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Sample records for programmed death type-1

  1. Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces Fulminant Type 1 Diabetes.

    PubMed

    Miyoshi, Yuka; Ogawa, Osamu; Oyama, Yu

    2016-01-01

    Programmed cell death-1 (PD-1), an immunoreceptor, is located on T cells and pro-B cells and interacts with its ligands to inhibit T cell activation and proliferation, thereby promoting immunological self-tolerance. Nivolumab, an anti-PD1 antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition. Autoimmune adverse events are expected with PD-1 therapy. Fulminant type 1 diabetes is the subtype of type 1 diabetes. The clinical feature is the extremely rapid progression of hyperglycemia and ketoacidosis. Here we describe a 66-year-old woman with advanced melanoma who was treated with nivolumab. After 4 months and six doses of the medicine, the patient was admitted to the hospital with complaints of nausea and vomiting. The laboratory data showed ketonuria, hyperglycemia (531 mg/dl), high anion gap metabolic acidosis, HbA1c (7.3%), and absence of insulin-secreting capacity. These data are compatible with the criteria of fulminant type 1 diabetes. The patient was diagnosed with diabetic ketoacidosis because of fulminant type 1 diabetes. The findings of this case indicated that nivolumab can cause fulminant type 1 diabetes. Diabetic ketoacidosis due to fulminant type 1 diabetes is potentially fatal condition. Thus, diabetic ketoacidosis due to fulminant type 1 diabetes should be considered in the differential diagnosis when patients treated with nivolumab complain of gastrointestinal symptoms. PMID:27297738

  2. Programmed cell death

    SciTech Connect

    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.

  3. Programmed death-1 (PD-1)/PD-1 ligand pathway-mediated immune responses against human T-lymphotropic virus type 1 (HTLV-1) in HTLV-1-associated myelopathy/tropical spastic paraparesis and carriers with autoimmune disorders.

    PubMed

    Kozako, Tomohiro; Yoshimitsu, Makoto; Akimoto, Masaki; White, Yohann; Matsushita, Kakushi; Soeda, Shinji; Shimeno, Hiroshi; Kubota, Ryuji; Izumo, Shuji; Arima, Naomichi

    2011-11-01

    Human T-lymphotropic virus-1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia-lymphoma in individuals with dysfunctional immune responses. In this study, to characterize the HTLV-1-specific cytotoxic T lymphocyte (CTL) populations in asymptomatic HTLV-1 carriers (ACs), HAM/TSP patients, and carriers with autoimmune disorders (CAIDs), we examined the role of programmed death-1 and its ligand (PD-1/PD-L1) in HTLV-1-specific CTL functions using an HTLV-1 Tax/HLA-A*0201 tetramer and an HTLV-1 Tax/HLA-A*2402 tetramer. Interestingly, the percentage of HTLV-1 Tax301-309/HLA-A*2402 tetramer(+)CD8(+) cells expressing PD-1 in ACs was significantly higher than the percentage of HTLV-1 Tax11-19/HLA-A*0201 tetramer(+)CD8(+) cells expressing PD-1. PD-1 expression was significantly downregulated on HTLV-1-specific CTLs in HAM/TSP compared with ACs. PD-L1 expression was observed in a small proportion of unstimulated lymphocytes from ACs and was greater in ACs than in HAM/TSP and CAIDs after short-term culture. Furthermore, CTL degranulation was impaired in HAM/TSP, whereas anti-PD-L1 blockade significantly increased CTL function in ACs. Downregulation of PD-1 on HTLV-1-specific CTLs and loss of PD-L1 expression in HAM/TSP and CAIDs, along with impaired function of HTLV-1-specific CTLs in HAM/TSP, may underlie the apparently dysfunctional immune response against HTLV-1. PMID:21851845

  4. Immune therapy and β-cell death in type 1 diabetes.

    PubMed

    Lebastchi, Jasmin; Deng, Songyan; Lebastchi, Amir H; Beshar, Isabel; Gitelman, Stephen; Willi, Steven; Gottlieb, Peter; Akirav, Eitan M; Bluestone, Jeffrey A; Herold, Kevan C

    2013-05-01

    Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells. The killing of β-cells is not currently measurable; β-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify β-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure β-cell death in a clinical trial of teplizumab. We studied 43 patients with recent-onset T1D, 13 nondiabetic subjects, and 37 patients with T1D treated with FcR nonbinding anti-CD3 monoclonal antibody (teplizumab) or placebo. Patients with recent-onset T1D had higher rates of β-cell death versus nondiabetic control subjects, but patients with long-standing T1D had lower levels. When patients with recent-onset T1D were treated with teplizumab, β-cell function was preserved (P < 0.05) and the rates of β-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of β-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased β-cell death. PMID:23423576

  5. Programmed Death in Bacteria

    PubMed Central

    Lewis, Kim

    2000-01-01

    Programmed cell death (PCD) in bacteria plays an important role in developmental processes, such as lysis of the mother cell during sporulation of Bacillus subtilis and lysis of vegetative cells in fruiting body formation of Myxococcus xanthus. The signal transduction pathway leading to autolysis of the mother cell includes the terminal sporulation sigma factor EςK, which induces the synthesis of autolysins CwlC and CwlH. An activator of autolysin in this and other PCD processes is yet to be identified. Autolysis plays a role in genetic exchange in Streptococcus pneumoniae, and the gene for the major autolysin, lytA, is located in the same operon with recA. DNA from lysed cells is picked up by their neighbors and recombined into the chromosome by RecA. LytA requires an unknown activator controlled by a sensory kinase, VncS. Deletion of vncS inhibits autolysis and also decreases killing by unrelated antibiotics. This observation suggests that PCD in bacteria serves to eliminate damaged cells, similar to apoptosis of defective cells in metazoa. The presence of genes affecting survival without changing growth sensitivity to antibiotics (vncS, lytA, hipAB, sulA, and mar) indicates that bacteria are able to control their fate. Elimination of defective cells could limit the spread of a viral infection and donate nutrients to healthy kin cells. An altruistic suicide would be challenged by the appearance of asocial mutants without PCD and by the possibility of maladaptive total suicide in response to a uniformly present lethal factor or nutrient depletion. It is proposed that a low rate of mutation serves to decrease the probability that asocial mutants without PCD will take over the population. It is suggested that PCD is disabled in persistors, rare cells that are resistant to killing, to ensure population survival. It is suggested that lack of nutrients leads to the stringent response that suppresses PCD, producing a state of tolerance to antibiotics, allowing cells to

  6. Causes of Death and Prognostic Factors in Multiple Endocrine Neoplasia Type 1: A Prospective Study

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato; Uehara, Hirotsugu; Berna, Marc J.; Jensen, Robert T.

    2013-01-01

    Abstract Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking. To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%–14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled

  7. Programmed cell death in neurodevelopment.

    PubMed

    Yamaguchi, Yoshifumi; Miura, Masayuki

    2015-02-23

    Programmed cell death (PCD) is an evolutionarily conserved contributor to nervous system development. In the vertebrate peripheral nervous system, PCD is the basis of the neurotrophic theory, whereby cell death results from a surplus of neurons relative to target and competition for neurotrophic factors. In addition to stochastic cell death, PCD can be intrinsically determined by cell lineage or position and timing in both invertebrate and vertebrate central nervous systems. The underlying PCD molecular mechanisms include intrinsic transcription factor cascades and regulators of competence/susceptibility to cell death. Here, we provide a framework for understanding neural PCD from its regulation to its functions.

  8. Analysis of β-cell death in type 1 diabetes by droplet digital PCR.

    PubMed

    Usmani-Brown, Sahar; Lebastchi, Jasmin; Steck, Andrea K; Beam, Craig; Herold, Kevan C; Ledizet, Michel

    2014-09-01

    Type 1 diabetes (T1D) and other forms of diabetes are due to the killing of β-cells. However, the loss of β-cells has only been assessed by functional studies with a liquid meal or glucose that can be affected by environmental factors. As an indirect measure of β-cell death, we developed an assay using a novel droplet digital PCR that detects INS DNA derived from β-cells. The release of INS DNA with epigenetic modifications (unmethylated CpG) identifies the β-cellular source of the DNA. The assay can detect unmethylated DNA between a range of approximately 600 copies/μL and 0.7 copies/μL, with a regression coefficient for the log transformed copy number of 0.99. The assay was specific for unmethylated INS DNA in mixtures with methylated INS DNA. We analyzed the levels of unmethylated INS DNA in patients with recent onset T1D and normoglycemia subjects at high risk for disease and found increased levels of unmethylated INS DNA compared with nondiabetic control subjects (P < .0001). More than one-third of T1D patients and one-half of at-risk subjects had levels that were more than 2 SD than the mean of nondiabetic control subjects. We conclude that droplet digital PCR is a useful method to detect β-cell death and is more specific and feasible than other methods, such as nested real-time PCR. This new method may be a valuable tool for analyzing pathogenic mechanisms and the effects of treatments in all forms of diabetes. PMID:25004096

  9. Programmed cell death in protists.

    PubMed

    Deponte, Marcel

    2008-07-01

    Programmed cell death in protists does not seem to make sense at first sight. However, apoptotic markers in unicellular organisms have been observed in all but one of the six/eight major groups of eukaryotes suggesting an ancient evolutionary origin of this regulated process. This review summarizes the available data on apoptotic markers in non-opisthokonts and elucidates potential functions and evolution of programmed cell death. A newly discovered family of caspase-like proteases, the metacaspases, is considered to exert the function of caspases in unicellular organisms. Important results on metacaspases, however, showed that they cannot be always correlated to the measured proteolytic activity during protist cell death. Thus, a major challenge for apoptosis research in a variety of protists remains the identification of the molecular cell death machinery.

  10. β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

    PubMed Central

    Herold, Kevan C.; Usmani-Brown, Sahar; Ghazi, Tara; Lebastchi, Jasmin; Beam, Craig A.; Bellin, Melena D.; Ledizet, Michel; Sosenko, Jay M.; Krischer, Jeffrey P.; Palmer, Jerry P.

    2015-01-01

    Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data. BACKGROUND. The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured. METHODS. Here, we measured β cell death with an assay that detects β cell–derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants. RESULTS. In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not. CONCLUSION. We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period. TRIAL REGISTRATION. Clinicaltrials.gov NCT00097292. FUNDING

  11. Effectiveness of a Regional Prepregnancy Care Program in Women With Type 1 and Type 2 Diabetes

    PubMed Central

    Murphy, Helen R.; Roland, Jonathan M; Skinner, Timothy C.; Simmons, David; Gurnell, Eleanor; Morrish, Nicholas J.; Soo, Shiu-Ching; Kelly, Suzannah; Lim, Boon; Randall, Joanne; Thompsett, Sarah; Temple, Rosemary C.

    2010-01-01

    OBJECTIVE To implement and evaluate a regional prepregnancy care program in women with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS Prepregnancy care was promoted among patients and health professionals and delivered across 10 regional maternity units. A prospective cohort study of 680 pregnancies in women with type 1 and type 2 diabetes was performed. Primary outcomes were adverse pregnancy outcome (congenital malformation, stillbirth, or neonatal death), congenital malformation, and indicators of pregnancy preparation (5 mg folic acid, gestational age, and A1C). Comparisons were made with a historical cohort (n = 613 pregnancies) from the same units during 1999–2004. RESULTS A total of 181 (27%) women attended, and 499 women (73%) did not attend prepregnancy care. Women with prepregnancy care presented earlier (6.7 vs. 7.7 weeks; P < 0.001), were more likely to take 5 mg preconception folic acid (88.2 vs. 26.7%; P < 0.0001) and had lower A1C levels (A1C 6.9 vs. 7.6%; P < 0.0001). They had fewer adverse pregnancy outcomes (1.3 vs. 7.8%; P = 0.009). Multivariate logistic regression confirmed that in addition to glycemic control, lack of prepregnancy care was independently associated with adverse outcome (odds ratio 0.2 [95% CI 0.05–0.89]; P = 0.03). Compared with 1999–2004, folic acid supplementation increased (40.7 vs. 32.5%; P = 0.006) and congenital malformations decreased (4.3 vs. 7.3%; P = 0.04). CONCLUSIONS Regional prepregnancy care was associated with improved pregnancy preparation and reduced risk of adverse pregnancy outcome in type 1 and type 2 diabetes. Prepregnancy care had benefits beyond improved glycemic control and was a stronger predictor of pregnancy outcome than maternal obesity, ethnicity, or social disadvantage. PMID:21115765

  12. Sudden death due to rupture of the right internal carotid artery in neurofibromatosis type 1: A case report.

    PubMed

    Liang, Yue; Tong, Fang; Zhang, Lin; Li, Wenhe; Zhou, Yiwu

    2016-07-01

    Vascular involvement is a well-recognized manifestation of neurofibromatosis type 1 (NF1) which has the potential to be fatal when disrupted. We here present a case of sudden death due to the fatal arterial rupture resulted from infiltration of the neurofibromas. A 42-year-old man who suffered from NF1 presented a 1-h history of sudden onset of pain in his right cervical region. His condition worsened and became unconscious on his way to the emergency room. Despite resuscitation efforts, he died 30min later without regaining consciousness. Autopsy examination showed that a neurofibroma located around the right internal carotid artery, confirmed immunohistochemically with S-100, vimentin and CD34. Furthermore, proliferation of spindle cells positive for S-100 was seen in the wall of right internal carotid artery, which was disrupted and resulted in a hemorrhage. These findings suggest that the artery was disrupted by neurofibromas in the vascular wall, which led to fragility of the vessel. On the basis of these findings, we concluded that the cause of death was asphyxia resulting from airway obstruction compressed by the hematoma due to the arterial rupture. As the locality of the neurofibroma and hemorrhage were closed to the carotid baroreflex, we considered another possible mechanism of his sudden death, which could be cardiac inhibition induced by vagal stimulation. We hope this case will increase recognition of NF-1 vasculopathy when encountering any sudden death in NF1 patients. PMID:27497331

  13. Programmed cell death in aging

    PubMed Central

    Tower, John

    2015-01-01

    Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. During aging the cell turnover rate declines for several highly-mitotic tissues. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction. PMID:25862945

  14. Programmed Cell Death During Caenorhabditis elegans Development.

    PubMed

    Conradt, Barbara; Wu, Yi-Chun; Xue, Ding

    2016-08-01

    Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general. PMID:27516615

  15. Death education in baccalaureate nursing programs.

    PubMed

    Dickinson, G E

    1986-01-01

    These findings reveal that an emphasis on death and dying in baccalaureate nursing schools has definitely increased over the past 20 years. Ninety-five percent of the schools reported here have some emphasis on death and dying. The majority of nursing students take the death and dying offerings. Overwhelmingly, the professional background of the instructor is nursing. While only 5 percent of the schools do not offer anything in death and dying, nearly half of these plan to offer something "within the next five years." If death and dying offerings influence students' attitudes, as is suggested in research cited above, baccalaureate nursing programs in the United States apparently have taken positive steps toward helping nurses cope with dying over the past 20 years. If nurses themselves cannot deal with death, caring for a dying patient may be difficult. With continued increased emphasis on death and dying in nursing curricula, both nurses, patients, and patients' families will hopefully benefit.

  16. Setting up a Death Row Psychiatry Program.

    PubMed

    Yanofski, Jason

    2011-02-01

    Death row psychiatry contains a complex set of clinical, ethical, and legal questions. This Forensic Files column makes a case for correctional institutions starting death row programs to address these issues through uniform policies. A list of the relevant issues is provided. Specific issues discussed include death row psychiatric assessment, considering "justifiable" depression, treating for competency to be executed, and balancing boundaries between clinical and forensic work.

  17. Setting up a Death Row Psychiatry Program.

    PubMed

    Yanofski, Jason

    2011-02-01

    Death row psychiatry contains a complex set of clinical, ethical, and legal questions. This Forensic Files column makes a case for correctional institutions starting death row programs to address these issues through uniform policies. A list of the relevant issues is provided. Specific issues discussed include death row psychiatric assessment, considering "justifiable" depression, treating for competency to be executed, and balancing boundaries between clinical and forensic work. PMID:21468293

  18. Sudden death of a 15-year-old girl due to fulminant type 1 diabetes mellitus-diabetic ketoacidosis induced cerebral edema?

    PubMed

    Dong, Hongmei; Liu, Liang; Zhou, Yiwu; Mu, Jiao; Zhang, Ji

    2014-08-01

    Sudden death from fulminant type 1 diabetes mellitus is uncommon in forensic practice. Here we report the sudden death of a 15-year-old girl who presented with vomiting, fever and abdominal pain and died unexpectedly. Postmortem examination showed severe pancreatic islet destruction, cerebral edema and lipid vacuolization of the epithelium of the renal proximal tubules and liver cells. The biochemical analysis in reserved heart blood and vitreous fluid indicated the elevated levels of glucose and ketone bodies and lower glycosylated hemoglobin and C-peptide. The cause of death was attributed to fulminant type 1 diabetes mellitus which led to diabetic ketoacidosis-associated cerebral edema. This report suggested that the histological examination of the pancreas, liver and kidney, insulin immunohistochemistry, as well as biochemical analysis could be useful for the diagnosis of diabetes related death.

  19. Feasibility of the SMART Project: A Text Message Program for Adolescents With Type 1 Diabetes

    PubMed Central

    Mehta, Priya; Monaghan, Maureen; Cogen, Fran; Streisand, Randi

    2014-01-01

    Abstract This study investigated response rates to the Self-Management and Research Technology Project, a 6-week text message program for adolescents with type 1 diabetes designed to provide diabetes self-management reminders and education. The rate of response to texts was high, with 78% of texts responded to during the 6-week period. Girls and participants who self-reported sending a large number of personal daily texts had higher response rates; other demographic and medical variables were unrelated to text response rates. Inclusion of mobile health technologies such as text messages in clinical care may be a unique, relevant method of intervention for youths with type 1 diabetes, regardless of age, socioeconomic status, or glycemic control. PMID:25647048

  20. Programmed cell death and hybrid incompatibility.

    PubMed

    Frank, S A; Barr, C M

    2003-01-01

    We propose a new theory to explain developmental aberrations in plant hybrids. In our theory, hybrid incompatibilities arise from imbalances in the mechanisms that cause male sterility in hermaphroditic plants. Mitochondria often cause male sterility by killing the tapetal tissue that nurtures pollen mother cells. Recent evidence suggests that mitochondria destroy the tapetum by triggering standard pathways of programmed cell death. Some nuclear genotypes repress mitochondrial male sterility and restore pollen fertility. Normal regulation of tapetal development therefore arises from a delicate balance between the disruptive effects of mitochondria and the defensive countermeasures of the nuclear genes. In hybrids, incompatibilities between male-sterile mitochondria and nuclear restorers may frequently upset the regulatory control of programmed cell death, causing tapetal abnormalities and male sterility. We propose that hybrid misregulation of programmed cell death may also spill over into other tissues, explaining various developmental aberrations observed in hybrids.

  1. Programmed cell death in seeds of angiosperms.

    PubMed

    López-Fernández, María Paula; Maldonado, Sara

    2015-12-01

    During the diversification of angiosperms, seeds have evolved structural, chemical, molecular and physiologically developing changes that specially affect the nucellus and endosperm. All through seed evolution, programmed cell death (PCD) has played a fundamental role. However, examples of PCD during seed development are limited. The present review examines PCD in integuments, nucellus, suspensor and endosperm in those representative examples of seeds studied to date.

  2. Arabidopsis ACCELERATED CELL DEATH2 modulates programmed cell death.

    PubMed

    Yao, Nan; Greenberg, Jean T

    2006-02-01

    The Arabidopsis thaliana chloroplast protein ACCELERATED CELL DEATH2 (ACD2) modulates the amount of programmed cell death (PCD) triggered by Pseudomonas syringae and protoporphyrin IX (PPIX) treatment. In vitro, ACD2 can reduce red chlorophyll catabolite, a chlorophyll derivative. We find that ACD2 shields root protoplasts that lack chlorophyll from light- and PPIX-induced PCD. Thus, chlorophyll catabolism is not obligatory for ACD2 anti-PCD function. Upon P. syringae infection, ACD2 levels and localization change in cells undergoing PCD and in their close neighbors. Thus, ACD2 shifts from being largely in chloroplasts to partitioning to chloroplasts, mitochondria, and, to a small extent, cytosol. ACD2 protects cells from PCD that requires the early mitochondrial oxidative burst. Later, the chloroplasts of dying cells generate NO, which only slightly affects cell viability. Finally, the mitochondria in dying cells have dramatically altered movements and cellular distribution. Overproduction of both ACD2 (localized to mitochondria and chloroplasts) and ascorbate peroxidase (localized to chloroplasts) greatly reduces P. syringae-induced PCD, suggesting a pro-PCD role for mitochondrial and chloroplast events. During infection, ACD2 may bind to and/or reduce PCD-inducing porphyrin-related molecules in mitochondria and possibly chloroplasts that generate reactive oxygen species, cause altered organelle behavior, and activate a cascade of PCD-inducing events.

  3. Costs of Development and Maintenance of an Internet Program for Teens with Type 1 Diabetes

    PubMed Central

    Grey, Margaret; Liberti, Lauren; Whittemore, Robin

    2015-01-01

    Many adolescents with type 1 diabetes (T1D) have difficulty completing self-management tasks within the context of their social environments. Group-based approaches to psycho-educational support have been shown to prevent declines in glucose control, but are challenging to implement due to youths’ many activities and costs. A novel solution is providing psycho-educational support via the internet. The purpose of this study is to describe the cost of developing and maintaining two internet psycho-educational programs, both of which have been shown to improve health outcomes in adolescents with T1D. We calculated actual costs of personnel and programming in the development of TEENCOPE™ and Managing Diabetes, two highly interactive programs that were evaluated in a multi-site clinical trial (n=320). Cost calculations were set at U.S. dollars and converted to value for 2013 as expenses were incurred over 6 years. Development costs over 1.5 years totaled $324,609, with the majority of costs being for personnel to develop and write content in a creative and engaging format, to get feedback from teens on content and a prototype, and IT programming. Maintenance of the program, including IT support, a part-time moderator to assure safety of the discussion board (0.5–1 hour/week), and yearly update of content was $43,845/year, or $137.00 per youth over 4.5 years. Overall, program and site development were relatively expensive, but the program reach was high, including non-white youth from 4 geographically distinct regions. Once developed, maintenance was minimal. With greater dissemination, cost-per-youth would decrease markedly, beginning to offset the high development expense. PMID:26213677

  4. Research Program on Type 1 Diabetes and Youth Depression in Puerto Rico

    PubMed Central

    Cumba-Avilés, Eduardo; Sáez-Santiago, Emily

    2016-01-01

    This work reviews the progress and current state of a research program on Diabetes and youth depression in Puerto Rico. Given the high depression rate, its impact in youth with Type 1 Diabetes (T1D), and the lack of interventions to target this link in an integrative way, the manual titled Cognitive-Behavioral Treatment for Depression in Adolescents with T1D was developed. After its first use in an Open Trial, we currently assess the initial efficacy of its revised version to reduce depression and improve glycemic control, self-care, and quality of life. We present its approach, and initial data on its feasibility, acceptability and potential to reduce emotional problems in T1D youth. We discuss implications of this line of research for health psychology, and its utility to model the development of interventions alike focused on other chronic illnesses.

