Deconstructing the Brain Disconnection–Brain Death Analogy and Clarifying the Rationale for the Neurological Criterion of Death

Science.gov (United States)

Moschella, Melissa

2016-01-01

This article explains the problems with Alan Shewmon’s critique of brain death as a valid sign of human death, beginning with a critical examination of his analogy between brain death and severe spinal cord injury. The article then goes on to assess his broader argument against the necessity of the brain for adult human organismal integration, arguing that he fails to translate correctly from biological to metaphysical claims. Finally, on the basis of a deeper metaphysical analysis, I offer a revised rationale for the validity of the neurological criterion of human death. PMID:27095749

Cylindromatosis mediates neuronal cell death in vitro and in vivo.

Science.gov (United States)

Ganjam, Goutham K; Terpolilli, Nicole Angela; Diemert, Sebastian; Eisenbach, Ina; Hoffmann, Lena; Reuther, Christina; Herden, Christiane; Roth, Joachim; Plesnila, Nikolaus; Culmsee, Carsten

2018-01-19

The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death. Similar protective effects were achieved by siRNA silencing of RIP1 or RIP3 or by pharmacological inhibition of RIP1 with necrostatin-1. In vivo, CYLD knockout mice were protected from trauma-induced brain damage compared to wild-type littermate controls. These findings unravel the mechanisms of CYLD-mediated cell death signaling in damaged neurons in vitro and suggest a cell death-mediating role of CYLD in vivo.

Benzyl isothiocyanate alters the gene expression with cell cycle regulation and cell death in human brain glioblastoma GBM 8401 cells.

Science.gov (United States)

Tang, Nou-Ying; Chueh, Fu-Shin; Yu, Chien-Chih; Liao, Ching-Lung; Lin, Jen-Jyh; Hsia, Te-Chun; Wu, King-Chuen; Liu, Hsin-Chung; Lu, Kung-Wen; Chung, Jing-Gung

2016-04-01

Glioblastoma multiforme (GBM) is a highly malignant devastating brain tumor in adults. Benzyl isothiocyanate (BITC) is one of the isothiocyanates that have been shown to induce human cancer cell apoptosis and cell cycle arrest. Herein, the effect of BITC on cell viability and apoptotic cell death and the genetic levels of human brain glioblastoma GBM 8401 cells in vitro were investigated. We found that BITC induced cell morphological changes, decreased cell viability and the induction of cell apoptosis in GBM 8401 cells was time-dependent. cDNA microarray was used to examine the effects of BITC on GBM 8401 cells and we found that numerous genes associated with cell death and cell cycle regulation in GBM 8401 cells were altered after BITC treatment. The results show that expression of 317 genes was upregulated, and two genes were associated with DNA damage, the DNA-damage-inducible transcript 3 (DDIT3) was increased 3.66-fold and the growth arrest and DNA-damage-inducible α (GADD45A) was increased 2.34-fold. We also found that expression of 182 genes was downregulated and two genes were associated with receptor for cell responses to stimuli, the EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1) was inhibited 2.01-fold and the TNF receptor-associated protein 1 (TRAP1) was inhibited 2.08-fold. BITC inhibited seven mitochondria ribosomal genes, the mitochondrial ribosomal protein; tumor protein D52 (MRPS28) was inhibited 2.06-fold, the mitochondria ribosomal protein S2 (MRPS2) decreased 2.07-fold, the mitochondria ribosomal protein L23 (MRPL23) decreased 2.08-fold, the mitochondria ribosomal protein S2 (MRPS2) decreased 2.07-fold, the mitochondria ribosomal protein S12 (MRPS12) decreased 2.08-fold, the mitochondria ribosomal protein L12 (MRPL12) decreased 2.25-fold and the mitochondria ribosomal protein S34 (MRPS34) was decreased 2.30-fold in GBM 8401 cells. These changes of gene expression can provide the effects of BITC on the genetic level and are

Deconstructing the Brain Disconnection-Brain Death Analogy and Clarifying the Rationale for the Neurological Criterion of Death.

Science.gov (United States)

Moschella, Melissa

2016-06-01

This article explains the problems with Alan Shewmon's critique of brain death as a valid sign of human death, beginning with a critical examination of his analogy between brain death and severe spinal cord injury. The article then goes on to assess his broader argument against the necessity of the brain for adult human organismal integration, arguing that he fails to translate correctly from biological to metaphysical claims. Finally, on the basis of a deeper metaphysical analysis, I offer a revised rationale for the validity of the neurological criterion of human death. © 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.

High Ca2+ Influx During Traumatic Brain Injury Leads to Caspase-1-Dependent Neuroinflammation and Cell Death.

Science.gov (United States)

Abdul-Muneer, P M; Long, Mathew; Conte, Adriano Andrea; Santhakumar, Vijayalakshmi; Pfister, Bryan J

2017-08-01

We investigated the hypothesis that high Ca 2+ influx during traumatic brain injury induces the activation of the caspase-1 enzyme, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury and an in vivo model of fluid percussion injury (FPI). We first established that stretch injury causes a rapid increase in the intracellular Ca 2+ level, which activates interleukin-converting enzyme caspase-1. The increase in the intracellular Ca 2+ level and subsequent caspase-1 activation culminates into neuroinflammation via the maturation of IL-1β. Further, we analyzed caspase-1-mediated apoptosis by TUNEL staining and PARP western blotting. The voltage-gated sodium channel blocker, tetrodotoxin, mitigated the stretch injury-induced neuroinflammation and subsequent apoptosis by blocking Ca 2+ influx during the injury. The effect of tetrodotoxin was similar to the caspase-1 inhibitor, zYVAD-fmk, in neuronal culture. To validate the in vitro results, we demonstrated an increase in caspase-1 activity, neuroinflammation and neurodegeneration in fluid percussion-injured animals. Our data suggest that neuronal injury/traumatic brain injury (TBI) can induce a high influx of Ca 2+ to the cells that cause neuroinflammation and cell death by activating caspase-1, IL-1β, and intrinsic apoptotic pathways. We conclude that excess IL-1β production and cell death may contribute to neuronal dysfunction and cognitive impairment associated with TBI.

The clinical diagnosis of brain death

African Journals Online (AJOL)

Key words: brain death, diagnostic criteria, heartbeat. Death has been analysed in a heterogeneous .... angiography studies have also been used in order to evaluate brain circulation. According to some authors, the elective ... reflex response of spinal origin provoked by a sudden flexion of the neck and characterised by a.

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

Science.gov (United States)

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.

Brain death revisited: it is not 'complete death' according to Islamic sources.

Science.gov (United States)

Bedir, Ahmet; Aksoy, Sahin

2011-05-01

Concepts, such as death, life and spirit cannot be known in their quintessential nature, but can be defined in accordance with their effects. In fact, those who think within the mode of pragmatism and Cartesian logic have ignored the metaphysical aspects of these terms. According to Islam, the entity that moves the body is named the soul. And the aliment of the soul is air. Cessation of breathing means leaving of the soul from the body. Those who agree on the diagnosis of brain death may not able to agree unanimously on the rules that lay down such diagnosis. That is to say, there are a heap of suspicions regarding the diagnosis of brain death, and these suspicions are on the increase. In fact, Islamic jurisprudence does not put provisions, decisions on suspicious grounds. By virtue of these facts, it can be asserted that brain death is not absolute death according to Islamic sources; for in the patients diagnosed with brain death the soul still has not abandoned the body. Therefore, these patients suffer in every operation performed on them.

Approach of Complex Networks for the Determination of Brain Death

Institute of Scientific and Technical Information of China (English)

SUN Wei-Gang; CAO Jian-Ting; WANG Ru-Bin

2011-01-01

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 Sndings might provide valuable insights on the determination of brain death.%@@ 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 axe 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.

MRI of 'brain death'

Energy Technology Data Exchange (ETDEWEB)

Nishino, Shigeki; Itoh, Takahiko; Tuchida, Shohei; Kinugasa, Kazushi; Asari, Shoji; Nishimoto, Akira (Okayama Univ. (Japan). School of Medicine); Sanou, Kazuo

1990-12-01

Magnetic resonance imaging (MRI) was undertaken for two patients who suffered from severe cerebrovascular diseases and were clinically brain dead. The MRI system we used was Resona (Yokogawa Medical Systems, superconductive system 0.5 T) and the CT apparatus was Toshiba TCT-300. Initial CT and MRI were undertaken as soon as possible after admission, and repeated sequentially. After diagnosis of brain death, we performed angiography to determine cerebral circulatory arrest, and MRI obtained at the same time was compared with the angiogram and CT. Case 1 was a 77-year-old man who was admitted in an unconscious state. CT and MRI on the second day after hospitalization revealed cerebellar infarction. He was diagnosed as brain dead on day 4. Case 2 was a 35-year-old man. When he was transferred to our hospital, he was in cardiorespiratory arrested. Cardiac resuscitation was successful but no spontaneous respiration appeared. CT and MRI on admission revealed right intracerebral hemorrhage. Angiography revealed cessation of contrast medium in intracranial vessels in both of the patients. We found no 'flow signal void sign' in the bilateral internal carotid and basilar arteries on MRI images in both cases after brain death. MRI, showing us the anatomical changes of the brain, clearly revealed brain herniations, even though only nuclear findings of 'brain tamponade' were seen on CT. But in Case 1, we could not see the infarct lesions in the cerebellum on MR images obtained after brain death. This phenomenon was caused by the whole brain ischemia masking the initial ischemic lesions. We concluded that MRI was useful not only the anatomical display of lesions and brain herniation with high contrast resolution but for obtaining information on cerebral circulation of brain death. (author).

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.

99mTc-HMPAO SPECT in brain death

International Nuclear Information System (INIS)

Tsuchida, Tatsuro; Sadato, Norihiro; Nishizawa, Sadahiko

1993-01-01

Brain single photon emission computed tomography (SPECT) with 99m Tc-d,l-hexamethyl-propyleneamine oxime (HMPAO) was performed twice in a 78-year-old man clinically diagnosed as brain death according to the standard criteria of the Japanese Ministry of Welfare. The first brain SPECT demonstrated the tracer accumulation in the brain, indicating preserved cerebral blood flow. The second brain SPECT performed 3 days later revealed cessation of the blood flow. In patients with preserved cerebral blood flow, the diagnosis of brain death cannot be made, even if they meet the existing criteria, because previous report noted the recovery in some of those patients. Brain perfusion SPECT plays an important role as a confirmatory test for the diagnosis of brain death. (author)

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.

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.

A Thomistic defense of whole-brain death.

Science.gov (United States)

Eberl, Jason T

2015-08-01

Michel Accad critiques the currently accepted whole-brain criterion for determining the death of a human being from a Thomistic metaphysical perspective and, in so doing, raises objections to a particular argument defending the whole-brain criterion by Patrick Lee and Germain Grisez. In this paper, I will respond to Accad's critique of the whole-brain criterion and defend its continued validity as a criterion for determining when a human being's death has occurred in accord with Thomistic metaphysical principles. I will, however, join Accad in criticizing Lee and Grisez's proposed defense of the whole-brain criterion as potentially leading to erroneous conclusions regarding the determination of human death. Lay summary: Catholic physicians and bioethicists currently debate the legally accepted clinical standard for determining when a human being has died-known as the "wholebrain criterion"-which has also been morally affirmed by the Magisterium. This paper responds to physician Michel Accad's critique of the whole-brain criterion based upon St. Thomas Aquinas's metaphysical account of human nature as a union of a rational soul and a material body. I defend the whole-brain criterion from the same Thomistic philosophical perspective, while agreeing with Accad's objection to an alternative Thomistic defense of whole-brain death by philosophers Patrick Lee and Germain Grisez.

CT findings as confirmatory criteria of brain death

International Nuclear Information System (INIS)

Shiogai, Toshiyuki; Takeuchi, Kazuo

1983-01-01

The absence of cerebral circulation and electrocerebral silence have served as an accurate index of irreversible brain death. It is proposed that computed tomography (CT) findings be evaluated as confirmatory criteria of brain death. To this end, CT evaluation of 14 patients satisfying the conventional criteria of brain death was performed. A CT finding of severe compression or dissappearance of the ventricular system, or so called ''brain tamponade'', was seen in 7 (50 %) of the 14 patients. Enhanced contrast CT, especially dynamic CT, usually distinctly reveals the cerebral vessels whenever the cerebral blood flow is preserved; conversely, the lack of enhanced brain structures, even comparing attenuation values, indicates the absence of cerebral blood flow. In 7 (70 %) of 10 patients, however, there was enhanced contrast of vascular brain structures, especially the circle of Willis, major cerebral arteries, choroid plexuses, and venous sinuses. It is suggested that this result is due to the improvement of demonstrability by CT. The usefulness of CT in the confirmation of brain death lies in visualization of the pathological changes associated with a dead brain, such as ''brain tamponade'', and the lack of enhanced contrast indicating the absence of cerebral blood flow. The latter point is still problematic as angiography revealed an extremely low cerebral blood flow in a few cases of ''dead brain'' patients. It is recommended that cerebral blood flow in brain death be evaluated by dynamic CT scanning and correlated with other methods of cerebral blood flow determination (e.g., intravenous digital subtraction angiography). (Author)

CT findings as confirmatory criteria of brain death

Energy Technology Data Exchange (ETDEWEB)

Shiogai, Toshiyuki; Takeuchi, Kazuo (Kyorin Univ., Mitaka, Tokyo (Japan). School of Medicine)

1983-12-01

The absence of cerebral circulation and electrocerebral silence have served as an accurate index of irreversible brain death. It is proposed that computed tomography (CT) findings be evaluated as confirmatory criteria of brain death. To this end, CT evaluation of 14 patients satisfying the conventional criteria of brain death was performed. A CT finding of severe compression or dissappearance of the ventricular system, or so called ''brain tamponade'', was seen in 7 (50 %) of the 14 patients. Enhanced contrast CT, especially dynamic CT, usually distinctly reveals the cerebral vessels whenever the cerebral blood flow is preserved; conversely, the lack of enhanced brain structures, even comparing attenuation values, indicates the absence of cerebral blood flow. In 7 (70 %) of 10 patients, however, there was enhanced contrast of vascular brain structures, especially the circle of Willis, major cerebral arteries, choroid plexuses, and venous sinuses. It is suggested that this result is due to the improvement of demonstrability by CT. The usefulness of CT in the confirmation of brain death lies in visualization of the pathological changes associated with a dead brain, such as ''brain tamponade'', and the lack of enhanced contrast indicating the absence of cerebral blood flow. The latter point is still problematic as angiography revealed an extremely low cerebral blood flow in a few cases of ''dead brain'' patients. It is recommended that cerebral blood flow in brain death be evaluated by dynamic CT scanning and correlated with other methods of cerebral blood flow determination (e.g., intravenous digital subtraction angiography).

Crotamine and crotoxin interact with tumor cells and trigger cell death

International Nuclear Information System (INIS)

Soares, Marcella Araugio; Pujatti, Priscilla Brunelli; Santos, Raquel Gouvea dos; Dias, Consuelo Latorre Fortes; Chavez Olortegui, Carlos Delfin; Santos, Wagner Gouvea dos

2007-01-01

Crotoxin (Crtx) and Crotamine (Crota) are polypeptides isolated from Crotalus durissus terrificus snake venom (CV). Previous reports have been shown therapeutic effects of Crotalus durissus terrificus venom and Crtx on skin, breast and lung tumours, although, the mechanisms of this antitumoral effect are still unknown. The aim of this work was to investigate the antitumoral effect of Crtx and Crota on brain tumours cells (GH3 and RT2) in vitro and their capacity of interaction with these tumour cells membranes. Cell survival after Crtx and Crota treatment was evaluated by MTT assay in different times post-treatment and apoptosis was evaluated by DAPI staining. In order to evaluate the specific interaction of Crtx and Crota, these polypeptides were radiolabelled, using 125 I as radiotracer and binding assays were performed. The results were compared with the binding in nontumoral brain tissue. Crtx and Crota induced apoptosis on both tumour cells lineages but, Crota was more powerful than Crtx 90% and 20% cell death for RT2 cells; 80% and 20% cell death for GH3 cells, respectively). Both 125 I-Crtx and 125 I-Crota bound specifically in glioblastoma membranes. Nonetheless, CV polypeptides recognised glioblastoma cells with higher specificity than normal brain tissue. These results suggest that the Crtx and Crota interactions with the plasmatic membrane of tumour cells may be the first step of the cascade of signalling that trigger their antitumoral effect. (author)

Approach of Complex Networks for the Determination of Brain Death

International Nuclear Information System (INIS)

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

2011-01-01

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. (cross-disciplinary physics and related areas of science and technology)

The role of 12/15-lipoxygenases in ROS-mediated neuronal cell death

OpenAIRE

Tobaben, Svenja

2011-01-01

Oxidative stress has been established as a key trigger of neuronal dysfunction and death in age-related neurodegenerative diseases and in delayed neuronal death after acute brain injury by ischemic stroke or brain trauma. Despite increasing knowledge on the toxicity of reactive oxygen species (ROS) and oxidized reaction products that may further accelerate neuronal cell death, the major sources of ROS formation and the mechanisms ...

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.

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.

CT Angiography in the Diagnosis of Brain Death

International Nuclear Information System (INIS)

Sawicki, Marcin; Bohatyrewicz, Romuald; Walecka, Anna; Sołek-Pastuszka, Joanna; Rowiński, Olgierd; Walecki, Jerzy

2014-01-01

Summary Brain death is defined as the irreversible cessation of functioning of the entire brain, including the brainstem. Brain death is principally established using clinical criteria including coma, absence of brainstem reflexes and loss of central drive to breathe assessed with apnea test. In situations in which clinical testing cannot be performed or when uncertainty exists about the reliability of its parts due to confounding conditions ancillary tests (i.a. imaging studies) may be useful. The objective of ancillary tests in the diagnosis of brain death is to demonstrate the absence of cerebral electrical activity (EEG and evoked potentials) or cerebral circulatory arrest. In clinical practice catheter cerebral angiography, perfusion scintigraphy, transcranial Doppler sonography, CT angiography and MR angiography are used. Other methods, like perfusion CT, xenon CT, MR spectroscopy, diffusion weighted MRI and functional MRI are being studied as potentially useful in the diagnosis of brain death. CT angiography has recently attracted attention as a promising alternative to catheter angiography – a reference test in the diagnosis of brain death. Since 1998 several major studies were published and national guidelines were introduced in several countries (e.g. in France, Austria, Switzerland, the Netherlands and Canada). This paper reviews technique, characteristic findings and criteria for the diagnosis of cerebral circulatory arrest in CT angiography

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 nucleus as an efficacious treatment for TBI. © 2016 John Wiley & Sons Ltd.

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

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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

Roles of inflammation and apoptosis in experimental brain death-induced right ventricular failure.

Science.gov (United States)

Belhaj, Asmae; Dewachter, Laurence; Rorive, Sandrine; Remmelink, Myriam; Weynand, Birgit; Melot, Christian; Galanti, Laurence; Hupkens, Emeline; Sprockeels, Thomas; Dewachter, Céline; Creteur, Jacques; McEntee, Kathleen; Naeije, Robert; Rondelet, Benoît

2016-12-01

Right ventricular (RV) dysfunction remains the leading cause of early death after cardiac transplantation. Methylprednisolone is used to improve graft quality; however, evidence for that remains empirical. We sought to determine whether methylprednisolone, acting on inflammation and apoptosis, might prevent brain death-induced RV dysfunction. After randomization to placebo (n = 11) or to methylprednisolone (n = 8; 15 mg/kg), 19 pigs were assigned to a brain-death procedure. The animals underwent hemodynamic evaluation at 1 and 5 hours after Cushing reflex (i.e., hypertension and bradycardia). The animals euthanized, and myocardial tissue was sampled. This was repeated in a control group (n = 8). At 5 hours after the Cushing reflex, brain death resulted in increased pulmonary artery pressure (27 ± 2 vs 18 ± 1 mm Hg) and in a 30% decreased ratio of end-systolic to pulmonary arterial elastances (Ees/Ea). Cardiac output and right atrial pressure did not change. This was prevented by methylprednisolone. Brain death-induced RV dysfunction was associated with increased RV expression of heme oxygenase-1, interleukin (IL)-6, IL-10, IL-1β, tumor necrosis factor (TNF)-α, IL-1 receptor-like (ST)-2, signal transducer and activator of transcription-3, intercellular adhesion molecules-1 and -2, vascular cell adhesion molecule-1, and neutrophil infiltration, whereas IL-33 expression decreased. RV apoptosis was confirmed by terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling staining. Methylprednisolone pre-treatment prevented RV-arterial uncoupling and decreased RV expression of TNF-α, IL-1 receptor-like-2, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and neutrophil infiltration. RV Ees/Ea was inversely correlated to RV TNF-α and IL-6 expression. Brain death-induced RV dysfunction is associated with RV activation of inflammation and apoptosis and is partly limited by methylprednisolone. Copyright © 2016

Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

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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.

Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells

International Nuclear Information System (INIS)

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

2014-01-01

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

Of wholes and parts: A Thomistic refutation of "Brain Death".

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Accad, Michel

2015-08-01

I propose a refutation of the two major arguments that support the concept of "brain death" as an ontological equivalent to death of the human organism. I begin with a critique of the notion that a body part, such as the brain, could act as "integrator" of a whole body. I then proceed with a rebuttal of the argument that destruction of a body part essential for rational operations-such as the brain-necessarily entails that the remaining whole is indisposed to accrue a rational soul. Next, I point to the equivocal use of the terms "alive" or "living" as being at the root of conceptual errors about brain death. I appeal to the Thomistic definition of life and to the hylomorphic concept of "virtual presence" to clarify this confusion. Finally, I show how the Thomistic definition of life supports the traditional criterion for the determination of death. Lay summary: By the mid-1960s, medical technology became available that could keep "alive" the bodies of patients who had sustained complete and irreversible brain injury. The concept of "brain death" emerged to describe such states. Physicians, philosophers, and ethicists then proposed that the state of brain death is equivalent to the state of death traditionally identified by the absence of spontaneous pulse and respiration. This article challenges the major philosophical arguments that have been advanced to draw this equivalence.

Simulation-based training in brain death determination.

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MacDougall, Benjamin J; Robinson, Jennifer D; Kappus, Liana; Sudikoff, Stephanie N; Greer, David M

2014-12-01

Despite straightforward guidelines on brain death determination by the American Academy of Neurology (AAN), substantial practice variability exists internationally, between states, and among institutions. We created a simulation-based training course on proper determination based on the AAN practice parameters to address and assess knowledge and practice gaps at our institution. Our intervention consisted of a didactic course and a simulation exercise, and was bookended by before and after multiple-choice tests. The 40-min didactic course, including a video demonstration, covered all aspects of the brain death examination. Simulation sessions utilized a SimMan 3G manikin and involved a complete examination, including an apnea test. Possible confounders and signs incompatible with brain death were embedded throughout. Facilitators evaluated performance with a 26-point checklist based on the most recent AAN guidelines. A senior neurologist conducted all aspects of the course, including the didactic session, simulation, and debriefing session. Ninety physicians from multiple specialties have participated in the didactic session, 38 of whom have completed the simulation. Pre-test scores were poor (41.4 %), with attendings scoring higher than residents (46.6 vs. 40.4 %, p = 0.07), and neurologists and neurosurgeons significantly outperforming other specialists (53.9 vs. 38.9 %, p = 0.003). Post-test scores (73.3 %) were notably higher than pre-test scores (45.4 %). Participant feedback has been uniformly positive. Baseline knowledge of brain death determination among providers was low but improved greatly after the course. Our intervention represents an effective model that can be replicated at other institutions to train clinicians in the determination of brain death according to evidence-based guidelines.

Public education and misinformation on brain death in mainstream media.

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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.

Repeated exposure of the developing rat brain to magnetic resonance imaging did not affect neurogenesis, cell death or memory function

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Zhu, Changlian; Gao, Jianfeng; Li, Qian; Huang, Zhiheng; Zhang, Yu; Li, Hongfu; Kuhn, Hans-Georg; Blomgren, Klas

2011-01-01

Research highlights: → The effect of MRI on the developing brain is a matter of debate. → Repeated exposure to MRI did not affect neurogenesis. → Memory function was not affected by repeated MRI during development. → Neither late gestation nor young postnatal brains were affected by MRI. → Repeated MRI did not cause cell death in the neurogenic region of the hippocampus. -- Abstract: The effect of magnetic fields on the brain is a matter of debate. The objective of this study was to investigate whether repeated exposure to strong magnetic fields, such as during magnetic resonance imaging (MRI), could elicit changes in the developing rat brain. Embryonic day 15 (E15) and postnatal day 14 (P14) rats were exposed to MRI using a 7.05 T MR system. The animals were anesthetized and exposed for 35 min per day for 4 successive days. Control animals were anesthetized but no MRI was performed. Body temperature was maintained at 37 o C. BrdU was injected after each session (50 mg/kg). One month later, cell proliferation, neurogenesis and astrogenesis in the dentate gyrus were evaluated, revealing no effects of MRI, neither in the E15, nor in the P14 group. DNA damage in the dentate gyrus in the P14 group was evaluated on P18, 1 day after the last session, using TUNEL staining. There was no difference in the number of TUNEL-positive cells after MRI compared with controls, neither in mature neurons, nor in newborn progenitors (BrdU/TUNEL double-labeled cells). Novel object recognition was performed to assess memory function 1 month after MRI. There was no difference in the recognition index observed after MRI compared with the control rats, neither for the E15, nor for the P14 group. In conclusion, repeated exposure to MRI did not appear to affect neurogenesis, cell death or memory function in rats, neither in late gestation (E15-E18) nor in young postnatal (P14-P17) rats.

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...

Quantitative in vivo detection of brain cell death after hypoxia ischemia using the lipid peak at 1.3 ppm of proton magnetic resonance spectroscopy in neonatal rats.

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Ahn, So Yoon; Yoo, Hye Soo; Lee, Jang Hoon; Sung, Dong Kyung; Jung, Yu Jin; Sung, Se In; Lim, Keun Ho; Chang, Yun Sil; Lee, Jung Hee; Kim, Ki Soo; Park, Won Soon

2013-07-01

This study was performed to determine the accuracy of proton magnetic spectroscopy ((1)H-MRS) lipid peak as a noninvasive tool for quantitative in vivo detection of brain cell death. Seven day-old Sprague Dawley rats were subjected to 8% oxygen following a unilateral carotid artery ligation. For treatment, cycloheximide was given immediately after hypoxic ischemia (HI). Lipid peak was measured using (1)H-MRS at 24 hr after HI, and then brains were harvested for fluorocytometric analyses with annexin V/propidium iodide (PI) and fluorescent probe JC-1, and for adenosine-5'-triphosphate (ATP) and lactate. Increased lipid peak at 1.3 ppm measured with (1)H-MRS, apoptotic and necrotic cells, and loss of mitochondrial membrane potential (ΔΨ) at 24 hr after HI were significantly improved with cycloheximide treatment. Significantly reduced brain ATP and increased lactate levels observed at 24 hr after HI showed a tendency to improve without statistical significance with cycloheximide treatment. Lipid peak at 1.3 ppm showed significant positive correlation with both apoptotic and necrotic cells and loss of ΔΨ, and negative correlation with normal live cells. Lipid peak at 1.3 ppm measured by (1)H-MRS might be a sensitive and reliable diagnostic tool for quantitative in vivo detection of brain cell death after HI.

Signal Transduction Pathways Involved in Brain Death-Induced Renal Injury

NARCIS (Netherlands)

Bouma, H. R.; Ploeg, R. J.; Schuurs, T. A.

Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to

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

Brain death and the historical understanding of bioethics.

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Belkin, Gary S

2003-07-01

In a 1968 Report, the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death promulgated influential criteria for the idea and practice known as "brain death." Before and since the Committee met, brain death has been a focal point of visions and nightmares of medical progress, purpose, and moral authority. Critics of the Committee felt it was deaf to apparently central moral considerations and focused on the self-serving purpose of expanding transplantation. Historical characterizations of the uses and meanings of brain death and the work of the Committee have tended to echo these themes, which means also generally repeating a widely held bioethical self-understanding of how the field appeared-that is, as a necessary antidote of moral expertise. This paper looks at the Committee and finds that historical depictions of it have been skewed by such a bioethical agenda. Entertaining different possibilities as to the motives and historical circumstances behind the Report it famously produced may point to not only different histories of the Committee, but also different perspectives on the historical legacy and role of bioethics as a discourse for addressing anxieties about medicine.

Autoradiographic studies on the cell kinetics after the whole body X-irradiation. 2. Regularities of the post-irradiation death of differentiating and proliferating cells of the rat brain subependimal zone

International Nuclear Information System (INIS)

Gracheva, N.D.

1982-01-01

A wave-like character of death of proliferating and differentiating (D) cells is shown autoradiographically using 3 H-thymidine introduced 60-80 min before the whole body X-ray irradiation in doses of 50, 150 or 300 R on subependymal cells of rat brain. Lethally damaged cells irradiated in G 2 and S-phases, resulted in 4 peaks of death in mitosis by following the first postradiational mitotic cycle (MC). Lethally damaged cells irradiated in G 1 -phase lost ability for DNA synthesis as cells irradiated in a dose of 300 R did not include additionally introduced (3 hrs before death) 14 C-thymidine from 12 to 17 hrs after 3 H-thymidine injection. However, in the first 4 hrs after irradiation there were no cells irradiated in G 1 -phase among dead ones, as indirec showed the calculations of data obtained tly/ while studying Pliss lymphosarcoma. A supposition is made that the death of cells irradiated in G 1 -phase is attributed to mitotic phase of the first MC after irradiation. Waves of death of lethally damaged D-cells repeated the peaks of death and corresponded to the mitotic peaks of proliferating cells, which permitted to presuppose the presence of ''short cycle'' (SC) in D-cells, which have the rhythm similar to MC and their death has been attributed to the final SC phase, which corresponds to MC mitotic phase in time. According to the peaks of cell death position of one hour block independent of dose in six MC(SC) points is determined. The cells have experienced the block in the point of MC(SC) in subphase of which they were caught by irradiation. Dose effect is manifested in the number of dead cells

Enriched Endogenous Omega-3 Fatty Acids in Mice Ameliorate Parenchymal Cell Death After Traumatic Brain Injury.

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Ren, Huixia; Yang, Zhen; Luo, Chuanming; Zeng, Haitao; Li, Peng; Kang, Jing X; Wan, Jian-Bo; He, Chengwei; Su, Huanxing

2017-07-01

Currently no effective therapies are available for the treatment of traumatic brain injury (TBI). Early intervention that specifically provides neuroprotection is of most importance which profoundly influences the outcome of TBI. In the present study, we adopted a closed-skull mild TBI model to investigate potential roles of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in protecting against TBI. Using two-photon laser scanning microscopy (2PLSM), parenchymal cell death and reactive oxidative species (ROS) expression were directly observed and recorded after TBI through a thinned skull bone window. Fat-1 mice with high endogenous ω-3 PUFAs significantly inhibited ROS expression and attenuated parenchymal cell death after compression injury during the early injury phase. Elevated generation of glutathione (GSH) and neuroprotectin D1 (NPD1) in the parenchyma of fat-1 mice could be the contributor to the beneficial role of ω-3 PUFAs in TBI. The results of the study suggest that ω-3 PUFAs is an effective neuroprotectant as an early pharmacological intervention for TBI and the information derived from this study may help guide dietary advice for those who are susceptible to repetitive mild TBI.

Comparison of outcomes of kidney transplantation from donation after brain death, donation after circulatory death, and donation after brain death followed by circulatory death donors.

