnia, presence of endorphins, ketamine, and serotonin, or abnormal activity of the temporal lobe or the limbic system. In spite of the fact that the physiological theories of NDEs have revolved around the derangements in brain, no study till date has taken up the task of evaluating the experiences of near-death in patients where specific injury has been to brain. Most of them have evaluated NDEs in cardiac-arrest patients. Post-traumatic coma is one such state regarding which the literature seriously lacks any information related to NDEs. Patients recollecting any memory of their post-traumatic coma are valuable assets for NDE researchers and needs special attention. Our present study was aimed at collecting this valuable information from survivors of severe head injury after a prolonged coma. The study was conducted in the head injury department of Guangdong 999 Brain hospital, Guangzhou, China. Patients included in the study were the ones Recovered from the posttraumatic coma following a severe head injury. A total of 86 patients

  14. Conserved metabolic energy production pathways govern Eiger/TNF-induced nonapoptotic cell death.

    Science.gov (United States)

    Kanda, Hiroshi; Igaki, Tatsushi; Okano, Hideyuki; Miura, Masayuki

    2011-11-22

    Caspase-independent cell death is known to be important in physiological and pathological conditions, but its molecular regulation is not well-understood. Eiger is the sole fly ortholog of TNF. The ectopic expression of Eiger in the developing eye primordium caused JNK-dependent but caspase-independent cell death. To understand the molecular basis of this Eiger-induced nonapoptotic cell death, we performed a large-scale genetic screen in Drosophila for suppressors of the Eiger-induced cell death phenotype. We found that molecules that regulate metabolic energy production are central to this form of cell death: it was dramatically suppressed by decreased levels of molecules that regulate cytosolic glycolysis, mitochondrial β-oxidation of fatty acids, the tricarboxylic acid cycle, and the electron transport chain. Importantly, reducing the expression of energy production-related genes did not affect the cell death triggered by proapoptotic genes, such as reaper, hid, or debcl, indicating that the energy production-related genes have a specific role in Eiger-induced nonapoptotic cell death. We also found that energy production-related genes regulate the Eiger-induced cell death downstream of JNK. In addition, Eiger induced the production of reactive oxygen species in a manner dependent on energy production-related genes. Furthermore, we showed that this cell death machinery is involved in Eiger's physiological function, because decreasing the energy production-related genes suppressed Eiger-dependent tumor suppression, an intrinsic mechanism for removing tumorigenic mutant clones from epithelia by inducing cell death. This result suggests a link between sensitivity to cell death and metabolic activity in cancer.

  15. An assessment of advance relatives approach for brain death organ donation.

    Science.gov (United States)

    Michaut, Carine; Baumann, Antoine; Gregoire, Hélène; Laviale, Corinne; Audibert, Gérard; Ducrocq, Xavier

    2017-01-01

    Advance announcement of forthcoming brain death has developed to enable intensivists and organ procurement organisation coordinators to more appropriately, and separately from each other, explain to relatives brain death and the subsequent post-mortem organ donation opportunity. Research aim: The aim was to assess how potentially involved healthcare professionals perceived ethical issues surrounding the strategy of advance approach. A multi-centre opinion survey using an anonymous self-administered questionnaire was conducted in the six-member hospitals of the publicly funded East of France regional organ and tissue procurement network called 'Prélor'. The study population comprised 460 physicians and nurses in the Neurosurgical, Surgical and Medical Intensive Care Units, the Stroke Units and the Emergency Departments. Ethical considerations: The project was approved by the board of the Lorraine University Diploma in Medical Ethics and the Prélor Network administrators. A slight majority of 53.5% of respondents had previously participated in an advance relatives approach: 83% of the physicians and 42% of the nurses. A majority of healthcare professionals (68%) think that the main justification for advance relatives approach is the comprehensive care of the dying patient and the research of his or her most likely opinion (74%). The misunderstanding of the related issues by relatives is an obstacle for 47% of healthcare professionals and 51% think that the answer given by the relatives regarding the most likely opinion of the person regarding post-mortem organ donation really corresponds to the person opinion in only 50% of the cases or less. Time given by advance approach should be employed to help and enable relatives to authentically bear the values and interests of the potential donor in the post-mortem organ donation discussion. Nurses' attendance of advance relatives approach seems necessary to enable them to optimally support the families facing death and

  16. Chronic Social Stress and Ethanol Increase Expression of KLF11, a Cell Death Mediator, in Rat Brain

    Science.gov (United States)

    Duncan, Jeremy; Wang, Niping; Zhang, Xiao; Johnson, Shakevia; Harris, Sharonda; Zheng, Baoying; Zhang, Qinli; Rajkowska, Grazyna; Miguel-Hidalgo, Jose Javier; Sittman, Donald; Ou, Xiao-Ming; Stockmeier, Craig A.; Wang, Jun Ming

    2015-01-01

    Major depressive disorder and alcoholism are significant health burdens that can affect executive functioning, cognitive ability, job responsibilities, and personal relationships. Studies in animal models related to depression or alcoholism reveal that the expression of Krüppel-like factor 11 (KLF11, also called TIEG2) is elevated in frontal cortex, which suggests that KLF11 may play a role in stress- or ethanol-induced psychiatric conditions. KLF11 is a transcriptional activator of monoamine oxidase (MAO) A and B, but also serves other functions in cell cycle regulation and apoptotic cell death. In the present study, immunohistochemistry was used to quantify intensity of nuclear KLF11, combined with an unbiased stereological approach to assess nuclei in fronto-limbic, limbic, and other brain regions of rats exposed chronically to social defeat or ethanol. KLF11 immunoreactivity was increased significantly in the medial prefrontal cortex, frontal cortex and hippocampus of both stressed rats and rats fed ethanol. However, expression of KLF11 protein was not significantly affected in the thalamus, hypothalamus or amygdala in either treatment group compared to respective control rats. Triple-label immunofluorescence revealed that KLF11 protein was localized in nuclei of neurons and astrocytes. KLF11 was also co-localized with the immunoreactivity of cleaved caspase 3. In addition, Western blot analysis revealed a significant reduction in anti-apoptotic protein, Bcl-xL, but an increase of caspase-3 expression in the frontal cortex of ethanol-treated rats compared to ethanol-preferring controls. Thus, KLF11 protein is up-regulated following chronic exposure to stress or ethanol in a region-specific manner and may contribute to pro-apoptotic signaling in ethanol-treated rats. Further investigation into the KLF11 signaling cascade as a mechanism for neurotoxicity and cell death in depression and alcoholism may provide novel pharmacological targets to lessen brain damage

  17. Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid.

    Science.gov (United States)

    Zhang, Dongxian; Lee, Brian; Nutter, Anthony; Song, Paul; Dolatabadi, Nima; Parker, James; Sanz-Blasco, Sara; Newmeyer, Traci; Ambasudhan, Rajesh; McKercher, Scott R; Masliah, Eliezer; Lipton, Stuart A

    2015-06-01

    Cyanide is a life-threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species. This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain barrier to up-regulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain. Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2). © 2015 International Society for Neurochemistry.

  18. Cloning and expression of the programmed cell death regulator Bad in the rat brain.

    Science.gov (United States)

    D'Agata, V; Magro, G; Travali, S; Musco, S; Cavallaro, S

    1998-02-27

    The Bcl-2 family of proteins consists of both antagonists (e.g. Bcl-2) and agonists (e.g. Bax) that regulate apoptosis and compete through dimerization. In the present study we cloned the cDNA encoding the rat brain BAD, a distant member of the Bcl-2 family that was shown to promote cell death. The cloned cDNA encoded a protein of 205 amino acids, containing three putative Bcl-2 homology domains (BH1, BH2 and BH3) and no C-terminal signal-anchor sequence. The predicted amino acid sequence was identical to the Bad-cDNA recently cloned from the rat ovary with the exception of a stretch of six amino acids, thus indicating the existence of two Bad alternative splice variants or a sequence artifact in the rat ovary Bad-cDNA. Immunohistochemical analysis in the rat brain revealed the exclusive expression of Bad in the epithelial cells of the choroid plexus, a result which is consistent with a very specialized function of Bad in the brain.

  19. Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice.

    Science.gov (United States)

    Izuo, Naotaka; Nojiri, Hidetoshi; Uchiyama, Satoshi; Noda, Yoshihiro; Kawakami, Satoru; Kojima, Shuji; Sasaki, Toru; Shirasawa, Takuji; Shimizu, Takahiko

    2015-01-01

    Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2(-/-)) using nestin-Cre-loxp system. B-Sod2(-/-) showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

  20. Quality of Care of Nursing from Brain Death Patient in ICU Wards

    Directory of Open Access Journals (Sweden)

    Seyedeh Toktam Masoumian Hoseini

    2015-04-01

    Full Text Available Introduction: Nowadays, Intensive Care Unit (ICU nurses play a significant and key role in the care of brain dead patients and their families, therefore their Practice extremely important to the success of organ donation. To assess ICU nurse's practice in relation to nurse's role in the organ donation process from brain dead patients in Iran. Materials and Methods:In a cross-sectional analytical study 90 ICU nurses in Ghaem and Imam Reza Hospitals in Mashhad through stratified random sampling allocation method were selected. Data collection tools included a questionnaire on demographic information, factors influencing nurse's practice during the organ donation process and surveying "nurse's practice in relation to their roles in the organ donation process." Results: 90 nurses participated in this study. (70.0% of the research subjects had spoken with their own families about organ donation, and (20.0% had organ donation cards. Practice scores were calculated on a scale of 100. The mean score of nurses' practice was (6.04± 3.66. 96.7% of nurses’ weak practice in terms of their roles in the organ donation process. Conclusion: As a result, they do not have adequate practice regard nurse's role in organ donation process and in relation to brain death patient and their families. Therefore it is suggested to include nursing courses in the organ donation process and organ transplantation as well as educational programs to acquaint nurses with their roles in the process to improve their practice by different training methods.

  1. Nitrates in drinking water and the risk of death from brain cancer: does hardness in drinking water matter?

    Science.gov (United States)

    Ho, Chi-Kung; Yang, Ya-Hui; Yang, Chun-Yuh

    2011-01-01

    The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and risk of death from brain cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the influence of nitrates on development of brain cancer. A matched cancer case-control study was used to investigate the relationship between the risk of death from brain cancer and exposure to nitrates in drinking water in Taiwan. All brain cancer deaths of Taiwan residents from 2003 through 2008 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO₃-N), Ca, and Mg in drinking water was obtained from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO₃-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO₃-N exposure level was water with a NO₃-N exposure ≥ 0.38 ppm. No marked effect modification was observed due to Ca and Mg intake via drinking water on brain cancer occurrence.

  2. Traumatic brain injury-induced sleep disorders

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    Viola-Saltzman M

    2016-02-01

    Full Text Available Mari Viola-Saltzman, Camelia Musleh Department of Neurology, NorthShore University HealthSystem, Evanston, IL, USA Abstract: Sleep disturbances are frequently identified following traumatic brain injury, affecting 30%–70% of persons, and often occur after mild head injury. Insomnia, fatigue, and sleepiness are the most frequent sleep complaints after traumatic brain injury. Sleep apnea, narcolepsy, periodic limb movement disorder, and parasomnias may also occur after a head injury. In addition, depression, anxiety, and pain are common brain injury comorbidities with significant influence on sleep quality. Two types of traumatic brain injury that may negatively impact sleep are acceleration/deceleration injuries causing generalized brain damage and contact injuries causing focal brain damage. Polysomnography, multiple sleep latency testing, and/or actigraphy may be utilized to diagnose sleep disorders after a head injury. Depending on the disorder, treatment may include the use of medications, positive airway pressure, and/or behavioral modifications. Unfortunately, the treatment of sleep disorders associated with traumatic brain injury may not improve neuropsychological function or sleepiness. Keywords: traumatic brain injury, insomnia, hypersomnia, sleep apnea, periodic limb movement disorder, fatigue

  3. Meeting the needs of the family: the role of the specialist nurse in the management of brain death.

    Science.gov (United States)

    Coyle, M A

    2000-02-01

    Clinical nurse specialist roles have existed in the USA for many years, yet here in the UK such roles are a relatively new concept for nurses and the profession of nursing. In the UK clinical nurse specialists have worked primarily in outpatient settings, however, the role is rapidly developing in primary care and specialized care settings. One specific dimension of the clinical nurse specialist role in critical care relates to the needs of the family when brain-stem death is suspected. This concept of death--brain death--is very difficult for most people to comprehend as it challenges all our previous beliefs concerning death and dying. During this traumatic time nurses and other health care professionals face the daunting task of supporting the family through this enforced emotional crisis as they attempt to come to terms with the diagnosis of clinical brain death. To enable families to understand brain death and the implications and outcomes of such a diagnosis it is vital they receive information, support and guidance from experienced health care personnel. The following account is a discussion of the key role of the specialist nurse in relation to meeting the needs of the families of brain-stem dead patients. This review seeks to highlight the clear dimensions of the clinical nurse specialist role within a critical care setting. It relates specifically to meeting the needs of families who have experienced clinical brain death in an immediate family member. It suggests that the infinite value of the role must be acknowledged and utilized to ensure the provision of holistic care for patients and families at this traumatic time.

  4. Hydrogen Peroxide-induced Cell Death in Arabidopsis : Transcriptional and Mutant Analysis Reveals a Role of an Oxoglutarate-dependent Dioxygenase Gene in the Cell Death Process

    NARCIS (Netherlands)

    Gechev, Tsanko S.; Minkov, Ivan N.; Hille, Jacques

    2005-01-01

    Hydrogen peroxide is a major regulator of plant programmed cell death (PCD) but little is known about the downstream genes from the H2O2-signaling network that mediate the cell death. To address this question, a novel system for studying H2O2-induced programmed cell death in Arabidopsis thaliana was

  5. Infrequent near death experiences in severe brain injury survivors - A quantitative and qualitative study

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    Yongmei Hou

    2013-01-01

    Full Text Available Background: Near death experiences (NDE are receiving increasing attention by the scientific community because not only do they provide a glimpse of the complexity of the mind-brain interactions in ′near-death′ circumstances but also because they have significant and long lasting effects on various psychological aspects of the survivors. The over-all incidence-reports of NDEs in literature have varied widely from a modest Figure of 10% to around 35%, even up to an incredible Figure of 72% in persons who have faced close brush with death. Somewhat similar to this range of difference in incidences are the differences prevalent in the opinions that theorists and researchers harbor around the world for explaining this phenomena. None the less, objective evidences have supported physiological theories the most. A wide range of physiological processes have been targeted for explaining NDEs. These include cerebral anoxia, chemical alterations like hypercapnia, presence of endorphins, ketamine, and serotonin, or abnormal activity of the temporal lobe or the limbic system. In spite of the fact that the physiological theories of NDEs have revolved around the derangements in brain, no study till date has taken up the task of evaluating the experiences of near-death in patients where specific injury has been to brain. Most of them have evaluated NDEs in cardiac-arrest patients. Post-traumatic coma is one such state regarding which the literature seriously lacks any information related to NDEs. Patients recollecting any memory of their post-traumatic coma are valuable assets for NDE researchers and needs special attention. Materials and Methods: Our present study was aimed at collecting this valuable information from survivors of severe head injury after a prolonged coma. The study was conducted in the head injury department of Guangdong 999 Brain hospital, Guangzhou, China. Patients included in the study were the ones Recovered from the posttraumatic

  6. Postresuscitative Changes of Brain-Derived Neurotrophic Factor (BDNF Protein Expression: Association With Neuronal Death

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    M. Sh. Avrushchenko

    2017-01-01

    Full Text Available Aim of the study: to evaluate expression level of BDNF and its association with the postresuscitative neuronal death in highly hypoxia-sensitive brain regions.Materials and methods. Cardiac arrest in adult albino male rats was evoked by intrathoracic clamping of supracardiac bundle of vessels for 10 min. Pyramidal neurons of the hippocampus and Purkinje cells of the cerebellum were analyzed at various time points after resuscitation (days 1, 4, 7, 14. Shame-operated rats served as controls. The expression of BDNF protein was immunohistochemically determined. The BDNF expression level was determined by evalution on the base of the average optical density. The number of neurons with different BDNF expression levels and the total number of neurons per 1 mm of the layer length were computed. Image analysis systems (Intel personal computer, Olympus BX-41 microscope, ImageScopeM, ImageJ 1,48v and MS Excel 2007 software packages were used in the study. Data statistical processing was performed with the aid of Statistica 7.0 program and Kolmogorov-Smirnov λ-test, Mann-Whitney U-test and Student's t-test.Results. The dynamics of postresuscitative shifts of BDNF immunoreactivity in neuronal populations of hippocampal pyramidal cells and cerebellar Purkinje cells was established. It was shown that the level of BDNF expression within the two neuronal populations decreased, that was accompanied by neuronal death. In the Purkinje cell population the neuronal death occurred by the 4th day after resuscitation, while in the hippocampus, it occurs only by the 7th day. Notably, only BDNF-negative neurons or neurons with low level of BDNF expression died in both neuronal populations.Conclusion. The results of the study indicate the existence of an interrelation between the shifts in BDNF expression and the postresuscitative neuronal death. It was shown that only the cells with none or poor BDNF expression underwent death in highly hypoxia-sensitive neuronal

  7. Inhibition of apoptic cell death induced by Pseudomonas syringae pv. Tabaci and mycotoxin fumonisin B1

    NARCIS (Netherlands)

    Iakimova, E.T.; Batchvorova, R.; Kapchina, V.; Popov, T.; Atanassov, A.; Woltering, E.J.

    2004-01-01

    The impact of programmed cell death (PCD) inhibitors on lesion formation and biochemical events in transgenic (ttr line) and non-transgenic (Nevrokop 1164) tobacco infected with Pseudomonas syringae pv. tabaci was tested. Programmed cell death in tomato cell culture was induced by Fumonisin B1 (FUM)

  8. Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line

    Science.gov (United States)

    Thomas, Andrew J.; Hailey, Dale W.; Stawicki, Tamara M.; Wu, Patricia; Coffin, Allison B.; Rubel, Edwin W.; Raible, David W.; Simon, Julian A.; Ou, Henry C.

    2013-01-01

    Cisplatin, one of the most commonly used anti-cancer drugs, is known to cause inner ear hair cell damage and hearing loss. Despite much investigation into mechanisms of cisplatin-induced hair cell death, little is known about the mechanism whereby cisplatin is selectively toxic to hair cells. Using hair cells of the zebrafish lateral line, we found that chemical inhibition of mechanotransduction with quinine and EGTA protected against cisplatin-induced hair cell death. Furthermore, we found that the zebrafish mutants mariner (myo7aa) and sputnik (cad23) that lack functional mechanotransduction were resistant to cisplatin-induced hair cell death. Using a fluorescent analogue of cisplatin, we found that chemical or genetic inhibition of mechanotransduction prevented its uptake. These findings demonstrate that cisplatin-induced hair cell death is dependent on functional mechanotransduction in the zebrafish lateral line. PMID:23467357

  9. Mechanisms of Virus-Induced Neural Cell Death

    Science.gov (United States)

    2005-03-01

    K. K. Wang. Mattmann, and J. Tschopp. 1999. Equine herpesvirus-2 Eli) gene product, 1999. Procaspase-3 and poly(ADP)ribose polymerase (PARP) are...manifestations. The drocyte nuclei of 12 (80%) of 15 brain pression, hypersensitivity syndromes, and next most common presentation is with specimens

  10. Transcranial Doppler ultrasound in the diagnosis of brain death. Is it useful or does it delay the diagnosis?

    Science.gov (United States)

    Escudero, D; Otero, J; Quindós, B; Viña, L

    2015-05-01

    Transcranial Doppler ultrasound is able to demonstrate cerebral circulatory arrest associated to brain death, being especially useful in sedated patients, or in those in which complete neurological exploration is not possible. Transcranial Doppler ulstrasound is a portable, noninvasive and high-availability technique. Among its limitations, mention must be made of the absence of acoustic windows and false-negative cases. In patients clinically diagnosed with brain death, with open skulls or with anoxia as the cause of death, cerebral blood flow can be observed by ultrasound, since cerebral circulatory arrest is not always synchronized to the clinical diagnosis. The diagnostic rate is therefore time-dependent, and this fact that must be recognized in order to avoid delays in death certification. Despite its limitations, transcranial Doppler ulstrasound helps solve common diagnostic problems, avoids the unnecessary consumption of resources, and can optimize organ harvesting for transplantation. Copyright © 2014 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

  11. Polish Guidelines on Diagnosing Brain Death in Adults vs the International Perspective: Are We in Need of an Update?

    Science.gov (United States)

    Nowak, E; Pfitzner, R; Przybyłowski, P

    2016-06-01

    The Polish definition of brain death originated from the original Harvard criteria and has been revised several times. Practitioners worldwide are required to regularly update their national guidelines on the definition of brain death to fit the latest international research concerning this topic. (1) Compare current Polish guidelines on diagnosing brain death in adults with the American, British, Australian, and New Zealand recommendations; and (2) evaluate existing differences for the purposes of updating the Polish guidelines. Current guidelines on diagnosing brain death published by The American Academy of Neurology (USA, 2010), the Academy of Medical Royal Colleges (United Kingdom, 2008), the Australian and New Zealand Intensive Care Society (AU/NZ, 2013), and the Polish Ministry of Health (Poland, 2007). All guidelines outline similar recommendations regarding the need for a suitable observation period before clinical examination and for basic medical conditions and exclusions to be evaluated before testing, the obligatory role of clinical examination including brain stem reflexes and apnea testing, and the nonobligatory role of ancillary tests. There is no consensus regarding: the recommended time period of pretesting observation, the number, seniority, and specialty of clinicians performing the testing, the role of additional exclusion criteria, the repeatability of clinical tests, the methodology of apnea testing, and recommended confirmatory tests. Current Polish guidelines on diagnosing brain death in adults remain up-to-date in comparison to the guidelines analyzed, though additional recommendations concerning apnea testing, drug and toxin clearance, and medical exclusion criteria for potential brain dead patients might be considered an important point of interest in the future. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. An institutional study of awareness of brain-death declaration among resident doctors for cadaver organ donation

    Directory of Open Access Journals (Sweden)

    Vaishali Mohod

    2017-01-01

    Full Text Available Background and Aims: Brain death is defined as irreversible and complete cessation of all brain function including that of the brainstem. The aim of this study was to assess the level of knowledge and awareness about brain-death declaration among resident doctors. Methods: This was an observational questionnaire-based study conducted in single institute in which 112 junior residents and 46 senior resident doctors in various medical specialities were included by universal sampling method. A prevalidated questionnaire consisting of questions related to knowledge, attitude and performance of brain-death declaration were distributed among residents as per the inclusion criteria to fill in the time limit of 30 min. Statistical tools used were mean and standard deviation, proportion and Chi-square test. Results: A total 87 resident doctors consisting of 71.26% males and 28.73% females responded to the questionnaire. About 91.95% correctly defined it as complete cessation of brain activity including brainstem reflexes. Most of the resident doctors (80.45% knew about the documentation of absence of brainstem reflexes at 6 h intervals and 64.36% were aware about positive apnoea test. When asked about whether there is legal sanction for disconnecting life support in India, 56.32% said no, and 43.67% said yes. Only 12.64% of resident doctors were aware about a panel of 4 physicians are mandatory to declare brain death in India. Conclusion: Awareness and attitude towards the identification of brain death and possible deceased donor organ transplantation were lacking amongst resident doctors.

  13. Design of coupling parameters for inducing amplitude death in Cartesian product networks of delayed coupled oscillators

    Science.gov (United States)

    Sugitani, Yoshiki; Konishi, Keiji

    2017-10-01

    The present study investigates amplitude death in Cartesian product networks of two subnetworks, where each subnetwork has a different coupling delay. The property of the Cartesian product helps us to analyze the stability of amplitude death. Our analysis reveals that amplitude death can occur for long coupling delays if there is a suitable difference in the coupling delays in the two subnetworks. Furthermore, based on the edge theorem in robust control theory, we propose two design procedures of coupling parameters for inducing amplitude death in the Cartesian product networks. Our procedures do not require any information of topologies of the subnetworks. The validity of these procedures is numerically confirmed.

  14. Chemotherapy induces death receptor 5 in epithelial ovarian carcinoma

    NARCIS (Netherlands)

    Arts, HJG; de Jong, S; Hollema, H; ten Hoor, K; van der Zee, AGJ; de Vries, EGE

    Objectives. Defects in the apoptotic pathway are a general cause for drug resistance. Chemotherapy in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be an effective strategy to induce apoptosis in vitro in ovarian tumor cells. Systemic TRAIL

  15. Brain stem death as the vital determinant for resumption of spontaneous circulation after cardiac arrest in rats.

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    Alice Y W Chang

    Full Text Available BACKGROUND: Spontaneous circulation returns to less than half of adult cardiac arrest victims who received in-hospital resuscitation. One clue for this disheartening outcome arises from the prognosis that asystole invariably takes place, after a time lag, on diagnosis of brain stem death. The designation of brain stem death as the point of no return further suggests that permanent impairment of the brain stem cardiovascular regulatory machinery precedes death. It follows that a crucial determinant for successful revival of an arrested heart is that spontaneous circulation must resume before brain stem death commences. Here, we evaluated the hypothesis that maintained functional integrity of the rostral ventrolateral medulla (RVLM, a neural substrate that is intimately related to brain stem death and central circulatory regulation, holds the key to the vital time-window between cardiac arrest and resumption of spontaneous circulation. METHODOLOGY/PRINCIPAL FINDINGS: An animal model of brain stem death employing the pesticide mevinphos as the experimental insult in Sprague-Dawley rats was used. Intravenous administration of lethal doses of mevinphos elicited an abrupt cardiac arrest, accompanied by elevated systemic arterial pressure and anoxia, augmented neuronal excitability and enhanced microvascular perfusion in RVLM. This period represents the vital time-window between cardiac arrest and resumption of spontaneous circulation in our experimental model. Animals with restored spontaneous circulation exhibited maintained neuronal functionality in RVLM beyond this critical time-window, alongside resumption of baseline tissue oxygen and enhancement of local blood flow. Intriguingly, animals that subsequently died manifested sustained anoxia, diminished local blood flow, depressed mitochondrial electron transport activities and reduced ATP production, leading to necrotic cell death in RVLM. That amelioration of mitochondrial dysfunction and

  16. Potential brain death organ donors - challenges and prospects: A single center retrospective review

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    Yousef Al-Maslamani

    2014-01-01

    Full Text Available Organ donation after brain death (BD is a major source for obtaining transplantable organs for patients with end-stage organ disease (ESOD. This retrospective, descriptive study was carried out on all potential BD patients admitted in different intensive care units (ICUs of the Hamad medical Corporation (HMC, Doha, Qatar during a period from January 2011 to April 2012. Our aim was to evaluate various demographic criteria and challenges of organ donation among potential BD organ donors and plan a strategy to improve the rate of organ donation in Qatar. Various aspects of BD patients in the ICUs and their possible effects on organ donation were studied. The time intervals analyzed to determine the possible causes of delay of organ retrieval were: time of diagnosing fixed dilated pupils in the ICU, to performing the first BD test, then to the second BD test, to family approach, to organ retrieval and/or circulatory death (CD without organ retrieval. There were a total of 116 potential BD organ donors of whom 96 (82.75% were males and 20 (17.25% were females. Brain hemorrhage and head injury contributed to 37 (31.9% and 32 (27.6% BD cases, respectively. Time interval between diagnosing fixed dilated pupil and performing the first test of BD was delayed >24 h in 79% of the cases and between the first and second BD tests was >6 h in 70.8% of the cases. This delay is not compatible with the Hamad Medical Corporation (HMC policy for BD diagnosis and resulted in a low number of organs retrieved. BD organ donation, a potential source for organs to save patients with ESOD has several pitfalls and every effort should be made to increase the awareness of the public as well as medical personnel to optimize donation efficacy.

  17. Ayanin diacetate-induced cell death is amplified by TRAIL in human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Marrero, Maria Teresa; Estevez, Sara; Negrin, Gledy; Quintana, Jose [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain); Lopez, Mariana; Perez, Francisco J.; Triana, Jorge [Departamento de Quimica, Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigacion del Cancer, 35017 Las Palmas de Gran Canaria (Spain); Leon, Francisco [Instituto de Productos Naturales y Agrobiologia, Consejo Superior de Investigaciones Cientificas, Avda. Astrofisico F. Sanchez 3, 38206 La Laguna, Tenerife (Spain); Estevez, Francisco, E-mail: festevez@dbbf.ulpgc.es [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain)

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer Ayanin diacetate as apoptotic inducer in leukemia cells. Black-Right-Pointing-Pointer Cell death was prevented by caspase inhibitors and by the overexpression of Bcl-x{sub L}. Black-Right-Pointing-Pointer The intrinsic and the extrinsic pathways are involved in the mechanism of action. Black-Right-Pointing-Pointer Death receptors are up-regulated and TRAIL enhances apoptotic cell death. -- Abstract: Here we demonstrate that the semi-synthetic flavonoid ayanin diacetate induces cell death selectively in leukemia cells without affecting the proliferation of normal lymphocytes. Incubation of human leukemia cells with ayanin diacetate induced G{sub 2}-M phase cell cycle arrest and apoptosis which was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by the overexpression of Bcl-x{sub L}. Ayanin diacetate-induced cell death was found to be associated with: (i) loss of inner mitochondrial membrane potential, (ii) the release of cytochrome c, (iii) the activation of multiple caspases, (iv) cleavage of poly(ADP-ribose) polymerase and (v) the up-regulation of death receptors for TRAIL, DR4 and DR5. Moreover, the combined treatment with ayanin diacetate and TRAIL amplified cell death, compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

  18. TOR regulates cell death induced by telomere dysfunction in budding yeast.

    Directory of Open Access Journals (Sweden)

    Haiyan Qi

    Full Text Available Telomere dysfunction is known to induce growth arrest (senescence and cell death. However, the regulation of the senescence-death process is poorly understood. Here using a yeast dysfunctional telomere model cdc13-1, which carries a temperature sensitive-mutant telomere binding protein Cdc13p, we demonstrate that inhibition of TOR (Target of Rapamycin, a central regulator of nutrient pathways for cell growth, prevents cell death, but not growth arrest, induced by inactivation of Cdc13-1p. This function of TOR is novel and separable from its G1 inhibition function, and not associated with alterations in the telomere length, the amount of G-tails, and the telomere position effect (TPE in cdc13-1 cells. Furthermore, antioxidants were also shown to prevent cell death initiated by inactivation of cdc13-1. Moreover, inhibition of TOR was also shown to prevent cell death induced by inactivation of telomerase in an est1 mutant. Interestingly, rapamycin did not prevent cell death induced by DNA damaging agents such as etoposide and UV. In the aggregate, our results suggest that the TOR signaling pathway is specifically involved in the regulation of cell death initiated by telomere dysfunction.

  19. The 'window of opportunity' for death after severe brain injury: family experiences.

    Science.gov (United States)

    Kitzinger, Jenny; Kitzinger, Celia

    2013-09-01

    This article builds on and develops the emerging bioethics literature on the 'window of opportunity' for allowing death by withholding or withdrawing treatment. Our findings are drawn from in-depth interviews with 26 people (from 14 different families) with severely brain injured relatives. These interviews were specifically selected from a larger study on the basis of interviewees' reports that their relatives would not have wanted to be kept alive in their current condition (e.g. in vegetative or minimally conscious states). Our analysis tracks the decision-making processes that have led to the situation in which life-sustaining treatments continue to be delivered to these patients--maintaining them in a state that some families describe as a 'fate worse than death'. We show how the medico-legal 'window of opportunity' for allowing the patient to die structures family experience and fails to deliver optimal outcomes for patients. We end with some suggestions for change. © 2012 The Authors. Sociology of Health & Illness © 2012 Foundation for the Sociology of Health & Illness/JohnWiley & Sons Ltd. Published by John Wiley & Sons Ltd.

  20. Hypernatremia severity and the risk of death after traumatic brain injury.

    Science.gov (United States)

    Li, M; Hu, Y H; Chen, G

    2013-09-01

    To investigate the relationship between severity of hypernatremia and the risk of death for patients with traumatic brain injury (TBI) who have been admitted to the neurosurgical intensive care unit (NICU). A total of 1044 patients with TBI were admitted to our NICU from January 2005 to January 2010. Of these patients, 881 were included in this study. Based on blood serum sodium level in the NICU the 881 patients were divided into four groups: 614 had normal serum sodium (Nahypernatremia (Na 150-hypernatremia (Na 155-160mmol/L) and 167 had severe hypernatremia (Na≥160mmol/L). The mortality rates for the mild, moderate, and severe hypernatremia groups were 20.6%, 42.4%, and 86.8%, respectively; the mortality rate for the normal group was 2.0%. In multivariable analysis, mild, moderate, and severe hypernatremia were independent risk factors for mortality; compared with the normal group the odds ratios of mild, moderate, and severe hypernatremia were 9.50, 4.34, and 29.35, respectively. Severe hypernatremia is an independent risk factor with extremely high odds ratio for death in patients with TBI who are admitted to the NICU. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Australian emergency doctors' and nurses' acceptance and knowledge regarding brain death: a national survey.

    Science.gov (United States)

    Marck, Claudia H; Weiland, Tracey J; Neate, Sandra L; Hickey, Bernadette B; Jelinek, George A

    2012-01-01

    Healthcare staff's acceptance of brain death (BD) being a valid determination of death is essential for optimized organ and tissue donation (OTD) rates. Recently, resources to increase Australian OTD rates have been aimed at emergency departments (ED) as a significant missed donor potential was discovered. A cross-sectional survey was conducted to assess Australian ED clinicians' acceptance and knowledge regarding BD. Most (86%) of the 599 medical and 212 nursing staff accepted BD, but only 60% passed a 5-item-validated BD knowledge tool. BD knowledge was related to the acceptance of BD. Accepting BD influenced attitudes toward OTD, including willingness to donate. BD acceptance and knowledge were related to education/training regarding OTD, years of experience in EDs, experience with OTD-related tasks, and increased perceived competence and comfort with OTD-related tasks. Of concern, more than half of respondents who did not pass the BD test reported feeling competent and comfortable explaining BD to next of kin; of respondents who had recent experience with this, more than a third failed the BD test. Despite being generally positive toward OTD, Australian ED clinicians do not have a sound knowledge of BD. This may be hampering efforts to increase donation rates from the ED. © 2012 John Wiley & Sons A/S.