  5. Drug Monitoring Programs Do Curb Overdose Deaths: Study

    MedlinePlus

    ... html Drug Monitoring Programs Do Curb Overdose Deaths: Study Opioid epidemic demands such measures, researcher says To ... deaths from prescription painkillers called opioids, a new study finds. In an effort to curb overdose deaths ...

  6. Programmed cell death in cereal aleurone.

    PubMed

    Fath, A; Bethke, P; Lonsdale, J; Meza-Romero, R; Jones, R

    2000-10-01

    Progress in understanding programmed cell death (PCD) in the cereal aleurone is described. Cereal aleurone cells are specialized endosperm cells that function to synthesize and secrete hydrolytic enzymes that break down reserves in the starchy endosperm. Unlike the cells of the starchy endosperm, aleurone cells are viable in mature grain but undergo PCD when germination is triggered or when isolated aleurone layers or protoplasts are incubated in gibberellic acid (GA). Abscisic acid (ABA) slows down the process of aleurone cell death and isolated aleurone protoplasts can be kept alive in media containing ABA for up to 6 months. Cell death in barley aleurone occurs only after cells become highly vacuolated and is manifested in an abrupt loss of plasma membrane integrity. Aleurone cell death does not follow the apoptotic pathway found in many animal cells. The hallmarks of apoptosis, including internucleosomal DNA cleavage, plasma membrane and nuclear blebbing and formation of apoptotic bodies, are not observed in dying aleurone cells. PCD in barley aleurone cells is accompanied by the accumulation of a spectrum of nuclease and protease activities and the loss of organelles as a result of cellular autolysis.

  7. Causes of death due to hematological and non-hematological cancers in 57 US patients with type 1 Gaucher Disease who were never treated with enzyme replacement therapy.

    PubMed

    Weinreb, Neal J; Lee, Robert E

    2013-01-01

    Patients with type 1 Gaucher disease (GD1) have increased risk of developing myeloma, other hematological cancers, hepatocellular carcinoma, and other solid tumors. Patient awareness of the GD1-cancer association causes anxiety and fear. Little is known about cancer as a cause of death in GD1, especially in patients never treated with GD1-specific therapies. Consequently, the effect of treatment on cancer mortality in GD1 patients is difficult to evaluate. In this review, starting with a population of 184 GD1 cases never treated, we annotate and analyze the causes of death of 57 GD1 patients who died of cancer. The proportional mortality ratio (PMR) for all malignancies in patients with GD1 is 1.57 (p = 0.0002), but it is much higher for myeloma (PMR = 9.66) and other hematological cancers, hepatocellular carcinoma, and kidney cancer (PMR = ≍4). However, deaths from colorectal and pancreatic cancers were not more frequent than expected, and deaths from lung, breast, gynecological, and prostate cancer occurred less than anticipated. Herein, we discuss whether GD1 is truly a hereditary cancer syndrome and the problem of comorbidities and cancer risk assessment, and we speculate as to whether the variability in death by cancer type might be attributable to biochemical sequelae of tumor cell and macrophage/stromal cell GBA1 mutation affecting signals for metastasis, the process most closely associated with cancer mortality.

  8. Programmed cell death during quinoa perisperm development.

    PubMed

    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.

  9. Antagonizing programmed death-1 and programmed death ligand-1 as a therapeutic approach for gastric cancer

    PubMed Central

    Liu, Xiaojun; Yang, Zhongxia; Latchoumanin, Olivier; Qiao, Liang

    2016-01-01

    Malignant tumor cells are equipped with mechanisms that can help them escape the surveillance by host immune system. Immune checkpoint molecules can transduce coinhibitory signals to immunocompetent cells and exert immunosuppressive roles in antitumor immunity. Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are the two important checkpoint molecules with great potential in targeted cancer therapy. Several antibodies targeting PD-1 and PD-L1 have been approved for clinical use. In this review, we focus on the recent development of targeting PD-1 and PD-L1 in gastric cancer (GC) therapy. PMID:27803740

  10. Hemoglobins, programmed cell death and somatic embryogenesis.

    PubMed

    Hill, Robert D; Huang, Shuanglong; Stasolla, Claudio

    2013-10-01

    Programmed cell death (PCD) is a universal process in all multicellular organisms. It is a critical component in a diverse number of processes ranging from growth and differentiation to response to stress. Somatic embryogenesis is one such process where PCD is significantly involved. Nitric oxide is increasingly being recognized as playing a significant role in regulating PCD in both mammalian and plant systems. Plant hemoglobins scavenge NO, and evidence is accumulating that events that modify NO levels in plants also affect hemoglobin expression. Here, we review the process of PCD, describing the involvement of NO and plant hemoglobins in the process. NO is an effector of cell death in both plants and vertebrates, triggering the cascade of events leading to targeted cell death that is a part of an organism's response to stress or to tissue differentiation and development. Expression of specific hemoglobins can alter this response in plants by scavenging the NO, thus, interrupting the death process. Somatic embryogenesis is used as a model system to demonstrate how cell-specific expression of different classes of hemoglobins can alter the embryogenic process, affecting hormone synthesis, cell metabolite levels and genes associated with PCD and embryogenic competence. We propose that plant hemoglobins influence somatic embryogenesis and PCD through cell-specific expression of a distinct plant hemoglobin. It is based on the premise that both embryogenic competence and PCD are strongly influenced by cellular NO levels. Increases in cellular NO levels result in elevated Zn(2+) and reactive-oxygen species associated with PCD, but they also result in decreased expression of MYC2, a transcription factor that is a negative effector of indoleacetic acid synthesis, a hormone that positively influences embryogenic competence. Cell-specific hemoglobin expression reduces NO levels as a result of NO scavenging, resulting in cell survival.

  11. Herpes simplex virus type 1-induced FasL expression in human monocytic cells and its implications for cell death, viral replication, and immune evasion.

    PubMed

    Iannello, Alexandre; Debbeche, Olfa; El Arabi, Raoudha; Samarani, Suzanne; Hamel, David; Rozenberg, Flore; Heveker, Nikolaus; Ahmad, Ali

    2011-02-01

    Herpes simplex virus type 1 (HSV-1) is a ubiquitously occurring pathogen that infects humans early in childhood. The virus persists as a latent infection in dorsal root ganglia, especially of the trigeminal nerve, and frequently becomes reactivated in humans under conditions of stress. Monocytic cells constitute an important component of the innate and adaptive immune responses. We show here for the first time that HSV-1 stimulates human FasL promoter and induces de novo expression of FasL on the surface of human monocytic cells, including monocytes and macrophages. This virus-induced FasL expression causes death of monocytic cells growing in suspension, but not in monolayers (e.g., macrophages). The addition of a broad-spectrum caspase inhibitor, as well as anti-FasL antibodies, reduced cell death but increased viral replication in the virus-infected cell cultures. We also show here for the first time that the virus-induced de novo expression of FasL on the cell surface acts as an immune evasion mechanism by causing the death of interacting human CD4+ T cells, CD8+ T cells, and natural killer (NK) cells. Our study provides novel insights on FasL expression and cell death in HSV-infected human monocytic cells and their impact on interacting immune cells.

  12. Programmed Cell Death in Unicellular Phytoplankton.

    PubMed

    Bidle, Kay D

    2016-07-11

    Unicellular, planktonic, prokaryotic and eukaryotic photoautotrophs (phytoplankton) have an ancient evolutionary history on Earth during which time they have played key roles in the regulation of marine food webs, biogeochemical cycles, and Earth's climate. Since they represent the basis of aquatic ecosystems, the manner in which phytoplankton die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining nutrient flow. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of abiotic (nutrient, light, osmotic) and biotic (virus infection, allelopathy) environmental stresses, have an integral grip on cell fate, and have shaped the ecological success and evolutionary trajectory of diverse phytoplankton lineages. A combination of physiological, biochemical, and genetic techniques in model algal systems has demonstrated a conserved molecular and mechanistic framework of stress surveillance, signaling, and death activation pathways, involving collective and coordinated participation of organelles, redox enzymes, metabolites, and caspase-like proteases. This mechanistic understanding has provided insight into the integration of sensing and transduction of stress signals into cellular responses, and the mechanistic interfaces between PCD, cell stress and virus infection pathways. It has also provided insight into the evolution of PCD in unicellular photoautotrophs, the impact of PCD on the fate of natural phytoplankton assemblages and its role in aquatic biogeochemical cycles. PMID:27404255

  13. Programmed Cell Death in Unicellular Phytoplankton.

    PubMed

    Bidle, Kay D

    2016-07-11

    Unicellular, planktonic, prokaryotic and eukaryotic photoautotrophs (phytoplankton) have an ancient evolutionary history on Earth during which time they have played key roles in the regulation of marine food webs, biogeochemical cycles, and Earth's climate. Since they represent the basis of aquatic ecosystems, the manner in which phytoplankton die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining nutrient flow. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of abiotic (nutrient, light, osmotic) and biotic (virus infection, allelopathy) environmental stresses, have an integral grip on cell fate, and have shaped the ecological success and evolutionary trajectory of diverse phytoplankton lineages. A combination of physiological, biochemical, and genetic techniques in model algal systems has demonstrated a conserved molecular and mechanistic framework of stress surveillance, signaling, and death activation pathways, involving collective and coordinated participation of organelles, redox enzymes, metabolites, and caspase-like proteases. This mechanistic understanding has provided insight into the integration of sensing and transduction of stress signals into cellular responses, and the mechanistic interfaces between PCD, cell stress and virus infection pathways. It has also provided insight into the evolution of PCD in unicellular photoautotrophs, the impact of PCD on the fate of natural phytoplankton assemblages and its role in aquatic biogeochemical cycles.

  14. The Fas death pathway controls coordinated expansions of type 1 CD8 and type 2 CD4 T cells in Trypanosoma cruzi infection.

    PubMed

    Guillermo, Landi V Costilla; Silva, Elisabeth M; Ribeiro-Gomes, Flávia L; De Meis, Juliana; Pereira, Wânia F; Yagita, Hideo; DosReis, George A; Lopes, Marcela F

    2007-04-01

    We investigated the role of the Fas ligand (FasL)/Fas death pathway on apoptosis and cytokine production by T cells in Trypanosoma cruzi infection. Anti-FasL, but not anti-TNF-alpha or anti-TRAIL, blocked activation-induced cell death of CD8 T cells and increased secretion of IL-10 and IL-4 by CD4 T cells from T. cruzi-infected mice. CD4 and CD8 T cells up-regulated Fas/FasL expression during T. cruzi infection. However, Fas expression increased earlier in CD8 T cells, and a higher proportion of CD8 T cells was activated and expressed IFN-gamma compared with CD4 T cells. Injection of anti-FasL in infected mice reduced parasitemia and CD8 T cell apoptosis and increased the ratio of CD8:CD4 T cells recovered from spleen and peritoneum. FasL blockade increased the number of activated T cells, enhanced NO production, and reduced parasite loads in peritoneal macrophages. Injection of anti-FasL increased IFN-gamma secretion by splenocytes responding to T. cruzi antigens but also exacerbated production of type 2 cytokines IL-10 and IL-4 at a late stage of acute infection. These results indicate that the FasL/Fas death pathway regulates apoptosis and coordinated cytokine responses by type 1 CD8 and type 2 CD4 T cells in T. cruzi infection.

  15. Programmed cell death in the plant immune system

    PubMed Central

    Coll, N S; Epple, P; Dangl, J L

    2011-01-01

    Cell death has a central role in innate immune responses in both plants and animals. Besides sharing striking convergences and similarities in the overall evolutionary organization of their innate immune systems, both plants and animals can respond to infection and pathogen recognition with programmed cell death. The fact that plant and animal pathogens have evolved strategies to subvert specific cell death modalities emphasizes the essential role of cell death during immune responses. The hypersensitive response (HR) cell death in plants displays morphological features, molecular architectures and mechanisms reminiscent of different inflammatory cell death types in animals (pyroptosis and necroptosis). In this review, we describe the molecular pathways leading to cell death during innate immune responses. Additionally, we present recently discovered caspase and caspase-like networks regulating cell death that have revealed fascinating analogies between cell death control across both kingdoms. PMID:21475301

  16. [Selective "death programs" or pleiotropic"life programs"? Looking for programmed cell death in the light of evolution].

    PubMed

    Ameisen, Jean-Claude

    2005-01-01

    "Nothing in biology makes sense except in the light of evolution", wrote Theodosius Dobzhansky, one of the founders of the Modern Synthesis that led to the unification of evolutionary theory and genetics in the midst of the 20th century. Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new, and somehow puzzling level of complexity has recently begun to emerge, suggesting i) that several different self destruction pathways may exist and operate in parallel in our cells, and ii) that molecular effectors of cell suicide might also perform other functions unrelated to cell death induction and crucial to cell survival, such as cell differentiation, metabolism, and the regulation of the cell cycle. These new findings, with important physiopathological and therapeutic implications, seem at odds with the paradigm of programmed cell death derived from the studies of Caenorhabditis elegans, which led to the concept of the existence of selective, bona fide death genes that emerged and became selected for their sole capacity to execute or repress cell death. In this review, I will argue that this new level of complexity might only make sense and be understood when considered in a broader evolutionary context than that of our phylogenetic divergence from C. elegans. A new view of the regulated cell death pathways emerges when one attempts to ask the question of when and how they may have become selected during a timeline of 4 billion years, at the level of ancestral single-celled organisms, including the bacteria. I will argue that there may be no such thing as a bona fide genetic cell death program. Rather, in the framework of

  17. New Areas for Preventive Programing: Sudden Infant Death Syndrome.

    ERIC Educational Resources Information Center

    Lowman, Joseph

    Crisis intervention programs for persons experiencing the sudden death of family members or surviving natural disasters have been advocated as methods of primary prevention, although few have actually been implemented. A program utilizing nurses to deliver grief intervention to parents losing a baby to Sudden Infant Death Syndrome (SIDS) was…

  18. Programmed cell death for defense against anomaly and tumor formation

    SciTech Connect

    Kondo, Sohei; Norimura, Toshiyuki; Nomura, Taisei

    1995-12-31

    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.

  19. Hydrogen peroxide as a signal controlling plant programmed cell death

    PubMed Central

    Gechev, Tsanko S.; Hille, Jacques

    2005-01-01

    Hydrogen peroxide (H2O2) has established itself as a key player in stress and programmed cell death responses, but little is known about the signaling pathways leading from H2O2 to programmed cell death in plants. Recently, identification of key regulatory mutants and near-full genome coverage microarray analysis of H2O2-induced cell death have begun to unravel the complexity of the H2O2 network. This review also describes a novel link between H2O2 and sphingolipids, two signals that can interplay and regulate plant cell death. PMID:15631987

  20. Network of vascular diseases, death and biochemical characteristics in a set of 4,197 patients with type 1 diabetes (The FinnDiane Study)

    PubMed Central

    Mäkinen, Ville-Petteri; Forsblom, Carol; Thorn, Lena M; Wadén, Johan; Kaski, Kimmo; Ala-Korpela, Mika; Groop, Per-Henrik

    2009-01-01

    Background Cardiovascular disease is the main cause of premature death in patients with type 1 diabetes. Patients with diabetic kidney disease have an increased risk of heart attack or stroke. Accurate knowledge of the complex inter-dependencies between the risk factors is critical for pinpointing the best targets for research and treatment. Therefore, the aim of this study was to describe the association patterns between clinical and biochemical features of diabetic complications. Methods Medical records and serum and urine samples of 4,197 patients with type 1 diabetes were collected from health care centers in Finland. At baseline, the mean diabetes duration was 22 years, 52% were male, 23% had kidney disease (urine albumin excretion over 300 mg/24 h or end-stage renal disease) and 8% had a history of macrovascular events. All-cause mortality was evaluated after an average of 6.5 years of follow-up (25,714 patient years). The dataset comprised 28 clinical and 25 biochemical variables that were regarded as the nodes of a network to assess their mutual relationships. Results The networks contained cliques that were densely inter-connected (r > 0.6), including cliques for high-density lipoprotein (HDL) markers, for triglycerides and cholesterol, for urinary excretion and for indices of body mass. The links between the cliques showed biologically relevant interactions: an inverse relationship between HDL cholesterol and the triglyceride clique (r < -0.3, P < 10-16), a connection between triglycerides and body mass via C-reactive protein (r > 0.3, P < 10-16) and intermediate-density cholesterol as the connector between lipoprotein metabolism and albuminuria (r > 0.3, P < 10-16). Aging and macrovascular disease were linked to death via working ability and retinopathy. Diabetic kidney disease, serum creatinine and potassium, retinopathy and blood pressure were inter-connected. Blood pressure correlations indicated accelerated vascular aging in individuals with kidney

  1. Modulation of programmed cell death by medicinal plants.

    PubMed

    Thatte, U; Bagadey, S; Dahanukar, S

    2000-02-01

    Programmed cell death (apoptosis), a form of cell death, described by Kerr and Wyllie some 20 years ago, has generated considerable interest in recent years. The mechanisms by which this mode of cell death (seen both in animal and plant cells), takes place have been examined in detail. Extracellular signals and intracellular events have been elaborated. Of interest to the clinician, is the concentrated effort to study pharmacological modulation of programmed cell death. The attempt to influence the natural phenomenon of programmed cell death stems from the fact that it is reduced (like in cancer) or increased (like in neurodegenerative diseases) in several clinical situations. Thus, chemicals that can modify programmed cell death are likely to be potentially useful drugs. From foxglove, which gave digitalis to the Pacific Yew from which came taxol, plants have been a source of research material for useful drugs. Recently, a variety of plant extracts have been investigated for their ability to influence the apoptotic process. This article discusses some of the interesting data. The ability of plants to influence programmed cell death in cancerous cells in an attempt to arrest their proliferation has been the topic of much research. Various cell-lines like HL60, human hepatocellular carcinoma cell line (KIM-1), a cholangiocarcinoma cell-line (KMC-1), B-cell hybridomas, U937 a monocytic cell-line, HeLa cells, human lymphoid leukemia (MOLT-4B) cells and K562 cells have been studied. The agents found to induce programmed cell death (measured either morphologically or flow cytometrically) included extracts of plants like mistletoe and Semicarpus anacardium. Isolated compounds like bryonolic acid (from Trichosanthes kirilowii var. Japonica, crocin (from saffron) and allicin (from Allium sativum) have also been found to induce programmed cell death and therefore arrest proliferation. Even Chinese herbal medicine "Sho-saiko-to" induces programmed cell death in selected

  2. Centenarian Rates and Life Expectancy Related to the Death Rates of Multiple Sclerosis, Asthma, and Rheumatoid Arthritis and the Incidence of Type 1 Diabetes in Children.

    PubMed

    Lens-Pechakova, Lilia S

    2016-02-01

    The autoimmune diseases are among the 10 leading causes of death for women and the number two cause of chronic illness in America as well as a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter life span and are a model of accelerated immunosenescence. Conversely, centenarians are used as a model of successful aging and have shown several immune parameters that are better preserved and lower levels of autoantibodies. The study reported here focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed Organisation for Economic Co-operation and Development (OECD) countries, because multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relationship pattern, help to identify common factors, and determine new important factors that contribute to longevity and healthy aging. The relationships between the mortality rates data of multiple sclerosis (MS), rheumatoid arthritis (RA), asthma, the incidence of type 1 diabetes (T1D) from one side and centenarian rates (two sets) as well as life expectancy data from the other side were assessed using regression models and Pearson correlation coefficients. The data obtained correspond to an inverse linear correlation with different degrees of linearity. This is the first observation of a clear tendency of diminishing centenarian rates or life expectancy in countries having higher death rates of asthma, MS, and RA and a higher incidence of T1D in children. The conclusion is that most probably there are common mechanistic pathways and factors affecting the above diseases and at the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways, and other factors connected to autoimmune diseases with those of longevity could clarify the processes involved, so as to promote longevity and limit the expansion of those

  3. Centenarian Rates and Life Expectancy Related to the Death Rates of Multiple Sclerosis, Asthma, and Rheumatoid Arthritis and the Incidence of Type 1 Diabetes in Children.

    PubMed

    Lens-Pechakova, Lilia S

    2016-02-01

    The autoimmune diseases are among the 10 leading causes of death for women and the number two cause of chronic illness in America as well as a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter life span and are a model of accelerated immunosenescence. Conversely, centenarians are used as a model of successful aging and have shown several immune parameters that are better preserved and lower levels of autoantibodies. The study reported here focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed Organisation for Economic Co-operation and Development (OECD) countries, because multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relationship pattern, help to identify common factors, and determine new important factors that contribute to longevity and healthy aging. The relationships between the mortality rates data of multiple sclerosis (MS), rheumatoid arthritis (RA), asthma, the incidence of type 1 diabetes (T1D) from one side and centenarian rates (two sets) as well as life expectancy data from the other side were assessed using regression models and Pearson correlation coefficients. The data obtained correspond to an inverse linear correlation with different degrees of linearity. This is the first observation of a clear tendency of diminishing centenarian rates or life expectancy in countries having higher death rates of asthma, MS, and RA and a higher incidence of T1D in children. The conclusion is that most probably there are common mechanistic pathways and factors affecting the above diseases and at the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways, and other factors connected to autoimmune diseases with those of longevity could clarify the processes involved, so as to promote longevity and limit the expansion of those

  4. Programming stress-induced altruistic death in engineered bacteria

    PubMed Central

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

    2012-01-01

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

  5. Death Education in Paramedic Programs: A Nationwide Assessment.

    ERIC Educational Resources Information Center

    Smith, Tracy L.; Walz, Bruce J.