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Chen, Guodong; Wang, Chang; Ko, Dicken Shiu-Chung; Qiu, Jiang; Yuan, Xiaopeng; Han, Ming; Wang, Changxi; He, Xiaoshun; Chen, Lizhong

2017-11-01

There are three categories of deceased donors of kidney transplantation in China, donation after brain death (DBD), donation after circulatory death (DCD), and donation after brain death followed by circulatory death (DBCD) donors. The aim of this study was to compare the outcomes of kidney transplantation from these three categories of deceased donors. We retrospectively reviewed 469 recipients who received deceased kidney transplantation in our hospital from February 2007 to June 2015. The recipients were divided into three groups according to the source of their donor kidneys: DBD, DCD, or DBCD. The primary endpoints were delayed graft function (DGF), graft loss, and patient death. The warm ischemia time was much longer in DCD group compared to DBCD group (18.4 minutes vs 12.9 minutes, P < .001). DGF rate was higher in DCD group than in DBD and DBCD groups (22.5% vs 10.2% and 13.8%, respectively, P = .021). Urinary leakage was much higher in DCD group (P = .049). Kaplan-Meier analysis showed that 1-, 2-, and 3-year patient survivals were all comparable among the three groups. DBCD kidney transplantation has lower incidences of DGF and urinary leakage than DCD kidney transplant. However, the overall patient and graft survival were comparable among DBD, DCD, and DBCD kidney transplantation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diagnosis of brain death by transcranial Doppler sonography.

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Bode, H; Sauer, M; Pringsheim, W

1988-12-01

The blood flow velocities in the basal cerebral arteries can be recorded at any age by transcranial Doppler sonography. We examined nine children with either initial or developing clinical signs of brain death. Soon after successful resuscitation increased diastolic flow velocities indicated a probable decrease in cerebrovascular resistance; this was of no particular prognostic importance. As soon as there was a clinical deterioration, there was a reduction in flow velocities with retrograde flow during early diastole, probably due to an increase in cerebrovascular resistance; this indicated a doubtful prognosis. In eight of the nine children with clinical signs of brain death a typical reverberating flow pattern was found, which was characterised by a counterbalancing short forward flow in systole and a short retrograde flow in early diastole. This indicated arrest of cerebral blood flow. One newborn showed normal systolic and end diastolic flow velocities in the basal cerebral arteries for two days despite clinical and electroencephalographic signs of brain death. Shunting of blood through the circle of Willis without effective cerebral perfusion may explain this phenomenon. No patient had the typical reverberating flow pattern without being clinically brain dead. Transcranial Doppler sonography is a reliable technique, which can be used at the bedside for the confirmation or the exclusion of brain death in children in addition to the clinical examination.

Quantification of cell death in developing cerebellum by a 14C tracer method

International Nuclear Information System (INIS)

Griffin, W.S.; Woodward, D.J.; Chanda, R.

1978-01-01

To study the question of whether or not cell death contributes significantly to normal or stressed postnatal brain development in a way which is biochemically quantifiable, we carried out an experiment to assess the amount of cell death in developing cerebellum. By measuring the loss of DNA content and the loss of 14 C from labelled thymidine previously incorporated into the DNA fraction (DNAF) in X-irradiated neonatal animals, shown by histological methods to have cell death to the degree of degranulating the external granular layer (EGL), we showed that when cells die both label and DNA content are greatly decreased in the cerebellum. Experiments on both normal and malnourished animals showed that cell death does not contribute significantly to cerebellar development in either malnutrition-stressed or normal animals. Here, we present a biochemical tool for assessing cell death and evidence that cell death does not contribute significantly to cerebellar development

99mTc HM-PAO brain perfusion SPECT in brain death

International Nuclear Information System (INIS)

Bonetti, M.G.; Ciritella, P.; Valle, G.; Perrone, E.

1995-01-01

We have easily carried out and interpreted 99m Tc HM-PAO SPECT in a consecutive series of 40 comatose patients with brain damage, without discontinuing therapy. Brain death was diagnosed in 7 patients, by recognising absence of brain perfusion, as shown by no intracranial radionuclide uptake. In patients in whom perfusion was seen on brain scans, HM-PAO SPECT improved assessment of the extent of injury, which in general was larger than suggested by CT. (orig.)

Brain death: close relatives' use of imagery as a descriptor of experience.

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Frid, Ingvar; Haljamäe, Hengo; Ohlén, Joakim; Bergbom, Ingegerd

2007-04-01

This paper is a report of a study to explore the use of imagery to describe the experience of confronting brain death in a close relative. The brain death of a loved one has been described as an extremely difficult experience for close relatives, evoking feelings of anger, emotional pain, disbelief, guilt and suffering. It can also be difficult for relatives to distinguish brain death from the state of coma and thus difficult to apprehend information about the diagnosis. Narrative theory and a hermeneutic phenomenological method guided the interpretation of 17 narratives from close relatives of brain dead patients. All narratives were scrutinized for experiences of brain death. Data were primarily collected in 1999. The primary analysis related to close relatives' experience of brain death in a loved one. A secondary analysis of the imagery they used to describe their experience was carried out in 2003. Six categories of imagery used to describe the experience of confronting a diagnosis of brain death in a loved one emerged: chaotic unreality; inner collapse; sense of forlornness; clinging to the hope of survival; reconciliation with the reality of death; receiving care which gives comfort. Participants also identified two pairs of dimensions to describe their feelings about the relationship between their brain dead relative's body and personhood: presence-absence and divisibility-indivisibility. Being confronted with brain death meant entering into the anteroom of death, facing a loved one who is 'living-dead', and experiencing a chaotic drama of suffering. It is very important for members of the intensive care unit team to recognize, face and respond to these relatives' chaotic experiences, which cause them to need affirmation, comfort and caring. Relatives' use of imagery could be the starting point for a caring conversation about their experiences, either in conversations at the time of the death or when relatives are contacted in a later follow-up.

Guideline of procedures 2003 for the gammagraphic study of brain death

International Nuclear Information System (INIS)

Mora R, R.A.

2003-01-01

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)

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

Xanthine oxidase activity regulates human embryonic brain cells growth

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Kevorkian G. A.

2011-10-01

Full Text Available Aim. Involvement of Xanthine Oxidase (XO; EC1.1.3.22 in cellular proliferation and differentiation has been suggested by the numerous investigations. We have proposed that XO might have undoubtedly important role during the development, maturation as well as the death of human embryos brain cells. Methods. Human abortion material was utilized for the cultivation of brain cells (E90. XO activity was measured by the formation of uric acid in tissue. Cell death was detected by the utility of Trypan Blue dye. Results. Allopurinol suppressed the XO activity in the brain tissue (0.12 ± 0.02; 0.20 ± 0.03 resp., p < 0.05. On day 12th the number of cells in the culture treated with the Allopurinol at the early stage of development was higher in comparison with the Control (2350.1 ± 199.0 vs 2123 ± 96 and higher in comparison with the late period of treatment (1479.6 ± 103.8, p < < 0.05. In all groups, the number of the dead cells was less than in Control, indicating the protective nature of Allopurinol as an inhibitor of XO. Conclusions. Allopurinol initiates cells proliferation in case of the early treatment of the human brain derived cell culture whereas at the late stages it has an opposite effect.

An educational initiative to improve medical student awareness about brain death.

Science.gov (United States)

Lewis, Ariane; Howard, Jonathan; Watsula-Morley, Amanda; Gillespie, Colleen

2018-04-01

Medical student knowledge about brain death determination is limited. We describe an educational initiative to improve medical student awareness about brain death and assess the impact of this initiative. Beginning in July 2016, students at our medical school were required to attend a 90-min brain death didactic and simulation session during their neurology clerkship. Students completed a test immediately before and after participating in the initiative. Of the 145 students who participated in this educational initiative between July 2016 and June 2017, 124 (86%) consented to have their data used for research purposes as part of a medical education registry. Students correctly answered a median of 53% of questions (IQR 47-58%) on the pretest and 86% of questions (IQR 78-89%) on the posttest (p initiative (18% of students were comfortable performing a brain death evaluation before the initiative and 86% were comfortable doing so after the initiative, p initiative and 76% were comfortable doing so after the initiative, p initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. Copyright © 2018 Elsevier B.V. All rights reserved.

Interplay between autophagy and programmed cell death in mammalian neural stem cells

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Kyung Min Chung

2013-08-01

Full Text Available Mammalian neural stem cells (NSCs are of particular interestbecause of their role in brain development and function. Recentfindings suggest the intimate involvement of programmed celldeath (PCD in the turnover of NSCs. However, the underlyingmechanisms of PCD are largely unknown. Although apoptosis isthe best-defined form of PCD, accumulating evidence hasrevealed a wide spectrum of PCD encompassing apoptosis,autophagic cell death (ACD and necrosis. This mini-reviewaims to illustrate a unique regulation of PCD in NSCs. Theresults of our recent studies on autophagic death of adulthippocampal neural stem (HCN cells are also discussed. HCNcell death following insulin withdrawal clearly provides areliable model that can be used to analyze the molecularmechanisms of ACD in the larger context of PCD. Moreresearch efforts are needed to increase our understanding of themolecular basis of NSC turnover under degenerating conditions,such as aging, stress and neurological diseases. Efforts aimed atprotecting and harnessing endogenous NSCs will offer novelopportunities for the development of new therapeutic strategiesfor neuropathologies. [BMB Reports 2013; 46(8: 383-390

Which experimental model can sensitively indicate brain death by functional near-infrared spectroscopy?

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Pan, Boan; Liu, Weichao; Fang, Xiang; Huang, Xiaobo; Li, Ting

2018-02-01

Brain death is defined as permanent loss of the brain functions. The evaluation of it has many meanings, such as the relief of organ transplantation stress and family burden. However, it is hard to be judged precisely. The standard clinical tests are expensive, time consuming and even dangerous, and some auxiliary methods have limitations. Functional near infrared spectroscopy (fNIRS), monitoring cerebral hemodynamic responses noninvasively, evaluate brain death in some papers published, but there is no discussion about which experimental mode can monitor brain death patient more sensitively. Here, we attempt to use our fNIRS to evaluate brain death and find which experimental mode is effective. In order to discuss the problem, we detected eleven brain death patients and twenty normal patients under natural state. They were provided different fraction of inspiration O2 (FIO2) in different phase. We found that the ratio of Δ[HbO2] (the concentration changes in oxyhemoglobin) to Δ[Hb] (the concentration changes in deoxyhemoglobin) in brain death patients is significantly higher than normal patients in FIO2 experiment. Combined with the data analysis result, restore oxygen change process and low-high-low paradigm is more sensitively.

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

2016-01-01

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. PMID:27097648

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

OpenAIRE

Galluzzi, L; Vitale, I; Aaronson, Sa; Abrams, Jm; Adam, D; Agostinis, P; Alnemri, Es; Altucci, L; Amelio, I; Andrews, Dw; Annicchiarico-Petruzzelli, M; Antonov, Av; Arama, E; Baehrecke, Eh; Barlev, Na

2018-01-01

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. A...

Islam, brain death, and transplantation: culture, faith, and jurisprudence.

Science.gov (United States)

Arbour, Richard; AlGhamdi, Hanan Mesfer Saad; Peters, Linda

2012-01-01

A significant gap exists between availability of organs for transplant and patients with end-stage organ failure for whom organ transplantation is the last treatment option. Reasons for this mismatch include inadequate approach to potential donor families and donor loss as a result of refractory cardiopulmonary instability during and after brainstem herniation. Other reasons include inadequate cultural competence and sensitivity when communicating with potential donor families. Clinicians may not have an understanding of the cultural and religious perspectives of Muslim families of critically ill patients who may be approached about brain death and organ donation. This review analyzes Islamic cultural and religious perspectives on organ donation, transplantation, and brain death, including faith-based directives from Islamic religious authorities, definitions of death in Islam, and communication strategies when discussing brain death and organ donation with Muslim families. Optimal family care and communication are highlighted using case studies and backgrounds illustrating barriers and approaches with Muslim families in the United States and in the Kingdom of Saudi Arabia that can improve cultural competence and family care as well as increase organ availability within the Muslim population and beyond.

The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors.

Directory of Open Access Journals (Sweden)

Jin Xu

Full Text Available The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD. The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD, we aimed to understand how ischemia/reperfusion (I/R injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration.Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13 and DBD (n = 10 livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22 and DBD (n = 13 livers.When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05 and C22 ceramide (p<0.05 were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST of DCD allografts had significantly increased.These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.

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

Mitochondrial permeability transition and cell death: the role of cyclophilin D

Directory of Open Access Journals (Sweden)

Sabzali eJavadov

2013-04-01

Full Text Available Mitochondria serve as a powerhouse which provides near 90% of ATP necessary for cell life. However, recent studies provide strong evidence that mitochondria also play a central role in cell death. Irreversible mitochondrial permeability transition (mPT at high conductance in response to oxidative or other cellular stresses is accompanied by formation of pathological and non-specific mPT pores (mPTP in the inner membrane of mitochondria. Mitochondrial PTP can serve as a target to prevent cell death under pathological conditions such as cardiac and brain ischemia/reperfusion injury and diabetes. On the other hand, mPTP can be used as an executioner to specifically induce cell death thus blocking tumorigenesis in cancer diseases. Despite many studies, the molecular identity of the mPTP remains unclear. At present, cyclophilin D (CyP-D represents the only mPTP protein which plays an essential role in pore formation. This review will discuss direct and indirect mechanisms underlying CyP-D interaction with a target protein of the mPTP complex. Understanding of the mechanisms of mPTP formation will be helpful to further develop new pharmacological agents targeting mitochondria-mediated cell death.

Outcome of pancreas transplantation from donation after circulatory death compared to donation after brain death

NARCIS (Netherlands)

van Loo, Ellen S.; Krikke, Christina; Hofker, Hendrik S.; Berger, Stefan P.; Leuvenink, Henri G. D.; Pol, Robert A.

Introduction: To overcome the gap of organ shortage grafts from donation after circulatory death (DCD) can be used. This review evaluates the outcomes after DCD pancreas donation compared to donation after brain death (DBD). Materials and methods: A literature search was performed using Medline,

A consideration of the ethics of brain death--what are the ethical guidelines for physician, family and society in dealing with brain death?

Science.gov (United States)

Brooks, C M

1985-06-01

There is at present considerable confusion with respect to ethical guidelines that should govern the behavior of society and the physician confronted by problems resulting from recent attainments of medicine and science. The use of life supporting devices raises the problem of determining when death has occurred and what is proper ethical procedure in dealing with the deficient half life caused by "Brain Death." Some guidance is obtained from a consideration of the nature of life, the nature of death, the nature of man, and the essence lost in death of man. A parallel consideration of the nature of ethics, the bases of ethics and of ethical decision can be helpful. An individual may have ideals which control behavior, even elevate ethical standards; others entertain concepts that destroy social ethics. Ethics control and direct social interactions; ethics determine the quality of social behavior--ethics are established by societies not by individuals. Numerous commissions have endeavored to define the requirements of physicians for diagnosing brain death and for appropriate subsequent actions. The rationales presented, however, are not invariably accepted by lay society. The problem is created by numerous trends. Among them are the "rightest" movement which, though possessing many virtues, has its excesses such as expressed in the "right to life movement." These have not been beneficial and have necessitated "right to death movements." Opposition is also due to the fact that society's concepts of the medical profession have changed. The practice of organ transplantation has created problems. Finally, the concept of death as other than evil is no longer generally accepted. As more biological manipulations are possible ever more difficult ethical problems will arise. It is a certainty, however, that when brain death has occurred life of man and that of the individual has ended. Although others might not agree, our ethic requires us to use life assist techniques to

Caspase-3 activation as a bifurcation point between plasticity and cell death

Institute of Scientific and Technical Information of China (English)

Shikha Snigdha; Erica D Smith; G Aleph Prieto; Carl W Cotman

2012-01-01

Death-mediating proteases such as caspases and caspase-3 in particular,have been implicated in neurodegenerative processes,aging and Alzheimer's disease.However,emerging evidence suggests that in addition to their classical role in cell death,caspases play a key role in modulating synaptic function.It is remarkable that active caspases-3,which can trigger widespread damage and degeneration,aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death.Here,we evaluate this dichotomy,and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling,able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling.We propose that temporal,spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons.This concept has implications for differential roles of caspase-3 activation across the lifespan.Specifically,we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain.

Cell Death in C. elegans Development.

Science.gov (United States)

Malin, Jennifer Zuckerman; Shaham, Shai

2015-01-01

Cell death is a common and important feature of animal development, and cell death defects underlie many human disease states. The nematode Caenorhabditis elegans has proven fertile ground for uncovering molecular and cellular processes controlling programmed cell death. A core pathway consisting of the conserved proteins EGL-1/BH3-only, CED-9/BCL2, CED-4/APAF1, and CED-3/caspase promotes most cell death in the nematode, and a conserved set of proteins ensures the engulfment and degradation of dying cells. Multiple regulatory pathways control cell death onset in C. elegans, and many reveal similarities with tumor formation pathways in mammals, supporting the idea that cell death plays key roles in malignant progression. Nonetheless, a number of observations suggest that our understanding of developmental cell death in C. elegans is incomplete. The interaction between dying and engulfing cells seems to be more complex than originally appreciated, and it appears that key aspects of cell death initiation are not fully understood. It has also become apparent that the conserved apoptotic pathway is dispensable for the demise of the C. elegans linker cell, leading to the discovery of a previously unexplored gene program promoting cell death. Here, we review studies that formed the foundation of cell death research in C. elegans and describe new observations that expand, and in some cases remodel, this edifice. We raise the possibility that, in some cells, more than one death program may be needed to ensure cell death fidelity. © 2015 Elsevier Inc. All rights reserved.

Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.

Science.gov (United States)

Chung, Kyung Min; Park, Hyunhee; Jung, Seonghee; Ha, Shinwon; Yoo, Seung-Jun; Woo, Hanwoong; Lee, Hyang Ju; Kim, Seong Who; Kim, Eun-Kyoung; Moon, Cheil; Yu, Seong-Woon

2015-10-01

Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death. © 2015 AlphaMed Press.

Effects of intracellular iron overload on cell death and identification of potent cell death inhibitors.

Science.gov (United States)

Fang, Shenglin; Yu, Xiaonan; Ding, Haoxuan; Han, Jianan; Feng, Jie

2018-06-11

Iron overload causes many diseases, while the underlying etiologies of these diseases are unclear. Cell death processes including apoptosis, necroptosis, cyclophilin D-(CypD)-dependent necrosis and a recently described additional form of regulated cell death called ferroptosis, are dependent on iron or iron-dependent reactive oxygen species (ROS). However, whether the accumulation of intracellular iron itself induces ferroptosis or other forms of cell death is largely elusive. In present study, we study the role of intracellular iron overload itself-induced cell death mechanisms by using ferric ammonium citrate (FAC) and a membrane-permeable Ferric 8-hydroxyquinoline complex (Fe-8HQ) respectively. We show that FAC-induced intracellular iron overload causes ferroptosis. We also identify 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitor GSK2334470 as a potent ferroptosis inhibitor. Whereas, Fe-8HQ-induced intracellular iron overload causes unregulated necrosis, but partially activates PARP-1 dependent parthanatos. Interestingly, we identify many phenolic compounds as potent inhibitors of Fe-8HQ-induced cell death. In conclusion, intracellular iron overload-induced cell death form might be dependent on the intracellular iron accumulation rate, newly identified cell death inhibitors in our study that target ferroptosis and unregulated oxidative cell death represent potential therapeutic strategies against iron overload related diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Depictions of 'brain death' in the media: medical and ethical implications.

Science.gov (United States)

Daoust, Ariane; Racine, Eric

2014-04-01

Debates and controversies have shaped the understanding and the practices related to death determined by neurological criterion (DNC). Confusion about DNC in the public domain could undermine this notion. This confusion could further jeopardise confidence in rigorous death determination procedures, and raise questions about the integrity, sustainability, and legitimacy of modern organ donation practices. We examined the depictions of 'brain death' in major American and Canadian print media to gain insights into possible common sources of confusion about DNC and the relationship between expert and lay views on this crucial concept. We gathered 940 articles, available in electronic databases, published between 2005 and 2009 from high-circulation Canadian and American newspapers containing keywords 'brain dead' or 'brain death'. Articles were systematically examined for content (eg, definitions of brain death and criteria for determination of death) using the NVivo 8 software. Our results showed problematic aspects in American and Canadian media, with some salient differences. DNC was used colloquially in 39% (N=366) of the articles and its medical meaning infrequently defined (2.7%; N=14 in the USA and 3.6%; N=15 in Canada). The neurological criterion for determination of death was mentioned in less than 10% of the articles, and life support in about 20% of the articles. Organ donation issues related to DNC were raised more often in Canadian articles than in American articles (33.5% vs 21.2%; p<0.0001). Further discussion is needed to develop innovative strategies to bridge media representations of DNC with experts' views in connection with organ donation practices.

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.

An Aminopyridazine Inhibitor of Death Associated Protein Kinase Attenuates Hypoxia-Ischemia Induced Brain Damage

Energy Technology Data Exchange (ETDEWEB)

Velentza, A.V.; Wainwright, M.S.; Zasadzki, M.; Mirzoeva, S.; Haiech, J.; Focia, P.J.; Egli, M.; Watterson, D.M.

2010-03-08

Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development.

Morphological and functional alterations in the adenohypophysis in cases of brain death.

Science.gov (United States)

Ishikawa, Takaki; Michiue, Tomomi; Quan, Li; Zhao, Dong; Komatsu, Ayumi; Bessho, Yasumori; Maeda, Hitoshi

2009-04-01

In order to examine the function of the adenohypophysis during brain death, levels of adrenocorticotropic hormone (ACTH), growth hormone (GH), and thyroid stimulating hormone (TSH) were investigated during forensic autopsy. Cases examined were those of brain death (n=12; within 24h postmortem; time to cardiac death after cerebral death was diagnosed, approximately 4-25 days), including those in which the cause of death was head injury (subdural hematoma or brain contusion, n=10) and asphyxia (strangulation, n=2). The concentrations of ACTH and TSH were measured by enzyme chemiluminescent immunoassay (ECLIA), and that of GH by radioimmunoassay (RIA). The immunoreactivities of ACTH, GH, and TSH in the adenohypophysis were observed and analyzed with electron microscopy. Morphological studies revealed partial necrosis of the central anterior lobe, but preservation of its periphery. Immunohistochemical staining revealed the appearance of peripheral adenohypophysis with each hormone. Ultrastructural findings for the pituitary and hypothalamus indicated swelling of the mitochondria and dilation of both the smooth endoplasmic reticulum and Golgi apparatus. Furthermore, in most cases, concentrations of the anterior pituitary hormones in the serum and cerebrospinal fluid (CSF) were generally within the clinical reference range. These results indicate that the pituitary is partially preserved after brain death.

Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction

Science.gov (United States)

Katzenberger, Rebeccah J; Chtarbanova, Stanislava; Rimkus, Stacey A; Fischer, Julie A; Kaur, Gulpreet; Seppala, Jocelyn M; Swanson, Laura C; Zajac, Jocelyn E; Ganetzky, Barry; Wassarman, David A

2015-01-01

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood–brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. Furthermore, we found that ingestion of glucose after a primary injury increases the probability of death through a secondary injury mechanism that exacerbates intestinal barrier dysfunction. Our results indicate that natural variation in the probability of death following TBI is due in part to genetic differences that affect intestinal barrier dysfunction. DOI: http://dx.doi.org/10.7554/eLife.04790.001 PMID:25742603

Involvement of Programmed Cell Death in Neurotoxicity of Metallic Nanoparticles: Recent Advances and Future Perspectives

Science.gov (United States)

Song, Bin; Zhou, Ting; Liu, Jia; Shao, LongQuan

2016-11-01

The widespread application of metallic nanoparticles (NPs) or NP-based products has increased the risk of exposure to NPs in humans. The brain is an important organ that is more susceptible to exogenous stimuli. Moreover, any impairment to the brain is irreversible. Recently, several in vivo studies have found that metallic NPs can be absorbed into the animal body and then translocated into the brain, mainly through the blood-brain barrier and olfactory pathway after systemic administration. Furthermore, metallic NPs can cross the placental barrier to accumulate in the fetal brain, causing developmental neurotoxicity on exposure during pregnancy. Therefore, metallic NPs become a big threat to the brain. However, the mechanisms underlying the neurotoxicity of metallic NPs remain unclear. Programmed cell death (PCD), which is different from necrosis, is defined as active cell death and is regulated by certain genes. PCD can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. It is involved in brain development, neurodegenerative disorders, psychiatric disorders, and brain injury. Given the pivotal role of PCD in neurological functions, we reviewed relevant articles and tried to summarize the recent advances and future perspectives of PCD involvement in the neurotoxicity of metallic NPs, with the purpose of comprehensively understanding the neurotoxic mechanisms of NPs.

Programmed cell death

Energy Technology Data Exchange (ETDEWEB)

NONE

1995-12-31

The purpose of this conference to provide a multidisciplinary forum for exchange of state-of-the-art information on the role programmed cell death plays in normal development and homeostasis of many organisms. This volume contains abstracts of papers in the following areas: invertebrate development; immunology/neurology; bcl-2 family; biochemistry; programmed cell death in viruses; oncogenesis; vertebrate development; and diseases.

Scintigraphic evaluation of brain death with 99mTc-d,l-hexamethyl-propyleneamine oxime (HMPAO)

International Nuclear Information System (INIS)

Takehara, Yasuo; Isoda, Haruo; Sakai, Tsuneo; Tanaka, Tokutaro; Sato, Haruhiko; Yamamoto, Takamichi; Takahashi, Motoichiro; Kaneko, Masao.

1989-01-01

Lately, the criteria of brain death is being discussed. Cerebral scintigram, especially scintigraphic evaluation of brain death by dynamic study, has been previously reported. Cerebral imaging using radiolabeled amines such as 123 I-IMP N-isopropyl-p-iodoamphetamin (IMP) or 99m Tc d, l-hexamethyl-propyleneamine oxime (HMPAO) offers a significant information of brain death by the finding of 'non visualized brain'. However, the dynamic scintigram acquired during the bolus injection of 99m Tc-HMPAO provides an additional information of brain death by classical 'hot nose sign'. 99m Tc-HMPAO is able to be administered relatively in a large amount of dose. This cerebral perfusion tracer is lipophilic and remains in the central nervous system, which characterize its role as a reliable indicator of cerebral blood flow. As a result, this compound became suitable for the non-invasive study of brain circulation when the diagnosis of brain death is uncertain. We report a case of brain death in which diagnosis was made by the classical 'hot nose sign' in dynamic scintigraphy performed when 99 mTc-HMPAO was injected as well as the SPECT which showed a lack of cerebral visualization at the equilibrium state. As far as we are informed, this additional procedure used in the diagnosis of brain death has not reported before. The importance of performing a dynamic scintigram at the administration of 99m Tc-HMPAO is also discussed in this report. (author)

Brain donation procedures in the Sudden Death Brain Bank in Edinburgh.

Science.gov (United States)

Smith, Colin; Millar, Tracey

2018-01-01

Brain banks typically receive donations through premortem consent procedures, often through disease-specific patient cohorts, such as dementia. While some control cases can be obtained through this route, access to age-matched control tissues, and some chronic neurologic conditions, particularly psychiatric disorders, can be challenging. The Edinburgh Sudden Death Brain Bank was established to try and increase access to control cases across all ages, and also access to psychiatric disorders through suicides. This chapter outlines the processes for establishing donations through medicolegal postmortems, which, although often with a prolonged postmortem interval, can provide high-quality well-characterized postmortem brain tissue to the neuroscience research community. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

NARCIS (Netherlands)

Galluzzi, Lorenzo; Vitale, Ilio; Aaronson, Stuart A.; Abrams, John M.; Adam, Dieter; Agostinis, Patrizia; Alnemri, Emad S.; Altucci, Lucia; Amelio, Ivano; Andrews, David W.; Annicchiarico-Petruzzelli, Margherita; Antonov, Alexey V.; Arama, Eli; Baehrecke, Eric H.; Barlev, Nickolai A.; Bazan, Nicolas G.; Bernassola, Francesca; Bertrand, Mathieu J. M.; Bianchi, Katiuscia; Blagosklonny, Mikhail V.; Blomgren, Klas; Borner, Christoph; Boya, Patricia; Brenner, Catherine; Campanella, Michelangelo; Candi, Eleonora; Carmona-Gutierrez, Didac; Cecconi, Francesco; Chan, Francis K.-M.; Chandel, Navdeep S.; Cheng, Emily H.; Chipuk, Jerry E.; Cidlowski, John A.; Ciechanover, Aaron; Cohen, Gerald M.; Conrad, Marcus; Cubillos-Ruiz, Juan R.; Czabotar, Peter E.; D'Angiolella, Vincenzo; Dawson, Ted M.; Dawson, Valina L.; de Laurenzi, Vincenzo; de Maria, Ruggero; Debatin, Klaus-Michael; DeBerardinis, Ralph J.; Deshmukh, Mohanish; Di Daniele, Nicola; Di Virgilio, Francesco; Dixit, Vishva M.; Dixon, Scott J.; Duckett, Colin S.; Dynlacht, Brian D.; El-Deiry, Wafik S.; Elrod, John W.; Fimia, Gian Maria; Fulda, Simone; García-Sáez, Ana J.; Garg, Abhishek D.; Garrido, Carmen; Gavathiotis, Evripidis; Golstein, Pierre; Gottlieb, Eyal; Green, Douglas R.; Greene, Lloyd A.; Gronemeyer, Hinrich; Gross, Atan; Hajnoczky, Gyorgy; Hardwick, J. Marie; Harris, Isaac S.; Hengartner, Michael O.; Hetz, Claudio; Ichijo, Hidenori; Jäättelä, Marja; Joseph, Bertrand; Jost, Philipp J.; Juin, Philippe P.; Kaiser, William J.; Karin, Michael; Kaufmann, Thomas; Kepp, Oliver; Kimchi, Adi; Kitsis, Richard N.; Klionsky, Daniel J.; Knight, Richard A.; Kumar, Sharad; Lee, Sam W.; Lemasters, John J.; Levine, Beth; Linkermann, Andreas; Lipton, Stuart A.; Lockshin, Richard A.; López-Otín, Carlos; Lowe, Scott W.; Luedde, Tom; Lugli, Enrico; MacFarlane, Marion; Madeo, Frank; Malewicz, Michal; Malorni, Walter; Manic, Gwenola; Marine, Jean-Christophe; Martin, Seamus J.; Martinou, Jean-Claude; Medema, Jan Paul; Mehlen, Patrick; Meier, Pascal; Melino, Sonia; Miao, Edward A.; Molkentin, Jeffery D.; Moll, Ute M.; Muñoz-Pinedo, Cristina; Nagata, Shigekazu; Nuñez, Gabriel; Oberst, Andrew; Oren, Moshe; Overholtzer, Michael; Pagano, Michele; Panaretakis, Theocharis; Pasparakis, Manolis; Penninger, Josef M.; Pereira, David M.; Pervaiz, Shazib; Peter, Marcus E.; Piacentini, Mauro; Pinton, Paolo; Prehn, Jochen H. M.; Puthalakath, Hamsa; Rabinovich, Gabriel A.; Rehm, Markus; Rizzuto, Rosario; Rodrigues, Cecilia M. P.; Rubinsztein, David C.; Rudel, Thomas; Ryan, Kevin M.; Sayan, Emre; Scorrano, Luca; Shao, Feng; Shi, Yufang; Silke, John; Simon, Hans-Uwe; Sistigu, Antonella; Stockwell, Brent R.; Strasser, Andreas; Szabadkai, Gyorgy; Tait, Stephen W. G.; Tang, Daolin; Tavernarakis, Nektarios; Thorburn, Andrew; Tsujimoto, Yoshihide; Turk, Boris; Vanden Berghe, Tom; Vandenabeele, Peter; Vander Heiden, Matthew G.; Villunger, Andreas; Virgin, Herbert W.; Vousden, Karen H.; Vucic, Domagoj; Wagner, Erwin F.; Walczak, Henning; Wallach, David; Wang, Ying; Wells, James A.; Wood, Will; Yuan, Junying; Zakeri, Zahra; Zhivotovsky, Boris; Zitvogel, Laurence; Melino, Gerry; Kroemer, Guido

2018-01-01

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell

Nonthermal-plasma-mediated animal cell death

Science.gov (United States)

Kim, Wanil; Woo, Kyung-Chul; Kim, Gyoo-Cheon; Kim, Kyong-Tai

2011-01-01

Animal cell death comprising necrosis and apoptosis occurred in a well-regulated manner upon specific stimuli. The physiological meanings and detailed molecular mechanisms of cell death have been continuously investigated over several decades. Necrotic cell death has typical morphological changes, such as cell swelling and cell lysis followed by DNA degradation, whereas apoptosis shows blebbing formation and regular DNA fragmentation. Cell death is usually adopted to terminate cancer cells in vivo. The current strategies against tumour are based on the induction of cell death by adopting various methods, including radiotherapy and chemotherapeutics. Among these, radiotherapy is the most frequently used treatment method, but it still has obvious limitations. Recent studies have suggested that the use of nonthermal air plasma can be a prominent method for inducing cancer cell death. Plasma-irradiated cells showed the loss of genomic integrity, mitochondrial dysfunction, plasma membrane damage, etc. Tumour elimination with plasma irradiation is an emerging concept in cancer therapy and can be accelerated by targeting certain tumour-specific proteins with gold nanoparticles. Here, some recent developments are described so that the mechanisms related to plasma-mediated cell death and its perspectives in cancer treatment can be understood.