  2. Inhibition of the autophagy flux by gingerol enhances TRAIL-induced tumor cell death.

    Science.gov (United States)

    Nazim, Uddin Md; Jeong, Jae-Kyo; Seol, Jae-Won; Hur, Jin; Eo, Seong-Kug; Lee, John-Hwa; Park, Sang-Youel

    2015-05-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a primary anticancer agent and a member of the tumor necrosis factor family that selectively induces apoptosis in various tumor cells, but not in normal cells. Gingerol is a major ginger component with anti-inflammatory and anti‑tumorigenic activities. Autophagy flux is the complete process of autophagy, in which the autophagosomes are lysed by lysosomes. The role of autophagy in cell death or cell survival is controversial. A549 adenocarcinoma cells are TRAIL-resistant. In the present study, we showed that treatment with TRAIL slightly induced cell death, but gingerol treatment enhanced the TRAIL-induced cell death in human lung cancer cells. The combination of gingerol and TRAIL increased accumulation of microtubule-associated protein light chain 3-II and p62, confirming the inhibited autophagy flux. Collectively, our results suggest that gingerol sensitizes human lung cancer cells to TRAIL-induced apoptosis by inhibiting the autophagy flux.

  3. Bacoside A Induces Tumor Cell Death in Human Glioblastoma Cell Lines through Catastrophic Macropinocytosis

    Directory of Open Access Journals (Sweden)

    Sebastian John

    2017-06-01

    Full Text Available Glioblastoma multiforme (GBM is a highly aggressive type of brain tumor with an extremely poor prognosis. Recent evidences have shown that the “biomechanical imbalances” induced in GBM patient-derived glioblastoma cells (GC and in vivo via the administration of synthetic small molecules, may effectively inhibit disease progression and prolong survival of GBM animal models. This novel concept associated with de novo anti-GBM drug development has however suffered obstacles in adequate clinical utility due to the appearance of unrelated toxicity in the prolonged therapeutic windows. Here, we took a “drug repurposing approach” to trigger similar physico-chemical disturbances in the GBM tumor cells, wherein, the candidate therapeutic agent has been previously well established for its neuro-protective roles, safety, efficacy, prolonged tolerance and excellent brain bioavailability in human subjects and mouse models. In this study, we show that the extracts of an Indian traditional medicinal plant Bacopa monnieri (BM and its bioactive component Bacoside A can generate dosage associated tumor specific disturbances in the hydrostatic pressure balance of the cell via a mechanism involving excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A enzyme that is further involved in the release of calcium from the smooth endoplasmic reticular networks. High intracellular calcium stimulated massive macropinocytotic extracellular fluid intake causing cell hypertrophy in the initial stages, excessive macropinosome enlargement and fluid accumulation associated organellar congestion, cell swelling, cell rounding and membrane rupture of glioblastoma cells; with all these events culminating into a non-apoptotic, physical non-homeostasis associated glioblastoma tumor cell death. These results identify glioblastoma tumor cells to be a specific target of the tested herbal medicine and therefore can be exploited as a safe anti

  4. Bacoside A Induces Tumor Cell Death in Human Glioblastoma Cell Lines through Catastrophic Macropinocytosis.

    Science.gov (United States)

    John, Sebastian; Sivakumar, K C; Mishra, Rashmi

    2017-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumor with an extremely poor prognosis. Recent evidences have shown that the "biomechanical imbalances" induced in GBM patient-derived glioblastoma cells (GC) and in vivo via the administration of synthetic small molecules, may effectively inhibit disease progression and prolong survival of GBM animal models. This novel concept associated with de novo anti-GBM drug development has however suffered obstacles in adequate clinical utility due to the appearance of unrelated toxicity in the prolonged therapeutic windows. Here, we took a "drug repurposing approach" to trigger similar physico-chemical disturbances in the GBM tumor cells, wherein, the candidate therapeutic agent has been previously well established for its neuro-protective roles, safety, efficacy, prolonged tolerance and excellent brain bioavailability in human subjects and mouse models. In this study, we show that the extracts of an Indian traditional medicinal plant Bacopa monnieri (BM) and its bioactive component Bacoside A can generate dosage associated tumor specific disturbances in the hydrostatic pressure balance of the cell via a mechanism involving excessive phosphorylation of calcium/calmodulin-dependent protein kinase IIA (CaMKIIA/CaMK2A) enzyme that is further involved in the release of calcium from the smooth endoplasmic reticular networks. High intracellular calcium stimulated massive macropinocytotic extracellular fluid intake causing cell hypertrophy in the initial stages, excessive macropinosome enlargement and fluid accumulation associated organellar congestion, cell swelling, cell rounding and membrane rupture of glioblastoma cells; with all these events culminating into a non-apoptotic, physical non-homeostasis associated glioblastoma tumor cell death. These results identify glioblastoma tumor cells to be a specific target of the tested herbal medicine and therefore can be exploited as a safe anti-GBM therapeutic.

  5. Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013.

    Science.gov (United States)

    Taylor, Christopher A; Bell, Jeneita M; Breiding, Matthew J; Xu, Likang

    2017-03-17

    Traumatic brain injury (TBI) has short- and long-term adverse clinical outcomes, including death and disability. TBI can be caused by a number of principal mechanisms, including motor-vehicle crashes, falls, and assaults. This report describes the estimated incidence of TBI-related emergency department (ED) visits, hospitalizations, and deaths during 2013 and makes comparisons to similar estimates from 2007. 2007 and 2013. State-based administrative health care data were used to calculate estimates of TBI-related ED visits and hospitalizations by principal mechanism of injury, age group, sex, and injury intent. Categories of injury intent included unintentional (motor-vehicle crashes, falls, being struck by or against an object, mechanism unspecified), intentional (self-harm and assault/homicide), and undetermined intent. These health records come from the Healthcare Cost and Utilization Project's National Emergency Department Sample and National Inpatient Sample. TBI-related death analyses used CDC multiple-cause-of-death public-use data files, which contain death certificate data from all 50 states and the District of Columbia. In 2013, a total of approximately 2.8 million TBI-related ED visits, hospitalizations, and deaths (TBI-EDHDs) occurred in the United States. This consisted of approximately 2.5 million TBI-related ED visits, approximately 282,000 TBI-related hospitalizations, and approximately 56,000 TBI-related deaths. TBIs were diagnosed in nearly 2.8 million (1.9%) of the approximately 149 million total injury- and noninjury-related EDHDs that occurred in the United States during 2013. Rates of TBI-EDHDs varied by age, with the highest rates observed among persons aged ≥75 years (2,232.2 per 100,000 population), 0-4 years (1,591.5), and 15-24 years (1,080.7). Overall, males had higher age-adjusted rates of TBI-EDHDs (959.0) compared with females (810.8) and the most common principal mechanisms of injury for all age groups included falls (413.2, age

  6. Factors Associated with a Family's Delay of Decision for Organ Donation After Brain Death.

    Science.gov (United States)

    Han, Sang Youb; Kim, Jae Il; Lee, Eun-Woo; Jang, Hye-Yeon; Han, Kum Hyun; Oh, Se Won; Roh, Young-Nam

    2017-01-17

    BACKGROUND This study aimed to explore the factors associated with a family's delay of decision for organ donation after brain death, and to investigate the effect of such a delay on organ donation. MATERIAL AND METHODS Medical records and data on counseling about organ donation with the families of 107 brain-dead potential donors between September 2012 and March 2016 at a single tertiary medical center were retrospectively reviewed. RESULTS The final consent rate was 58% (62/107), and successful donation was performed in 40% (43/107). Ninety-two families (86%) made a decision within 48 hours, whereas 15 (14%) required more than 48 hours for a final decision. In univariate and multivariate analyses, the independent factors associated with a decision delay were mean arterial pressure ≤60 mm Hg and coma therapy. In the early decision group (donation rates were 55% (51/92) and 39% (36/92), respectively, whereas in the delayed decision group (≥48 hours), these rates were 73% (11/15) and 47% (7/15), respectively. The consent and successful donation rates were not inferior in the delayed decision group. CONCLUSIONS These findings justify continuous efforts to maintain organ viability and to extend counseling to encourage donation even if the family cannot decide immediately.

  7. Neuroprotective effects of nitric oxide donor NOC-18 against brain ischemia-induced mitochondrial damages: role of PKG and PKC.

    Science.gov (United States)

    Arandarcikaite, Odeta; Jokubka, Ramunas; Borutaite, Vilmante

    2015-01-23

    In this study we sought to determine whether NO donor NOC-18 can protect brain mitochondria against ischemia-induced dysfunction, particularly opening of mitochondrial permeability transition pore (MPTP), and cell death. We found that inhibition of respiration with NAD-dependent substrates, but not with succinate, was observed after 30 min ischemia indicating that complex I of the mitochondrial respiratory chain is the primary site affected by ischemia. There was no loss of mitochondrial cytochrome c during 30-120 min of brain ischemia. Prolonged, 90 min ischemia substantially decreased calcium retention capacity of brain mitochondria suggesting sensitization of mitochondria to Ca(2+)-induced MPTP opening, and this was prevented by NOC-18 infusion prior to ischemia. NOC-18 did not prevent ischemia-induced inhibition of mitochondrial respiration, however, it partially protected against ischemia-induced necrosis. Protective effects of NOC-18 were abolished in the presence of selective inhibitors of protein kinase G (PKG) and protein kinase C (PKC). These results indicate that pre-treatment with NOC-18 protected brain mitochondria against ischemia-induced MPTP opening by decreasing mitochondrial sensitivity to calcium and partly protected brain cells against necrotic death in PKG- and PKC-depending manner. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. NADPH Oxidase Activation Contributes to Heavy Ion Irradiation–Induced Cell Death

    Directory of Open Access Journals (Sweden)

    Yupei Wang

    2017-03-01

    Full Text Available Increased oxidative stress plays an important role in heavy ion radiation–induced cell death. The mechanism involved in the generation of elevated reactive oxygen species (ROS is not fully illustrated. Here we show that NADPH oxidase activation is closely related to heavy ion radiation–induced cell death via excessive ROS generation. Cell death and cellular ROS can be greatly reduced in irradiated cancer cells with the preincubation of diphenyleneiodium, an inhibitor of NADPH oxidase. Most of the NADPH oxidase (NOX family proteins (NOX1, NOX2, NOX3, NOX4, and NOX5 showed increased expression after heavy ion irradiation. Meanwhile, the cytoplasmic subunit p47phox was translocated to the cell membrane and localized with NOX2 to form reactive NADPH oxidase. Our data suggest for the first time that ROS generation, as mediated by NADPH oxidase activation, could be an important contributor to heavy ion irradiation–induced cell death.

  9. Traumatic brain injury and obesity induce persistent central insulin resistance.

    Science.gov (United States)

    Karelina, Kate; Sarac, Benjamin; Freeman, Lindsey M; Gaier, Kristopher R; Weil, Zachary M

    2016-04-01

    Traumatic brain injury (TBI)-induced impairments in cerebral energy metabolism impede tissue repair and contribute to delayed functional recovery. Moreover, the transient alteration in brain glucose utilization corresponds to a period of increased vulnerability to the negative effects of a subsequent TBI. In order to better understand the factors contributing to TBI-induced central metabolic dysfunction, we examined the effect of single and repeated TBIs on brain insulin signalling. Here we show that TBI induced acute brain insulin resistance, which resolved within 7 days following a single injury but persisted until 28 days following repeated injuries. Obesity, which causes brain insulin resistance and neuroinflammation, exacerbated the consequences of TBI. Obese mice that underwent a TBI exhibited a prolonged reduction of Akt (also known as protein kinase B) signalling, exacerbated neuroinflammation (microglial activation), learning and memory deficits, and anxiety-like behaviours. Taken together, the transient changes in brain insulin sensitivity following TBI suggest a reduced capacity of the injured brain to respond to the neuroprotective and anti-inflammatory actions of insulin and Akt signalling, and thus may be a contributing factor for the damaging neuroinflammation and long-lasting deficits that occur following TBI. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  10. Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells.

    Science.gov (United States)

    Jung, So Young; Lee, Kang-Woo; Choi, Sun-Mi; Yang, Eun Jin

    2015-09-21

    Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A₂. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death.

  11. Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells

    Directory of Open Access Journals (Sweden)

    So Young Jung

    2015-09-01

    Full Text Available Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A2. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death.

  12. N-methyl bases of ethanolamine prevent apoptotic cell death induced by oxidative stress in cells of oligodendroglia origin.

    Science.gov (United States)

    Brand, A; Gil, S; Yavin, E

    2000-04-01

    A major reason for brain tissue vulnerability to oxidative damage is the high content of polyunsaturated fatty acids (PUFAs). Oligodendroglia-like OLN 93 cells lack PUFAs and are relatively insensitive to oxidative stress. When grown in serum-free defined medium in the presence of 0.1 mM docosahexaenoic acid (DHA; 22:6 n-3) for 3 days, OLN 93 cells release in the medium 2.6-fold more thiobarbituric acid-reactive substances (TBARS) after a 30-min exposure to 0.1 mM H2O2 and 50 microM Fe2+. Release of TBARS was substantially decreased by approximately 20 and 30% on coincubation with either 1 mM N-monomethylethanolamine or N,N'-dimethylethanolamine (dEa), respectively. The protective effect of dEa was concentration- and time-dependent and was still visible after dEa removal, suggesting a long-lasting mechanism of protection. After 24 h following H2O2-induced stress, cell death monitored by cell sorting showed 16% of the cells in the sub-G1 area, indicative of apoptotic cell death. DHA-supplemented cultures showed 35% cell death, whereas cosupplements with dEa reduced cell death to 12%, indicating cell rescue. Although the exact mechanism for this protection is not known, the nature of the polar head group and the degree of unsaturation may determine the ultimate resistance of nerve cells to oxidative stress.

  13. Protective effect of pyruvate against ethanol-induced apoptotic neurodegeneration in the developing rat brain.

    Science.gov (United States)

    Ullah, Najeeb; Naseer, Muhammad Imran; Ullah, Ikram; Lee, Hae Young; Koh, Phil Ok; Kim, Myeong Ok

    2011-12-01

    Exposure to alcohol during the early stages of brain development can lead to neurological disorders in the CNS. Apoptotic neurodegeneration due to ethanol exposure is a main feature of alcoholism. Exposure of developing animals to alcohol (during the growth spurt period in particular) elicits apoptotic neuronal death and causes fetal alcohol effects (FAE) or fetal alcohol syndrome (FAS). A single episode of ethanol intoxication (at 5 g/kg) in a seven-day-old developing rat can activate the apoptotic cascade, leading to widespread neuronal death in the brain. In the present study, we investigated the potential protective effect of pyruvate against ethanol-induced neuroapoptosis. After 4h, a single dose of ethanol induced upregulation of Bax, release of mitochondrial cytochrome-c into the cytosol, activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP-1), all of which promote apoptosis. These effects were all reversed by co-treatment with pyruvate at a well-tolerated dosage (1000 mg/kg). Histopathology performed at 24 and 48 h with Fluoro-Jade-B and cresyl violet stains showed that pyruvate significantly reduced the number of dead cells in the cerebral cortex, hippocampus and thalamus. Immunohistochemical analysis at 24h confirmed that ethanol-induced cell death is both apoptotic and inhibited by pyruvate. These findings suggest that pyruvate treatment attenuates ethanol-induced neuronal cell loss in the developing rat brain and holds promise as a safe therapeutic and neuroprotective agent in the treatment of neurodegenerative disorders in newborns and infants. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. Cyclic Mechanical Stretching Induces Autophagic Cell Death in Tenofibroblasts Through Activation of Prostaglandin E2 Production

    Directory of Open Access Journals (Sweden)

    Hua Chen

    2015-04-01

    Full Text Available Background/Aims: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2, a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs in vitro. Methods: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles and the expression of LC3-II and BECN1 (by western blot. Stretching-induced PGE2 release was determined by ELISA. Results: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching-induced autophagy and cell death. Conclusion: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production.

  15. Betulinic acid induces cell death by necrosis in Trypanosoma cruzi.

    Science.gov (United States)

    Sousa, Paloma Leão; Souza, Racquel Oliveira da Silva; Tessarolo, Louise Donadello; de Menezes, Ramon Róseo Paula Pessoa Bezerra; Sampaio, Tiago Lima; Canuto, Jader Almeida; Martins, Alice Maria Costa

    2017-10-01

    Chagas' disease is a neglected disease caused by the protozoan parasite Trypanosoma cruzi and constitutes a serious health problem worldwide. The treatment is limited, with variable efficacy of benznidazole and nifurtimox. Betulinic Acid (BA), a triterpene, can be found in medicinal herbs and has a wide variety of biological and pharmacological activities. The objective was to evaluate betulinic acid effects on the cell death mechanism in Trypanosoma cruzi strain Y. BA inhibited the growth of epimastigotes in periods of 24h (IC 50 =73.43μM), 48h (IC 50 =119.8μM) and 72h (IC 50 =212.2μM) of incubation; of trypomastigotes (IC 50 =51.88μM) in periods of 24h and intracellular amastigotes (IC 50 =25.94μM) in periods of 24 and 48h of incubation, no toxicity on LLC-MK 2 cells at the concentrations used. Analysis of the possible mechanism of parasite cell death showed alterations in mitochondrial membrane potential, alterations in cell membrane integrity, an increase in the formation of reactive oxygen species and increase swelling of the reservosomes. In conclusion, betulinic acid was be able to inhibition all developmental forms of Trypanosoma cruzi Y strain with necrotic mechanism and involvement of mitochondrial membrane potential alteration and increase in reactive oxygen species. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. CHIP has a protective role against oxidative stress-induced cell death through specific regulation of Endonuclease G

    Science.gov (United States)

    Lee, J S; Seo, T W; Yi, J H; Shin, K S; Yoo, S J

    2013-01-01

    Oxidative stress is implicated in carcinogenesis, aging, and neurodegenerative diseases. The E3 ligase C terminus of Hsc-70 interacting protein (CHIP) has a protective role against various stresses by targeting damaged proteins for proteasomal degradation, and thus maintains protein quality control. However, the detailed mechanism by which CHIP protects cells from oxidative stress has not been demonstrated. Here, we show that depletion of CHIP led to elevated Endonuclease G (EndoG) levels and enhanced cell death upon oxidative stress. In contrast, CHIP overexpression reduced EndoG levels, and resulted in reduced or no oxidative stress-induced cell death in cancer cells and primary rat cortical neurons. Under normal conditions Hsp70 mediated the interaction between EndoG and CHIP, downregulating EndoG levels in a Hsp70/proteasome-dependent manner. However, under oxidative stress Hsp70 no longer interacted with EndoG, and the stabilized EndoG translocated to the nucleus and degraded chromosomal DNA. Our data suggest that regulation of the level of EndoG by CHIP in normal conditions may determine the sensitivity to cell death upon oxidative stress. Indeed, injection of H2O2 into the rat brain markedly increased cell death in aged mice compared with young mice, which correlated with elevated levels of EndoG and concurrent downregulation of CHIP in aged mice. Taken together, our findings demonstrate a novel protective mechanism of CHIP against oxidative stress through regulation of EndoG, and provide an opportunity to modulate oxidative stress-induced cell death in cancer and aging. PMID:23764847

  17. Technical aids in the diagnosis of brain death: a comparison of SEP, AEP, EEG, TCD and CT angiography.

    Science.gov (United States)

    Welschehold, Stefan; Boor, Stephan; Reuland, Katharina; Thömke, Frank; Kerz, Thomas; Reuland, André; Beyer, Christian; Gartenschläger, Martin; Wagner, Wolfgang; Giese, Alf; Müller-Forell, Wibke

    2012-09-01

    The use of technical aids to confirm brain death is a controversial matter. Angiography with the intra-arterial administration of contrast medium is the international gold standard, but it is not allowed in Germany except in cases where it provides a potential mode of treatment. The currently approved tests in Germany are recordings of somatosensory evoked potentials (SSEP), brain perfusion scintigraphy, transcranial Doppler ultrasonography (TCD), and electroencephalography (EEG). CT angiography (CTA), a promising new alternative, is being increasingly used as well. In a prospective, single-center study that was carried out from 2008 to 2011, 71 consecutive patients in whom brain death was diagnosed on clinical grounds underwent recording of auditory evoked potentials (AEP) and SSEP as well as EEG, TCD and CTA. The validity of CTA for the confirmation of brain death was 94%; the validity of the other tests was: 94% for EEG, 92% for TCD, 82% for SSEP, and 2% for AEP. In 61 of the 71 patients (86%), the EEG, TCD and CTA findings all accorded with the clinical diagnosis. The diagnosis of brain death was established beyond doubt in all patients. In this study, the technical aids yielded discordant results in 14% of cases, necessitating interpretation by an expert examiner. The perfusion tests, in particular, can give false-positive results in patients with large cranial defects, skull fractures, or cerebrospinal fluid drainage. In such cases, electrophysiologic tests or a repeated clinical examination should be performed instead. CTA is a promising, highly reliable new method for demonstrating absent intracranial blood flow. In our view, it should be incorporated into the German guidelines for the diagnosis of brain death.

  18. Crystalline structure of pulverized dental calculus induces cell death in oral epithelial cells.

    Science.gov (United States)

    Ziauddin, S M; Yoshimura, A; Montenegro Raudales, J L; Ozaki, Y; Higuchi, K; Ukai, T; Kaneko, T; Miyazaki, T; Latz, E; Hara, Y

    2017-11-20

    Dental calculus is a mineralized deposit attached to the tooth surface. We have shown that cellular uptake of dental calculus triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, leading to the processing of the interleukin-1β precursor into its mature form in mouse and human phagocytes. The activation of the NLRP3 inflammasome also induced a lytic form of programmed cell death, pyroptosis, in these cells. However, the effects of dental calculus on other cell types in periodontal tissue have not been investigated. The aim of this study was to determine whether dental calculus can induce cell death in oral epithelial cells. HSC-2 human oral squamous carcinoma cells, HOMK107 human primary oral epithelial cells and immortalized mouse macrophages were exposed to dental calculus or 1 of its components, hydroxyapatite crystals. For inhibition assays, the cells were exposed to dental calculus in the presence or absence of cytochalasin D (endocytosis inhibitor), z-YVAD-fmk (caspase-1 inhibitor) or glyburide (NLRP3 inflammasome inhibitor). Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release and staining with propidium iodide. Tumor necrosis factor-α production was quantified by enzyme-linked immunosorbent assay. Oral epithelial barrier function was examined by permeability assay. Dental calculus induced cell death in HSC-2 cells, as judged by LDH release and propidium iodide staining. Dental calculus also induced LDH release from HOMK107 cells. Following heat treatment, dental calculus lost its capacity to induce tumor necrosis factor-α in mouse macrophages, but could induce LDH release in HSC-2 cells, indicating a major role of inorganic components in cell death. Hydroxyapatite crystals also induced cell death in both HSC-2 and HOMK107 cells, as judged by LDH release, indicating the capacity of crystal particles to induce cell death. Cell death induced by dental

  19. D-galactose-induced brain ageing model

    DEFF Research Database (Denmark)

    Sadigh-Eteghad, Saeed; Majdi, Alireza; McCann, Sarah K.

    2017-01-01

    Animal models are commonly used in brain ageing research. Amongst these, models where rodents are exposed to d-galactose are held to recapitulate a number of features of ageing including neurobehavioral and neurochemical changes. However, results from animal studies are often inconsistent...

  20. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

    Directory of Open Access Journals (Sweden)

    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  1. Drosophila Chk2 and p53 proteins induce stage -specific cell death independently during oogenesis

    Science.gov (United States)

    Bakhrat, Anna; Pritchett, Tracy; Peretz, Gabriella; McCall, Kimberly; Abdu, Uri

    2011-01-01

    In Drosophila, the checkpoint protein-2 kinase (DmChk2) and its downstream effector protein, Dmp53, are required for DNA damage-mediated cell cycle arrest, DNA repair and apoptosis. In this study we focus on understanding the function of these two apoptosis inducing factors during ovarian development. We found that expression of Dmp53, but not DmChk2, led to loss of ovarian stem cells. We demonstrate that expression of DmChk2, but not Dmp53, induced mid-oogenesis cell death. DmChk2 induced cell death was not suppressed by Dmp53 mutant, revealing for the first time that in Drosophila, overexpression of DmChk2 can induce cell death which is independent of Dmp53. We found that over-expression of caspase inhibitors such as DIAP1, p35 and p49 did not suppress DmChk2- and Dmp53-induced cell death. Thus, our study reveals stage -specific effects of Dmp53 and DmChk2 in oogenesis. Moreover, our results demonstrate that although DmChk2 and Dmp53 affect different stages of ovarian development, loss of ovarian stem cells by p53 expression and mid-oogenesis cell death induced by DmChk2 do not require caspase activity. PMID:20838898

  2. Cadmium-induced programmed cell death signaling in tomato suspension cells

    NARCIS (Netherlands)

    Yakimova, E.T.; Woltering, E.J.; Kapchina-Toteva, V.M.

    2009-01-01

    Here we present a summary of our study on cadmium-induced cell death signaling in a model system of suspension-cultured tomato cells. Exposure of the cells to CdSO4 induced typical for PCD (cytoplasm shrinkage and nuclear condensation) morphological changes of the dead cells. Ethylene and hydrogen

  3. Renaissance of criticism on the concept of brain death--the role of legal medicine in the context of the interdisciplinary discussion.

    Science.gov (United States)

    Markert, L; Bockholdt, B; Verhoff, M A; Heinze, S; Parzeller, M

    2016-03-01

    In the practice of legal medicine in Germany, the assessment of brain death is of minor importance and attracts little attention. However, since several years, international criticism on the concept of brain death has culminated. By reviewing literature and the results of a questionnaire distributed among the participants of the 93rd Annual Congress of the Germany Society of Legal Medicine, the state of knowledge and the current views on brain death were evaluated. Literature search of recent publications regarding brain death was performed (PubMed database, references of legal medicine, Report of the President's Council on Bioethics, USA 2008). A questionnaire was developed and distributed among the participants of the Congress. The assumption that individual and brain death are synonymous is criticized. Internationally, there are trends to harmonize the very different clinical criteria to assess brain death. The diagnostic advantage of novel techniques such as CT angiography is controversially discussed. It becomes apparent that procedures which record the blood flow and perfusion of the brain will be applied more in the future. Regrettably, these developments are not described in the literature of legal medicine. Moreover, among German forensic scientists, different views concerning brain death exist. The majority favors its equivalent treatment with individual death. The thanatological background can be improved concerning certain aspects of brain death as well as its legal implications. Teaching and research in legal medicine should include the subject brain death. Expertise in forensic science may contribute to the interdisciplinary discussion on brain death. The transfer of actual knowledge, also on disputed ethical aspects of thanatology, to physicians of all disciplines is of great importance.

  4. Isosorbide delays gentamicin-induced vestibular sensory cell death.

    Science.gov (United States)

    Takumida, Masaya; Anniko, Matti

    2005-01-01

    The efficacy of isosorbide for protection from vestibular sensory cell damage was investigated. The effects of isosorbide on gentamicin-induced production of nitric oxide (NO) and reactive oxygen species (ROS) were studied by means of the fluorescence indicators 4,5-diaminofluorescein diacetate and dihydrotetramethylrosamine. The effect on gentamicin-induced vestibular sensory cell damage was examined by using an in vitro LIVE/DEAD system. Isosorbide inhibited the production of both NO and ROS. Isosorbide limited the vestibular sensory cell damage caused by gentamicin. It is, therefore, suggested that isosorbide may help to treat inner ear disorders.

  5. Omega-3 docosahexaenoic acid induces pyroptosis cell death in triple-negative breast cancer cells.

    Science.gov (United States)

    Pizato, Nathalia; Luzete, Beatriz Christina; Kiffer, Larissa Fernanda Melo Vasconcelos; Corrêa, Luís Henrique; de Oliveira Santos, Igor; Assumpção, José Antônio Fagundes; Ito, Marina Kiyomi; Magalhães, Kelly Grace

    2018-01-31

    The implication of inflammation in pathophysiology of several type of cancers has been under intense investigation. Omega-3 fatty acids can modulate inflammation and present anticancer effects, promoting cancer cell death. Pyroptosis is an inflammation related cell death and so far, the function of docosahexaenoic acid (DHA) in pyroptosis cell death has not been described. This study investigated the role of DHA in triggering pyroptosis activation in breast cancer cells. MDA-MB-231 breast cancer cells were supplemented with DHA and inflammation cell death was analyzed. DHA-treated breast cancer cells triggered increased caspase-1and gasdermin D activation, enhanced IL-1β secretion, translocated HMGB1 towards the cytoplasm, and membrane pore formation when compared to untreated cells, suggesting DHA induces pyroptosis programmed cell death in breast cancer cells. Moreover, caspase-1 inhibitor (YVAD) could protect breast cancer cells from DHA-induced pyroptotic cell death. In addition, membrane pore formation showed to be a lysosomal damage and ROS formation-depended event in breast cancer cells. DHA triggered pyroptosis cell death in MDA-MB-231by activating several pyroptosis markers in these cells. This is the first study that shows the effect of DHA triggering pyroptosis programmed cell death in breast cancer cells and it could improve the understanding of the omega-3 supplementation during breast cancer treatment.

  6. Early events in kidney donation : Progression of endothelial activation, oxidative stress and tubular injury after brain death

    NARCIS (Netherlands)

    Morariu, Aurora M.; Schuurs, Theo A.; Leuvenink, Henri G. D.; van Oeveren, Wim; Rakhorst, Gerhard; Ploeg, Rutger J.

    Cerebral injury leading to brain death (BD) causes major physiologic derangements in potential organ donors, which may result in vascular-endothelial activation and affect posttransplant graft function. We investigated the kinetic of pro-coagulatory and pro-inflammatory endothelial activation and

  7. Staphylococcus aureus induces eosinophil cell death mediated by α-hemolysin.

    Directory of Open Access Journals (Sweden)

    Lynne R Prince

    Full Text Available Staphylococcus aureus, a major human pathogen, exacerbates allergic disorders, including atopic dermatitis, nasal polyps and asthma, which are characterized by tissue eosinophilia. Eosinophils, via their destructive granule contents, can cause significant tissue damage, resulting in inflammation and further recruitment of inflammatory cells. We hypothesised that the relationship between S. aureus and eosinophils may contribute to disease pathology. We found that supernatants from S. aureus (SH1000 strain cultures cause rapid and profound eosinophil necrosis, resulting in dramatic cell loss within 2 hours. This is in marked contrast to neutrophil granulocytes where no significant cell death was observed (at equivalent dilutions. Supernatants prepared from a strain deficient in the accessory gene regulator (agr that produces reduced levels of many important virulence factors, including the abundantly produced α-hemolysin (Hla, failed to induce eosinophil death. The role of Hla in mediating eosinophil death was investigated using both an Hla deficient SH1000-modified strain, which did not induce eosinophil death, and purified Hla, which induced concentration-dependent eosinophil death via both apoptosis and necrosis. We conclude that S. aureus Hla induces aberrant eosinophil cell death in vitro and that this may increase tissue injury in allergic disease.

  8. Staphylococcus aureus induces eosinophil cell death mediated by α-hemolysin.

    Science.gov (United States)

    Prince, Lynne R; Graham, Kirstie J; Connolly, John; Anwar, Sadia; Ridley, Robert; Sabroe, Ian; Foster, Simon J; Whyte, Moira K B

    2012-01-01

    Staphylococcus aureus, a major human pathogen, exacerbates allergic disorders, including atopic dermatitis, nasal polyps and asthma, which are characterized by tissue eosinophilia. Eosinophils, via their destructive granule contents, can cause significant tissue damage, resulting in inflammation and further recruitment of inflammatory cells. We hypothesised that the relationship between S. aureus and eosinophils may contribute to disease pathology. We found that supernatants from S. aureus (SH1000 strain) cultures cause rapid and profound eosinophil necrosis, resulting in dramatic cell loss within 2 hours. This is in marked contrast to neutrophil granulocytes where no significant cell death was observed (at equivalent dilutions). Supernatants prepared from a strain deficient in the accessory gene regulator (agr) that produces reduced levels of many important virulence factors, including the abundantly produced α-hemolysin (Hla), failed to induce eosinophil death. The role of Hla in mediating eosinophil death was investigated using both an Hla deficient SH1000-modified strain, which did not induce eosinophil death, and purified Hla, which induced concentration-dependent eosinophil death via both apoptosis and necrosis. We conclude that S. aureus Hla induces aberrant eosinophil cell death in vitro and that this may increase tissue injury in allergic disease.

  9. Effect of sesaminol glucosides on beta-amyloid-induced PC12 cell death through antioxidant mechanisms.

    Science.gov (United States)

    Lee, Sun Young; Ha, Tae Youl; Son, Dong Ju; Kim, Sung Ran; Hong, Jin Tae

    2005-08-01

    Several lines of evidence support that beta-amyloid (Abeta)-induced neurotoxicity is mediated through the generation of reactive oxygen species (ROS) and elevation of intracellular calcium. In this study, we have investigated protective effects of sesaminol glucosides on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. Sesaminol glucoside (50-250microg/ml) decreased Abeta(25-35)-induced ROS generation, formation of 8-oxodG, a form of oxidative DNA and elevation of intracellular calcium level concomitant with prevention of apoptotic cell death dose dependently. Sesaminol glucoside (50-250microg/ml) also effectively decreased Abeta1-42 and ADDL form of Abeta1-42 as well as the combination of H2O2 with FeSO4-induced cell damages. In mechanistic study, sesaminol glucosides attenuated Abeta25-35-induced activation of redox transcription factor nuclear factor-kappaB NF-kappaB through inhibition of p50 translocation and IkappaB phosphorylation, and blocked NF-kappaB-dependent luciferase activity in addition to the inhibitory effect on Abeta25-35-induced activation of ERK kinase signal pathway. Consistent with the inhibitory effect on Abeta25-35-induced stress-induced cell death, sesaminol glucosides decreased expression of pro-apoptotic gene p53, and Bax and caspase-3, but enhanced expression of anti-apoptotic Bcl-2. Moreover, the protective effects of sesaminol glucoside on Abeta25-35-induced ROS generation, NF-kappaB activation and cell death were further enhanced with glutathione. This study therefore suggests that sesaminol glucosides have protective effect on Abeta-induced neuronal cell death, and its effect may be through antioxidative property.