    1995-01-01

    A self-administered survey was sent to all U.S. paramedic programs (n=537) concerning aspects of death education, including method of instruction, educational supplements, assessment techniques, and integration into general course work. Of the 51% that responded, 95% offered death education, with the most common subjects being legal and ethical…

  6. Triggering of Programmed Erythrocyte Death by Alantolactone

    PubMed Central

    Alzoubi, Kousi; Calabrò, Salvatrice; Egler, Jasmin; Faggio, Caterina; Lang, Florian

    2014-01-01

    The sesquiterpene alantolactone counteracts malignancy, an effect at least in part due to stimulation of suicidal death or apoptosis of tumor cells. Signaling of alantolactone induced apoptosis involves altered gene expression and mitochondrial depolarization. Erythrocytes lack mitochondria and nuclei but may enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Cellular mechanisms involved in triggering of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i) and oxidative stress. The present study explored, whether alantolactone stimulates eryptosis. To this end, erythrocyte volume was estimated from forward scatter, phosphatidylserine-exposure at the erythrocyte surface from FITC-annexin-V-binding, [Ca2+]i from Fluo3-fluorescence, ceramide abundance from binding of fluorescent antibodies, and oxidative stress from 2',7'-dichlorodihydrofluorescein-diacetate (DCFDA) fluorescence. As a result, a 48 h exposure of human erythrocytes to alantolactone (≥20 μM) significantly decreased erythrocyte forward scatter and increased the percentage of annexin-V-binding cells. Alantolactone significantly increased Fluo3 fluorescence (60 μM), ceramide abundance (60 μM) and DCFDA fluorescence (≥40 μM). The effect of alantolactone (60 μM) on annexin-V-binding was not significantly modified by removal of extracellular Ca2+. In conclusion, alantolactone stimulates suicidal erythrocyte death or eryptosis, an effect paralleled by increase of [Ca2+]i, ceramide abundance and oxidative stress. PMID:25533522

  7. Type 1 diabetes

    MedlinePlus

    ... your diabetes. But, you are the most important person in managing your diabetes. You should know the basic steps ... to your doctor before starting any exercise program. People with type 1 ... MANAGING YOUR BLOOD SUGAR Checking your blood sugar level ...

  8. [Programmed cell death: history and future of a concept].

    PubMed

    Lockshin, Richard A

    2005-01-01

    Cell death was observed and understood since the 19th century, but there was no experimental examination until the mid-20th century. Beginning in the 1960's, several laboratories demonstrated that cell death was biologically controlled (programmed) and that the morphology was common and not readily explained (apoptosis). By 1990 the genetic basis of programmed cell death had been established and the first components of the cell death machinery (caspase 3, bcl-2 and Fas) had been identified, sequenced, and recognized as highly conserved in evolution. The rapid development of the field has given us substantial understanding of how cell death is achieved. However, capitalizing on our knowledge for therapeutic purposes requires us to learn much more about how a cell commits to death, as well as recognizing that apoptosis may be the most common and efficient means of death, but that there are alternative pathways that can result in cell death even when the conventional pathway is blocked. Interestingly enough, many of the arguments and missteps in the history of the field were anticipated by Claude Bernard, and his warnings and recommendations remain valid today.

  9. Programmed Cell Death and Complexity in Microbial Systems.

    PubMed

    Durand, Pierre M; Sym, Stuart; Michod, Richard E

    2016-07-11

    Programmed cell death (PCD) is central to organism development and for a long time was considered a hallmark of multicellularity. Its discovery, therefore, in unicellular organisms presents compelling questions. Why did PCD evolve? What is its ecological effect on communities? To answer these questions, one is compelled to consider the impacts of PCD beyond the cell, for death obviously lowers the fitness of the cell. Here, we examine the ecological effects of PCD in different microbial scenarios and conclude that PCD can increase biological complexity. In mixed microbial communities, the mode of death affects the microenvironment, impacting the interactions between taxa. Where the population comprises groups of relatives, death has a more explicit effect. Death by lysis or other means can be harmful, while PCD can evolve by providing advantages to relatives. The synchronization of death between individuals suggests a group level property is being maintained and the mode of death also appears to have had an impact during the origin of multicellularity. PCD can result in the export of fitness from the cell to the group level via re-usable resources and PCD may also provide a mechanism for how groups beget new groups comprising kin. Furthermore, PCD is a means for solving a central problem of group living - the toxic effects of death - by making resources in dying cells beneficial to others. What emerges from the data reviewed here is that while PCD carries an obvious cost to the cell, it can be a driver of complexity in microbial communities. PMID:27404254

  10. Let’s Empower and Prepare (LEAP): Evaluation of a Structured Transition Program for Young Adults With Type 1 Diabetes

    PubMed Central

    Pyatak, Elizabeth A.; Weigensberg, Marc J.; Vigen, Cheryl P.; Wood, Jamie R.; Ruelas, Valerie; Montoya, Lucy; Cohen, Marisa; Speer, Heather; Clark, Susan; Peters, Anne L.

    2015-01-01

    OBJECTIVE To evaluate the efficacy of a structured transition program compared with usual care in improving routine follow-up, clinical, and psychosocial outcomes among young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS Eighty-one young adults in their last year of pediatric care were recruited from three clinics. Intervention group (IG) participants (n = 51) received a structured transition program incorporating tailored diabetes education, case management, group education classes, and access to a newly developed young adult diabetes clinic and transition website. Control group (CG) participants (n = 30) received usual care. The primary outcome was the number of routine clinic visits. Secondary outcomes included glycemic control, hypoglycemia, health care use, and psychosocial well-being. Assessments were conducted at baseline, and 6 and 12 months. RESULTS Limitations in CG follow-up prevented direct comparisons of adult care visits; however, at the 12-month follow-up among IG participants discharged from pediatric care (n = 32), 78% had one or more adult visits. Among IG participants, the total number of clinic visits did not differ between those who transitioned and those who remained in pediatric care (3.0 ± 1.24 vs. 3.11 ± 0.94, P = 0.74). IG compared with CG participants had improved glycemic control (−0.40 ± 1.16% vs. 0.42 ± 1.51% [4.4 ± 12.7 mmol/mol vs. 4.6 ± 16.5 mmol/mol], P = 0.01), incidence of severe hypoglycemia (0.0% vs. 16%, P = 0.02), and global well-being (P = 0.02) at 12 months. CONCLUSIONS A structured transition program was successful in facilitating transition to adult care without a decrease in clinical follow-up. Compared with usual care, the transition program facilitated improvements in glycemic control, hypoglycemia, and psychosocial well-being. PMID:25906787

  11. A computer program for the estimation of time of death.

    PubMed

    Lynnerup, N

    1993-07-01

    In the 1960s Marshall and Hoare presented a "Standard Cooling Curve" based on their mathematical analyses on the postmortem cooling of bodies. Although fairly accurate under standard conditions, the "curve" or formula is based on the assumption that the ambience temperature is constant and that the temperature at death is known. Also, Marshall and Hoare's formula expresses the temperature as a function of time, and not vice versa, the latter being the problem most often encountered by forensic scientists. A simple BASIC program that enables solving of Marshall and Hoare's equation for the postmortem cooling of bodies is presented. It is proposed that by having a computer program that solves the equation, giving the length of the cooling period in response to a certain rectal temperature, and which allows easy comparison of multiple solutions, the uncertainties related to ambience temperature and temperature at death can be quantified, substantiating estimations of time of death.

  12. Programed Death is Favored by Natural Selection in Spatial Systems.

    PubMed

    Werfel, Justin; Ingber, Donald E; Bar-Yam, Yaneer

    2015-06-12

    Standard evolutionary theories of aging and mortality, implicitly based on mean-field assumptions, hold that programed mortality is untenable, as it opposes direct individual benefit. We show that in spatial models with local reproduction, programed deaths instead robustly result in long-term benefit to a lineage, by reducing local environmental resource depletion via spatiotemporal patterns causing feedback over many generations. Results are robust to model variations, implying that direct selection for shorter life span may be quite widespread in nature.

  13. CD40L induces functional tunneling nanotube networks exclusively in dendritic cells programmed by mediators of type-1 immunity

    PubMed Central

    Zaccard, Colleen R.; Watkins, Simon C.; Kalinski, Pawel; Fecek, Ronald J.; Yates, Aarika L.; Salter, Russell D.; Ayyavoo, Velpandi; Rinaldo, Charles R.; Mailliard, Robbie B.

    2014-01-01

    The ability of dendritic cells (DC) to mediate CD4+ T cell help for cellular immunity is guided by instructive signals received during DC maturation, and the resulting pattern of DC responsiveness to the Th signal, CD40L. Furthermore, the professional transfer of antigenic information from migratory DC to lymph node-residing DC is critical for the effective induction of cellular immune responses. Here we report that, in addition to their enhanced IL-12p70 producing capacity, human DC matured in the presence of inflammatory mediators of type-1 immunity (DC1) are uniquely programmed to form networks of tunneling nanotube-like structures in response to CD40L-expressing Th cells or recombinant CD40L. This immunologic process of DC ‘reticulation’ facilitates intercellular trafficking of endosome-associated vesicles and Ag, but also pathogens such HIV-1, and is regulated by the opposing roles of IFN-γ and IL-4. The initiation of DC reticulation represents a novel helper function of CD40L and a superior mechanism of intercellular communication possessed by DC1, as well as a target for exploitation by pathogens to enhance direct cell-to-cell spread. PMID:25548234

  14. Ceramide Synthase-dependent Ceramide Generation and Programmed Cell Death

    PubMed Central

    Mullen, Thomas D.; Jenkins, Russell W.; Clarke, Christopher J.; Bielawski, Jacek; Hannun, Yusuf A.; Obeid, Lina M.

    2011-01-01

    The sphingolipid ceramide has been widely implicated in the regulation of programmed cell death or apoptosis. The accumulation of ceramide has been demonstrated in a wide variety of experimental models of apoptosis and in response to a myriad of stimuli and cellular stresses. However, the detailed mechanisms of its generation and regulatory role during apoptosis are poorly understood. We sought to determine the regulation and roles of ceramide production in a model of ultraviolet light-C (UV-C)-induced programmed cell death. We found that UV-C irradiation induces the accumulation of multiple sphingolipid species including ceramide, dihydroceramide, sphingomyelin, and hexosylceramide. Late ceramide generation was also found to be regulated by Bcl-xL, Bak, and caspases. Surprisingly, inhibition of de novo synthesis using myriocin or fumonisin B1 resulted in decreased overall cellular ceramide levels basally and in response to UV-C, but only fumonisin B1 inhibited cell death, suggesting the presence of a ceramide synthase (CerS)-dependent, sphingosine-derived pool of ceramide in regulating programmed cell death. We found that this pool did not regulate the mitochondrial pathway, but it did partially regulate activation of caspase-7 and, more importantly, was necessary for late plasma membrane permeabilization. Attempting to identify the CerS responsible for this effect, we found that combined knockdown of CerS5 and CerS6 was able to decrease long-chain ceramide accumulation and plasma membrane permeabilization. These data identify a novel role for CerS and the sphingosine salvage pathway in regulating membrane permeability in the execution phase of programmed cell death. PMID:21388949

  15. Oxidative Stress and Programmed Cell Death in Yeast

    PubMed Central

    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. PMID:22737670

  16. Death of mitochondria during programmed cell death of leaf mesophyll cells.

    PubMed

    Selga, Tūrs; Selga, Maija; Pāvila, Vineta

    2005-12-01

    The role of plant mitochondria in the programmed cell death (PCD) is widely discussed. However, spectrum and sequence of mitochondrial structural changes during different types of PCD in leaves are poorly described. Pea, cucumber and rye plants were grown under controlled growing conditions. A part of them were sprinkled with ethylene releaser to accelerate cell death. During yellowing the palisade parenchyma mitochondria were attracted to nuclear envelope. Mitochondrial matrix became electron translucent. Mitochondria entered vacuole by invagination of tonoplast and formed multivesicular bodies. Ethephon treatment increased the frequency of sticking of mitochondria to the nuclear envelope or chloroplasts and peroxisomes. Mitochondria divided by different mechanisms and became enclosed in Golgi and ER derived authopagic vacuoles or in the central vacuole. Several fold increase of the diameter of cristae became typical. In all cases mitochondria were attached to nuclear envelope. It can be considered as structural mechanism of promoting of PCD.

  17. Detection of programmed cell death using fluorescence energy transfer.

    PubMed Central

    Xu, X; Gerard, A L; Huang, B C; Anderson, D C; Payan, D G; Luo, Y

    1998-01-01

    Fluorescence energy transfer (FRET) can be generated when green fluorescent protein (GFP) and blue fluorescent protein (BFP) are covalently linked together by a short peptide. Cleavage of this linkage by protease completely eliminates FRET effect. Caspase-3 (CPP32) is an important cellular protease activated during programmed cell death. An 18 amino acid peptide containing CPP32 recognition sequence, DEVD, was used to link GFP and BFP together. CPP32 activation can be monitored by FRET assay during the apoptosis process. PMID:9518501

  18. Sulfur dioxide induced programmed cell death in Vicia guard cells.

    PubMed

    Yi, Huilan; Yin, Jingjing; Liu, Xin; Jing, Xiuqing; Fan, Sanhong; Zhang, Hufang

    2012-04-01

    Sulfur dioxide (SO(2)) induced nuclear condensation and nuclear fragmentation and rapid loss of guard cell viability in detached epidermis of Vicia leaves at concentrations of 1 mM and higher (3 h exposure). Caspase inhibitors Z-Asp-CH(2)-DCB (0.1 mM) and TLCK (0.1 mM) markedly suppressed SO(2)-induced cell death. The typical nuclear morphological changes and the inhibition effects of caspase inhibitors suggest the activation of a programmed cell death (PCD) pathway. SO(2)-induced cell death can be blocked by either antioxidants (0.1 mM AsA or 200 U/mL CAT) or Ca(2+) antagonists (0.1mM EGTA or LaCl(3)). AsA and CAT also blocked SO(2)-induced ROS production and [Ca(2+)](cyt) increase. However, EGTA and LaCl(3) can inhibit SO(2)-induced [Ca(2+)](cyt) increase, but cannot suppress SO(2)-induced ROS production. Our results indicate that high concentrations of SO(2) induce guard cell death via a PCD pathway through ROS mediating [Ca(2+)](cyt) elevation, which causes harmful effects to plants.

  19. Megasporogenesis and programmed cell death in Tillandsia (Bromeliaceae).

    PubMed

    Papini, Alessio; Mosti, Stefano; Milocani, Eva; Tani, Gabriele; Di Falco, Pietro; Brighigna, Luigi

    2011-10-01

    The degeneration of three of four meiotic products is a very common process in the female gender of oogamous eukaryotes. In Tillandsia (and many other angiosperms), the surviving megaspore has a callose-free wall in chalazal position while the other three megaspores are completely embedded in callose. Therefore, nutrients and signals can reach more easily the functional megaspore from the nucellus through the chalazal pole with respect to the other megaspores. The abortion of three of four megaspores was already recognized as the result of a programmed cell death (PCD) process. We investigated the process to understand the modality of this specific type of PCD and its relationship to the asymmetric callose deposition around the tetrad. The decision on which of the four megaspores will be the supernumerary megaspores in angiosperms, and hence destined to undergo programmed cell death, appears to be linked to the callose layer deposition around the tetrad. During supernumerary megaspores degeneration, events leading to the deletion of the cells do not appear to belong to a single type of cell death. The first morphological signs are typical of autophagy, including the formation of autophagosomes. The TUNEL positivity and a change in morphology of mitochondria and chloroplasts indicate the passage to an apoptotic-like PCD phase, while the cellular remnants undergo a final process resembling at least partially (ER swelling) necrotic morphological syndromes, eventually leading to a mainly lipidic cell corpse still separated from the functional megaspore by a callose layer.

  20. [Death].

    PubMed

    Ribas, Jordi Domingo

    2003-12-01

    Intercultural factors are essential for reflection. In this article, the authors deals with a more direct vision on the special edition about Grief and Mourning, about the topic which lies in the depths of all of our consciences: death and the question what lies beyond death? The author provides us elements to reflect about concepts, some accepted in various cases, rejected in others, but always polemical, which help us to penetrate farther into the real mystery of life: death and what follows death.

  1. Programmed cell death in plants: lessons from bacteria?

    PubMed Central

    Wang, Junhui; Bayles, Kenneth W.

    2012-01-01

    Programmed cell death (PCD) has well-established roles in the development and physiology of animals, plants, and fungi. Although aspects of PCD control appear evolutionarily conserved between these organisms, the extent of conservation remains controversial. Recently, a putative bacterial PCD protein homolog in plants was found to play a significant role in cell death control, indicating a conservation of function between these highly divergent organisms. Interestingly, these bacterial proteins are thought to be evolutionarily linked to the Bcl-2 family of proteins. In this Opinion article, we propose a new unifying model to describe the relationship between bacterial and plant PCD systems and propose that the underlying control of PCD is conserved across at least three Kingdoms of life. PMID:23083702

  2. A Conserved Core of Programmed Cell Death Indicator Genes Discriminates Developmentally and Environmentally Induced Programmed Cell Death in Plants.

    PubMed

    Olvera-Carrillo, Yadira; Van Bel, Michiel; Van Hautegem, Tom; Fendrych, Matyáš; Huysmans, Marlies; Simaskova, Maria; van Durme, Matthias; Buscaill, Pierre; Rivas, Susana; S Coll, Nuria; Coppens, Frederik; Maere, Steven; Nowack, Moritz K

    2015-12-01

    A plethora of diverse programmed cell death (PCD) processes has been described in living organisms. In animals and plants, different forms of PCD play crucial roles in development, immunity, and responses to the environment. While the molecular control of some animal PCD forms such as apoptosis is known in great detail, we still know comparatively little about the regulation of the diverse types of plant PCD. In part, this deficiency in molecular understanding is caused by the lack of reliable reporters to detect PCD processes. Here, we addressed this issue by using a combination of bioinformatics approaches to identify commonly regulated genes during diverse plant PCD processes in Arabidopsis (Arabidopsis thaliana). Our results indicate that the transcriptional signatures of developmentally controlled cell death are largely distinct from the ones associated with environmentally induced cell death. Moreover, different cases of developmental PCD share a set of cell death-associated genes. Most of these genes are evolutionary conserved within the green plant lineage, arguing for an evolutionary conserved core machinery of developmental PCD. Based on this information, we established an array of specific promoter-reporter lines for developmental PCD in Arabidopsis. These PCD indicators represent a powerful resource that can be used in addition to established morphological and biochemical methods to detect and analyze PCD processes in vivo and in planta.

  3. The metabolism beyond programmed cell death in yeast

    PubMed Central

    Ring, Julia; Sommer, Cornelia; Carmona-Gutierrez, Didac; Ruckenstuhl, Christoph; Eisenberg, Tobias; Madeo, Frank

    2012-01-01

    A cell's reaction to any change in the endogenous or exogenous conditions often involves a complex response that eventually either leads to cell adaptation and survival or to the initiation and execution of (programmed) cell death. The molecular decision whether to live or die, while depending on a cell's genome, is fundamentally influenced by its actual metabolic status. Thus, the collection of all metabolites present in a biological system at a certain time point (the so-called metabolome) defines its physiological, developmental and pathological state and determines its fate during changing and stressful conditions. The budding yeast Saccharomyces cerevisiae is a unicellular organism that allows to easily modify and monitor conditions affecting the cell's metabolome, for instance through a simple change of the nutrition source. Such changes can be used to mimic and study (patho)physiological scenarios, including caloric restriction and longevity, the Warburg effect in cancer cells or changes in mitochondrial mass affecting cell death. In addition, disruption of single genes or generation of respiratory deficiency (via abrogation of mitochondrial DNA) assists in revealing connections between metabolism and apoptosis. In this minireview, we discuss recent studies using the potential of the yeast model to provide new insights into the processes of stress defense, cell death and longevity. PMID:22480867

  4. Perturbations in the Lipid Profile of Individuals with Newly Diagnosed Type 1 Diabetes Mellitus: Lipidomics Analysis of a Diabetes Antibody Standardization Program Sample Subset

    SciTech Connect

    Sorensen, Christina M.; Ding, Jie; Zhang, Qibin; Alquier, Thierry; Zhao, Rui; Mueller, Patricia W.; Smith, Richard D.; Metz, Thomas O.

    2010-08-01

    Objectives: To characterize the lipid profile of individuals with newly diagnosed type 1 diabetes mellitus using LC-MS-based lipidomics and the accurate mass and time (AMT) tag approach. Design and methods: Lipids were extracted from plasma and sera of 10 subjects from the Diabetes Antibody Standardization Program (years 2000-2005) and 10 non-diabetic subjects and analyzed by capillary liquid chromatography coupled with a hybrid ion-trap-Fourier transform ion cyclotron resonance mass spectrometer. Lipids were identified and quantified using the AMT tag approach. Results: Five hundred sixty lipid features differentiated (q < 0.05) diabetic from healthy individuals in a partial least-squares analysis, characterizing of individuals with recently diagnosed type 1 diabetes mellitus. Conclusions: A lipid profile associated with newly diagnosed type 1 diabetes may aid in further characterization of biochemical pathways involved in lipid regulation or mobilization and lipotoxicity of pancreatic beta-cells.

  5. Arabidopsis ACCELERATED CELL DEATH2 Modulates Programmed Cell DeathW⃞

    PubMed Central

    Yao, Nan; Greenberg, Jean T.