Nonthermal-plasma-mediated animal cell death

Energy Technology Data Exchange (ETDEWEB)

Kim, Wanil; Woo, Kyung-Chul; Kim, Kyong-Tai [Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, San 31, Hyoja Dong, Pohang 790-784 (Korea, Republic of); Kim, Gyoo-Cheon, E-mail: ktk@postech.ac.kr [Department of Oral Anatomy and Cell Biology, School of Dentistry, Pusan National University, Yangsan 626-810 (Korea, Republic of)

2011-01-12

Animal cell death comprising necrosis and apoptosis occurred in a well-regulated manner upon specific stimuli. The physiological meanings and detailed molecular mechanisms of cell death have been continuously investigated over several decades. Necrotic cell death has typical morphological changes, such as cell swelling and cell lysis followed by DNA degradation, whereas apoptosis shows blebbing formation and regular DNA fragmentation. Cell death is usually adopted to terminate cancer cells in vivo. The current strategies against tumour are based on the induction of cell death by adopting various methods, including radiotherapy and chemotherapeutics. Among these, radiotherapy is the most frequently used treatment method, but it still has obvious limitations. Recent studies have suggested that the use of nonthermal air plasma can be a prominent method for inducing cancer cell death. Plasma-irradiated cells showed the loss of genomic integrity, mitochondrial dysfunction, plasma membrane damage, etc. Tumour elimination with plasma irradiation is an emerging concept in cancer therapy and can be accelerated by targeting certain tumour-specific proteins with gold nanoparticles. Here, some recent developments are described so that the mechanisms related to plasma-mediated cell death and its perspectives in cancer treatment can be understood. (topical review)

Nonthermal-plasma-mediated animal cell death

International Nuclear Information System (INIS)

Kim, Wanil; Woo, Kyung-Chul; Kim, Kyong-Tai; Kim, Gyoo-Cheon

2011-01-01

Animal cell death comprising necrosis and apoptosis occurred in a well-regulated manner upon specific stimuli. The physiological meanings and detailed molecular mechanisms of cell death have been continuously investigated over several decades. Necrotic cell death has typical morphological changes, such as cell swelling and cell lysis followed by DNA degradation, whereas apoptosis shows blebbing formation and regular DNA fragmentation. Cell death is usually adopted to terminate cancer cells in vivo. The current strategies against tumour are based on the induction of cell death by adopting various methods, including radiotherapy and chemotherapeutics. Among these, radiotherapy is the most frequently used treatment method, but it still has obvious limitations. Recent studies have suggested that the use of nonthermal air plasma can be a prominent method for inducing cancer cell death. Plasma-irradiated cells showed the loss of genomic integrity, mitochondrial dysfunction, plasma membrane damage, etc. Tumour elimination with plasma irradiation is an emerging concept in cancer therapy and can be accelerated by targeting certain tumour-specific proteins with gold nanoparticles. Here, some recent developments are described so that the mechanisms related to plasma-mediated cell death and its perspectives in cancer treatment can be understood. (topical review)

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.

Alternative Cell Death Pathways and Cell Metabolism

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Simone Fulda

2013-01-01

Full Text Available While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases.

NAD+ depletion or PAR polymer formation: which plays the role of executioner in ischaemic cell death?

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Siegel, C; McCullough, L D

2011-09-01

Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase-independent pathway triggered by poly-ADP-ribose polymers (PARP) activation. Caspase-induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase-independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high-molecular-weight (50 kbp) DNA fragmentation. Although caspase-independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro-apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly-ADP-ribose (PAR) polymers as byproducts of PARP activation. PAR polymers

Glutathione in Cancer Cell Death

Energy Technology Data Exchange (ETDEWEB)

Ortega, Angel L. [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 17 Av. Blasco Ibanez, 46010 Valencia (Spain); Mena, Salvador [Green Molecular SL, Pol. Ind. La Coma-Parc Cientific, 46190 Paterna, Valencia (Spain); Estrela, Jose M., E-mail: jose.m.estrela@uv.es [Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 17 Av. Blasco Ibanez, 46010 Valencia (Spain)

2011-03-11

Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy.

The significance of faint visualization of the superior sagittal sinus in brain scintigraphy for the diagnosis of brain death

International Nuclear Information System (INIS)

Bisset, R.; Sfakianakis, G.; Ihmedian, I.; Holzman, B.; Curless, R.; Serafini, A.

1985-01-01

Brain death is associated with cessation of blood flow to the brain. Tc-99m brain flow studies are used as a laboratory confirmatory test for the establishment of the diagnosis of brain death. Criteria for the diagnosis of cessation of blood flow to the brain are 1) visualization of carotid artery activity in the neck of the patient and 2) no visualization of activity in the distribution of the anterior and middle cerebral arteries. The authors noticed that in a significant number of patients, although there was no visualization of arterial blood flow to the brain the static images demonstrated faint accumulation of activity in the region of the superior sagittal sinus (SSS). In a four year period 212 brain flow studies were performed in 154 patients for diagnosis of brain death; of them 137 studies (65%) showed no evidence of arterial flow. In 103 out of the 137 studies (75%) there was no visualization of the SSS; in the remaining 34 studies (3l patients) however three patterns of faint activity attributed to partial and or faint visualization of the SSS could be recognized at the midline of the immediate anterior static view: a) linear from the cranial vault floor up b) disk shaped at the apex of the vault and c) disk shaped at the apex tailing caudad. All of the 3l patients in this group satisfied brain death criteria within four days of the last study which showed faint visualization of the superior sagittal sinus. The authors conclude that even in the presence of a faint visualization of the superior sagittal sinus on static post brain flow scintigraphy, the diagnosis of cessation of blood flow to the brain can be made if there is no evidence of arterial blood flow

[Brain death in children--how to deal with the parents?].

Science.gov (United States)

Schindler, Nicola; Vagts, Dierk

2008-07-01

For parents the death of children is hard to bear and to accept. In situations where a brain death needs to be diagnosed, the psychological stress for parents who lose their child is aggravated due to a mostly sudden and unprepared confrontation with this situation. The rationality to accept the death of a their child is opposed by the hope for recovery as long as the children are "warm and dead" instead of "cold and dead" due to the maintenance of cardiac circulation. In Germany in this situation, after diagnosing the brain death, doctors are forced by legislation to ask the parents to agree for organ donation. However, to our knowledge, no literature is available how doctors should conduct such an important conversation to the parents. This manuscript tries to give some hints for conducting a conversation from the psychological background of mourning and from our own experience gained during the last 5 years.

Polycation-mediated integrated cell death processes

DEFF Research Database (Denmark)

Parhamifar, Ladan; Andersen, Helene; Wu, Linping

2014-01-01

standard. PEIs are highly efficient transfectants, but depending on their architecture and size they induce cytotoxicity through different modes of cell death pathways. Here, we briefly review dynamic and integrated cell death processes and pathways, and discuss considerations in cell death assay design...

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders.

Science.gov (United States)

Kaminsky, Natalie; Bihari, Ofer; Kanner, Sivan; Barzilai, Ari

2016-06-01

The DNA damage response (DDR) is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes). Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a "hostile" environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

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Natalie Kaminsky

2016-06-01

Full Text Available The DNA damage response (DDR is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes. Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a “hostile” environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.

East-West differences in perception of brain death. Review of history, current understandings, and directions for future research.

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Yang, Qing; Miller, Geoffrey

2015-06-01

The concept of brain death as equivalent to cardiopulmonary death was initially conceived following developments in neuroscience, critical care, and transplant technology. It is now a routine part of medicine in Western countries, including the United States. In contrast, Eastern countries have been reluctant to incorporate brain death into legislation and medical practice. Several countries, most notably China, still lack laws recognizing brain death and national medical standards for making the diagnosis. The perception is that Asians are less likely to approve of brain death or organ transplant from brain dead donors. Cultural and religious traditions have been referenced to explain this apparent difference. In the West, the status of the brain as home to the soul in Enlightenment philosophy, combined with pragmatism and utilitarianism, supports the concept of brain death. In the East, the integration of body with spirit and nature in Buddhist and folk beliefs, along with the Confucian social structure that builds upon interpersonal relationships, argues against brain death. However, it is unclear whether these reasoning strategies are explicitly used when families and medical providers are faced with acknowledging brain death. Their decisions are more likely to involve a prioritization of values and a rationalization of intuitive responses. Why and whether there might be differences between East and West in the acceptance of the brain death concept requires further empirical testing, which would help inform policy-making and facilitate communication between providers and patients from different cultural and ethnic backgrounds.

Police Officers' Knowledge and Attitudes Toward Brain Death and Organ Donation in Korea.

Science.gov (United States)

Kim, H S; Yoo, Y S; Cho, O-H; Lee, C E; Choi, Y-H; Kim, H J; Park, J Y; Park, H S; Kwon, Y J

2018-05-01

Administrative processing by the police may affect the process involved in organ donation in the event of an accidental brain injury. The purpose of this study was to evaluate the knowledge and attitude of police toward brain-dead donors and organ donation. This was a descriptive research study using a 41-item questionnaire. As of July 19, 2017, 11 police stations in Seoul had collected questionnaires completed by 115 police officers. Data were analyzed using SAS (version 9.4) software. There were statistically significant differences in the scores on knowledge about brain death/donation according to religion (P = .022). Attitude was significantly positively correlated with the knowledge about brain-death organ donation (P = .029). It is necessary to understand and cooperate with the police when processing brain death organs from accidents. Education about organ donation can enhance the information and knowledge of the police and can also help to establish a positive attitude about organ donation. Copyright © 2018 Elsevier Inc. All rights reserved.

Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL

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Han Seol

2011-07-01

Full Text Available Abstract Background At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. Methods Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C. diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay. Results In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL. Conclusion To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally

Serial recording of median nerve stimulated subcortical somatosensory evoked potentials (SEPs) in developing brain death.

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Buchner, H; Ferbert, A; Hacke, W

1988-01-01

Subcortical somatosensory evoked potentials (SEPs) to median nerve stimulation were recorded serially in 35 patients during the evolution towards brain death and in brain death. Neuropathological alterations of the central nervous system down to the C1/C2 spinal cord segment in brain death are well known. SEP components supposed to be generated above this level should be lost in brain death, while components generated below should not be altered. Erb's point, scalp and neck potentials were recorded at C3/4, or over the spinous process C7, using an Fz reference. In 10 patients additional montages, including spinous process C2-Fz, a non-cephalic reference (Fz-contralateral shoulder) and a posterior to anterior neck montage (spinous process C7-jugulum) were used. The cephalic referenced N9 and N11 peaks remained unchanged until brain death. N9 and N11 decreased in parallel in amplitude and increased in latency after systemic effects like hypoxia or hypothermia occurred. The cephalic referenced 'N14' decreased in amplitude and increased in latency after the clinical brain death syndrome was observed, while N13 in the posterior to anterior neck montage remained unchanged. The alteration of 'N14' went parallel to the decrease of the P14 amplitude. The subcortical SEPs in the cephalic referenced lead are supposed to be a peak composed by a horizontally orientated dorsal horn generated N13 and a rostrally orientated P14 arising at the level of the foramen magnum. The deterioration of the non-cephalic referenced P14 and of its cephalic referenced reflection 'N14' seems to provide an additional objective criterion for the diagnosis of brain death.

Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes.

Science.gov (United States)

Lee, Sook-Jeong; Koh, Jae-Young

2010-10-26

Zinc dyshomeostasis has been recognized as an important mechanism for cell death in acute brain injury. An increase in the level of free or histochemically reactive zinc in astrocytes and neurons is considered one of the major causes of death of these cells in ischemia and trauma. Although zinc dyshomeostasis can lead to cell death via diverse routes, the major pathway appears to involve oxidative stress.Recently, we found that a rise of zinc in autophagic vacuoles, including autolysosomes, is a prerequisite for lysosomal membrane permeabilization and cell death in cultured brain cells exposed to oxidative stress conditions. The source of zinc in this process is likely redox-sensitive zinc-binding proteins such as metallothioneins, which release zinc under oxidative conditions. Of the metallothioneins, metallothionein-3 is especially enriched in the central nervous system, but its physiologic role in this tissue is not well established. Like other metallothioneins, metallothionein-3 may function as metal detoxicant, but is also known to inhibit neurite outgrowth and, sometimes, promote neuronal death, likely by serving as a source of toxic zinc release. In addition, metallothionein-3 regulates lysosomal functions. In the absence of metallothionein-3, there are changes in lysosome-associated membrane protein-1 and -2, and reductions in certain lysosomal enzymes that result in decreased autophagic flux. This may have dual effects on cell survival. In acute oxidative injury, zinc dyshomeostasis and lysosomal membrane permeabilization are diminished in metallothionein-3 null cells, resulting in less cell death. But over the longer term, diminished lysosomal function may lead to the accumulation of abnormal proteins and cause cytotoxicity.The roles of zinc and metallothionein-3 in autophagy and/or lysosomal function have just begun to be investigated. In light of evidence that autophagy and lysosomes may play significant roles in the pathogenesis of various neurological

Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes

Directory of Open Access Journals (Sweden)

Lee Sook-Jeong

2010-10-01

Full Text Available Abstract Zinc dyshomeostasis has been recognized as an important mechanism for cell death in acute brain injury. An increase in the level of free or histochemically reactive zinc in astrocytes and neurons is considered one of the major causes of death of these cells in ischemia and trauma. Although zinc dyshomeostasis can lead to cell death via diverse routes, the major pathway appears to involve oxidative stress. Recently, we found that a rise of zinc in autophagic vacuoles, including autolysosomes, is a prerequisite for lysosomal membrane permeabilization and cell death in cultured brain cells exposed to oxidative stress conditions. The source of zinc in this process is likely redox-sensitive zinc-binding proteins such as metallothioneins, which release zinc under oxidative conditions. Of the metallothioneins, metallothionein-3 is especially enriched in the central nervous system, but its physiologic role in this tissue is not well established. Like other metallothioneins, metallothionein-3 may function as metal detoxicant, but is also known to inhibit neurite outgrowth and, sometimes, promote neuronal death, likely by serving as a source of toxic zinc release. In addition, metallothionein-3 regulates lysosomal functions. In the absence of metallothionein-3, there are changes in lysosome-associated membrane protein-1 and -2, and reductions in certain lysosomal enzymes that result in decreased autophagic flux. This may have dual effects on cell survival. In acute oxidative injury, zinc dyshomeostasis and lysosomal membrane permeabilization are diminished in metallothionein-3 null cells, resulting in less cell death. But over the longer term, diminished lysosomal function may lead to the accumulation of abnormal proteins and cause cytotoxicity. The roles of zinc and metallothionein-3 in autophagy and/or lysosomal function have just begun to be investigated. In light of evidence that autophagy and lysosomes may play significant roles in the

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.

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

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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

Pupil diameter for confirmation of brain death in adult organ donors in Japan.

Science.gov (United States)

Sagishima, Katsuyuki; Kinoshita, Yoshihiro

2017-01-01

The criteria for brain death in Japan include a bilateral pupil diameter of ≥4 mm. We evaluated the appropriateness of a 4-mm pupil diameter in adult brain-dead donors in Japan. We retrospectively reviewed the records of 148 consecutive adult brain-dead donors with an average age of 46 years. All records were anonymously registered to the Japanese Ministry of Health, Labour and Welfare (the Japanese Ministry of Health and Welfare before 2001) from the various designated emergency institutes that performed organ donation under brain death from 1999 to 2012 in Japan. All donors had a Glasgow Coma Scale score of 3, absence of all seven brain stem reflexes, an isoelectric electroencephalogram for >30 min, and apnea as tested by the standard method. All of these examinations were repeated approximately 6 h later for confirmation. The pupil diameter (average ± standard deviation) was 6.1 ± 1.1 mm at the first assessment and 6.4 ± 1.1 mm approximately 6 h later. The 95% probability distribution as calculated by statistical analysis was 3.93-8.30 mm in the left eye and 3.88-8.28 mm in the right eye in the first assessment, and 4.25-8.58 mm in the left eye and 4.32-8.43 mm in the right eye approximately 6 h later. Despite the various original causes of brain death, we conclude that a pupil diameter of ≥4 mm is a reasonable criterion for brain death in adults.

Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling.

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Md Shamim Hossain

Full Text Available Neuronal cells are susceptible to many stresses, which will cause the apoptosis and neurodegenerative diseases. The precise molecular mechanism behind the neuronal protection against these apoptotic stimuli is necessary for drug discovery. In the present study, we have found that plasmalogens (Pls, which are glycerophospholipids containing vinyl ether linkage at sn-1 position, can protect the neuronal cell death upon serum deprivation. Interestingly, caspse-9, but not caspase-8 and caspase-12, was cleaved upon the serum starvation in Neuro-2A cells. Pls treatments effectively reduced the activation of caspase-9. Furthermore, cellular signaling experiments showed that Pls enhanced phosphorylation of the phosphoinositide 3-kinase (PI3K-dependent serine/threonine-specific protein kinase AKT and extracellular-signal-regulated kinases ERK1/2. PI3K/AKT inhibitor LY294002 and MAPK/ERK kinase (MEK inhibitor U0126 treatments study clearly indicated that Pls-mediated cell survival was dependent on the activation of these kinases. In addition, Pls also inhibited primary mouse hippocampal neuronal cell death induced by nutrient deprivation, which was associated with the inhibition of caspase-9 and caspase-3 cleavages. It was reported that Pls content decreased in the brain of the Alzheimer's patients, which indicated that the reduction of Pls content could endanger neurons. The present findings, taken together, suggest that Pls have an anti-apoptotic action in the brain. Further studies on precise mechanisms of Pls-mediated protection against cell death may lead us to establish a novel therapeutic approach to cure neurodegenerative disorders.

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

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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.

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

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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.

The effects of glycemic control on seizures and seizure-induced excitotoxic cell death

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Schauwecker Paula

2012-08-01

Full Text Available Abstract Background Epilepsy is the most common neurological disorder after stroke, affecting more than 50 million persons worldwide. Metabolic disturbances are often associated with epileptic seizures, but the pathogenesis of this relationship is poorly understood. It is known that seizures result in altered glucose metabolism, the reduction of intracellular energy metabolites such as ATP, ADP and phosphocreatine and the accumulation of metabolic intermediates, such as lactate and adenosine. In particular, it has been suggested that the duration and extent of glucose dysregulation may be a predictor of the pathological outcome of status. However, little is known about neither the effects of glycemic control on brain metabolism nor the effects of managing systemic glucose concentrations in epilepsy. Results In this study, we examined glycemic modulation of kainate-induced seizure sensitivity and its neuropathological consequences. To investigate the relationship between glycemic modulation, seizure susceptibility and its neuropathological consequences, C57BL/6 mice (excitotoxin cell death resistant were subjected to hypoglycemia or hyperglycemia, followed by systemic administration of kainic acid to induce seizures. Glycemic modulation resulted in minimal consequences with regard to seizure severity but increased hippocampal pathology, irrespective of whether mice were hypoglycemic or hyperglycemic prior to kainate administration. Moreover, we found that exogenous administration of glucose following kainic acid seizures significantly reduced the extent of hippocampal pathology in FVB/N mice (excitotoxin cell death susceptible following systemic administration of kainic acid. Conclusion These findings demonstrate that modulation of the glycemic index can modify the outcome of brain injury in the kainate model of seizure induction. Moreover, modulation of the glycemic index through glucose rescue greatly diminishes the extent of seizure

Pitfalls in diagnosing brain death in infancy

International Nuclear Information System (INIS)

Toffol, G.J.; Lansky, L.L.; Hughes, J.R.; Blend, M.J.; Pavel, D.G.; Kecskes, S.A.; Ortega, R.E.; Tan, W.S.

1987-01-01

A 3-year-old child with phenotypic trisomy 18 syndrome survived 26 days after a cardiopulmonary arrest, secondary to an acute viral illness. The child was deeply comatose. No barbiturates, other sedatives, or aminoglycoside antibiotics had been recently administered. The child was normothermic with adequate cardiovascular function. Brain stem function was absent, as assessed by testing of brain stem reflexes. Serial cerebral radionuclide angiograms (CRAG) documented intact cerebral blood flow while electrocerebral silence (ECS) was present on two consecutive EEG recordings within 24 hours. Preservation of intracranial circulation was confirmed by rapid rotational computed tomographic (CT) scans. Cranial CT scans also revealed communicating hydrocephalus, and bilateral basal ganglia hemorrhages. This unusual case illustrates discordance between apparent irreversible loss of cortical function as indicated by electrocerebral silence with preserved cerebral blood flow. The implications of these apparent paradoxical events will be discussed in the context of defining brain death in children

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

2018-04-01

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.

Modelling radiation-induced cell death and tumour re-oxygenation: local versus global and instant versus delayed cell death

International Nuclear Information System (INIS)

Gago-Arias, Araceli; Espinoza, Ignacio; Sánchez-Nieto, Beatriz; Aguiar, Pablo; Pardo-Montero, Juan

2016-01-01

The resistance of hypoxic cells to radiation, due to the oxygen dependence of radiosensitivity, is well known and must be taken into account to accurately calculate the radiation induced cell death. A proper modelling of the response of tumours to radiation requires deriving the distribution of oxygen at a microscopic scale. This usually involves solving the reaction-diffusion equation in tumour voxels using a vascularization distribution model. Moreover, re-oxygenation arises during the course of radiotherapy, one reason being the increase of available oxygen caused by cell killing, which can turn hypoxic tumours into oxic. In this work we study the effect of cell death kinetics in tumour oxygenation modelling, analysing how it affects the timing of re-oxygenation, surviving fraction and tumour control. Two models of cell death are compared, an instantaneous cell killing, mimicking early apoptosis, and a delayed cell death scenario in which cells can die shortly after being damaged, as well as long after irradiation. For each of these scenarios, the decrease in oxygen consumption due to cell death can be computed globally (macroscopic voxel average) or locally (microscopic). A re-oxygenation model already used in the literature, the so called full re-oxygenation, is also considered. The impact of cell death kinetics and re-oxygenation on tumour responses is illustrated for two radiotherapy fractionation schemes: a conventional schedule, and a hypofractionated treatment. The results show large differences in the doses needed to achieve 50% tumour control for the investigated cell death models. Moreover, the models affect the tumour responses differently depending on the treatment schedule. This corroborates the complex nature of re-oxygenation, showing the need to take into account the kinetics of cell death in radiation response models. (paper)

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

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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.

Exploration of protective strategies against oligodendrocyte cell death in Krabbe disease models

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Gonzalo Arboleda

2015-02-01

Full Text Available Krabbe disease (KD patients accumulate psychosine (galactosylsphingosine, a cytotoxic metabolite for oligodendrocytes, inducing early demyelination. Apoptosis has been suggested that plays an important role in psychosine-induced oligodendrocytes cell death in culture and in brains of Krabbe patients and an animal model of the disease (twitcher mouse. However, the molecular mechanism that triggers the activation of the apoptotic pathway, and hence the development/progression of the disease, still is not well understood. Here we report that silencing GALC gene expression induces cell death of the human derived oligodendrocyte cell line MO3.13. The induction of cell death is associated with the activation of caspase 3 and increase in Bax expression, suggesting that mitochondria is compromise, and decrease in cell survival signaling pathways such as PI3K/AKT, MAPK/ERK and AMPK, as observed by western blot analysis, 2 days after silencing. The data suggests an important psychosine-induced deregulation in apoptotic and anti-apoptotic cellular pathways. Moreover, pre-treatment with insuline-like growth factor (IGF-1 and PPARalfa agonist (WY 14643, significantly provides protection against the psychosine-induced changes described. Our data indicates that oligodendrocytes have a marked susceptibility to endogenous accumulation of psychosine and identified potential compounds that may offer protection against psychosine-induced apoptosis in vivo.

[Methuosis: a novel type of cell death].

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Cai, Hongbing; Liu, Jinkun; Fan, Qin; Li, Xin

2013-12-01

Cell death is a major physiological or pathological phenomenon in life activities. The classic forms of cell death include apoptosis, necrosis, and autophagy. Recently, a novel type of cell death has been observed and termed as methuosis, in which excessive stimuli can induce cytoplasmic uptake and accumulation of small bubbles that gradually merge into giant vacuoles, eventually leading to decreased cellular metabolic activity, cell membrane rupture and cell death. In this article, we describe the nomenclature, morphological characteristics and underlying mechanisms of methuosis, compare methuosis with autophagy, oncosis and paraptosis, and review the related researches.

Morphological classification of plant cell deaths.

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van Doorn, W G; Beers, E P; Dangl, J L; Franklin-Tong, V E; Gallois, P; Hara-Nishimura, I; Jones, A M; Kawai-Yamada, M; Lam, E; Mundy, J; Mur, L A J; Petersen, M; Smertenko, A; Taliansky, M; Van Breusegem, F; Wolpert, T; Woltering, E; Zhivotovsky, B; Bozhkov, P V

2011-08-01

Programmed cell death (PCD) is an integral part of plant development and of responses to abiotic stress or pathogens. Although the morphology of plant PCD is, in some cases, well characterised and molecular mechanisms controlling plant PCD are beginning to emerge, there is still confusion about the classification of PCD in plants. Here we suggest a classification based on morphological criteria. According to this classification, the use of the term 'apoptosis' is not justified in plants, but at least two classes of PCD can be distinguished: vacuolar cell death and necrosis. During vacuolar cell death, the cell contents are removed by a combination of autophagy-like process and release of hydrolases from collapsed lytic vacuoles. Necrosis is characterised by early rupture of the plasma membrane, shrinkage of the protoplast and absence of vacuolar cell death features. Vacuolar cell death is common during tissue and organ formation and elimination, whereas necrosis is typically found under abiotic stress. Some examples of plant PCD cannot be ascribed to either major class and are therefore classified as separate modalities. These are PCD associated with the hypersensitive response to biotrophic pathogens, which can express features of both necrosis and vacuolar cell death, PCD in starchy cereal endosperm and during self-incompatibility. The present classification is not static, but will be subject to further revision, especially when specific biochemical pathways are better defined.

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

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

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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.

Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP

OpenAIRE

Sander, Philip; Mostafa, Haouraa; Soboh, Ayman; Schneider, Julian M.; Pala, Andrej; Baron, Ann-Kathrin; Moepps, Barbara; Wirtz, C. Rainer; Georgieff, Michael; Schneider, Marion

2017-01-01

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-...

Autophagic cell death: Loch Ness monster or endangered species?

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Shen, Han-Ming; Codogno, Patrice

2011-05-01

The concept of autophagic cell death was first established based on observations of increased autophagic markers in dying cells. The major limitation of such a morphology-based definition of autophagic cell death is that it fails to establish the functional role of autophagy in the cell death process, and thus contributes to the confusion in the literature regarding the role of autophagy in cell death and cell survival. Here we propose to define autophagic cell death as a modality of non-apoptotic or necrotic programmed cell death in which autophagy serves as a cell death mechanism, upon meeting the following set of criteria: (i) cell death occurs without the involvement of apoptosis; (ii) there is an increase of autophagic flux, and not just an increase of the autophagic markers, in the dying cells; and (iii) suppression of autophagy via both pharmacological inhibitors and genetic approaches is able to rescue or prevent cell death. In light of this new definition, we will discuss some of the common problems and difficulties in the study of autophagic cell death and also revisit some well-reported cases of autophagic cell death, aiming to achieve a better understanding of whether autophagy is a real killer, an accomplice or just an innocent bystander in the course of cell death. At present, the physiological relevance of autophagic cell death is mainly observed in lower eukaryotes and invertebrates such as Dictyostelium discoideum and Drosophila melanogaster. We believe that such a clear definition of autophagic cell death will help us study and understand the physiological or pathological relevance of autophagic cell death in mammals.

Porcine circovirus-2 capsid protein induces cell death in PK15 cells

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Walia, Rupali; Dardari, Rkia, E-mail: rdardari@ucalgary.ca; Chaiyakul, Mark; Czub, Markus

2014-11-15

Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathways involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization.

Radiation-induced cell death in embryogenic cells of coniferous plants

International Nuclear Information System (INIS)

Watanabe, Yoshito; Homma-Takeda, Shino; Yukawa, Masae; Nishimura, Yoshikazu; Sasamoto, Hamako; Takahagi, Masahiko

2004-01-01

Reproductive processes are particularly radiosensitive in plant development, which was clearly illustrated in reduction of seed formation in native coniferous plants around Chernobyl after the nuclear accident. For the purpose to investigate the effects of ionizing radiation on embryonic formation in coniferous plants, we used an embryo-derived embryogenic cell culture of a Japanese native coniferous plant, Japanese cedar (Cryplomeria japonica). The embryogenic cells were so radiosensitive that most of the cells died by X-ray irradiation of 5 Gy. This indicated that the embryogenic cells are as radiosensitive as some mammalian cells including lymphocytes. We considered that this type of radiosensitive cell death in the embryogenic cells should be responsible for reproductive damages of coniferous plants by low dose of ionizing radiation. The cell death of the embryogenic cells was characteristic of nuclear DNA fragmentation, which is typically observed in radiation-induced programmed cell death, i.e. apoptosis, in mammalian cells. On the other hand, cell death with nuclear DNA fragmentation did not develop by X-ray irradiation in vegetative cells including meristematic cells of Japanese cedar. This suggests that an apoptosis-like programmed cell death should develop cell-specifically in embryogenic cells by ionizing radiation. The abortion of embryogenic cells may work to prevent transmission of radiation-induced genetic damages to the descendants. (author)

Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP.

Science.gov (United States)

Sander, Philip; Mostafa, Haouraa; Soboh, Ayman; Schneider, Julian M; Pala, Andrej; Baron, Ann-Kathrin; Moepps, Barbara; Wirtz, C Rainer; Georgieff, Michael; Schneider, Marion

2017-05-23

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-pulp stem cells (DPSCs) served as controls. A major finding was that an exogenous ATP concentration of as little as 1 μM counter regulated the Vac-induced cell death. Studies using carvacrol, an inhibitor of transient receptor potential cation channel, subfamily M, member 7 (TRPM7), demonstrated that the ATP-inducible inhibitory effect is likely to be via TRPM7. Exogenous ATP is of relevance in GBM with large necrotic areas. Our results support the use of GBM cultures with different grades of malignancy to address their sensitivity to methuosis. The video-microscopy approach presented here allows decoding of signaling pathways as well as mechanisms of chemotherapeutic resistance by long-term observation. Before implementing Vac as a novel therapeutic drug in GBM, cells from each individual patient need to be assessed for their ATP sensitivity. In summary, the current investigation supports the concept of methuosis, described as non-apoptotic cell death and a promising approach for GBM treatment. Tissue-resident ATP/necrosis may interfere with this cell-death pathway but can be overcome by a natural compound, carvacrol that even penetrates the blood-brain barrier.

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

Cell death in neural precursor cells and neurons before neurite formation prevents the emergence of abnormal neural structures in the Drosophila optic lobe.