  10. Interplay of Oxidative Stress and Autophagy in PAMAM Dendrimers-Induced Neuronal Cell Death.

    Science.gov (United States)

    Li, Yubin; Zhu, Haiyan; Wang, Shaofei; Qian, Xiaolu; Fan, Jiajun; Wang, Ziyu; Song, Ping; Zhang, Xuesai; Lu, Weiyue; Ju, Dianwen

    2015-01-01

    Poly-amidoamine (PAMAM) dendrimers are proposed to be one of the most promising drug-delivery nanomaterials. However, the toxicity of PAMAM dendrimers on the central nervous system seriously hinders their medical applications. The relationship between oxidative stress and autophagy induced by PAMAM dendrimers, and its underlying mechanism remain confusing. In this study, we reported that PAMAM dendrimers induced both reactive oxygen species and autophagy flux in neuronal cells. Interestingly, autophagy might be triggered by the formation of reactive oxygen species induced by PAMAM dendrimers. Suppression of reactive oxygen species could not only impair PAMAM dendrimers-induced autophagic effects, but also reduce PAMAM dendrimers-induced neuronal cell death. Moreover, inhibition of autophagy could protect against PAMAM dendrimers-induced neuronal cell death. These findings systematically elucidated the interplay between oxidative stress and autophagy in the neurotoxicity of PAMAM dendrimers, which might encourage the application of antioxidants and autophagy inhibitors to ameliorate the neurotoxicity of PAMAM dendrimers in clinic.

  11. Cannabinoid-induced autophagy: Protective or death role?

    Science.gov (United States)

    Costa, Lia; Amaral, Cristina; Teixeira, Natércia; Correia-da-Silva, Georgina; Fonseca, Bruno M

    2016-01-01

    Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Δ(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Lyu, Qing [School of Life Sciences, Tsinghua University, Beijing, 100084 (China); Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055 (China); Tou, Fangfang [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China); Su, Hong; Wu, Xiaoyong [First Affiliated Hospital, Guiyang College of Traditional Chinese Medicine, Guiyang, 550002 (China); Chen, Xinyi [Department of Hematology and Oncology, Beijing University of Chinese Medicine, Beijing, 100029 (China); Zheng, Zhi, E-mail: zheng_sheva@hotmail.com [Jiangxi Provincial Key Lab of Oncology Translation Medicine, Jiangxi Cancer Hospital, Nanchang, 330029 (China)

    2015-06-19

    Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death. - Highlights: • Peiminine induces autophagy and upregulates autophagic flux. • Peiminine represses colorectal carcinoma tumor growth. • Peiminine induces autophagic cell death. • Peiminine represses mTOR phosphorylation by influencing PI3K/Akt and AMPK pathway.

  13. Pseudomonas aeruginosa pyocyanin induces neutrophil death via mitochondrial reactive oxygen species and mitochondrial acid sphingomyelinase.

    Science.gov (United States)

    Managò, Antonella; Becker, Katrin Anne; Carpinteiro, Alexander; Wilker, Barbara; Soddemann, Matthias; Seitz, Aaron P; Edwards, Michael J; Grassmé, Heike; Szabò, Ildiko; Gulbins, Erich

    2015-05-01

    Pulmonary infections with Pseudomonas aeruginosa are a serious clinical problem and are often lethal. Because many strains of P. aeruginosa are resistant to antibiotics, therapeutic options are limited. Neutrophils play an important role in the host's early acute defense against pulmonary P. aeruginosa. Therefore, it is important to define the mechanisms by which P. aeruginosa interacts with host cells, particularly neutrophils. Here, we report that pyocyanin, a membrane-permeable pigment and toxin released by P. aeruginosa, induces the death of wild-type neutrophils; its interaction with the mitochondrial respiratory chain results in the release of reactive oxygen species (ROS), the activation of mitochondrial acid sphingomyelinase, the formation of mitochondrial ceramide, and the release of cytochrome c from mitochondria. A genetic deficiency in acid sphingomyelinase prevents both the activation of this pathway and pyocyanin-induced neutrophil death. This reduced death, on the other hand, is associated with an increase in the release of interleukin-8 from pyocyanin-activated acid sphingomyelinase-deficient neutrophils but not from wild-type cells. These studies identified the mechanisms by which pyocyanin induces the release of mitochondrial ROS and by which ROS induce neutrophil death via mitochondrial acid sphingomyelinase. These findings demonstrate a novel mechanism of pyocyanin-induced death of neutrophils and show how this apoptosis balances innate immune reactions.

  14. Exposure to electromagnetic field attenuates oxygen-glucose deprivation-induced microglial cell death by reducing intracellular Ca(2+) and ROS.

    Science.gov (United States)

    Duong, Cao Nguyen; Kim, Jae Young

    2016-01-01

    Purpose The aim of this research was to demonstrate the protective effects of electromagnetic field (EMF) exposure on the human microglial cell line, HMO6, against ischemic cell death induced by in vitro oxygen-glucose deprivation (OGD). Materials and methods HMO6 cells were cultured for 4 h under OGD with or without exposure to EMF with different combinations of frequencies and intensities (10, 50, or 100 Hz/1 mT and 50 Hz/0.01, 0.1, or 1 mT). Cell survival, intracellular calcium and reactive oxygen species (ROS) levels were measured. Results OGD caused significant HMO6 cell death as well as elevation of intracellular Ca(2+) and ROS levels. Among different combinations of EMF frequencies and intensities, 50 Hz/1 mT EMF was the most potent to attenuate OGD-induced cell death and intracellular Ca(2+) and ROS levels. A significant but less potent protective effect was also found at 10 Hz/1 mT, whereas no protective effect was found at other combinations of EMF. A xanthine oxidase inhibitor reversed OGD-induced ROS production and cell death, while NADPH oxidase and mitochondrial respiration chain complex II inhibitors did not affect cell death. Conclusions 50 Hz/1 mT EMF protects human microglial cells from OGD-induced cell death by interfering with OGD-induced elevation of intracellular Ca(2+) and ROS levels, and xanthine oxidase is one of the main mediators involved in OGD-induced HMO6 cell death. Non-invasive treatment of EMF radiation may be clinically useful to attenuate hypoxic-ischemic brain injury.

  15. Turkish propolis supresses MCF-7 cell death induced by homocysteine.

    Science.gov (United States)

    Tartik, Musa; Darendelioglu, Ekrem; Aykutoglu, Gurkan; Baydas, Giyasettin

    2016-08-01

    Elevated plasma homocysteine (Hcy) level is a most important risk factor for various vascular diseases including coronary, cerebral and peripheral arterial and venous thrombosis. Propolis is produced by honeybee from various oils, pollens and wax materials. Therefore, it has various biological properties including antioxidant, antitumor and antimicrobial activities. This study investigated the effects of propolis and Hcy on apoptosis in cancer cells. According to our findings, Hcy induced apoptosis in human breast adenocarcinoma (MCF-7) cells by regulating numerous genes and proteins involved in the apoptotic signal transduction pathway. In contrast, treatment with propolis inhibited caspase- 3 and -9 induced by Hcy in MCF-7 cells. It can be concluded that Hcy may augment the activity of anticancer agents that induce excessive reactive oxygen species (ROS) generation and apoptosis in their target cells. In contrast to the previous studies herein we found that propolis in low doses protected cancer cells inhibiting cellular apoptosis mediated by intracellular ROS-dependent mitochondrial pathway. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

    DEFF Research Database (Denmark)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

    2015-01-01

    of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high...... densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor...... agonist, Compound 21 (C21) penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped from the cell death, displayed activation of the mitochondrial apoptotic pathway, i...

  17. Danger signaling protein HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria.

    Science.gov (United States)

    Gdynia, Georg; Keith, Martina; Kopitz, Jürgen; Bergmann, Marion; Fassl, Anne; Weber, Alexander N R; George, Julie; Kees, Tim; Zentgraf, Hans-Walter; Wiestler, Otmar D; Schirmacher, Peter; Roth, Wilfried

    2010-11-01

    Cells dying by necrosis release the high-mobility group box 1 (HMGB1) protein, which has immunostimulatory effects. However, little is known about the direct actions of extracellular HMGB1 protein on cancer cells. Here, we show that recombinant human HMGB1 (rhHMGB1) exerts strong cytotoxic effects on malignant tumor cells. The rhHMGB1-induced cytotoxicity depends on the presence of mitochondria and leads to fast depletion of mitochondrial DNA, severe damage of the mitochondrial proteome by toxic malondialdehyde adducts, and formation of giant mitochondria. The formation of giant mitochondria is independent of direct nuclear signaling events, because giant mitochondria are also observed in cytoplasts lacking nuclei. Further, the reactive oxygen species scavenger N-acetylcysteine as well as c-Jun NH(2)-terminal kinase blockade inhibited the cytotoxic effect of rhHMGB1. Importantly, glioblastoma cells, but not normal astrocytes, were highly susceptible to rhHMGB1-induced cell death. Systemic treatment with rhHMGB1 results in significant growth inhibition of xenografted tumors in vivo. In summary, rhHMGB1 induces a distinct form of cell death in cancer cells, which differs from the known forms of apoptosis, autophagy, and senescence, possibly representing an important novel mechanism of specialized necrosis. Further, our findings suggest that rhHMGB1 may offer therapeutic applications in treatment of patients with malignant brain tumors. ©2010 AACR.

  18. Brain-dead patients are not cadavers: the need to revise the definition of death in Muslim communities.

    Science.gov (United States)

    Rady, Mohamed Y; Verheijde, Joseph L

    2013-03-01

    The utilitarian construct of two alternative criteria of human death increases the supply of transplantable organs at the end of life. Neither the neurological criterion (heart-beating donation) nor the circulatory criterion (non-heart-beating donation) is grounded in scientific evidence but based on philosophical reasoning. A utilitarian death definition can have unintended consequences for dying Muslim patients: (1) the expedited process of determining death for retrieval of transplantable organs can lead to diagnostic errors, (2) the equivalence of brain death with human death may be incorrect, and (3) end-of-life religious values and traditional rituals may be sacrificed. Therefore, it is imperative to reevaluate the two different types and criteria of death introduced by the Resolution (Fatwa) of the Council of Islamic Jurisprudence on Resuscitation Apparatus in 1986. Although we recognize that this Fatwa was based on best scientific evidence available at that time, more recent evidence shows that it rests on outdated knowledge and understanding of the phenomenon of human death. We recommend redefining death in Islam to reaffirm the singularity of this biological phenomenon as revealed in the Quran 14 centuries ago.

  19. Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells

    Energy Technology Data Exchange (ETDEWEB)

    Kikuchi, Kiyoshi [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Department of Neurosurgery, Omuta City General Hospital, 2-19-1 Takarazaka, Omuta-City, Fukuoka 836-8567 (Japan); Kawahara, Ko-ichi; Biswas, Kamal Krishna; Ito, Takashi [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Tancharoen, Salunya [Department of Pharmacology, Faculty of Dentistry, Mahidol University, 6 Yothe Rd., Rajthevee Bangkok 10400 (Thailand); Morimoto, Yoko [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Matsuda, Fumiyo [Division of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8560 (Japan); Oyama, Yoko; Takenouchi, Kazunori [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Miura, Naoki [Laboratory of Veterinary Diagnostic Imaging, Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065 (Japan); Arimura, Noboru; Nawa, Yuko; Meng, Xiaojie; Shrestha, Binita; Arimura, Shinichiro [Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); and others

    2009-07-24

    High mobility group box-1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic insult and exacerbates brain tissue damage in rats. Minocycline is a semisynthetic second-generation tetracycline antibiotic which has recently been shown to be a promising neuroprotective agent. In this study, we found that minocycline inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated PC12 cells and triggered the activation of p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2). The ERK kinase (MEK)1/2 inhibitor U-0126 and p38MAPK inhibitor SB203580 blocked HMGB1 release in response to OGD. Furthermore, HMGB1 triggered cell death in a dose-dependent fashion. Minocycline significantly rescued HMGB1-induced cell death in a dose-dependent manner. In light of recent observations as well as the good safety profile of minocycline in humans, we propose that minocycline might play a potent neuroprotective role through the inhibition of HMGB1-induced neuronal cell death in cerebral infarction.

  20. Autophagy modulates endoplasmic reticulum stress-induced cell death in podocytes: a protective role.

    Science.gov (United States)

    Cheng, Yu-Chi; Chang, Jer-Ming; Chen, Chien-An; Chen, Hung-Chun

    2015-04-01

    Endoplasmic reticulum stress occurs in a variety of patho-physiological mechanisms and there has been great interest in managing this pathway for the treatment of clinical diseases. Autophagy is closely interconnected with endoplasmic reticulum stress to counteract the possible injurious effects related with the impairment of protein folding. Studies have shown that glomerular podocytes exhibit high rate of autophagy to maintain as terminally differentiated cells. In this study, podocytes were exposed to tunicamycin and thapsigargin to induce endoplasmic reticulum stress. Thapsigargin/tunicamycin treatment induced a significant increase in endoplasmic reticulum stress and of cell death, represented by higher GADD153 and GRP78 expression and propidium iodide flow cytometry, respectively. However, thapsigargin/tunicamycin stimulation also enhanced autophagy development, demonstrated by monodansylcadaverine assay and LC3 conversion. To evaluate the regulatory effects of autophagy on endoplasmic reticulum stress-induced cell death, rapamycin (Rap) or 3-methyladenine (3-MA) was added to enhance or inhibit autophagosome formation. Endoplasmic reticulum stress-induced cell death was decreased at 6 h, but was not reduced at 24 h after Rap+TG or Rap+TM treatment. In contrast, endoplasmic reticulum stress-induced cell death increased at 6 and 24 h after 3-MA+TG or 3-MA+TM treatment. Our study demonstrated that thapsigargin/tunicamycin treatment induced endoplasmic reticulum stress which resulted in podocytes death. Autophagy, which counteracted the induced endoplasmic reticulum stress, was simultaneously enhanced. The salvational role of autophagy was supported by adding Rap/3-MA to mechanistically regulate the expression of autophagy and autophagosome formation. In summary, autophagy helps the podocytes from cell death and may contribute to sustain the longevity as a highly differentiated cell lineage. © 2014 by the Society for Experimental Biology and Medicine.

  1. Closed-loop regulation of arterial pressure after acute brain death.

    Science.gov (United States)

    Soltesz, Kristian; Sjöberg, Trygve; Jansson, Tomas; Johansson, Rolf; Robertsson, Anders; Paskevicius, Audrius; Liao, Quiming; Qin, Guangqi; Steen, Stig

    2017-06-10

    The purpose of this concept study was to investigate the possibility of automatic mean arterial pressure (MAP) regulation in a porcine heart-beating brain death (BD) model. Hemodynamic stability of BD donors is necessary for maintaining acceptable quality of donated organs for transplantation. Manual stabilization is challenging, due to the lack of vasomotor function in BD donors. Closed-loop stabilization therefore has the potential of increasing availability of acceptable donor organs, and serves to indicate feasibility within less demanding patient groups. A dynamic model of nitroglycerine pharmacology, suitable for controller synthesis, was identified from an experiment involving an anesthetized pig, using a gradient-based output error method. The model was used to synthesize a robust PID controller for hypertension prevention, evaluated in a second experiment, on a second, brain dead, pig. Hypotension was simultaneously prevented using closed-loop controlled infusion of noradrenaline, by means of a previously published controller. A linear model of low order, with variable (uncertain) gain, was sufficient to describe the dynamics to be controlled. The robustly tuned PID controller utilized in the second experiment kept the MAP within a user-defined range. The system was able to prevent hypertension, exceeding a reference of 100 mmHg by more than 10%, during 98% of a 12 h experiment. This early work demonstrates feasibility of the investigated modelling and control synthesis approach, for the purpose of maintaining normotension in a porcine BD model. There remains a need to characterize individual variability, in order to ensure robust performance over the expected population.

  2. A Comparison of Brain Death Criteria between China and the United States

    Directory of Open Access Journals (Sweden)

    Ze-Yu Ding

    2015-01-01

    Full Text Available Background: Criteria for determining brain death (BD vary between China and the United States. We reported the results of an investigation designed to compare procedures to determine BD in two countries. Methods: The latest criteria in the United states were published in 2010. The latest criteria in China were published in 2009. We used these two types of BD criteria to evaluate patients who were considered to be BD. The time, cost, and accuracy of the diagnosis were compared. Results: From January 1, 2012 to October 8, 2013, there were 37 patients which were applied for BD evaluation in the Neurological Intensive Care Unit of Beijing Tiantan Hospital. The cause of coma were known as subarachnoid hemorrhage (18 patients, 48.6%, intracerebral hemorrhage (8 patients, 21.6%, cerebral ischemia (9 patients, 24.3%, brain stem tumor (1 patient, 2.7%, and intracranial infection (1 patient, 2.7%. The clinical examinations were done for all of the patients except 1 patient who had low blood pressure. Three patients had brainstem reflexes that were excluded from BD. Twenty-five patients had apnea tests, and 20 tests were completed that were all positive. Confirmatory tests were completed differently: Transcranial Doppler (30 patients, positive rate 86.7%, electroencephalogram (25 patients, positive rate 100%, and somatosensory evoked potential (16 patients, positive rate 100%. Thirty-three patients were diagnosed BD by criteria of the United States. Only 9 patients were diagnosed BD by Chinese criteria. The use of time and money in the USA criteria was obviously fewer than those in Chinese criteria (P = 0.000. Conclusion: Compared with BD criteria of the United States, Chinese criteria were stricter, lower positive rate, more cost in money and time, and more reliable by families and doctors.

  3. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

    Directory of Open Access Journals (Sweden)

    Anders P Hakansson

    Full Text Available BACKGROUND: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. METHODOLOGY/PRINCIPAL FINDINGS: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity to execute cell death. CONCLUSIONS/SIGNIFICANCE: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

  4. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

    Science.gov (United States)

    Hakansson, Anders P; Roche-Hakansson, Hazeline; Mossberg, Ann-Kristin; Svanborg, Catharina

    2011-03-10

    Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

  5. Hepatocyte growth factor enhances death receptor-induced apoptosis by up-regulating DR5

    Directory of Open Access Journals (Sweden)

    Goodwin C Rory

    2008-11-01

    Full Text Available Abstract Background Hepatocyte growth factor (HGF and its receptor c-MET are commonly expressed in malignant gliomas and embryonic neuroectodermal tumors including medulloblastoma and appear to play an important role in the growth and dissemination of these malignancies. Dependent on cell context and the involvement of specific downstream effectors, both pro- and anti-apoptotic effects of HGF have been reported. Methods Human medulloblastoma cells were treated with HGF for 24–72 hours followed by death receptor ligand TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand for 24 hours. Cell death was measured by MTT and Annexin-V/PI flow cytometric analysis. Changes in expression levels of targets of interest were measured by Northern blot analysis, quantitative reverse transcription-PCR, Western blot analysis as well as immunoprecipitation. Results In this study, we show that HGF promotes medulloblastoma cell death induced by TRAIL. TRAIL alone triggered apoptosis in DAOY cells and death was enhanced by pre-treating the cells with HGF for 24–72 h prior to the addition of TRAIL. HGF (100 ng/ml enhanced TRAIL (10 ng/ml induced cell death by 36% (P Conclusion Taken together, these and previous findings indicate that HGF:c-Met pathway either promotes or inhibits medulloblastoma cell death via pathway and context specific mechanisms.

  6. Guideline of procedures 2003 for the gammagraphic study of brain death; Guia de procedimientos 2003 para el estudio gammagrafico de muerte cerebral

    Energy Technology Data Exchange (ETDEWEB)

    Mora R, R.A. [Instituto Nacional de Pediatria, Mexico D.F. (Mexico)

    2003-07-01

    The diagnosis of brain death is a clinical diagnosis that is sometimes made with the help of cerebral perfusion scintigraphy. It is important that all physicians be knowledgeable about the clinical requirements for the diagnosis of brain death, especially the need to establish irreversible cessation of all function of the cerebrum and brain stem. Institutions performing scintigraphy for the evaluation of possible brain death should develop clinical guidelines and procedures for the clinical diagnosis that incorporate both clinical evaluations and the integration of ancillary tests such as perfusion scintigraphy. (Author)

  7. Genistein suppresses aerobic glycolysis and induces hepatocellular carcinoma cell death.

    Science.gov (United States)

    Li, Sainan; Li, Jingjing; Dai, Weiqi; Zhang, Qinghui; Feng, Jiao; Wu, Liwei; Liu, Tong; Yu, Qiang; Xu, Shizan; Wang, Wenwen; Lu, Xiya; Chen, Kan; Xia, Yujing; Lu, Jie; Zhou, Yingqun; Fan, Xiaoming; Mo, Wenhui; Xu, Ling; Guo, Chuanyong

    2017-11-07

    Genistein is a natural isoflavone with many health benefits, including antitumour effects. Increased hypoxia-inducible factor 1 α (HIF-1α) levels and glycolysis in tumour cells are associated with an increased risk of mortality, cancer progression, and resistance to therapy. However, the effect of genistein on HIF-1α and glycolysis in hepatocellular carcinoma (HCC) is still unclear. Cell viability, apoptosis rate, lactate production, and glucose uptake were measured in HCC cell lines with genistein incubation. Lentivirus-expressed glucose transporter 1 (GLUT1) or/and hexokinase 2 (HK2) and siRNA of HIF-1α were used to test the direct target of genistein. Subcutaneous xenograft mouse models were used to measure in vivo efficacy of genistein and its combination with sorafenib. Genistein inhibited aerobic glycolysis and induced mitochondrial apoptosis in HCC cells. Neither inhibitors nor overexpression of HK2 or GLUTs enhance or alleviate this effect. Although stabiliser of HIF-1α reversed the effect of genistein, genistein no longer has effects on HIF-1α siRNA knockdown HCC cells. In addition, genistein enhanced the antitumour effect of sorafenib in sorafenib-resistant HCC cells and HCC-bearing mice. Genistein sensitised aerobic glycolytic HCC cells to apoptosis by directly downregulating HIF-1α, therefore inactivating GLUT1 and HK2 to suppress aerobic glycolysis. The inhibitory effect of genistein on tumour cell growth and glycolysis may help identify effective treatments for HCC patients at advanced stages.

  8. Sesquiterpene lactones induce distinct forms of cell death that modulate human monocyte-derived macrophage responses.

    Science.gov (United States)

    López-Antón, Nancy; Hermann, Corinna; Murillo, Renato; Merfort, Irmgard; Wanner, Gerhard; Vollmar, Angelika M; Dirsch, Verena M

    2007-01-01

    Sesquiterpene lactones (SQTLs) are shown to possess anti-inflammatory as well as cytotoxic activity. No study, however, links both activities. We, therefore, hypothesized that SQTL-treated, dying cells might induce an anti-inflammatory response in cocultured THP-1 macrophages. Here we show that SQTLs bearing either an alpha,beta-unsaturated cyclopentenone or an alpha-methylene-gamma-lactone induce different forms of cell death. Whereas the cyclopentenone SQTL induced typical apoptosis, the alpha-methylene-gamma-lactone SQTLs-induced cell death lacked partly classical signs of apoptosis, such as DNA fragmentation. All SQTLs, however, activated caspases and the nuclear morphology of cell death was dependent on caspase activation. Most interestingly, alpha-methylene-gamma-lactone SQTLs induced a more pronounced phosphatidylserine (PS) exposure than the cyclopentenone SQTL. Especially, 7-hydroxycostunolide (HC), with an alpha-methylene-gamma-lactone substituted with a hydroxyl group, showed a striking fast and pronounced PS translocation. This result was in agreement with a strong activation of phagocytosis in cocultured THP-1 macrophages. Interestingly, HC-treated Jurkat cells led to an early (3.5 h) but transient increase in TNF-alpha levels in macrophage coculture. Release of TGF-beta remained unaffected after 18 h. We propose that this type of SQTL may influence local inflammation by transiently activating the immune system and help to clear cells by inducing a form of cell death that promotes phagocytosis.

  9. Optical monitoring of shock wave-induced spreading depolarization and concomitant hypoxemia in rat brain

    Science.gov (United States)

    Okuda, Wataru; Kawauchi, Satoko; Ashida, Hiroshi; Sato, Shunichi; Nishidate, Izumi

    2014-03-01

    Blast-induced traumatic brain injury is a growing concern, but its underlying pathophysiology and mechanism are still unknown. Thus, study using an animal model is needed. We have been proposing the use of a laser-induced shock wave (LISW), whose energy is highly controllable and reproducible, to mimic blast-related injury. We previously observed the occurrence of spreading depolarization (SD) and prolonged hypoxemia in the rat brain exposed to an LISW. However, the relationship between these two events is unclear. In this study, we investigated the spatiotemporal characteristics of hypoxemia and SD to examine their correlation, for which multichannel fiber measurement and multispectral imaging of the diffuse reflectance were performed for the rat brain exposed to an LISW. We also quantified tissue oxygen saturation (StO2) in the hypoxemic phase, which is associated with possible neuronal cell death, based on an inverse Monte Carlo simulation. Fiber measurement showed that the region of hypoxemia was expanding from the site of LISW application to the distant region over the brain; the speed of expansion was similar to that of the propagation speed of SD. Simulation showed that oxygen saturation was decreased by ~40%. Multispectral imaging showed that after LISW application, a vasodilatation occurred for ~1 min, which was followed by a long-lasting vasoconstriction. In the phase of vasoconstriction, StO2 declined all over the field of view. These results indicate a strong correlation between SD and hypoxemia; the estimated StO2 seems to be low enough to induce neuronal cell death.

  10. Gender differences in alcohol-induced neurotoxicity and brain damage.

    Science.gov (United States)

    Alfonso-Loeches, Silvia; Pascual, María; Guerri, Consuelo

    2013-09-06

    Considerable evidence has demonstrated that women are more vulnerable than men to the toxic effects of alcohol, although the results as to whether gender differences exist in ethanol-induced brain damage are contradictory. We have reported that ethanol, by activating the neuroimmune system and Toll-like receptors 4 (TLR4), can cause neuroinflammation and brain injury. However, whether there are gender differences in alcohol-induced neuroinflammation and brain injury are currently controversial. Using the brains of TLR4(+/+) and TLR4(-/-) (TLR4-KO) mice, we report that chronic ethanol treatment induces inflammatory mediators (iNOS and COX-2), cytokines (IL-1β, TNF-α), gliosis processes, caspase-3 activation and neuronal loss in the cerebral cortex of both female and male mice. Conversely, the levels of these parameters tend to be higher in female than in male mice. Using an in vivo imaging technique, our results further evidence that ethanol treatment triggers higher GFAP levels and lower MAP-2 levels in female than in male mice, suggesting a greater effect of ethanol-induced astrogliosis and less MAP-2(+) neurons in female than in male mice. Our results further confirm the pivotal role of TLR4 in alcohol-induced neuroinflammation and brain damage since the elimination of TLR4 protects the brain of males and females against the deleterious effects of ethanol. In short, the present findings demonstrate that, during the same period of ethanol treatment, females are more vulnerable than males to the neurotoxic/neuroinflammatory effects of ethanol, thus supporting the view that women are more susceptible than men to the medical consequences of alcohol abuse. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. (-)-Epigallocatechin-3-gallate protects against neuronal cell death and improves cerebral function after traumatic brain injury in rats.

    Science.gov (United States)

    Itoh, Tatsuki; Imano, Motohiro; Nishida, Shozo; Tsubaki, Masahiro; Hashimoto, Shigeo; Ito, Akihiko; Satou, Takao

    2011-12-01

    A major component of green tea, a widely consumed beverage, is (-)-epigallocatechin gallate (EGCG), which has strong antioxidant properties. Our previous study has indicated that free radical production following rat traumatic brain injury (TBI) induces neural degeneration. In this study, we investigated the effects of EGCG on cerebral function and morphology following TBI. Six-week-old male Wistar rats that had access to normal drinking water, or water containing 0.1% (w/v) EGCG ad libitum, received TBI with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3 and 7 days post-TBI, the number of 8-hydroxy-2'-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and the levels of malondialdehyde (MDA) around the damaged area after TBI, significantly decreased in the EGCG treatment group compared with the water group (P water group co-localized with neuronal cells. However, in the EGCG treatment group, few ssDNA-positive cells co-localized with neurons. In addition, there was a significant increase in the number of surviving neuronal cells and an improvement in cerebral dysfunction after TBI in the EGCG treatment group compared with the water group (P consumption of water containing EGCG pre- and post-TBI inhibits free radical-induced neuronal degeneration and apoptotic cell death around the damaged area, resulting in the improvement of cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.

  12. The effect of brain death protocol duration on potential donor losses due to cardiac arrest.

    Science.gov (United States)

    Westphal, Glauco Adrieno; Slaviero, Tiago Amaral; Montemezzo, Artur; Lingiardi, Gabriel Torres; de Souza, Fernanda Carolina Cani; Carnin, Tiago Costa; Soares, Diego Roberto; Hachiya, Alisson Hideto; Ferraz, Letícia Lopes; de Andrade, Joel

    2016-11-01

    The severe inflammatory reaction that occurs after brain death (BD) tends to amplify over time, contributing to cardiovascular deterioration and occurrence of cardiac arrest (CA). Our purpose is to evaluate the effect of BD protocol duration (BDPD) on potential donor losses due to CA. This retrospective analysis included potential donors reported during the period from May 2012 to April 2014. The risk of losses due to CA was analyzed to identify the chronological threshold at which the probability of loss due to CA increases. Three hundred and eighty-four potential donors were analyzed. There was a greater chance of CA after a 30-hour threshold (OR 1.67, 95% CI: 1.38-1.83), and the lowest risk of was identified for the range from 12 to 30 hours (OR 0.32, 95% CI: 0.19-0.52). Multivariate analysis identified the following variables as being associated with lower occurrence of CA: BDPD between 12 and 30 hours, management of a potential donor inside the intensive care unit, and the adherence to a goal-directed protocol. A long duration between the first clinical test for BD diagnosis and the procurement of organs may be an important risk factor for the occurrence of cardiac arrest in deceased potential donors. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Physical Exercise Can Induce Brain Plasticity and Regulate Mental Function

    OpenAIRE

    Ichiro, KITA; Graduate School of Human Health Science, Tokyo Metropolitan University

    2014-01-01

    Physical exercise can enhance learning and memory, and improve stress-related psychiatric disorders such as depression and anxiety. There is accumulating evidence that physical exercise can induce morphological and functional alterations in the brain via changes in molecular and cellular plasticity. Thus, it is suggested that the neuroplasticity produced by physical exercise underlies the exercise-induced changes in mental function, including learning and psychological health. Although the ne...

  14. Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers-The possible involvement of maternal methemoglobinemia

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    Corna Melissa F

    2011-07-01

    Full Text Available Abstract Background Iron is involved in important vital functions as an essential component of the oxygen-transporting heme mechanism. In this study we aimed to evaluate whether oxidative metabolites from maternal cigarette smoke could affect iron homeostasis in the brain of victims of sudden unexplained fetal and infant death, maybe through the induction of maternal hemoglobin damage, such as in case of methemoglobinemia. Methods Histochemical investigations by Prussian blue reaction were made on brain nonheme ferric iron deposits, gaining detailed data on their localization in the brainstem and cerebellum of victims of sudden death and controls. The Gless and Marsland's modification of Bielschowsky's was used to identify neuronal cell bodies and neurofilaments. Results Our approach highlighted accumulations of blue granulations, indicative of iron positive reactions, in the brainstem and cerebellum of 33% of victims of sudden death and in none of the control group. The modified Bielschowsky's method confirmed that the cells with iron accumulations were neuronal cells. Conclusions We propose that the free iron deposition in the brain of sudden fetal and infant death victims could be a catabolic product of maternal methemoglobinemia, a biomarker of oxidative stress likely due to nicotine absorption.

  15. Induction of the Vitamin D Receptor Attenuates Autophagy Dysfunction-Mediated Cell Death Following Traumatic Brain Injury

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    Changmeng Cui

    2017-08-01

    Full Text Available Background/Aims: Traumatic brain injury (TBI is a major public health problem in the world and causes high rates of mortality and disability. Recent evidence suggests that vitamin D (VD has neuroprotective actions and can promote function recovery after TBI. In vitro and in vivo studies have demonstrated that autophagy could be enhanced following supplementation with an active metabolite of VD (calcitriol. However, it is unclear whether autophagy participates in the protective effects of calcitriol after TBI. To test this hypothesis, we examined the protective effects of calcitriol on TBI-induced neurological impairment and further investigated whether calcitriol could modulate autophagy dysfunction-mediated cell death in the cortex region of rat brain. Methods: Eighty-five male rats (250-280 g were randomly assigned to sham (n=15, TBI model (TBI, n=35 and calcitriol treatment (calcitriol, n=35 groups. Rats were injected intraperitoneally with calcitriol (1 µg/kg at 30 min, 24 h and 48 h post-TBI in the calcitriol group. The lysosomal inhibitor, chloroquine (CQ, was used to evaluate autophagic flux in the TBI and calcitriol groups. Neurological functions were evaluated via the modified neurological severity score test at 1-7 days after TBI or sham operation, and the terminal deoxynucleotidyl transferase-mediated FITC-dUTP nick-end labeling method was used to evaluate the ability of calcitriol to inhibit apoptosis. The expression of VDR, LC3 and p62 proteins was measured by western blot analysis at 1, 3 and 7 days post-injury Results: Calcitriol treatment attenuated mNSS at 2-7 days post-TBI (P < 0.05 versus TBI group. Calcitriol dramatically increased VDR protein expression compared with the untreated counterparts at 1, 3 and 7 days post-TBI (P < 0.05. The rate of apoptotic cells in calcitriol-treated rats was significantly reduced compared to that observed in the TBI group (P < 0.05. The LC3II/LC3I ratio was decreased in the cortex region at 1

  16. Age-dependent effect of treadmill exercise on hemorrhage-induced neuronal cell death in rats

    OpenAIRE

    Yoon, Jin-Hwan; Lee, Hee-Hyuk; Yi, Eun-Surk; Baek, Soon Gi

    2013-01-01

    Intracerebral hemorrhage (ICH) is a major cause of death and disability in the elderly. In the present study, we examined the age-dependence of the effect of treadmill exercise on the intrastriatal hemorrhage-induced neuronal cell death in rats. Young (8 weeks old) and old (64 weeks old) Sprague-Dawley male rats were used in the present study. Intrastriatal hemorrhage was induced by injection of 0.2 U collagenase (1 μL volume) into the striatum using a stereotaxic instrument. The rats in the ...