    2006-01-01

    The Arabidopsis thaliana chloroplast protein ACCELERATED CELL DEATH2 (ACD2) modulates the amount of programmed cell death (PCD) triggered by Pseudomonas syringae and protoporphyrin IX (PPIX) treatment. In vitro, ACD2 can reduce red chlorophyll catabolite, a chlorophyll derivative. We find that ACD2 shields root protoplasts that lack chlorophyll from light- and PPIX-induced PCD. Thus, chlorophyll catabolism is not obligatory for ACD2 anti-PCD function. Upon P. syringae infection, ACD2 levels and localization change in cells undergoing PCD and in their close neighbors. Thus, ACD2 shifts from being largely in chloroplasts to partitioning to chloroplasts, mitochondria, and, to a small extent, cytosol. ACD2 protects cells from PCD that requires the early mitochondrial oxidative burst. Later, the chloroplasts of dying cells generate NO, which only slightly affects cell viability. Finally, the mitochondria in dying cells have dramatically altered movements and cellular distribution. Overproduction of both ACD2 (localized to mitochondria and chloroplasts) and ascorbate peroxidase (localized to chloroplasts) greatly reduces P. syringae–induced PCD, suggesting a pro-PCD role for mitochondrial and chloroplast events. During infection, ACD2 may bind to and/or reduce PCD-inducing porphyrin-related molecules in mitochondria and possibly chloroplasts that generate reactive oxygen species, cause altered organelle behavior, and activate a cascade of PCD-inducing events. PMID:16387834

  6. Statins and Voriconazole Induce Programmed Cell Death in Acanthamoeba castellanii

    PubMed Central

    López-Arencibia, Atteneri; Sifaoui, Ines; Reyes-Batlle, María; Valladares, Basilio; Martínez-Carretero, Enrique; Piñero, José E.; Maciver, Sutherland K.; Lorenzo-Morales, Jacob

    2015-01-01

    Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a life-threatening encephalitis. In order to treat those infections properly, it is necessary to target the treatment not only to the trophozoite but also to the cyst. Furthermore, it may be advantageous to avoid parasite killing by necrosis, which may induce local inflammation. We must also avoid toxicity of host tissue. Many drugs which target eukaryotes are known to induce programmed cell death (PCD), but this process is poorly characterized in Acanthamoeba. Here, we study the processes of programmed cell death in Acanthamoeba, induced by several drugs, such as statins and voriconazole. We tested atorvastatin, fluvastatin, simvastatin, and voriconazole at the 50% inhibitory concentrations (IC50s) and IC90s that we have previously established. In order to evaluate this phenomenon, we investigated the DNA fragmentation, one of the main characteristics of PCD, with quantitative and qualitative techniques. Also, the changes related to phosphatidylserine exposure on the external cell membrane and cell permeability were studied. Finally, because caspases are key to PCD pathways, caspase activity was evaluated in Acanthamoeba. All the drugs assayed in this study induced PCD in Acanthamoeba. To the best of our knowledge, this is the first study where PCD induced by drugs is described quantitatively and qualitatively in Acanthamoeba. PMID:25733513

  7. Bacterial programmed cell death of cerebral endothelial cells involves dual death pathways

    PubMed Central

    Bermpohl, Daniela; Halle, Annett; Freyer, Dorette; Dagand, Emilie; Braun, Johann S.; Bechmann, Ingo; Schröder, Nicolas W.J.; Weber, Joerg R.

    2005-01-01

    Major barriers separating the blood from tissue compartments in the body are composed of endothelial cells. Interaction of bacteria with such barriers defines the course of invasive infections, and meningitis has served as a model system to study endothelial cell injury. Here we report the impressive ability of Streptococcus pneumoniae, clinically one of the most important pathogens, to induce 2 morphologically distinct forms of programmed cell death (PCD) in brain-derived endothelial cells. Pneumococci and the major cytotoxins H202 and pneumolysin induce apoptosis-like PCD independent of TLR2 and TLR4. On the other hand, pneumococcal cell wall, a major proinflammatory component, causes caspase-driven classical apoptosis that is mediated through TLR2. These findings broaden the scope of bacterial-induced PCD, link these effects to innate immune TLRs, and provide insight into the acute and persistent phases of damage during meningitis. PMID:15902310

  8. Elevated Expression of Programmed Death-1 and Programmed Death Ligand-1 Negatively Regulates Immune Response against Cervical Cancer Cells

    PubMed Central

    Chen, Zhifang; Pang, Nannan; Du, Rong; Zhu, Yuejie; Fan, Lingling; Cai, Donghui

    2016-01-01

    The present study is to measure the expression of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), as well as its clinical significance in cervical cancer patients. Our results showed that different T cell subsets in patients with cervical cancer had high expression of PD-1, and DCs had high expression of PD-L1. High expression of PD-1 on Treg cells in cervical cancer patients facilitated the production of TGF-β and IL-10 but inhibited the production of IFN-γ. Cervical cancer elevated the expression of PD-1 and PD-L1 in mRNA level. PD-1 expression in peripheral blood of cervical cancer patients was related with tumor differentiation, lymph node metastasis, and invasiveness. PD-1/PD-L1 pathway inhibited lymphocyte proliferation but enhanced the secretion of IL-10 and TGF-β in vitro. In summary, our findings demonstrate that elevated levels of PD-1/PD-L1, TGF-β, and IL-10 in peripheral blood of cervical cancer patients may negatively regulate immune response against cervical cancer cells and contribute to the progression of cervical cancer. Therefore, PD-1/PD-L1 pathway may become an immunotherapy target in the future. PMID:27721577

  9. Programmed cell death in C. elegans, mammals and plants.

    PubMed

    Lord, Christina E N; Gunawardena, Arunika H L A N

    2012-08-01

    Programmed cell death (PCD) is the regulated removal of cells within an organism and plays a fundamental role in growth and development in nearly all eukaryotes. In animals, the model organism Caenorhabditis elegans (C. elegans) has aided in elucidating many of the pathways involved in the cell death process. Various analogous PCD processes can also be found within mammalian PCD systems, including vertebrate limb development. Plants and animals also appear to share hallmarks of PCD, both on the cellular and molecular level. Cellular events visualized during plant PCD resemble those seen in animals including: nuclear condensation, DNA fragmentation, cytoplasmic condensation, and plasma membrane shrinkage. Recently the molecular mechanisms involved in plant PCD have begun to be elucidated. Although few regulatory proteins have been identified as conserved across all eukaryotes, molecular features such as the participation of caspase-like proteases, Bcl-2-like family members and mitochondrial proteins appear to be conserved between plant and animal systems. Transgenic expression of mammalian and C. elegans pro- and anti-apoptotic genes in plants has been observed to dramatically influence the regulatory pathways of plant PCD. Although these genes often show little to no sequence similarity they can frequently act as functional substitutes for one another, thus suggesting that action may be more important than sequence resemblance. Here we present a summary of these findings, focusing on the similarities, between mammals, C. elegans, and plants. An emphasis will be placed on the mitochondria and its role in the cell death pathway within each organism. Through the comparison of these systems on both a cellular and molecular level we can begin to better understand PCD in plant systems, and perhaps shed light on the pathways, which are controlling the process. This manuscript adds to the field of PCD in plant systems by profiling apoptotic factors, to scale on a protein

  10. Comparative analysis of programmed cell death pathways in filamentous fungi

    PubMed Central

    Fedorova, Natalie D; Badger, Jonathan H; Robson, Geoff D; Wortman, Jennifer R; Nierman, William C

    2005-01-01

    Background Fungi can undergo autophagic- or apoptotic-type programmed cell death (PCD) on exposure to antifungal agents, developmental signals, and stress factors. Filamentous fungi can also exhibit a form of cell death called heterokaryon incompatibility (HI) triggered by fusion between two genetically incompatible individuals. With the availability of recently sequenced genomes of Aspergillus fumigatus and several related species, we were able to define putative components of fungi-specific death pathways and the ancestral core apoptotic machinery shared by all fungi and metazoa. Results Phylogenetic profiling of HI-associated proteins from four Aspergilli and seven other fungal species revealed lineage-specific protein families, orphan genes, and core genes conserved across all fungi and metazoa. The Aspergilli-specific domain architectures include NACHT family NTPases, which may function as key integrators of stress and nutrient availability signals. They are often found fused to putative effector domains such as Pfs, SesB/LipA, and a newly identified domain, HET-s/LopB. Many putative HI inducers and mediators are specific to filamentous fungi and not found in unicellular yeasts. In addition to their role in HI, several of them appear to be involved in regulation of cell cycle, development and sexual differentiation. Finally, the Aspergilli possess many putative downstream components of the mammalian apoptotic machinery including several proteins not found in the model yeast, Saccharomyces cerevisiae. Conclusion Our analysis identified more than 100 putative PCD associated genes in the Aspergilli, which may help expand the range of currently available treatments for aspergillosis and other invasive fungal diseases. The list includes species-specific protein families as well as conserved core components of the ancestral PCD machinery shared by fungi and metazoa. PMID:16336669

  11. Programmed Cell Death Initiation and Execution in Budding Yeast

    PubMed Central

    Strich, Randy

    2015-01-01

    Apoptosis or programmed cell death (PCD) was initially described in metazoans as a genetically controlled process leading to intracellular breakdown and engulfment by a neighboring cell . This process was distinguished from other forms of cell death like necrosis by maintenance of plasma membrane integrity prior to engulfment and the well-defined genetic system controlling this process. Apoptosis was originally described as a mechanism to reshape tissues during development. Given this context, the assumption was made that this process would not be found in simpler eukaryotes such as budding yeast. Although basic components of the apoptotic pathway were identified in yeast, initial observations suggested that it was devoid of prosurvival and prodeath regulatory proteins identified in mammalian cells. However, as apoptosis became extensively linked to the elimination of damaged cells, key PCD regulatory proteins were identified in yeast that play similar roles in mammals. This review highlights recent discoveries that have permitted information regarding PCD regulation in yeast to now inform experiments in animals. PMID:26272996

  12. The Molecular Ecophysiology of Programmed Cell Death in Marine Phytoplankton

    NASA Astrophysics Data System (ADS)

    Bidle, Kay D.

    2015-01-01

    Planktonic, prokaryotic, and eukaryotic photoautotrophs (phytoplankton) share a diverse and ancient evolutionary history, during which time they have played key roles in regulating marine food webs, biogeochemical cycles, and Earth's climate. Because phytoplankton represent the basis of marine ecosystems, the manner in which they die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining upper-ocean biogeochemistry. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of nutrient stressors and are employed by parasitic viruses, play an integral role in determining the cell fate of diverse photoautotrophs in the modern ocean. Indeed, these multifaceted death pathways continue to shape the success and evolutionary trajectory of diverse phytoplankton lineages at sea. Research over the past two decades has employed physiological, biochemical, and genetic techniques to provide a novel, comprehensive, mechanistic understanding of the factors controlling this key process. Here, I discuss the current understanding of the genetics, activation, and regulation of PCD pathways in marine model systems; how PCD evolved in unicellular photoautotrophs; how it mechanistically interfaces with viral infection pathways; how stress signals are sensed and transduced into cellular responses; and how novel molecular and biochemical tools are revealing the impact of PCD genes on the fate of natural phytoplankton assemblages.

  13. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    PubMed

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

  14. Programmed Cell Death in Animal Development and Disease

    PubMed Central

    Fuchs, Yaron; Steller, Hermann

    2015-01-01

    Programmed Cell Death (PCD) plays a fundamental role in animal development and tissue homeostasis. Abnormal regulation of this process is associated with a wide variety of human diseases, including immunological and developmental disorders, neuro-degeneration, and cancer. Here, we provide a brief historical overview of the field and reflect on myriad functions carried out by PCD during development and explore how PCD is regulated. We also focus on the function and regulation of apoptotic proteins, including caspases, the key executioners of apoptosis, highlighting the non-lethal functions of these proteins in diverse developmental processes including cell differentiation and tissue remodeling. Finally, we explore a growing body of work about the connections between apoptosis, stem cells and cancer, focusing on how apoptotic cells release a variety of signals to communicate with their cellular environment, including factors that promote cell division, tissue regeneration, and wound healing. PMID:22078876

  15. Identification of the death zone: a spatially restricted region for programmed cell death that sculpts the fly eye.

    PubMed

    Monserrate, J P; Brachmann, C Baker

    2007-02-01

    Programmed cell death (PCD) sculpts many developing tissues. The final patterning step of the Drosophila retina is the elimination, through PCD, of a subset of interommatidial lattice cells during pupation. It is not understood how this process is spatially regulated to ensure that cells die in the proper positions. To address this, we observed PCD of lattice cells in the pupal retina in real time. This live-visualization method demonstrates that lattice cell apoptosis is a highly specific process. In all, 85% of lattice cells die in exclusive 'death zone' positions between adjacent ommatidia. In contrast, cells that make specific contacts with primary pigment cells are protected from death. Two signaling pathways, Drosophila epidermal growth factor receptor (dEgfr) and Notch, that are thought to be central to the regulation of lattice cell survival and death, are not sufficient to establish the death zone. Thus, application of live visualization to the fly eye gives new insight into a dynamic developmental process.

  16. Caspase-like activity in programmed nuclear death during conjugation of Tetrahymena thermophila.

    PubMed

    Kobayashi, T; Endoh, H

    2003-06-01

    Apoptosis, or programmed cell death, is common in a variety of eucaryotes, from unicellular protozoa to vertebrates. The ciliated protozoan Tetrahymena thermophila has a unique apoptosis-like nuclear death during conjugation, called programmed nuclear death. This death program involves nuclear condensation (pyknosis) and oligonucleosomal DNA fragmentation in the parental macronucleus. Subsequently, the condensed nucleus is entirely resorbed in the autophagosome. Here we demonstrate that caspase-8- and -9-like activity was detected, but no caspase-3-like activity, by in vitro assay during the nuclear resorption process, suggesting that caspase-like activity is associated with both programmed cell death and apoptosis-like nuclear death in Tetrahymena. The use of indicator dye to detect the loss of mitochondrial membrane potential suggested the uptake of mitochondria and the degenerating macronucleus by the autophagosome. An involvement of mitochondria in the programmed nuclear death is discussed.

  17. Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death.

    PubMed

    Darshan, N; Manonmani, H K

    2016-12-01

    The antimicrobial activity of prodigiosin from Serratia nematodiphila darsh1, a bacterial pigment was tested against few food borne bacterial pathogens Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. The mode of action of prodigiosin was studied. Prodigiosin induced bactericidal activity indicating a stereotypical set of biochemical and morphological feature of Programmed cell death (PCD). PCD involves DNA fragmentation, generation of ROS, and expression of a protein with caspase-like substrate specificity in bacterial cells. Prodigiosin was observed to be internalized into bacterial cells and was localized predominantly in the membrane and the nuclear fraction, thus, facilitating intracellular trafficking and then binding of prodigiosin to the bacterial DNA. Corresponding to an increasing concentration of prodigiosin, the level of certain proteases were observed to increase in bacteria studied, thus initiating the onset of PCD. Prodigiosin at a sub-inhibitory concentration inhibits motility of pathogens. Our observations indicated that prodigiosin could be a promising antibacterial agent and could be used in the prevention of bacterial infections. PMID:27460563

  18. Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death.

    PubMed

    Darshan, N; Manonmani, H K

    2016-12-01

    The antimicrobial activity of prodigiosin from Serratia nematodiphila darsh1, a bacterial pigment was tested against few food borne bacterial pathogens Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. The mode of action of prodigiosin was studied. Prodigiosin induced bactericidal activity indicating a stereotypical set of biochemical and morphological feature of Programmed cell death (PCD). PCD involves DNA fragmentation, generation of ROS, and expression of a protein with caspase-like substrate specificity in bacterial cells. Prodigiosin was observed to be internalized into bacterial cells and was localized predominantly in the membrane and the nuclear fraction, thus, facilitating intracellular trafficking and then binding of prodigiosin to the bacterial DNA. Corresponding to an increasing concentration of prodigiosin, the level of certain proteases were observed to increase in bacteria studied, thus initiating the onset of PCD. Prodigiosin at a sub-inhibitory concentration inhibits motility of pathogens. Our observations indicated that prodigiosin could be a promising antibacterial agent and could be used in the prevention of bacterial infections.

  19. Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model.

    PubMed

    Jiang, Xin; Zhang, Chi; Xin, Ying; Huang, Zhifeng; Tan, Yi; Huang, Yadong; Wang, Yonggang; Feng, Wenke; Li, Xiaokun; Li, Wei; Qu, Yaqin; Cai, Lu

    2013-05-10

    Fibroblast growth factor 21 (FGF21) is a novel member identified and was reported to express predominantly in pancreas, liver and adipose tissue, and relatively less in other organs, such as the testis. However, the role of FGF21 in the testis has never been addressed. The present study examined FGF21 expression at mRNA level by real-time RT-PCR assay in the testis of fasting and non-fasting mice or mice with type 1 diabetes that was induced with streptozotocin. We also examined the effect of Fgf21 gene deletion or supplementation of the exogenous FGF21 on the testicular apoptotic cell death spontaneously or induced by type 1 diabetes in FGF21 knockout (FGF21-KO) mice. Deletion of Fgf21 gene does not affect testicular cell proliferation, but significantly increases the spontaneous incidence of testicular TUNEL positive cells with increases in the Bax/Bcl2 expression ratio and apoptosis-inducing factor (AIF) expression. Diabetes induced significant increases in testicular TUNEL positive cells, Bax/Bcl2 expression ratio, AIF expression, CHOP and cleaved caspase-12 expression, and oxidative damage, but did not change the expression of cleaved caspase-3 and caspase-8. Deletion of Fgf21 gene also significantly enhances diabetes-induced TUNEL positive cells along with the increased expression of Bax/Bcl2 ratio, AIF, CHOP, cleaved caspase-12, and oxidative damage, which was significantly prevented by the supplementation of exogenous FGF21. These results suggest that Fgf21 gene may involve in maintaining normal spermatogenesis and also protect the germ cells from diabetes-induced apoptotic cell death probably via the prevention of diabetes-induced oxidative damage. PMID:23499715

  20. Programmed cell death in plants: A chloroplastic connection

    PubMed Central

    Ambastha, Vivek; Tripathy, Baishnab C; Tiwari, Budhi Sagar

    2015-01-01

    Programmed cell death (PCD) is an integral cellular program by which targeted cells culminate to demise under certain developmental and pathological conditions. It is essential for controlling cell number, removing unwanted diseased or damaged cells and maintaining the cellular homeostasis. The details of PCD process has been very well elucidated and characterized in animals but similar understanding of the process in plants has not been achieved rather the field is still in its infancy that sees some sporadic reports every now and then. The plants have 2 energy generating sub-cellular organelles- mitochondria and chloroplasts unlike animals that just have mitochondria. The presence of chloroplast as an additional energy transducing and ROS generating compartment in a plant cell inclines to advocate the involvement of chloroplasts in PCD execution process. As chloroplasts are supposed to be progenies of unicellular photosynthetic organisms that evolved as a result of endosymbiosis, the possibility of retaining some of the components involved in bacterial PCD by chloroplasts cannot be ruled out. Despite several excellent reviews on PCD in plants, there is a void on an update of information at a place on the regulation of PCD by chloroplast. This review has been written to provide an update on the information supporting the involvement of chloroplast in PCD process and the possible future course of the field. PMID:25760871

  1. Temporal rhythm of petal programmed cell death in Ipomoea purpurea.

    PubMed

    Gui, M-Y; Ni, X-L; Wang, H-B; Liu, W-Z

    2016-09-01

    Flowers are the main sexual reproductive organs in plants. The shapes, colours and scents of corolla of plant flowers are involved in attracting insect pollinators and increasing reproductive success. The process of corolla senescence was investigated in Ipomoea purpurea (Convolvulaceae) in this study. In the research methods of plant anatomy, cytology, cell chemistry and molecular biology were used. The results showed that at the flowering stage cells already began to show distortion, chromatin condensation, mitochondrial membrane degradation and tonoplast dissolution and rupture. At this stage genomic DNA underwent massive but gradual random degradation. However, judging from the shape and structure, aging characteristics did not appear until the early flower senescence stage. The senescence process was slow, and it was completed at the late stage of flower senescence with a withering corolla. We may safely arrive at the conclusion that corolla senescence of I. purpurea was mediated by programmed cell death (PCD) that occurred at the flowering stage. The corolla senescence exhibited an obvious temporal rhythm, which demonstrated a high degree of coordination with pollination and fertilization. PMID:27259176

  2. Acetylsalicylic acid induces programmed cell death in Arabidopsis cell cultures.

    PubMed

    García-Heredia, José M; Hervás, Manuel; De la Rosa, Miguel A; Navarro, José A

    2008-06-01

    Acetylsalicylic acid (ASA), a derivative from the plant hormone salicylic acid (SA), is a commonly used drug that has a dual role in animal organisms as an anti-inflammatory and anticancer agent. It acts as an inhibitor of cyclooxygenases (COXs), which catalyze prostaglandins production. It is known that ASA serves as an apoptotic agent on cancer cells through the inhibition of the COX-2 enzyme. Here, we provide evidences that ASA also behaves as an agent inducing programmed cell death (PCD) in cell cultures of the model plant Arabidopsis thaliana, in a similar way than the well-established PCD-inducing agent H(2)O(2), although the induction of PCD by ASA requires much lower inducer concentrations. Moreover, ASA is herein shown to be a more efficient PCD-inducing agent than salicylic acid. ASA treatment of Arabidopsis cells induces typical PCD-linked morphological and biochemical changes, namely cell shrinkage, nuclear DNA degradation, loss of mitochondrial membrane potential, cytochrome c release from mitochondria and induction of caspase-like activity. However, the ASA effect can be partially reverted by jasmonic acid. Taking together, these results reveal the existence of common features in ASA-induced animal apoptosis and plant PCD, and also suggest that there are similarities between the pathways of synthesis and function of prostanoid-like lipid mediators in animal and plant organisms.

  3. Gigantic macroautophagy in programmed nuclear death of Tetrahymena thermophila.

    PubMed

    Akematsu, Takahiko; Pearlman, Ronald E; Endoh, Hiroshi

    2010-10-01

    Programmed nuclear death (PND) in Tetrahymena is a unique process during conjugation, in which only the parental macronucleus is degraded and then eliminated from the progeny cytoplasm, but other co-existing nuclei such as new micro- and macronuclei are unaffected. PND through autophagic elimination is expected to be strictly controlled, considering the significant roles in ciliates such as turnover of disused organelles and production of the next generation. Here we demonstrate that PND in Tetrahymena involves peculiar aspects of autophagy, which differ from mammalian or yeast macroautophagy. Drastic change of the parental macronucleus occurs when differentiation of new macronuclei is initiated. Combined use of monodansylcadaverine and a lysosome indicator LysoTracker Red showed that prior to nuclear condensation, the envelope of the parental macronucleus changed its nature as if it is an autophagic membrane, without the accumulation of a pre-autophagosomal structure from the cytoplasm. Subsequently, lysosomes approached only to the parental macronucleus and localized at the envelope until a final resorption stage. In addition, we found that the parental macronucleus exhibits certain sugars and phosphatidylserine on the envelope, which are possible "attack me" signals, that are not found on other types of nuclei. These findings suggest that PND is a highly elaborated process, different from the typical macroautophagy seen in other systems, and is executed through interaction between specific molecular signals on the parental macronuclear envelope and autophagic/lysosomal machineries.

  4. Cell death programs in Yersinia immunity and pathogenesis

    PubMed Central

    Philip, Naomi H.; Brodsky, Igor E.