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Hara, Yusuke; Sudo, Tatsuya; Togane, Yu; Akagawa, Hiromi; Tsujimura, Hidenobu

2018-04-01

Programmed cell death is a conserved strategy for neural development both in vertebrates and invertebrates and is recognized at various developmental stages in the brain from neurogenesis to adulthood. To understand the development of the central nervous system, it is essential to reveal not only molecular mechanisms but also the role of neural cell death (Pinto-Teixeira et al., 2016). To understand the role of cell death in neural development, we investigated the effect of inhibition of cell death on optic lobe development. Our data demonstrate that, in the optic lobe of Drosophila, cell death occurs in neural precursor cells and neurons before neurite formation and functions to prevent various developmental abnormalities. When neuronal cell death was inhibited by an effector caspase inhibitor, p35, multiple abnormal neuropil structures arose during optic lobe development-e.g., enlarged or fused neuropils, misrouted neurons and abnormal neurite lumps. Inhibition of cell death also induced morphogenetic defects in the lamina and medulla development-e.g., failures in the separation of the lamina and medulla cortices and the medulla rotation. These defects were reproduced in the mutant of an initiator caspase, dronc. If cell death was a mechanism for removing the abnormal neuropil structures, we would also expect to observe them in mutants defective for corpse clearance. However, they were not observed in these mutants. When dead cell-membranes were visualized with Apoliner, they were observed only in cortices and not in neuropils. These results suggest that the cell death occurs before mature neurite formation. Moreover, we found that inhibition of cell death induced ectopic neuroepithelial cells, neuroblasts and ganglion mother cells in late pupal stages, at sites where the outer and inner proliferation centers were located at earlier developmental stages. Caspase-3 activation was observed in the neuroepithelial cells and neuroblasts in the proliferation centers

Non-Canonical Cell Death Induced by p53

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Atul Ranjan

2016-12-01

Full Text Available Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA, ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells.

Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway

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Penelope Koraka

2018-03-01

Full Text Available Rabies is an important neglected disease, characterized by invariably fatal encephalitis. Several studies focus on understanding the pathogenic mechanisms of the prototype lyssavirus rabies virus (RABV infection, and little is known about the pathogenesis of rabies caused by other lyssaviruses. We sought to characterize the host response to Duvenhage virus infection and compare it with responses observed during RABV infection by gene expression profiling of brains of mice with the respective infections. We found in both infections differentially expressed genes leading to increased expression of type I interferons (IFNs, chemokines, and proinflammatory cytokines. In addition several genes of the IFN signaling pathway are up-regulated, indicating a strong antiviral response and activation of the negative feedback mechanism to limit type I IFN responses. Furthermore we provide evidence that in the absence of significant neuronal apoptotic death, cell death of neurons is mediated via the pyroptotic pathway in both infections. Taken together, we have identified several genes and/or pathways for both infections that could be used to explore novel approaches for intervention strategies against rabies.

Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells.

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Fonseca, Ana Catarina R G; Ferreiro, Elisabete; Oliveira, Catarina R; Cardoso, Sandra M; Pereira, Cláudia F

2013-12-01

Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration. © 2013.

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

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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.

Mitochondrial fission proteins regulate programmed cell death in yeast.

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Fannjiang, Yihru; Cheng, Wen-Chih; Lee, Sarah J; Qi, Bing; Pevsner, Jonathan; McCaffery, J Michael; Hill, R Blake; Basañez, Gorka; Hardwick, J Marie

2004-11-15

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we found that the Saccharomyces cerevisiae homolog of human Drp1, Dnm1, promotes mitochondrial fragmentation/degradation and cell death following treatment with several death stimuli. Two Dnm1-interacting factors also regulate yeast cell death. The WD40 repeat protein Mdv1/Net2 promotes cell death, consistent with its role in mitochondrial fission. In contrast to its fission function in healthy cells, Fis1 unexpectedly inhibits Dnm1-mediated mitochondrial fission and cysteine protease-dependent cell death in yeast. Furthermore, the ability of yeast Fis1 to inhibit mitochondrial fission and cell death can be functionally replaced by human Bcl-2 and Bcl-xL. Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function.

Early death, late death and repair factor in three human tumour cell lines

International Nuclear Information System (INIS)

Courdi, A.; Gioanni, J.; Mari, D.; Chauvel, P.

1997-01-01

The in vivo colony method used to generate survival curves following exposure to ionizing irradiation allows to score large clones, representing surviving cells, and small colonies, representing late reproductive death. By subtraction, early-dying cells can be estimated. In the three human tumour cell lines examined, we have observed that early cell death is a major mode of action of irradiation. The contribution of early cell death to total mortality increases as the dose increases. Moreover, repair due to dose-splitting and delayed plating in densely-inhibited cells is not observed in early-dying cells. (authors)

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

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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.

Brain death in the pediatric patient: historical, sociological, medical, religious, cultural, legal, and ethical considerations.

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Farrell, M M; Levin, D L

1993-12-01

To detail the origins of the definition of death, the development of the criterion of whole brain death as fulfilling the definition of death, and the tests used to fulfill that criterion. A review of the literature was performed. No Institutional Review Board approval was necessary. In 1959, patients were described as being in "coma dépassé" or beyond coma. In 1967, the first successful heart transplantation took place, with the organ coming from a brain-dead, beating-heart donor. However, anxiety over the definitions of death did not begin with the modern, technological era, and death itself has never been definable in objective terms. It has always been a subjective and value-based construct. During ancient times, most people agreed that death occurred when a person's heartbeat and breathing stopped. For the Greeks, the heart was the center of life; for the ancient Hebrews and Christians, the breath was the center of life. In the 12th century, Maimonides pointed toward the head, and the loss thereof, as the reason for lack of central guidance of the soul. Physicians neither diagnosed nor certified death. During the Enlightenment, the necessity of heartbeat, breath, and consciousness for the definition of life was questioned, leading to questioning regarding the definition of death. Tests to fulfill the criteria of death, and tests to determine the absence of integration between functions of respiration, circulation, and neurology were introduced. Sensorimotor potential was becoming recognized as defining life, rather than heartbeat and respiration. As new tests were devised to fulfill criteria of death, the physician developed a professional monopoly on meeting the criteria of brain death. In the modern era, the boundary between life and death has been blurred, but the intensive care unit straddles this boundary. We may have situations where the patient is alive but in a coma, without functioning heart, lungs, kidneys, or gastrointestinal tract, with a

Heart rate variability and QT dispersion study in brain death patients and comatose patients with normal brainstem function

International Nuclear Information System (INIS)

Vakilian, A.R.; Iranmanesh, F.; Nadimi, A.E.; Kahnali, J.A.

2011-01-01

To compare heart rate variability (HRV) and QT dispersion in comatose patients with normal brainstem function and with brain death. Fourteen brain death patients with clinical signs of imminent brain death and 15 comatose patients were examined by neurologist in intensive care unit. HRV, RR interval and QT dispersion on ECG were assessed for 24 hours in both groups. Independent t-test and chi-square test were used for statistical analysis to determine significance which was set at p < 0.05. According to Holter findings, mean of standard deviation of RR-interval in the comatose and brain death groups was 48.33 and 35 respectively (p = 0.045). Mean of covariance coefficient of RR-interval was 0.065 in the comatose group and 0.043 in the brain deaths (p = 0.006). QT dispersion was not significant difference in two groups. HRV and RR-interval analysis appeared as an early finding for the diagnosis of brainstem death in comparison to comatose patients with normal brainstem function. QT dispersion had not significant in this regard. (author)

Morphological classification of plant cell deaths

DEFF Research Database (Denmark)

van Doorn, W.G.; Beers, E.P.; Dangl, J.L.

2011-01-01

, which can express features of both necrosis and vacuolar cell death, PCD in starchy cereal endosperm and during self-incompatibility. The present classification is not static, but will be subject to further revision, especially when specific biochemical pathways are better defined....... the classification of PCD in plants. Here we suggest a classification based on morphological criteria. According to this classification, the use of the term 'apoptosis' is not justified in plants, but at least two classes of PCD can be distinguished: vacuolar cell death and necrosis. During vacuolar cell death...

Drosophila Ninjurin A induces nonapoptotic cell death.

Directory of Open Access Journals (Sweden)

Sarah Broderick

Full Text Available Ninjurins are conserved transmembrane proteins that are upregulated across species in response to injury and stress. Their biological functions are not understood, in part because there have been few in vivo studies of their function. We analyzed the expression and function of one of three Drosophila Ninjurins, NijA. We found that NijA protein is redistributed to the cell surface in larval immune tissues after septic injury and is upregulated by the Toll pathway. We generated a null mutant of NijA, which displayed no detectable phenotype. In ectopic expression studies, NijA induced cell death, as evidenced by cell loss and acridine orange staining. These dying cells did not display hallmarks of apoptotic cells including TUNEL staining and inhibition by p35, indicating that NijA induced nonapoptotic cell death. In cell culture, NijA also induced cell death, which appeared to be cell autonomous. These in vivo studies identify a new role for the Ninjurin family in inducing nonapoptotic cell death.

Live-cell visualization of gasdermin D-driven pyroptotic cell death.

Science.gov (United States)

Rathkey, Joseph K; Benson, Bryan L; Chirieleison, Steven M; Yang, Jie; Xiao, Tsan S; Dubyak, George R; Huang, Alex Y; Abbott, Derek W

2017-09-01

Pyroptosis is a form of cell death important in defenses against pathogens that can also result in a potent and sometimes pathological inflammatory response. During pyroptosis, GSDMD (gasdermin D), the pore-forming effector protein, is cleaved, forms oligomers, and inserts into the membranes of the cell, resulting in rapid cell death. However, the potent cell death induction caused by GSDMD has complicated our ability to understand the biology of this protein. Studies aimed at visualizing GSDMD have relied on expression of GSDMD fragments in epithelial cell lines that naturally lack GSDMD expression and also lack the proteases necessary to cleave GSDMD. In this work, we performed mutagenesis and molecular modeling to strategically place tags and fluorescent proteins within GSDMD that support native pyroptosis and facilitate live-cell imaging of pyroptotic cell death. Here, we demonstrate that these fusion proteins are cleaved by caspases-1 and -11 at Asp-276. Mutations that disrupted the predicted p30-p20 autoinhibitory interface resulted in GSDMD aggregation, supporting the oligomerizing activity of these mutations. Furthermore, we show that these novel GSDMD fusions execute inflammasome-dependent pyroptotic cell death in response to multiple stimuli and allow for visualization of the morphological changes associated with pyroptotic cell death in real time. This work therefore provides new tools that not only expand the molecular understanding of pyroptosis but also enable its direct visualization. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

How important is the duration of the brain death period for the outcome in kidney transplantation?

NARCIS (Netherlands)

Nijboer, Willemijn N.; Moers, Cyril; Leuvenink, Henri G. D.; Ploeg, Rutger J.

P>In kidney transplantation, graft survival using grafts from donation after brain death (DBD) donors is inferior to results after living donation. However, little is known about the effect of the duration of brain death (BDdur) on outcome after transplantation. This is a retrospective Organ

Endoplasmic reticulum involvement in yeast cell death

International Nuclear Information System (INIS)

Nicanor Austriaco, O.

2012-01-01

Yeast cells undergo programed cell death (PCD) with characteristic markers associated with apoptosis in mammalian cells including chromatin breakage, nuclear fragmentation, reactive oxygen species generation, and metacaspase activation. Though significant research has focused on mitochondrial involvement in this phenomenon, more recent work with both Saccharomyces cerevisiae and Schizosaccharomyces pombe has also implicated the endoplasmic reticulum (ER) in yeast PCD. This minireview provides an overview of ER stress-associated cell death (ER-SAD) in yeast. It begins with a description of ER structure and function in yeast before moving to a discussion of ER-SAD in both mammalian and yeast cells. Three examples of yeast cell death associated with the ER will be highlighted here including inositol starvation, lipid toxicity, and the inhibition of N-glycosylation. It closes by suggesting ways to further examine the involvement of the ER in yeast cell death.

Letter: Can Islamic Jurisprudence Justify Procurement of Transplantable Vital Organs in Brain Death?

Science.gov (United States)

Rady, Mohamed Y

2018-01-01

In their article, "An International Legal Review of the Relationship between Brain Death and Organ Transplantation," in The Journal of Clinical Ethics 29, no. 1, Aramesh, Arima, Gardiner, and Shah reported on diverse international legislative approaches for justifying procurement of transplantable vital organs in brain death. They stated, "In Islamic traditions in particular, the notion of unstable life is a way to justify organ donation from brain-dead patients that we believe has not been fully described previously in the literature." This commentary queries the extent to which this concept is valid in accordance with the primary source of Islamic law, that is, the Quran. Copyright 2018 The Journal of Clinical Ethics. All rights reserved.

Curcumin induces autophagic cell death in Spodoptera frugiperda cells.

Science.gov (United States)

Veeran, Sethuraman; Shu, Benshui; Cui, Gaofeng; Fu, Shengjiao; Zhong, Guohua

2017-06-01

The increasing interest in the role of autophagy (type II cell death) in the regulation of insect toxicology has propelled study of investigating autophagic cell death pathways. Turmeric, the rhizome of the herb Curcuma longa (Mañjaḷ in Tamil, India and Jiānghuáng in Chinese) have been traditionally used for the pest control either alone or combination with other botanical pesticides. However, the mechanisms by which Curcuma longa or curcumin exerts cytotoxicity in pests are not well understood. In this study, we investigated the potency of Curcuma longa (curcumin) as a natural pesticide employing Sf9 insect line. Autophagy induction effect of curcumin on Spodoptera frugiperda (Sf9) cells was investigated using various techniques including cell proliferation assay, morphology analysis with inverted phase contrast microscope and Transmission Electron Microscope (TEM) analysis. Autophagy was evaluated using the fluorescent dye monodansylcadaverine (MDC). Cell death measurement was examined using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) within the concentrations of 5-15μg/mL. Curcumin inhibited the growth of the Sf9 cells and induced autophagic cell death in a time and dose dependent manner. Staining the cells with MDC showed the presence of autophagic vacuoles while increased in a dose and time dependent manner. At the ultrastructural level transmission electron microscopy, cells revealed massive autophagy vacuole accumulation and absence of chromatin condensation. Protein expression levels of ATG8-I and ATG8-II, well-established markers of autophagy related protein were elevated in a time dependent manner after curcumin treatment. The present study proves that curcumin induces autophagic cell death in Sf9 insect cell line and this is the first report of cytotoxic effect of curcumin in insect cells and that will be utilized as natural pesticides in future. Copyright © 2017. Published by Elsevier Inc.

Methods for assessing autophagy and autophagic cell death.

Science.gov (United States)

Tasdemir, Ezgi; Galluzzi, Lorenzo; Maiuri, M Chiara; Criollo, Alfredo; Vitale, Ilio; Hangen, Emilie; Modjtahedi, Nazanine; Kroemer, Guido

2008-01-01

Autophagic (or type 2) cell death is characterized by the massive accumulation of autophagic vacuoles (autophagosomes) in the cytoplasm of cells that lack signs of apoptosis (type 1 cell death). Here we detail and critically assess a series of methods to promote and inhibit autophagy via pharmacological and genetic manipulations. We also review the techniques currently available to detect autophagy, including transmission electron microscopy, half-life assessments of long-lived proteins, detection of LC3 maturation/aggregation, fluorescence microscopy, and colocalization of mitochondrion- or endoplasmic reticulum-specific markers with lysosomal proteins. Massive autophagic vacuolization may cause cellular stress and represent a frustrated attempt of adaptation. In this case, cell death occurs with (or in spite of) autophagy. When cell death occurs through autophagy, on the contrary, the inhibition of the autophagic process should prevent cellular demise. Accordingly, we describe a strategy for discriminating cell death with autophagy from cell death through autophagy.

Can deaths in police cells be prevented? Experience from Norway and death rates in other countries.

Science.gov (United States)

Aasebø, Willy; Orskaug, Gunnar; Erikssen, Jan

2016-01-01

To describe the changes in death rates and causes of deaths in Norwegian police cells during the last 2 decades. To review reports on death rates in police cells that have been published in medical journals and elsewhere, and discuss the difficulties of comparing death rates between countries. Data on deaths in Norwegian police cells were collected retrospectively in 2002 and 2012 for two time periods: 1993-2001 (period 1) and 2003-2012 (period 2). Several databases were searched to find reports on deaths in police cells from as many countries as possible. The death rates in Norwegian police cells reduced significantly from 0.83 deaths per year per million inhabitants (DYM) in period 1 to 0.22 DYM in period 2 (p police cells reduced by about 75% over a period of approximately 10 years. This is probably mainly due to individuals with severe alcohol intoxication no longer being placed in police cells. However, there remain large methodology difficulties in comparing deaths rates between countries. Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Lysosomal cell death at a glance

DEFF Research Database (Denmark)

Aits, Sonja; Jaattela, Marja

2013-01-01

Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called "lysosomal cell death". This form...... of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream...... mechanisms that lead to lysosomal membrane permeabilization....

Understanding cell cycle and cell death regulation provides novel weapons against human diseases.

Science.gov (United States)

Wiman, K G; Zhivotovsky, B

2017-05-01

Cell division, cell differentiation and cell death are the three principal physiological processes that regulate tissue homoeostasis in multicellular organisms. The growth and survival of cells as well as the integrity of the genome are regulated by a complex network of pathways, in which cell cycle checkpoints, DNA repair and programmed cell death have critical roles. Disruption of genomic integrity and impaired regulation of cell death may both lead to uncontrolled cell growth. Compromised cell death can also favour genomic instability. It is becoming increasingly clear that dysregulation of cell cycle and cell death processes plays an important role in the development of major disorders such as cancer, cardiovascular disease, infection, inflammation and neurodegenerative diseases. Research achievements in these fields have led to the development of novel approaches for treatment of various conditions associated with abnormalities in the regulation of cell cycle progression or cell death. A better understanding of how cellular life-and-death processes are regulated is essential for this development. To highlight these important advances, the Third Nobel Conference entitled 'The Cell Cycle and Cell Death in Disease' was organized at Karolinska Institutet in 2016. In this review we will summarize current understanding of cell cycle progression and cell death and discuss some of the recent advances in therapeutic applications in pathological conditions such as cancer, neurological disorders and inflammation. © 2017 The Association for the Publication of the Journal of Internal Medicine.

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.

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

International Nuclear Information System (INIS)

Kikuchi, Kiyoshi; Kawahara, Ko-ichi; Biswas, Kamal Krishna; Ito, Takashi; Tancharoen, Salunya; Morimoto, Yoko; Matsuda, Fumiyo; Oyama, Yoko; Takenouchi, Kazunori; Miura, Naoki; Arimura, Noboru; Nawa, Yuko; Meng, Xiaojie; Shrestha, Binita; Arimura, Shinichiro

2009-01-01

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.

Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice

Directory of Open Access Journals (Sweden)

Cheng Chen

2014-06-01

Full Text Available Major depression disorder (MDD or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ-induced diabetic mice. These mice had blood glucose levels threefold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL-positive cells in the frontal cortex and hippocampus of the comorbid mice, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1 and dynamin-related protein 1 (Drp1, and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1, mitofusin 2 (Mfn2 and optical atrophy 1 (Opa1. Representative assessment of the proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes.

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

Directory of Open Access Journals (Sweden)

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.

Life and death of neurons in the aging brain

Science.gov (United States)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Occupational risk factors for brain tumors. A case-referent death-certificate analysis

Energy Technology Data Exchange (ETDEWEB)

Thomas, T.L.; Fontham, E.T.; Norman, S.A.; Stemhagen, A.; Hoover, R.N.

1986-04-01

Numerous studies have suggested that employment in the oil refining and chemical manufacturing industries may be associated with excess brain tumor risk. A case-referent study was undertaken to evaluate brain tumor risk by occupation and industry in three geographic areas (northern New Jersey, Philadelphia, and the Gulf Coast of Louisiana) with a heavy concentration of these industries. Seven hundred and eighteen white men dying from brain tumor at age 30 years or older were ascertained from death certificates for 1978-1981. The referents were men who died of other causes, excluding epilepsy and stroke. Usual occupation and industry were obtained from the death certificates, and the maximum likelihood estimates of the relative risk were calculated for specific industries and occupations. Small nonsignificant excess risks of brain tumors were seen among persons whose usual employment was in the petroleum refining, electrical equipment manufacturing, health services, and educational services industries. Compared with other white-collar professionals, health diagnosticians, teachers, and artists/designers had a significantly elevated brain tumor risk. Among blue-collar workers, the only group with a significantly elevated brain tumor risk was precision metal workers, who are exposed to metal dusts and fumes and substances used as coolants, lubricants, and degreasers.

BID links ferroptosis to mitochondrial cell death pathways

Directory of Open Access Journals (Sweden)

Sandra Neitemeier

2017-08-01

Full Text Available Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc- system or inhibition of glutathione peroxidase 4 (Gpx4 to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation.In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc- inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death. Keywords: Ferroptosis, BID, Mitochondria, CRISPR, Oxytosis, Neuronal death

Nitrosothiol signaling and protein nitrosation in cell death.

Science.gov (United States)

Iyer, Anand Krishnan V; Rojanasakul, Yon; Azad, Neelam

2014-11-15

Nitric oxide, a reactive free radical, is an important signaling molecule that can lead to a plethora of cellular effects affecting homeostasis. A well-established mechanism by which NO manifests its effect on cellular functions is the post-translational chemical modification of cysteine thiols in substrate proteins by a process known as S-nitrosation. Studies that investigate regulation of cellular functions through NO have increasingly established S-nitrosation as the primary modulatory mechanism in their respective systems. There has been a substantial increase in the number of reports citing various candidate proteins undergoing S-nitrosation, which affects cell-death and -survival pathways in a number of tissues including heart, lung, brain and blood. With an exponentially growing list of proteins being identified as substrates for S-nitrosation, it is important to assimilate this information in different cell/tissue systems in order to gain an overall view of protein regulation of both individual proteins and a class of protein substrates. This will allow for broad mapping of proteins as a function of S-nitrosation, and help delineate their global effects on pathophysiological responses including cell death and survival. This information will not only provide a much better understanding of overall functional relevance of NO in the context of various disease states, it will also facilitate the generation of novel therapeutics to combat specific diseases that are driven by NO-mediated S-nitrosation. Copyright © 2014 Elsevier Inc. All rights reserved.

Mir-34a mimics are potential therapeutic agents for p53-mutated and chemo-resistant brain tumour cells.

Directory of Open Access Journals (Sweden)

Yuen Ngan Fan

Full Text Available Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma and adult (glioblastoma brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1. Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells.

The control and execution of programmed cell death

International Nuclear Information System (INIS)

Begum, R.; Pathak, N.; Hasnain, S.E.; Sah, N.K.; Athar, M.

1999-01-01

Apoptosis or programmed cell death is a highly conserved genetically controlled response of metazoan cells to commit suicide. Non apoptotic programmed cell death seems to operate in single celled eukaryotes implying that evolution of PCD has preceded the evolution of multicellularity. PCD plays a crucial role in the regulation of cellular and tissue homeostasis and any aberrations in apoptosis leads to several diseases including cancer, neurodegenerative disorders and AIDS. The mechanisms by which apoptosis is controlled are varied. In some cells, members of bcl-2 family or p53 are crucial for regulating the apoptosis programme, whereas in other cells Fas ligand is more important. bcl-2 family members have a prime role in the regulation of cell death at all stages including development, whereas cell death during development is independent of p53. bcl-2 family members being localized on the outer mitochondrial membrane, control the mitochondrial homeostasis and cytochrome c redistribution and thereby regulate the cell death process. p53 promotes DNA damage mediated cell death after growth arrest and failed DNA repair. Caspases play a key role in the execution of cell death by mediating highly specific cleavages of crucial cellular proteins collectively manifesting the apoptotic phenotype. Protein inhibitors like crm A, p35 and IAPs could prevent/control apoptosis induced by a broad array of cell death stimuli by several mechanisms specially interfering in caspase activation or caspase activity. Among endonucleases, caspase activated DNase (CAD) plays a crucial role in DNA fragmentation, a biochemical hallmark of apoptosis. As regulation of cell death seems to be as complex as regulation of cell proliferation, multiple kinase mediated regulatory mechanisms might control the apoptotic process. Thus, in spite of intensive research over the past few years, the field of apoptosis still remains fertile to unravel among others, the molecular mechanisms of cytochrome c

The control and execution of programmed cell death

Energy Technology Data Exchange (ETDEWEB)

Begum, R.; Pathak, N.; Hasnain, S.E.; Sah, N.K. [National Inst. of Immunology, New Delhi (India). Eukaryotic Gene Expression Lab.; Taneja, T.K.; Mohan, M. [National Inst. of Immunology, New Delhi (India). Eukaryotic Gene Expression Lab.]|[Dept. of Medical Elementology and Toxicology, New Delhi (India); Athar, M. [Dept. of Medical Elementology and Toxicology, New Delhi (India)

1999-07-01

Apoptosis or programmed cell death is a highly conserved genetically controlled response of metazoan cells to commit suicide. Non apoptotic programmed cell death seems to operate in single celled eukaryotes implying that evolution of PCD has preceded the evolution of multicellularity. PCD plays a crucial role in the regulation of cellular and tissue homeostasis and any aberrations in apoptosis leads to several diseases including cancer, neurodegenerative disorders and AIDS. The mechanisms by which apoptosis is controlled are varied. In some cells, members of bcl-2 family or p53 are crucial for regulating the apoptosis programme, whereas in other cells Fas ligand is more important. bcl-2 family members have a prime role in the regulation of cell death at all stages including development, whereas cell death during development is independent of p53. bcl-2 family members being localized on the outer mitochondrial membrane, control the mitochondrial homeostasis and cytochrome c redistribution and thereby regulate the cell death process. p53 promotes DNA damage mediated cell death after growth arrest and failed DNA repair. Caspases play a key role in the execution of cell death by mediating highly specific cleavages of crucial cellular proteins collectivley manifesting the apoptotic phenotype. Protein inhibitors like crm A, p35 and IAPs could prevent/control apoptosis induced by a broad array of cell death stimuli by several mechanisms specially interfering in caspase activation or caspase activity. Among endonucleases, caspase activated DNase (CAD) plays a crucial role in DNA fragmentation, a biochemical hallmark of apoptosis. As regulation of cell death seems to be as complex as regulation of cell proliferation, multiple kinase mediated regulatory mechanisms might control the apoptotic process. Thus, in spite of intensive research over the past few years, the field of apoptosis still remains fertile to unravel among others, the molecular mechanisms of cytochrome c

Pathways to ischemic neuronal cell death: are sex differences relevant?

Directory of Open Access Journals (Sweden)

McCullough Louise D

2008-06-01

Full Text Available Abstract We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. Now, a new concept is emerging: the mechanisms and outcome of cerebral ischemic injury are influenced strongly by biological sex as well as the availability of sex steroids to the brain. The principal mammalian estrogen (17 β estradiol or E2 is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However, it is becoming increasingly clear that although hormones are a major contributor to sex-specific outcomes, they do not fully account for sex-specific responses to cerebral ischemia. The purpose of this review is to highlight recent studies in cell culture and animal models that suggest that genetic sex determines experimental stroke outcome and that divergent cell death pathways are activated after an ischemic insult. These sex differences need to be identified if we are to develop efficacious neuroprotective agents for use in stroke patients.

Mitochondrial fission proteins regulate programmed cell death in yeast

OpenAIRE

Fannjiang, Yihru; Cheng, Wen-Chih; Lee, Sarah J.; Qi, Bing; Pevsner, Jonathan; McCaffery, J. Michael; Hill, R. Blake; Basañez, Gorka; Hardwick, J. Marie

2004-01-01

The possibility that single-cell organisms undergo programmed cell death has been questioned in part because they lack several key components of the mammalian cell death machinery. However, yeast encode a homolog of human Drp1, a mitochondrial fission protein that was shown previously to promote mammalian cell death and the excessive mitochondrial fragmentation characteristic of apoptotic mammalian cells. In support of a primordial origin of programmed cell death involving mitochondria, we fo...

Retinal Cell Death Caused by Sodium Iodate Involves Multiple Caspase-Dependent and Caspase-Independent Cell-Death Pathways

Directory of Open Access Journals (Sweden)

Jasmin Balmer

2015-07-01

Full Text Available Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO3 both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO3 (35 mg/kg. Morphological changes in the retina post NaIO3 injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE cells, primary retinal cells, and the cone photoreceptor (PRC cell line 661W were assessed in vitro after NaIO3 treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1 was administered to the NaIO3-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO3-treated animals. In vitro, NaIO3 induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO3-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO3.

Cell death induced by hydroxyapatite on L929 fibroblast cells.

Science.gov (United States)

Inayat-Hussain, S H; Rajab, N F; Roslie, H; Hussin, A A; Ali, A M; Annuar, B O

2004-05-01

Biomaterials intended for end-use application as bone-graft substitutes have to undergo safety evaluation. In this study, we investigated the in vitro cytotoxic effects especially to determine the mode of death of two hydroxyapatite compounds (HA2, HA3) which were synthesized locally. The methods used for cytotoxicity was the standard MTT assay whereas AO/PI staining was performed to determine the mode of cell death in HA treated L929 fibroblasts. Our results demonstrated that both HA2 and HA3 were not significantly cytotoxic as more than 75% cells after 72 hours treatment were viable. Furthermore, we found that the major mode of cell death in HA treated cells was apoptosis. In conclusion, our results demonstrated that these hydroxyapatite compounds are not cytotoxic where the mode of death was primarily via apoptosis.

Significance of apoptotic cell death after γ-irradiation

International Nuclear Information System (INIS)

Wu, H.G.; Kim, I.H.; Ha, S.W.; Park, C.I.

2003-01-01

Full text: The objectives of this study are to investigate the significance of apoptotic death compared to total cell death after γ-ray irradiation in human Hand N cancer cell lines and to find out correlation between apoptosis and radiation sensitivity. Materials and Method: Head and neck cancer cell lines (PCI-1, PCI-13, and SNU-1066), leukemia cell line (CCRF-CEM), and fibroblast cell line (LM217) as a normal control were used for this study. Cells were irradiated using Cs-137 animal experiment irradiator. Total cell death was measured by clonogenic assay. Annexin-V staining was used to detect the fraction of apoptotic death. The resulting data was analyzed with two parameters, apoptotic index (AI) and apoptotic fraction(AF). AI is ratio of apoptotic cells to total cells, and AF is ration of apoptotic cell death to mutant frequencytion ex(Number of apoptotic cells) / (Number of total cells counted) AF = {(AI) / (1-survival fraction)} x 100 (%) Results. Surviving fraction at 2 Gy (SF2) were 0.741, 0.544, 0.313, 0.302, and 0.100 for PCI-1, PCI-13, SNU-1066, CCRF-CEM, and LM217 cell lines, respectively. Apoptosis was detected in all cell lines. Apoptotic index reached peak value at 72 hours after irradiation in head and neck cancer cell lines, and that was at 24 hours in CCRF-CEM and LM217. Total cell death increased exponentially with increasing radiation dose from 0 Gy to 8 Gy, but the change was minimal in apoptotic index (Fig. 1.). Apoptotic fractions at 2 Gy were 46%, 48%, 46%, 24%, and 19% and at 6 Gy were 20%, 33%, 35%, 17%, and 20% for PCI-1, PCI-13, SNU-1066, CCRF-CEM, and LM217, respectively. The radioresistant cell lines showed more higher apoptotic fraction at 2 Gy (Table 1.), but there was not such correlation at 6 Gy. Conclusion: All cell lines used in this study showed apoptosis after irradiation, but time course of apoptosis was different from that of leukemia cell line and normal fibroblast cell line. Reproductive cell death was more important

The slow cell death response when screening chemotherapeutic agents.

Science.gov (United States)

Blois, Joseph; Smith, Adam; Josephson, Lee

2011-09-01

To examine the correlation between cell death and a common surrogate of death used in screening assays, we compared cell death responses to those obtained with the sulforhodamine B (SRB) cell protein-based "cytotoxicity" assay. With the SRB assay, the Hill equation was used to obtain an IC50 and final cell mass, or cell mass present at infinite agent concentrations, with eight adherent cell lines and four agents (32 agent/cell combinations). Cells were treated with high agent concentrations (well above the SRB IC50) and the death response determined as the time-dependent decrease in cells failing to bind both annexin V and vital fluorochromes by flow cytometry. Death kinetics were categorized as fast (5/32) (similar to the reference nonadherent Jurkat line), slow (17/32), or none (10/32), despite positive responses in the SRB assay in all cases. With slow cell death, a single exposure to a chemotherapeutic agent caused a slow, progressive increase in dead (necrotic) and dying (apoptotic) cells for at least 72 h. Cell death (defined by annexin and/or fluorochrome binding) did not correlate with the standard SRB "cytotoxicity" assay. With the slow cell death response, a single exposure to an agent caused a slow conversion from vital to apoptotic and necrotic cells over at least 72 h (the longest time point examined). Here, increasing the time of exposure to agent concentrations modestly above the SRB IC50 provides a method of maximizing cell kill. If tumors respond similarly, sustained low doses of chemotherapeutic agents, rather than a log-kill, maximum tolerated dose strategy may be an optimal strategy of maximizing tumor cell death.