  17. Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

    OpenAIRE

    Okuda, S; Nishiyama, N.; Saito, H.; Katsuki, H

    1996-01-01

    3-Hydroxykynurenine (3-HK) is a tryptophan metabolite whose level in the brain is markedly elevated under several pathological conditions, including Huntington disease and human immunodeficiency virus infection. Here we demonstrate that micromolar concentrations (1-100 microM) of 3-HK cause cell death in primary neuronal cultures prepared from rat striatum. The neurotoxicity of 3-HK was blocked by catalase and desferrioxamine but not by superoxide dismutase, indicating that the generation of ...

  18. Expression of Inflammatory and Cell Death Program Genes and Comet DNA Damage Assay Induced by Escherichia coli in Layer Hens

    Science.gov (United States)

    Mehaisen, Gamal M. K.; Eshak, Mariam G.; El Sabry, M. I.; Abass, Ahmed O.

    2016-01-01

    Modern methods of industrial poultry and egg production systems involve stressful practices that stimulate Escherichia coli (E. coli) activity causing endotoxic shock. This investigation was conducted to evaluate the expression of pro-inflammatory cytokines and cell death program genes and DNA damage induced by E. coli in the brain and liver tissues of laying hens. A total of two hundred and ten H&N brown layer hens with 20 week age, were used in this research. First, preliminary experiments were designed (60 hens in total) to establish the optimal exposure dose of E. coli and to determine the nearest time of notable response to be used in the remainder studies of this research. At 35-wk of age, 150 hens were randomly assigned into 2 groups with 3 replicates of 25 birds each; the first group was injected in the brachial wing vein with 107 E. coli colony/hen, while the second group was injected with saline and served as a control. The body temperature and plasma corticosterone concentration were measured 3 hr after injection. Specimens of liver and brain were obtained from each group and the gene expression of p38 mitogen-activated protein kinase, interlukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), Bax, and caspase-3 genes were measured by quantitative real-time PCR. DNA damage in the brain and liver tissues were also measured by comet assay. Hens treated with E. coli showed significant (Pchickens. It is also important to note that hens injected with E. coli showed an increase in DNA damage in the brain and liver cells (Pchickens, respectively (PE. coli injection induces inflammatory physiological response and triggers cell death program in the brain and liver. Our results provide more understanding to endotoxic shock by E. coli in chickens at cellular level. Further studies are required to confirm if such responses are destructive or protective to set the means through which a chicken mounts a successful defense against avian pathogenic E. coli. PMID

  19. Caspase-2 mediated apoptotic and necrotic murine macrophage cell death induced by rough Brucella abortus.

    Directory of Open Access Journals (Sweden)

    Fang Chen

    Full Text Available Brucella species are Gram-negative, facultative intracellular bacteria that cause zoonotic brucellosis. Survival and replication inside macrophages is critical for establishment of chronic Brucella infection. Virulent smooth B. abortus strain 2308 inhibits programmed macrophage cell death and replicates inside macrophages. Cattle B. abortus vaccine strain RB51 is an attenuated rough, lipopolysaccharide O antigen-deficient mutant derived from smooth strain 2308. B. abortus rough mutant RA1 contains a single wboA gene mutation in strain 2308. Our studies demonstrated that live RB51 and RA1, but not strain 2308 or heat-killed Brucella, induced both apoptotic and necrotic cell death in murine RAW264.7 macrophages and bone marrow derived macrophages. The same phenomenon was also observed in primary mouse peritoneal macrophages from mice immunized intraperitoneally with vaccine strain RB51 using the same dose as regularly performed in protection studies. Programmed macrophage cell death induced by RB51 and RA1 was inhibited by a caspase-2 inhibitor (Z-VDVAD-FMK. Caspase-2 enzyme activation and cleavage were observed at the early infection stage in macrophages infected with RB51 and RA1 but not strain 2308. The inhibition of macrophage cell death promoted the survival of rough Brucella cells inside macrophages. The critical role of caspase-2 in mediating rough B. abortus induced macrophage cell death was confirmed using caspase-2 specific shRNA. The mitochondrial apoptosis pathway was activated in macrophages infected with rough B. abortus as demonstrated by increase in mitochondrial membrane permeability and the release of cytochrome c to cytoplasm in macrophages infected with rough Brucella. These results demonstrate that rough B. abortus strains RB51 and RA1 induce apoptotic and necrotic murine macrophage cell death that is mediated by caspase-2. The biological relevance of Brucella O antigen and caspase-2-mediated macrophage cell death in Brucella

  20. Caspase-2 mediated apoptotic and necrotic murine macrophage cell death induced by rough Brucella abortus.

    Science.gov (United States)

    Chen, Fang; He, Yongqun

    2009-08-28

    Brucella species are Gram-negative, facultative intracellular bacteria that cause zoonotic brucellosis. Survival and replication inside macrophages is critical for establishment of chronic Brucella infection. Virulent smooth B. abortus strain 2308 inhibits programmed macrophage cell death and replicates inside macrophages. Cattle B. abortus vaccine strain RB51 is an attenuated rough, lipopolysaccharide O antigen-deficient mutant derived from smooth strain 2308. B. abortus rough mutant RA1 contains a single wboA gene mutation in strain 2308. Our studies demonstrated that live RB51 and RA1, but not strain 2308 or heat-killed Brucella, induced both apoptotic and necrotic cell death in murine RAW264.7 macrophages and bone marrow derived macrophages. The same phenomenon was also observed in primary mouse peritoneal macrophages from mice immunized intraperitoneally with vaccine strain RB51 using the same dose as regularly performed in protection studies. Programmed macrophage cell death induced by RB51 and RA1 was inhibited by a caspase-2 inhibitor (Z-VDVAD-FMK). Caspase-2 enzyme activation and cleavage were observed at the early infection stage in macrophages infected with RB51 and RA1 but not strain 2308. The inhibition of macrophage cell death promoted the survival of rough Brucella cells inside macrophages. The critical role of caspase-2 in mediating rough B. abortus induced macrophage cell death was confirmed using caspase-2 specific shRNA. The mitochondrial apoptosis pathway was activated in macrophages infected with rough B. abortus as demonstrated by increase in mitochondrial membrane permeability and the release of cytochrome c to cytoplasm in macrophages infected with rough Brucella. These results demonstrate that rough B. abortus strains RB51 and RA1 induce apoptotic and necrotic murine macrophage cell death that is mediated by caspase-2. The biological relevance of Brucella O antigen and caspase-2-mediated macrophage cell death in Brucella pathogenesis and

  1. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization.

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    Haibo Wang

    Full Text Available Inhibition of chemokine C-C motif receptor 3 (CCR3 signaling has been considered as treatment for neovascular age-related macular degeneration (AMD. However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs that develop into choroidal neovascularization (CNV. In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF. In cultured human Műller cells exposed to eotaxin (CCL11 and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2 in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3

  2. Effect of Polyphenols on Oxidative Stress and Mitochondrial Dysfunction in Neuronal Death and Brain Edema in Cerebral Ischemia

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    Richard A. Anderson

    2011-11-01

    Full Text Available Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. In addition to their well-known antioxidant effects, select polyphenols also have insulin-potentiating, anti-inflammatory, anti-carcinogenic, anti-viral, anti-ulcer, and anti-apoptotic properties. One important consequence of ischemia is neuronal death and oxidative stress plays a key role in neuronal viability. In addition, neuronal death may be initiated by the activation of mitochondria-associated cell death pathways. Another consequence of ischemia that is possibly mediated by oxidative stress and mitochondrial dysfunction is glial swelling, a component of cytotoxic brain edema. The purpose of this article is to review the current literature on the contribution of oxidative stress and mitochondrial dysfunction to neuronal death, cell swelling, and brain edema in ischemia. A review of currently known mechanisms underlying neuronal death and edema/cell swelling will be undertaken and the potential of dietary polyphenols to reduce such neural damage will be critically reviewed.

  3. The calcimimetic R-568 induces apoptotic cell death in prostate cancer cells

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    Cheng Guangming

    2009-07-01

    Full Text Available Abstract Background Increased serum level of parathyroid hormone (PTH was found in metastatic prostate cancers. Calcimimetic R-568 was reported to reduce PTH expression, to suppress cell proliferation and to induce apoptosis in parathyroid cells. In this study, we investigated the effect of R-568 on cellular survival of prostate cancer cells. Methods Prostate cancer cell lines LNCaP and PC-3 were used in this study. Cellular survival was determined with MTT, trypan blue exclusion and fluorescent Live/Death assays. Western blot assay was utilized to assess apoptotic events induced by R-568 treatment. JC-1 staining was used to evaluate mitochondrial membrane potential. Results In cultured prostate cancer LNCaP and PC-3 cells, R-568 treatment significantly reduced cellular survival in a dose- and time-dependent manner. R-568-induced cell death was an apoptotic event, as evidenced by caspase-3 processing and PARP cleavage, as well as JC-1 color change in mitochondria. Knocking down calcium sensing receptor (CaSR significantly reduced R-568-induced cytotoxicity. Enforced expression of Bcl-xL gene abolished R-568-induced cell death, while loss of Bcl-xL expression led to increased cell death in R-568-treated LNCaP cells,. Conclusion Taken together, our data demonstrated that calcimimetic R-568 triggers an intrinsic mitochondria-related apoptotic pathway, which is dependent on the CaSR and is modulated by Bcl-xL anti-apoptotic pathway.

  4. Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus.

    Science.gov (United States)

    Kim, D H; Lee, H E; Kwon, K J; Park, S J; Heo, H; Lee, Y; Choi, J W; Shin, C Y; Ryu, J H

    2015-01-22

    Throughout adulthood, neurons are continuously replaced by new cells in the dentate gyrus (DG) of the hippocampus, and this neurogenesis is increased by various neuronal injuries including ischemic stroke and seizure. While several mechanisms of this injury-induced neurogenesis have been elucidated, the initiation factor remains unclear. Here, we investigated which signal(s) trigger(s) ischemia-induced cell proliferation and neurogenesis in the hippocampal DG region. We found that early apoptotic cell death of the immature neurons occurred in the DG region following transient forebrain ischemia/reperfusion in mice. Moreover, early immature neuronal death in the DG initiated transient forebrain ischemia/reperfusion-induced neurogenesis through glycogen synthase kinase-3β/β-catenin signaling, which was mediated by microglia-derived insulin-like growth factor-1 (IGF-1). Additionally, we observed that the blockade of immature neuronal cell death, early microglial activation, or IGF-1 signaling attenuated ischemia-induced neurogenesis. These results suggest that early immature neuronal cell death initiates ischemia-induced neurogenesis through microglial IGF-1 in mice. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Romo1 expression contributes to oxidative stress-induced death of lung epithelial cells

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    Shin, Jung Ar [Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul 135-270 (Korea, Republic of); Chung, Jin Sil [Laboratory of Molecular Cell Biology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Cho, Sang-Ho [Department of Pathology, Pochon CHA University, College of Medicine, Gyeonggi-do (Korea, Republic of); Kim, Hyung Jung, E-mail: khj57@yuhs.ac.kr [Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, Seoul 135-270 (Korea, Republic of); Yoo, Young Do, E-mail: ydy1130@korea.ac.kr [Laboratory of Molecular Cell Biology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2013-09-20

    Highlights: •Romo1 mediates oxidative stress-induced mitochondrial ROS production. •Romo1 induction by oxidative stress plays an important role in oxidative stress-induced apoptosis. •Romo1 overexpression correlates with epithelial cell death in patients with IPF. -- Abstract: Oxidant-mediated death of lung epithelial cells due to cigarette smoking plays an important role in pathogenesis in lung diseases such as idiopathic pulmonary fibrosis (IPF). However, the exact mechanism by which oxidants induce epithelial cell death is not fully understood. Reactive oxygen species (ROS) modulator 1 (Romo1) is localized in the mitochondria and mediates mitochondrial ROS production through complex III of the mitochondrial electron transport chain. Here, we show that Romo1 mediates mitochondrial ROS production and apoptosis induced by oxidative stress in lung epithelial cells. Hydrogen peroxide (H{sub 2}O{sub 2}) treatment increased Romo1 expression, and Romo1 knockdown suppressed the cellular ROS levels and cell death triggered by H{sub 2}O{sub 2} treatment. In immunohistochemical staining of lung tissues from patients with IPF, Romo1 was mainly localized in hyperplastic alveolar and bronchial epithelial cells. Romo1 overexpression was detected in 14 of 18 patients with IPF. TUNEL-positive alveolar epithelial cells were also detected in most patients with IPF but not in normal controls. These findings suggest that Romo1 mediates apoptosis induced by oxidative stress in lung epithelial cells.

  6. Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

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    Paris Jafari

    Full Text Available Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i 3-OHGA causes the death of astrocytes, (ii deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.

  7. A CRISPR-Based Screen Identifies Genes Essential for West-Nile-Virus-Induced Cell Death.

    Science.gov (United States)

    Ma, Hongming; Dang, Ying; Wu, Yonggan; Jia, Gengxiang; Anaya, Edgar; Zhang, Junli; Abraham, Sojan; Choi, Jang-Gi; Shi, Guojun; Qi, Ling; Manjunath, N; Wu, Haoquan

    2015-07-28

    West Nile virus (WNV) causes an acute neurological infection attended by massive neuronal cell death. However, the mechanism(s) behind the virus-induced cell death is poorly understood. Using a library containing 77,406 sgRNAs targeting 20,121 genes, we performed a genome-wide screen followed by a second screen with a sub-library. Among the genes identified, seven genes, EMC2, EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1, stood out as having the strongest phenotype, whose knockout conferred strong protection against WNV-induced cell death with two different WNV strains and in three cell lines. Interestingly, knockout of these genes did not block WNV replication. Thus, these appear to be essential genes that link WNV replication to downstream cell death pathway(s). In addition, the fact that all of these genes belong to the ER-associated protein degradation (ERAD) pathway suggests that this might be the primary driver of WNV-induced cell death. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. ECT: its brain enabling effects: a review of electroconvulsive therapy-induced structural brain plasticity.

    Science.gov (United States)

    Bouckaert, Filip; Sienaert, Pascal; Obbels, Jasmien; Dols, Annemieke; Vandenbulcke, Mathieu; Stek, Max; Bolwig, Tom

    2014-06-01

    Since the past 2 decades, new evidence for brain plasticity has caused a shift in both preclinical and clinical ECT research from falsifying the "brain damage hypothesis" toward exploring ECT's enabling brain (neuro)plasticity effects. By reviewing the available animal and human literature, we examined the theory that seizure-induced structural changes are crucial for the therapeutic efficacy of ECT. Both animal and human studies suggest electroconvulsive stimulation/electroconvulsive therapy (ECT)-related neuroplasticity (neurogenesis, synaptogenesis, angiogenesis, or gliogenesis). It remains unclear whether structural changes might explain the therapeutic efficacy and/or be related to the (transient) learning and memory impairment after ECT. Methods to assess in vivo brain plasticity of patients treated with ECT will be of particular importance for future longitudinal studies to give support to the currently available correlational data.

  9. Death from seizures induced by chronic alcohol abuse--does it exist?

    DEFF Research Database (Denmark)

    Christoffersen, S

    2007-01-01

    In a forensic setting, deaths due to seizures, either epileptic or other, present a well-known problem. Cause of death is rarely established on the basis of physical evidence, but on circumstantial evidence such as tongue biting or discharge of urine or faeces. Seizures have several different...... may die from these seizures. A literature study was performed of deaths due to alcohol-induced seizures, either during withdrawal or as late-onset seizures where the aetiology was established as long time alcohol abuse and a necropsy had shown no other possible cause of death than a seizure. RESULTS......: It was not possible to find any well-documented cases. It is, however, difficult to compare cases in the literature, as there is no generally accepted classification or nomenclature of seizures related to alcohol abuse....

  10. Absence of Doppler signal in transcranial color-coded ultrasonography may be confirmatory for brain death: A case report

    Directory of Open Access Journals (Sweden)

    Mehmet Akif Topçuoğlu

    2015-08-01

    Full Text Available Transcranial Doppler ultrasonography (TCD is a valuable tool for demonstrating cerebral circulatory arrest (CCA in the setting of brain death. Complete reversal of diastolic flow (to-and-fro flow and systolic spikes in bilateral terminal internal carotid arteries and vertebrobasilar circulation are considered as specific sonogram configurations supporting the diagnosis of CCA. Because of the possibility of sonic bone window impermeability, absence of any waveform in TCD is not confirmatory for CCA unless there is documentation of disappearance of a previously well detected signal by the same recording settings. Transcranial color-coded sonography (TCCS with B-mode imaging can reliably detect adequacy of bone windows with clarity contralateral skull and ipsilateral planum temporale visualization. Therefore, absence of detectable intracranial Doppler signal along with available ultrasound window in TCCS can confirm clinical diagnosis of brain death. We herein discuss this entity from the frame of a representative case.

  11. Pinacidil and levamisole prevent glutamate-induced death of hippocampal neuronal cells through reducing ROS production.

    Science.gov (United States)

    Shukry, Mustafa; Kamal, Tarek; Ali, Radi; Farrag, Foad; Almadaly, Essam; Saleh, Ayman A; Abu El-Magd, Mohammed

    2015-10-01

    Activators of both adenosine 5'-triphosphate (ATP)-sensitive K(+) (KATP) channel and cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel have significant in vivo and in vitro neuroprotection against glutamate-induced death of some neuronal cells. Here, the effect of the KATP channel activator, pinacidil, and the CFTR Cl(-) channel opener, levamisole, against glutamate-induced oxidative stress were investigated in mouse hippocampal cells, HT22. The results from cell viability assay (WST-1) showed that pinacidil and levamisole weakly protected cells against glutamate-induced toxicity at 10 μM and their effect increased in a dose-dependent manner till reach maximum protection at 300 μM. Pretreatment with pinacidil or levamisole significantly suppressed the elevation of reactive oxygen species (ROS) triggered by glutamate through stabilising mitochondrial membrane potential and subsequently protected HT22 cells against glutamate-induced death. HT22 cells viability was maintained by pinacidil and levamisole in presence of glutathione inhibitor, BSO. Also, pinacidil and levamisole pretreatment did not induce recovery of glutathione levels decreased by glutamate Expectedly, this protection was abolished by the KATP and CFTR Cl(-) channels blocker, glibenclamide. Thus, both pinacidil and levamisole protect HT22 cells against glutamate-induced cell death through stabilising mitochondrial membrane potential and subsequently decreasing ROS production.

  12. Inflammatory cytokines protect retinal pigment epithelial cells from oxidative stress-induced death

    DEFF Research Database (Denmark)

    Juel, Helene B; Faber, Carsten; Svendsen, Signe Goul

    2013-01-01

    -cultured with activated T cells, or treated with cytokines showed increased expression of anti-oxidative genes, with upregulation of superoxide dismutase 2 protein following PCM treatment. CONCLUSION: Oxidative stress-induced cell death was reduced by concomitant inflammatory stress. This is likely due to the cytokine...

  13. Investigations of primary blast-induced traumatic brain injury

    Science.gov (United States)

    Sawyer, T. W.; Josey, T.; Wang, Y.; Villanueva, M.; Ritzel, D. V.; Nelson, P.; Lee, J. J.

    2017-09-01

    The development of an advanced blast simulator (ABS) has enabled the reproducible generation of single-pulse shock waves that simulate free-field blast with high fidelity. Studies with rodents in the ABS demonstrated the necessity of head restraint during head-only exposures. When the head was not restrained, violent global head motion was induced by pressures that would not produce similar movement of a target the size and mass of a human head. This scaling artefact produced changes in brain function that were reminiscent of traumatic brain injury (TBI) due to impact-acceleration effects. Restraint of the rodent head eliminated these, but still produced subtle changes in brain biochemistry, showing that blast-induced pressure waves do cause brain deficits. Further experiments were carried out with rat brain cell aggregate cultures that enabled the conduct of studies without the gross movement encountered when using rodents. The suspension nature of this model was also exploited to minimize the boundary effects that complicate the interpretation of primary blast studies using surface cultures. Using this system, brain tissue was found not only to be sensitive to pressure changes, but also able to discriminate between the highly defined single-pulse shock waves produced by underwater blast and the complex pressure history exposures experienced by aggregates encased within a sphere and subjected to simulated air blast. The nature of blast-induced primary TBI requires a multidisciplinary research approach that addresses the fidelity of the blast insult, its accurate measurement and characterization, as well as the limitations of the biological models used.

  14. Evaluation of Early Kidney Damage Caused by Brain Death Using Real-Time Ultrasound Elastography in a Bama Pig Model.

    Science.gov (United States)

    Tang, Ying; Zhao, Jingwen; Liu, Dongyang; Niu, Ningning; Yu, Huimin

    2017-10-01

    The aim of this study was to investigate the value of real-time tissue elastography (RTE) in the evaluation of early graft damage resulting from brain death. We performed RTE before and 0, 3, 6 and 9 h after brain death in a Bama pig model. Eleven RTE parameters were compared among time groups, and their correlations with electron microscopic findings were analyzed. Receiver operating characteristic curve analysis was used to find the RTE parameter cutoff values. The mean relative strain value within the region of interest (MEAN), standard deviation of the relative strain value within the region of interest (SD), percentage area of low strain within the region of interest (%AREA), complexity of low-strain area within the region of interest (COMP), kurtosis (KURT), skewness (SKEW), contrast (CONT) and entropy (ENT) and inverse difference moment (IDM) differed statistically significantly between groups (p < 0.05). Electron microscopy of kidney tissue revealed that irreversible damage gradually occurred with longer brain death duration and was marked at 9 h (p < 0.05). These findings correlated best with MEAN (r = 0.632, p < 0.05). Receiver operating characteristic curve analysis of RTE parameters identified a cutoff value of 63.43 for MEAN for optimal diagnostic performance. RTE allows non-invasive, preliminary evaluation of early renal graft damage resulting from brain death. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  15. comparative study on effective factors on consent to organ donation among families of brain death victims in Isfahan, 2013

    Directory of Open Access Journals (Sweden)

    Fereshte Zamani

    2015-05-01

    Full Text Available Introduction: According to the previous studies, several social, cultural, and organizational factors are involved in the decision of families of brain death victims for organ donation. The present study was performed to determine the effective factors in the decision of organ donation among families of brain death victims. Methods: In this descriptive-comparative study data were gathered through a self-made questionnaire. The reliability of questionnaire was determined by calculating Cronbach’s alpha (0.81 and the face and content validity were studied and approved by a number of experts. Statistical population included all family members of brain death victims in Isfahan/Iran during 2012-2013. They were divided into two groups of with and without consent to organ donation. The whole population was considered as the study sample. Data analysis were done through SPSS using independent T-test, ANOVA, and Chi-square tests. Results: According to the present study, age and marital status of the victims have no effect on their families’ consent to organ donation (P> 0.05; but sex, duration of hospitalization in the emergency department, having organ donation card ,and personal opinion of the brain death victim showed significant relationship with consent to organ donation (P< 0.05. Conclusion: Since the rate of awareness, knowledge, and attitude of family members are effective in their decision for organ donation, improving cultural backgrounds required for this decision and increasing awareness and knowledge of people can improve the attitude of people in this regard and facilitate the acceptance of family members

  16. C5a induces caspase-dependent apoptosis in brain vascular endothelial cells in experimental lupus.

    Science.gov (United States)

    Mahajan, Supriya D; Tutino, Vincent M; Redae, Yonas; Meng, Hui; Siddiqui, Adnan; Woodruff, Trent M; Jarvis, James N; Hennon, Teresa; Schwartz, Stanley; Quigg, Richard J; Alexander, Jessy J

    2016-08-01

    Blood-brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become 'leaky'. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and pro-apoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in

  17. Inflammation Following Traumatic Brain Injury in Humans: Insights from Data-Driven and Mechanistic Models into Survival and Death

    Directory of Open Access Journals (Sweden)

    Andrew Abboud

    2016-09-01

    Full Text Available Inflammation induced by traumatic brain injury (TBI is a complex mediator of morbidity and mortality. We have previously demonstrated the utility of both data-driven and mechanistic models in settings of traumatic injury. We hypothesized that differential dynamic inflammation programs characterize TBI survivors vs. non-survivors, and sought to leverage computational modeling to derive novel insights into this life/death bifurcation. Thirteen inflammatory cytokines and chemokines were determined using Luminex™ in serial cerebrospinal fluid (CSF samples from 31 TBI patients over 5 days. In this cohort, 5 were non-survivors (Glasgow Outcome Scale [GOS] score = 1 and 26 were survivors (GOS > 1. A Pearson correlation analysis of initial injury (Glasgow Coma Scale [GCS] vs. GOS suggested that survivors and non-survivors had distinct clinical response trajectories to injury. Statistically significant differences in interleukin (IL-4, IL-5, IL-6, IL-8, IL-13, and tumor necrosis factor-α (TNF-α were observed between TBI survivors vs. non-survivors over 5 days. Principal Component Analysis and Dynamic Bayesian Network inference suggested differential roles of chemokines, TNF-α, IL-6, and IL-10, based upon which an ordinary differential equation model of TBI was generated. This model was calibrated separately to the time course data of TBI survivors vs. non-survivors as a function of initial GCS. Analysis of parameter values in ensembles of simulations from these models suggested differences in microglial and damage responses in TBI survivors vs. non-survivors. These studies suggest the utility of combined data-driven and mechanistic models in the context of human TBI.

  18. Necrosis, and then stress induced necrosis-like cell death, but not apoptosis, should be the preferred cell death mode for chemotherapy: clearance of a few misconceptions.

    Science.gov (United States)

    Zhang, Ju; Lou, Xiaomin; Jin, Longyu; Zhou, Rongjia; Liu, Siqi; Xu, Ningzhi; Liao, D Joshua

    2014-01-01

    Cell death overarches carcinogenesis and is a center of cancer researches, especially therapy studies. There have been many nomenclatures on cell death, but only three cell death modes are genuine, i.e. apoptosis, necrosis and stress-induced cell death (SICD). Like apoptosis, SICD is programmed. Like necrosis, SICD is a pathological event and may trigger regeneration and scar formation. Therefore, SICD has subtypes of stress-induced apoptosis-like cell death (SIaLCD) and stress-induced necrosis-like cell death (SInLCD). Whereas apoptosis removes redundant but healthy cells, SICD removes useful but ill or damaged cells. Many studies on cell death involve cancer tissues that resemble parasites in the host patients, which is a complicated system as it involves immune clearance of the alien cancer cells by the host. Cancer resembles an evolutionarily lower-level organism having a weaker apoptosis potential and poorer DNA repair mechanisms. Hence, targeting apoptosis for cancer therapy, i.e. killing via SIaLCD, will be less efficacious and more toxic. On the other hand, necrosis of cancer cells releases cellular debris and components to stimulate immune function, thus counteracting therapy-caused immune suppression and making necrosis better than SIaLCD for chemo drug development.

  19. The rate of brain death and organ donation in patients resuscitated from cardiac arrest: a systematic review and meta-analysis.

    Science.gov (United States)

    Sandroni, Claudio; D'Arrigo, Sonia; Callaway, Clifton W; Cariou, Alain; Dragancea, Irina; Taccone, Fabio Silvio; Antonelli, Massimo

    2016-11-01

    The occurrence of brain death in patients with hypoxic-ischaemic brain injury after resuscitation from cardiac arrest creates opportunities for organ donation. However, its prevalence is currently unknown. Systematic review. MEDLINE via PubMed, ISI Web of Science and the Cochrane Database of Systematic Reviews were searched for eligible studies (2002-2016). The prevalence of brain death in adult patients resuscitated from cardiac arrest and the rate of organ donation among brain dead patients were summarised using a random effect model with double-arcsine transformation. The quality of evidence (QOE) was evaluated according to the GRADE guidelines. 26 studies [16 on conventional cardiopulmonary resuscitation (c-CPR), 10 on extracorporeal CPR (e-CPR)] included a total of 23,388 patients, 1830 of whom developed brain death at a mean time of 3.2 ± 0.4 days after recovery of circulation. The overall prevalence of brain death among patients who died before hospital discharge was 12.6 [10.2-15.2] %. Prevalence was significantly higher in e-CPR vs. c-CPR patients (27.9 [19.7-36.6] vs. 8.3 [6.5-10.4] %; p organ donation among brain dead patients was 41.8 [20.2-51.0] % (9/26 studies, 1264 patients; range 0-100 %). The QOE was very low for both outcomes. In patients with hypoxic-ischaemic brain injury following CPR, more than 10 % of deaths were due to brain death. More than 40 % of brain-dead patients could donate organs. Patients who are unconscious after resuscitation from cardiac arrest, especially when resuscitated using e-CPR, should be carefully screened for signs of brain death.

  20. A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death.

    Science.gov (United States)

    Wood, Tabitha E; Dalili, Shadi; Simpson, Craig D; Hurren, Rose; Mao, Xinliang; Saiz, Fernando Suarez; Gronda, Marcela; Eberhard, Yanina; Minden, Mark D; Bilan, Philip J; Klip, Amira; Batey, Robert A; Schimmer, Aaron D

    2008-11-01

    Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands.

  1. Copper dopamine complex induces mitochondrial autophagy preceding caspase-independent apoptotic cell death.

    Science.gov (United States)

    Paris, Irmgard; Perez-Pastene, Carolina; Couve, Eduardo; Caviedes, Pablo; Ledoux, Susan; Segura-Aguilar, Juan

    2009-05-15

    Parkinsonism is one of the major neurological symptoms in Wilson disease, and young workers who worked in the copper smelting industry also developed Parkinsonism. We have reported the specific neurotoxic action of copper dopamine complex in neurons with dopamine uptake. Copper dopamine complex (100 microm) induces cell death in RCSN-3 cells by disrupting the cellular redox state, as demonstrated by a 1.9-fold increase in oxidized glutathione levels and a 56% cell death inhibition in the presence of 500 microm ascorbic acid; disruption of mitochondrial membrane potential with a spherical shape and well preserved morphology determined by transmission electron microscopy; inhibition (72%, p copper dopamine complex induces mitochondrial autophagy followed by caspase-3-independent apoptotic cell death. However, a different cell death mechanism was observed when 100 microm copper dopamine complex was incubated in the presence of 100 microm dicoumarol, an inhibitor of NAD(P)H quinone:oxidoreductase (EC 1.6.99.2, also known as DT-diaphorase and NQ01), because a more extensive and rapid cell death was observed. In addition, cyclosporine A had no effect on phosphatidylserine externalization, significant portions of compact chromatin were observed within a vacuolated nuclear membrane, DNA laddering was less pronounced, the mitochondria morphology was more affected, and the number of cells with autophagic vacuoles was a near 4-fold less.

  2. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death.

    Science.gov (United States)

    Kim, Hyun-Ji; Joo, Hong-Gu

    2016-12-30

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death.

  3. Critical role for BIM in T cell receptor restimulation-induced death

    Directory of Open Access Journals (Sweden)

    Fleisher Thomas A

    2008-08-01

    Full Text Available Abstract Background Upon repeated or chronic antigen stimulation, activated T cells undergo a T cell receptor (TCR-triggered propriocidal cell death important for governing the intensity of immune responses. This is thought to be chiefly mediated by an extrinsic signal through the Fas-FasL pathway. However, we observed that TCR restimulation still potently induced apoptosis when this interaction was blocked, or genetically impaired in T cells derived from autoimmune lymphoproliferative syndrome (ALPS patients, prompting us to examine Fas-independent, intrinsic signals. Results Upon TCR restimulation, we specifically noted a marked increase in the expression of BIM, a pro-apoptotic Bcl-2 family protein known to mediate lymphocyte apoptosis induced by cytokine withdrawal. In fact, T cells from an ALPS type IV patient in which BIM expression is suppressed were more resistant to restimulation-induced death. Strikingly, knockdown of BIM expression rescued normal T cells from TCR-induced death to as great an extent as Fas disruption. Conclusion Our data implicates BIM as a critical mediator of apoptosis induced by restimulation as well as growth cytokine withdrawal. These findings suggest an important role for BIM in eliminating activated T cells even when IL-2 is abundant, working in conjunction with Fas to eliminate chronically stimulated T cells and maintain immune homeostasis. Reviewers This article was reviewed by Dr. Wendy Davidson (nominated by Dr. David Scott, Dr. Mark Williams (nominated by Dr. Neil Greenspan, and Dr. Laurence C. Eisenlohr.

  4. Type of cell death induced by alpha-trifluoromethyl acyloins in oral squamous cell carcinoma.

    Science.gov (United States)

    Ideo, Atsushi; Hashimoto, Ken; Shimada, Jun; Kawase, Masami; Sakagami, Hiroshi

    2009-01-01

    We previously reported that alpha-trifluoromethyl acyloins (TFs) induced various types of cell death, depending on the target cancer cell line. We investigated here what type of cell death is induced by a-trifluoromethyl acyloins in two human oral squamous cell carcinoma cell lines (HSC-2, HSC-4). TFs produced few TUNEL-positive cells. TFs induced annexin V/PI-double positive HSC-2 cells and annexin V-positive/PI-negative HSC-4 cells, respectively, but failed to activate caspase-3, capase-8 and caspase-9 in both HSC-2 and HSC-4 cells. On the other hand, TFs induced the formation of acidic organelles (detected by acridine orange staining) in both HSC-2 and HSC-4 cells. When HSC-2 and HSC-4 cells that had been transfected with expression vector encording the microtubule-associated protein 1 light chain 3 (LC3) gene fused to green fluorescent protein (GFP) were treated with TFs, LC3-GFP fusion protein was accumulated as granular dots in autophagosomes. Pretreatment with 3-methyladenine, an inhibitor of autophagy, partially inhibited the cytotoxicity of TFs, the formation of acidic organelles and LC3 accumulation in the autophagosome. These data suggest that alpha-trifluoromethyl acyloins may induce autophagic cell death in HSC-2 and HSC-4 cells following the early stage of necrosis or apoptosis, respectively.