    2012-01-01

    Cell death plays a central role in host-pathogen interactions, as it can eliminate the pathogen's replicative niche and provide pro-inflammatory signals necessary for an effective immune response; conversely, cell death can allow pathogens to eliminate immune cells and evade anti-microbial effector mechanisms. In response to developmental signals or cell-intrinsic stresses, the executioner caspases-3 and -7 mediate apoptotic cell death, which is generally viewed as immunologically silent or immunosuppressive. A proinflammatory form of cell death that requires caspase-1, termed pyroptosis, is activated in response to microbial products within the host cytosol or disruption of cellular membranes by microbial pathogens. Infection by the bacterial pathogen Yersinia has features of both apoptosis and pyroptosis. Cell death and caspase-1 processing in Yersinia-infected cells occur in response to inhibition of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ. However, the molecular basis of YopJ-induced cell death, and the role of different death pathways in anti-Yersinia immune responses remain enigmatic. Here, we discuss the role that cell death may play in inducing specific pro-inflammatory signals that shape innate and adaptive immune responses against Yersinia infection. PMID:23226685

  5. A Traumatic Death Support Group Program: Applying an Integrated Conceptual Framework

    ERIC Educational Resources Information Center

    Walijarvi, Corrine M.; Weiss, Ann H.; Weinman, Maxine L.

    2012-01-01

    This article describes an 8-week, curriculum-based traumatic death support group program that is offered at Bo's Place, a grief and bereavement center in Houston, Texas. The program was implemented in 2006 in an effort to help family members who had experienced a death in the family by suicide, murder, accident, or sudden medical problem. The…

  6. Exposure at the cell surface is required for gas3/PMP22 To regulate both cell death and cell spreading: implication for the Charcot-Marie-Tooth type 1A and Dejerine-Sottas diseases.

    PubMed

    Brancolini, C; Edomi, P; Marzinotto, S; Schneider, C

    2000-09-01

    Gas3/PMP22 is a tetraspan membrane protein highly expressed in myelinating Schwann cells. Point mutations in the gas3/PMP22 gene account for the dominant inherited peripheral neuropathies Charcot-Marie-Tooth type 1A disease (CMT1A) and Dejerine-Sottas syndrome (DSS). Gas3/PMP22 can regulate apoptosis and cell spreading in cultured cells. Gas3/PMP22 point mutations, which are responsible for these diseases, are defective in this respect. In this report, we demonstrate that Gas3/PMP22-WT is exposed at the cell surface, while its point-mutated derivatives are intracellularly retained, colocalizing mainly with the endoplasmic reticulum (ER). The putative retrieval motif present in the carboxyl terminus of Gas3/PMP22 is not sufficient for the intracellular sequestration of its point-mutated forms. On the contrary, the introduction of a retrieval signal at the carboxyl terminus of Gas3/PMP22-WT leads to its intracellular accumulation, which is accompanied by a failure to trigger cell death as well as by changes in cell spreading. In addition, by substituting the Asn at position 41 required for N-glycosylation, we provide evidence that N-glycosylation is required for the full effect on cell spreading, but it is not necessary for triggering cell death. In conclusion, we suggest that the DSS and the CMT1A neuropathies derived from point mutations of Gas3/PMP22 might arise, at the molecular level, from a reduced exposure of Gas3/PMP22 at the cell surface, which is required to exert its biological functions. PMID:10982389

  7. Induction of Cell Death in Growing Human T-Cells and Cell Survival in Resting Cells in Response to the Human T-Cell Leukemia Virus Type 1 Tax

    PubMed Central

    Mizuguchi, Mariko; Sasaki, Yuka; Hara, Toshifumi; Higuchi, Masaya; Tanaka, Yuetsu; Funato, Noriko; Tanaka, Nobuyuki; Fujii, Masahiro; Nakamura, Masataka

    2016-01-01

    Tax1 encoded by the human T-cell leukemia virus type 1 (HTLV-1) has been believed to dysregulate the expression of cellular genes involved in cell survival and mortality, leading to the development of adult T-cell leukemia (ATL). The function of Tax1 in ATL development however is still controversial, primarily because Tax1 induces cell cycle progression and apoptosis. To systemically understand cell growth phase-dependent induction of cell survival or cell death by Tax1, we established a single experimental system using an interleukin 2 (IL-2)-dependent human T-cell line Kit 225 that can be forced into resting phase by IL-2 deprivation. Introduction of Tax1 and HTLV-2 Tax (Tax2B) decreased mitochondrial activity alongside apoptosis in growing cells but not in resting cells. Cell cycle profile analysis indicated that Tax1 and Tax2B were likely to perturb the S phase in growing cells. Studies with Tax1 mutants and siRNA for NF-κB/RelA revealed that Tax1-mediated cell growth inhibition and apoptosis in growing Kit 225 cells depend on RelA. Interestingly, inactivation of the non-canonical NF-κB and p38 MAPK pathways relieved Tax1-mediated apoptosis, suggesting that the Tax1-NF-κB-p38 MAPK axis may be associated with apoptosis in growing cells. Inflammatory mediators such as CCL3 and CCL4, which are involved in oncogene-induced senescence (OIS), were induced by Tax1 and Tax2B in growing cells. In contrast, RelA silencing in resting cells reduced mitochondrial activity, indicating that NF-κB/RelA is also critical for Tax1-mediated cell survival. These findings suggest that Tax1-mediated cell survival and death depend on the cell growth phase. Both effects of Tax1 may be implicated in the long latency of HTLV-1 infection. PMID:26829041

  8. Diabetes Type 1

    MedlinePlus

    Diabetes means your blood glucose, or blood sugar, levels are too high. With type 1 diabetes, your pancreas does not make insulin. Insulin is ... kidneys, nerves, and gums and teeth. Type 1 diabetes happens most often in children and young adults ...

  9. Programmed death-1/programmed death-L1 signaling pathway and its blockade in hepatitis C virus immunotherapy

    PubMed Central

    Salem, Mohamed L; El-Badawy, Ahmed

    2015-01-01

    Chronic hepatitis C virus (HCV) infection is a public health issue that often progresses to life-threatening complications, including liver cirrhosis, fibrosis, and hepatocellular carcinoma. Impaired immune responses to HCV are key features of chronic HCV infection. Therefore, intervention strategies usually involve enhancing the immune responses against HCV. Cytotoxic CD8+ T lymphocytes (CTLs) play a critical role in the control of HCV infection. However, their cytolytic function can be impaired by the expression of co-inhibitory molecules. Programmed death-1 (PD-1) receptor and its ligand PD-L1 function in a T cell co-inhibitory pathway, which either blocks the function of CTLs or the differentiation of CD8+ T cells. During chronic HCV infection, the immune inhibitory receptor PD-1 is upregulated on dysfunctional HCV-specific CD8+ T cells. As such, blockade of the PD-1/PD-L1 pathway in these CD8+ T cells might restore their functional capabilities. Indeed, clinical trials using therapies to block this pathway have shown promise in the fostering of anti-HCV immunity. Understanding how chronic HCV infection induces upregulation of PD-1 on HCV specific T cells and how the PD-1/PD-L1 interaction develops HCV specific T cell dysfunction will accelerate the development of an efficacious prophylactic and therapeutic vaccination against chronic HCV infections, which will significantly improve HCV treatments and patient survival. In this review, we discuss the relationship between PD-1 expression and clinical responses and the potential use of PD-1 blockade for anti-HCV therapy. PMID:26483866

  10. Type 1 diabetes

    PubMed Central

    Atkinson, Mark A; Eisenbarth, George S; Michels, Aaron W

    2015-01-01

    Over the past decade, knowledge of the pathogenesis and natural history of type 1 diabetes has grown substantially, particularly with regard to disease prediction and heterogeneity, pancreatic pathology, and epidemiology. Technological improvements in insulin pumps and continuous glucose monitors help patients with type 1 diabetes manage the challenge of lifelong insulin administration. Agents that show promise for averting debilitating disease-associated complications have also been identified. However, despite broad organisational, intellectual, and fiscal investments, no means for preventing or curing type 1 diabetes exists, and, globally, the quality of diabetes management remains uneven. This Seminar discusses current progress in epidemiology, pathology, diagnosis, and treatment of type 1 diabetes, and prospects for an improved future for individuals with this disease. PMID:23890997

  11. PROGRAMMED CELL DEATH IN EXTRAOCULAR MUSCLE TENDON/SCLERA PRECURSORS

    EPA Science Inventory

    Abstract

    Purpose: This study was designed to examine the occurrence of natural cell death in the periocular mesenchyme of mouse embryos.

    Methods: Vital staining with LysoTracker Red and Nile blue sulphate as well as terminal nick end labeling (TUNEL) were utiliz...

  12. CompuTOD, a computer program to estimate time of death of deer.

    PubMed

    Cox, R J; Mitchell, S L; Espinoza, E O

    1994-09-01

    A statistical program named CompuTOD has been written which calculates the time since death of white-tailed deer. The data used for the regression analysis (n = 378) was obtained from a controlled hunt in 1982. The results obtained compare favorably with previous studies but additionally gives upper and lower confidence limits for the calculated time interval since death.

  13. Implementation Of Prescription Drug Monitoring Programs Associated With Reductions In Opioid-Related Death Rates.

    PubMed

    Patrick, Stephen W; Fry, Carrie E; Jones, Timothy F; Buntin, Melinda B

    2016-07-01

    Over the past two decades the number of opioid pain relievers sold in the United States rose dramatically. This rise in sales was accompanied by an increase in opioid-related overdose deaths. In response, forty-nine states (all but Missouri) created prescription drug monitoring programs to detect high-risk prescribing and patient behaviors. Our objectives were to determine whether the implementation or particular characteristics of the programs were effective in reducing opioid-related overdose deaths. In adjusted analyses we found that a state's implementation of a program was associated with an average reduction of 1.12 opioid-related overdose deaths per 100,000 population in the year after implementation. Additionally, states whose programs had robust characteristics-including monitoring greater numbers of drugs with abuse potential and updating their data at least weekly-had greater reductions in deaths, compared to states whose programs did not have these characteristics. We estimate that if Missouri adopted a prescription drug monitoring program and other states enhanced their programs with robust features, there would be more than 600 fewer overdose deaths nationwide in 2016, preventing approximately two deaths each day. PMID:27335101

  14. Reducing stress and supporting positive relations in families of young children with type 1 diabetes: A randomized controlled study for evaluating the effects of the DELFIN parenting program

    PubMed Central

    2012-01-01

    Background To assess initial efficacy and feasibility of a structured behavioural group training (DELFIN) for parents of children with diabetes type 1, in order to reduce parenting stress and to improve parenting skills. Methods A randomized controlled study was conducted between July 2008 and September 2010, at a children’s hospital in Hannover with parents of children with type 1 diabetes (2–10 yrs) (intervention group n = 37; control group n = 28). Parenting skills, parents’ psychological burden, children’s behavioural difficulties and quality of metabolic control were assessed before, 3 months after and 12 months after participating in the training program. Results In the intervention group parenting behaviour in conflict situations improved significantly after 3 months (Z = −3.28; p ≤ 0.001). It remained stable over 12 months (Z = −2.94; p ≤ 0.01). Depression and anxiety scores of parents decreased (Z = −1.93; p ≤ .05; Z = −2.02; p ≤ .05). Even though the outcome in the intervention group was more positive, the differences between both study arms failed to reach statistical significance. Unexpectedly parenting behaviour in the control group improved also (Z = −2.45; p ≤ .05). Anxiety as well as stress scores decreased in this group (Z = −2.02; p ≤ .05 and Z = −2.11; p ≤ .05). In both groups the initial metabolic control was good and without significant differences (A1c 7.2±0.8% vs. 7.1±0.4%; p > 0.5). It remained stable in the DELFIN group (A1c 7.1±0.8%; p > 0.5), but it increased slightly in controls (A1c 7.3±0.5%; Z = −2.79; p = .005). Conclusions This study has brought first evidence for the efficacy and feasibility of the program. A multicentre study with a larger sample is necessary to confirm these first results. PMID:22994843

  15. Programmed death in a unicellular organism has species-specific fitness effects.

    PubMed

    Durand, Pierre M; Choudhury, Rajdeep; Rashidi, Armin; Michod, Richard E

    2014-02-01

    Programmed cell death (PCD) is an ancient phenomenon and its origin and maintenance in unicellular life is unclear. We report that programmed death provides differential fitness effects that are species specific in the model organism Chlamydomonas reinhardtii. Remarkably, PCD in this organism not only benefits others of the same species, but also has an inhibitory effect on the growth of other species. These data reveal that the fitness effects of PCD can depend upon genetic relatedness.

  16. Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

    PubMed Central

    McClanahan, Fabienne; Sharp, Thomas G.; Gribben, John G.

    2016-01-01

    Therapeutic strategies targeting the programmed cell death-ligand 1/programmed cell death-1 pathway have shown significant responses and good tolerability in solid malignancies. Although preclinical studies suggest that inhibiting programmed cell death-ligand 1/programmed cell death-1 interactions might also be highly effective in hematological malignancies, remarkably few clinical trials have been published. Determining patients who will benefit most from programmed cell death-ligand 1/programmed cell death-1-directed immunotherapy and whether programmed cell death-ligand 1/programmed cell death-1 are adequate prognostic markers becomes an increasingly important clinical question, especially as aberrant programmed cell death-ligand 1/programmed cell death-1 expression are key mediators of impaired anti-tumor immune responses in a range of B-cell lymphomas. Herein, we systematically review the published literature on the expression and prognostic value of programmed cell death-ligand 1/programmed cell death-1 in these patients and identify considerable differences in expression patterns, distribution and numbers of programmed cell death-ligand 1+/programmed cell death-1+cells, both between and within lymphoma subtypes, which is reflected in conflicting findings regarding the prognostic value of programmed cell death-ligand 1+/programmed cell death-1+ cells. This can be partly explained by differences in methodologies (techniques, protocols, cutoff values) and definitions of positivity. Moreover, lymphomagenesis, disease progression, and prognosis appear to be determined not only by the presence, numbers and distribution of specific subtypes of T cells, but also by other cells and additional immune checkpoints. Collectively, our findings indicate that programmed cell death-ligand 1/programmed cell death-1 interactions play an essential role in B-cell lymphoma biology and are of clinical importance, but that the overall outcome is determined by additional components

  17. Queen pheromone regulates programmed cell death in the honey bee worker ovary.

    PubMed

    Ronai, I; Oldroyd, B P; Vergoz, V

    2016-10-01

    In social insect colonies the presence of a queen, secreting her pheromones, is a key environmental cue for regulating the reproductive state of workers. However, until recently the proximate molecular mechanisms underlying facultative worker sterility were unidentified. Studies into worker oogenesis in the honey bee (Apis mellifera) have indicated that programmed cell death is central to the regulation of oogenesis. Here we investigate how queen pheromone, age of the worker and ovary state affect both programmed cell death and cell number in worker ovaries. We describe a novel method to simultaneously measure programmed cell death (caspase activity) and live cell number (estimated from the amount of adenosine triphosphate) in an insect tissue. Workers exposed to queen pheromone have higher levels of caspase activity in the ovary than those not exposed. Our results suggest that queen pheromone triggers programmed cell death at the mid-oogenesis checkpoint causing the abortion of worker oocytes and reproductive inhibition of the worker caste. Nonetheless, high caspase activity is present in activated ovaries from workers not exposed to queen pheromone. This caspase activity is most likely to be from the nurse cells undergoing programmed cell death, in late oogenesis, for normal oocyte development. Our study shows that the social environment of an organism can influence programmed cell death within a tissue. PMID:27321063

  18. How France launched its donation after cardiac death program.

    PubMed

    Antoine, C; Mourey, F; Prada-Bordenave, E

    2014-02-01

    On the basis of the literature and results presented at the 6th International Conference, donation after cardio-circulatory death provides a significant, practical, additional high quality source of transplantable organs. The vast majority of DCD are 'controlled' Maastricht category III donors. In 2010, the parliamentary information mission on the revision of the bioethics laws invited the Intensive Care Societies to debate and to make recommendations to implement controlled donation after circulatory death. They came to the conclusion that such retrieval is possible in France and insisted on the medical criteria that frame it: the writing of the medical procedures, the ethical aspects and the delay. The major recommendations of the ethics committees were firstly, The WLST decision is independent of the possibility of organ donation; secondly, the strict respect of "The dead donor and organ transplantation rule" and the updated national guidance for the WLST; thirdly, the drafting of a nationally agreed protocol defining the mandatory conditions to determine death and to perform procurement and transplantation. Organ donation after WLST will be authorised only in pilot centres with a locally agreed WLST policy including external second opinion and written transcript of the WLST decision, experienced intensive care staff, a local organ procurement coordination team familiar with DBD and DCD protocols and only in hospitals authorised for organ procurement. It is important to have an optimal and standardized national guidance to limit the known risk factors of graft failure (donor and recipient choice, warm and cold ischemia time), to increase acceptance by medical community and civil society and to improve results and allow more powerful analysis.

  19. Anoikis: a necessary death program for anchorage-dependent cells.

    PubMed

    Chiarugi, Paola; Giannoni, Elisa

    2008-12-01

    Cell to matrix adhesion is a key factor for cellular homeostasis and disruption of such interaction has adverse effects on cell survival. It leads to a specific type of apoptosis known as "anoikis" in most non-transformed cell types. This kind of apoptosis following loss of cell anchorage is important for development, tissue homeostasis and several diseases. Integrins sense mechanical forces arising from the matrix, thereby converting these stimuli to downstream signals modulating cell viability. Anchorage-independent growth is a crucial step during tumorigenesis and in particular during the metastatic spreading of cancer cells. The disruption of the tight control leading an "homeless" cell to death is therefore able to violate the cell defences against transformation. This review analyses the recent investigations into the molecular mechanisms governing anoikis, discussing the different ways in which adhesion can influence this process and addressing the relevance of this unique apoptosis mode in the development of metastatic cancers, as well as in other diseases.

  20. Baicalein induces programmed cell death in Candida albicans.

    PubMed

    Dai, Bao-Di; Cao, Ying-Ying; Huang, Shan; Xu, Yong-Gang; Gao, Ping-Hui; Wang, Yan; Jiang, Yuan-Ying

    2009-08-01

    Recent evidence has revealed the occurrence of an apoptotic phenotype in Candida albicans that is inducible with environmental stresses such as acetic acid, hydrogen peroxide, and amphotericin B. In the present study, we found that the Chinese herbal medicine Baicalein (BE), which was one of the skullcapflavones, can induce apoptosis in C. albicans. The apoptotic effects of BE were detected by flow cytometry using Annexin V-FITC and DAPI, and it was confirmed by transmission electron microscopy analysis. After exposure to 4 microg/ml BE for 12 h, about 10% of C. albicans cells were apoptotic. Both the increasing intracellular levels of reactive oxygen species (ROS) and upregulation of some redox-related genes (CAP1, SOD2, TRR1) were observed. Furthermore, we compared the survivals of CAP1 deleted, wild-type, and overexpressed strains and found that Cap1p attenuated BE-initiated cell death, which was coherent with a higher mRNA level of the CAP1 gene. In addition, the mitochondrial membrane potential of C. albicans cells changed significantly ( p<0.001) upon BE treatment compared with control. Taken together, our results indicate that BE treatment induces apoptosis in C.albicans cells, and the apoptosis was associated with the breakdown of mitochondrial membrane potential. PMID:19734718

  1. Tales of cannibalism, suicide, and murder: Programmed cell death in C. elegans.

    PubMed

    Kinchen, Jason M; Hengartner, Michael O

    2005-01-01

    "Life is pleasant. Death is peaceful. It's the transition that's troublesome," said Isaac Asimov. Indeed, much scientific work over the last hundred years centered around attempts either to stave off or to induce the onset of death, at both the organismal and the cellular levels. In this quest, the nematode C. elegans has proven an invaluable tool, first, in the articulation of the genetic pathway by which programmed cell death proceeds, and also as a continuing source of inspiration. It is our purpose in this Chapter to familiarize the reader with the topic of programmed cell death in C. elegans and its relevance to current research in the fields of apoptosis and cell corpse clearance.

  2. The effect of chemotherapy on programmed cell death 1/programmed cell death 1 ligand axis: some chemotherapeutical drugs may finally work through immune response

    PubMed Central

    Luo, Min; Fu, Liwu

    2016-01-01

    Most tumors are immunogenic which would trigger some immune response. Chemotherapy also has immune potentiating mechanisms of action. But it is unknown whether the immune response is associated with the efficacy of chemotherapy and the development of chemoresistance. Recently, there is a growing interest in immunotherapy, among which the co-inhibitory molecules, programmed cell death 1/programmed cell death 1 ligand (PD-1/PD-L1) leads to immune evasion. Since some reports showed that conventional chemotherapeutics can induce the expression of PD-L1, we try to summarize the effect of chemotherapy on PD-1/PD-L1 axis and some potential molecules relevant to PD-1/PD-L1 in chemoresistance in this review. PMID:26919108

  3. Programmed cell death and clearance of cell corpses in Caenorhabditis elegans.

    PubMed

    Wang, Xiaochen; Yang, Chonglin

    2016-06-01

    Programmed cell death is critical to the development of diverse animal species from C. elegans to humans. In C. elegans, the cell death program has three genetically distinguishable phases. During the cell suicide phase, the core cell death machinery is activated through a protein interaction cascade. This activates the caspase CED-3, which promotes numerous pro-apoptotic activities including DNA degradation and exposure of the phosphatidylserine "eat me" signal on the cell corpse surface. Specification of the cell death fate involves transcriptional activation of the cell death initiator EGL-1 or the caspase CED-3 by coordinated actions of specific transcription factors in distinct cell types. In the cell corpse clearance stage, recognition of cell corpses by phagocytes triggers several signaling pathways to induce phagocytosis of apoptotic cell corpses. Cell corpse-enclosing phagosomes ultimately fuse with lysosomes for digestion of phagosomal contents. This article summarizes our current knowledge about programmed cell death and clearance of cell corpses in C. elegans. PMID:27048817

  4. LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission.

    PubMed

    Kim, J-E; Ryu, H J; Kim, M J; Kang, T-C

    2014-07-01

    Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27(Kip1) expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27(Kip1)-cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death.