Ionizing radiation-induced cell death

International Nuclear Information System (INIS)

Szumiel, I.

1994-01-01

Selected aspects of radiation-induced cell death, connected with signal transduction pathways are reviewed. Cell death is defined as insufficiency of the cellular signal transducing system to maintain the cell's physiological functions. The insufficiency may be due to impaired signal reception and/or transduction, lack or erroneous transcription activation, and eventual cellular ''misexpression'' of the signal. The molecular basis of this insufficiency would be damage to genomic (but also other cellular) structures and closing of specific signalling pathways or opening of others (like those leading to apoptosis). I describe experimental data that suggest an important role of RAS/NFI and p53/p105 Rb proteins in cell cycle control-coupled responses to DNA damage. (Author)

Ras and Rheb Signaling in Survival and Cell Death

International Nuclear Information System (INIS)

Ehrkamp, Anja; Herrmann, Christian; Stoll, Raphael; Heumann, Rolf

2013-01-01

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively

Ras and Rheb Signaling in Survival and Cell Death

Energy Technology Data Exchange (ETDEWEB)

Ehrkamp, Anja [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany); Herrmann, Christian [Department of Physical Chemistry1, Protein Interaction, Ruhr University of Bochum, 44780 Bochum (Germany); Stoll, Raphael [Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum (Germany); Heumann, Rolf, E-mail: rolf.heumann@rub.de [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany)

2013-05-28

One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

Arguments against promoting organ transplants from brain-dead donors, and views of contemporary Japanese on life and death.

Science.gov (United States)

Asai, Atsushi; Kadooka, Yasuhiro; Aizawa, Kuniko

2012-05-01

As of 2009, the number of donors in Japan is the lowest among developed countries. On July 13, 2009, Japan's Organ Transplant Law was revised for the first time in 12 years. The revised and old laws differ greatly on four primary points: the definition of death, age requirements for donors, requirements for brain-death determination and organ extraction, and the appropriateness of priority transplants for relatives. In the four months of deliberations in the National Diet before the new law was established, various arguments regarding brain death and organ transplantation were offered. An amazing variety of opinions continue to be offered, even after more than 40 years have elapsed since the first heart organ transplant in Japan. Some are of the opinion that with the passage of the revised law, Japan will finally become capable of performing transplants according to global standards. Contrarily, there are assertions that organ transplants from brain-dead donors are unacceptable because they result in organs being taken from living human beings. Considering the current conditions, we will organize and introduce the arguments for and against organ transplants from brain-dead donors in contemporary Japan. Subsequently, we will discuss the primary arguments against organ transplants from brain-dead donors from the perspective of contemporary Japanese views on life and death. After introducing the recent view that brain death should not be regarded as equivalent to the death of a human being, we would like to probe the deeply-rooted views on life and death upon which it is based. © 2010 Blackwell Publishing Ltd.

A Case Report of Successful Kidney Donation After Brain Death Following Nicotine Intoxication.

Science.gov (United States)

Räsänen, M; Helanterä, I; Kalliomäki, J; Savikko, J; Parry, M; Lempinen, M

Nicotine intoxication is a rare cause of death and can lead to brain death after respiratory arrest and hypoxic-ischemic encephalopathy. To our knowledge, no previous reports regarding organ donation after nicotine intoxication have been described. We present a successful case of kidney donation after brain death caused by subcutaneous nicotine overdose from liquid nicotine from an e-cigarette cartridge in an attempted suicide. Both kidneys were transplanted successfully with immediate graft function, and both recipients were discharged at postoperative day 9 with normal plasma creatinine levels. Graft function has remained excellent in follow-up. This case suggests that kidneys from a donor with fatal nicotine intoxication may be successfully used for kidney transplantation in the absence of other contraindications for donation. Copyright © 2016 Elsevier Inc. All rights reserved.

Redefining Death

Institute of Scientific and Technical Information of China (English)

2009-01-01

The results of 20 years of research on brain death will be released to the public, the Chinese Ministry of Health reported in early April. A special ministry team has drafted the criteria for brain death in Criteria for the Diagnosis of Brain Death in Adults (Revised Edition) and Technical Specifications for the Diagnosis

Hypothalamic-Pituitary Function in Brain Death: A Review.

Science.gov (United States)

Nair-Collins, Michael; Northrup, Jesse; Olcese, James

2016-01-01

The Uniform Determination of Death Act (UDDA) states that an individual is dead when "all functions of the entire brain" have ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some modest generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these findings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggesting that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord. © The Author(s) 2014.

Cell death in Pseudomonas aeruginosa biofilm development

DEFF Research Database (Denmark)

Webb, J.S.; Thompson, L.S.; James, S.

2003-01-01

Bacteria growing in biofilms often develop multicellular, three-dimensional structures known as microcolonies. Complex differentiation within biofilms of Pseudomonas aeruginosa occurs, leading to the creation of voids inside microcolonies and to the dispersal of cells from within these voids....... However, key developmental processes regulating these events are poorly understood. A normal component of multicellular development is cell death. Here we report that a repeatable pattern of cell death and lysis occurs in biofilms of P. aeruginosa during the normal course of development. Cell death...... occurred with temporal and spatial organization within biofilms, inside microcolonies, when the biofilms were allowed to develop in continuous-culture flow cells. A subpopulation of viable cells was always observed in these regions. During the onset of biofilm killing and during biofilm development...

The anti-cell death FNK protein protects cells from death induced by freezing and thawing

International Nuclear Information System (INIS)

Sudo, Kentaro; Asoh, Sadamitsu; Ohsawa, Ikuroh; Ozaki, Daiya; Yamagata, Kumi; Ito, Hiromoto; Ohta, Shigeo

2005-01-01

The FNK protein, constructed from anti-apoptotic Bcl-x L with enhanced activity, was fused with the protein transduction domain (PTD) of the HIV/Tat protein to mediate the delivery of FNK into cells. The fusion protein PTD-FNK was introduced into chondrocytes in isolated articular cartilage-bone sections, cultured neurons, and isolated bone marrow mononuclear cells to evaluate its ability to prevent cell death induced by freezing and thawing. PTD-FNK protected the cells from freeze-thaw damage in a concentration-dependent manner. Addition of PTD-FNK with conventional cryoprotectants (dimethyl sulfoxide and hydroxyethyl starch) increased surviving cell numbers around 2-fold compared with controls treated only with the cryoprotectants. Notably, PTD-FNK allowed CD34 + cells among bone marrow mononuclear cells to survive more efficiently (12-fold more than the control cells) from two successive freeze-thaw cycles. Thus, PTD-FNK prevented cell death induced by freezing and thawing, suggesting that it provides for the successful cryopreservation of biological materials

Iron and cell death in Parkinson's disease: a nuclear microscopic study into iron-rich granules in the parkinsonian substantia nigra of primate models

Energy Technology Data Exchange (ETDEWEB)

Thong, P.S.P.; Watt, F. E-mail: phywattf@nus.edu.sg; Ponraj, D.; Leong, S.K.; He, Y.; Lee, T.K.Y

1999-09-02

Parkinson's disease is a degenerative brain disease characterised by a loss of cells in the substantia nigra (SN) region of the brain and accompanying biochemical changes such as inhibition of mitochondrial function, increased iron concentrations and decreased glutathione levels in the parkinsonian SN. Though the aetiology of the disease is still unknown, the observed biochemical changes point to the involvement of oxidative stress. In particular, iron is suspected to play a role by promoting free radical production, leading to oxidative stress and cell death. The increase in iron in the parkinsonian SN has been confirmed by several research groups, both in human post-mortem brains and in brain tissue from parkinsonian animal models. However, the question remains as to whether the observed increase in iron is a cause or a consequence of the SN cell death process. Our previous study using unilaterally 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-lesioned monkeys in a time sequence experiment has shown that the increase in bulk iron concentrations follow rather than precede dopaminergic cell death. However, changes in the localised iron concentrations, which may play a more direct role in SN cell death, may not be reflected at the bulk level. Indeed, we have observed iron-rich granules in parkinsonian SNs. From this time sequence study into the iron content of iron-rich granules in the SNs of an untreated control and unilaterally MPTP-lesioned parkinsonian models, we present the following observations: (1) Iron-rich granules are found in both control and parkinsonian SNs and are variable in size and iron content in any one model. (2) These iron-rich granules may be associated with neuromelanin granules found in the SN and are known to accumulate transition metal ions such as iron. (3) The early onset of bulk SN cell loss (35%) was accompanied by a significant elevation of iron in granules found in the MPTP-injected SN compared to the contra-lateral SN

Mechanisms of Betulinic acid‐induced cell death

NARCIS (Netherlands)

Potze, L.

2015-01-01

The scope of this thesis was to investigate the mechanisms by which BetA induces cell death in cancer cells in more detail. At the start of the studies described in this thesis several questions urgently needed an answer. Although BetA induces cell death via apoptosis, when blocking this form of

Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene.

Directory of Open Access Journals (Sweden)

Rebecca L Skalsky

Full Text Available Glioblastoma is a highly aggressive malignant tumor involving glial cells in the human brain. We used high-throughput sequencing to comprehensively profile the small RNAs expressed in glioblastoma and non-tumor brain tissues. MicroRNAs (miRNAs made up the large majority of small RNAs, and we identified over 400 different cellular pre-miRNAs. No known viral miRNAs were detected in any of the samples analyzed. Cluster analysis revealed several miRNAs that were significantly down-regulated in glioblastomas, including miR-128, miR-124, miR-7, miR-139, miR-95, and miR-873. Post-transcriptional editing was observed for several miRNAs, including the miR-376 family, miR-411, miR-381, and miR-379. Using the deep sequencing information, we designed a lentiviral vector expressing a cell suicide gene, the herpes simplex virus thymidine kinase (HSV-TK gene, under the regulation of a miRNA, miR-128, that was found to be enriched in non-tumor brain tissue yet down-regulated in glioblastomas, Glioblastoma cells transduced with this vector were selectively killed when cultured in the presence of ganciclovir. Using an in vitro model to recapitulate expression of brain-enriched miRNAs, we demonstrated that neuronally differentiated SH-SY5Y cells transduced with the miRNA-regulated HSV-TK vector are protected from killing by expression of endogenous miR-128. Together, these results provide an in-depth analysis of miRNA dysregulation in glioblastoma and demonstrate the potential utility of these data in the design of miRNA-regulated therapies for the treatment of brain cancers.

BID links ferroptosis to mitochondrial cell death pathways.

Science.gov (United States)

Neitemeier, Sandra; Jelinek, Anja; Laino, Vincenzo; Hoffmann, Lena; Eisenbach, Ina; Eying, Roman; Ganjam, Goutham K; Dolga, Amalia M; Oppermann, Sina; Culmsee, Carsten

2017-08-01

Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the X c - system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation. In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by X c - inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

Science.gov (United States)

Hsu, Li-Jin; Hong, Qunying; Chen, Shur-Tzu; Kuo, Hsiang-Lin; Schultz, Lori; Heath, John; Lin, Sing-Ru; Lee, Ming-Hui; Li, Dong-Zhang; Li, Zih-Ling; Cheng, Hui-Ching; Armand, Gerard; Chang, Nan-Shan

2017-03-21

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

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.

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

International Nuclear Information System (INIS)

Sun, Hengwen; Yang, Shana; Li, Jianhua; Zhang, Yajie; Gao, Dongsheng; Zhao, Shenting

2016-01-01

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.

Neuroprotective effect of α-mangostin and curcumin against iodoacetate-induced cell death.

Science.gov (United States)

Reyes-Fermín, Laura María; González-Reyes, Susana; Tarco-Álvarez, Nadia Gabriela; Hernández-Nava, Marisol; Orozco-Ibarra, Marisol; Pedraza-Chaverri, José

2012-09-01

Curcumin is a phenolic yellow curry pigment with anti-inflammatory and antioxidant activities and α-mangostin is a xanthone isolated from mangosteen fruit with antioxidant properties. Iodoacetate (IAA) is an inhibitor of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase that induces a model of metabolic inhibition in neurons where reactive oxygen species (ROS) production is a significant mechanism. Furthermore, it has been shown that the induction of heme oxygenase-1 (HO-1) protects against IAA-induced neuronal death. To study the effects of α-mangostin and curcumin against the IAA-induced cell death and on HO-1 expression in primary cultures of cerebellar granule neurons (CGNs). CGNs were treated with curcumin or α-mangostin before the addition of IAA. Cell viability and ROS production were measured 24 and 4 hours after IAA addition, respectively. HO-1 expression was measured by western blot. Both α-mangostin and curcumin pretreatment ameliorated the neuronal death induced by IAA in a concentration-dependent way, which was associated with an amelioration of IAA-induced ROS formation. In addition, it was found that α-mangostin and curcumin induced HO-1 expression. Treatment with α-mangostin and curcumin provided a neuroprotective effect against IAA in primary cultures of CGNs, an effect associated with an amelioration of the IAA-induced ROS production. HO-1 induced by these antioxidants may also be involved in the neuroprotective effect. Future work will be required to determine whether α-mangostin may cross the blood-brain barrier and achieve enough bioavailability to elicit a protective response in the brain being an effective nutraceutical compound for preventive therapy of neurodegenerative diseases.

The regulation of apoptotic cell death

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Amarante-Mendes G.P.

1999-01-01

Full Text Available Apoptosis is a fundamental biological phenomenon in which the death of a cell is genetically and biochemically regulated. Different molecules are involved in the regulation of the apoptotic process. Death receptors, coupled to distinct members of the caspases as well as other adapter molecules, are involved in the initiation of the stress signals (The Indictment. Members of the Bcl-2 family control at the mitochondrial level the decision between life and death (The Judgement. The effector caspases are responsible for all morphological and biochemical changes related to apoptosis including the "eat-me" signals perceived by phagocytes and neighboring cells (The Execution. Finally, apoptosis would have little biological significance without the recognition and removal of the dying cells (The Burial.

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

International Nuclear Information System (INIS)

Marrero, María Teresa; Estévez, Sara; Negrín, Gledy; Quintana, José; López, Mariana; Pérez, Francisco J.; Triana, Jorge; León, Francisco; Estévez, Francisco

2012-01-01

Highlights: ► Ayanin diacetate as apoptotic inducer in leukemia cells. ► Cell death was prevented by caspase inhibitors and by the overexpression of Bcl-x L . ► The intrinsic and the extrinsic pathways are involved in the mechanism of action. ► 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 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 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.

Considering ethical dilemmas related to brain death in newborns

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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.

Taxifolin synergizes Andrographolide-induced cell death by attenuation of autophagy and augmentation of caspase dependent and independent cell death in HeLa cells.

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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.

Taxifolin synergizes Andrographolide-induced cell death by attenuation of autophagy and augmentation of caspase dependent and independent cell death in HeLa cells

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Alzaharna, Mazen; Alqouqa, Iyad; Cheung, Hon-Yeung

2017-01-01

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. PMID:28182713

Proliferating cell nuclear antigen binds DNA polymerase-β and mediates 1-methyl-4-phenylpyridinium-induced neuronal death.

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Zhentao Zhang

Full Text Available The mechanisms leading to dopaminergic neuronal loss in the substantia nigra of patients with Parkinson disease (PD remain poorly understood. We recently reported that aberrant DNA replication mediated by DNA polymerase-β (DNA pol-β plays a causal role in the death of postmitotic neurons in an in vitro model of PD. In the present study, we show that both proliferating cell nuclear antigen (PCNA and DNA pol-β are required for MPP(+-induced neuronal death. PCNA binds to the catalytic domain of DNA pol-β in MPP(+-treated neurons and in post-mortem brain tissues of PD patients. The PCNA-DNA pol-β complex is loaded into DNA replication forks and mediates DNA replication in postmitotic neurons. The aberrant DNA replication mediated by the PCNA-DNA pol-β complex induces p53-dependent neuronal cell death. Our results indicate that the interaction of PCNA and DNA pol-β contributes to neuronal death in PD.

Sorafenib-induced defective autophagy promotes cell death by necroptosis.

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Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Björklund, Ann-Charlotte; Zhivotovsky, Boris; Grandér, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

2015-11-10

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencing ULK1 and Beclin1 rescues DU145 cells from cell death indicating that, in this setting, autophagy promotes cell death. Re-expression of Atg5 restores the lipidation of LC3 and rescues DU145 and MEF atg5-/- cells from sorafenib-induced cell death. Despite the lack of Atg5 expression and LC3 lipidation, DU145 cells form autophagosomes as demonstrated by transmission and immuno-electron microscopy, and the formation of LC3 positive foci. However, the lack of cellular content in the autophagosomes, the accumulation of long-lived proteins, the presence of GFP-RFP-LC3 positive foci and the accumulated p62 protein levels indicate that these autophagosomes may not be fully functional. DU145 cells treated with sorafenib undergo a caspase-independent cell death that is inhibited by the RIPK1 inhibitor, necrostatin-1. Furthermore, treatment with sorafenib induces the interaction of RIPK1 with p62, as demonstrated by immunoprecipitation and a proximity ligation assay. Silencing of p62 decreases the RIPK1 protein levels and renders necrostatin-1 ineffective in blocking sorafenib-induced cell death. In summary, the formation of Atg5-deficient autophagosomes in response to sorafenib promotes the interaction of p62 with RIPK leading to cell death by necroptosis.

Plant programmed cell death, ethylene and flower senescence

NARCIS (Netherlands)

Woltering, E.J.; Jong, de A.; Hoeberichts, F.A.; Iakimova, E.T.; Kapchina, V.

2005-01-01

Programmed cell death (PCD) applies to cell death that is part of the normal life of multicellular organisms. PCD is found throughout the animal and plant kingdoms; it is an active process in which a cell suicide pathway is activated resulting in controlled disassembly of the cell. Most cases of PCD

Multiple Modes of Cell Death Discovered in a Prokaryotic (Cyanobacterial) Endosymbiont

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Zheng, Weiwen; Rasmussen, Ulla; Zheng, Siping; Bao, Xiaodong; Chen, Bin; Gao, Yuan; Guan, Xiong; Larsson, John; Bergman, Birgitta

2013-01-01

Programmed cell death (PCD) is a genetically-based cell death mechanism with vital roles in eukaryotes. Although there is limited consensus on similar death mode programs in prokaryotes, emerging evidence suggest that PCD events are operative. Here we present cell death events in a cyanobacterium living endophytically in the fern Azolla microphylla, suggestive of PCD. This symbiosis is characterized by some unique traits such as a synchronized development, a vertical transfer of the cyanobacterium between plant generations, and a highly eroding cyanobacterial genome. A combination of methods was used to identify cell death modes in the cyanobacterium. Light- and electron microscopy analyses showed that the proportion of cells undergoing cell death peaked at 53.6% (average 20%) of the total cell population, depending on the cell type and host developmental stage. Biochemical markers used for early and late programmed cell death events related to apoptosis (Annexin V-EGFP and TUNEL staining assays), together with visualization of cytoskeleton alterations (FITC-phalloidin staining), showed that all cyanobacterial cell categories were affected by cell death. Transmission electron microscopy revealed four modes of cell death: apoptotic-like, autophagic-like, necrotic-like and autolytic-like. Abiotic stresses further enhanced cell death in a dose and time dependent manner. The data also suggest that dynamic changes in the peptidoglycan cell wall layer and in the cytoskeleton distribution patterns may act as markers for the various cell death modes. The presence of a metacaspase homolog (domain p20) further suggests that the death modes are genetically programmed. It is therefore concluded that multiple, likely genetically programmed, cell death modes exist in cyanobacteria, a finding that may be connected with the evolution of cell death in the plant kingdom. PMID:23822984

Multiple Modes of Cell Death Discovered in a Prokaryotic (Cyanobacterial Endosymbiont.

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Weiwen Zheng

Full Text Available Programmed cell death (PCD is a genetically-based cell death mechanism with vital roles in eukaryotes. Although there is limited consensus on similar death mode programs in prokaryotes, emerging evidence suggest that PCD events are operative. Here we present cell death events in a cyanobacterium living endophytically in the fern Azolla microphylla, suggestive of PCD. This symbiosis is characterized by some unique traits such as a synchronized development, a vertical transfer of the cyanobacterium between plant generations, and a highly eroding cyanobacterial genome. A combination of methods was used to identify cell death modes in the cyanobacterium. Light- and electron microscopy analyses showed that the proportion of cells undergoing cell death peaked at 53.6% (average 20% of the total cell population, depending on the cell type and host developmental stage. Biochemical markers used for early and late programmed cell death events related to apoptosis (Annexin V-EGFP and TUNEL staining assays, together with visualization of cytoskeleton alterations (FITC-phalloidin staining, showed that all cyanobacterial cell categories were affected by cell death. Transmission electron microscopy revealed four modes of cell death: apoptotic-like, autophagic-like, necrotic-like and autolytic-like. Abiotic stresses further enhanced cell death in a dose and time dependent manner. The data also suggest that dynamic changes in the peptidoglycan cell wall layer and in the cytoskeleton distribution patterns may act as markers for the various cell death modes. The presence of a metacaspase homolog (domain p20 further suggests that the death modes are genetically programmed. It is therefore concluded that multiple, likely genetically programmed, cell death modes exist in cyanobacteria, a finding that may be connected with the evolution of cell death in the plant kingdom.

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.

Early cell death detection with digital holographic microscopy.

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Nicolas Pavillon

Full Text Available BACKGROUND: Digital holography provides a non-invasive measurement of the quantitative phase shifts induced by cells in culture, which can be related to cell volume changes. It has been shown previously that regulation of cell volume, in particular as it relates to ionic homeostasis, is crucially involved in the activation/inactivation of the cell death processes. We thus present here an application of digital holographic microscopy (DHM dedicated to early and label-free detection of cell death. METHODS AND FINDINGS: We provide quantitative measurements of phase signal obtained on mouse cortical neurons, and caused by early neuronal cell volume regulation triggered by excitotoxic concentrations of L-glutamate. We show that the efficiency of this early regulation of cell volume detected by DHM, is correlated with the occurrence of subsequent neuronal death assessed with the widely accepted trypan blue method for detection of cell viability. CONCLUSIONS: The determination of the phase signal by DHM provides a simple and rapid optical method for the early detection of cell death.

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

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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.

A study on knowledge and attitude toward brain death and organ retrieval among health care professionals in Korea.

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Jeon, K O; Kim, B N; Kim, H S; Byeon, N-I; Hong, J J; Bae, S H; Son, S Y

2012-05-01

The practice of retrieving vital organs from brain-dead donors is legally and medically accepted in Korea, but health care professionals' beliefs and opinions regarding these matters have not been sufficiently explored. The purpose of this study was to evaluate the knowledge and attitudes of health care professionals to the concepts of brain death and organ retrieval. Data were collected using a 41-item questionnaire during a week in June 2011. Sixty-one doctors and 109 nurses from five hospitals with more than 2000 beds in Seoul, Korea, participated in the survey. The data was analyzed using SPSS version 17.0 (SPSS Inc. Chicago, Illinois, USA). There were statistically significant differences in the scores on knowledge according to marital status (P = .001) education level (P = .019), whether the participants were informed about organ donation from a brain-dead donor (P = .002), and the participant's experience managing potential brain-dead patients (P = .037). There were statistically significant differences in the scores on the attitude according to gender (P based organ procurement organization (P = .001). Significantly, attitude's positively correlated with knowledge about brain-dead organ donation (P < .001). Compared with previous studies, the knowledge and attitudes of health care professionals' regarding brain death and organ retrieval were not improved. There are passive attitudes to brain death and organ retrieval. More research must be performed to promote knowledge and understanding toward brain death and organ retrieval among health care professionals. Copyright © 2012 Elsevier Inc. All rights reserved.

Signal transduction events in aluminum-induced cell death in tomato suspension cells

NARCIS (Netherlands)

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

2007-01-01

In this study, some of the signal transduction events involved in AlCl3-induced cell death in tomato (Lycopersicon esculentum Mill.) suspension cells were elucidated. Cells treated with 100 ¿M AlCl3 showed typical features of programmed cell death (PCD) such as nuclear and cytoplasmic condensation.

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

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Hsu, Li-Jin; Hong, Qunying; Chen, Shur-Tzu; Kuo, Hsiang-Lin; Schultz, Lori; Heath, John; Lin, Sing-Ru; Lee, Ming-Hui; Li, Dong-Zhang; Li, Zih-Ling; Cheng, Hui-Ching; Armand, Gerard; Chang, Nan-Shan

2017-01-01

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. PMID:27845895

Epidermal cell death in frogs with chytridiomycosis

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Laura A. Brannelly

2017-02-01

Full Text Available Background Amphibians are declining at an alarming rate, and one of the major causes of decline is the infectious disease chytridiomycosis. Parasitic fungal sporangia occur within epidermal cells causing epidermal disruption, but these changes have not been well characterised. Apoptosis (planned cell death can be a damaging response to the host but may alternatively be a mechanism of pathogen removal for some intracellular infections. Methods In this study we experimentally infected two endangered amphibian species Pseudophryne corroboree and Litoria verreauxii alpina with the causal agent of chytridiomycosis. We quantified cell death in the epidermis through two assays: terminal transferase-mediated dUTP nick end-labelling (TUNEL and caspase 3/7. Results Cell death was positively associated with infection load and morbidity of clinically infected animals. In infected amphibians, TUNEL positive cells were concentrated in epidermal layers, correlating to the localisation of infection within the skin. Caspase activity was stable and low in early infection, where pathogen loads were light but increasing. In animals that recovered from infection, caspase activity gradually returned to normal as the infection cleared. Whereas, in amphibians that did not recover, caspase activity increased dramatically when infection loads peaked. Discussion Increased cell death may be a pathology of the fungal parasite, likely contributing to loss of skin homeostatic functions, but it is also possible that apoptosis suppression may be used initially by the pathogen to help establish infection. Further research should explore the specific mechanisms of cell death and more specifically apoptosis regulation during fungal infection.

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

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

2018-06-01

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

Short Chemical Ischemia Triggers Phosphorylation of eIF2α and Death of SH-SY5Y Cells but not Proteasome Stress and Heat Shock Protein Response in both SH-SY5Y and T98G Cells.

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Klacanova, Katarina; Pilchova, Ivana; Klikova, Katarina; Racay, Peter

2016-04-01

Both translation arrest and proteasome stress associated with accumulation of ubiquitin-conjugated protein aggregates were considered as a cause of delayed neuronal death after transient global brain ischemia; however, exact mechanisms as well as possible relationships are not fully understood. The aim of this study was to compare the effect of chemical ischemia and proteasome stress on cellular stress responses and viability of neuroblastoma SH-SY5Y and glioblastoma T98G cells. Chemical ischemia was induced by transient treatment of the cells with sodium azide in combination with 2-deoxyglucose. Proteasome stress was induced by treatment of the cells with bortezomib. Treatment of SH-SY5Y cells with sodium azide/2-deoxyglucose for 15 min was associated with cell death observed 24 h after treatment, while glioblastoma T98G cells were resistant to the same treatment. Treatment of both SH-SY5Y and T98G cells with bortezomib was associated with cell death, accumulation of ubiquitin-conjugated proteins, and increased expression of Hsp70. These typical cellular responses to proteasome stress, observed also after transient global brain ischemia, were not observed after chemical ischemia. Finally, chemical ischemia, but not proteasome stress, was in SH-SY5Y cells associated with increased phosphorylation of eIF2α, another typical cellular response triggered after transient global brain ischemia. Our results showed that short chemical ischemia of SH-SY5Y cells is not sufficient to induce both proteasome stress associated with accumulation of ubiquitin-conjugated proteins and stress response at the level of heat shock proteins despite induction of cell death and eIF2α phosphorylation.

Increasing RpoS expression causes cell death in Borrelia burgdorferi.

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Linxu Chen

Full Text Available RpoS, one of the two alternative σ factors in Borrelia burgdorferi, is tightly controlled by multiple regulators and, in turn, determines expression of many critical virulence factors. Here we show that increasing RpoS expression causes cell death. The immediate effect of increasing RpoS expression was to promote bacterial division and as a consequence result in a rapid increase in cell number before causing bacterial death. No DNA fragmentation or degradation was observed during this induced cell death. Cryo-electron microscopy showed induced cells first formed blebs, which were eventually released from dying cells. Apparently blebbing initiated cell disintegration leading to cell death. These findings led us to hypothesize that increasing RpoS expression triggers intracellular programs and/or pathways that cause spirochete death. The potential biological significance of induced cell death may help B. burgdorferi regulate its population to maintain its life cycle in nature.

Attitudes to brain death and organ procurement among university students and critical care physicians in poland.

Science.gov (United States)

Kubler, A; Lipinska-Gediga, M; Kedziora, J; Kubler, M

2009-06-01

The practice of retrieving vital organs from brain-dead heart-beating donors is legally and medically accepted in Poland, but public beliefs and opinions regarding these matters have not been sufficiently explored. The purpose of this study was to evaluate the attitude of university students to the concepts of brain death and organ retrieval, compared with the attitude of critical care physicians. The cohorts of 989 students and 139 physicians completed a questionnaire based on a survey instrument developed in an earlier reported study on Ohio residents. Participants assessed 3 scenarios: (1) brain death, (2) coma, and (3) vegetative state. More than 48% of students classified the patient from the brain death scenario as alive, and 51% of them were willing to donate organs of this patient. Ninety percent of students classified the patients in coma and in a vegetative state as alive, but still 34% of them would donate organs of those patients. The group of physicians properly determined the patients' diagnoses, but 10% of them accepted organ procurement from patients in coma and in a vegetative state. Our results supported the earlier observations of low public knowledge and inadequate understanding of brain death criteria and organ procurement processes. The majority of students were willing to accept organ procurement from severely ill but alive patients, in contrast with physicians. A considerable increase in public educational activity in this field is urgently recommended.

The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

International Nuclear Information System (INIS)

Kim, Jee-Youn; Kim, Yong-Jun; Lee, Sun; Park, Jae-Hoon

2009-01-01

The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenotypic changes triggered by chronic repeated hypoxia. Hypoxia-resistant T98G (HRT98G) cells were selected by repeated exposure to hypoxia and reoxygenation. Cell death rate was determined by the trypan blue exclusion method and protein expression levels were examined by western blot analysis. The invasive phenotype of the tumor cells was determined by the Matrigel invasion assay. Immunohistochemistry was performed to analyze the expression of proteins in the brain tumor samples. The Student T-test and Pearson Chi-Square test was used for statistical analyses. We demonstrate that chronic repeated hypoxic exposures cause T98G cells to survive low oxygen tension. As compared with parent cells, hypoxia-selected T98G cells not only express higher levels of anti-apoptotic proteins such as Bcl-2, Bcl-X L , and phosphorylated ERK, but they also have a more invasive potential in Matrigel invasion chambers. Activation or suppression of ERK pathways with a specific activator or inhibitor, respectively, indicates that ERK is a key molecule responsible for death resistance under hypoxic conditions and a more invasive phenotype. Finally, we show that the activation of ERK is more prominent in malignant glioblastomas exposed to hypoxia than in low grade astrocytic glial tumors. Our study suggests that activation of ERK plays a pivotal role in death resistance under chronic hypoxia and phenotypic changes related to the invasive phenotype of HRT98G cells compared to parent cells

Triglyceride-induced macrophage cell death is triggered by caspase-1.

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Son, Sin Jee; Rhee, Ki-Jong; Lim, Jaewon; Kim, Tae Ue; Kim, Tack-Joong; Kim, Yoon Suk

2013-01-01

Triglyceride (TG) induces macrophage cell death which contributes to the development of atherosclerosis. We confirmed that exogenous TG accumulates in human THP-1 macrophages and causes cell death. TG treated THP-1 macrophages exhibited no change in tumor necrosis factor (TNF)-α, interleukin (IL)-18, macrophage inflammatory protein (MIP)-1α, and IL-1R1 receptor mRNA expression. However, there was a marked decrease in IL-1β mRNA expression but an increase in IL-1β protein secretion. Decreased expression of IL-1β mRNA and increased secretion of IL-1β protein was not the direct cause of cell death. Until now, TG was assumed to induce necrotic cell death in macrophages. Since caspase-1 is known to be involved in activation and secretion of IL-1β protein and pyroptotic cell death, next we determined whether caspase-1 is associated with TG-induced macrophage cell death. We found an increase in caspase-1 activity in TG-treated THP-1 macrophages and inhibition of caspase-1 activity using a specific inhibitor partially rescued cell death. These results suggest activation of the pyroptotic pathway by TG. This is the first report implicating the activation of caspase-1 and the triggering of the pyroptosis pathway in TG-induced macrophage cell death.

Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

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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

Mechanical Stress Promotes Cisplatin-Induced Hepatocellular Carcinoma Cell Death

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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.

The convergence of radiation and immunogenic cell death signaling pathways

International Nuclear Information System (INIS)

Golden, Encouse B.; Pellicciotta, Ilenia; Demaria, Sandra; Barcellos-Hoff, Mary H.; Formenti, Silvia C.

2012-01-01

Ionizing radiation (IR) triggers programmed cell death in tumor cells through a variety of highly regulated processes. Radiation-induced tumor cell death has been studied extensively in vitro and is widely attributed to multiple distinct mechanisms, including apoptosis, necrosis, mitotic catastrophe (MC), autophagy, and senescence, which may occur concurrently. When considering tumor cell death in the context of an organism, an emerging body of evidence suggests there is a reciprocal relationship in which radiation stimulates the immune system, which in turn contributes to tumor cell kill. As a result, traditional measurements of radiation-induced tumor cell death, in vitro, fail to represent the extent of clinically observed responses, including reductions in loco-regional failure rates and improvements in metastases free and overall survival. Hence, understanding the immunological responses to the type of radiation-induced cell death is critical. In this review, the mechanisms of radiation-induced tumor cell death are described, with particular focus on immunogenic cell death (ICD). Strategies combining radiotherapy with specific chemotherapies or immunotherapies capable of inducing a repertoire of cancer specific immunogens might potentiate tumor control not only by enhancing cell kill but also through the induction of a successful anti-tumor vaccination that improves patient survival.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury

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Xie, Cuicui; Ginet, Vanessa; Sun, Yanyan; Koike, Masato; Zhou, Kai; Li, Tao; Li, Hongfu; Li, Qian; Wang, Xiaoyang; Uchiyama, Yasuo; Truttmann, Anita C.; Kroemer, Guido; Puyal, Julien; Blomgren, Klas; Zhu, Changlian

2016-01-01

ABSTRACT Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy. PMID:26727396

The prolongation of somatic support in a pregnant woman with brain-death: a case report

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Amaral Eliana

2006-04-01

Full Text Available Abstract Background Medical literature has increasingly reported cases of maternal brain death during pregnancy. This is a rare situation which demands the decision and, depending on the gestational age, the implementation of a set of measures to prolong the homeostasis of the human body after brain death for the purpose of maintaining the foetus alive until its viability. Case presentation A 40 year old woman suffered an intracranial haemorrhage during the 25th week of pregnancy. Despite neurosurgical drainage of a gross intraparenchymatous haematoma, the patient developed brain death. Upon confirmation of this diagnosis, she received full ventilatory and nutritional support, vasoactive drugs, maintenance of normothermia, hormone replacement and other supportive measures required to prolong gestation and improve the survival prognosis of her foetus. All decisions regarding the patient's treatment were taken in consensus with her family. She also received corticosteroids to accelerate foetal lung maturity. During the twenty-five days of somatic support, the woman's condition remained stable; however, during the last seven days the foetus developed oligohydramnios and brain-sparring, which led the medical team to take the decision to perform a Caesarean section at that moment. After delivery, the patient's organs were removed for donation. The male infant was born weighing 815 g, with an Apgar score of 9 and 10 at the first and fifth minutes, respectively. The infant was admitted to the neonatal intensive care unit, but did not require mechanical ventilation and had no major complications. He was discharged at 40 days of life, with no sequelae and weighing 1850 g. Conclusion These results are in accordance with findings from previous studies and case reports suggesting the appropriateness and safety of extended somatic support during pregnancy under certain circumstances. They also suggest the need for prompt diagnosis of brain death before the

Cell death triggered by alpha-emitting 213Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

International Nuclear Information System (INIS)

Seidl, Christof; Schroeck, Hedwig; Seidenschwang, Sabine; Beck, Roswitha; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard; Schmid, Ernst; Abend, Michael; Becker, Karl-Friedrich; Apostolidis, Christos; Nikula, Tuomo K.; Kremmer, Elisabeth

2005-01-01

Radioimmunotherapy with α-particle-emitting nuclides, such as 213 Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by 213 Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of 213 Bi-d9MAb targeting d9-E-cadherin and 213 Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as 213 Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213 Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213 Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of α-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213 Bi-d9MAb compared with unspecific 213 Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound 213 Bi-immunoconjugates per cell exceeded 2 x 10 4 , most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by 213 Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. 213 Bi-immunoconjugates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells

Guidelines and recommendations on yeast cell death nomenclature

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Didac Carmona-Gutierrez

2018-01-01

Full Text Available Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.

Guidelines and recommendations on yeast cell death nomenclature

Science.gov (United States)

Carmona-Gutierrez, Didac; Bauer, Maria Anna; Zimmermann, Andreas; Aguilera, Andrés; Austriaco, Nicanor; Ayscough, Kathryn; Balzan, Rena; Bar-Nun, Shoshana; Barrientos, Antonio; Belenky, Peter; Blondel, Marc; Braun, Ralf J.; Breitenbach, Michael; Burhans, William C.; Büttner, Sabrina; Cavalieri, Duccio; Chang, Michael; Cooper, Katrina F.; Côrte-Real, Manuela; Costa, Vítor; Cullin, Christophe; Dawes, Ian; Dengjel, Jörn; Dickman, Martin B.; Eisenberg, Tobias; Fahrenkrog, Birthe; Fasel, Nicolas; Fröhlich, Kai-Uwe; Gargouri, Ali; Giannattasio, Sergio; Goffrini, Paola; Gourlay, Campbell W.; Grant, Chris M.; Greenwood, Michael T.; Guaragnella, Nicoletta; Heger, Thomas; Heinisch, Jürgen; Herker, Eva; Herrmann, Johannes M.; Hofer, Sebastian; Jiménez-Ruiz, Antonio; Jungwirth, Helmut; Kainz, Katharina; Kontoyiannis, Dimitrios P.; Ludovico, Paula; Manon, Stéphen; Martegani, Enzo; Mazzoni, Cristina; Megeney, Lynn A.; Meisinger, Chris; Nielsen, Jens; Nyström, Thomas; Osiewacz, Heinz D.; Outeiro, Tiago F.; Park, Hay-Oak; Pendl, Tobias; Petranovic, Dina; Picot, Stephane; Polčic, Peter; Powers, Ted; Ramsdale, Mark; Rinnerthaler, Mark; Rockenfeller, Patrick; Ruckenstuhl, Christoph; Schaffrath, Raffael; Segovia, Maria; Severin, Fedor F.; Sharon, Amir; Sigrist, Stephan J.; Sommer-Ruck, Cornelia; Sousa, Maria João; Thevelein, Johan M.; Thevissen, Karin; Titorenko, Vladimir; Toledano, Michel B.; Tuite, Mick; Vögtle, F.-Nora; Westermann, Benedikt; Winderickx, Joris; Wissing, Silke; Wölfl, Stefan; Zhang, Zhaojie J.; Zhao, Richard Y.; Zhou, Bing; Galluzzi, Lorenzo; Kroemer, Guido; Madeo, Frank

2018-01-01

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research. PMID:29354647

Pneumothorax as a Complication of Apnea Testing for Brain Death.

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Gorton, Lauren Elizabeth; Dhar, Rajat; Woodworth, Lindsey; Anand, Nitin J; Hayes, Benjamin; Ramiro, Joanna Isabelle; Kumar, Abhay

2016-10-01

Pneumothorax is an under-recognized complication of apnea testing performed as part of the neurological determination of death. It may result in hemodynamic instability or even cardiac arrest, compromising ability to declare brain death (BD) and viability of organs for transplantation. We report three cases of pneumothorax with apnea testing (PAT) and review the available literature of this phenomenon. Series of three cases supplemented with a systematic review of literature (including discussion of apnea testing in major brain death guidelines). Two patients were diagnosed with PAT due to immediate hemodynamic compromise, while the third was diagnosed many hours after BD. An additional nine cases of PAT were found in the literature. Information regarding oxygen cannula diameter was available for nine patients (range 2.3-5.3 mm), and flow rate was available for ten patients (mean 11 L/min). Pneumothorax was treated to resolution in the majority of patients (n = 8), although only six completed apnea testing following diagnosis/treatment of pneumothorax and only three patients became organ donors afterward. Review of major BD guidelines showed that although use of low oxygen flow rate (usually ≤ 6 L/min) during apnea testing is suggested, the risk of PAT was explicitly mentioned in just one. Development of PAT may adversely affect the process of BD determination and could limit the opportunity for organ donation. Each institution should have preventive measures in place.

Transglutaminase induction by various cell death and apoptosis pathways.

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Fesus, L; Madi, A; Balajthy, Z; Nemes, Z; Szondy, Z

1996-10-31

Clarification of the molecular details of forms of natural cell death, including apoptosis, has become one of the most challenging issues of contemporary biomedical sciences. One of the effector elements of various cell death pathways is the covalent cross-linking of cellular proteins by transglutaminases. This review will discuss the accumulating data related to the induction and regulation of these enzymes, particularly of tissue type transglutaminase, in the molecular program of cell death. A wide range of signalling pathways can lead to the parallel induction of apoptosis and transglutaminase, providing a handle for better understanding the exact molecular interactions responsible for the mechanism of regulated cell death.

Radiation-induced apoptosis in undifferentiated cells of the developing brain as a biological defense mechanism

International Nuclear Information System (INIS)

Inouye, Minioru; Tamaru, Masao.

1994-01-01

Undifferentiated neural (UN) cells of the developing mammalian brain are highly sensitive to the lethal effects of ionizing radiation. Nuclear and cytoplasmic condensation, transglutaminase activation, and internucleosomal DNA cleavage reveal radiation-induced cell death in the ventricular zone of the cerebral mantle and external granular layer of the cerebellum to be due to apoptosis. A statistically significant increase of cell mortality can be induced by 0.03 Gy X-irradiation, and the mortality increases linearly with increasing doses. It is not changed by split doses, probably because of the very slow repair of cellular damage and a lack of adaptive response. Although extensive apoptosis in the UN cell population results in microcephaly and mental retardation, it possesses the ability to recover from a considerable cell loss and to form the normal structure of the central nervous system. The number of cell deaths needed to induce tissue adnormalities in the adult murine brain rises in the range of 15-25% of the germinal cell population; with the threshold doses at about 0.3 Gy for cerebral anomalies and 1 Gy for cerebellar abnormalities. Threshold level is similarly suggested in prenatally exposed A-bomb survivors. High radiosensitivity of UN cells is assumed to be a manifestation of the ability of the cell to commit suicide when injured. Repeated replication of DNA and extensive gene expression are required in future proliferation and differentiation. Once an abnormality in DNA was induced and fixed in the UN cell, it would be greatly amplified and prove a danger in producing malformations and tumors. These cells would thus commit suicide for the benefit of the individual to eliminate their acquired genetic abnormalities rather than make DNA repair. UN cells in the developing brain are highly radiosensitive and readily involved in apoptosis. Paradoxically, however, this may be to protect individuals against teratogenesis and tumorigenesis. (J.P.N.)

Radiation-induced apoptosis in undifferentiated cells of the developing brain as a biological defense mechanism

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Inouye, Minioru [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine; Tamaru, Masao

1994-12-31

Undifferentiated neural (UN) cells of the developing mammalian brain are highly sensitive to the lethal effects of ionizing radiation. Nuclear and cytoplasmic condensation, transglutaminase activation, and internucleosomal DNA cleavage reveal radiation-induced cell death in the ventricular zone of the cerebral mantle and external granular layer of the cerebellum to be due to apoptosis. A statistically significant increase of cell mortality can be induced by 0.03 Gy X-irradiation, and the mortality increases linearly with increasing doses. It is not changed by split doses, probably because of the very slow repair of cellular damage and a lack of adaptive response. Although extensive apoptosis in the UN cell population results in microcephaly and mental retardation, it possesses the ability to recover from a considerable cell loss and to form the normal structure of the central nervous system. The number of cell deaths needed to induce tissue adnormalities in the adult murine brain rises in the range of 15-25% of the germinal cell population; with the threshold doses at about 0.3 Gy for cerebral anomalies and 1 Gy for cerebellar abnormalities. Threshold level is similarly suggested in prenatally exposed A-bomb survivors. High radiosensitivity of UN cells is assumed to be a manifestation of the ability of the cell to commit suicide when injured. Repeated replication of DNA and extensive gene expression are required in future proliferation and differentiation. Once an abnormality in DNA was induced and fixed in the UN cell, it would be greatly amplified and prove a danger in producing malformations and tumors. These cells would thus commit suicide for the benefit of the individual to eliminate their acquired genetic abnormalities rather than make DNA repair. UN cells in the developing brain are highly radiosensitive and readily involved in apoptosis. Paradoxically, however, this may be to protect individuals against teratogenesis and tumorigenesis. (J.P.N.).

The process and promotion of radiation-induced cell death

International Nuclear Information System (INIS)

Sasaki, Hiroshi

1998-01-01

Radiation-induced cell death is divided into reproductive and interphase death, whose process can be revealed by time-lapse observations. Pedigree analyses of progenies derived from a surviving progenitor cell have shown that moribund cells appear in clusters among cells which are apparently undamaged (lethal sectoring). Sister cell fusion, which likely results from chromosome bridge, is the most frequently observed cell abnormality leading to reproductive death. While interphase death does not occur unless the dose exceeds 10 Gy for low LET radiation such as X-rays, high-LET radiation is very effective at inducing interphase death (RBE: ≅3 at 230 keV/μm). Expression or fixation of potentially lethal damage (PLD) is closely associated with cell cycle events and enhanced by inducing premature chromosome condensation (PCC) at a nonpermissive temperature in tsBN2 cells with a ts-defect in RCC1 protein (a regulator of chromatin condensation) which monitors the completion of DNA replication. Furthermore, higher-order structural changes in nuclear matrix such as induced by leptomycin B, an inhibitor of CRM1 (chromosome region maintenance) protein, also play an important role in the fixation of PLD. (author)

Anencefalia e morte cerebral (neurológica Anencephaly and brain death

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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

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

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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 cancer occurrence was 1.04 (0.85-1.27) for individuals who resided in municipalities served by drinking 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.

UV-Induced Cell Death in Plants

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Nawkar, Ganesh M.; Maibam, Punyakishore; Park, Jung Hoon; Sahi, Vaidurya Pratap; Lee, Sang Yeol; Kang, Chang Ho

2013-01-01

Plants are photosynthetic organisms that depend on sunlight for energy. Plants respond to light through different photoreceptors and show photomorphogenic development. Apart from Photosynthetically Active Radiation (PAR; 400–700 nm), plants are exposed to UV light, which is comprised of UV-C (below 280 nm), UV-B (280–320 nm) and UV-A (320–390 nm). The atmospheric ozone layer protects UV-C radiation from reaching earth while the UVR8 protein acts as a receptor for UV-B radiation. Low levels of UV-B exposure initiate signaling through UVR8 and induce secondary metabolite genes involved in protection against UV while higher dosages are very detrimental to plants. It has also been reported that genes involved in MAPK cascade help the plant in providing tolerance against UV radiation. The important targets of UV radiation in plant cells are DNA, lipids and proteins and also vital processes such as photosynthesis. Recent studies showed that, in response to UV radiation, mitochondria and chloroplasts produce a reactive oxygen species (ROS). Arabidopsis metacaspase-8 (AtMC8) is induced in response to oxidative stress caused by ROS, which acts downstream of the radical induced cell death (AtRCD1) gene making plants vulnerable to cell death. The studies on salicylic and jasmonic acid signaling mutants revealed that SA and JA regulate the ROS level and antagonize ROS mediated cell death. Recently, molecular studies have revealed genes involved in response to UV exposure, with respect to programmed cell death (PCD). PMID:23344059

Neuroprotective effects of corn silk maysin via inhibition of H2O2-induced apoptotic cell death in SK-N-MC cells.

Science.gov (United States)

Choi, Doo Jin; Kim, Sun-Lim; Choi, Ji Won; Park, Yong Il

2014-07-25

Neuroprotective effects of maysin, which is a flavone glycoside that was isolated from the corn silk (CS, Zea mays L.) of a Korean hybrid corn Kwangpyeongok, against oxidative stress (H2O2)-induced apoptotic cell death of human neuroblastoma SK-N-MC cells were investigated. Maysin cytotoxicity was determined by measuring cell viability using MTT and lactate dehydrogenase (LDH) assays. Intracellular reactive oxygen species (ROS) were measured using a 2,7-dichlorofluorescein diacetate (DCF-DA) assay. Apoptotic cell death was monitored by annexin V-FITC/PI double staining and by a TUNEL assay. Antioxidant enzyme mRNA levels were determined by real-time PCR. The cleavage of poly (ADP-ribose) polymerase (PARP) was measured by western blotting. Maysin pretreatment reduced the cytotoxic effect of H2O2 on SK-N-MC cells, as shown by the increase in cell viability and by reduced LDH release. Maysin pretreatment also dose-dependently reduced the intracellular ROS level and inhibited PARP cleavage. In addition, DNA damage and H2O2-induced apoptotic cell death were significantly attenuated by maysin pretreatment. Moreover, maysin pretreatment (5-50 μg/ml) for 2h significantly and dose-dependently increased the mRNA levels of antioxidant enzymes (CAT, GPx-1, SOD-1, SOD-2 and HO-1) in H2O2 (200 μM)-insulted cells. These results suggest that CS maysin has neuroprotective effects against oxidative stress (H2O2)-induced apoptotic death of human brain SK-N-MC cells through its antioxidative action. This report is the first regarding neuroprotective health benefits of corn silk maysin by its anti-apoptotic action and by triggering the expression of intracellular antioxidant enzyme systems in SK-N-MC cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Ruta graveolens L. induces death of glioblastoma cells and neural progenitors, but not of neurons, via ERK 1/2 and AKT activation.

Directory of Open Access Journals (Sweden)

Maria Teresa Gentile

Full Text Available Glioblastoma multiforme is a highly aggressive brain tumor whose prognosis is very poor. Due to early invasion of brain parenchyma, its complete surgical removal is nearly impossible, and even after aggressive combined treatment (association of surgery and chemo- and radio-therapy five-year survival is only about 10%. Natural products are sources of novel compounds endowed with therapeutic properties in many human diseases, including cancer. Here, we report that the water extract of Ruta graveolens L., commonly known as rue, induces death in different glioblastoma cell lines (U87MG, C6 and U138 widely used to test novel drugs in preclinical studies. Ruta graveolens' effect was mediated by ERK1/2 and AKT activation, and the inhibition of these pathways, via PD98058 and wortmannin, reverted its antiproliferative activity. Rue extract also affects survival of neural precursor cells (A1 obtained from embryonic mouse CNS. As in the case of glioma cells, rue stimulates the activation of ERK1/2 and AKT in A1 cells, whereas their blockade by pharmacological inhibitors prevents cell death. Interestingly, upon induction of differentiation and cell cycle exit, A1 cells become resistant to rue's noxious effects but not to those of temozolomide and cisplatin, two alkylating agents widely used in glioblastoma therapy. Finally, rutin, a major component of the Ruta graveolens water extract, failed to cause cell death, suggesting that rutin by itself is not responsible for the observed effects. In conclusion, we report that rue extracts induce glioma cell death, discriminating between proliferating/undifferentiated and non-proliferating/differentiated neurons. Thus, it can be a promising tool to isolate novel drugs and also to discover targets for therapeutic intervention.

Expression of death receptor 4 induces caspase-independent cell death in MMS-treated yeast.

Science.gov (United States)

Kang, Mi-Sun; Lee, Sung-Keun; Park, Chang-Shin; Kang, Ju-Hee; Bae, Sung-Ho; Yu, Sung-Lim

2008-11-14

DR4, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, is a key element in the extrinsic pathway of TRAIL/TRAIL receptor-related apoptosis that exerts a preferential toxic effect against tumor cells. However, TRAIL and DR4 are expressed in various normal cells, and recent studies indicate that DR4 has a number of non-apoptotic functions. In this study, we evaluated the effects of human DR4 expression in yeast to determine the function of DR4 in normal cells. The expression of DR4 in yeast caused G1 arrest, which resulted in transient growth inhibition. Moreover, treatment of DR4-expressing yeast with a DNA damaging agent, MMS, elicited drastic, and sustained cell growth inhibition accompanied with massive apoptotic cell death. Further analysis revealed that cell death in the presence of DNA damage and DR4 expression was not dependent on the yeast caspase, YCA1. Taken together, these results indicate that DR4 triggers caspase-independent programmed cell death during the response of normal cells to DNA damage.

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...

Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators

International Nuclear Information System (INIS)

Claveria, Cristina; Torres, Miguel

2003-01-01

Multicellular organisms eliminate unwanted or damaged cells by cell death, a process essential to the maintenance of tissue homeostasis. Cell death is a tightly regulated event, whose alteration by excess or defect is involved in the pathogenesis of many diseases such as cancer, autoimmune syndromes, and neurodegenerative processes. Studies in model organisms, especially in the nematode Caenorhabditis elegans, have been crucial in identifying the key molecules implicated in the regulation and execution of programmed cell death. In contrast, the study of cell death in Drosophila melanogaster, often an excellent model organism, has identified regulators and mechanisms not obviously conserved in other metazoans. Recent molecular and cellular analyses suggest, however, that the mechanisms of action of the main programmed cell death regulators in Drosophila include a canonical mitochondrial pathway

Sickle cell trait and sudden death--bringing it home.

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Mitchell, Bruce L.

2007-01-01

Sickle cell trait continues to be the leading cause of sudden death for young African Americans in military basic training and civilian organized sports. The syndrome may have caused the death of up to 10 college football players since 1974 and, as recently as 2000, was suspected as the cause of death of three U.S. Army recruits. The penal military-style boot camps in the United States and the recent death of two teenagers with sickle cell trait merits renewed vigor in the education of athletic instructors, the military and the public about conditions associated with sudden death in individuals with sickle cell trait. Images Figure 1 Figure 2 PMID:17393956

Clinical translation of stem cell therapy in traumatic brain injury: the potential of encapsulated mesenchymal cell biodelivery of glucagon-like peptide-1

OpenAIRE

Heile, Anna; Brinker, Thomas

2011-01-01

Traumatic brain injury remains a major cause of death and disability; it is estimated that annually 10 million people are affected. Preclinical studies have shown the potential therapeutic value of stem cell therapies. Neuroprotective as well as regenerative properties of stem cells have been suggested to be the mechanism of action in preclinical studies. However, up to now stem cell therapy has not been studied extensively in clinical trials. This article summarizes the current experimental ...

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.

Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

Science.gov (United States)

Liu, Zhan; Huang, Yan; Cao, Bei-Bei; Qiu, Yi-Hua; Peng, Yu-Ping

2017-12-01

T helper (Th)17 cells, a subset of CD4 + T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP + )-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP + -treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

Bifurcate effects of glucose on caspase-independent cell death during hypoxia

International Nuclear Information System (INIS)

Aki, Toshihiko; Nara, Akina; Funakoshi, Takeshi; Uemura, Koichi

2010-01-01

We investigated the effect of glucose on hypoxic death of rat cardiomyocyte-derived H9c2 cells and found that there is an optimal glucose concentration for protection against hypoxic cell death. Hypoxic cell death in the absence of glucose is accompanied by rapid ATP depletion, release of apoptosis-inducing factor from mitochondria, and nuclear chromatin condensation, all of which are inhibited by glucose in a dose-dependent manner. In contrast, excessive glucose also induces hypoxic cell death that is not accompanied by these events, suggesting a change in the mode of cell death between hypoxic cells with and without glucose supplementation.

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)

C/EBPβ LIP augments cell death by inducing osteoglycin.

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Wassermann-Dozorets, Rina; Rubinstein, Menachem

2017-04-06

Many types of tumor cell are devoid of the extracellular matrix proteoglycan osteoglycin (Ogn), but its role in tumor biology is poorly studied. Here we show that RNAi of Ogn attenuates stress-triggered cell death, whereas its overexpression increases cell death. We found that the transcription factor C/EBPβ regulates the expression of Ogn. C/EBPβ is expressed as a full-length, active form (LAP) and as a truncated, dominant-negative form (LIP), and the LIP/LAP ratio is positively correlated with the extent of cell death under stress. For example, we reported that drug-resistant tumor cells lack LIP altogether, and its supplementation abolished their resistance to chemotherapy and to endoplasmic reticulum (ER) stress. Here we further show that elevated LIP/LAP ratio robustly increased Ogn expression and cell death under stress by modulating the mitogen-activated protein kinase/activator protein 1 pathway (MAPK/AP-1). Our findings suggest that LIP deficiency renders tumor cell resistant to ER stress by preventing the induction of Ogn.

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.

Cell death triggered by alpha-emitting {sup 213}Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death

Energy Technology Data Exchange (ETDEWEB)

Seidl, Christof; Schroeck, Hedwig; Seidenschwang, Sabine; Beck, Roswitha; Schwaiger, Markus; Senekowitsch-Schmidtke, Reingard [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Schmid, Ernst [National Research Center for Environment and Health, Institute of Radiation Biology, GSF, Neuherberg (Germany); Abend, Michael [German Armed Forces, Institute of Radiobiology, Munich (Germany); Becker, Karl-Friedrich [Technische Universitaet Muenchen, Institute of Pathology, Munich (Germany); National Research Center for Environment and Health, Institute of Pathology, GSF, Neuherberg (Germany); National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany); Apostolidis, Christos; Nikula, Tuomo K. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Kremmer, Elisabeth [National Research Center for Environment and Health, Institute of Molecular Immunology, GSF, Munich (Germany)

2005-03-01

Radioimmunotherapy with {alpha}-particle-emitting nuclides, such as{sup 213}Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by {sup 213}Bi-immunoconjugates. Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of {sup 213}Bi-d9MAb targeting d9-E-cadherin and {sup 213}Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as {sup 213}Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and {sup 213}Bi-d9MAb was analysed via Western blotting. Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with {sup 213}Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of {alpha}-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific {sup 213}Bi-d9MAb compared with unspecific {sup 213}Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound {sup 213}Bi-immunoconjugates per cell exceeded 2 x 10{sup 4}, most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by {sup 213}Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. {sup 213}Bi-immunoconjugates seem

Sigma-2 ligands and PARP inhibitors synergistically trigger cell death in breast cancer cells

International Nuclear Information System (INIS)

McDonald, Elizabeth S.; Mankoff, Julia; Makvandi, Mehran; Chu, Wenhua; Chu, Yunxiang; Mach, Robert H.; Zeng, Chenbo

2017-01-01

The sigma-2 receptor is overexpressed in proliferating cells compared to quiescent cells and has been used as a target for imaging solid tumors by positron emission tomography. Recent work has suggested that the sigma-2 receptor may also be an effective therapeutic target for cancer therapy. Poly (ADP-ribose) polymerase (PARP) is a family of enzymes involved in DNA damage response. In this study, we looked for potential synergy of cytotoxicity between PARP inhibitors and sigma-2 receptor ligands in breast cancer cell lines. We showed that the PARP inhibitor, YUN3-6, sensitized mouse breast cancer cell line, EMT6, to sigma-2 receptor ligand (SV119, WC-26, and RHM-138) induced cell death determined by cell viability assay and colony forming assay. The PARP inhibitor, olaparib, sensitized tumor cells to a different sigma-2 receptor ligand SW43-induced apoptosis and cell death in human triple negative cell line, MDA-MB-231. Olaparib inhibited PARP activity and cell proliferation, and arrested cells in G2/M phase of the cell cycle in MDA-MB-231 cells. Subsequently cells became sensitized to SW43 induced cell death. In conclusion, the combination of sigma-2 receptor ligands and PARP inhibitors appears to hold promise for synergistically triggering cell death in certain types of breast cancer cells and merits further investigation. - Highlights: • PARPi, YUN3-6 and olaparib, and σ2 ligands, SV119 and SW43, were evaluated. • Mouse and human breast cancer cells, EMT6 and MDA-MB-231 respectively, were used. • YUN3-6 and SV119 synergistically triggered cell death in EMT6 cells. • Olaparib and SW43 additively triggered cell death in MDA-MB-231 cells. • Olaparib arrested cells in G2/M in MDA-MB-231 cells.

Characterization of a serine protease-mediated cell death program activated in human leukemia cells

International Nuclear Information System (INIS)

O'Connell, A.R.; Holohan, C.; Torriglia, A.; Lee, B.F.; Stenson-Cox, C.

2006-01-01

Tightly controlled proteolysis is a defining feature of apoptosis and caspases are critical in this regard. Significant roles for non-caspase proteases in cell death have been highlighted. Staurosporine causes a rapid induction of apoptosis in virtually all mammalian cell types. Numerous studies demonstrate that staurosporine can activate cell death under caspase-inhibiting circumstances. The aim of this study was to investigate the proteolytic mechanisms responsible for cell death under these conditions. To that end, we show that inhibitors of serine proteases can delay cell death in one such system. Furthermore, through profiling of proteolytic activation, we demonstrate, for the first time, that staurosporine activates a chymotrypsin-like serine protease-dependent cell death in HL-60 cells independently, but in parallel with the caspase controlled systems. Features of the serine protease-mediated system include cell shrinkage and apoptotic morphology, regulation of caspase-3, altered nuclear morphology, generation of an endonuclease and DNA degradation. We also demonstrate a staurosporine-induced activation of a putative 16 kDa chymotrypsin-like protein during apoptosis

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.

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.

Radiation-induced cell death by chromatin loss

International Nuclear Information System (INIS)

Campbell, I.R.; Warenius, H.M.

1989-01-01

A model is proposed which relates reproductive death of cells caused by radiation to loss of chromatin at cell division. This loss of chromatin can occur through chromosomal deletions or through the formation of asymmetrical chromosomal exchanges. It is proposed that smaller doses of radiation produce fewer chromatin breaks, which are more likely to be accurately repaired, compared with larger doses. Consequently, smaller doses of radiation are less efficient in causing cell death, leading to a shoulder on the cell survival curve. Experimental evidence supports this model, and the fit between the derived formula and experimental cell survival curves is good. The derived formula approximates to the linear-quadratic equation at low doses of radiation. (author)

Jasmonic acid signaling modulates ozone-induced hypersensitive cell death.

Science.gov (United States)

Rao, M V; Lee, H; Creelman, R A; Mullet, J E; Davis, K R

2000-09-01

Recent studies suggest that cross-talk between salicylic acid (SA)-, jasmonic acid (JA)-, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O(3)) exposure activates a hypersensitive response (HR)-like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O(3)-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O(3)-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O(3)-induced H(2)O(2) content and SA concentrations and completely abolished O(3)-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O(3) exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O(3) of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O(3)-induced HR-like cell death.

Brain Death in Pediatric Patients in Japan: Diagnosis and Unresolved Issues.

Science.gov (United States)

Araki, Takashi; Yokota, Hiroyuki; Fuse, Akira

2016-01-01

Brain death (BD) is a physiological state defined as complete and irreversible loss of brain function. Organ transplantation from a patient with BD is controversial in Japan because there are two classifications of BD: legal BD in which the organs can be donated and general BD in which the organs cannot be donated. The significance of BD in the terminal phase remains in the realm of scientific debate. As indicated by the increasing number of organ transplants from brain-dead donors, certain clinical diagnosis for determining BD in adults is becoming established. However, regardless of whether or not organ transplantation is involved, there are many unresolved issues regarding BD in children. Here, we will discuss the historical background of BD determination in children, pediatric emergencies and BD, and unresolved issues related to pediatric BD.

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

Programmed cell death for defense against anomaly and tumor formation

International Nuclear Information System (INIS)

Kondo, Sohei; Norimura, Toshiyuki; Nomura, Taisei

1995-01-01

Cell death after exposure to low-level radiation is often considered evidence that radiation is poisonous, however small the dose. Evidence has been accumulating to support the notion that cell death after low-level exposure to radiation results from activation of suicidal genes open-quote programmed cell death close-quote or open-quote apoptosis close-quote - for the health of the whole body. This paper gives experimental evidence that embryos of fruit flies and mouse fetuses have potent defense mechanisms against teratogenic or tumorigenic injury caused by radiation and carcinogens, which function through programmed cell death

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.