  5. Ysp2 mediates death of yeast induced by amiodarone or intracellular acidification.

    Science.gov (United States)

    Sokolov, Sviatoslav; Knorre, Dmitry; Smirnova, Ekaterina; Markova, Olga; Pozniakovsky, Andrey; Skulachev, Vladimir; Severin, Fedor

    2006-01-01

    Recently we have found that the drug amiodarone induces apoptosis in yeast, which is mediated by reactive oxygen species (ROS). Here we have used this finding as a tool to screen for genes involved in the death program. We have described a novel mitochondrial protein, Ysp2, acting in the amiodarone-induced death cascade. After amiodarone addition both the control and amiodarone-resistant ysp2-deleted cells formed ROS, but the mutant (unlike the control) did not undergo the mitochondrial thread-to-grain transition. To test whether the action of Ysp2 is amiodarone-specific we tried to induce PCD by other agents. We have found that acetic acid-induced PCD also depends on Ysp2. We also demonstrate that, like acetic acid, propionic acid or nigericin triggered intracellular acidification causing ROS-dependent death. We suggest that intracellular acidification results in the protonation of superoxide anion (O2-*) to form HO2, one of the most aggressive ROS, which in turn induces Ysp2-mediated PCD.

  6. Stress-induced cell death is mediated by ceramide synthesis in Neurospora crassa

    DEFF Research Database (Denmark)

    Plesofsky, Nora S; Levery, Steven B; Castle, Sherry A

    2008-01-01

    The combined stresses of moderate heat shock (45 degrees C) and analog-induced glucose deprivation constitute a lethal stress for Neurospora crassa. We found that this cell death requires fatty acid synthesis and the cofactor biotin. In the absence of the cofactor, the stressed cells are particul...... type, and phosphorylated OS-2 increased in wild-type cells in response to heat shock and combined heat and carbon stress.......The combined stresses of moderate heat shock (45 degrees C) and analog-induced glucose deprivation constitute a lethal stress for Neurospora crassa. We found that this cell death requires fatty acid synthesis and the cofactor biotin. In the absence of the cofactor, the stressed cells...... are particularly sensitive to exogenous ceramide, which is lethal at low concentrations. When we extracted endogenous sphingolipids, we found that unique ceramides were induced (i) by the inhibitory glucose analog 2-deoxyglucose and (ii) by combined heat shock and 2-deoxyglucose. We determined that the former...

  7. Increased anion channel activity is an unavoidable event in ozone-induced programmed cell death.

    Directory of Open Access Journals (Sweden)

    Takashi Kadono

    Full Text Available BACKGROUND: Ozone is a major secondary air pollutant often reaching high concentrations in urban areas under strong daylight, high temperature and stagnant high-pressure systems. Ozone in the troposphere is a pollutant that is harmful to the plant. PRINCIPAL FINDINGS: By exposing cells to a strong pulse of ozonized air, an acute cell death was observed in suspension cells of Arabidopsis thaliana used as a model. We demonstrated that O(3 treatment induced the activation of a plasma membrane anion channel that is an early prerequisite of O(3-induced cell death in A. thaliana. Our data further suggest interplay of anion channel activation with well known plant responses to O(3, Ca(2+ influx and NADPH-oxidase generated reactive oxygen species (ROS in mediating the oxidative cell death. This interplay might be fuelled by several mechanisms in addition to the direct ROS generation by O(3; namely, H(2O(2 generation by salicylic and abscisic acids. Anion channel activation was also shown to promote the accumulation of transcripts encoding vacuolar processing enzymes, a family of proteases previously reported to contribute to the disruption of vacuole integrity observed during programmed cell death. SIGNIFICANCE: Collectively, our data indicate that anion efflux is an early key component of morphological and biochemical events leading to O(3-induced programmed cell death. Because ion channels and more specifically anion channels assume a crucial position in cells, an understanding about the underlying role(s for ion channels in the signalling pathway leading to programmed cell death is a subject that warrants future investigation.

  8. Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

    Directory of Open Access Journals (Sweden)

    Ryan Ruth CM

    2011-10-01

    Full Text Available Abstract Background Dendritic cells (DCs connect innate and adaptive immunity, and are necessary for an efficient CD4+ and CD8+ T cell response after infection with Mycobacterium tuberculosis (Mtb. We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival. Results Infection of DCs with live Mtb (H37Ra or H37Rv led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth. Conclusions Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.

  9. Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

    LENUS (Irish Health Repository)

    Ryan, Ruth CM

    2011-10-24

    Abstract Background Dendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4+ and CD8+ T cell response after infection with Mycobacterium tuberculosis (Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival. Results Infection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3\\/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth. Conclusions Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.

  10. Sulforaphane Prevents Angiotensin II-Induced Testicular Cell Death via Activation of NRF2

    Directory of Open Access Journals (Sweden)

    Yonggang Wang

    2017-01-01

    Full Text Available Although angiotensin II (Ang II was reported to facilitate sperm motility and intratesticular sperm transport, recent findings shed light on the efficacy of Ang II in stimulating inflammatory events in testicular peritubular cells, effect of which may play a role in male infertility. It is still unknown whether Ang II can induce testicular apoptotic cell death, which may be a more direct action of Ang II in male infertility. Therefore, the present study aims to determine whether Ang II can induce testicular apoptotic cell death and whether this action can be prevented by sulforaphane (SFN via activating nuclear factor (erythroid-derived 2-like 2 (NRF2, the governor of antioxidant-redox signalling. Eight-week-old male C57BL/6J wild type (WT and Nrf2 gene knockout mice were treated with Ang II, in the presence or absence of SFN. In WT mice, SFN activated testicular NRF2 expression and function, along with a marked attenuation in Ang II-induced testicular oxidative stress, inflammation, endoplasmic reticulum stress, and apoptotic cell death. Deletion of the Nrf2 gene led to a complete abolishment of these efficacies of SFN. The present study indicated that Ang II may result in testicular apoptotic cell death, which can be prevented by SFN via the activation of NRF2.

  11. N-Desmethyldauricine Induces Autophagic Cell Death in Apoptosis-Defective Cells via Ca(2+) Mobilization.

    Science.gov (United States)

    Law, Betty Y K; Mok, Simon W F; Chen, Juan; Michelangeli, Francesco; Jiang, Zhi-Hong; Han, Yu; Qu, Yuan Q; Qiu, Alena C L; Xu, Su-Wei; Xue, Wei-Wei; Yao, Xiao-Jun; Gao, Jia Y; Javed, Masood-Ul-Hassan; Coghi, Paolo; Liu, Liang; Wong, Vincent K W

    2017-01-01

    Resistance of cancer cells to chemotherapy remains a significant problem in oncology. Mechanisms regulating programmed cell death, including apoptosis, autophagy or necrosis, in the treatment of cancers have been extensively investigated over the last few decades. Autophagy is now emerging as an important pathway in regulating cell death or survival in cancer therapy. Recent studies demonstrated variety of natural small-molecules could induce autophagic cell death in apoptosis-resistant cancer cells, therefore, discovery of novel autophagic enhancers from natural products could be a promising strategy for treatment of chemotherapy-resistant cancer. By computational virtual docking analysis, biochemical assays, and advanced live-cell imaging techniques, we have identified N-desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca(2+)/Calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK-mTOR signaling cascades, via mobilizing calcium release through inhibition of SERCA, and importantly, lead to autophagic cell death in a panel of cancer cells, apoptosis-defective and apoptosis-resistant cells. Taken together, this study provides detailed insights into the cytotoxic mechanism of a novel autophagic compound that targeting the apoptosis resistant cancer cells, and new implication on drug discovery from natural products for drug resistant cancer therapy.

  12. Seizure-induced neuronal death is suppressed in the absence of the endogenous lectin Galectin-1.

    Science.gov (United States)

    Bischoff, Vincent; Deogracias, Rubén; Poirier, Françoise; Barde, Yves-Alain

    2012-10-31

    Pilocarpine injection induces epileptic seizures in rodents, an experimental paradigm extensively used to model temporal lobe epilepsy in humans. It includes conspicuous neuronal death in the forebrain and previous work has demonstrated an involvement of the neurotrophin receptor p75(NTR) in this process. Following the identification of Galectin-1 (Gal-1) as a downstream effector of p75(NTR), we examine here the role of this endogenous lectin in pilocarpine-induced cell death in adult mice. We found that most somatostatin-positive neurons also express Gal-1 and that in mice lacking the corresponding gene Lgals1, pilocarpine-induced neuronal death was essentially abolished in the forebrain. We also found that the related lectin Galectin-3 (Gal-3) was strongly upregulated by pilocarpine in microglial cells. This upregulation was absent in Lgals1 mutants and our results with Lgals3-null animals show that Gal-3 is not required for neuronal death in the hippocampus. These findings provide new insights into the roles and regulation of endogenous lectins in the adult CNS and a surprisingly selective proapoptotic role of Gal-1 for a subpopulation of GABAergic interneurons.

  13. Sigma-2 ligands induce tumour cell death by multiple signalling pathways.

    Science.gov (United States)

    Zeng, C; Rothfuss, J; Zhang, J; Chu, W; Vangveravong, S; Tu, Z; Pan, F; Chang, K C; Hotchkiss, R; Mach, R H

    2012-02-14

    The sigma-2 receptor has been identified as a biomarker of proliferating cells in solid tumours. In the present study, we studied the mechanisms of sigma-2 ligand-induced cell death in the mouse breast cancer cell line EMT-6 and the human melanoma cell line MDA-MB-435. EMT-6 and MDA-MB-435 cells were treated with sigma-2 ligands. The modulation of multiple signaling pathways of cell death was evaluated. Three sigma-2 ligands (WC-26, SV119 and RHM-138) induced DNA fragmentation, caspase-3 activation and PARP-1 cleavage. The caspase inhibitor Z-VAD-FMK partially blocked DNA fragmentation and cytotoxicity caused by these compounds. These data suggest that sigma-2 ligand-induced apoptosis and caspase activation are partially responsible for the cell death. WC-26 and siramesine induced formation of vacuoles in the cells. WC-26, SV119, RHM-138 and siramesine increased the synthesis and processing of microtubule-associated protein light chain 3, an autophagosome marker, and decreased the expression levels of the downstream effectors of mammalian target of rapamycin (mTOR), p70S6K and 4EBP1, suggesting that sigma-2 ligands induce autophagy, probably by inhibition of the mTOR pathway. All four sigma-2 ligands decreased the expression of cyclin D1 in a time-dependent manner. In addition, WC-26 and SV119 mainly decreased cyclin B1, E2 and phosphorylation of retinoblastoma protein (pRb); RHM-138 mainly decreased cyclin E2; and 10 μM siramesine mainly decreased cyclin B1 and pRb. These data suggest that sigma-2 ligands also impair cell-cycle progression in multiple phases of the cell cycle. Sigma-2 ligands induce cell death by multiple signalling pathways.

  14. Cationic polystyrene nanospheres induce autophagic cell death through the induction of endoplasmic reticulum stress

    Science.gov (United States)

    Chiu, Hui-Wen; Xia, Tian; Lee, Yu-Hsuan; Chen, Chun-Wan; Tsai, Jui-Chen; Wang, Ying-Jan

    2014-12-01

    Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung epithelial (BEAS-2B) cells. Furthermore, NH2-PS could induce autophagic cell death. NH2-PS increased autophagic flux due to reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress caused by misfolded protein aggregation. The inhibition of ER stress decreased cytotoxicity and autophagy in the NH2-PS-treated cells. In addition, the Akt/mTOR and AMPK signaling pathways were involved in the regulation of NH2-PS-triggered autophagic cell death. These results suggest an important role of autophagy in cationic NP-induced cell death and provide mechanistic insights into the inhibition of the toxicity and safe material design.Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung

  15. Brain injury induces specific changes in the caecal microbiota of mice via altered autonomic activity and mucoprotein production.

    Science.gov (United States)

    Houlden, A; Goldrick, M; Brough, D; Vizi, E S; Lénárt, N; Martinecz, B; Roberts, I S; Denes, A

    2016-10-01

    Intestinal microbiota are critical for health with changes associated with diverse human diseases. Research suggests that altered intestinal microbiota can profoundly affect brain function. However, whether altering brain function directly affects the microbiota is unknown. Since it is currently unclear how brain injury induces clinical complications such as infections or paralytic ileus, key contributors to prolonged hospitalization and death post-stroke, we tested in mice the hypothesis that brain damage induced changes in the intestinal microbiota. Experimental stroke altered the composition of caecal microbiota, with specific changes in Peptococcaceae and Prevotellaceae correlating with the extent of injury. These effects are mediated by noradrenaline release from the autonomic nervous system with altered caecal mucoprotein production and goblet cell numbers. Traumatic brain injury also caused changes in the gut microbiota, confirming brain injury effects gut microbiota. Changes in intestinal microbiota after brain injury may affect recovery and treatment of patients should appreciate such changes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Palmitate-induced NO production has a dual action to reduce cell death through NO and accentuate cell death through peroxynitrite formation.

    Science.gov (United States)

    Rabkin, Simon W; Klassen, Shaun S

    2008-02-01

    The objective of this study was to determine the role of palmitate-induced stimulation of nitric oxide synthase (NOS) on palmitate-induced cell death, specifically distinguishing the effects of the subtype NOS2 from NOS3, defining the effect of NO on mitochondria death pathways, and determining whether palmitate induces peroxynitrite formation which may impact cardiomyocyte cell survival. Cardiomyocytes from embryonic chick hearts were treated with palmitate 300-500 microM. Cell death was assessed by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The ability of palmitate to induce NO production and its consequences were tested by using the NOS inhibitor 7-nitroindazole (7-N) and the peroxynitrite scavenger (5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) chloride) (FeTPPS). The effect of palmitate on the mitochondria was assessed by Western blotting for cytochrome c release into the cytosol, and assessment of mitochondrial transmembrane potential (DeltaPsi(m)) by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolyl-carbocyanine iodide staining and immunocytochemistry. The NOS inhibitor 7-N, which is selective for NOS2 and not for NOS3, significantly (poxidative phosphorylation. The mitochondrial actions of palmitate, specifically palmitate-induced translocation of mitochondrial cytochrome c to cytosol and loss of mitochondrial transmembrane potential, were not altered by pretreatment with 7-N. FeTPPS, which isomerizes peroxynitrite to nitrate and thereby reduces the toxic effects of peroxynitrite, produced a significant reduction in palmitate-induced cell death. In summary, these data suggest that palmitate stimulates NO production, which has a dual action to protect against cell death or to induce cell death. Palmitate-induced cell death is mediated, in part, through NO generation, which leads to peroxynitrite formation. The protective effect of NO is operative through stimulation of NOS2 but not NOS3. The actions

  17. Ownership of an artificial limb induced by electrical brain stimulation.

    Science.gov (United States)

    Collins, Kelly L; Guterstam, Arvid; Cronin, Jeneva; Olson, Jared D; Ehrsson, H Henrik; Ojemann, Jeffrey G

    2017-01-03

    Replacing the function of a missing or paralyzed limb with a prosthetic device that acts and feels like one's own limb is a major goal in applied neuroscience. Recent studies in nonhuman primates have shown that motor control and sensory feedback can be achieved by connecting sensors in a robotic arm to electrodes implanted in the brain. However, it remains unknown whether electrical brain stimulation can be used to create a sense of ownership of an artificial limb. In this study on two human subjects, we show that ownership of an artificial hand can be induced via the electrical stimulation of the hand section of the somatosensory (SI) cortex in synchrony with touches applied to a rubber hand. Importantly, the illusion was not elicited when the electrical stimulation was delivered asynchronously or to a portion of the SI cortex representing a body part other than the hand, suggesting that multisensory integration according to basic spatial and temporal congruence rules is the underlying mechanism of the illusion. These findings show that the brain is capable of integrating "natural" visual input and direct cortical-somatosensory stimulation to create the multisensory perception that an artificial limb belongs to one's own body. Thus, they serve as a proof of concept that electrical brain stimulation can be used to "bypass" the peripheral nervous system to induce multisensory illusions and ownership of artificial body parts, which has important implications for patients who lack peripheral sensory input due to spinal cord or nerve lesions.

  18. Zika Virus Infects Human Fetal Brain Microglia and Induces Inflammation.

    Science.gov (United States)

    Lum, Fok-Moon; Low, Donovan K S; Fan, Yiping; Tan, Jeslin J L; Lee, Bernett; Chan, Jerry K Y; Rénia, Laurent; Ginhoux, Florent; Ng, Lisa F P

    2017-04-01

    The unprecedented reemergence of Zika virus (ZIKV) has startled the world with reports of increased microcephaly in Brazil. ZIKV can infect human neural progenitors and impair brain growth. However, direct evidence of ZIKV infection in human fetal brain tissues remains elusive. Investigations were performed with brain cell preparations obtained from 9 donors. Virus infectivity was assessed by detection of virus antigen by flow cytometry together with various hematopoietic cell surface markers. Virus replication was determined by viral RNA quantification. Cytokine levels in supernatant obtained from virus-infected fetal brain cells were measured simultaneously in microbead-based immunoassays. We also show that ZIKV infection was particularly evident in hematopoietic cells with microglia, the brain-resident macrophage population being one of the main targets. Infection induces high levels of proinflammatory immune mediators such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and monocyte chemotactic protein 1 (MCP-1). Our results highlight an important role for microglia and neuroinflammation during congenital ZIKV pathogenesis.

  19. Occurrence of specific environmental risk factors in brain tissues of sudden infant death and sudden intrauterine unexpected death victims assessed with gas chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Termopoli, Veronica; Famiglini, Giorgio; Palma, Pierangela; Magrini, Laura; Cappiello, Achille

    2015-03-01

    Sudden infant death syndrome (SIDS) and sudden intrauterine unexpected death syndrome (SIUDS) are an unresolved teaser in the social-medical and health setting of modern medicine and are the result of multifactorial interactions. Recently, prenatal exposure to environmental contaminants has been associated with negative pregnancy outcomes, and verification of their presence in fetal and newborn tissues is of crucial importance. A gas chromatography-tandem mass spectrometry (MS/MS) method, using a triple quadrupole analyzer, is proposed to assess the presence of 20 organochlorine pesticides, two organophosphate pesticides, one carbamate (boscalid), and a phenol (bisphenol A) in human brain tissues. Samples were collected during autopsies of infants and fetuses that died suddenly without any evident cause. The method involves a liquid-solid extraction using n-hexane as the extraction solvent. The extracts were purified with Florisil cartridges prior to the final determination. Recovery experiments using lamb brain spiked at three different concentrations in the range of 1-50 ng g(-1) were performed, with recoveries ranging from 79 to 106%. Intraday and interday repeatability were evaluated, and relative standard deviations lower than 10% and 18%, respectively, were obtained. The selectivity and sensitivity achieved in multiple reaction monitoring mode allowed us to achieve quantification and confirmation in a real matrix at levels as low as 0.2-0.6 ng g(-1). Two MS/MS transitions were acquired for each analyte, using the Q/q ratio as the confirmatory parameter. This method was applied to the analysis of 14 cerebral cortex samples (ten SIUDS and four SIDS cases), and confirmed the presence of several selected compounds.

  20. Non confirmatory electroencephalography in patients meeting clinical criteria for brain death: scenario and impact on organ donation.

    Science.gov (United States)

    Fernández-Torre, José L; Hernández-Hernández, Miguel A; Muñoz-Esteban, Cristina

    2013-12-01

    To describe the causes and outcome of adult patients with preserved electroencephalographic activity despite clinical findings suggesting brain death (BD), and its impact on organ donation. Retrospective study of the clinical and electroencephalography (EEG) data of all adult patients admitted to our hospital between January 2001 and December 2011 in whom a comprehensive clinical diagnosis of BD was reached following absence of brainstem reflexes and confirmatory apnea tests, were obtained. All patients with clinical findings suggesting BD and an EEG showing brain activity were selected for the analysis. We calculated the brain death interval (BDI) as the time between the first complete clinical examination and confirmatory ancillary test, or the time between the first and second complete clinical examination for BD, in order to analyze the impact on family consent for organ donation. A complete clinical examination and EEG were diagnostic in 289 patients. In 279 (96.5%), the first EEG showed electrocerebral inactivity corroborating the clinical findings of BD. The mean BDI in this group was 4.2 ± 5.8h (median; 1.8[1.0-3.5]). This value was significantly lower than in the group in which only two full clinical evaluations were performed (p6h, was positively associated with a family refusal for organ donation (p=0.02). The rate of EEGs with electrocerebral activity despite clinical findings suggesting BD was only 3.5%. It occurred most frequently with severe brainstem damage. Although in this small percentage of patients, BD diagnosis was notably delayed, in the great majority of cases the use of EEG shortened the BDI. In our series, a BD diagnosis delay >6h negatively affected consent for organ donation. The use of EEG can decrease the time interval for brain death diagnosis. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  1. Lipid peroxidation is essential for α-synuclein-induced cell death.

    Science.gov (United States)

    Angelova, Plamena R; Horrocks, Mathew H; Klenerman, David; Gandhi, Sonia; Abramov, Andrey Y; Shchepinov, Mikhail S

    2015-05-01

    Parkinson's disease is the second most common neurodegenerative disease and its pathogenesis is closely associated with oxidative stress. Deposition of aggregated α-synuclein (α-Syn) occurs in familial and sporadic forms of Parkinson's disease. Here, we studied the effect of oligomeric α-Syn on one of the major markers of oxidative stress, lipid peroxidation, in primary co-cultures of neurons and astrocytes. We found that oligomeric but not monomeric α-Syn significantly increases the rate of production of reactive oxygen species, subsequently inducing lipid peroxidation in both neurons and astrocytes. Pre-incubation of cells with isotope-reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of oligomeric α-Syn on lipid peroxidation. Inhibition of lipid peroxidation with D-PUFAs further protected cells from cell death induced by oligomeric α-Syn. Thus, lipid peroxidation induced by misfolding of α-Syn may play an important role in the cellular mechanism of neuronal cell loss in Parkinson's disease. We have found that aggregated α-synuclein-induced production of reactive oxygen species (ROS) that subsequently stimulates lipid peroxidation and cell death in neurons and astrocytes. Specific inhibition of lipid peroxidation by incubation with reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of α-synuclein on lipid peroxidation and cell death. © 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry.

  2. Acupuncture inhibits kainic Acid-induced hippocampal cell death in mice.

    Science.gov (United States)

    Kim, Seung-Tae; Jeon, Songhee; Park, Hae Jeong; Hong, Mee-Sook; Jeong, Wu Byung; Kim, Jang-Hyun; Kim, Yeonjung; Lee, Hye-Jung; Park, Hi-Joon; Chung, Joo-Ho

    2008-02-01

    We examined whether acupuncture can reduce both the incidence of seizures and hippocampal cell death using a mouse model of kainic acid (KA)-induced epilepsy. ICR mice were given acupuncture once a day at acupoint HT8 (sobu) bilaterally during 2 days before KA injection. After an intracerebroventricular injection of 0.1 microg of KA, acupuncture treatment was subsequently administered once more (total 3 times), and the degree of seizure was observed for 20 min. Three hours after injection, the survival of neuronal cells and the expressions of c-Fos, c-Jun, and glutamate decarboxylase (GAD)-67 in the CA1 and CA3 were determined using immunohistochemistry and Western blotting techniques. Acupuncture reduced the severity of the KA-induced epileptic seizure and the rate of neural cell death, and it also decreased the expressions of c-Fos and c-Jun induced by KA in the hippocampus. Furthermore, acupuncture increased GAD-67 expressions in the same areas. These results demonstrated that it could inhibit the KA-induced epileptic seizure and hippocampal cell death by increasing GAD-67 expressions.

  3. Oxidative Stress, Cell Death, and Other Damage to Alveolar Epithelial Cells Induced by Cigarette Smoke

    Directory of Open Access Journals (Sweden)

    Nagai A

    2003-09-01

    Full Text Available Abstract Cigarette smoking is a major risk factor in the development of various lung diseases, including pulmonary emphysema, pulmonary fibrosis, and lung cancer. The mechanisms of these diseases include alterations in alveolar epithelial cells, which are essential in the maintenance of normal alveolar architecture and function. Following cigarette smoking, alterations in alveolar epithelial cells induce an increase in epithelial permeability, a decrease in surfactant production, the inappropriate production of inflammatory cytokines and growth factors, and an increased risk of lung cancer. However, the most deleterious effect of cigarette smoke on alveolar epithelial cells is cell death, i.e., either apoptosis or necrosis depending on the magnitude of cigarette smoke exposure. Cell death induced by cigarette smoke exposure can largely be accounted for by an enhancement in oxidative stress. In fact, cigarette smoke contains and generates many reactive oxygen species that damage alveolar epithelial cells. Whether apoptosis and/or necrosis in alveolar epithelial cells is enhanced in healthy cigarette smokers is presently unclear. However, recent evidence indicates that the apoptosis of alveolar epithelial cells and alveolar endothelial cells is involved in the pathogenesis of pulmonary emphysema, an important cigarette smoke-induced lung disease characterized by the loss of alveolar structures. This review will discuss oxidative stress, cell death, and other damage to alveolar epithelial cells induced by cigarette smoke.

  4. Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells.

    Science.gov (United States)

    Sonnemann, Jürgen; Hüls, Isabel; Sigler, Michael; Palani, Chithra D; Hong, Le Thi Thu; Völker, Uwe; Kroemer, Heyo K; Beck, James F

    2008-07-01

    Histone deacetylase inhibitors (HDIs) as well as non-steroidal anti-inflammatory drugs including aspirin show promise as antineoplastic agents. The treatment with both HDIs and aspirin can result in hyperacetylation of proteins. In this study, we investigated whether HDIs and aspirin interacted in inducing anticancer activity and histone acetylation. We found that the HDIs, suberoylanilide hydroxamic acid and sodium butyrate, and aspirin cooperated to induce cell death in the ovarian cancer cell line, A2780. The effect was synergistic, as evidenced by CI-isobologram analysis. However, aspirin had no effect on histone acetylation, neither in the absence nor presence of HDIs. To gain insight into the mechanism underlying the synergistic action of HDIs and aspirin, we employed the deacetylated metabolite of aspirin, salicylic acid, and the cyclooxygenase-1- and -2-selective inhibitors, SC-560 and NS-398, respectively. We found that HDIs and salicylic acid interacted synergistically, albeit less efficiently than HDIs and aspirin, to induce cancer cell death, suggesting that the acetyl and the salicyl moiety contributed to the cooperative interaction of aspirin with HDIs. SC-560 and NS-398 had little effect both when applied alone or in conjunction with HDIs, indicating that the combinatorial effect of HDIs and aspirin was not the result of cyclo-oxygenase inhibition. In conclusion, our study demonstrates that HDIs and aspirin synergize to induce cancer cell death and, thus, provides a rationale for a more in-depth exploration into the potential of combining HDIs and aspirin as a strategy for anticancer therapy.

  5. Colistin-Induced Nephrotoxicity in Mice Involves the Mitochondrial, Death Receptor, and Endoplasmic Reticulum Pathways

    Science.gov (United States)

    Dai, Chongshan; Li, Jichang; Tang, Shusheng

    2014-01-01

    Nephrotoxicity is the dose-limiting factor for colistin, but the exact mechanism is unknown. This study aimed to investigate the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in colistin-induced nephrotoxicity. Mice were intravenously administered 7.5 or 15 mg of colistin/kg of body weight/day (via a 3-min infusion and divided into two doses) for 7 days. Renal function, oxidative stress, and apoptosis were measured. Representative biomarkers involved in the mitochondrial, death receptor, and endoplasmic reticulum pathways were investigated, and the key markers involved in apoptosis and autophagy were examined. After 7-day colistin treatment, significant increase was observed with blood urea nitrogen, serum creatinine, and malondialdehyde, while activities of superoxide dismutase (SOD) and catalase decreased in the kidneys. Acute tubular necrosis and mitochondrial dysfunction were detected, and colistin-induced apoptosis was characterized by DNA fragmentation, cleavage of poly(ADP-ribose) polymerase (PARP-1), increase of 8-hydroxydeoxyguanosine (8-OHdG), and activation of caspases (caspase-8, -9, and -3). It was evident that colistin-induced apoptosis involved the mitochondrial pathway (downregulation of Bcl-2 and upregulation of cytochrome C [cytC] and Bax), death receptor pathway (upregulation of Fas, FasL, and Fas-associated death domain [FADD]), and endoplasmic reticulum pathway (upregulation of Grp78/Bip, ATF6, GADD153/CHOP, and caspase-12). In the 15-mg/kg/day colistin group, expression of the cyclin-dependent kinase 2 (CDK2) and phosphorylated JNK (p-JNK) significantly increased (P colistin group, a large number of autophagolysosomes and classic autophagy were observed. Western blot results of Beclin-1 and LC3B indicated that autophagy may play a protective role in colistin-induced nephrotoxicity. In conclusion, this is the first study to demonstrate that all three major apoptosis pathways and autophagy are involved in

  6. The roles of mitochondria in radiation-induced autophagic cell death in cervical cancer cells.

    Science.gov (United States)

    Chen, Zongyan; Wang, Benli; Yu, Feifei; Chen, Qiao; Tian, Yuxi; Ma, Shumei; Liu, Xiaodong

    2016-03-01

    Mitochondria as the critical powerhouse of eukaryotic cells play important roles in regulating cell survival or cell death. Under numerous stimuli, impaired mitochondria will generate massive reactive oxygen species (ROS) which participate in the regulation of vital signals and could even determine the fate of cancer cells. While the roles of mitochondria in radiation-induced autophagic cell death still need to be elucidated. Human cervical cancer cell line, Hela, was used, and the SOD2 silencing model (SOD2-Ri) was established by gene engineering. Cell viability was detected by methyl thiazolyl tetrazolium (MTT) assays, MitoTracker Green staining was used to detect mitochondrial mass, Western blot was used to detect protein expression, and the level of ROS, autophagy, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. Ionizing radiation (IR) could induce the increase of MAPLC3-II/MAPLC3-I ratio, Beclin1 expression, and ROS generation but decrease the MMP in a time-dependent manner. After SOD2 silencing, the IR-induced changes of ROS and the MMP were significantly enhanced. Moreover, both the radio sensitivity and autophagy increased in SOD2-Ri cells. Whereas, compared with SOD2-Ri, the opposite results were obtained by NAC, an antioxidant. After the treatment with the inhibitor of mitochondrial electron-transport chain complex II, thenoyltrifluoroacetone (TTFA), the rate of autophagy, ROS, and the total cell death induced by IR increased. In addition, the decrease of MMP was more obvious. However, these results were reversed by cyclosporine A (CsA). IR could induce ROS generation and mitochondrial damage which lead to autophagic cell death in Hela cells.

  7. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration.

    Science.gov (United States)

    Singh, Sandeep; Singh, Abhishek Kumar; Garg, Geetika; Rizvi, Syed Ibrahim

    2018-01-15

    In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Fisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury.

    Science.gov (United States)

    Drommelschmidt, Karla; Serdar, Meray; Bendix, Ivo; Herz, Josephine; Bertling, Frederik; Prager, Sebastian; Keller, Matthias; Ludwig, Anna-Kristin; Duhan, Vikas; Radtke, Stefan; de Miroschedji, Kyra; Horn, Peter A; van de Looij, Yohan; Giebel, Bernd; Felderhoff-Müser, Ursula

    2017-02-01

    Preterm brain injury is a major cause of disability in later life, and may result in motor, cognitive and behavioural impairment for which no treatment is currently available. The aetiology is considered as multifactorial, and one underlying key player is inflammation leading to white and grey matter injury. Extracellular vesicles secreted by mesenchymal stem/stromal cells (MSC-EVs) have shown therapeutic potential in regenerative medicine. Here, we investigated the effects of MSC-EV treatment on brain microstructure and maturation, inflammatory processes and long-time outcome in a rodent model of inflammation-induced brain injury. 3-Day-old Wistar rats (P3) were intraperitoneally injected with 0.25mg/kg lipopolysaccharide or saline and treated with two repetitive doses of 1×10 8 cell equivalents of MSC-EVs per kg bodyweight. Cellular degeneration and reactive gliosis at P5 and myelination at P11 were evaluated by immunohistochemistry and western blot. Long-term cognitive and motor function was assessed by behavioural testing. Diffusion tensor imaging at P125 evaluated long-term microstructural white matter alterations. MSC-EV treatment significantly ameliorated inflammation-induced neuronal cellular degeneration reduced microgliosis and prevented reactive astrogliosis. Short-term myelination deficits and long-term microstructural abnormalities of the white matter were restored by MSC-EV administration. Morphological effects of MSC-EV treatment resulted in improved long-lasting cognitive functions INTERPRETATION: MSC-EVs ameliorate inflammation-induced cellular damage in a rat model of preterm brain injury. MSC-EVs may serve as a novel therapeutic option by prevention of neuronal cell death, restoration of white matter microstructure, reduction of gliosis and long-term functional improvement. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

    DEFF Research Database (Denmark)

    De Bruin, M L; Pettersson, M; Meyboom, R H B

    2005-01-01

    AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS...... defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value......, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. CONCLUSION: Anti-HERG activity is associated...

  10. Autophagy induced by purple pitanga (Eugenia uniflora L.) extract triggered a cooperative effect on inducing the hepatic stellate cell death.

    Science.gov (United States)

    Denardin, Cristiane C; Martins, Leo A M; Parisi, Mariana M; Vieira, Moema Queiroz; Terra, Silvia R; Barbé-Tuana, Florencia M; Borojevic, Radovan; Vizzotto, Márcia; Emanuelli, Tatiana; Guma, Fátima Costa Rodrigues

    2017-04-01

    Activated hepatic stellate cells (HSC) are the major source of collagen I in liver fibrosis. Eugenia uniflora L. is a tree species that is widely distributed in South America. E. uniflora L. fruit-popularly known as pitanga-has been shown to exert beneficial properties. Autophagy contributes to the maintenance of cellular homeostasis and survival under stress situation, but it has also been suggested to be an alternative cell death pathway. Mitochondria play a pivotal role on signaling cell death. Mitophagy of damaged mitochondria is an important cell defense mechanism against organelle-mediated cell death signaling. We previously found that purple pitanga extract induced mitochondrial dysfunction, cell cycle arrest, and death by apoptosis and necrosis in GRX cells, a well-established activated HSC line. We evaluated the effects of 72-h treatment with crescent concentrations of purple pitanga extract (5 to 100 μg/mL) on triggering autophagy in GRX cells, as this is an important mechanism to cells under cytotoxic conditions. We found that all treated cells presented an increase in the mRNA expression of autophagy-related protein 7 (ATG7). Concomitantly, flow cytometry and ultrastructural analysis of treated cells revealed an increase of autophagosomes/autolysosomes that consequentially led to an increased mitophagy. As purple pitanga extract was previously found to be broadly cytotoxic to GRX cells, we postulated that autophagy contributes to this scenario, where cell death seems to be an inevitable fate. Altogether, the effectiveness on inducing activated HSC death can make purple pitanga extract a good candidate on treating liver fibrosis.