  5. Type 1 autoimmune pancreatitis.

    PubMed

    Zen, Yoh; Bogdanos, Dimitrios P; Kawa, Shigeyuki

    2011-12-07

    Before the concept of autoimmune pancreatitis (AIP) was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP) has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney) and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of regulatory T-cells are assumed

  6. A Conserved Core of Programmed Cell Death Indicator Genes Discriminates Developmentally and Environmentally Induced Programmed Cell Death in Plants1[OPEN

    PubMed Central

    Van Bel, Michiel; Van Hautegem, Tom; Fendrych, Matyáš; Simaskova, Maria; van Durme, Matthias; Buscaill, Pierre; Rivas, Susana; S. Coll, Nuria; Maere, Steven

    2015-01-01

    A plethora of diverse programmed cell death (PCD) processes has been described in living organisms. In animals and plants, different forms of PCD play crucial roles in development, immunity, and responses to the environment. While the molecular control of some animal PCD forms such as apoptosis is known in great detail, we still know comparatively little about the regulation of the diverse types of plant PCD. In part, this deficiency in molecular understanding is caused by the lack of reliable reporters to detect PCD processes. Here, we addressed this issue by using a combination of bioinformatics approaches to identify commonly regulated genes during diverse plant PCD processes in Arabidopsis (Arabidopsis thaliana). Our results indicate that the transcriptional signatures of developmentally controlled cell death are largely distinct from the ones associated with environmentally induced cell death. Moreover, different cases of developmental PCD share a set of cell death-associated genes. Most of these genes are evolutionary conserved within the green plant lineage, arguing for an evolutionary conserved core machinery of developmental PCD. Based on this information, we established an array of specific promoter-reporter lines for developmental PCD in Arabidopsis. These PCD indicators represent a powerful resource that can be used in addition to established morphological and biochemical methods to detect and analyze PCD processes in vivo and in planta. PMID:26438786

  7. Mastoparan-induced programmed cell death in the unicellular alga Chlamydomonas reinhardtii

    PubMed Central

    Yordanova, Zhenya P.; Woltering, Ernst J.; Kapchina-Toteva, Veneta M.; Iakimova, Elena T.

    2013-01-01

    Background and Aims Under stress-promoting conditions unicellular algae can undergo programmed cell death (PCD) but the mechanisms of algal cellular suicide are still poorly understood. In this work, the involvement of caspase-like proteases, DNA cleavage and the morphological occurrence of cell death in wasp venom mastoparan (MP)-treated Chlamydomonas reinhardtii were studied. Methods Algal cells were exposed to MP and cell death was analysed over time. Specific caspase inhibitors were employed to elucidate the possible role of caspase-like proteases. YVADase activity (presumably a vacuolar processing enzyme) was assayed by using a fluorogenic caspase-1 substrate. DNA breakdown was evaluated by DNA laddering and Comet analysis. Cellular morphology was examined by confocal laser scanning microscopy. Key Results MP-treated C. reinhardtii cells expressed several features of necrosis (protoplast shrinkage) and vacuolar cell death (lytic vesicles, vacuolization, empty cell-walled corpse-containing remains of digested protoplast) sometimes within one single cell and in different individual cells. Nucleus compaction and DNA fragmentation were detected. YVADase activity was rapidly stimulated in response to MP but the early cell death was not inhibited by caspase inhibitors. At later time points, however, the caspase inhibitors were effective in cell-death suppression. Conditioned medium from MP-treated cells offered protection against MP-induced cell death. Conclusions In C. reinhardtii MP triggered PCD of atypical phenotype comprising features of vacuolar and necrotic cell deaths, reminiscent of the modality of hypersensitive response. It was assumed that depending on the physiological state and sensitivity of the cells to MP, the early cell-death phase might be not mediated by caspase-like enzymes, whereas later cell death may involve caspase-like-dependent proteolysis. The findings substantiate the hypothesis that, depending on the mode of induction and sensitivity of

  8. Nuclear alterations associated to programmed cell death in larval salivary glands of Apis mellifera (Hymenoptera: Apidae).

    PubMed

    Silva-Zacarin, E C M; Taboga, S R; Silva de Moraes, R L M

    2008-01-01

    The silk glands of bees are a good model for the study of cell death in insects. With the objective to detect the nuclear features during glandular regression stage, larvae at the last instar and pre-pupae were collected and their silk glands were dissected and processed for ultrastructural analysis and histologically for cytochemical and imunocytochemical analysis. The results showed that the cellular nuclei exhibited characteristics of death by atypical apoptosis as well as autophagic cell death. Among the apoptosis characteristic were: nuclear strangulation with bleb formation in some nuclei, DNA fragmentation in most of the nuclei and nucleolar fragmentation. Centripetal chromatin compaction was observed in many nuclei, forming a perichromatin halo differing from typical apoptotic nuclei. With regards to the characteristics of autophagic-programmed cell death, most relevant was the delay in the collapse of many nuclei.

  9. Using linked birth and infant death files for program planning and evaluation: NIMS workshop lessons.

    PubMed

    Zahniser, C; Halpin, G; Hollinshead, W; Kessel, S; Koontz, A

    1987-01-01

    Health planners should base program decisions on the best information available. Combining information from different sources can be valuable in identifying problems--the essential first step in program planning. To facilitate this process, a workshop was conducted during the National Infant Mortality Surveillance Conference in Atlanta, GA. Maternal and child health directors explored the use of linked birth and infant death data for program planning and evaluation. Linked birth and infant death certificate files permit evaluation of infant mortality by birth weight and other infant and maternal characteristics, thus providing more detailed information than birth or death certificates alone. An assessment of the birth weight distribution of live births, birth weight specific-mortality risks, distribution of deaths by birth weight, and birth weight-specific causes of death can help identify problems in the childbearing population and with the delivery of health services. Once the infant health problems are defined clearly, the selection and delivery of services can be better targeted and evaluated for the reduction of these problems.

  10. Cyclosporin A inhibits programmed cell death and cytochrome c release induced by fusicoccin in sycamore cells.

    PubMed

    Contran, N; Cerana, R; Crosti, P; Malerba, M

    2007-01-01

    Programmed cell death plays a vital role in normal plant development, response to environmental stresses, and defense against pathogen attack. Different types of programmed cell death occur in plants and the involvement of mitochondria is still under investigation. In sycamore (Acer pseudoplatanus L.) cultured cells, the phytotoxin fusicoccin induces cell death that shows apoptotic features, including chromatin condensation, DNA fragmentation, and release of cytochrome c from mitochondria. In this work, we show that cyclosporin A, an inhibitor of the permeability transition pore of animal mitochondria, inhibits the cell death, DNA fragmentation, and cytochrome c release induced by fusicoccin. In addition, we show that fusicoccin induces a change in the shape of mitochondria which is not prevented by cyclosporin A. These results suggest that the release of cytochrome c induced by fusicoccin occurs through a cyclosporin A-sensitive system that is similar to the permeability transition pore of animal mitochondria and they make it tempting to speculate that this release may be involved in the phytotoxin-induced programmed cell death of sycamore cells.

  11. NO way back: nitric oxide and programmed cell death in Arabidopsis thaliana suspension cultures.

    PubMed

    Clarke, A; Desikan, R; Hurst, R D; Hancock, J T; Neill, S J

    2000-12-01

    Recent research has implicated nitric oxide (NO) in the induction of the hypersensitive response (HR) during plant-pathogen interactions. Here we demonstrate that Arabidopsis suspension cultures generate elevated levels of NO in response to challenge by avirulent bacteria, and, using NO donors, show that these elevated levels of NO are sufficient to induce cell death in Arabidopsis cells independently of reactive oxygen species (ROS). We also provide evidence that NO-induced cell death is a form of programmed cell death (PCD), requiring gene expression, and has a number of characteristics of PCD of mammalian cells: NO induced chromatin condensation and caspase-like activity in Arabidopsis cells, while the caspase-1 inhibitor, Ac-YVAD-CMK, blocked NO-induced cell death. A well-established second messenger mediating NO responses in mammalian cells is cGMP, produced by the enzyme guanylate cyclase. A specific inhibitor of guanylate cyclase blocked NO-induced cell death in Arabidopsis cells, and this inhibition was reversed by the cell-permeable cGMP analogue, 8Br-cGMP, although 8Br-cGMP alone did not induce cell death or potentiate NO-induced cell death. This suggests that cGMP synthesis is required but not sufficient for NO-induced cell death in Arabidopsis. In-gel protein kinase assays showed that NO activates a potential mitogen-activated protein kinase (MAPK), although a specific inhibitor of mammalian MAPK activation, PD98059, which blocked H2O2-induced cell death, did not inhibit the effects of NO.

  12. Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.

    PubMed Central

    Gulbins, E; Brenner, B; Schlottmann, K; Welsch, J; Heinle, H; Koppenhoefer, U; Linderkamp, O; Coggeshall, K M; Lang, F

    1996-01-01

    Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death. Images Figure 1 Figure 3 PMID:8943716

  13. Programmed cell death in plants: a pathogen-triggered response activated coordinately with multiple defense functions.

    PubMed

    Greenberg, J T; Guo, A; Klessig, D F; Ausubel, F M

    1994-05-20

    In plants, the hypersensitive response (HR) to pathogens involves rapid cell death, which is hypothesized to arise from the activation of a cell death program. We describe mutant A. thaliana plants that contain lesions in a single accelerated cell death (ACD) gene called ACD2 and that bypass the need for pathogen exposure to induce the HR. acd2 plants that develop spontaneous lesions show typical HR characteristics both within the necrotic tissue and within the healthy part of the plant, including: modification of plant cell walls, resistance to bacterial pathogens, and accumulation of defense-related gene transcripts, the signal molecule salicylic acid and an antimicrobial compound. We propose that the ACD2 gene is involved in a pathway(s) that negatively regulates a genetically programmed HR.

  14. A Kunitz-type protease inhibitor regulates programmed cell death during flower development in Arabidopsis thaliana.

    PubMed

    Boex-Fontvieille, Edouard; Rustgi, Sachin; Reinbothe, Steffen; Reinbothe, Christiane

    2015-10-01

    Flower development and fertilization are tightly controlled in Arabidopsis thaliana. In order to permit the fertilization of a maximum amount of ovules as well as proper embryo and seed development, a subtle balance between pollen tube growth inside the transmitting tract and pollen tube exit from the septum is needed. Both processes depend on a type of programmed cell death that is still poorly understood. Here, it is shown that a Kunitz protease inhibitor related to water-soluble chlorophyll proteins of Brassicaceae (AtWSCP, encoded by At1g72290) is involved in controlling cell death during flower development in A. thaliana. Genetic, biochemical, and cell biology approaches revealed that WSCP physically interacts with RD21 (RESPONSIVE TO DESICCATION) and that this interaction in turn inhibits the activity of RD21 as a pro-death protein. The regulatory circuit identified depends on the restricted expression of WSCP in the transmitting tract and the septum epidermis. In a respective Atwscp knock-out mutant, flowers exhibited precocious cell death in the transmitting tract and unnatural death of septum epidermis cells. As a consequence, apical-basal pollen tube growth, fertilization of ovules, as well as embryo development and seed formation were perturbed. Together, the data identify a unique mechanism of cell death regulation that fine-tunes pollen tube growth.

  15. Metallomics insights into the programmed cell death induced by metal-based anticancer compounds.

    PubMed

    Tan, Cai-Ping; Lu, Yi-Ying; Ji, Liang-Nian; Mao, Zong-Wan

    2014-05-01

    Since the discovery of cisplatin more than 40 years ago, enormous research efforts have been dedicated to developing metal-based anticancer agents and to elucidating the mechanisms involved in the action of these compounds. Abnormal metabolism and the evasion of apoptosis are important hallmarks of malignant transformation, and the induction of apoptotic cell death has been considered to be a main pathway by which cytotoxic metal complexes combat cancer. However, many cancers have cellular defects involving the apoptotic machinery, which results in an acquired resistance to apoptotic cell death and therefore reduced chemotherapeutic effectiveness. Over the past decade, it has been revealed that a growing number of cell death pathways induced by metal complexes are not dependent on apoptosis. Metal complexes specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. In this review, we discuss recent examples of metallomics studies on the different types of cell death induced by metal-based anticancer drugs, especially on the three major forms of programmed cell death (PCD) in mammalian cells: apoptosis, autophagy and regulated necrosis, also called necroptosis.

  16. Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death

    PubMed Central

    Thomenius, M; Freel, C D; Horn, S; Krieser, R; Abdelwahid, E; Cannon, R; Balasundaram, S; White, K; Kornbluth, S

    2011-01-01

    In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die. PMID:21475305

  17. Increased Anion Channel Activity Is an Unavoidable Event in Ozone-Induced Programmed Cell Death

    PubMed Central

    Errakhi, Rafik; Hiramatsu, Takuya; Meimoun, Patrice; Briand, Joël; Iwaya-Inoue, Mari; Kawano, Tomonori; Bouteau, François

    2010-01-01

    Background Ozone is a major secondary air pollutant often reaching high concentrations in urban areas under strong daylight, high temperature and stagnant high-pressure systems. Ozone in the troposphere is a pollutant that is harmful to the plant. Principal Findings By exposing cells to a strong pulse of ozonized air, an acute cell death was observed in suspension cells of Arabidopsis thaliana used as a model. We demonstrated that O3 treatment induced the activation of a plasma membrane anion channel that is an early prerequisite of O3-induced cell death in A. thaliana. Our data further suggest interplay of anion channel activation with well known plant responses to O3, Ca2+ influx and NADPH-oxidase generated reactive oxygen species (ROS) in mediating the oxidative cell death. This interplay might be fuelled by several mechanisms in addition to the direct ROS generation by O3; namely, H2O2 generation by salicylic and abscisic acids. Anion channel activation was also shown to promote the accumulation of transcripts encoding vacuolar processing enzymes, a family of proteases previously reported to contribute to the disruption of vacuole integrity observed during programmed cell death. Significance Collectively, our data indicate that anion efflux is an early key component of morphological and biochemical events leading to O3-induced programmed cell death. Because ion channels and more specifically anion channels assume a crucial position in cells, an understanding about the underlying role(s) for ion channels in the signalling pathway leading to programmed cell death is a subject that warrants future investigation. PMID:20967217

  18. Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti–programed death-ligand 1 (Avelumab)

    PubMed Central

    Gill, Amanda L.; Green, Samantha A.; Abdullah, Shahed; Le Saout, Cecile; Pittaluga, Stefania; Chen, Hui; Turnier, Refika; Lifson, Jeffrey; Godin, Steven; Qin, Jing; Sneller, Michael C.; Cuillerot, Jean-Marie; Sabzevari, Helen; Lane, H. Clifford; Catalfamo, Marta

    2016-01-01

    Objective: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. Methods: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. Results: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. Conclusion: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans. PMID:27490642

  19. Molecular mechanisms of Saccharomyces cerevisiae stress adaptation and programmed cell death in response to acetic acid

    PubMed Central

    Giannattasio, Sergio; Guaragnella, Nicoletta; Ždralević, Maša; Marra, Ersilia

    2013-01-01

    Beyond its classical biotechnological applications such as food and beverage production or as a cell factory, the yeast Saccharomyces cerevisiae is a valuable model organism to study fundamental mechanisms of cell response to stressful environmental changes. Acetic acid is a physiological product of yeast fermentation and it is a well-known food preservative due to its antimicrobial action. Acetic acid has recently been shown to cause yeast cell death and aging. Here we shall focus on the molecular mechanisms of S. cerevisiae stress adaptation and programmed cell death in response to acetic acid. We shall elaborate on the intracellular signaling pathways involved in the cross-talk of pro-survival and pro-death pathways underlying the importance of understanding fundamental aspects of yeast cell homeostasis to improve the performance of a given yeast strain in biotechnological applications. PMID:23430312

  20. Molecular mechanisms of Saccharomyces cerevisiae stress adaptation and programmed cell death in response to acetic acid.

    PubMed

    Giannattasio, Sergio; Guaragnella, Nicoletta; Zdralević, Maša; Marra, Ersilia

    2013-01-01

    Beyond its classical biotechnological applications such as food and beverage production or as a cell factory, the yeast Saccharomyces cerevisiae is a valuable model organism to study fundamental mechanisms of cell response to stressful environmental changes. Acetic acid is a physiological product of yeast fermentation and it is a well-known food preservative due to its antimicrobial action. Acetic acid has recently been shown to cause yeast cell death and aging. Here we shall focus on the molecular mechanisms of S. cerevisiae stress adaptation and programmed cell death in response to acetic acid. We shall elaborate on the intracellular signaling pathways involved in the cross-talk of pro-survival and pro-death pathways underlying the importance of understanding fundamental aspects of yeast cell homeostasis to improve the performance of a given yeast strain in biotechnological applications. PMID:23430312

  1. TRPV1 Activation in Primary Cortical Neurons Induces Calcium-Dependent Programmed Cell Death.

    PubMed

    Song, Juhyun; Lee, Jun Hong; Lee, Sung Ho; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

    2013-03-01

    Transient receptor potential cation channel, subfamily V, member 1 (TRPV1, also known as vanilloid receptor 1) is a receptor that detects capsaicin, a pungent component of chili peppers, and noxious heat. Although its function in the primary nociceptor as a pain receptor is well established, whether TRPV1 is expressed in the brain is still under debate. In this study, the responses of primary cortical neurons were investigated. Here, we report that 1) capsaicin induces caspase-3-dependent programmed cell death, which coincides with increased production of nitric oxide and peroxynitrite ; that 2) the prolonged capsaicin treatment induces a steady increase in the degree of capase-3 activation, which is prevented by the removal of capsaicin; 3) and that blocking calcium entry and calcium-mediated signaling prevents capsaicin-induced cell death. These results indicate that cortical neurons express TRPV1 whose prolonged activation causes cell death. PMID:23585723

  2. Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases

    PubMed Central

    Strasser, Andreas; Cory, Suzanne; Adams, Jerry M

    2011-01-01

    Apoptosis, the major form of programmed cell death in metazoan organisms, plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation contributes to many pathological states, including cancer, autoimmunity, infection and degenerative disorders. In vertebrates, it can be triggered either by engagement of ‘death receptors' of the tumour necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the Bcl-2 protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both pathways lead to cellular demolition by dedicated proteases termed caspases. This review discusses the groundbreaking experiments from many laboratories that have clarified cell death regulation and galvanised efforts to translate this knowledge into novel therapeutic strategies for the treatment of malignant and perhaps certain autoimmune and infectious diseases. PMID:21863020

  3. High fat programming of beta cell compensation, exhaustion, death and dysfunction.

    PubMed

    Cerf, Marlon E

    2015-03-01

    Programming refers to events during critical developmental windows that shape progeny health outcomes. Fetal programming refers to the effects of intrauterine (in utero) events. Lactational programming refers to the effects of events during suckling (weaning). Developmental programming refers to the effects of events during both fetal and lactational life. Postnatal programming refers to the effects of events either from birth (lactational life) to adolescence or from weaning (end of lactation) to adolescence. Islets are most plastic during the early life course; hence programming during fetal and lactational life is most potent. High fat (HF) programming is the maintenance on a HF diet (HFD) during critical developmental life stages that alters progeny metabolism and physiology. HF programming induces variable diabetogenic phenotypes dependent on the timing and duration of the dietary insult. Maternal obesity reinforces HF programming effects in progeny. HF programming, through acute hyperglycemia, initiates beta cell compensation. However, HF programming eventually leads to chronic hyperglycemia that triggers beta cell exhaustion, death and dysfunction. In HF programming, beta cell dysfunction often co-presents with insulin resistance. Balanced, healthy nutrition during developmental windows is critical for preserving beta cell structure and function. Thus early positive nutritional interventions that coincide with the development of beta cells may reduce the overwhelming burden of diabetes and metabolic disease.

  4. Formic acid and acetic acid induce a programmed cell death in pathogenic Candida species.

    PubMed

    Lastauskienė, Eglė; Zinkevičienė, Auksė; Girkontaitė, Irutė; Kaunietis, Arnoldas; Kvedarienė, Violeta

    2014-09-01

    Cutaneous fungal infections are common and widespread. Antifungal agents used for the treatment of these infections often have undesirable side effects. Furthermore, increased resistance of the microorganisms to the antifungal drugs becomes the growing problem. Accordingly, the search for natural antifungal compounds continues to receive attention. Apoptosis is highly regulated programmed cell death. During yeast cell apoptosis, amino acids and peptides are released and can stimulate regeneration of human epithelium cells. Thus, detection of chemical compounds inducing apoptosis in yeast and nontoxic for humans is of great medical relevance. The aim of this study was to detect chemical compound inducing apoptosis in pathogenic Candida species with the lowest toxicity to the mammalian cells. Five chemical compounds--acetic acid, sodium bicarbonate, potassium carbonate, lithium acetate, and formic acid--were tested for evaluation of antifungal activity on C. albicans, C. guilliermondii, and C. lusitaniae. The results showed that acetic acid and formic acid at the lowest concentrations induced yeast cells death. Apoptosis analysis revealed that cells death was accompanied by activation of caspase. Minimal inhibitory concentrations of potassium carbonate and sodium bicarbonate induced Candida cells necrosis. Toxicity test with mammalian cell cultures showed that formic acid has the lowest effect on the growth of Jurkat and NIH 3T3 cells. In conclusion, our results show that a low concentration of formic acid induces apoptosis-like programmed cell death in the Candida yeast and has a minimal effect on the survivability of mammalian cells, suggesting potential applications in the treatment of these infections. PMID:24752490

  5. Human salivary histatin 5 fungicidal action does not induce programmed cell death pathways in Candida albicans.

    PubMed

    Wunder, David; Dong, Jin; Baev, Didi; Edgerton, Mira

    2004-01-01

    Salivary histatins (Hsts) are potent candidacidal proteins that induce a nonlytic form of cell death in Candida albicans accompanied by loss of mean cell volume, cell cycle arrest, and elevation of intracellular levels of reactive oxygen species (ROS). Since these phenotypes are often markers of programmed cell death and apoptosis, we investigated whether other classical markers of apoptosis, including generation of intracellular ROS and protein carbonyl groups, chromosomal fragmentation (laddering), and cytochrome c release, are found in Hst 5-mediated cell death. Increased intracellular levels of ROS in C. albicans were detected in cells both following exogenous application of Hst 5 and following intracellular expression of Hst 5. However, Western blot analysis failed to detect specifically increased protein carbonylation in Hst 5-treated cells. There was no evidence of chromosomal laddering and no cytochrome c release was observed following treatment of C. albicans mitochondria with Hst 5. Superoxide dismutase enzymes of C. albicans and Saccharomyces cerevisiae provide essential protection against oxidative stress; therefore, we tested whether SOD mutants have increased susceptibility to Hst 5, as expected if ROS mediate fungicidal effects. Cell survival of S. cerevisiae SOD1/SOD2 mutants and C. albicans SOD1 mutants following Hst 5 treatment (31 micro M) was indistinguishable from the survival of wild-type cells treated with Hst 5. We conclude that ROS may not play a direct role in fungicidal activity and that Hst 5 does not initiate apoptosis or programmed cell death pathways. PMID:14693527

  6. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

    SciTech Connect

    Nagy, Gabor; Szarka, Andras; Lotz, Gabor; Doczi, Judit; Wunderlich, Livius; Kiss, Andras; Jemnitz, Katalin; Veres, Zsuzsa; Banhegyi, Gabor; Schaff, Zsuzsa; Suemegi, Balazs; Mandl, Jozsef

    2010-02-15

    It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

  7. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury.