Reprogramming Cells for Brain Repair

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Randall D. McKinnon

2013-08-01

Full Text Available At present there are no clinical therapies that can repair traumatic brain injury, spinal cord injury or degenerative brain disease. While redundancy and rewiring of surviving circuits can recover some lost function, the brain and spinal column lack sufficient endogenous stem cells to replace lost neurons or their supporting glia. In contrast, pre-clinical studies have demonstrated that exogenous transplants can have remarkable efficacy for brain repair in animal models. Mesenchymal stromal cells (MSCs can provide paracrine factors that repair damage caused by ischemic injury, and oligodendrocyte progenitor cell (OPC grafts give dramatic functional recovery from spinal cord injury. These studies have progressed to clinical trials, including human embryonic stem cell (hESC-derived OPCs for spinal cord repair. However, ESC-derived allografts are less than optimal, and we need to identify a more appropriate donor graft population. The cell reprogramming field has developed the ability to trans-differentiate somatic cells into distinct cell types, a technology that has the potential to generate autologous neurons and glia which address the histocompatibility concerns of allografts and the tumorigenicity concerns of ESC-derived grafts. Further clarifying how cell reprogramming works may lead to more efficient direct reprogram approaches, and possibly in vivo reprogramming, in order to promote brain and spinal cord repair.

Nerve Growth Factor in Cancer Cell Death and Survival

International Nuclear Information System (INIS)

Molloy, Niamh H.; Read, Danielle E.; Gorman, Adrienne M.

2011-01-01

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75 NTR , a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75 NTR . For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75 NTR . This latter signaling through p75 NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75 NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer

Brain mesenchymal stem cells: The other stem cells of the brain?

Science.gov (United States)

Appaix, Florence; Nissou, Marie-France; van der Sanden, Boudewijn; Dreyfus, Matthieu; Berger, François; Issartel, Jean-Paul; Wion, Didier

2014-04-26

Multipotent mesenchymal stromal cells (MSC), have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation. The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair. However, some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist. In brain, perivascular MSCs like pericytes and adventitial cells, could constitute another stem cell population distinct to the neural stem cell pool. The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes, the demonstration of neural biomarkers expression, electrophysiological recordings, and the absence of cell fusion. The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells. It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.

Autophagic components contribute to hypersensitive cell death in Arabidopsis

DEFF Research Database (Denmark)

Hofius, Daniel; Schultz-Larsen, Torsten; Joensen, Jan

2009-01-01

Autophagy has been implicated as a prosurvival mechanism to restrict programmed cell death (PCD) associated with the pathogen-triggered hypersensitive response (HR) during plant innate immunity. This model is based on the observation that HR lesions spread in plants with reduced autophagy gene...... expression. Here, we examined receptor-mediated HR PCD responses in autophagy-deficient Arabidopsis knockout mutants (atg), and show that infection-induced lesions are contained in atg mutants. We also provide evidence that HR cell death initiated via Toll/Interleukin-1 (TIR)-type immune receptors through...... the defense regulator EDS1 is suppressed in atg mutants. Furthermore, we demonstrate that PCD triggered by coiled-coil (CC)-type immune receptors via NDR1 is either autophagy-independent or engages autophagic components with cathepsins and other unidentified cell death mediators. Thus, autophagic cell death...

Mechanisms of Ionizing Radiation-Induced Cell Death in Primary Lung Cells

Science.gov (United States)

2013-03-05

lose their capacity to replicate after a certain number       10 of passages. This finite number was termed the “ Hayflick limit ” and cells...Upstream and downstream of mTOR. Genes & development 18:1926-45 78. Hayflick L. 1965. The Limited in Vitro Lifetime of Human Diploid Cell Strains...can lead to death. During the course of radiotherapy, the use of IR for the treatment of thoracic cancers is limited by IR-induced cell death to the

Cytokine-induced activation of glial cells in the mouse brain is enhanced at an advanced age.

Science.gov (United States)

Deng, X-H; Bertini, G; Xu, Y-Z; Yan, Z; Bentivoglio, M

2006-08-25

Numerous neurological diseases which include neuroinflammatory components exhibit an age-related prevalence. The aging process is characterized by an increase of inflammatory mediators both systemically and in the brain, which may prime glial cells. However, little information is available on age-related changes in the glial response of the healthy aging brain to an inflammatory challenge. This problem was here examined using a mixture of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha, which was injected intracerebroventricularly in young (2-3.5 months), middle-aged (10-11 months) and aged (18-21 months) mice. Vehicle (phosphate-buffered saline) was used as control. After a survival of 1 or 2 days (all age groups) or 4 days (young and middle-aged animals), immunohistochemically labeled astrocytes and microglia were investigated both qualitatively and quantitatively. In all age groups, astrocytes were markedly activated in periventricular as well as in deeper brain regions 2 days following cytokine treatment, whereas microglia activation was already evident at 24 h. Interestingly, cytokine-induced activation of both astrocytes and microglia was significantly more marked in the brain of aged animals, in which it included numerous ameboid microglia, than of younger age groups. Moderate astrocytic activation was also seen in the hippocampal CA1 field of vehicle-treated aged mice. FluoroJade B histochemistry and the terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling technique, performed at 2 days after cytokine administration, did not reveal ongoing cell death phenomena in young or aged animals. This indicated that glial cell changes were not secondary to neuronal death. Altogether, the findings demonstrate for the first time enhanced activation of glial cells in the old brain, compared with young and middle-aged subjects, in response to cytokine exposure. Interestingly, the results also suggest that such enhancement

Non-apoptotic cell death associated with perturbations of macropinocytosis.

Science.gov (United States)

Maltese, William A; Overmeyer, Jean H

2015-01-01

Although macropinocytosis is widely recognized as a distinct form of fluid-phase endocytosis in antigen-presenting dendritic cells, it also occurs constitutively in many other normal and transformed cell types. Recent studies have established that various genetic or pharmacological manipulations can hyperstimulate macropinocytosis or disrupt normal macropinosome trafficking pathways, leading to accumulation of greatly enlarged cytoplasmic vacuoles. In some cases, this extreme vacuolization is associated with a unique form of non-apoptotic cell death termed "methuosis," from the Greek methuo (to drink to intoxication). It remains unclear whether cell death related to dysfunctional macropinocytosis occurs in normal physiological contexts. However, the finding that some types of cancer cells are particularly vulnerable to this unusual form of cell death has raised the possibility that small molecules capable of altering macropinosome trafficking or function might be useful as therapeutic agents against cancers that are resistant to drugs that work by inducing apoptosis. Herein we review examples of cell death associated with dysfunctional macropinocytosis and summarize what is known about the underlying mechanisms.

Non-apoptotic cell death associated with perturbations of macropinocytosis

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William A. Maltese

2015-02-01

Full Text Available Although macropinocytosis is widely recognized as a distinct form of fluid-phase endocytosis in antigen-presenting dendritic cells, it also occurs constitutively in many other normal and transformed cell types. Recent studies have established that various genetic or pharmacological manipulations can hyperstimulate macropinocytosis or disrupt normal macropinosome trafficking pathways, leading to accumulation of greatly enlarged cytoplasmic vacuoles. In some cases, this extreme vacuolization is associated with a unique form of non-apoptotic cell death termed ‘methuosis’, from the Greek methuo (to drink to intoxication. It remains unclear whether cell death related to dysfunctional macropinocytosis occurs in normal physiological contexts. However, the finding that some types of cancer cells are particularly vulnerable to this unusual form of cell death has raised the possibility that small molecules capable of altering macropinosome trafficking or function might be useful as therapeutic agents against cancers that are resistant to drugs that work by inducing apoptosis. Herein we review examples of cell death associated with dysfunctional macropinocytosis and summarize what is known about the underlying mechanisms.

NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease.

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Machado, Roberto F; Hildesheim, Mariana; Mendelsohn, Laurel; Remaley, Alan T; Kato, Gregory J; Gladwin, Mark T

2011-08-01

Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160ng/l was present in 27·6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0·001), high lactate dehydrogenase (P<0·001), and high total bilirubin levels (P<0·007). A NT-proBNP level ≥160ng/l was an independent predictor of mortality (RR 6·24, 95% CI 2·9-13·3, P<0·0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population. © 2011 Blackwell Publishing Ltd.

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

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A Ra Ko

2015-09-01

Full Text Available 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.

Stem cell death and survival in heart regeneration and repair.

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Abdelwahid, Eltyeb; Kalvelyte, Audrone; Stulpinas, Aurimas; de Carvalho, Katherine Athayde Teixeira; Guarita-Souza, Luiz Cesar; Foldes, Gabor

2016-03-01

Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

Acrolein-induced cell death in PC12 cells: role of mitochondria-mediated oxidative stress.

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Luo, Jian; Robinson, J Paul; Shi, Riyi

2005-12-01

Oxidative stress has been implicated in acrolein cytotoxicity in various cell types, including mammalian spinal cord tissue. In this study we report that acrolein also decreases PC12 cell viability in a reactive oxygen species (ROS)-dependent manner. Specifically, acrolein-induced cell death, mainly necrosis, is accompanied by the accumulation of cellular ROS. Elevating ROS scavengers can alleviate acrolein-induced cell death. Furthermore, we show that exposure to acrolein leads to mitochondrial dysfunction, denoted by the loss of mitochondrial transmembrane potential, reduction of cellular oxygen consumption, and decrease of ATP level. This raises the possibility that the cellular accumulation of ROS could result from the increased production of ROS in the mitochondria of PC12 cells as a result of exposure to acrolein. The acrolein-induced significant decrease of ATP production in mitochondria may also explain why necrosis, not apoptosis, is the dominant type of cell death. In conclusion, our data suggest that one possible mechanism of acrolein-induced cell death could be through mitochondria as its initial target. The subsequent increase of ROS then inflicts cell death and further worsens mitochondria function. Such mechanism may play an important role in CNS trauma and neurodegenerative diseases.

Activation of Cyclin-Dependent Kinase 5 Is a Consequence of Cell Death

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Yixia Ye

2009-01-01

Full Text Available Cyclin-dependent kinase 5 (Cdk5 is similar to other Cdks but is activated during cell differentiation and cell death rather than cell division. Since activation of Cdk5 has been reported in many situations leading to cell death, we attempted to determine if it was required for any form of cell death. We found that Cdk5 is activated during apoptotic deaths and that the activation can be detected even when the cells continue to secondary necrosis. This activation can occur in the absence of Bim, calpain, or neutral cathepsins. The kinase is typically activated by p25, derived from p35 by calpain-mediated cleavage, but inhibition of calpain does not affect cell death or the activation of Cdk5. Likewise, RNAi-forced suppression of the synthesis of Cdk5 does not affect the incidence or kinetics of cell death. We conclude that Cdk5 is activated as a consequence of metabolic changes that are common to many forms of cell death. Thus its activation suggests processes during cell death that will be interesting or important to understand, but activation of Cdk5 is not necessary for cells to die.

Vacuolar processing enzyme: an executor of plant cell death.

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Hara-Nishimura, Ikuko; Hatsugai, Noriyuki; Nakaune, Satoru; Kuroyanagi, Miwa; Nishimura, Mikio

2005-08-01

Apoptotic cell death in animals is regulated by cysteine proteinases called caspases. Recently, vacuolar processing enzyme (VPE) was identified as a plant caspase. VPE deficiency prevents cell death during hypersensitive response and cell death of limited cell layers at the early stage of embryogenesis. Because plants do not have macrophages, dying cells must degrade their materials by themselves. VPE plays an essential role in the regulation of the lytic system of plants during the processes of defense and development. VPE is localized in the vacuoles, unlike animal caspases, which are localized in the cytosol. Thus, plants might have evolved a regulated cellular suicide strategy that, unlike animal apoptosis, is mediated by VPE and the vacuoles.

Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities.

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Xiong, Ye; Mahmood, Asim; Chopp, Michael

2018-04-24

Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI. Copyright © 2018 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

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

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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.

Induction of apoptotic cell death by putrescine

DEFF Research Database (Denmark)

Takao, Koichi; Rickhag, Karl Mattias; Hegardt, Cecilia

2006-01-01

that overexpression of a metabolically stable ODC in CHO cells induced a massive cell death unless the cells were grown in the presence of the ODC inhibitor alpha-difluoromethylornithine (DFMO). Cells overexpressing wild-type (unstable) ODC, on the other hand, were not dependent on the presence of DFMO...... for their growth. The induction of cell death was correlated with a dramatic increase in cellular putrescine levels. Analysis using flow cytometry revealed perturbed cell cycle kinetics, with a large accumulation of cells with sub-G1 amounts of DNA, which is a typical sign of apoptosis. Another strong indication...... of apoptosis was the finding that one of the key enzymes in the apoptotic process, caspase-3, was induced when DFMO was omitted from the growth medium. Furthermore, inhibition of the caspase activity significantly reduced the recruitment of cells to the sub-G1 fraction. In conclusion, deregulation of polyamine...

Oxidative Stress and Programmed Cell Death in Yeast

International Nuclear Information System (INIS)

Farrugia, Gianluca; Balzan, Rena

2012-01-01

Yeasts, such as Saccharomyces cerevisiae, have long served as useful models for the study of oxidative stress, an event associated with cell death and severe human pathologies. This review will discuss oxidative stress in yeast, in terms of sources of reactive oxygen species (ROS), their molecular targets, and the metabolic responses elicited by cellular ROS accumulation. Responses of yeast to accumulated ROS include upregulation of antioxidants mediated by complex transcriptional changes, activation of pro-survival pathways such as mitophagy, and programmed cell death (PCD) which, apart from apoptosis, includes pathways such as autophagy and necrosis, a form of cell death long considered accidental and uncoordinated. The role of ROS in yeast aging will also be discussed.

Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

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Yu Qiu

2015-10-01

Full Text Available Hypoxia, which is common during tumor progression, plays important roles in tumor biology. Failure in cell death in response to hypoxia contributes to progression and metastasis of tumors. On the one hand, the metabolic and oxidative stress following hypoxia could lead to cell death by triggering signal cascades, like LKB1/AMPK, PI3K/AKT/mTOR, and altering the levels of effective components, such as the Bcl-2 family, Atg and p62. On the other hand, hypoxia-induced autophagy can serve as a mechanism to turn over nutrients, so as to mitigate the adverse condition and then avoid cell death potentially. Due to the effective role of hypoxia, this review focuses on the crosstalk in cell death under hypoxia in tumor progression. Additionally, the illumination of cell death in hypoxia could shed light on the clinical applications of cell death targeted therapy.

Effects of epigallocatechin gallate on ultra-violet-induced cell death in PC12 cells

International Nuclear Information System (INIS)

Takahashi, Hideo; Seki, Sakiko; Sakamoto, Naotaka; Nakagawa, Shigeki

2002-01-01

We examined the effects of catechin on ultra-violet-induced cell death in PC12 cells. PC12 cells were irradiated by ultra-violet C (254 nm) (UVC). We found that the lactate dehydrogenase (LDH) activities in culture media and lipid peroxide in PC12 cells, which indicate cell death and cell membrane damage, respectively, were increased by UVC irradiation in a time-dependent manner. Cell death was gradually stimulated for 9 hours of cultivation after a UVC irradiation period of 10 or 30 min. Epigallocatechin gallate (EGCG), which is one of the main catechins found in green tea, suppressed the increase in LDH activity in culture medium and also inhibited the formation of lipid peroxide. IκB, a member of the cell death signaling system, was phosphorylated at 1 hour after 10 min of UVC irradiation. Stimulation of phosphorylation of IκB by UVC was suppressed by the addition of EGCG. We concluded that EGCG protects the PC12 cell from cell damage caused by UVC irradiation. (author)

Mitochondrial calcium uniporter silencing potentiates caspase-independent cell death in MDA-MB-231 breast cancer cells

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Curry, Merril C.; Peters, Amelia A. [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia); Kenny, Paraic A. [Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461 (United States); Roberts-Thomson, Sarah J. [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia); Monteith, Gregory R., E-mail: gregm@uq.edu.au [School of Pharmacy, The University of Queensland, Brisbane, Queensland 4072 (Australia)

2013-05-10

Highlights: •Some clinical breast cancers are associated with MCU overexpression. •MCU silencing did not alter cell death initiated with the Bcl-2 inhibitor ABT-263. •MCU silencing potentiated caspase-independent cell death initiated by ionomycin. •MCU silencing promoted ionomycin-mediated cell death without changes in bulk Ca{sup 2+}. -- Abstract: The mitochondrial calcium uniporter (MCU) transports free ionic Ca{sup 2+} into the mitochondrial matrix. We assessed MCU expression in clinical breast cancer samples using microarray analysis and the consequences of MCU silencing in a breast cancer cell line. Our results indicate that estrogen receptor negative and basal-like breast cancers are characterized by elevated levels of MCU. Silencing of MCU expression in the basal-like MDA-MB-231 breast cancer cell line produced no change in proliferation or cell viability. However, distinct consequences of MCU silencing were seen on cell death pathways. Caspase-dependent cell death initiated by the Bcl-2 inhibitor ABT-263 was not altered by MCU silencing; whereas caspase-independent cell death induced by the calcium ionophore ionomycin was potentiated by MCU silencing. Measurement of cytosolic Ca{sup 2+} levels showed that the promotion of ionomycin-induced cell death by MCU silencing occurs independently of changes in bulk cytosolic Ca{sup 2+} levels. This study demonstrates that MCU overexpression is a feature of some breast cancers and that MCU overexpression may offer a survival advantage against some cell death pathways. MCU inhibitors may be a strategy to increase the effectiveness of therapies that act through the induction of caspase-independent cell death pathways in estrogen receptor negative and basal-like breast cancers.

Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the Alzheimer's disease brain.

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Love, Julia E; Day, Ryan J; Gause, Justin W; Brown, Raquel J; Pu, Xinzhu; Theis, Dustin I; Caraway, Chad A; Poon, Wayne W; Rahman, Abir A; Morrison, Brad E; Rohn, Troy T

2017-01-01

Although harboring the apolipoprotein E4 ( APOE4 ) allele is a well known risk factor in Alzheimer's disease (AD), the mechanism by which it contributes to disease risk remains elusive. To investigate the role of proteolysis of apoE4 as a potential mechanism, we designed and characterized a site-directed cleavage antibody directed at position D151 of the mature form of apoE4 and E3. Characterization of this antibody indicated a high specificity for detecting synthesized recombinant proteins corresponding to the amino acid sequences 1-151 of apoE3 and E4 that would generate the 17 kDa (p17) fragment. In addition, this antibody also detected a ~17 kDa amino-terminal fragment of apoE4 following incubation with collagenase and matrix metalloproteinase-9 (MMP-9), but did not react with full-length apoE4. Application of this amino-terminal apoE cleavage-fragment (nApoECFp17) antibody, revealed nuclear labeling within glial cells and labeling of a subset of neurofibrillary tangles in the human AD brain. A quantitative analysis indicated that roughly 80% of labeled nuclei were microglia. To confirm these findings, cultured BV2 microglia cells were incubated with the amino-terminal fragment of apoE4 corresponding to the cleavage site at D151. The results indicated efficient uptake of this fragment and trafficking to the nucleus that also resulted in significant cell death. In contrast, a similarly designed apoE3 fragment showed no toxicity and primarily localized within the cytoplasm. These data suggest a novel cleavage event by which apoE4 is cleaved by the extracellular proteases, collagenase and MMP-9, generating an amino-terminal fragment that is then taken up by microglia, traffics to the nucleus and promotes cell death. Collectively, these findings provide important mechanistic insights into the mechanism by which harboring the APOE4 allele may elevate dementia risk observed in AD.

Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer.

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Sun, Yiming; Liu, Zhe; Zou, Xue; Lan, Yadong; Sun, Xiaojin; Wang, Xiu; Zhao, Surong; Jiang, Chenchen; Liu, Hao

2015-08-01

3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores.

Programmed cell death during quinoa perisperm development.

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López-Fernández, María Paula; Maldonado, Sara

2013-08-01

At seed maturity, quinoa (Chenopodium quinoa Willd.) perisperm consists of uniform, non-living, thin-walled cells full of starch grains. The objective of the present study was to study quinoa perisperm development and describe the programme of cell death that affects the entire tissue. A number of parameters typically measured during programmed cell death (PCD), such as cellular morphological changes in nuclei and cytoplasm, endoreduplication, DNA fragmentation, and the participation of nucleases and caspase-like proteases in nucleus dismantling, were evaluated; morphological changes in cytoplasm included subcellular aspects related to starch accumulation. This study proved that, following fertilization, the perisperm of quinoa simultaneously accumulates storage reserves and degenerates, both processes mediated by a programme of developmentally controlled cell death. The novel findings regarding perisperm development provide a starting point for further research in the Amaranthaceae genera, such as comparing seeds with and without perisperm, and specifying phylogeny and evolution within this taxon. Wherever possible and appropriate, differences between quinoa perisperm and grass starchy endosperm--a morphologically and functionally similar, although genetically different tissue--were highlighted and discussed.

Maitotoxin-induced liver cell death involving loss of cell ATP following influx of calcium

International Nuclear Information System (INIS)

Kutty, R.K.; Singh, Y.; Santostasi, G.; Krishna, G.

1989-01-01

Maitotoxin, one of the most potent marine toxins known, produced cell death in cultures of rat hepatocytes with a TD50 of 80 pM at 24 hr. The cell death, as indicated by a dose- and time-dependent leakage of lactate dehydrogenase (LDH), was also associated with the leakage of [14C]adenine nucleotides from hepatocytes prelabeled with [14C]-adenine. The toxic effect of maitotoxin was completely abolished by the omission of calcium from the culture medium. The cell death induced by maitotoxin increased with increasing concentrations of calcium in the medium. Treatment of hepatocytes with low concentrations of the toxin (less than 0.5 ng/ml) resulted in increases in 45Ca influx into the cells. At higher concentrations of maitotoxin (greater than 1ng/ml), the initial increase in 45Ca influx was followed by the release of the 45Ca from the cells into the medium. Since the 45Ca release paralleled the LDH leakage, the release of calcium was due to cell death. The 45Ca influx, [14C]adenine nucleotide leakage, and LDH leakage were effectively inhibited by verapamil, a calcium channel blocker. Maitotoxin also induced a time- and dose-dependent loss of ATP from hepatocytes, which preceded the [14C]adenine nucleotide and LDH leakage. Thus, it appears that the cell death resulting from maitotoxin treatment is caused by the elevated intracellular calcium, which in turn inhibits mitochondrial oxidative phosphorylation causing depletion of cell ATP. Loss of cell ATP may be the causative event in the maitotoxin-induced cell death

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.

Nerve Growth Factor in Cancer Cell Death and Survival

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Molloy, Niamh H.; Read, Danielle E.; Gorman, Adrienne M., E-mail: adrienne.gorman@nuigalway.ie [Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway (Ireland)

2011-02-01

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75{sup NTR}, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75{sup NTR}. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75{sup NTR}. This latter signaling through p75{sup NTR} promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75{sup NTR} mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.

The extrinsic cell death pathway and the élan mortel.

Science.gov (United States)

Wallach, D; Kang, T-B; Kovalenko, A

2008-10-01

Early in the exploration of the chemical nature of life, it was widely believed that the molecules of living organisms, by their very nature, differ from those of inorganic material molecules and possess a vital force ('élan vital'). Similarly, early scientific thinking on the subject of cell death and its induction by cytotoxic cells of the immune system was pervaded by a sense that the molecules mediating these functions possess intrinsic deadly activity and are dedicated exclusively to death-related tasks. This impression was also reflected in the initial notions of the mode of action of intracellular proteins that signal for death. It is now gradually becoming clear, however, that proteins participating in death induction also have functions unrelated to death. Nevertheless, as exemplified by studies of the function of caspase-8 (an enzyme that signals both for activation of the extrinsic cell-death pathway and for non-death-related effects), analysis of the mechanistic basis for such heterogeneity might allow identification of distinct structural determinants in the proteins participating in death induction that do bear death specificity.

Mechanisms of gender-linked ischemic brain injury

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Liu, Mingyue; Dziennis, Suzan; Hurn, Patricia D.; Alkayed, Nabil J.

2010-01-01

Biological sex is an important determinant of stroke risk and outcome. Women are protected from cerebrovascular disease relative to men, an observation commonly attributed to the protective effect of female sex hormones, estrogen and progesterone. However, sex differences in brain injury persist well beyond the menopause and can be found in the pediatric population, suggesting that the effects of reproductive steroids may not completely explain sexual dimorphism in stroke. We review recent advances in our understanding of sex steroids (estradiol, progesterone and testosterone) in the context of ischemic cell death and neuroprotection. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury will lead to a better understanding of basic mechanisms of brain cell death and is an important step toward designing more effective therapeutic interventions in stroke. PMID:19531872

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.

[Short-term outcomes of lung transplant recipients using organs from brain death donors].

Science.gov (United States)

He, W X; Jiang, C; Liu, X G; Huang, W; Chen, C; Jiang, L; Yang, B; Wu, K; Chen, Q K; Yang, Y; Yu, Y M; Jiang, G N

2016-12-01

Objective: To assess short-term outcomes after lung transplantation with organs procured following brain death. Methods: Between April 2015 and July 2016, all 17 recipients after lung transplantation using organs from brain death donors (DBD) at Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine were enrolled in this study. All patients were male, aging (60±7) years, including 11 chronic obstructive pulmonary disease, 5 idiopathic pulmonary fibrosis, 1 silicosis. Seventeen donors were 16 males and 1 female, with 10 traumatic brain injury, 5 cerebrovascular accident and 2 sudden cardiac death. Of 17 recipients receiving DBD lung transplant, 16 were single lung transplant. Data were collected including intubation duration of mechanical ventilation, hospital length of stay, incidence of pulmonary infection bronchus anastomosis complications, primary graft dysfunction (PGD), and acute rejection, bronchiolitis obliterans syndrome (BOS) as well as mortality of 90-day after lung transplantation. Results: Median duration of intubation were 2 (2) days ( M ( Q R )) in recipients after lung transplantation. The incidence of pulmonary infection and bronchus anastomosis complications were 15/17 and 5/17, respectively. Median length of stay in hospital were 56 (19) days. The ratio of readmission 1 month after discharge were 10/17. Mortality of 90-day post-transplant were 2/17. The incidence of PGD and BOS were 1/17 and 2/17, respectively. Conclusion: Recipients with DBD lung transplantation have an acceptable survival during short-term follow-up, but with higher incidences of complications related to infection post-transplantation.

Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

Energy Technology Data Exchange (ETDEWEB)

Chen, Ruochan [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Fu, Sha; Fan, Xue-Gong [Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Lotze, Michael T.; Zeh, Herbert J. [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Tang, Daolin, E-mail: tangd2@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Kang, Rui, E-mail: kangr@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

2015-03-13

High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-L-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death. - Highlights: • Nuclear DAMP complexes (nDCs) selectively induce cell death in macrophages, but not cancer cells. • TNFα-mediated oxidative stress is required for nDC-induced death. • RAGE-mediated Akt activation is required for nDC-induced TNFα release. • Blocking RAGE and TNFα inhibits nDC-induced macrophage cell death.

A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors.

Directory of Open Access Journals (Sweden)

Andrew R Schwendeman

Full Text Available Programmed cell death is a ubiquitous process in metazoan development. Apoptosis, one cell death form, has been studied extensively. However, mutations inactivating key mammalian apoptosis regulators do not block most developmental cell culling, suggesting that other cell death pathways are likely important. Recent work in the nematode Caenorhabditis elegans identified a non-apoptotic cell death form mediating the demise of the male-specific linker cell. This cell death process (LCD, linker cell-type death is morphologically conserved, and its molecular effectors also mediate axon degeneration in mammals and Drosophila. To develop reagents to manipulate LCD, we established a simple high-throughput screening protocol for interrogating the effects of small molecules on C. elegans linker cell death in vivo. From 23,797 compounds assayed, 11 reproducibly block linker cell death onset. Of these, five induce animal lethality, and six promote a reversible developmental delay. These results provide proof-of principle validation of our screening protocol, demonstrate that developmental progression is required for linker cell death, and suggest that larger scale screens may identify LCD-specific small-molecule regulators that target the LCD execution machinery.

Sugar for the brain: the role of glucose in physiological and pathological brain function.

Science.gov (United States)

Mergenthaler, Philipp; Lindauer, Ute; Dienel, Gerald A; Meisel, Andreas

2013-10-01

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We synthesize these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Sorafenib-induced defective autophagy promotes cell death by necroptosis

OpenAIRE

Kharaziha, Pedram; Chioureas, Dimitris; Baltatzis, George; Fonseca, Pedro; Rodriguez, Patricia; Gogvadze, Vladimir; Lennartsson, Lena; Bj?rklund, Ann-Charlotte; Zhivotovsky, Boris; Grand?r, Dan; Egevad, Lars; Nilsson, Sten; Panaretakis, Theocharis

2015-01-01

Autophagy is one of the main cytoprotective mechanisms that cancer cells deploy to withstand the cytotoxic stress and survive the lethal damage induced by anti-cancer drugs. However, under specific conditions, autophagy may, directly or indirectly, induce cell death. In our study, treatment of the Atg5-deficient DU145 prostate cancer cells, with the multi-tyrosine kinase inhibitor, sorafenib, induces mitochondrial damage, autophagy and cell death. Molecular inhibition of autophagy by silencin...

Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion.

Science.gov (United States)

Giménez-Cassina, Alfredo; Lim, Filip; Díaz-Nido, Javier

2012-12-07

Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. Likewise, activation of glycogen synthase kinase-3 (GSK-3) has been proposed to play an important role in neurodegeneration. This multifunctional protein kinase is involved in a number of cellular functions and we previously showed that chronic inhibition of GSK-3 protects neuronal cells against mitochondrial dysfunction-elicited cell death, through a mechanism involving increased glucose metabolism and the translocation of hexokinase II (HKII) to mitochondria. Here, we sought to gain deeper insight into the molecular basis of this neuroprotection. We found that chronic inhibition of GSK-3, either genetically or pharmacologically, elicited a marked increase in brain-derived neurotrophic factor (BDNF) secretion, which in turn conferred resistance to mitochondrial dysfunction through subcellular re-distribution of HKII. These results define a molecular pathway through which chronic inhibition of GSK-3 may protect neuronal cells from death. Moreover, they highlight the potential benefits of enhanced neurotrophic factor secretion as a therapeutic approach to treat neurodegenerative diseases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Sensory hair cell death and regeneration in fishes

Directory of Open Access Journals (Sweden)

Jerry D. Monroe

2015-04-01

Full Text Available Sensory hair cells are specialized mechanotransductive receptors required for hearing and vestibular function. Loss of hair cells in humans and other mammals is permanent and causes reduced hearing and balance. In the early 1980’s, it was shown that hair cells continue to be added to the inner ear sensory epithelia in cartilaginous and bony fishes. Soon thereafter, hair cell regeneration was documented in the chick cochlea following acoustic trauma. Since then, research using chick and other avian models has led to great insights into hair cell death and regeneration. However, with the rise of the zebrafish as a model organism for studying disease and developmental processes, there has been an increased interest in studying sensory hair cell death and regeneration in its lateral line and inner ears. Advances derived from studies in zebrafish and other fish species include understanding the effect of ototoxins on hair cells and finding otoprotectants to mitigate ototoxin damage, the role of cellular proliferation versus direct transdifferentiation during hair cell regeneration, and elucidating cellular pathways involved in the regeneration process. This review will summarize research on hair cell death and regeneration using fish models, indicate the potential strengths and weaknesses of these models, and discuss several emerging areas of future studies.

Mechanisms of Virus-Induced Neural Cell Death

National Research Council Canada - National Science Library

Tyler, Kenneth

2002-01-01

Virtually all known neurotropic viruses are capable of killing infected cells by inducing a specific pattern of cell death known as apoptosis, yet the mechanism by which this occurs and its relevance...