  11. The Ketogenic Diet Suppresses the Cathepsin E Expression Induced by Kainic Acid in the Rat Brain

    Science.gov (United States)

    Jeong, Hyun Jeong; Kim, Hojeong; Kim, Yoon-Kyoung; Park, Sang-Kyu; Kang, Dong-Won

    2010-01-01

    Purpose The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, we analyzed the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model. Materials and Methods KA-administered rats were fed the ketogenic diet or a normal diet for 4 weeks, and microarray analysis was performed with their brain tissues. The effects of the ketogenic diet on cathepsin E messenger ribonucleic acid (mRNA) expression were analyzed in KA-administered and normal saline-administered groups with semi-quantitative and real-time reverse transcription polymerase chain reaction (RT-PCR). Brain tissues were dissected into 8 regions to compare differential effects of the ketogenic diet on cathepsin E mRNA expression. Immunohistochemistry with an anti-cathepsin E antibody was performed on slides of hippocampus obtained from whole brain paraffin blocks. Results The microarray data and subsequent RT-PCR experiments showed that KA increased the mRNA expression of cathepsin E, known to be related to neuronal cell death, in most brain areas except the brain stem, and these increases of cathepsin E mRNA expression were suppressed by the ketogenic diet. The expression of cathepsin E mRNA in the control group, however, was not significantly affected by the ketogenic diet. The change in cathepsin E mRNA expression was greatest in the hippocampus. The protein level of cathepsin E in the hippocampus of KA-administered rat was elevated in immunohistochemistry and the ketogenic diet suppressed this increase. Conclusion Our results showed that KA administration increased cathepsin E expression in the rat brain and its increase was suppressed by the ketogenic diet. PMID:20635438

  12. An international comparison of the effect of policy shifts to organ donation following cardiocirculatory death (DCD on donation rates after brain death (DBD and transplantation rates.

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    Aric Bendorf

    Full Text Available During the past decade an increasing number of countries have adopted policies that emphasize donation after cardiocirculatory death (DCD in an attempt to address the widening gap between the demand for transplantable organs and the availability of organs from donation after brain death (DBD donors. In order to examine how these policy shifts have affected overall deceased organ donor (DD and DBD rates, we analyzed deceased donation rates from 82 countries from 2000-2010. On average, overall DD, DBD and DCD rates have increased over time, with the proportion of DCD increasing 0.3% per year (p = 0.01. Countries with higher DCD rates have, on average, lower DBD rates. For every one-per million population (pmp increase in the DCD rate, the average DBD rate decreased by 1.02 pmp (95% CI: 0.73, 1.32; p<0.0001. We also found that the number of organs transplanted per donor was significantly lower in DCD when compared to DBD donors with 1.51 less transplants per DCD compared to DBD (95% CI: 1.23, 1.79; p<0.001. Whilst the results do not infer a causal relationship between increased DCD and decreased DBD rates, the significant correlation between higher DCD and lower DBD rates coupled with the reduced number of organs transplanted per DCD donor suggests that a national policy focus on DCD may lead to an overall reduction in the number of transplants performed.

  13. Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells.

    Science.gov (United States)

    Kim, Han Sung; Choi, Seung-Il; Jeung, Eui-Bae; Yoo, Yeong-Min

    2014-01-01

    Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 µM) decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 µM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 µM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD) showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 µM CsA), but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels.

  14. Alcohol consumption in relation to maternal deaths from induced-abortions in Ghana.

    Science.gov (United States)

    Asamoah, Benedict O; Agardh, Anette

    2012-08-06

    The fight against maternal deaths has gained attention as the target date for Millennium Development Goal 5 approaches. Induced-abortion is one of the leading causes of maternal deaths in developing countries which hamper this effort. In Ghana, alcohol consumption and unwanted pregnancies are on the ascendancy. We examined the association between alcohol consumption and maternal mortality from induced-abortion. We further analyzed the factors that lie behind the alcohol consumption patterns in the study population. The data we used was extracted from the Ghana Maternal Health Survey 2007. This was a national survey conducted across the 10 administrative regions of Ghana. The survey identified 4203 female deaths through verbal autopsy, among which 605 were maternal deaths in the 12 to 49 year-old age group. Analysis was done using Statistical software IBM SPSS Statistics 20. A case control study design was used. Cross-tabulations and logistic regression models were used to investigate associations between the different variables. Alcohol consumption was significantly associated with abortion-related maternal deaths. Women who had ever consumed alcohol (OR (adjusted) 2.6, 95% CI 1.38-4.87), frequent consumers (OR (adjusted) 2.6, 95% CI 0.89-7.40) and occasional consumers (OR (adjusted) 2.7, 95% CI 1.29-5.46) were about three times as likely to die from abortion-related causes compared to those who abstained from alcohol. Maternal age, marital status and educational level were found to have a confounding effect on the observed association. Policy actions directed toward reducing abortion-related deaths should consider alcohol consumption, especially among younger women. Policy makers in Ghana should consider increasing the legal age for alcohol consumption. We suggest that information on the health risks posed by alcohol and abortion be disseminated to communities in the informal sector where vulnerable groups can best be reached.

  15. Relationship of angiogenesis and microglial activation to seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy.

    Science.gov (United States)

    Sakurai, Masashi; Morita, Takehito; Takeuchi, Takashi; Shimada, Akinori

    2013-05-01

    To determine whether angiogenesis and microglial activation were related to seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. Cadavers of 10 Shetland Sheepdogs from the same family (6 dogs with seizures and 4 dogs without seizures) and 4 age-matched unrelated Shetland Sheepdogs. Samples of brain tissues were collected after euthanasia and then fixed in neutral phosphate-buffered 10% formalin and routinely embedded in paraffin. The fixed samples were sectioned for H&E staining and immunohistochemical analysis. Evidence of seizure-induced neuronal death was detected exclusively in samples of cerebral cortical tissue from the dogs with familial epilepsy in which seizures had been observed. The seizure-induced neuronal death was restricted to tissues from the cingulate cortex and sulci surrounding the cerebral cortex. In almost the same locations as where seizure-induced neuronal death was identified, microvessels appeared longer and more tortuous and the number of microvessels was greater than in the dogs without seizures and control dogs. Occasionally, the microvessels were surrounded by oval to flat cells, which had positive immunohistochemical results for von Willebrand factor. Immunohistochemical results for neurons and glial cells (astrocytes and microglia) were positive for vascular endothelial growth factor, and microglia positive for ionized calcium-binding adapter molecule 1 were activated (ie, had swollen cell bodies and long processes) in almost all the same locations as where seizure-induced neuronal death was detected. Double-label immunofluorescence techniques revealed that the activated microglia had positive results for tumor necrosis factor-α, interleukin-6, and vascular endothelial growth factor receptor 1. These findings were not observed in the cerebrum of dogs without seizures, whether the dogs were from the same family as those with epilepsy or were unrelated to them. Signs of angiogenesis and

  16. MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes.

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    Emeric Deruy

    Full Text Available Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2O(2 overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2O(2 level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2O(2. This H(2O(2-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria.

  17. Melatonin Modulates Neuronal Cell Death Induced by Endoplasmic Reticulum Stress under Insulin Resistance Condition

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    Juhyun Song

    2017-06-01

    Full Text Available Insulin resistance (IR is an important stress factor in the central nervous system, thereby aggravating neuropathogenesis and triggering cognitive decline. Melatonin, which is an antioxidant phytochemical and synthesized by the pineal gland, has multiple functions in cellular responses such as apoptosis and survival against stress. This study investigated whether melatonin modulates the signaling of neuronal cell death induced by endoplasmic reticulum (ER stress under IR condition using SH-SY5Y neuroblastoma cells. Apoptosis cell death signaling markers (cleaved Poly [ADP-ribose] polymerase 1 (PARP, p53, and Bax and ER stress markers (phosphorylated eIF2α (p-eIF2α, ATF4, CHOP, p-IRE1, and spliced XBP1 (sXBP1 were measured using reverse transcription-PCR, quantitative PCR, and western blottings. Immunofluorescence staining was also performed for p-ASK1 and p-IRE1. The mRNA or protein expressions of cell death signaling markers and ER stress markers were increased under IR condition, but significantly attenuated by melatonin treatment. Insulin-induced activation of ASK1 (p-ASK1 was also dose dependently attenuated by melatonin treatment. The regulatory effect of melatonin on neuronal cells under IR condition was associated with ASK1 signaling. In conclusion, the result suggested that melatonin may alleviate ER stress under IR condition, thereby regulating neuronal cell death signaling.

  18. Anti-apoptotic peptides protect against radiation-induced cell death.

    Science.gov (United States)

    McConnell, Kevin W; Muenzer, Jared T; Chang, Kathy C; Davis, Chris G; McDunn, Jonathan E; Coopersmith, Craig M; Hilliard, Carolyn A; Hotchkiss, Richard S; Grigsby, Perry W; Hunt, Clayton R

    2007-04-06

    The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15Gy radiation. In mice exposed to 5Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues.

  19. Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death.

    Science.gov (United States)

    Thiepold, Anna-Luisa; Lorenz, Nadja I; Foltyn, Martha; Engel, Anna L; Divé, Iris; Urban, Hans; Heller, Sonja; Bruns, Ines; Hofmann, Ute; Dröse, Stefan; Harter, Patrick N; Mittelbronn, Michel; Steinbach, Joachim P; Ronellenfitsch, Michael W

    2017-10-01

    Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations. © The Author (2017). Published by

  20. TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

    Science.gov (United States)

    Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

    2012-01-01

    Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. PMID:23254290

  1. TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner.

    Science.gov (United States)

    Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

    2012-12-20

    Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage.

  2. Doxorubicin-induced cell death requires cathepsin B in HeLa cells.

    Science.gov (United States)

    Bien, S; Rimmbach, C; Neumann, H; Niessen, J; Reimer, E; Ritter, C A; Rosskopf, D; Cinatl, J; Michaelis, M; Schroeder, H W S; Kroemer, H K

    2010-11-15

    The cysteine protease cathepsin B acts as a key player in apoptosis. Cathepsin B-mediated cell death is induced by various stimuli such as ischemia, bile acids or TNFα. Whether cathepsin B can be influenced by anticancer drugs, however, has not been studied in detail. Here, we describe the modulation of doxorubicin-induced cell death by silencing of cathepsin B expression. Previously, it was shown that doxorubicin, in contrast to other drugs, selectively regulates expression and activity of cathepsin B. Selective silencing of cathepsin B by siRNA or the cathepsin B specific inhibitor CA074Me modified doxorubicin-mediated cell death in Hela tumor cells. Both Caspase 3 activation and PARP cleavage were significantly reduced in cells lacking cathepsin B. Moreover, mitochondrial membrane permeabilization as well as the release of cytochrome C and AIF from mitochondria into cytosol induced by doxorubicin were significantly diminished in cathepsin B suppressed cells. In addition, doxorubicin associated down-regulation of XIAP was not observed in cathepsin B silenced cells. Lack of cathepsin B significantly modified cell cycle regulatory proteins such as cdk1, Wee1 and p21 without significant changes in G(1), S or G(2)M cell cycle phases maybe indicating further cell cycle independent actions of these proteins. Consequently, cell viability following doxorubicin was significantly elevated in cells with cathepsin B silencing. In summary, our data strongly suggest a role of cathepsin B in doxorubicin-induced cell death. Therefore, increased expression of cathepsin B in various types of cancer can modify susceptibility towards doxorubicin. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Intracellular serine protease inhibitor SERPINB4 inhibits granzyme M-induced cell death.

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    Pieter J A de Koning

    Full Text Available Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1' triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×10(4 M(-1 s(-1. SERPINB4 abolished cleavage of the macromolecular GrM substrates α-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death.

  4. Molecular Characterization of Propolis-Induced Cell Death in Saccharomyces cerevisiae▿†

    OpenAIRE

    de Castro, Patrícia Alves; Savoldi, Marcela; Bonatto, Diego; Barros, Mário Henrique; Goldman, Maria Helena S.; Berretta, Andresa A.; Goldman, Gustavo Henrique

    2011-01-01

    Propolis, a natural product of plant resins, is used by the bees to seal holes in their honeycombs and protect the hive entrance. However, propolis has also been used in folk medicine for centuries. Here, we apply the power of Saccharomyces cerevisiae as a model organism for studies of genetics, cell biology, and genomics to determine how propolis affects fungi at the cellular level. Propolis is able to induce an apoptosis cell death response. However, increased exposure to propolis provides ...

  5. Lercanidipine Rescues Hippocampus Pyramidal Neurons from Mild Ischemia-Induced Delayed Neuronal Death in SHRSP.

    OpenAIRE

    Sakurai-Yamashita, Yasuko; Harada, Noboru; Niwa, Masami

    2011-01-01

    Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipi...

  6. Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats.

    Science.gov (United States)

    Faria, Juliana; Barbosa, Joana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Moreira, Roxana; Queirós, Odília; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2017-06-15

    Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50mg/kg - typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. A novel initiation mechanism of death in Streptococcus pneumoniae induced by the human milk protein-lipid complex HAMLET and activated during physiological death.

    Science.gov (United States)

    Clementi, Emily A; Marks, Laura R; Duffey, Michael E; Hakansson, Anders P

    2012-08-03

    To cause colonization or infection, most bacteria grow in biofilms where differentiation and death of subpopulations is critical for optimal survival of the whole population. However, little is known about initiation of bacterial death under physiological conditions. Membrane depolarization has been suggested, but never shown to be involved, due to the difficulty of performing such studies in bacteria and the paucity of information that exists regarding ion transport mechanisms in prokaryotes. In this study, we performed the first extensive investigation of ion transport and membrane depolarization in a bacterial system. We found that HAMLET, a human milk protein-lipid complex, kills Streptococcus pneumoniae (the pneumococcus) in a manner that shares features with activation of physiological death from starvation. Addition of HAMLET to pneumococci dissipated membrane polarity, but depolarization per se was not enough to trigger death. Rather, both HAMLET- and starvation-induced death of pneumococci specifically required a sodium-dependent calcium influx, as shown using calcium and sodium transport inhibitors. This mechanism was verified under low sodium conditions, and in the presence of ionomycin or monensin, which enhanced pneumococcal sensitivity to HAMLET- and starvation-induced death. Pneumococcal death was also inhibited by kinase inhibitors, and indicated the involvement of Ser/Thr kinases in these processes. The importance of this activation mechanism was made evident, as dysregulation and manipulation of physiological death was detrimental to biofilm formation, a hallmark of bacterial colonization. Overall, our findings provide novel information on the role of ion transport during bacterial death, with the potential to uncover future antimicrobial targets.

  8. A Novel Initiation Mechanism of Death in Streptococcus pneumoniae Induced by the Human Milk Protein-Lipid Complex HAMLET and Activated during Physiological Death*

    Science.gov (United States)

    Clementi, Emily A.; Marks, Laura R.; Duffey, Michael E.; Hakansson, Anders P.

    2012-01-01

    To cause colonization or infection, most bacteria grow in biofilms where differentiation and death of subpopulations is critical for optimal survival of the whole population. However, little is known about initiation of bacterial death under physiological conditions. Membrane depolarization has been suggested, but never shown to be involved, due to the difficulty of performing such studies in bacteria and the paucity of information that exists regarding ion transport mechanisms in prokaryotes. In this study, we performed the first extensive investigation of ion transport and membrane depolarization in a bacterial system. We found that HAMLET, a human milk protein-lipid complex, kills Streptococcus pneumoniae (the pneumococcus) in a manner that shares features with activation of physiological death from starvation. Addition of HAMLET to pneumococci dissipated membrane polarity, but depolarization per se was not enough to trigger death. Rather, both HAMLET- and starvation-induced death of pneumococci specifically required a sodium-dependent calcium influx, as shown using calcium and sodium transport inhibitors. This mechanism was verified under low sodium conditions, and in the presence of ionomycin or monensin, which enhanced pneumococcal sensitivity to HAMLET- and starvation-induced death. Pneumococcal death was also inhibited by kinase inhibitors, and indicated the involvement of Ser/Thr kinases in these processes. The importance of this activation mechanism was made evident, as dysregulation and manipulation of physiological death was detrimental to biofilm formation, a hallmark of bacterial colonization. Overall, our findings provide novel information on the role of ion transport during bacterial death, with the potential to uncover future antimicrobial targets. PMID:22700972

  9. The efficiency of adjusted-da-chai-ling-tang in radiation-induced brain edema in patients with brain tumors

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    Da-Tong Ju

    2015-01-01

    Full Text Available Background: Brain edema induced by radiotherapy is a common complication in patients with brain tumors, for which medical treatment is the treatment of choice. Adjusted-Da-Chai-Ling-Tang, a Chinese herbal formulation, has been confirmed to be protective against the radiation-induced edema. In this study, we investigated the efficiency of adjusted-Da-Chai-Ling-Tang in radiation-induced brain edema in patients with brain tumors. Materials and Methods: A total of 46 patients with brain tumors treated with radiotherapy alone or combined with surgery were enrolled. These patients were divided into two groups: The experimental group with adjusted-Da-Chai-Ling-Tang and the control group with conventional medical treatment. Clinical data including symptoms and serologic results were collected pretreatment and on the 4 th , 7 th and 10 th day posttreatment. Magnetic resonance imaging of the brain was performed to investigate changes in brain edema. Results: Clinical symptoms including headache, dizziness, nausea/vomiting and fatigue significantly improved in the experimental group (P < 0.05. No difference in serological results was observed. Brain edema was significantly reduced in the experimental group in magnetic resonance imaging (P < 0.05. Conclusion: Adjusted-Da-Chai-Ling-Tang is effective in the treatment of radiation-induced brain edema in patients with brain tumors. No obvious side effects were observed.

  10. Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampus.

    Science.gov (United States)

    Kim, Seung-Tae; Doo, Ah-Reum; Kim, Seung-Nam; Kim, Song-Yi; Kim, Yoon Young; Kim, Jang-Hyun; Lee, Hyejung; Yin, Chang Shik; Park, Hi-Joon

    2012-09-01

    The administration of kainic acid (KA) causes seizures and produces neurodegeneration in hippocampal CA3 pyramidal cells. The present study investigated a possible role of acupuncture in reducing hippocampal cell death and inflammatory events, using a mouse model of kainic acid-induced epilepsy. Male C57BL/6 mice received acupuncture treatments at acupoint HT8 or in the tail area bilaterally once a day for 2 days and again immediately after an intraperitoneal injection of KA (30 mg/kg). HT8 is located on the palmar surface of the forelimbs, between the fourth and fifth metacarpal bones. Twenty-four hours after the KA injection, neuronal cell survival, the activations of microglia and astrocytes, and mRNA expression of two proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were measured in the hippocampus. Acupuncture stimulation at HT8, but not in the tail area, significantly reduced the KA-induced seizure, neuron death, microglial and astrocyte activations, and IL-1β mRNA expression in the hippocampus. The acupuncture stimulation also decreased the mRNA expression of TNF-α, but it was not significant. These results indicate that acupuncture at HT8 can inhibit hippocampal cell death and suppress KA-induced inflammatory events, suggesting a possible role for acupuncture in the treatment of epilepsy.

  11. Natural compound Alternol induces oxidative stress-dependent apoptotic cell death preferentially in prostate cancer cells.

    Science.gov (United States)

    Tang, Yuzhe; Chen, Ruibao; Huang, Yan; Li, Guodong; Huang, Yiling; Chen, Jiepeng; Duan, Lili; Zhu, Bao-Ting; Thrasher, J Brantley; Zhang, Xu; Li, Benyi

    2014-06-01

    Prostate cancers at the late stage of castration resistance are not responding well to most of current therapies available in clinic, reflecting a desperate need of novel treatment for this life-threatening disease. In this study, we evaluated the anticancer effect of a recently isolated natural compound, Alternol, in multiple prostate cancer cell lines with the properties of advanced prostate cancers in comparison to prostate-derived nonmalignant cells. As assessed by trypan blue exclusion assay, significant cell death was observed in all prostate cancer cell lines except DU145 but not in nonmalignant (RWPE-1 and BPH1) cells. Further analyses revealed that Alternol-induced cell death was an apoptotic response in a dose- and time-dependent manner, as evidenced by the appearance of apoptosis hallmarks such as caspase-3 processing and PARP cleavage. Interestingly, Alternol-induced cell death was completely abolished by reactive oxygen species scavengers N-acetylcysteine and dihydrolipoic acid. We also demonstrated that the proapoptotic Bax protein was activated after Alternol treatment and was critical for Alternol-induced apoptosis. Animal xenograft experiments in nude mice showed that Alternol treatment largely suppressed tumor growth of PC-3 xenografts but not Bax-null DU-145 xenografts in vivo. These data suggest that Alternol might serve as a novel anticancer agent for patients with late-stage prostate cancer. ©2014 American Association for Cancer Research.

  12. Ammonium is toxic for aging yeast cells, inducing death and shortening of the chronological lifespan.

    Directory of Open Access Journals (Sweden)

    Júlia Santos

    Full Text Available Here we show that in aging Saccharomyces cerevisiae (budding yeast cells, NH(4 (+ induces cell death associated with shortening of chronological life span. This effect is positively correlated with the concentration of NH(4 (+ added to the culture medium and is particularly evident when cells are starved for auxotrophy-complementing amino acids. NH(4 (+-induced cell death is accompanied by an initial small increase of apoptotic cells followed by extensive necrosis. Autophagy is inhibited by NH(4 (+, but this does not cause a decrease in cell viability. We propose that the toxic effects of NH(4 (+ are mediated by activation of PKA and TOR and inhibition of Sch9p. Our data show that NH(4 (+ induces cell death in aging cultures through the regulation of evolutionary conserved pathways. They may also provide new insights into longevity regulation in multicellular organisms and increase our understanding of human disorders such as hyperammonemia as well as effects of amino acid deprivation employed as a therapeutic strategy.

  13. Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death.

    Science.gov (United States)

    Antunes, Fernanda; Corazzari, Marco; Pereira, Gustavo; Fimia, Gian Maria; Piacentini, Mauro; Smaili, Soraya

    2017-03-25

    Melanoma is one of leading cause of tumor death worldwide. Anti-cancer strategy includes combination of different chemo-therapeutic agents as well as radiation; however these treatments have limited efficacy and induce significant toxic effects on healthy cells. One of most promising novel therapeutic approach to cancer therapy is the combination of anti-cancer drugs with calorie restriction. Here we investigated the effect Cisplatin (CDDP), one of the most potent chemotherapeutic agent used to treat tumors, in association with fasting in wild type and mutated BRAF(V600E) melanoma cell lines. Here we show that nutrient deprivation can consistently enhance the sensitivity of tumor cells to cell death induction by CDDP, also of those malignancies particularly resistant to any treatment, such as oncogenic BRAF melanomas. Mechanistic studies revealed that the combined therapy induced cell death is characterized by ROS accumulation and ATF4 in the absence of ER-stress. In addition, we show that autophagy is not involved in the enhanced sensitivity of melanoma cells to combined CDDP/EBSS-induced apoptosis. While, the exposure to 2-DG further enhanced the apoptotic rate observed in SK Mel 28 cells upon treatment with both CDDP and EBSS. Copyright © 2016. Published by Elsevier Inc.

  14. Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

    Science.gov (United States)

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J; Bergeson, Susan E; Henderson, George I; Kruman, Inna I

    2012-12-21

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.

  15. Induced synthesis of oestrogens by glia in the songbird brain.

    Science.gov (United States)

    Saldanha, C J; Burstein, S R; Duncan, K A

    2013-11-01

    Studies on birds have long provided landmarks and touchstones in the fields of neuroendocrinology, immunology and neuroplasticity. The passerine brain is an excellent model for studying the actions of hormones, including steroids, on a diversity of behavioural endpoints. Oestrogens, for example, have profound effects on avian neuroanatomy and neurophysiology throughout life and, importantly, are synthesised at high levels within neurones of the songbird brain. More recently, aromatisation in another set of neural cells has been identified. Specifically, aromatase expression is induced in astrocytes and radial glia following disruption of the neuropil by multiple forms of perturbation. The avian brain, therefore, can be provided with high levels of oestrogens constitutively or via induction, by aromatisation in neurones and glia, respectively. In this review, we begin with the initial discovery of aromatisation by non-neuronal cells and discuss the mechanisms underlying the induction of aromatase expression in glial cells. We then focus on the emerging interactions between the neuroendocrine and neuroimmune systems with respect to brain injury. Next, we briefly review the extensive literature on the influence of glial aromatisation on neuroplasticity, and end with some recent data on sex differences in the induction of glial aromatase in the zebra finch. Throughout this review, we consider the unanswered questions and future studies that may emerge from these findings. © 2013 British Society for Neuroendocrinology.

  16. Type I collagen gel protects murine fibrosarcoma L929 cells from TNFα-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hong-Ju; He, Wen-Qi; Chen, Ling; Liu, Wei-Wei; Xu, Qian; Xia, Ming-Yu; Hayashi, Toshihiko [China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016 (China); Fujisaki, Hitomi; Hattori, Shunji [Nippi Research Institute of Biomatrix, Toride, Ibaraki 302-0017 (Japan); Tashiro, Shin-ichi [Institute for Clinical and Biomedical Sciences, Kyoto 603-8072 (Japan); Onodera, Satoshi [Department of Clinical and Pharmaceutical Sciences, Showa Pharmaceutical University, Tokyo 194-8543 (Japan); Ikejima, Takashi, E-mail: ikejimat@vip.sina.com [China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016 (China)

    2015-02-20

    Murine fibrosarcoma L929 cells have been used to test efficacy of proinflammatory cytokine TNFα. In the present study, we reported on protective effect of type I collagen gel used as L929 cell culture. L929 cell grew and proliferated well on collagen gel. However, the L929 cells exhibited cobblestone-like morphology which was much different from the spread fusiform shape when cultured on conventional cell dishes as well as the cells tended to aggregate. On conventional cell culture dishes, the cells treated with TNFα became round in shape and eventually died in a necroptotic manner. The cells cultured on collagen gel, however, were completely unaffected. TNFα treatment was reported to induce autophagy in L929 cells on the plastic dish, and therefore we investigated the effect of collagen gel on induction of autophagy. The results indicated that autophagy induced by TNFα treatment was much reduced when the cells were cultured on collagen gel. In conclusion, type I collagen gel protected L929 cell from TNFα-induced cell death. - Highlights: • Collagen gel culture changed the morphology of L929 cells. • L929 cell cultured on collagen gel were resistant to TNFα-induced cell death. • Collagen gel culture inhibited TNFα-induced autophagy in L929 cells.

  17. Attenuated Mycobacterium tuberculosis SO2 vaccine candidate is unable to induce cell death.

    Directory of Open Access Journals (Sweden)

    Adriana Aporta

    Full Text Available It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death. The parental M. tuberculosis MT103 strain and the current vaccine against tuberculosis Bacillus Calmette-Guérin (BCG were used as comparators in mouse models in vitro and in vivo. Our data reveal that attenuated SO2 was unable to induce apoptotic events neither in mouse macrophages in vitro nor during lung infection in vivo. In contrast, virulent MT103 triggers typical apoptotic events with phosphatidylserine exposure, caspase-3 activation and nuclear condensation and fragmentation. BCG strain behaved like SO2 and did not induce apoptosis. A clonogenic survival assay confirmed that viability of BCG- or SO2-infected macrophages was unaffected. Our results discard apoptosis as the protective mechanism induced by SO2 vaccine and provide evidence for positive correlation between classical apoptosis induction and virulent strains, suggesting apoptosis as a possible virulence determinant during M. tuberculosis infection.

  18. Eclalbasaponin II induces autophagic and apoptotic cell death in human ovarian cancer cells

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    Yoon Jin Cho

    2016-09-01

    Full Text Available Triterpenoids echinocystic acid and its glycosides, isolated from several Eclipta prostrata, have been reported to possess various biological activities such as anti-inflammatory, anti-bacterial, and anti-diabetic activity. However, the cytotoxicity of the triterpenoids in human cancer cells and their molecular mechanism of action are poorly understood. In the present study, we found that eclalbasaponin II with one glucose moiety has potent cytotoxicity in three ovarian cancer cells and two endometrial cancer cells compared to an aglycone echinocystic acid and eclalbasaponin I with two glucose moiety. Eclalbasaponin II treatment dose-dependently increased sub G1 population. Annexin V staining revealed that eclalbasaponin II induced apoptosis in SKOV3 and A2780 ovarian cancer cells. In addition, eclalbasaponin II-induced cell death was associated with characteristics of autophagy; an increase in acidic vesicular organelle content and elevation of the levels of LC3-II. Interestingly, autophagy inhibitor BaF1 suppressed the eclalbasaponin II-induced apoptosis. Moreover, eclalbasaponin II activated JNK and p38 signaling and inhibited the mTOR signaling. We further demonstrated that pre-treatment with a JNK and p38 inhibitor and mTOR activator attenuated the eclalbasaponin II-induced autophagy. This suggests that eclalbasaponin II induces apoptotic and autophagic cell death through the regulation of JNK, p38, and mTOR signaling in human ovarian cancer cells.

  19. Unravelling the Mechanism of TrkA-Induced Cell Death by Macropinocytosis in Medulloblastoma Daoy Cells.

    Science.gov (United States)

    Li, Chunhui; MacDonald, James I S; Talebian, Asghar; Leuenberger, Jennifer; Seah, Claudia; Pasternak, Stephen H; Michnick, Stephen W; Meakin, Susan O

    2016-10-15

    Macropinocytosis is a normal cellular process by which cells internalize extracellular fluids and nutrients from their environment and is one strategy that Ras-transformed pancreatic cancer cells use to increase uptake of amino acids to meet the needs of rapid growth. Paradoxically, in non-Ras transformed medulloblastoma brain tumors, we have shown that expression and activation of the receptor tyrosine kinase TrkA overactivates macropinocytosis, resulting in the catastrophic disintegration of the cell membrane and in tumor cell death. The molecular basis of this uncontrolled form of macropinocytosis has not been previously understood. Here, we demonstrate that the overactivation of macropinocytosis is caused by the simultaneous activation of two TrkA-mediated pathways: (i) inhibition of RhoB via phosphorylation at Ser(185) by casein kinase 1, which relieves actin stress fibers, and (ii) FRS2-scaffolded Src and H-Ras activation of RhoA, which stimulate actin reorganization and the formation of lamellipodia. Since catastrophic macropinocytosis results in brain tumor cell death, improved understanding of the mechanisms involved will facilitate future efforts to reprogram tumors, even those resistant to apoptosis, to die. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  20. B-Amyloid Precursor Protein Staining of the Brain in Sudden Infant and Early Childhood Death

    DEFF Research Database (Denmark)

    Jensen, Lisbeth Lund; Banner, Jytte; Ulhøi, Benedicte Parm

    2013-01-01

    To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children.......To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children....

  1. Levels of glutathione and some biogenic amines in the human brain putamen after traumatic death.

    Science.gov (United States)

    Calderón-Guzmán, David; Osnaya-Brizuela, Norma; García-Alvarez, Raquel; Hernández García, Ernestina; Guillé Pérez, Adrián; Juárez Olguín, Hugo

    2008-01-01

    Mexico City is among the world's largest metropolitan city centers and one of the most difficult and challenging cities in which to drive a motor vehicle. During peak transit hours and maximum congestion, numerous accidents occur, many of them fatal. The aim of the study presented here was to analyze the levels of select indicators against oxidative stress and levels of biogenic amines as a consequence of accident or altercation and fear deaths. Eighteen cases were studied (sixteen males, two females). Subjects ranged from twelve to eighty-one years of age. Nine of the deaths studied were the result of motor vehicle or subway accidents. Eight of the eighteen deaths were the result of a violent altercation, while one of the deaths resulted from a drug overdose and cardiac arrest. Biopsies of cadaver putamen were homogenized and analyzed for Tryptophan (Trp), 5-hydroxyindole acetic acid (5-HIAA), Dopamine (DA), and Glutathione (GSH) levels by fluorometric methods. Trp, 5-HIAA, DA, and GSH levels showed an increase in the subjects who's death was caused by violent altercation combined with fear, while DA levels showed significant differences in all accident groups. This data suggest that biogenic amines in cadaver putamen tissue, such as DA, can be telling biochemical markers, indicative of altercation and fear deaths.

  2. Near-death-like experiences without life-threatening conditions or brain disorders: a hypothesis from a case report

    Directory of Open Access Journals (Sweden)

    Enrico eFacco

    2012-11-01

    Full Text Available Near-death experiences (NDEs are profound psychic experiences commonly occurring in life-threatening conditions. They include feeling a sense of peace, of seeing a bright light, encountering deceased relatives or religious figures, and of transcending space and time. To explain them, it has been suggested that they stem from brain disorders and/or psychological reactions to approaching death, a sort of wishful thinking in response to the perceived threat.This is a report on a case with most of the features typical of NDEs except that it occurred entirely without any life-threatening conditions. This evidence is theoretically incompatible with either of the above hypotheses, suggesting that a broader interpretation of the phenomenon is needed.

  3. Improved Time to Notification of Impending Brain Death and Increased Organ Donation Using an Electronic Clinical Decision Support System.