    PubMed

    Nagy, Gábor; Szarka, András; Lotz, Gábor; Dóczi, Judit; Wunderlich, Lívius; Kiss, András; Jemnitz, Katalin; Veres, Zsuzsa; Bánhegyi, Gábor; Schaff, Zsuzsa; Sümegi, Balázs; Mandl, József

    2010-02-15

    It has been recently shown that acute acetaminophen toxicity results in endoplasmic reticulum redox stress and an increase in cells with apoptotic phenotype in liver. Since activation of effector caspases was absent, the relevance of caspase-independent mechanisms in acetaminophen-induced programmed cell death was investigated. BGP-15, a drug with known protective actions in conditions involving redox imbalance, has been co-administered with a single sublethal dose of acetaminophen. Proapoptotic events and outcome of the injury were investigated. ER redox alterations and early ER-stress-related signaling events induced by acetaminophen, such as ER glutathione depletion, phosphorylation of eIF2alpha and JNK and induction of the transcription factor GADD153, were not counteracted by co-treatment with BGP-15. However, BGP-15 prevented AIF mitochondria-to-nucleus translocation and mitochondrial depolarization. BGP-15 co-treatment attenuated the rate of acetaminophen-induced cell death as assessed by apoptotic index and enzyme serum release. These results reaffirm that acute acetaminophen toxicity involves oxidative stress-induced caspase-independent cell death. In addition, pharmacological inhibition of AIF translocation may effectively protect against or at least delay acetaminophen-induced programmed cell death.

  8. Utilization of GaN:Eu 3+ nanocrystals for the detection of programmed cell death

    NASA Astrophysics Data System (ADS)

    Bilyy, R.; Podhorodecki, A.; Nyk, M.; Stoika, R.; Zaichenko, A.; Zatryb, G.; Misiewicz, J.; Strek, W.

    2008-04-01

    In the current study we propose to use a new system for labeling biological processes. Gallium nitride nanocrystals doped by europium ions (nc-GaN:Eu 3+) have been obtained and used to identify the cells undergoing process of programmed cell death. Obtained by combustion method, GaN:Eu 3+ fluorescent nanocrystals have been covered with the polymeric envelope, bearing epoxy groups. Carbohydrate-binding protein-lectin-specifically recognizing cells undergoing programmed cell death was conjugated to the envelope of nanoparticles. Incubation of alive and dead cells with nanoparticles suspension and subsequent analysis using fluorescent and phase-contrast microscopy revealed predominate binding of nanoparticles to dead cells, while intact cell did not bind nanoparticles under the same conditions.

  9. Involvement of ethylene and lipid signalling in cadmium-induced programmed cell death in tomato suspension cells.

    PubMed

    Yakimova, E T; Kapchina-Toteva, V M; Laarhoven, L-J; Harren, F M; Woltering, E J

    2006-10-01

    Cadmium-induced cell death was studied in suspension-cultured tomato (Lycopersicon esculentum Mill.) cells (line MsK8) treated with CdSO(4). Within 24 h, cadmium treatment induced cell death in a concentration-dependent manner. Cell cultures showed recovery after 2-3 days which indicates the existence of an adaptation mechanism. Cadmium-induced cell death was alleviated by the addition of sub muM concentrations of peptide inhibitors specific to human caspases indicating that cell death proceeds through a mechanism with similarities to animal programmed cell death (PCD, apoptosis). Cadmium-induced cell death was accompanied by an increased production of hydrogen peroxide (H(2)O(2)) and simultaneous addition of antioxidants greatly reduced cell death. Inhibitors of phospholipase C (PLC) and phospholipase D (PLD) signalling pathway intermediates reduced cadmium-induced cell death. Treatment with the G-protein activator mastoparan and a cell permeable analogue of the lipid signal second messenger phosphatidic acid (PA) induced cell death. Ethylene, while not inducing cell death when applied alone, stimulated cadmium-induced cell death. Application of the ethylene biosynthesis inhibitor aminoethoxy vinylglycine (AVG) reduced cadmium-induced cell death, and this effect was alleviated by simultaneous treatment with ethylene. Together the results show that cadmium induces PCD exhibiting apoptotic-like features. The cell death process requires increased H(2)O(2) production and activation of PLC, PLD and ethylene signalling pathways.

  10. Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast

    PubMed Central

    Pozniakovsky, Andrei I.; Knorre, Dmitry A.; Markova, Olga V.; Hyman, Anthony A.; Skulachev, Vladimir P.; Severin, Fedor F.

    2005-01-01

    Although programmed cell death (PCD) is extensively studied in multicellular organisms, in recent years it has been shown that a unicellular organism, yeast Saccharomyces cerevisiae, also possesses death program(s). In particular, we have found that a high doses of yeast pheromone is a natural stimulus inducing PCD. Here, we show that the death cascades triggered by pheromone and by a drug amiodarone are very similar. We focused on the role of mitochondria during the pheromone/amiodarone-induced PCD. For the first time, a functional chain of the mitochondria-related events required for a particular case of yeast PCD has been revealed: an enhancement of mitochondrial respiration and of its energy coupling, a strong increase of mitochondrial membrane potential, both events triggered by the rise of cytoplasmic [Ca2+], a burst in generation of reactive oxygen species in center o of the respiratory chain complex III, mitochondrial thread-grain transition, and cytochrome c release from mitochondria. A novel mitochondrial protein required for thread-grain transition is identified. PMID:15657396

  11. Chloroplast Activity and 3'phosphadenosine 5'phosphate Signaling Regulate Programmed Cell Death in Arabidopsis.

    PubMed

    Bruggeman, Quentin; Mazubert, Christelle; Prunier, Florence; Lugan, Raphaël; Chan, Kai Xun; Phua, Su Yin; Pogson, Barry James; Krieger-Liszkay, Anja; Delarue, Marianne; Benhamed, Moussa; Bergounioux, Catherine; Raynaud, Cécile

    2016-03-01

    Programmed cell death (PCD) is a crucial process both for plant development and responses to biotic and abiotic stress. There is accumulating evidence that chloroplasts may play a central role during plant PCD as for mitochondria in animal cells, but it is still unclear whether they participate in PCD onset, execution, or both. To tackle this question, we have analyzed the contribution of chloroplast function to the cell death phenotype of the myoinositol phosphate synthase1 (mips1) mutant that forms spontaneous lesions in a light-dependent manner. We show that photosynthetically active chloroplasts are required for PCD to occur in mips1, but this process is independent of the redox state of the chloroplast. Systematic genetic analyses with retrograde signaling mutants reveal that 3'-phosphoadenosine 5'-phosphate, a chloroplast retrograde signal that modulates nuclear gene expression in response to stress, can inhibit cell death and compromises plant innate immunity via inhibition of the RNA-processing 5'-3' exoribonucleases. Our results provide evidence for the role of chloroplast-derived signal and RNA metabolism in the control of cell death and biotic stress response. PMID:26747283

  12. Alaska's model program for surveillance and prevention of occupational injury deaths.

    PubMed Central

    Conway, G A; Lincoln, J M; Husberg, B J; Manwaring, J C; Klatt, M L; Thomas, T K

    1999-01-01

    The National Institute for Occupational Safety and Health (NIOSH) established its Alaska Field Station in Anchorage in 1991 after identifying Alaska as the highest-risk state for traumatic worker fatalities. Since then, the Field Station, working in collaboration with other agencies, organizations, and individuals, has established a program for occupational injury surveillance in Alaska and formed interagency working groups to address the risk factors leading to occupational death and injury in the state. Collaborative efforts have contributed to reducing crash rates and mortality in Alaska's rapidly expanding helicopter logging industry and have played an important supportive role in the substantial progress made in reducing the mortality rate in Alaska's commercial fishing industry (historically Alaska's and America's most dangerous industry). Alaska experienced a 46% overall decline in work-related acute traumatic injury deaths from 1991 to 1998, a 64% decline in commercial fishing deaths, and a very sharp decline in helicopter logging-related deaths. Extending this regional approach to other parts of the country and applying these strategies to the entire spectrum of occupational injury and disease hazards could have a broad effect on reducing occupational injuries. PMID:10670623

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

    PubMed

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

    2016-04-21

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

  14. Programmed Cell Death during Pollination-Induced Petal Senescence in Petunia1

    PubMed Central

    Xu, Yan; Hanson, Maureen R.

    2000-01-01

    Petal senescence, one type of programmed cell death (PCD) in plants, is a genetically controlled sequence of events comprising its final developmental stage. We characterized the pollination-induced petal senescence process in Petunia inflata using a number of cell performance markers, including fresh/dry weight, protein amount, RNA amount, RNase activity, and cellular membrane leakage. Membrane disruption and DNA fragmentation with preferential oligonucleosomal cleavage, events characteristic of PCD, were found to be present in the advanced stage of petal senescence, indicating that plant and animal cell death phenomena share one of the molecular events in the execution phase. As in apoptosis in animals, both single-stranded DNase and double-stranded DNase activities are induced during petal cell death and are enhanced by Ca2+. In contrast, the release of cytochrome c from mitochondria, one commitment step in signaling of apoptosis in animal cells, was found to be dispensable in petal cell death. Some components of the signal transduction pathway for PCD in plants are likely to differ from those in animal cells. PMID:10759529

  15. Photodynamic therapy-induced programmed cell death in carcinoma cell lines

    NASA Astrophysics Data System (ADS)

    He, Xiao-Yan; Sikes, Robert A.; Thomsen, Sharon L.; Chung, L.; Jacques, Steven L.

    1993-06-01

    The mode of cell death following photodynamic therapy (PDT) was investigated from the perspective of programmed cell death (apoptosis). Human prostate carcinoma cells (PC3), human non-small cell lung carcinoma (H322a), and rat mammary carcinoma (MTF7) were treated by PDT following sensitization with dihematoporphyrin ether (DHE). The response of these carcinoma cell lines to PDT was variable. An examination of extracted cellular DNA by gel electrophoresis showed the characteristic DNA ladder pattern indicative of internucleosomal cleavage of DNA during apoptosis. MTF7 and PC3 responded to PDT by inducing apoptosis while H322a had no apoptotic response. The magnitude of the response and the PDT dosage required to induce the effect were different in PC3 and MTF7. MTF7 cells responded with rapid apoptosis at the dose of light and drug that yielded 50% cell death (LD50). In contrast, PC3 showed only marginal apoptosis at the LD50 but had a marked response at the LD85. Furthermore, the onset of apoptosis followed slower kinetics in PC3 (2 hr - 4 hr) than in MTF7 (< 1 hr). H322a cells were killed by PDT but failed to exhibit any apoptotic response. This study indicates that apoptosis may occur during PDT induced cell death, but this pathway is not universal for all cancer cell lines.

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

    PubMed Central

    Chung, Kyung Min; Yu, Seong-Woon

    2013-01-01

    Mammalian neural stem cells (NSCs) are of particular interest because of their role in brain development and function. Recent findings suggest the intimate involvement of programmed cell death (PCD) in the turnover of NSCs. However, the underlying mechanisms of PCD are largely unknown. Although apoptosis is the best-defined form of PCD, accumulating evidence has revealed a wide spectrum of PCD encompassing apoptosis, autophagic cell death (ACD) and necrosis. This mini-review aims to illustrate a unique regulation of PCD in NSCs. The results of our recent studies on autophagic death of adult hippocampal neural stem (HCN) cells are also discussed. HCN cell death following insulin withdrawal clearly provides a reliable model that can be used to analyze the molecular mechanisms of ACD in the larger context of PCD. More research efforts are needed to increase our understanding of the molecular basis of NSC turnover under degenerating conditions, such as aging, stress and neurological diseases. Efforts aimed at protecting and harnessing endogenous NSCs will offer novel opportunities for the development of new therapeutic strategies for neuropathologies. [BMB Reports 2013; 46(8): 383-390] PMID:23977985

  17. The effect of a community-based police surveillance program on snowmobile injuries and deaths.

    PubMed

    Rowe, B H; Therrien, S A; Bretzlaff, J A; Sahai, V S; Nagarajan, K V; Bota, G W

    1998-01-01

    Serious snowmobile injuries are preventable and associated with late-night travel, alcohol use, and speed. We studied the effectiveness of a community-based policing (STOP) program in the prevention of serious injuries related to snowmobile trauma in Sudbury, Ontario. Volunteers were trained in police protocol and were appointed special constables to increase policing on snowmobile trails from 1993-95. Snowmobile admissions and deaths in Sudbury were examined; the pre- (1990-1992) and post- (1993-1995) STOP seasons were compared. In the pre-STOP period, 102 injuries, 87 admissions, and 15 deaths occurred compared to 57 injuries (p = 0.0004), 53 admissions (p = 0.00001) and 4 deaths (p = 0.13) in the post-STOP period. All other event and demographic features of the crashes remained similar. Significant economic savings were realized from this intervention; acute care costs savings exceeded $70,000/year and costs from death decreased by $5 million. An intervention involving enforcement on snowmobile trails can reduce the incidence of injuries from snowmobile-related trauma.

  18. Infertility in the hyperplasic ovary of freshwater planarians: the role of programmed cell death.

    PubMed

    Harrath, Abdel Halim; Semlali, Abdelhabib; Mansour, Lamjed; Ahmed, Mukhtar; Sirotkin, Alexander V; Al Omar, Suliman Y; Arfah, Maha; Al Anazi, Mohamed S; Alhazza, Ibrahim M; Nyengaard, Jens R; Alwasel, Saleh

    2014-11-01

    Ex-fissiparous planarians produce infertile cocoons or, in very rare cases, cocoons with very low fertility. Here, we describe the features of programmed cell death (PCD) occurring in the hyperplasic ovary of the ex-fissiparous freshwater planarian Dugesia arabica that may explain this infertility. Based on TEM results, we demonstrate a novel extensive co-clustering of cytoplasmic organelles, such as lysosomes and microtubules, and their fusion with autophagosomes during the early stage of oocyte cell death occurring through an autophagic pattern. During a later stage of cell death, the generation of apoptotic vesicles in the cytoplasm can be observed. The immunohistochemical labeling supports the ultrastructural results because it has been shown that the proapoptotic protein bax was more highly expressed in the hyperplasic ovary than in the normal one, whereas the anti-apoptotic protein bcl2 was slightly more highly expressed in the normal ovary compared to the hyperplasic one. TUNEL analysis of the hyperplasic ovary confirmed that the nuclei of the majority of differentiating oocytes were TUNEL-positive, whereas the nuclei of oogonia and young oocytes were TUNEL-negative; in the normal ovary, oocytes are TUNEL-negative. Considering all of these data, we suggest that the cell death mechanism of differentiating oocytes in the hyperplasic ovary of freshwater planarians is one of the most important factors that cause ex-fissiparous planarian infertility. We propose that autophagy precedes apoptosis during oogenesis, whereas apoptotic features can be observed later.

  19. C-Peptide Prevents Hippocampal Apoptosis in Type 1 Diabetes

    PubMed Central

    Li, Zhen-guo; Zhang, Weixian

    2002-01-01

    To explore mechanisms underlying central nervous system (CNS) complications in diabetes, we examined hippocampal neuronal apoptosis and loss, and the effect of C-peptide replacement in type 1 diabetic BB/W rats. Apoptosis was demonstrated after 8 months of diabetes, by DNA fragmentation, increased number of apoptotic cells, and an elevated ratio of Bax/Bcl-xL, accompanied by reduced neuronal density in the hippocampus. No apoptotic activity was detected and neuronal density was unchanged in 2-month diabetic hippocampus, whereas insulin-like growth factor (IGF) activities were impaired. In type 1 diabetic BB/W rats replaced with C-peptide, no TdT-mediated dUTP nick-end labeling (TUNEL)- positive cells were shown and DNA laddering was not evident in hippocampus at either 2 or 8 months. C-peptide administration prevented the preceding perturbation of IGF expression and reduced the elevated ratio of Bax/Bcl-xL. Our data suggest that type 1 diabetes causes a duration-dependent programmed cell death of the hippocampus, which is partially prevented by C-peptide. PMID:12546277

  20. Stress Management in Cyst-Forming Free-Living Protists: Programmed Cell Death and/or Encystment

    PubMed Central

    Khan, Naveed Ahmed; Iqbal, Junaid

    2015-01-01

    In the face of harsh conditions and given a choice, a cell may (i) undergo programmed cell death, (ii) transform into a cancer cell, or (iii) enclose itself into a cyst form. In metazoans, the available evidence suggests that cellular machinery exists only to execute or avoid programmed cell death, while the ability to form a cyst was either lost or never developed. For cyst-forming free-living protists, here we pose the question whether the ability to encyst was gained at the expense of the programmed cell death or both functions coexist to counter unfavorable environmental conditions with mutually exclusive phenotypes. PMID:25648302

  1. Stress management in cyst-forming free-living protists: programmed cell death and/or encystment.

    PubMed

    Khan, Naveed Ahmed; Iqbal, Junaid; Siddiqui, Ruqaiyyah

    2015-01-01

    In the face of harsh conditions and given a choice, a cell may (i) undergo programmed cell death, (ii) transform into a cancer cell, or (iii) enclose itself into a cyst form. In metazoans, the available evidence suggests that cellular machinery exists only to execute or avoid programmed cell death, while the ability to form a cyst was either lost or never developed. For cyst-forming free-living protists, here we pose the question whether the ability to encyst was gained at the expense of the programmed cell death or both functions coexist to counter unfavorable environmental conditions with mutually exclusive phenotypes.

  2. Effect of Ca2+ on programmed death of guard and epidermal cells of pea leaves.

    PubMed

    Kiselevsky, D B; Kuznetsova, Yu E; Vasil'ev, L A; Lobysheva, N V; Zinovkin, R A; Nesov, A V; Shestak, A A; Samuilov, V D

    2010-05-01

    The effect of Ca2+ on programmed death of guard cells (GC) and epidermal cells (EC) determined from destruction of the cell nucleus was investigated in epidermis of pea leaves. Ca2+ at concentrations of 1-100 microM increased and at a concentration of 1 mM prevented the CN(-)-induced destruction of the nucleus in GC, disrupting the permeability barrier of GC plasma membrane for propidium iodide (PI). Ca2+ at concentrations of 0.1-1 mM enhanced drastically the number of EC nuclei stained by PI in epidermis treated with chitosan, an inducer of programmed cell death. The internucleosomal DNA fragmentation caused by CN(-) was suppressed by 2 mM Ca2+ on 6 h incubation, but fragmentation was stimulated on more prolonged treatment (16 h). Presumably, the disruption of the permeability barrier of plasma membrane for PI is not a sign of necrosis in plant cells. Quinacrine and diphenylene iodonium at 50 microM concentration prevented GC death induced by CN(-) or CN(-) + 0.1 mM Ca2+ but had no influence on respiration and photosynthetic O2 evolution in pea leaf slices. The generation of reactive oxygen species determined from 2',7'-dichlorofluorescein fluorescence was promoted by Ca2+ in epidermal peels from pea leaves.

  3. Evolution of apoptosis-like programmed cell death in unicellular protozoan parasites.

    PubMed

    Kaczanowski, Szymon; Sajid, Mohammed; Reece, Sarah E

    2011-01-01

    Apoptosis-like programmed cell death (PCD) has recently been described in multiple taxa of unicellular protists, including the protozoan parasites Plasmodium, Trypanosoma and Leishmania. Apoptosis-like PCD in protozoan parasites shares a number of morphological features with programmed cell death in multicellular organisms. However, both the evolutionary explanations and mechanisms involved in parasite PCD are poorly understood. Explaining why unicellular organisms appear to undergo 'suicide' is a challenge for evolutionary biology and uncovering death executors and pathways is a challenge for molecular and cell biology. Bioinformatics has the potential to integrate these approaches by revealing homologies in the PCD machinery of diverse taxa and evaluating their evolutionary trajectories. As the molecular mechanisms of apoptosis in model organisms are well characterised, and recent data suggest similar mechanisms operate in protozoan parasites, key questions can now be addressed. These questions include: which elements of apoptosis machinery appear to be shared between protozoan parasites and multicellular taxa and, have these mechanisms arisen through convergent or divergent evolution? We use bioinformatics to address these questions and our analyses suggest that apoptosis mechanisms in protozoan parasites and other taxa have diverged during their evolution, that some apoptosis factors are shared across taxa whilst others have been replaced by proteins with similar biochemical activities.

  4. Developmental programmed cell death during asymmetric microsporogenesis in holocentric species of Rhynchospora (Cyperaceae)

    PubMed Central

    Rocha, Danilo M.; Marques, André; Andrade, Celia G.T.J.; Guyot, Romain; Chaluvadi, Srinivasa R.; Pedrosa-Harand, Andrea; Houben, Andreas; Bennetzen, Jeffrey L.; Vanzela, André L.L.

    2016-01-01

    Members of the Cyperaceae family exhibit an asymmetric microsporogenesis that results in the degeneration of three out of four meiotic products. Efforts have been made previously to describe the resulting structure, named the pseudomonad, but mechanisms concerning the establishment of cell domains, nuclear development, and programmed cell death are largely unknown. Using the Rhynchospora genus as a model, evidence for cell asymmetry, cytoplasmic isolation, and programmed cell death was obtained by a combination of electron microscopic, cytochemical, immunocytochemical, in situ hybridization, and flow cytometric methods. Degenerative cells were identified at the abaxial region, with the cytoskeleton marking their delimitation from the functional domain after meiosis. After attempting to initiate cell division with an unreplicated genome and abnormal spindle assembly, these cells exhibited a gradual process of cytoplasmic contraction associated with hypermethylation of cytosines and differential loss of DNA. These results indicate that the asymmetric tetrad establishes a functional cell, where one nucleus is preferentially selected to survive. Degenerative haploid cells are then eliminated in a multistep process associated with mitotic disorder, non-random elimination of repetitive DNA, vacuolar cell death, and DNA fragmentation. PMID:27492982

  5. Developmental cell death programs license cytotoxic cells to eliminate histocompatible partners.

    PubMed

    Corey, Daniel M; Rosental, Benyamin; Kowarsky, Mark; Sinha, Rahul; Ishizuka, Katherine J; Palmeri, Karla J; Quake, Stephen R; Voskoboynik, Ayelet; Weissman, Irving L

    2016-06-01

    In a primitive chordate model of natural chimerism, one chimeric partner is often eliminated in a process of allogeneic resorption. Here, we identify the cellular framework underlying loss of tolerance to one partner within a natural Botryllus schlosseri chimera. We show that the principal cell type mediating chimeric partner elimination is a cytotoxic morula cell (MC). Proinflammatory, developmental cell death programs render MCs cytotoxic and, in collaboration with activated phagocytes, eliminate chimeric partners during the "takeover" phase of blastogenic development. Among these genes, the proinflammatory cytokine IL-17 enhances cytotoxicity in allorecognition assays. Cellular transfer of FACS-purified MCs from allogeneic donors into recipients shows that the resorption response can be adoptively acquired. Transfer of 1 × 10(5) allogeneic MCs eliminated 33 of 78 (42%) recipient primary buds and 20 of 76 (20.5%) adult parental adult organisms (zooids) by 14 d whereas transfer of allogeneic cell populations lacking MCs had only minimal effects on recipient colonies. Furthermore, reactivity of transferred cells coincided with the onset of developmental-regulated cell death programs and disproportionately affected developing tissues within a chimera. Among chimeric partner "losers," severe developmental defects were observed in asexually propagating tissues, reflecting a pathologic switch in gene expression in developmental programs. These studies provide evidence that elimination of one partner in a chimera is an immune cell-based rejection that operates within histocompatible pairs and that maximal allogeneic responses involve the coordination of both phagocytic programs and the "arming" of cytotoxic cells.