Deaths of cancer cells observed after X-Ray irradiation

International Nuclear Information System (INIS)

Kuwahara, Yoshikazu; Oikawa, Toshiyuki; Ochiai, Yasushi; Fukumoto, Motoi; Kurihara, Ai; Noma, Naoto; Shimura, Tsutomu; Fukumoto, Manabu; Ohkubo, Yasuhito

2011-01-01

Radiation induces cell death by apoptosis, autophagy (autophagic cell death, APCD), necrosis, which are respectively called type I, II, III programmed cell death, senescence, mitotic catastrophe, etc. This paper mainly describes details of authors' studies on APCD of clinically relevant radioresistant (CRR) HepG2-8960-R cells established from proliferating survivor even after repeated X-irradiation of >30 days x 2 Gy/day to the parent HepG2 cells. Autophagy forms autophagosome where many proteins are thoroughly degraded differing from proteasomal ubiquitin system, has been known essentially related to death and survival of injured cells under certain tissue conditions, and is distinguishable from other modes of cell death by morphological and cytochemical means. One of important authors' findings is as follows. APCD of CRR cells is normally seen in 20% and of the parent strain, 5%. When they are X-irradiated at 10 Gy, APCD of the latter is more (70%) than the former (40%), and no APCD is induced by 2 Gy x 5 days in the former in contrast to the latter. APCD by radiation is thus conceivably suppressed in CRR cells, suggesting that their radioresistance can be reversed by treatment to induce APCD. Autophagy is usually suppressed by mammalian target of rapamycin (mTOR), and when CRR cells are treated with rapamycin, they become radiosensitive to the comparable level to the parent HepG2. When HepG2 cells are treated with 3-methyladenine, an inhibitor of autophagy, or Beclin siRNA, they become radioresistant. For effectiveness of APCD induction and suppression on cancer therapy, results are contradictory in certain reports and autophagy should be a problem to be further elucidated from radiation biology aspect. (author)

Targeting Cellular Calcium Homeostasis to Prevent Cytokine-Mediated Beta Cell Death.

Science.gov (United States)

Clark, Amy L; Kanekura, Kohsuke; Lavagnino, Zeno; Spears, Larry D; Abreu, Damien; Mahadevan, Jana; Yagi, Takuya; Semenkovich, Clay F; Piston, David W; Urano, Fumihiko

2017-07-17

Pro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.

Biosensor Technology Reveals the Disruption of the Endothelial Barrier Function and the Subsequent Death of Blood Brain Barrier Endothelial Cells to Sodium Azide and Its Gaseous Products.

Science.gov (United States)

Kho, Dan T; Johnson, Rebecca H; O'Carroll, Simon J; Angel, Catherine E; Graham, E Scott

2017-09-21

Herein we demonstrate the sensitive nature of human blood-brain barrier (BBB) endothelial cells to sodium azide and its gaseous product. Sodium azide is known to be acutely cytotoxic at low millimolar concentrations, hence its use as a biological preservative (e.g., in antibodies). Loss of barrier integrity was noticed in experiments using Electric Cell-substrate Impedance Sensing (ECIS) biosensor technology, to measure endothelial barrier integrity continuously in real-time. Initially the effect of sodium azide was observed as an artefact where it was present in antibodies being employed in neutralisation experiments. This was confirmed where antibody clones that were azide-free did not mediate loss of barrier function. A delayed loss of barrier function in neighbouring wells implied the influence of a liberated gaseous product. ECIS technology demonstrated that the BBB endothelial cells had a lower level of direct sensitivity to sodium azide of ~3 µM. Evidence of gaseous toxicity was consistently observed at 30 µM and above, with disrupted barrier function and cell death in neighbouring wells. We highlight the ability of this cellular biosensor technology to reveal both the direct and gaseous toxicity mediated by sodium azide. The sensitivity and temporal dimension of ECIS technology was instrumental in these observations. These findings have substantial implications for the wide use of sodium azide in biological reagents, raising issues of their application in live-cell assays and with regard to the protection of the user. This research also has wider relevance highlighting the sensitivity of brain endothelial cells to a known mitochondrial disruptor. It is logical to hypothesise that BBB endothelial dysfunction due to mitochondrial dys-regulation could have an important but underappreciated role in a range of neurological diseases.

Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death

International Nuclear Information System (INIS)

Ozaki, Kei-ichi; Minoda, Ai; Kishikawa, Futaba; Kohno, Michiaki

2006-01-01

Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated

The BRAIN Initiative Cell Census Consortium: Lessons Learned toward Generating a Comprehensive Brain Cell Atlas.

Science.gov (United States)

Ecker, Joseph R; Geschwind, Daniel H; Kriegstein, Arnold R; Ngai, John; Osten, Pavel; Polioudakis, Damon; Regev, Aviv; Sestan, Nenad; Wickersham, Ian R; Zeng, Hongkui

2017-11-01

A comprehensive characterization of neuronal cell types, their distributions, and patterns of connectivity is critical for understanding the properties of neural circuits and how they generate behaviors. Here we review the experiences of the BRAIN Initiative Cell Census Consortium, ten pilot projects funded by the U.S. BRAIN Initiative, in developing, validating, and scaling up emerging genomic and anatomical mapping technologies for creating a complete inventory of neuronal cell types and their connections in multiple species and during development. These projects lay the foundation for a larger and longer-term effort to generate whole-brain cell atlases in species including mice and humans. Copyright © 2017 Elsevier Inc. All rights reserved.

Cell death and autophagy: Cytokines, drugs, and nutritional factors

International Nuclear Information System (INIS)

Bursch, Wilfried; Karwan, Anneliese; Mayer, Miriam; Dornetshuber, Julia; Froehwein, Ulrike; Schulte-Hermann, Rolf; Fazi, Barbara; Di Sano, Federica; Piredda, Lucia; Piacentini, Mauro; Petrovski, Goran; Fesues, Laszlo; Gerner, Christopher

2008-01-01

Cells may use multiple pathways to commit suicide. In certain contexts, dying cells generate large amounts of autophagic vacuoles and clear large proportions of their cytoplasm, before they finally die, as exemplified by the treatment of human mammary carcinoma cells with the anti-estrogen tamoxifen (TAM, ≤1 μM). Protein analysis during autophagic cell death revealed distinct proteins of the nuclear fraction including GST-π and some proteasomal subunit constituents to be affected during autophagic cell death. Depending on the functional status of caspase-3, MCF-7 cells may switch between autophagic and apoptotic features of cell death [Fazi, B., Bursch, W., Fimia, G.M., Nardacci R., Piacentini, M., Di Sano, F., Piredda, L., 2008. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy 4(4), 435-441]. Furthermore, the self-destruction of MCF-7 cells was found to be completed by phagocytosis of cell residues [Petrovski, G., Zahuczky, G., Katona, K., Vereb, G., Martinet, W., Nemes, Z., Bursch, W., Fesues, L., 2007. Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes. Cell Death Diff. 14 (6), 1117-1128]. Autophagy also constitutes a cell's strategy of defense upon cell damage by eliminating damaged bulk proteins/organelles. This biological condition may be exemplified by the treatment of MCF-7 cells with a necrogenic TAM-dose (10 μM), resulting in the lysis of almost all cells within 24 h. However, a transient (1 h) challenge of MCF-7 cells with the same dose allowed the recovery of cells involving autophagy. Enrichment of chaperones in the insoluble cytoplasmic protein fraction indicated the formation of aggresomes, a potential trigger for autophagy. In a further experimental model HL60 cells were treated with TAM, causing dose-dependent distinct responses: 1-5 μM TAM, autophagy predominant; 7-9 μM, apoptosis predominant; 15 μM, necrosis. These phenomena might be

Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

Science.gov (United States)

Doitsh, Gilad; Galloway, Nicole L. K.; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

2014-01-01

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of `anti-AIDS' therapeutics targeting the host rather than the virus.

Radiation-induced apoptosis and developmental disturbance of the brain

Energy Technology Data Exchange (ETDEWEB)

Inouye, Minoru [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine

1995-03-01

The developing mammalian brain is highly susceptible to ionizing radiation. A significant increase in small head size and mental retardation has been noted in prenatally exposed survivors of the atomic bombing, with the highest risk in those exposed during 8-15 weeks after fertilization. This stage corresponds to day 13 of pregnancy for mice and day 15 for rats in terms of brain development. The initial damage produced by radiation at this stage is cell death in the ventricular zone (VZ) of the brain mantle, the radiosensitive germinal cell population. During histogenesis of the cerebellum the external granular layer (EGL) is also radiosensitive. Although extensive cell death results in microcephaly and histological abnormlity, both VZ and EGL have an ability to recover from a considerable cell loss and form the normal structure of the central nervous system. The number of cell deaths to induce tissue abnormalities in adult brain rises in the range of 15-25% of the germinal cell population; and the threshold doses are about 0.3 Gy for cerebral defects and 1 Gy for cerebellar anomalies in both mice and rats. A similar threshold level is suggested in human cases in induction of mental retardation. Radiation-induced cell death in the VZ and EGL has been revealed as apoptosis, by the nuclear and cytoplasmic condensation, transglutaminase activation, required macromolecular synthesis, and internucleosomal DNA cleavage. Apoptosis of the germinal cell is assumed to eliminate acquired genetic damage. Once an abnormality in DNA has been induced and fixed in a germinal cell, it would be greatly amplified during future proliferation. These cells would commit suicide when injured for replacement by healthy cells, rather than undertake DNA repair. In fact they show very slow repair of cellular damage. Thus the high sensitivity of undifferentiated neural cells to the lethal effect of radiation may constitute a biological defense mechanism. (author) 69 refs.

Radiation-induced apoptosis and developmental disturbance of the brain

International Nuclear Information System (INIS)

Inouye, Minoru

1995-01-01

The developing mammalian brain is highly susceptible to ionizing radiation. A significant increase in small head size and mental retardation has been noted in prenatally exposed survivors of the atomic bombing, with the highest risk in those exposed during 8-15 weeks after fertilization. This stage corresponds to day 13 of pregnancy for mice and day 15 for rats in terms of brain development. The initial damage produced by radiation at this stage is cell death in the ventricular zone (VZ) of the brain mantle, the radiosensitive germinal cell population. During histogenesis of the cerebellum the external granular layer (EGL) is also radiosensitive. Although extensive cell death results in microcephaly and histological abnormlity, both VZ and EGL have an ability to recover from a considerable cell loss and form the normal structure of the central nervous system. The number of cell deaths to induce tissue abnormalities in adult brain rises in the range of 15-25% of the germinal cell population; and the threshold doses are about 0.3 Gy for cerebral defects and 1 Gy for cerebellar anomalies in both mice and rats. A similar threshold level is suggested in human cases in induction of mental retardation. Radiation-induced cell death in the VZ and EGL has been revealed as apoptosis, by the nuclear and cytoplasmic condensation, transglutaminase activation, required macromolecular synthesis, and internucleosomal DNA cleavage. Apoptosis of the germinal cell is assumed to eliminate acquired genetic damage. Once an abnormality in DNA has been induced and fixed in a germinal cell, it would be greatly amplified during future proliferation. These cells would commit suicide when injured for replacement by healthy cells, rather than undertake DNA repair. In fact they show very slow repair of cellular damage. Thus the high sensitivity of undifferentiated neural cells to the lethal effect of radiation may constitute a biological defense mechanism. (author) 69 refs

Nonlinear Dynamic Theory of Acute Cell Injuries and Brain Ischemia

Science.gov (United States)

Taha, Doaa; Anggraini, Fika; Degracia, Donald; Huang, Zhi-Feng

2015-03-01

Cerebral ischemia in the form of stroke and cardiac arrest brain damage affect over 1 million people per year in the USA alone. In spite of close to 200 clinical trials and decades of research, there are no treatments to stop post-ischemic neuron death. We have argued that a major weakness of current brain ischemia research is lack of a deductive theoretical framework of acute cell injury to guide empirical studies. A previously published autonomous model based on the concept of nonlinear dynamic network was shown to capture important facets of cell injury, linking the concept of therapeutic to bistable dynamics. Here we present an improved, non-autonomous formulation of the nonlinear dynamic model of cell injury that allows multiple acute injuries over time, thereby allowing simulations of both therapeutic treatment and preconditioning. Our results are connected to the experimental data of gene expression and proteomics of neuron cells. Importantly, this new model may be construed as a novel approach to pharmacodynamics of acute cell injury. The model makes explicit that any pro-survival therapy is always a form of sub-lethal injury. This insight is expected to widely influence treatment of acute injury conditions that have defied successful treatment to date. This work is supported by NIH NINDS (NS081347) and Wayne State University President's Research Enhancement Award.

Edaravone suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma

Science.gov (United States)

Akaiwa, Kei; Namekata, Kazuhiko; Azuchi, Yuriko; Guo, Xiaoli; Kimura, Atsuko; Harada, Chikako; Mitamura, Yoshinori; Harada, Takayuki

2017-01-01

Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino-acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs. Loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP) and exhibits glaucomatous pathology including glutamate neurotoxicity and oxidative stress. In the present study, we found that edaravone, a free radical scavenger that is used for treatment of acute brain infarction and amyotrophic lateral sclerosis (ALS), reduces oxidative stress and prevents RGC death and thinning of the inner retinal layer in EAAC1-deficient (KO) mice. In addition, in vivo electrophysiological analyses demonstrated that visual impairment in EAAC1 KO mice was ameliorated with edaravone treatment, clearly establishing that edaravone beneficially affects both histological and functional aspects of the glaucomatous retina. Our findings raise intriguing possibilities for the management of glaucoma by utilizing a widely prescribed drug for the treatment of acute brain infarction and ALS, edaravone, in combination with conventional treatments to lower IOP. PMID:28703795

Transient Receptor Potential Vanilloid 1 Expression Mediates Capsaicin-Induced Cell Death

Directory of Open Access Journals (Sweden)

Ricardo Ramírez-Barrantes

2018-06-01

Full Text Available The transient receptor potential (TRP ion channel family consists of a broad variety of non-selective cation channels that integrate environmental physicochemical signals for dynamic homeostatic control. Involved in a variety of cellular physiological processes, TRP channels are fundamental to the control of the cell life cycle. TRP channels from the vanilloid (TRPV family have been directly implicated in cell death. TRPV1 is activated by pain-inducing stimuli, including inflammatory endovanilloids and pungent exovanilloids, such as capsaicin (CAP. TRPV1 activation by high doses of CAP (>10 μM leads to necrosis, but also exhibits apoptotic characteristics. However, CAP dose–response studies are lacking in order to determine whether CAP-induced cell death occurs preferentially via necrosis or apoptosis. In addition, it is not known whether cytosolic Ca2+ and mitochondrial dysfunction participates in CAP-induced TRPV1-mediated cell death. By using TRPV1-transfected HeLa cells, we investigated the underlying mechanisms involved in CAP-induced TRPV1-mediated cell death, the dependence of CAP dose, and the participation of mitochondrial dysfunction and cytosolic Ca2+ increase. Together, our results contribute to elucidate the pathophysiological steps that follow after TRPV1 stimulation with CAP. Low concentrations of CAP (1 μM induce cell death by a mechanism involving a TRPV1-mediated rapid and transient intracellular Ca2+ increase that stimulates plasma membrane depolarization, thereby compromising plasma membrane integrity and ultimately leading to cell death. Meanwhile, higher doses of CAP induce cell death via a TRPV1-independent mechanism, involving a slow and persistent intracellular Ca2+ increase that induces mitochondrial dysfunction, plasma membrane depolarization, plasma membrane loss of integrity, and ultimately, cell death.

Methuosis: Nonapoptotic Cell Death Associated with Vacuolization of Macropinosome and Endosome Compartments

OpenAIRE

Maltese, William A.; Overmeyer, Jean H.

2014-01-01

Apoptosis is the most widely recognized form of physiological programmed cell death. During the past three decades, various nonapoptotic forms of cell death have gained increasing attention, largely because of their potential importance in pathological processes, toxicology, and cancer therapy. A recent addition to the panoply of cell death phenotypes is methuosis. The neologism is derived from the Greek methuo (to drink to intoxication) because the hallmark of this form of cell death is disp...

Endothelial cell marker PAL-E reactivity in brain tumor, developing brain, and brain disease

NARCIS (Netherlands)

Leenstra, S.; Troost, D.; Das, P. K.; Claessen, N.; Becker, A. E.; Bosch, D. A.

1993-01-01

The endothelial cell marker PAL-E is not reactive to vessels in the normal brain. The present study concerns the PAL-E reactivity in brain tumors in contrast to normal brain and nonneoplastic brain disease. A total of 122 specimens were examined: brain tumors (n = 94), nonneoplastic brain disease (n

Therapeutic approaches to preventing cell death in Huntington disease.

Science.gov (United States)

Kaplan, Anna; Stockwell, Brent R

2012-12-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death.

Science.gov (United States)

Hegedűs, Csaba; Lakatos, Petra; Kiss-Szikszai, Attila; Patonay, Tamás; Gergely, Szabolcs; Gregus, Andrea; Bai, Péter; Haskó, György; Szabó, Éva; Virág, László

2013-06-01

Screening of a small in-house library of 1863 compounds identified 29 compounds that protected Jurkat cells from hydrogen peroxide-induced cytotoxicity. From the cytoprotective compounds eleven proved to possess antioxidant activity (ABTS radical scavenger effect) and two were found to inhibit poly(ADP-ribosyl)ation (PARylation), a cytotoxic pathway operating in severely injured cells. Four cytoprotective dibenzoylmethane (DBM) derivatives were investigated in more detail as they did not scavenge hydrogen peroxide nor did they inhibit PARylation. These compounds protected cells from necrotic cell death while caspase activation, a parameter of apoptotic cell death was not affected. Hydrogen peroxide activated extracellular signal regulated kinase (ERK1/2) and p38 MAP kinases but not c-Jun N-terminal kinase (JNK). The cytoprotective DBMs suppressed the activation of Erk1/2 but not that of p38. Cytoprotection was confirmed in another cell type (A549 lung epithelial cells), indicating that the cytoprotective effect is not cell type specific. In conclusion we identified DBM analogs as a novel class of cytoprotective compounds inhibiting ERK1/2 kinase and protecting from necrotic cell death by a mechanism independent of poly(ADP-ribose) polymerase inhibition. Copyright © 2013 Elsevier Ltd. All rights reserved.

HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

Science.gov (United States)

Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

2009-03-01

HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

Zinc as a paracrine effector in pancreatic islet cell death.

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Kim, B J; Kim, Y H; Kim, S; Kim, J W; Koh, J Y; Oh, S H; Lee, M K; Kim, K W; Lee, M S

2000-03-01

Because of a huge amount of Zn2+ in secretory granules of pancreatic islet beta-cells, Zn2+ released in certain conditions might affect the function or survival of islet cells. We studied potential paracrine effects of endogenous Zn2+ on beta-cell death. Zn2+ induced insulinoma/islet cell death in a dose-dependent manner. Chelation of released endogenous Zn2+ by CaEDTA significantly decreased streptozotocin (STZ)-induced islet cell death in an in vitro culture system simulating in vivo circumstances but not in the conventional culture system. Zn2+ chelation in vivo by continuous CaEDTA infusion significantly decreased the incidence of diabetes after STZ administration. N-(6-methoxy-quinolyl)-para-toluene-sulfonamide staining revealed that Zn2+ was densely deposited in degenerating islet cells 24 h after STZ treatment, which was decreased by CaEDTA infusion. We show here that Zn2+ is not a passive element for insulin storage but an active participant in islet cell death in certain conditions, which in time might contribute to the development of diabetes in aged people.

Proliferation and cell death in an experimental model of brain tissue heterotopia in the lung Proliferação e morte celular na heterotopia encefálica experimental

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Paulo Roberto Veiga Quemelo

2010-08-01

Full Text Available PURPOSE: To investigate the proliferation and neuronal death in brain tissue heterotopia in the lung in an experimental model during both fetal and neonatal periods. METHODS: Twenty four pregnant female Swiss mice were used to induce brain tissue heterotopia on the 15th gestational day. Briefly, the brain of one fetus of each dam was extracted, disaggregated and injected into the right hemithorax of siblings. Six of these fetuses with pulmonary brain tissue implantation (PBI were collected on the 18th gestational day (group E18 and six other on the 8th postnatal day (group P8. Immunohistochemical staining for PCNA and Bcl2 were used to assess proliferation and cell death. RESULTS: PCNA Labelling Index (LI in heterotopic brain tissue was greater in fetal than postnatal period (E18 > P8 (pOBJETIVO: Investigar a proliferação e morte neuronal na heterotopia encefálica pulmonar em modelo experimental durante o período fetal e neonatal. MÉTODOS: Foram utilizados 24 camundongos Swiss fêmeas prenhes para induzir a heterotopia encefálica no pulmão. O tecido encefálico de um feto de cada fêmea prenha foi removido, picotado e injetado no pulmão dos irmãos. Seis fetos com Implantação Encefálica Pulmonar (IEP foram coletados no 18º dia gestacional (grupo E18 e seis outros fetos no 8º dia pós-natal (grupo P8. Foi realizada a reação Imuno-histoquímica para PCNA e Bcl2 para analisar a proliferação e morte celular. RESULTADOS: O índice de marcação (IM para PCNA era maior no período fetal quando comparado com o período pós-natal (E8 > P18 (p<0,05 e a imunomarcação para o anticorpo Bcl2 não apresentou diferença. CONCLUSÃO: A proliferação celular foi mantida no tecido heterotópico encefálico, embora a apoptose também foi observada.

Active ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis.

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Overmeyer, Jean H; Kaul, Aparna; Johnson, Erin E; Maltese, William A

2008-06-01

Expression of activated Ras in glioblastoma cells induces accumulation of large phase-lucent cytoplasmic vacuoles, followed by cell death. This was previously described as autophagic cell death. However, unlike autophagosomes, the Ras-induced vacuoles are not bounded by a double membrane and do not sequester organelles or cytoplasm. Moreover, they are not acidic and do not contain the autophagosomal membrane protein LC3-II. Here we show that the vacuoles are enlarged macropinosomes. They rapidly incorporate extracellular fluid-phase tracers but do not sequester transferrin or the endosomal protein EEA1. Ultimately, the cells expressing activated Ras detach from the substratum and rupture, coincident with the displacement of cytoplasm with huge macropinosome-derived vacuoles. These changes are accompanied by caspase activation, but the broad-spectrum caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone does not prevent cell death. Moreover, the majority of degenerating cells do not exhibit chromatin condensation typical of apoptosis. These observations provide evidence for a necrosis-like form of cell death initiated by dysregulation of macropinocytosis, which we have dubbed "methuosis." An activated form of the Rac1 GTPase induces a similar form of cell death, suggesting that Ras acts through Rac-dependent signaling pathways to hyperstimulate macropinocytosis in glioblastoma. Further study of these signaling pathways may lead to the identification of other chemical and physiologic triggers for this unusual form of cell death.

A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors

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Li Shengwen

2008-05-01

Full Text Available Abstract Brain tumors are now the leading cause of cancer-related deaths in children under age 15. Malignant gliomas are, for all practical purposes, incurable and new therapeutic approaches are desperately needed. One emerging strategy is to use the tumor tracking capacity inherent in many stem cell populations to deliver therapeutic agents to the brain cancer cells. Current limitations of the stem cell therapy strategy include that stem cells are treated as a single entity and lack of uniform technology is adopted for selection of clinically relevant sub-populations of stem cells. Specifically, therapeutic success relies on the selection of a clinically competent stem cell population based on their capacity of targeting brain tumors. A novel and generalizable organotypic slice platform to evaluate stem cell potential for targeting pediatric brain tumors is proposed to fill the gap in the current work flow of stem cell-based therapy. The organotypic slice platform has advantages of being mimic in vivo model, easier to manipulate to optimize parameters than in vivo models such as rodents and primates. This model serves as a framework to address the discrepancy between anticipated in vivo results and actual in vivo results, a critical barrier to timely progress in the field of the use of stem cells for the treatment of neurological disorders.

Long-term treatment of anterior pituitary cells with nitric oxide induces programmed cell death.

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Velardez, Miguel Omar; Poliandri, Ariel Hernán; Cabilla, Jimena Paula; Bodo, Cristian Carlos Armando; Machiavelli, Leticia Inés; Duvilanski, Beatriz Haydeé

2004-04-01

Nitric oxide (NO) plays a complex role in modulating programmed cell death. It can either protect the cell from apoptotic death or mediate apoptosis, depending on its concentration and the cell type and/or status. In this study, we demonstrate that long-term exposition to NO induces cell death of anterior pituitary cells from Wistar female rats. DETA NONOate (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, 1 mm], a NO donor that releases NO for an extended period of time, decreased cellular viability and prolactin release from primary cultures of anterior pituitary cells. Morphological studies showed an increase in the number of cells with chromatin condensation and nuclear fragmentation at 24 and 48 h after DETA/NO exposure. DNA internucleosomal fragmentation was also observed at the same time. Reversibility of the NO effect on cellular viability and prolactin release was observed only when the cells were incubated with DETA/NO for less than 6 h. Most apoptotic cells were immunopositive for prolactin, suggesting a high susceptibility of lactotrophs to the effect of NO. The cytotoxic effect of NO is dependent of caspase-9 and caspase-3, but seems to be independent of oxidative stress or nitrosative stress. Our results show that the exposition of anterior pituitary cells to NO for long periods induces programmed cell death of anterior pituitary cells.

Spirulina maxima extract prevents cell death through BDNF activation against amyloid beta 1-42 (Aβ1-42) induced neurotoxicity in PC12 cells.

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Koh, Eun-Jeong; Kim, Kui-Jin; Choi, Jia; Kang, Do-Hyung; Lee, Boo-Yong

2018-04-23

Spirulina maxima is a blue-green micro alga that contains abundant amounts of proteins (60-70%), vitamins, chlorophyll a, and C-phycocyanin (C-PC). It has been shown to reduce oxidative stress, and prevent diabetes and non-alcoholic fatty liver disease. However, it is unclear whether Spirulina maxima 70% ethanol extract (SM70EE), chlorophyll a, and C-PC prevent Aβ 1-42 -induced neurotoxicity in PC12 cells. The aim of this study was to investigate whether SM70EE, chlorophyll a, and C-PC prevent Aβ 1-42 -induced cell death. SM70EE, chlorophyll a, and C-PC suppressed the Aβ 1-42 -induced increase in poly-ADP ribose polymerase-1 (PARP-1) cleavage and reduced Aβ 1-42 -induced decreases in glutathione and its associated factors. The level of brain-derived neurotrophic factor (BDNF), which plays a critical role in neuronal survival and neuroprotection, was increased by SM70EE, chlorophyll a, and C-PC in Aβ 1-42 -treated cells. SM70EE treatment decreased oxidative stress and cell death in response to Aβ 1-42 treatment, while simultaneously suppressing PARP cleavage and increasing the levels of glutathione (GSH) and its associated factors. Moreover, SM70EE lowered the levels of APP and BACE1, two major factors involved in APP processing, and increased BDNF expression during Aβ 1-42 -induced neurotoxicity in PC12 cells. We suggest that SM70EE prevents cell death caused by Aβ 1-42 -induced neurotoxicity via the activation of BDNF signaling. Copyright © 2018 Elsevier B.V. All rights reserved.

Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

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Maria Dolores Boyano

2011-03-01

Full Text Available Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies.

Redox dynamics of manganese as a mitochondrial life-death switch

International Nuclear Information System (INIS)

Smith, Matthew Ryan; Fernandes, Jolyn; Go, Young-Mi; Jones, Dean P.

2017-01-01

Sten Orrenius, M.D., Ph.D., pioneered many areas of cellular and molecular toxicology and made seminal contributions to our knowledge of oxidative stress and glutathione (GSH) metabolism, organellar functions and Ca +2 -dependent mechanisms of cell death, and mechanisms of apoptosis. On the occasion of his 80 th birthday, we summarize current knowledge on redox biology of manganese (Mn) and its role in mechanisms of cell death. Mn is found in all organisms and has critical roles in cell survival and death mechanisms by regulating Mn-containing enzymes such as manganese superoxide dismutase (SOD2) or affecting expression and activity of caspases. Occupational exposures to Mn cause “manganism”, a Parkinson's disease-like condition of neurotoxicity, and experimental studies show that Mn exposure leads to accumulation of Mn in the brain, especially in mitochondria, and neuronal cell death occurs with features of an apoptotic mechanism. Interesting questions are why a ubiquitous metal that is essential for mitochondrial function would accumulate to excessive levels, cause increased H 2 O 2 production and lead to cell death. Is this due to the interactions of Mn with other essential metals, such as iron, or with toxic metals, such as cadmium? Why is the Mn loading in the human brain so variable, and why is there such a narrow window between dietary adequacy and toxicity? Are non-neuronal tissues similarly vulnerable to insufficiency and excess, yet not characterized? We conclude that Mn is an important component of the redox interface between an organism and its environment and warrants detailed studies to understand the role of Mn as a mitochondrial life-death switch. - Highlights: • Either insufficient or excess manganese activates mitochondria-mediated cell death. • The optimal healthy Mn exposure window is very narrow. • Mitochondrial H 2 O 2 production depends on Mn across physiologic to toxicologic range. • Integrative omics needed to understand

Modulating cell-to-cell variability and sensitivity to death ligands by co-drugging

International Nuclear Information System (INIS)

Flusberg, Deborah A; Sorger, Peter K

2013-01-01

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell-to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization. (paper)

Lipid raft involvement in yeast cell growth and death

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Mollinedo, Faustino, E-mail: fmollin@usal.es [Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas - Universidad de Salamanca, Salamanca (Spain)

2012-10-10

The notion that cellular membranes contain distinct microdomains, acting as scaffolds for signal transduction processes, has gained considerable momentum. In particular, a class of such domains that is rich in sphingolipids and cholesterol, termed as lipid rafts, is thought to compartmentalize the plasma membrane, and to have important roles in survival and cell death signaling in mammalian cells. Likewise, yeast lipid rafts are membrane domains enriched in sphingolipids and ergosterol, the yeast counterpart of mammalian cholesterol. Sterol-rich membrane domains have been identified in several fungal species, including the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe as well as the pathogens Candida albicans and Cryptococcus neoformans. Yeast rafts have been mainly involved in membrane trafficking, but increasing evidence implicates rafts in a wide range of additional cellular processes. Yeast lipid rafts house biologically important proteins involved in the proper function of yeast, such as proteins that control Na{sup +}, K{sup +}, and pH homeostasis, which influence many cellular processes, including cell growth and death. Membrane raft constituents affect drug susceptibility, and drugs interacting with sterols alter raft composition and membrane integrity, leading to yeast cell death. Because of the genetic tractability of yeast, analysis of yeast rafts could be an excellent model to approach unanswered questions of mammalian raft biology, and to understand the role of lipid rafts in the regulation of cell death and survival in human cells. A better insight in raft biology might lead to envisage new raft-mediated approaches to the treatment of human diseases where regulation of cell death and survival is critical, such as cancer and neurodegenerative diseases.

Lipid raft involvement in yeast cell growth and death

International Nuclear Information System (INIS)

Mollinedo, Faustino

2012-01-01

The notion that cellular membranes contain distinct microdomains, acting as scaffolds for signal transduction processes, has gained considerable momentum. In particular, a class of such domains that is rich in sphingolipids and cholesterol, termed as lipid rafts, is thought to compartmentalize the plasma membrane, and to have important roles in survival and cell death signaling in mammalian cells. Likewise, yeast lipid rafts are membrane domains enriched in sphingolipids and ergosterol, the yeast counterpart of mammalian cholesterol. Sterol-rich membrane domains have been identified in several fungal species, including the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe as well as the pathogens Candida albicans and Cryptococcus neoformans. Yeast rafts have been mainly involved in membrane trafficking, but increasing evidence implicates rafts in a wide range of additional cellular processes. Yeast lipid rafts house biologically important proteins involved in the proper function of yeast, such as proteins that control Na + , K + , and pH homeostasis, which influence many cellular processes, including cell growth and death. Membrane raft constituents affect drug susceptibility, and drugs interacting with sterols alter raft composition and membrane integrity, leading to yeast cell death. Because of the genetic tractability of yeast, analysis of yeast rafts could be an excellent model to approach unanswered questions of mammalian raft biology, and to understand the role of lipid rafts in the regulation of cell death and survival in human cells. A better insight in raft biology might lead to envisage new raft-mediated approaches to the treatment of human diseases where regulation of cell death and survival is critical, such as cancer and neurodegenerative diseases.

Sodium nitroprusside induces autophagic cell death in glutathione-depleted osteoblasts.