    Science.gov (United States)

    Zier, J L; Spaulding, A B; Finch, M; Verschaetse, T; Tarrago, R

    2017-08-01

    Early referral of patients to an organ procurement organization (OPO) may positively affect donation outcomes. We implemented an electronic clinic decision support (CDS) system to automatically notify our OPO of children meeting clinical triggers indicating impending brain death. Medical records of all patients who died in a pediatric critical care unit or were referred for imminent death for 3 years prior to installation of the initial CDS (pre-CDS) and for 1 year after implementation of the final CDS (post-CDS) were reviewed. Mean time to OPO notification decreased from 30.2 h pre-CDS to 1.7 h post-CDS (p = 0.015). Notification within 1 h of meeting criteria increased from 36% pre-CDS to 70% post-CDS (p = 0.003). Although an increase in donor conversion from 50% pre-CDS to 90% post-CDS did not reach statistical significance (p = 0.0743), there were more organ donors post-CDS (11 of 24 deaths) than pre-CDS (seven of 57 deaths; p = 0.002). Positive outcomes were achieved with the use of a fully automated CDS system while simultaneously realizing few false-positive notifications, low costs, and minimal workflow interruption. Use of an electronic CDS system in a pediatric hospital setting improved timely OPO notification and was associated with increased organ donation. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  4. Blockage of NOX2/MAPK/NF-κB Pathway Protects Photoreceptors against Glucose Deprivation-Induced Cell Death

    Directory of Open Access Journals (Sweden)

    Bin Fan

    2017-01-01

    Full Text Available Acute energy failure is one of the critical factors contributing to the pathogenic mechanisms of retinal ischemia. Our previous study demonstrated that glucose deprivation can lead to a caspase-dependent cell death of photoreceptors. The aim of this study was to decipher the upstream signal pathway in glucose deprivation- (GD- induced cell death. We mimicked acute energy failure by using glucose deprivation in photoreceptor cells (661W cells. GD-induced oxidative stress was evaluated by measuring ROS with the DCFH-DA assay and HO-1 expression by Western blot analysis. The activation of NOX2/MAPK/NF-κB signal was assessed by Western blot and immunohistochemical assays. The roles of these signals in GD-induced cell death were measured by using their specific inhibitors. Inhibition of Rac-1 and NOX2 suppressed GD-induced oxidative stress and protected photoreceptors against GD-induced cell death. NOX2 was an upstream signal in the caspase-dependent cell death cascade, yet the downstream MAPK pathways were activated and blocking MAPK signals rescued 661W cells from GD-induced death. In addition, GD caused the activation of NF-κB signal and inhibiting NF-κB significantly protected 661W cells. These observations may provide insights for treating retinal ischemic diseases and protecting retinal neurons from ischemia-induced cell death.

  5. killerFLIP: a novel lytic peptide specifically inducing cancer cell death.

    Science.gov (United States)

    Pennarun, B; Gaidos, G; Bucur, O; Tinari, A; Rupasinghe, C; Jin, T; Dewar, R; Song, K; Santos, M T; Malorni, W; Mierke, D; Khosravi-Far, R

    2013-10-31

    One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killerFLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using electron microscopy demonstrated that killerFLIP-E triggers cell death accompanied by rapid (within minutes) plasma membrane permeabilization. Studies of the structure of the active core of killerFLIP (-E) indicated that it possesses amphiphilic properties and self-assembles into micellar structures in aqueous solution. The biochemical properties of killerFLIP are comparable to those of cationic lytic peptides, which participate in defense against pathogens and have also demonstrated anticancer properties. We show that the pro-cell death effects of killerFLIP are independent of its sequence similarity with c-FLIPL as killerFLIP-induced cell death was largely apoptosis and necroptosis independent. A killerFLIP-E variant containing a scrambled c-FLIPL motif indeed induced similar cell death, suggesting the importance of the c-FLIPL residues but not of their sequence. Thus, we report the discovery of a promising synthetic peptide with novel anticancer activity in vitro and in vivo.

  6. Early detection of brain death using the Bispectral Index (BIS) in patients treated by extracorporeal cardiopulmonary resuscitation (E-CPR) for refractory cardiac arrest.

    Science.gov (United States)

    Jouffroy, Romain; Lamhaut, Lionel; Guyard, Alexandra; Philippe, Pascal; An, Kim; Spaulding, Christian; Baud, Frédéric; Carli, Pierre; Vivien, Benoît

    2017-11-01

    Despite increasing use of extracorporeal cardiopulmonary resuscitation (E-CPR) for treatment of refractory cardiac arrest patients, prognosis remains dismal, often resulting in brain-death. However, clinical assessment of brain-death occurence is difficult in post-cardiac arrest patients, sedated, paralyzed, under mild therapeutic hypothermia (MTH). Our objective was to assess the usefulness of Bispectral-Index (BIS) monitoring at bedside for an early detection of brain-death occurrence in refractory cardiac arrest patients treated by E-CPR. This prospective study was performed in an intensive care unit of an university hospital. Forty-six patients suffering from refractory cardiac arrest treated by E-CPR were included. BIS was continuously recorded during ICU hospitalization. Clinical brain-death was confirmed when appropriate by EEG and/or cerebral CT angiography. Twenty-nine patients evolved into brain-death and had average BIS values under MTH and after rewarming (temperature ≥35°C) of 4 (0-47) and 0 (0-82), respectively. Among these, 11 (38%) entered into a procedure of organs donation. Among the 17 non-brain-dead patients, the average BIS values at admission and after rewarming were 39 (0-65) and 59 (22-82), respectively. Two patients had on admission a BIS value equal to zero and evolved to a poor prognostic (CPC 4) and died after care limitations. BIS values were significantly different between patients who developed brain death and those who did not. In both groups, no differences were observed between the AUCs of ROC curves for BIS values under MTH and after rewarming (respectively 0.86 vs 0.83, NS). Initial values of BIS could be used as an assessment tool for early detection of brain-death in refractory cardiac arrest patients treated by mild therapeutic hypothermia and E-CPR. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Developing a standard method for apnea testing in the determination of brain death for patients on venoarterial extracorporeal membrane oxygenation: a pediatric case series.

    Science.gov (United States)

    Jarrah, Rima J; Ajizian, Samuel J; Agarwal, Swati; Copus, Scott C; Nakagawa, Thomas A

    2014-02-01

    The revised guidelines for the determination of brain death in infants and children stress that apnea testing is an integral component in determining brain death based on clinical criteria. Unfortunately, these guidelines provide no process for apnea testing during the determination of brain death in patients supported on venoarterial extracorporeal membrane oxygenation. We review three pediatric patients supported on venoarterial extracorporeal membrane oxygenation who underwent apnea testing during their brain death evaluation. This is the only published report to elucidate a reliable, successful method for apnea testing in pediatric patients supported on venoarterial extracorporeal membrane oxygenation. Retrospective case series. Two tertiary care PICUs in university teaching hospitals. Three pediatric patients supported by venoarterial extracorporeal membrane oxygenation after cardiopulmonary arrest. After neurologic examinations demonstrated cessation of brain function in accordance with current pediatric brain death guidelines, apnea testing was performed on each child while supported on venoarterial extracorporeal membrane oxygenation. In two of the three cases, the patients remained hemodynamically stable with normal oxygen saturations as venoarterial extracorporeal membrane oxygenation sweep gas was weaned and apnea testing was undertaken. Apnea testing demonstrating no respiratory effort was successfully completed in these two cases. The third patient became hemodynamically unstable, invalidating the apnea test. Apnea testing on venoarterial extracorporeal membrane oxygenation can be successfully undertaken in the evaluation of brain death. We provide a suggested protocol for apnea testing while on venoarterial extracorporeal membrane oxygenation that is consistent with the updated pediatric brain death guidelines. This is the only published report to elucidate a reliable, successful method for apnea testing in pediatric patients supported on venoarterial

  8. Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death.

    Science.gov (United States)

    Girard, Brian J; Regan Anderson, Tarah M; Welch, Siya Lem; Nicely, Julie; Seewaldt, Victoria L; Ostrander, Julie H

    2015-01-01

    Tamoxifen (Tam) is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+) breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1) promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS) mutant of PELP1 (PELP1-cyto) were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERRγ) promoted cell survival in the presence of Tam. Overexpression of ERRγ in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRγ sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERRγ reduced Tam-induced LC3-II accumulation, and knockdown of ERRγ increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERRγ target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERRγ activation could be developed as tissue biomarkers for Tam responsiveness.

  9. Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death.

    Directory of Open Access Journals (Sweden)

    Brian J Girard

    Full Text Available Tamoxifen (Tam is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+ breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1 promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS mutant of PELP1 (PELP1-cyto were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERRγ promoted cell survival in the presence of Tam. Overexpression of ERRγ in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRγ sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERRγ reduced Tam-induced LC3-II accumulation, and knockdown of ERRγ increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERRγ target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERRγ activation could be developed as tissue biomarkers for Tam responsiveness.

  10. In vitro surfactant mitigation of gas bubble contact-induced endothelial cell death.

    Science.gov (United States)

    Kobayashi, Shunji; Crooks, Steven D; Eckmann, David M

    2011-01-01

    Interactions of gas embolism bubbles with endothelial cells, as can occur during decompression events or other forms of intravascular gas entry, are poorly characterized. Endothelial cells respond to microbubble contact via mechanotransduction responses that can lead to cell death or aberrant cellular function. Cultured bovine aortic endothelial cells were individually contacted with microbubbles. Cells were loaded with fluorescent dyes indicating calcium- and nitric oxide-signaling and cell viability. A surfactant, Pluronic F-127, and/or albumin were added to the culture media. Control experiments utilized calcium-free media as well as probe-poking in place of microbubble contact. We acquired fluorescence microscopy time-lapse images of cell responses to bubble and probe contact and determined contact effects on cell signaling and cell death. Calcium influx was essential for cell death to occur with bubble contact. Bubble contact stimulated extracellular calcium entry without altering nitric oxide levels unless cell death was provoked. Cell responses were independent of bubble contact duration lasting either one or 30 seconds. Microbubble contact provoked cell death over seven times more frequently than micropipette poking. Albumin and the surfactant each attenuated the calcium response to bubble contact and also reduced the lethality of microbubble contact by 67.4% and 76.0%, respectively, when used alone, and by 91.2% when used together. This suggests that surface interactions between the bubble or probe interface and plasma- and cell surface-borne macromolecules differentially modulate the mechanism of calcium trafficking such that microbubble contact more substantially induces cell death or aberrant cellular function. The surfactant findings provide a cytoprotective approach to mitigate this form of mechanical injury.

  11. Key players of singlet oxygen-induced cell death in plants

    Directory of Open Access Journals (Sweden)

    Christophe eLaloi

    2015-02-01

    Full Text Available The production of reactive oxygen species (ROS is an unavoidable consequence of oxygenic photosynthesis. Singlet oxygen (1O2 is a highly reactive species to which has been attributed a major destructive role during the execution of ROS-induced cell death in photosynthetic tissues exposed to excess light. The study of the specific biological activity of 1O2 in plants has been hindered by its high reactivity and short lifetime, the concurrent production of other ROS under photooxidative stress, and limited in vivo detection methods. However, during the last fifteen years, the isolation and characterization of two 1O2-overproducing mutants in Arabidopsis thaliana, flu and ch1, has allowed the identification of genetically controlled 1O2 cell death pathways and a 1O2 acclimation pathway that are triggered at sub-cytotoxic concentrations of 1O2. The study of flu has revealed the control of cell death by the plastid proteins EXECUTER (EX1 and EX2. In ch1, oxidized derivatives of beta-carotene, such as beta-cyclocitral and dihydroactinidiolide, have been identified as important upstream messengers in the 1O2 signaling pathway that leads to stress acclimation. In both the flu and ch1 mutants, phytohormones act as important promoters or inhibitors of cell death. In particular, jasmonate has emerged as a key player in the decision between acclimation and cell death in response to 1O2. Although the flu and ch1 mutants show many similarities, especially regarding their gene expression profiles, key differences, such as EXECUTER-independent cell death in ch1, have also been observed and will need further investigation to be fully understood.

  12. Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

    Science.gov (United States)

    Okuda, S; Nishiyama, N; Saito, H; Katsuki, H

    1996-10-29

    3-Hydroxykynurenine (3-HK) is a tryptophan metabolite whose level in the brain is markedly elevated under several pathological conditions, including Huntington disease and human immunodeficiency virus infection. Here we demonstrate that micromolar concentrations (1-100 microM) of 3-HK cause cell death in primary neuronal cultures prepared from rat striatum. The neurotoxicity of 3-HK was blocked by catalase and desferrioxamine but not by superoxide dismutase, indicating that the generation of hydrogen peroxide and hydroxyl radical is involved in the toxicity. Measurement of peroxide levels revealed that 3-HK caused intracellular accumulation of peroxide, which was largely attenuated by application of catalase. The peroxide accumulation and cell death caused by 1-10 microM 3-HK were also blocked by pretreatment with allopurinol or oxypurinol, suggesting that endogenous xanthine oxidase activity is involved in exacerbation of 3-HK neurotoxicity. Furthermore, NADPH diaphorase-containing neurons were spared from toxicity of these concentrations of 3-HK, a finding reminiscent of the pathological characteristics of several neurodegenerative disorders such as Huntington disease. These results suggest that 3-HK at pathologically relevant concentrations renders neuronal cells subject to oxidative stress leading to cell death, and therefore that this endogenous compound should be regarded as an important factor in pathogenesis of neurodegenerative disorders.

  13. Deregulation of the Egfr/Ras Signaling Pathway Induces Age-related Brain Degeneration in the Drosophila Mutant vap

    Science.gov (United States)

    Botella, José A.; Kretzschmar, Doris; Kiermayer, Claudia; Feldmann, Pascale; Hughes, David A.; Schneuwly, Stephan

    2003-01-01

    Ras signaling has been shown to play an important role in promoting cell survival in many different tissues. Here we show that upregulation of Ras activity in adult Drosophila neurons induces neuronal cell death, as evident from the phenotype of vacuolar peduncle (vap) mutants defective in the Drosophila RasGAP gene, which encodes a Ras GTPase-activating protein. These mutants show age-related brain degeneration that is dependent on activation of the EGF receptor signaling pathway in adult neurons, leading to autophagic cell death (cell death type 2). These results provide the first evidence for a requirement of Egf receptor activity in differentiated adult Drosophila neurons and show that a delicate balance of Ras activity is essential for the survival of adult neurons. PMID:12529440

  14. LSD-induced entropic brain activity predicts subsequent personality change.

    Science.gov (United States)

    Lebedev, A V; Kaelen, M; Lövdén, M; Nilsson, J; Feilding, A; Nutt, D J; Carhart-Harris, R L

    2016-09-01

    Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced-order, placebo-controlled study, we investigated biological predictors of post-lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO-PI-R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5-min eyes-closed resting-state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time-series. Mixed-effects models were used to evaluate drug-induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2-week follow-up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music-listening scans and when "ego-dissolution" was reported during the acute experience. These results shed new light on how LSD-induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp 37:3203-3213, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Neuroprotection by Caffeine in Hyperoxia-Induced Neonatal Brain Injury.

    Science.gov (United States)

    Endesfelder, Stefanie; Weichelt, Ulrike; Strauß, Evelyn; Schlör, Anja; Sifringer, Marco; Scheuer, Till; Bührer, Christoph; Schmitz, Thomas

    2017-01-18

    Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

  16. Neither xenon nor fentanyl induces neuroapoptosis in the newborn pig brain.

    Science.gov (United States)

    Sabir, Hemmen; Bishop, Sarah; Cohen, Nicki; Maes, Elke; Liu, Xun; Dingley, John; Thoresen, Marianne

    2013-08-01

    Some inhalation anesthetics increase apoptotic cell death in the developing brain. Xenon, an inhalation anesthetic, increases neuroprotection when combined with therapeutic hypothermia after hypoxic-ischemic brain injury in newborn animals. The authors, therefore, examined whether there was any neuroapoptotic effect of breathing 50% xenon with continuous fentanyl sedation for 24 h at normothermia or hypothermia on newborn pigs. Twenty-six healthy pigs (inhaled xenon with fentanyl at hypothermia (Trec = 33.5 °C), (2) 24 h of 50% inhaled xenon with fentanyl at normothermia (Trec = 38.5 °C), (3) 24 h of fentanyl at normothermia, or (4) nonventilated juvenile controls at normothermia. Five additional nonrandomized pigs inhaled 2% isoflurane at normothermia for 24 h to verify any proapoptotic effect of inhalation anesthetics in our model. Pathological cells were morphologically assessed in cortex, putamen, hippocampus, thalamus, and white matter. To quantify the findings, immunostained cells (caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine-triphosphate nick-end labeling) were counted in the same brain regions. For groups (1) to (4), the total number of apoptotic cells was less than 5 per brain region, representing normal developmental neuroapoptosis. After immunostaining and cell counting, regression analysis showed that neither 50% xenon with fentanyl nor fentanyl alone increased neuroapoptosis. Isoflurane caused on average a 5- to 10-fold increase of immunostained cells. At normothermia or hypothermia, neither 24 h of inhaled 50% xenon with fentanyl sedation nor fentanyl alone induces neuroapoptosis in the neonatal pig brain. Breathing 2% isoflurane increases neuroapoptosis in neonatal pigs.

  17. Apoptotic Cell Death Induced by Resveratrol Is Partially Mediated by the Autophagy Pathway in Human Ovarian Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Fangfang Lang

    Full Text Available Resveratrol (trans-3,4,5'-trihydroxystilbene is an active compound in food, such as red grapes, peanuts, and berries. Resveratrol exhibits an anticancer effect on various human cancer cells. However, the mechanism of resveratrol-induced anti-cancer effect at the molecular level remains to be elucidated. In this study, the mechanism underlying the anti-cancer effect of resveratrol in human ovarian cancer cells (OVCAR-3 and Caov-3 was investigated using various molecular biology techniques, such as flow cytometry, western blotting, and RNA interference, with a major focus on the potential role of autophagy in resveratrol-induced apoptotic cell death. We demonstrated that resveratrol induced reactive oxygen species (ROS generation, which triggers autophagy and subsequent apoptotic cell death. Resveratrol induced ATG5 expression and promoted LC3 cleavage. The apoptotic cell death induced by resveratrol was attenuated by both pharmacological and genetic inhibition of autophagy. The autophagy inhibitor chloroquine, which functions at the late stage of autophagy, significantly reduced resveratrol-induced cell death and caspase 3 activity in human ovarian cancer cells. We also demonstrated that targeting ATG5 by siRNA also suppressed resveratrol-induced apoptotic cell death. Thus, we concluded that a common pathway between autophagy and apoptosis exists in resveratrol-induced cell death in OVCAR-3 human ovarian cancer cells.

  18. Marine Benthic Diatoms Contain Compounds Able to Induce Leukemia Cell Death and Modulate Blood Platelet Activity

    Directory of Open Access Journals (Sweden)

    Lars Herfindal

    2009-11-01

    Full Text Available In spite of the high abundance and species diversity of diatoms, only a few bioactive compounds from them have been described. The present study reveals a high number of mammalian cell death inducing substances in biofilm-associated diatoms sampled from the intertidal zone. Extracts from the genera Melosira, Amphora, Phaeodactylum and Nitzschia were all found to induce leukemia cell death, with either classical apoptotic or autophagic features. Several extracts also contained inhibitors of thrombin-induced blood platelet activation. Some of this activity was caused by a high content of adenosine in the diatoms, ranging from 0.07 to 0.31 μg/mg dry weight. However, most of the bioactivity was adenosine deaminase-resistant. An adenosine deaminase-resistant active fraction from one of the extracts was partially purified and shown to induce apoptosis with a distinct phenotype. The results show that benthic diatoms typically found in the intertidal zone may represent a richer source of interesting bioactive compounds than hitherto recognized.

  19. Piperlongumine induces pancreatic cancer cell death by enhancing reactive oxygen species and DNA damage

    Directory of Open Access Journals (Sweden)

    Harsharan Dhillon

    2014-01-01

    Full Text Available Pancreatic cancer is one of the most deadly cancers with a nearly 95% mortality rate. The poor response of pancreatic cancer to currently available therapies and the extremely low survival rate of pancreatic cancer patients point to a critical need for alternative therapeutic strategies. The use of reactive oxygen species (ROS-inducing agents has emerged as an innovative and effective strategy to treat various cancers. In this study, we investigated the potential of a known ROS inducer, piperlongumine (PPLGM, a bioactive agent found in long peppers, to induce pancreatic cancer cell death in cell culture and animal models. We found that PPLGM inhibited the growth of pancreatic cancer cell cultures by elevating ROS levels and causing DNA damage. PPLGM-induced DNA damage and pancreatic cancer cell death was reversed by treating the cells with an exogenous antioxidant. Similar to the in vitro studies, PPLGM caused a reduction in tumor growth in a xenograft mouse model of human pancreatic cancer. Tumors from the PPLGM-treated animals showed decreased Ki-67 and increased 8-OHdG expression, suggesting PPLGM inhibited tumor cell proliferation and enhanced oxidative stress. Taken together, our results show that PPLGM is an effective inhibitor for in vitro and in vivo growth of pancreatic cancer cells, and that it works through a ROS-mediated DNA damage pathway. These findings suggest that PPLGM has the potential to be used for treatment of pancreatic cancer.

  20. The effect of hydroxybenzoate calcium compounds in inducing cell death in epithelial breast cancer cells

    Directory of Open Access Journals (Sweden)

    Nada M Merghani

    2015-12-01

    Full Text Available Hydroxybenzoate (HB compounds have shown their significance in inducing apoptosis in primary chronic lymphocytic leukemia (CLL and cancer cell lines, including HT-1080. The current study focuses on assessing the effects of 2-, 3- and 4-hydroxybenzoate calcium (HBCa compounds on MCF-10A, MDA-MB231 and MCF-7 epithelial breast cell lines. The HBCa-treated cells were examined using annexin V, to measure apoptosis in the three epithelial breast cell lines, after 48 h of treatment. The results indicated that 0.5 and 2.5 mmol/L of HBCa induced cell death in a dose-dependent manner. The induction of cell death in normal MCF-10A cells was found to be significantly less (p = 0.0003–0.0068, in comparison to the malignant cell lines (MDA-MB231 and MCF-7. HBCa compounds were also found to cause cell cycle arrest in the epithelial breast cells at G1/G0. Furthermore, HBCa compounds induced the upregulation of apoptotic proteins (p53, p21, Bax and caspase-3, as well as the downregulation of the anti-apoptotic protein Bcl-2, which may suggest that apoptosis is induced via the intrinsic pathway.

  1. DHA Hydroperoxides as a Potential Inducer of Neuronal Cell Death: a Mitochondrial Dysfunction-Mediated Pathway

    Science.gov (United States)

    Liu, Xuebo; Shibata, Takahiro; Hisaka, Shinsuke; Kawai, Yoshichika; Osawa, Toshihiko

    2008-01-01

    During the lipid peroxidation reaction, lipid hydroperoxides are formed as primary products. Several lines of evidence suggest that lipid hydroperoxides can trigger cell death in many cell types, including neurons. In a screening of lipid hydroperoxides which can induce toxicity in neuronal cells, we found docosahexaenoic acid hydroperoxides (DHA-OOH) induced much severe levels of reactive oxygen species generation and cell death in human neuroblastoma SH-SY5Y cells compared to the hydroperoxides of linoleic acid and arachidonic acid. Therefore, we focused on DHA-OOH, and demonstrated that DHA-OOH apparently induced an apoptosis in the neuronal cells through several apoptotic hallmarks including nuclei condensation, DNA fragmentation, poly (ADP-ribose) polymerase cleavage and increased activity of caspase-3. We also found the signaling changes in mitochondria-mediated apoptosis, such as cytochrome c release and increased expression of Bcl-2, as well as a dose-dependent attenuation of mitochondrial membrane potential in the DHA-OOH treated cells. These data indicated DHA hydroperoxide as a potential inducer of apoptosis in human neuroblastoma SH-SY5Y cells, which may be mediated by mitochondria dysfunction pathway. PMID:18648656

  2. Age-dependent effect of treadmill exercise on hemorrhage-induced neuronal cell death in rats.

    Science.gov (United States)

    Yoon, Jin-Hwan; Lee, Hee-Hyuk; Yi, Eun-Surk; Baek, Soon Gi

    2013-01-01

    Intracerebral hemorrhage (ICH) is a major cause of death and disability in the elderly. In the present study, we examined the age-dependence of the effect of treadmill exercise on the intrastriatal hemorrhage-induced neuronal cell death in rats. Young (8 weeks old) and old (64 weeks old) Sprague-Dawley male rats were used in the present study. Intrastriatal hemorrhage was induced by injection of 0.2 U collagenase (1 μL volume) into the striatum using a stereotaxic instrument. The rats in the exercise groups were forced to run on a treadmill for 30 min daily for 7 days. Lesion size was determined by Nissl staining. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. In the present results, induction of hemorrhage increased lesion size and enhanced apoptosis. Treadmill exercise decreased the lesion size with suppressing apoptosis. However, the size of lesion induced by hemorrhage and the number of apoptotic cells were not different between young and old rats. Treadmill exercise significantly reduced the ICH-induced lesion size and the number of apoptotic cells irrespective of age. The data suggest that treadmill exercise may provide therapeutic value against ICH by suppressing neuronal apoptosis regardless of age.

  3. Peripheral nerve injury induces adult brain neurogenesis and remodelling.

    Science.gov (United States)

    Rusanescu, Gabriel; Mao, Jianren

    2017-02-01

    Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  4. Macrophage alternative activation confers protection against lipotoxicity-induced cell death.

    Science.gov (United States)

    Dai, Lingling; Bhargava, Prerna; Stanya, Kristopher J; Alexander, Ryan K; Liou, Yae-Huei; Jacobi, David; Knudsen, Nelson H; Hyde, Alexander; Gangl, Matthew R; Liu, Sihao; Lee, Chih-Hao

    2017-10-01

    Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and β-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Pparδ/γ-/- macrophages. In concert, β-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ-/- or Stat6-/- mice. Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state

  5. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    Science.gov (United States)

    Pattani, Varun P.; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W.

    2015-01-01

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of `clean' cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm2 laser fluence rate led to maximum cell destruction with the `cleaner' method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue.

  6. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    Energy Technology Data Exchange (ETDEWEB)

    Pattani, Varun P., E-mail: varun.pattani@utexas.edu; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W. [The University of Texas at Austin, Department of Biomedical Engineering (United States)

    2015-01-15

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of ‘clean’ cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm{sup 2} laser fluence rate led to maximum cell destruction with the ‘cleaner’ method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue.

  7. Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell death.

    Science.gov (United States)

    Schroeder, Anne; Warnken, Uwe; Röth, Daniel; Klika, Karel D; Vobis, Diana; Barnert, Andrea; Bujupi, Fatmire; Oberacker, Tina; Schnölzer, Martina; Nicolay, Jan P; Krammer, Peter H; Gülow, Karsten

    2017-02-24

    Constitutively active NFκB promotes survival of many cancers, especially T-cell lymphomas and leukemias by upregulating antiapoptotic proteins such as inhibitors of apoptosis (IAPs) and FLICE-like inhibitory proteins (cFLIPs). IAPs and cFLIPs negatively regulate the ripoptosome, which mediates cell death in an apoptotic or necroptotic manner. Here, we demonstrate for the first time, that DMF antagonizes NFκB by suppressing Thioredoxin-1 (Trx1), a major regulator of NFκB transcriptional activity. DMF-mediated inhibition of NFκB causes ripoptosome formation via downregulation of IAPs and cFLIPs. In addition, DMF promotes mitochondrial Smac release and subsequent degradation of IAPs, further enhancing cell death in tumor cells displaying constitutive NFκB activity. Significantly, CTCL patients treated with DMF display substantial ripoptosome formation and caspase-3 cleavage in T-cells. DMF induces cell death predominantly in malignant or activated T-cells. Further, we show that malignant T-cells can die by both apoptosis and necroptosis, in contrast to resting T-cells, which are restricted to apoptosis upon DMF administration. In summary, our data provide new mechanistic insight in the regulation of cell death by targeting NFκB via Trx1 in cancer. Thus, interference with Trx1 activity is a novel approach for treatment of NFκB-dependent tumors.

  8. Molecular characterization of propolis-induced cell death in Saccharomyces cerevisiae.

    Science.gov (United States)

    de Castro, Patrícia Alves; Savoldi, Marcela; Bonatto, Diego; Barros, Mário Henrique; Goldman, Maria Helena S; Berretta, Andresa A; Goldman, Gustavo Henrique

    2011-03-01

    Propolis, a natural product of plant resins, is used by the bees to seal holes in their honeycombs and protect the hive entrance. However, propolis has also been used in folk medicine for centuries. Here, we apply the power of Saccharomyces cerevisiae as a model organism for studies of genetics, cell biology, and genomics to determine how propolis affects fungi at the cellular level. Propolis is able to induce an apoptosis cell death response. However, increased exposure to propolis provides a corresponding increase in the necrosis response. We showed that cytochrome c but not endonuclease G (Nuc1p) is involved in propolis-mediated cell death in S. cerevisiae. We also observed that the metacaspase YCA1 gene is important for propolis-mediated cell death. To elucidate the gene functions that may be required for propolis sensitivity in eukaryotes, the full collection of about 4,800 haploid S. cerevisiae deletion strains was screened for propolis sensitivity. We were able to identify 138 deletion strains that have different degrees of propolis sensitivity compared to the corresponding wild-type strains. Systems biology revealed enrichment for genes involved in the mitochondrial electron transport chain, vacuolar acidification, negative regulation of transcription from RNA polymerase II promoter, regulation of macroautophagy associated with protein targeting to vacuoles, and cellular response to starvation. Validation studies indicated that propolis sensitivity is dependent on the mitochondrial function and that vacuolar acidification and autophagy are important for yeast cell death caused by propolis.

  9. Molecular Characterization of Propolis-Induced Cell Death in Saccharomyces cerevisiae▿†

    Science.gov (United States)

    de Castro, Patrícia Alves; Savoldi, Marcela; Bonatto, Diego; Barros, Mário Henrique; Goldman, Maria Helena S.; Berretta, Andresa A.; Goldman, Gustavo Henrique

    2011-01-01

    Propolis, a natural product of plant resins, is used by the bees to seal holes in their honeycombs and protect the hive entrance. However, propolis has also been used in folk medicine for centuries. Here, we apply the power of Saccharomyces cerevisiae as a model organism for studies of genetics, cell biology, and genomics to determine how propolis affects fungi at the cellular level. Propolis is able to induce an apoptosis cell death response. However, increased exposure to propolis provides a corresponding increase in the necrosis response. We showed that cytochrome c but not endonuclease G (Nuc1p) is involved in propolis-mediated cell death in S. cerevisiae. We also observed that the metacaspase YCA1 gene is important for propolis-mediated cell death. To elucidate the gene functions that may be required for propolis sensitivity in eukaryotes, the full collection of about 4,800 haploid S. cerevisiae deletion strains was screened for propolis sensitivity. We were able to identify 138 deletion strains that have different degrees of propolis sensitivity compared to the corresponding wild-type strains. Systems biology revealed enrichment for genes involved in the mitochondrial electron transport chain, vacuolar acidification, negative regulation of transcription from RNA polymerase II promoter, regulation of macroautophagy associated with protein targeting to vacuoles, and cellular response to starvation. Validation studies indicated that propolis sensitivity is dependent on the mitochondrial function and that vacuolar acidification and autophagy are important for yeast cell death caused by propolis. PMID:21193549

  10. Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity

    National Research Council Canada - National Science Library

    Sripetchwandee, Jirapas; Pipatpiboon, Noppamas; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2014-01-01

    .... We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine...

  11. Impact of Low-Level Thyroid Hormone Disruption Induced by Propylthiouracil on Brain Development and Function.*

    Science.gov (United States)

    The critical role of thyroid hormone (TH) in brain development is well established, severe deficiencies leading to significant neurological dysfunction. Much less information is available on more modest perturbations of TH on brain function. The present study induced varying degr...

  12. Estrogen reduces endoplasmic reticulum stress to protect against glucotoxicity induced-pancreatic β-cell death.

    Science.gov (United States)

    Kooptiwut, Suwattanee; Mahawong, Pitchnischa; Hanchang, Wanthanee; Semprasert, Namoiy; Kaewin, Suchada; Limjindaporn, Thawornchai; Yenchitsomanus, Pa-Thai

    2014-01-01

    Estrogen can improve glucose homeostasis not only in diabetic rodents but also in humans. However, the molecular mechanism by which estrogen prevents pancreatic β-cell death remains unclear. To investigate this issue, INS-1 cells, a rat insulinoma cell line, were cultured in medium with either 11.1mM or 40mM glucose in the presence or the absence of estrogen. Estrogen significantly reduced apoptotic β-cell death by decreasing nitrogen-induced oxidative stress and the expression of the ER stress markers GRP 78, ATF6, P-PERK, PERK, uXBP1, sXBP1, and CHOP in INS-1 cells after prolonged culture in medium with 40mM glucose. In contrast, estrogen increased the expression of survival proteins, including sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA-2), Bcl-2, and P-p38, in INS-1 cells after prolonged culture in medium with 40mM glucose. The cytoprotective effect of estrogen was attenuated by addition of the estrogen receptor (ERα and ERβ) antagonist ICI 182,780 and the estrogen membrane receptor inhibitor G15. We showed that estrogen decreases not only oxidative stress but also ER stress to protect against 40mM glucose-induced pancreatic β-cell death. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Plant cell death and cellular alterations induced by ozone: Key studies in Mediterranean conditions

    Energy Technology Data Exchange (ETDEWEB)

    Faoro, Franco, E-mail: franco.faoro@unimi.i [Istituto di Patologia Vegetale, Universita di Milano and CNR, Istituto di Virologia Vegetale, U.O.T di Milano, Via Celoria 2, 20133 Milan (Italy); Iriti, Marcello [Istituto di Patologia Vegetale, Universita di Milano and CNR, Istituto di Virologia Vegetale, U.O.T di Milano, Via Celoria 2, 20133 Milan (Italy)

    2009-05-15

    An account of histo-cytological and ultrastructural studies on ozone effect on crop and forest species in Italy is given, with emphasis on induced cell death and the underlying mechanisms. Cell death phenomena possibly due to ambient O{sub 3} were recorded in crop and forest species. In contrast, visible O{sub 3} effects on Mediterranean vegetation are often unclear. Microscopy is thus suggested as an effective tool to validate and evaluate O{sub 3} injury to Mediterranean vegetation. A DAB-Evans blue staining was proposed to validate O{sub 3} symptoms at the microscopic level and for a pre-visual diagnosis of O{sub 3} injury. The method has been positively tested in some of the most important crop species, such as wheat, tomato, bean and onion and, with some restriction, in forest species, and it also allows one to gain some very useful insights into the mechanisms at the base of O{sub 3} sensitivity or tolerance. - Ozone-induced cell death is a frequent phenomenon in Mediterranean conditions, not only in the most sensitive crops but also in forest species.

  14. Transmembrane TNF-α promotes activation-induced cell death by forward and reverse signaling

    Science.gov (United States)

    Jia, Lingwei; Huang, Jin; He, Cheng; Hu, Fuqing; Yuan, Lifei; Wang, Guihua; Yu, Mingxia; Li, Zhuoya

    2017-01-01

    Secretory tumor necrosis factor-alpha (sTNF-α) is known to mediate activation- induced cell death (AICD). However, the role of tmTNF-α in AICD is still obscure. Here, we demonstrated that tmTNF-α expression significantly increased accompanied with enhanced apoptosis during AICD in Jurkat and primary human T cells. Knockdown or enhancement of tmTNF-α expression in activated T cells suppressed or promoted AICD, respectively. Treatment of activated T cells with exogenous tmTNF-α significantly augmented AICD, indicating that tmTNF-α as an effector molecule mediates AICD. As tmTNF-α can function as a receptor, an anti-TNF-α polyclonal antibody was used to trigger reverse signaling of tmTNF-α. This antibody treatment upregulated the expression of Fas ligand, TNF-related apoptosis-inducing ligand and tmTNF-α to amplify AICD, and promoted activated T cells expressing death receptor 4, TNF receptor (TNFR) 1 and TNFR2 to enhance their sensitivity to AICD. Knockdown of TNFR1 or TNFR2 expression totally blocked tmTNF-α reverse signaling increased sensitivity to sTNF-α- or tmTNF-α-mediated AICD, respectively. Our results indicate that tmTNF-α functions as a death ligand in mediation of AICD and as a receptor in sensitization of activated T cells to AICD. Targeting tmTNF-α in activated T cells may be helpful in facilitating AICD for treatment of autoimmune diseases. PMID:28969030

  15. Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast.

    Science.gov (United States)

    Pozniakovsky, Andrei I; Knorre, Dmitry A; Markova, Olga V; Hyman, Anthony A; Skulachev, Vladimir P; Severin, Fedor F

    2005-01-17

    Although programmed cell death (PCD) is extensively studied in multicellular organisms, in recent years it has been shown that a unicellular organism, yeast Saccharomyces cerevisiae, also possesses death program(s). In particular, we have found that a high doses of yeast pheromone is a natural stimulus inducing PCD. Here, we show that the death cascades triggered by pheromone and by a drug amiodarone are very similar. We focused on the role of mitochondria during the pheromone/amiodarone-induced PCD. For the first time, a functional chain of the mitochondria-related events required for a particular case of yeast PCD has been revealed: an enhancement of mitochondrial respiration and of its energy coupling, a strong increase of mitochondrial membrane potential, both events triggered by the rise of cytoplasmic [Ca2+], a burst in generation of reactive oxygen species in center o of the respiratory chain complex III, mitochondrial thread-grain transition, and cytochrome c release from mitochondria. A novel mitochondrial protein required for thread-grain transition is identified.

  16. Neonatal Death

    Science.gov (United States)

    ... a premature baby include pneumonia (a lung infection), sepsis (a blood infection) and meningitis (an infection in the fluid around the brain and spinal cord). What birth defects most often cause neonatal death? The most common birth defects that cause ...

  17. Idebenone induces apoptotic cell death in the human dopaminergic neuroblastoma SHSY-5Y cells.

    Science.gov (United States)

    Tai, Kwok-Keung; Pham, L; Truong, D D

    2011-11-01

    Idebenone is a coenzyme Q10 analog and an antioxidant that has been used clinically to treat Friedreich Ataxia. Being an antioxidant, idebenone could have potential therapeutic potential to treat other neurodegenerative diseases such as Parkinson's disease in which oxidative stress plays a role in their pathogenesis. But whether idebenone can be used to treat Parkinson's disease has not been evaluated. In this study, we found that exposure of the dopaminergic neuroblastoma SHSY-5Y cells to 1-10 μM idebenone for 72 h had no effect on the cell viability revealed by trypan blue exclusion assay and MTT assay. However, cells exposed to 25 μM or higher concentrations of idebenone showed extensive trypan blue-positive staining and significant reduction in cell viability revealed by MTT assay indicating that most of the cells were no longer viable. Idebenone-induced cell death was characterized by genomic DNA fragmentation and accumulation of cytochrome c in the cytosol indicating that the death was apoptotic in nature. In addition, idebenone induced an increase in the total RNA of the pro-apoptosis protein BAX, it also increased the caspase-3 activity in the cell lysates when compared with the untreated control cells or cells exposed to 10 μM or lower concentrations of idebenone. The detrimental effect of idebenone was attenuated by glutathione, an antioxidant, suggesting that oxidative stress contributed to the idebenone-induced cell death. In conclusion, our results suggest that antioxidant idebenone induced apoptosis when used in high concentrations.

  18. Taxifolin synergizes Andrographolide-induced cell death by attenuation of autophagy and augmentation of caspase dependent and independent cell death in HeLa cells.

    Directory of Open Access Journals (Sweden)

    Mazen Alzaharna

    Full Text Available Andrographolide (Andro has emerged recently as a potential and effective anticancer agent with induction of apoptosis in some cancer cell lines while induction of G2/M arrest with weak apoptosis in others. Few studies have proved that Andro is also effective in combination therapy. The flavonoid Taxifolin (Taxi has showed anti-oxidant and antiproliferative effects against different cancer cells. Therefore, the present study investigated the cytotoxic effects of Andro alone or in combination with Taxi on HeLa cells. The combination of Andro with Taxi was synergistic at all tested concentrations and combination ratios. Andro alone induced caspase-dependent apoptosis which was enhanced by the combination with Taxi and attenuated partly by using Z-Vad-Fmk. Andro induced a protective reactive oxygen species (ROS-dependent autophagy which was attenuated by Taxi. The activation of p53 was involved in Andro-induced autophagy where the use of Taxi or pifithrin-α (PFT-α decreased it while the activation of JNK was involved in the cell death of HeLa cells but not in the induction of autophagy. The mitochondrial outer-membrane permeabilization (MOMP plays an important role in Andro-induced cell death in HeLa cells. Andro alone increased the MOMP which was further increased in the case of combination. This led to the increase in AIF and cytochrome c release from mitochondria which consequently increased caspase-dependent and independent cell death. In conclusion, Andro induced a protective autophagy in HeLa cells which was reduced by Taxi and the cell death was increased by increasing the MOMP and subsequently the caspase-dependent and independent cell death.

  19. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology.

    Science.gov (United States)

    Wijdicks, Eelco F M; Varelas, Panayiotis N; Gronseth, Gary S; Greer, David M

    2010-06-08

    To provide an update of the 1995 American Academy of Neurology guideline with regard to the following questions: Are there patients who fulfill the clinical criteria of brain death who recover neurologic function? What is an adequate observation period to ensure that cessation of neurologic function is permanent? Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death? What is the comparative safety of techniques for determining apnea? Are there new ancillary tests that accurately identify patients with brain death? A systematic literature search was conducted and included a review of MEDLINE and EMBASE from January 1996 to May 2009. Studies were limited to adults. In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 American Academy of Neurology practice parameter. Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead. There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly. Apneic oxygenation diffusion to determine apnea is safe, but there is insufficient evidence to determine the comparative safety of techniques used for apnea testing. There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain.

  20. Laminin-1 induces endocytosis of 67KDa laminin receptor and protects Neuroscreen-1 cells against death induced by serum withdrawal.

    Science.gov (United States)

    Gopalakrishna, Rayudu; Gundimeda, Usha; Zhou, Sarah; Bui, Helena; Davis, Andrew; McNeill, Thomas; Mack, William

    2018-01-01

    Although the function of laminin in the basement membrane is known, the function of soluble "neuronal" laminin is unknown. Since laminin is neuroprotective, we determined whether the soluble laminin-1 induces signaling for neuroprotection via its 67KDa laminin-1 receptor (67LR). Treatment of Neuroscreen-1 (NS-1) cells with laminin-1 or YIGSR peptide, which corresponds to a sequence in laminin-1 β1 chain that binds to 67LR, induced a decrease in the cell-surface expression of 67LR and caused its internalization. Furthermore, intracellular cAMP-elevating agents, dibutyryl-cAMP, forskolin, and rolipram, also induced this internalization. Both soluble laminin-1 and YIGSR induced a sustained elevation of intracellular cAMP under defined conditions, suggesting a causal role of cAMP in the endocytosis of 67LR. This endocytosis was not observed in cells deficient in protein kinase A (PKA) nor in cells treated with either SQ 22536, an inhibitor for adenylyl cyclase, or ESI-09, an inhibitor for the exchange protein directly activated by cAMP (Epac). In addition, when internalization occurred in NS-1 cells, 67LR and adenylyl cyclase were localized in early endosomes. Under conditions in which endocytosis had occurred, both laminin-1 and YIGSR protected NS-1 cells from cell death induced by serum withdrawal. However, under conditions in which endocytosis did not occur, neither laminin-1 nor YIGSR protected these cells. Conceivably, the binding of laminin-1 to 67LR causes initial signaling through PKA and Epac, which causes the internalization of 67LR, along with signaling enzymes, such as adenylyl cyclase, into early endosomes. This causes sustained signaling for protection against cell death induced by serum withdrawal. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Sitosterol-containing lipoproteins trigger free sterol-induced caspase-independent death in ACAT-competent macrophages.

    Science.gov (United States)

    Bao, Liping; Li, Yankun; Deng, Shi-Xian; Landry, Donald; Tabas, Ira

    2006-11-03

    Sitosterolemia is a disease characterized by very high levels of sitosterol and other plant sterols and premature atherothrombotic vascular disease. One theory holds that plant sterols can directly promote atherosclerosis, but the mechanism is not known. Unesterified, or "free," cholesterol (FC) is a potent inducer of macrophage death, which causes plaque necrosis, a precursor to atherothrombosis. FC-induced macrophage death, however, requires dysfunction of the sterol esterifying enzyme acyl-coenzyme A-cholesterol acyltransferase (ACAT), which likely occurs slowly during lesion progression. In contrast, plant sterols are relatively poorly esterified by ACAT, and so they may cause macrophage death and plaque necrosis in an accelerated manner. In support of this hypothesis, we show here that macrophages incubated with sitosterol-containing lipoproteins accumulate free sterols and undergo death in the absence of an ACAT inhibitor. As with FC loading, sitosterol-induced macrophage death requires sterol trafficking to the endoplasmic reticulum, and sitosterol-enriched endoplasmic reticulum membranes show evidence of membrane protein dysfunction. However, whereas FC induces caspase-dependent apoptosis through activation of the unfolded protein response and JNK, sitosterol-induced death is caspase-independent and involves neither the unfolded protein response nor JNK. Rather, cell death shows signs of necroptosis and autophagy and is suppressed by inhibitors of both processes. These data establish two new concepts. First, a relatively subtle change in sterol structure fundamentally alters the type of death program triggered in macrophages. Understanding the basis of this alteration should provide new insights into the molecular basis of death pathway signaling. Second, sitosterol-induced macrophage death does not require ACAT dysfunction and so may occur in an accelerated fashion. Pending future in vivo studies, this concept may provide at least one mechanism for

  2. EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia in Female Mice

    Directory of Open Access Journals (Sweden)

    Bo Young Choi

    2014-10-01

    Full Text Available EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.

  3. The organ preservation and enhancement of donation success ratio effect of extracorporeal membrane oxygenation in circulatory unstable brain death donor.

    Science.gov (United States)

    Fan, Xiaoli; Chen, Zhiquan; Nasralla, David; Zeng, Xianpeng; Yang, Jing; Ye, Shaojun; Zhang, Yi; Peng, Guizhu; Wang, Yanfeng; Ye, Qifa

    2016-10-01

    Between 2010 and 2013, we recorded 66 cases of failed organ donation after brain death (DBD) due to the excessive use of the vasoactive drugs resulting in impaired hepatic and/or renal function. To investigate the effect of extracorporeal membrane oxygenation (ECMO) in donor management, ECMO was used to provide support for DBD donors with circulatory and/or respiratory failure from 2013 to 2015. A retrospective cohort study between circulatory non-stable DBD with vasoactive drugs (DBD-drug) and circulatory non-stable DBD with ECMO (DBD-ECMO) was designed to compare the transplant outcomes. A total of 19 brain death donors were supported by ECMO. The incidence rate of post-transplant liver primary non-function (PNF) was 10% (two of 20) in DBD-drug group and zero in DBD-ECMO group. Kidney function indicators, including creatinine clearance and urine production, were significantly better in DBD-ECMO group, as well as the kidney delayed graft function (DGF) rate was found to be decreased by the use of ECMO in our study. Donation success rate increased steadily from 47.8% in 2011 to 84.6% in 2014 after the ECMO intervention. The use of ECMO in assisting circulatory and respiratory function of DBD can reduce liver and kidney injury from vasoactive drugs, thereby improving organ quality and reducing the organ discard rates. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Changing Patterns of Organ Donation: Brain Dead Donors Are Not Being Lost by Donation After Circulatory Death.

    Science.gov (United States)

    Nelson, Helen M; Glazier, Alexandra K; Delmonico, Francis L

    2016-02-01

    The clinical characteristics of all New England Organ Bank (NEOB) donors after circulatory death (DCD) donors were analyzed between July 1, 2009, and June 30, 2014. During that 5-year period, there were 494 authorized medically suitable potential DCDs that the NEOB evaluated, constituting more than 30% of deceased donors coordinated annually by the NEOB. From the cohort of 494 authorized potential DCDs, 331 (67%) became actual DCD, 82 (17%) were attempted as a DCD but did not progress to donation, and 81 (16%) transitioned to an actual donor after brain death (DBD). Two hundred seventy-six organs were transplanted from the 81 donors that transitioned from DCD to actual DBD, including 24 heart, 70 liver, 12 single and 14 bilateral lung, and 12 pancreas transplants. When patients with devastating brain injury admitted to the intensive care units are registered donors, the Organ Procurement Organization staff should share the patient's donation decision with the health care team and the patient's family, as early as possible after the comfort measures only discussion has been initiated. The experience of the NEOB becomes an important reference of the successful implementation of DCD that enables an expansion of deceased donation (inclusive of DBD).

  5. Exploiting Cell Death Pathways for Inducible Cell Elimination to Modulate Graft-versus-Host-Disease

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    Corey Falcon

    2017-06-01

    Full Text Available Hematopoietic stem cell transplantation is a potent form of immunotherapy, potentially life-saving for many malignant hematologic diseases. However, donor lymphocytes infused with the graft while exerting a graft versus malignancy effect can also cause potentially fatal graft versus host disease (GVHD. Our group has previously validated the inducible caspase-9 suicide gene in the haploidentical stem cell transplant setting, which proved successful in reversing signs and symptoms of GVHD within hours, using a non-therapeutic dimerizing agent. Cellular death pathways such as apoptosis and necroptosis are important processes in maintaining healthy cellular homeostasis within the human body. Here, we review two of the most widely investigated cell death pathways active in T-cells (apoptosis and necroptosis, as well as the emerging strategies that can be exploited for the safety of T-cell therapies. Furthermore, such strategies could be exploited for the safety of other cellular therapeutics as well.

  6. Exploiting Cell Death Pathways for Inducible Cell Elimination to Modulate Graft-versus-Host-Disease.

    Science.gov (United States)

    Falcon, Corey; Al-Obaidi, Mustafa; Di Stasi, Antonio

    2017-06-14

    Hematopoietic stem cell transplantation is a potent form of immunotherapy, potentially life-saving for many malignant hematologic diseases. However, donor lymphocytes infused with the graft while exerting a graft versus malignancy effect can also cause potentially fatal graft versus host disease (GVHD). Our group has previously validated the inducible caspase-9 suicide gene in the haploidentical stem cell transplant setting, which proved successful in reversing signs and symptoms of GVHD within hours, using a non-therapeutic dimerizing agent. Cellular death pathways such as apoptosis and necroptosis are important processes in maintaining healthy cellular homeostasis within the human body. Here, we review two of the most widely investigated cell death pathways active in T-cells (apoptosis and necroptosis), as well as the emerging strategies that can be exploited for the safety of T-cell therapies. Furthermore, such strategies could be exploited for the safety of other cellular therapeutics as well.

  7. Alkaloids Induce Programmed Cell Death in Bloodstream Forms of Trypanosomes (Trypanosoma b. brucei

    Directory of Open Access Journals (Sweden)

    Michael Wink

    2008-10-01

    Full Text Available The potential induction of a programmed cell death (PCD in Trypanosoma b. brucei by 55 alkaloids of the quinoline, quinolizidine, isoquinoline, indole, terpene, tropane, steroid, and piperidine type was studied by measuring DNA fragmentation and changes in mitochondrial membrane potential. For comparison, the induction of apoptosis by the same alkaloids in human leukemia cells (Jurkat APO-S was tested. Several alkaloids of the isoquinoline, quinoline, indole and steroidal type (berberine, chelerythrine, emetine, sanguinarine, quinine, ajmalicine, ergotamine, harmine, vinblastine, vincristine, colchicine, chaconine, demissidine and veratridine induced programmed cell death, whereas quinolizidine, tropane, terpene and piperidine alkaloids were mostly inactive. Effective PCD induction (EC50 below 10 µM was caused in T. brucei by chelerythrine, emetine, sanguinarine, and chaconine. The active alkaloids can be characterized by their general property to inhibit protein biosynthesis, to intercalate DNA, to disturb membrane fluidity or to inhibit microtubule formation.

  8. Evidence for Radiation-Induced Disseminated Intravascular Coagulation as a Major Cause of Radiation-Induced Death in Ferrets

    Energy Technology Data Exchange (ETDEWEB)

    Krigsfeld, Gabriel S.; Savage, Alexandria R.; Billings, Paul C.; Lin, Liyong; Kennedy, Ann R., E-mail: akennedy@mail.med.upenn.edu

    2014-03-15

    Purpose: The studies reported here were performed as part of a program in space radiation biology in which proton radiation like that present in solar particle events, as well as conventional gamma radiation, were being evaluated in terms of the ability to affect hemostasis. Methods and Materials: Ferrets were exposed to 0 to 2 Gy of whole-body proton or gamma radiation and monitored for 30 days. Blood was analyzed for blood cell counts, platelet clumping, thromboelastometry, and fibrin clot formation. Results: The lethal dose of radiation to 50% of the population (LD{sub 50}) of the ferrets was established at ∼1.5 Gy, with 100% mortality at 2 Gy. Hypocoagulability was present as early as day 7 postirradiation, with animals unable to generate a stable clot and exhibiting signs of platelet aggregation, thrombocytopenia, and fibrin clots in blood vessels of organs. Platelet counts were at normal levels during the early time points postirradiation when coagulopathies were present and becoming progressively more severe; platelet counts were greatly reduced at the time of the white blood cell nadir of 13 days. Conclusions: Data presented here provide evidence that death at the LD{sub 50} in ferrets is most likely due to disseminated intravascular coagulation (DIC). These data question the current hypothesis that death at relatively low doses of radiation is due solely to the cell-killing effects of hematopoietic cells. The recognition that radiation-induced DIC is the most likely mechanism of death in ferrets raises the question of whether DIC is a contributing mechanism to radiation-induced death at relatively low doses in large mammals.

  9. Structural brain plasticity in Parkinson's disease induced by balance training.

    Science.gov (United States)

    Sehm, Bernhard; Taubert, Marco; Conde, Virginia; Weise, David; Classen, Joseph; Dukart, Juergen; Draganski, Bogdan; Villringer, Arno; Ragert, Patrick

    2014-01-01

    We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ∼20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME × GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Regeneration, Plasticity, and Induced Molecular Programs in Adult Zebrafish Brain

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    Mehmet Ilyas Cosacak

    2015-01-01

    Full Text Available Regenerative capacity of the brain is a variable trait within animals. Aquatic vertebrates such as zebrafish have widespread ability to renew their brains upon damage, while mammals have—if not none—very limited overall regenerative competence. Underlying cause of such a disparity is not fully evident; however, one of the reasons could be activation of peculiar molecular programs, which might have specific roles after injury or damage, by the organisms that regenerate. If this hypothesis is correct, then there must be genes and pathways that (a are expressed only after injury or damage in tissues, (b are biologically and functionally relevant to restoration of neural tissue, and (c are not detected in regenerating organisms. Presence of such programs might circumvent the initial detrimental effects of the damage and subsequently set up the stage for tissue redevelopment to take place by modulating the plasticity of the neural stem/progenitor cells. Additionally, if transferable, those “molecular mechanisms of regeneration” could open up new avenues for regenerative therapies of humans in clinical settings. This review focuses on the recent studies addressing injury/damage-induced molecular programs in zebrafish brain, underscoring the possibility of the presence of genes that could be used as biomarkers of neural plasticity and regeneration.

  11. Discovery of Small Molecules That Induce Lysosomal Cell Death in Cancer Cell Lines Using an Image-Based Screening Platform

    NARCIS (Netherlands)

    Pagliero, Romina J; D'Astolfo, Diego S; Lelieveld, Daphne; Pratiwi, Riyona D; Aits, Sonja; Jaattela, Marja; Martin, Nathaniel I; Klumperman, Judith; Egan, David A

    2016-01-01

    The lysosomal cell death (LCD) pathway is a caspase 3-independent cell death pathway that has been suggested as a possible target for cancer therapy, making the development of sensitive and specific high-throughput (HT) assays to identify LCD inducers highly desirable. In this study, we report a

  12. p73 engages A2B receptor signalling to prime cancer cells to chemotherapy-induced death

    NARCIS (Netherlands)

    Long, J. S.; Schoonen, P. M.; Graczyk, D.; O'Prey, J.; Ryan, K. M.

    2015-01-01

    Tumour cells often acquire the ability to escape cell death, a key event leading to the development of cancer. In almost half of all human cancers, the capability to induce cell death is reduced by the mutation and inactivation of p53, a tumour suppressor protein that is a central regulator of

  13. Imminent brain death: Point of departure for potential heart-beating organ donor recognition

    NARCIS (Netherlands)

    Y.J. de Groot (Yorick); N.E. Jansen (Nichon); J. Bakker (Jan); M.A. Kuiper (Michael); S. Aerdts (Stan); A.I.R. Maas (Andrew); E.F.M. Wijdicks (Eelco); H.A. van Leiden (Hendrik); A.J. Hoitsma (Andries); H.P.H. Kremer (Berry); E.J.O. Kompanje (Erwin)

    2010-01-01

    textabstractPurpose: There is, in European countries that conduct medical chart review of intensive care unit (ICU) deaths, no consensus on uniform criteria for defining a potential organ donor. Although the term is increasingly being used in recent literature, it is seldom defined in detail. We

  14. Carbon monoxide-induced delayed amnesia, delayed neuronal death and change in acetylcholine concentration in mice

    Energy Technology Data Exchange (ETDEWEB)

    Nabeshima, T.; Katoh, A.; Ishimaru, H.; Yoneda, Y.; Ogita, K.; Murase, K.; Ohtsuka, H.; Inari, K.; Fukuta, T.; Kameyama, T. (Meijo Univ., Nagoya (Japan))

    1991-01-01

    We investigated the interrelationship of delayed amnesia, delayed neuronal death and changes in acetylcholine concentration induced by carbon monoxide (CO)-exposure in mice. In the test for retention of the passive avoidance task, amnesia was observed 5 and 7 days after CO-exposure when the mice were exposed to CO 1 day after training; in the case when the mice were exposed to CO 5 and 7 days before training, amnesia was also observed in a retention test given 1 day after training. The number of pyramidal cells in the hippocampal CA1 subfield was lower than that of the control 3, 5 and 7 days after CO-exposure. But the neurodegeneration in the parietal cortex, area 1, was not observed until 7 days after CO-exposure. The findings indicated that the amnesia and the neuronal death were produced after a delay when the mice were exposed to CO. In addition, the delayed amnesia was closely related to the delayed neuronal death in the hippocampal CA1 subfield. Moreover, (3H)glutamate and (3H)glycine binding sites did not change after CO-exposure but, 7 days after CO-exposure, the concentration of acetylcholine and the binding of (3H)quinuclidinyl benzilate in the frontal cortex and the striatum were found to have significantly changed, but those in the hippocampus did not show significant change. Therefore, we suggest that delayed amnesia induced by CO-exposure may result from delayed neuronal death in the hippocampal CA1 subfield and dysfunction in the acetylcholinergic neurons, in the frontal cortex, the striatum and/or the hippocampus.

  15. Punicalagin induces apoptotic and autophagic cell death in human U87MG glioma cells.

    Science.gov (United States)

    Wang, Shyang-guang; Huang, Ming-hung; Li, Jui-hsiang; Lai, Fu-i; Lee, Horng-mo; Hsu, Yuan-nian

    2013-11-01

    To investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human U87MG glioma cells in vitro. The viability of human U87MG glioma cells was evaluated using MTT assay. Cell cycle was detected with flow cytometry analysis. The levels of Bcl-2, cleaved caspase-9, cleaved poly(ADP-ribose) polymerase (PARP), phosphor-AMPK and phosphor-p27 at Thr198 were measured using immunoblot analyses. Caspase-3 activity was determined with spectrophotometer. To determine autophagy, LC3 cleavage and punctate patterns were examined. Punicalagin (1-30 μg/mL) dose-dependently inhibited the cell viability in association with increased cyclin E level and decreased cyclin B and cyclin A levels. The treatment also induced apoptosis as shown by the cleavage of PARP, activation of caspase-9, and increase of caspase-3 activity in the cells. However, pretreatment of the cells with the pan-caspase inhibitor z-DEVD-fmk (50 μmol/L) did not completely prevent the cell death. On the other hand, punicalagin treatment increased LC3-II cleavage and caused GFP-LC3-II-stained punctate pattern in the cells. Suppressing autophagy of cells with chloroquine (1-10 μmol/L) dose-dependently alleviated the cell death caused by punicalagin. Punicalagin (1-30 μg/mL) also increased the levels phosphor-AMPK and phosphor-p27 at Thr198 in the cells, which were correlated with the induction of autophagic cell death. Punicalagin induces human U87MG glioma cell death through both apoptotic and autophagic pathways.

  16. Triptolide induces lysosomal-mediated programmed cell death in MCF-7 breast cancer cells

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    Owa C

    2013-09-01

    Full Text Available Chie Owa, Michael E Messina Jr, Reginald HalabyDepartment of Biology, Montclair State University, Montclair, NJ, USABackground: Breast cancer is a major cause of death; in fact, it is the most common type, in order of the number of global deaths, of cancer in women worldwide. This research seeks to investigate how triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, induces apoptosis in MCF-7 human breast cancer cells. Accumulating evidence suggests a role for lysosomal proteases in the activation of apoptosis. However, there is also some controversy regarding the direct participation of lysosomal proteases in activation of key apoptosis-related caspases and release of mitochondrial cytochrome c. In the present study, we demonstrate that triptolide induces an atypical, lysosomal-mediated apoptotic cell death in MCF-7 cells because they lack caspase-3.Methods: MCF-7 cell death was characterized via cellular morphology, chromatin condensation, 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide colorimetric cell growth inhibition assay and the expression levels of proapoptotic proteins. Acridine orange and LysoTracker® staining were performed to visualize lysosomes. Lysosomal enzymatic activity was monitored using an acid phosphatase assay and western blotting of cathepsin B protein levels in the cytosolic fraction, which showed increased enzymatic activity in drug-treated cells.Results: These experiments suggest that triptolide-treated MCF-7 cells undergo atypical apoptosis and that, during the early stages, lysosomal enzymes leak into the cytosol, indicating lysosomal membrane permeability.Conclusion: Our results suggest that further studies are warranted to investigate triptolide's potential as an anticancer therapeutic agent.Keywords: triptolide, MCF-7 breast cancer cells, apoptosis, lysosomes, lysosomal membrane permeabilization (LMP

  17. Myricetin ameliorates scopolamine-induced memory impairment in mice via inhibiting acetylcholinesterase and down-regulating brain iron.

    Science.gov (United States)

    Wang, Beiyun; Zhong, Yuan; Gao, Chengjie; Li, Jingbo

    2017-08-19

    The aim of our study was to investigate to investigate the effect of myricetin on Alzheimer's disease (AD) and its underlying mechanisms. In our study, Myricetin effectively attenuated Fe(2+)-induced cell death in SH-SY5Y cells in vitro. In a mouse model of AD, myricetin treatment significantly reversed scopolamine-induced cognitive deficits deriving from a novel action of inhibiting acetylcholinesterase (AChE) and down-regulating brain iron. Furthermore, Myricetin treatment reduced oxidative damage and increased antioxidant enzymes activity in mice. Interestingly, the effect of myricetin was largely abolished by high iron diet. Therefore we suggested that treatment with myricetin attenuated cognitive deficits in mice via inhibiting AChE and brain iron regulation. In addition, myricetin reduce iron contents may via inhibiting transferrin receptor 1 (TrR1) expression. In conclusion, accumulated data demonstrates that myricetin is a potential multifunctional drug for AD. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation

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    Huber-Lang Markus

    2006-07-01

    Full Text Available Abstract Background Neuroprotective strategies for prevention of the neuropathological sequelae of traumatic brain injury (TBI have largely failed in translation to clinical treatment. Thus, there is a substantial need for further understanding the molecular mechanisms and pathways which lead to secondary neuronal cell death in the injured brain. The intracerebral activation of the complement cascade was shown to mediate inflammation and tissue destruction after TBI. However, the exact pathways of complement activation involved in the induction of posttraumatic neurodegeneration have not yet been assessed. In the present study, we investigated the role of the alternative complement activation pathway in contributing to neuronal cell death, based on a standardized TBI model in mice with targeted deletion of the factor B gene (fB-/-, a "key" component required for activation of the alternative complement pathway. Results After experimental TBI in wild-type (fB+/+ mice, there was a massive time-dependent systemic complement activation, as determined by enhanced C5a serum levels for up to 7 days. In contrast, the extent of systemic complement activation was significantly attenuated in fB-/- mice (P fB-/- vs. fB+/+; t = 4 h, 24 h, and 7 days after TBI. TUNEL histochemistry experiments revealed that posttraumatic neuronal cell death was clearly reduced for up to 7 days in the injured brain hemispheres of fB-/- mice, compared to fB+/+ littermates. Furthermore, a strong upregulation of the anti-apoptotic mediator Bcl-2 and downregulation of the pro-apoptotic Fas receptor was detected in brain homogenates of head-injured fB-/- vs. fB+/+ mice by Western blot analysis. Conclusion The alternative pathway of complement activation appears to play a more crucial role in the pathophysiology of TBI than previously appreciated. This notion is based on the findings of (a the significant attenuation of overall complement activation in head-injured fB-/- mice, as

  19. Analysis on the training effect of criteria and practical guidance for determination of brain death: transcranial Doppler

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    Lin-lin FAN

    2015-12-01

    Full Text Available Objective To analyze the training effects of transcranial Doppler (TCD for brain death determination conducted by Brain Injury Evaluation Quality Control Centre of National Health and Family Planning Commission to optimize the training program and improve the training effects. Methods A total of 106 trainees received theoretical training, simulation skill training, bedside skill training and test analysis on TCD confirmatory test for brain death determination. The composition of trainees was analyzed and the error rates of 6 knowledge points were calculated. Univariate and multivariate backward Logistic regression analyses were used to analyze the influence of factors including sex, age, specialty, professional category professional qualification and hospital level on the error rates. Results The trainees including 42 males and 64 females, came from 69 hospitals. Trainees of 30-49 years old occupied 77.36% (82/106. In the trainees, 96.23% (102/106 were from third grade, grade A hospitals, and most of them were from Department of Neurology (64.15% , 68/106 and Ultrasound (19.81% , 21/106. There were 82 clinicians (77.36%. Thirty four (32.08% trainees had senior certificate and 49 (46.23% had intermediate certificate. Total error rate of 6 knowledge points was 7.26% (149/2052. Of the 6 knowledge points, the error rate of parameter setting was the highest (9.43%, 10/106, followed by checking position (8.73%, 37/424, artery recognition (8.67%, 43/496, result determination (7.41%, 55/742, equipment (1.89%, 2/106 and pitfalls (1.12%, 2/178. Univariate and multivariate Logistic regression analyses showed that specialty (OR = 1.313, 95% CI: 1.072-1.610; P = 0.009 and hospital level (OR = 2.943, 95% CI: 1.623-5.338; P = 0.000 were independent risk factors associated with high error rates. Conclusions Among the trainees, degree of mastering the knowledge points is different, and the characteristics of trainees influence the training effect. The training

  20. Drug induced mortality: a multiple cause approach on Italian causes of death Register

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    Francesco Grippo

    2015-04-01

    Full Text Available Background: Drug-related mortality is a complex phenomenon that has several health, social and economic effects. In this paper trends of drug-induced mortality in Italy are analysed. Two approaches have been followed: the traditional analysis of the underlying cause of death (UC (data refers to the Istat mortality database from 1980 to 2011, and the multiple cause (MCanalysis, that is the analysis of all conditions reported on the death certificate (data for 2003-2011 period.Methods: Data presented in this paper are based on the Italian mortality register. The selection of Icd codes used for the analysis follows the definition of the European Monitoring Centre for Drugs and Drug Addiction. Using different indicators (crude and standardized rates, ratio multiple to underlying, the results obtained from the two approaches (UC and MC have been compared. Moreover, as a measure of association between drug-related causes and specific conditions on the death certificate, an estimation of the age-standardized relative risk (RR has been used.Results: In the years 2009-2011, the total number of certificates whit mention of drug use was 1,293, 60% higher than the number UC based. The groups of conditions more strongly associated with drug-related causes are the mental and behavioral disorders (especially alcohol consumption, viral hepatitis, cirrhosis and fibrosis of liver, AIDS and endocarditis.Conclusions : The analysis based on multiple cause approach shows, for the first time, a more detailed picture of the drug related death; it allows to better describe the mortality profiles and to re-evaluate  the contribution of a specific cause to death.

  1. An Integrative Analysis Reveals a Central Role of P53 Activation via MDM2 in Zika Virus Infection Induced Cell Death

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    Yue Teng

    2017-07-01

    Full Text Available Zika virus (ZIKV infection is an emerging global threat that is suspected to be associated with fetal microcephaly. However, the molecular mechanisms underlying ZIKV disease pathogene