  6. Programmed cell death during development of cowpea (Vigna unguiculata (L.) Walp.) seed coat.

    PubMed

    Lima, Nathália Bastos; Trindade, Fernanda Gomes; da Cunha, Maura; Oliveira, Antônia Elenir Amâncio; Topping, Jennifer; Lindsey, Keith; Fernandes, Kátia Valevski Sales

    2015-04-01

    The seed coat develops primarily from maternal tissues and comprises multiple cell layers at maturity, providing a metabolically dynamic interface between the developing embryo and the environment during embryogenesis, dormancy and germination of seeds. Seed coat development involves dramatic cellular changes, and the aim of this research was to investigate the role of programmed cell death (PCD) events during the development of seed coats of cowpea [Vigna unguiculata (L.) Walp.]. We demonstrate that cells of the developing cowpea seed coats undergo a programme of autolytic cell death, detected as cellular morphological changes in nuclei, mitochondria, chloroplasts and vacuoles, DNA fragmentation and oligonucleosome accumulation in the cytoplasm, and loss of membrane viability. We show for the first time that classes 6 and 8 caspase-like enzymes are active during seed coat development, and that these activities may be compartmentalized by translocation between vacuoles and cytoplasm during PCD events. PMID:25142352

  7. Programmed cell death during development of cowpea (Vigna unguiculata (L.) Walp.) seed coat.

    PubMed

    Lima, Nathália Bastos; Trindade, Fernanda Gomes; da Cunha, Maura; Oliveira, Antônia Elenir Amâncio; Topping, Jennifer; Lindsey, Keith; Fernandes, Kátia Valevski Sales

    2015-04-01

    The seed coat develops primarily from maternal tissues and comprises multiple cell layers at maturity, providing a metabolically dynamic interface between the developing embryo and the environment during embryogenesis, dormancy and germination of seeds. Seed coat development involves dramatic cellular changes, and the aim of this research was to investigate the role of programmed cell death (PCD) events during the development of seed coats of cowpea [Vigna unguiculata (L.) Walp.]. We demonstrate that cells of the developing cowpea seed coats undergo a programme of autolytic cell death, detected as cellular morphological changes in nuclei, mitochondria, chloroplasts and vacuoles, DNA fragmentation and oligonucleosome accumulation in the cytoplasm, and loss of membrane viability. We show for the first time that classes 6 and 8 caspase-like enzymes are active during seed coat development, and that these activities may be compartmentalized by translocation between vacuoles and cytoplasm during PCD events.

  8. Fusaric acid induction of programmed cell death modulated through nitric oxide signalling in tobacco suspension cells.

    PubMed

    Jiao, Jiao; Zhou, Benguo; Zhu, Xiaoping; Gao, Zhengliang; Liang, Yuancun

    2013-10-01

    Fusaric acid (FA) is a nonhost-selective toxin mainly produced by Fusarium oxysporum, the causal agent of plant wilt diseases. We demonstrate that FA can induce programmed cell death (PCD) in tobacco suspension cells and the FA-induced PCD is modulated by nitric oxide (NO) signalling. Cells undergoing cell death induced by FA treatment exhibited typical characteristics of PCD including cytoplasmic shrinkage, chromatin condensation, DNA fragmentation, membrane plasmolysis, and formation of small cytoplasmic vacuoles. In addition, caspase-3-like activity was activated upon the FA treatment. The process of FA-induced PCD was accompanied by a rapid accumulation of NO in a FA dose-dependent manner. Pre-treatment of cells with NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) or NO synthase inhibitor N(G)-monomethyl-arginine monoacetate (L-NMMA) significantly reduced the rate of FA-induced cell death. Furthermore, the caspase-3-like activity and the expression of PAL and Hsr203J genes were alleviated by application of cPTIO or L-NMMA to FA-treated tobacco cells. This indicates that NO is an important factor involved in the FA-induced PCD. Our results also show that pre-treatment of tobacco cells with a caspase-3-specific inhibitor, Ac-DEVD-CHO, can reduce the rate of FA-induced cell death. These results demonstrate that the FA-induced cell death is a PCD and is modulated by NO signalling through caspase-3-like activation. PMID:23838885

  9. Type 1 diabetes in Japan.

    PubMed

    Kawasaki, E; Matsuura, N; Eguchi, K

    2006-05-01

    Type 1 diabetes is a multifactorial disease which results from a T-cell-mediated autoimmune destruction of the pancreatic beta cells in genetically predisposed individuals. The risk for individuals of developing type 1 diabetes varies remarkably according to country of residence and race. Japan has one of the lowest incidence rates of type 1 diabetes in the world, and recognises at least three subtypes of the condition: acute-onset ('classical'), slow-onset, and fulminant type 1 diabetes. The incidence rate of type 1 diabetes in children aged 0-14 years in Japan increased over the period from 1973-1992, but remained constant over the last decade, averaging 2.37 cases per 100,000 persons per year; the incidence does not appear to have increased in older age groups. Although there are few reports regarding the incidence and prevalence of type 1 diabetes in adult-onset patients, it appears that the prevalence of type 1 diabetes in adults is more than twice that in childhood-onset patients and that two-thirds of them have a slow-onset form of type 1 diabetes. Differences and similarities in the association of MHC and non-MHC genes with type 1 diabetes are observed in Japan and in countries with Caucasoid populations. Highly susceptible class II HLA haplotypes identified in patients of Caucasoid origin are rarely seen in Japanese patients, whereas protective haplotypes are universal. Non-MHC genes associated with susceptibility to type 1 diabetes in both Japanese and Caucasoid patients include polymorphisms in the insulin gene, the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, the interleukin-18 (IL18) gene and the major histocompatibility complex class I chain-related gene A (MICA) gene. Fulminant type 1 diabetes is a unique subtype of type 1 diabetes that accounts for about 20% of acute-onset type 1 diabetes, and is seen mainly in adults. The challenge for the future is to investigate the underlying pathogenesis of beta cell destruction, including the genetic or

  10. Programmed cell death in trypanosomatids: is it an altruistic mechanism for survival of the fittest?

    PubMed

    Debrabant, Alain; Nakhasi, Hira

    2003-06-25

    The protozoan parasites Leishmania, Trypanosoma cruzi and Trypanosoma brucei show multiple features consistent with a form of programmed cell death (PCD). Despite some similarities with apoptosis of mammalian cells, PCD in trypanosomatid protozoans appears to be significantly different. In these unicellular organisms, PCD could represent an altruistic mechanism for the selection of cells, from the parasite population, that are fit to be transmitted to the next host. Alternatively, PCD could help in controlling the population of parasites in the host, thereby increasing host survival and favoring parasite transmission, as proposed by Seed and Wenk. Therefore, PCD in trypanosomatid parasites may represent a pathway involved both in survival and propagation of the species.

  11. Direct involvement of p53 in programmed cell death of oligodendrocytes.

    PubMed Central

    Eizenberg, O; Faber-Elman, A; Gottlieb, E; Oren, M; Rotter, V; Schwartz, M

    1995-01-01

    A covalent dimer of interleukin (IL)-2, produced in vitro by the action of a nerve-derived transglutaminase, has been shown previously to be cytotoxic to mature rat brain oligodendrocytes. Here we report that this cytotoxic effect operates via programmed cell death (apoptosis) and that the p53 tumor suppressor gene is involved directly in the process. The apoptotic death of mature rat brain oligodendrocytes in culture following treatment with dimeric IL-2 was demonstrated by chromatin condensation and internucleosomal DNA fragmentation. The peak of apoptosis was observed 16-24 h after treatment, while the commitment to death was already observed after 3-4 h. An involvement of p53 in this process was indicated by the shift in location of constitutively expressed endogenous p53 from the cytoplasm to the nucleus, as early as 15 min after exposure to dimeric IL-2. Moreover, infection with a recombinant retrovirus encoding a C-terminal p53 miniprotein, shown previously to act as a dominant negative inhibitor of endogenous wild-type p53 activity, protected these cells from apoptosis. Images PMID:7720704

  12. Ricinosomes predict programmed cell death leading to anther dehiscence in tomato.

    PubMed

    Senatore, Adriano; Trobacher, Christopher P; Greenwood, John S

    2009-02-01

    Successful development and dehiscence of the anther and release of pollen are dependent upon the programmed cell death (PCD) of the tapetum and other sporophytic tissues. Ultrastructural examination of the developing and dehiscing anther of tomato (Solanum lycopersicum) revealed that cells of the interlocular septum, the connective tissue, the middle layer/endothecium, and the epidermal cells surrounding the stomium all exhibit features consistent with progression through PCD. Ricinosomes, a subset of precursor protease vesicles that are unique to some incidents of plant PCD, were also present in all of these cell types. These novel organelles are known to harbor KDEL-tailed cysteine proteinases that act in the final stages of corpse processing following cell death. Indeed, a tomato KDEL-tailed cysteine proteinase, SlCysEP, was identified and its gene was cloned, sequenced, and characterized. SlCysEP transcript and protein were restricted to the anthers of the senescing tomato flower. Present in the interlocular septum and in the epidermal cells surrounding the stomium relatively early in development, SlCysEP accumulates later in the sporophytic tissues surrounding the locules as dehiscence ensues. At the ultrastuctural level, immunogold labeling localized SlCysEP to the ricinosomes within the cells of these tissues, but not in the tapetum. It is suggested that the accumulation of SlCysEP and the appearance of ricinosomes act as very early predictors of cell death in the tomato anther.

  13. Identification of a novel cell death-inducing domain reveals that fungal amyloid-controlled programmed cell death is related to necroptosis

    PubMed Central

    Daskalov, Asen; Habenstein, Birgit; Sabaté, Raimon; Berbon, Mélanie; Martinez, Denis; Chaignepain, Stéphane; Coulary-Salin, Bénédicte; Hofmann, Kay; Loquet, Antoine; Saupe, Sven J.

    2016-01-01

    Recent findings have revealed the role of prion-like mechanisms in the control of host defense and programmed cell death cascades. In fungi, HET-S, a cell death-inducing protein containing a HeLo pore-forming domain, is activated through amyloid templating by a Nod-like receptor (NLR). Here we characterize the HELLP protein behaving analogously to HET-S and bearing a new type of N-terminal cell death-inducing domain termed HeLo-like (HELL) and a C-terminal regulatory amyloid motif known as PP. The gene encoding HELLP is part of a three-gene cluster also encoding a lipase (SBP) and a Nod-like receptor, both of which display the PP motif. The PP motif is similar to the RHIM amyloid motif directing formation of the RIP1/RIP3 necrosome in humans. The C-terminal region of HELLP, HELLP(215-278), encompassing the motif, allows prion propagation and assembles into amyloid fibrils, as demonstrated by X-ray diffraction and FTIR analyses. Solid-state NMR studies reveal a well-ordered local structure of the amyloid core residues and a primary sequence that is almost entirely arranged in a rigid conformation, and confirm a β-sheet structure in an assigned stretch of three amino acids. HELLP is activated by amyloid templating and displays membrane-targeting and cell death-inducing activity. HELLP targets the SBP lipase to the membrane, suggesting a synergy between HELLP and SBP in membrane dismantling. Remarkably, the HeLo-like domain of HELLP is homologous to the pore-forming domain of MLKL, the cell death-execution protein in necroptosis, revealing a transkingdom evolutionary relationship between amyloid-controlled fungal programmed cell death and mammalian necroptosis. PMID:26903619

  14. Identification of a novel cell death-inducing domain reveals that fungal amyloid-controlled programmed cell death is related to necroptosis.

    PubMed

    Daskalov, Asen; Habenstein, Birgit; Sabaté, Raimon; Berbon, Mélanie; Martinez, Denis; Chaignepain, Stéphane; Coulary-Salin, Bénédicte; Hofmann, Kay; Loquet, Antoine; Saupe, Sven J

    2016-03-01

    Recent findings have revealed the role of prion-like mechanisms in the control of host defense and programmed cell death cascades. In fungi, HET-S, a cell death-inducing protein containing a HeLo pore-forming domain, is activated through amyloid templating by a Nod-like receptor (NLR). Here we characterize the HELLP protein behaving analogously to HET-S and bearing a new type of N-terminal cell death-inducing domain termed HeLo-like (HELL) and a C-terminal regulatory amyloid motif known as PP. The gene encoding HELLP is part of a three-gene cluster also encoding a lipase (SBP) and a Nod-like receptor, both of which display the PP motif. The PP motif is similar to the RHIM amyloid motif directing formation of the RIP1/RIP3 necrosome in humans. The C-terminal region of HELLP, HELLP(215-278), encompassing the motif, allows prion propagation and assembles into amyloid fibrils, as demonstrated by X-ray diffraction and FTIR analyses. Solid-state NMR studies reveal a well-ordered local structure of the amyloid core residues and a primary sequence that is almost entirely arranged in a rigid conformation, and confirm a β-sheet structure in an assigned stretch of three amino acids. HELLP is activated by amyloid templating and displays membrane-targeting and cell death-inducing activity. HELLP targets the SBP lipase to the membrane, suggesting a synergy between HELLP and SBP in membrane dismantling. Remarkably, the HeLo-like domain of HELLP is homologous to the pore-forming domain of MLKL, the cell death-execution protein in necroptosis, revealing a transkingdom evolutionary relationship between amyloid-controlled fungal programmed cell death and mammalian necroptosis. PMID:26903619

  15. Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell death

    PubMed Central

    1996-01-01

    In the accompanying paper by Weil et al. (1996) we show that staurosporine (STS), in the presence of cycloheximide (CHX) to inhibit protein synthesis, induces apoptotic cell death in a large variety of nucleated mammalian cell types, suggesting that all nucleated mammalian cells constitutively express all of the proteins required to undergo programmed cell death (PCD). The reliability of that conclusion depends on the evidence that STS-induced, and (STS + CHS)-induced, cell deaths are bona fide examples of PCD. There is rapidly accumulating evidence that some members of the Ced-3/Interleukin-1 beta converting enzyme (ICE) family of cysteine proteases are part of the basic machinery of PCD. Here we show that Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a cell-permeable, irreversible, tripeptide inhibitor of some of these proteases, suppresses STS-induced and (STS + CHX)-induced cell death in a wide variety of mammalian cell types, including anucleate cytoplasts, providing strong evidence that these are all bona fide examples of PCD. We show that the Ced-3/ICE family member CPP32 becomes activated in STS- induced PCD, and that Bcl-2 inhibits this activation. Most important, we show that, in some cells at least, one or more CPP32-family members, but not ICE itself, is required for STS-induced PCD. Finally, we show that zVAD-fmk suppresses PCD in the interdigital webs in developing mouse paws and blocks the removal of web tissue during digit development, suggesting that this inhibition will be a useful tool for investigating the roles of PCD in various developmental processes. PMID:8655577

  16. The mitochondrion--an organelle commonly involved in programmed cell death in Arabidopsis thaliana.

    PubMed

    Yao, Nan; Eisfelder, Bartholomew J; Marvin, James; Greenberg, Jean T

    2004-11-01

    Plant cells undergoing programmed cell death (PCD) at late stages typically show chromatin condensation and endonucleolytic cleavage prior to obvious membrane or organelle ultrastructural changes. To investigate possible early PCD-associated events, we used microscopic observations and flow cytometry to quantitate mitochondrial membrane potential (DeltaPsim) changes during PCD at the single cell and population levels using Arabidopsis protoplasts. A DeltaPsim loss was commonly induced early during plant PCD and was important for PCD execution, as evidenced by the concomitant reduction of the change in DeltaPsim and PCD by cyclosporin A, which inhibits mitochondrial permeability transition pores in animal cells. DeltaPsim loss occurred prior to nuclear morphological changes and was only associated with mitochondrial cytochrome c release (an apoptotic trigger in animals) in response to one of three PCD elicitors. Three different stimuli in wild type implicated DeltaPsim changes in PCD: ceramide, protoporphyrin IX, and the hypersensitive response elicitor AvrRpt2. Additionally, the behavior of the conditional ectopic cell death mutant accelerated cell death2 and ACD2-overproducing plants also implicated DeltaPsim alteration as key for PCD execution. Because ACD2 is largely a chloroplast component in mature plants, the observation that the cell death in acd2 mutants requires changes in mitochondrial functions implicates communication between chloroplasts and mitochondria in mediating PCD activation. We suggest that DeltaPsim loss is a common early marker in plant PCD, similar to what has been documented in animals. However, unlike in animal cells, in plant cells, mitochondrial cytochrome c release is not an obligatory step in PCD control.

  17. Neutrophils in type 1 diabetes.

    PubMed

    Huang, Juan; Xiao, Yang; Xu, Aimin; Zhou, Zhiguang

    2016-09-01

    Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin-producing pancreatic β-cells triggered by genetic and environmental factors. The initiation and progression of the disease involves a complicated interaction between β-cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil-derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell-cell interactions with other immune and non-immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes. PMID:27181374

  18. Where Do Programmed Death-1 Inhibitors Fit in the Management of Malignant Lymphoma?

    PubMed

    Ansell, Stephen M

    2016-02-01

    Tumor-specific cytotoxic T cells have the capacity to target and eradicate malignant B cells in patients with Hodgkin and non-Hodgkin lymphoma; however, multiple mechanisms, including regulatory T cells, immunosuppressive ligands, and immune exhaustion, suppress an effective antitumor immune response. One mechanism that is used by malignant cells to inhibit the immune response is overexpression of programmed death ligand 1 or 2 (PD-L1 or PD-L2) on the cancer cell surface. These ligands interact with the programmed death-1 (PD-1) receptor expressed on intratumoral T cells and provide an inhibitory signal, thereby suppressing the antitumor immune response. Monoclonal antibodies that block PD-1 signaling prevent T-cell inhibition and promote a T-cell-mediated antilymphoma response. Blocking antibodies that are directed against PD-1 or PD-L1 are currently being tested in patients with lymphoma and have shown remarkable efficacy, particularly in patients with relapsed Hodgkin lymphoma. On the basis of the promising activity of this approach, PD-1 inhibitors are being used as single-agent therapy in patients with relapsed Hodgkin lymphoma, and these inhibitors are also being tested in combination with standard chemotherapy or targeted agents in ongoing clinical trials. PMID:26869644

  19. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity.

    PubMed

    Li, Chia-Wei; Lim, Seung-Oe; Xia, Weiya; Lee, Heng-Huan; Chan, Li-Chuan; Kuo, Chu-Wei; Khoo, Kay-Hooi; Chang, Shih-Shin; Cha, Jong-Ho; Kim, Taewan; Hsu, Jennifer L; Wu, Yun; Hsu, Jung-Mao; Yamaguchi, Hirohito; Ding, Qingqing; Wang, Yan; Yao, Jun; Lee, Cheng-Chung; Wu, Hsing-Ju; Sahin, Aysegul A; Allison, James P; Yu, Dihua; Hortobagyi, Gabriel N; Hung, Mien-Chie

    2016-01-01

    Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy. PMID:27572267

  20. Sarcomatoid lung carcinomas show high levels of Programmed death Ligand-1 (PD-L1)

    PubMed Central

    Velcheti, Vamsidhar; Rimm, David L.; Schalper, Kurt A.

    2013-01-01

    Programmed death-1 (PD-1) is a co-inhibitory inducible receptor present on T-cells and macrophages. Tumor cells with increased programmed death ligand-1 (PD-L1) are believed to escape immunity through activation of PD-1/PD-L1 pathway and suppression of effector immune responses. Recent strategies targeting the PD-1/PD-L1 axis have shown promising results in patients with several tumors types, including lung carcinomas. Preliminary data suggests that PD-L1 protein expression might predictive response to such therapies. Sarcomatoid carcinomas (SCs) of the lung include rare subtypes of poorly differentiated non-small cell lung carcinomas (NSCLC) of high grade and aggressive behavior. The biology of these neoplasms is poorly understood and they frequently show increased local inflammatory and lymphocytic infiltration. Here, we report the expression of PD-L1 in 13 SCs from two large retrospective lung cancer cohorts. Using automated quantitative immunofloresence (aqIF/AQUA®) and a mouse monoclonal antibody directed against the extra-cellular domain of PD-L1, we show that 9 of 13 (69.2%) patients with SCs are positive for PD-L1 and their levels are higher than in conventional NSCLC. These results provide rationale for the potential use of targeted immunetherapy in lung SCs. PMID:23676558

  1. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity

    PubMed Central

    Li, Chia-Wei; Lim, Seung-Oe; Xia, Weiya; Lee, Heng-Huan; Chan, Li-Chuan; Kuo, Chu-Wei; Khoo, Kay-Hooi; Chang, Shih-Shin; Cha, Jong-Ho; Kim, Taewan; Hsu, Jennifer L.; Wu, Yun; Hsu, Jung-Mao; Yamaguchi, Hirohito; Ding, Qingqing; Wang, Yan; Yao, Jun; Lee, Cheng-Chung; Wu, Hsing-Ju; Sahin, Aysegul A.; Allison, James P.; Yu, Dihua; Hortobagyi, Gabriel N.; Hung, Mien-Chie

    2016-01-01

    Extracellular interaction between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) leads to tumour-associated immune escape. Here we show that the immunosuppression activity of PD-L1 is stringently modulated by ubiquitination and N-glycosylation. We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. In-depth analysis of PD-L1 N192, N200 and N219 glycosylation suggests that glycosylation antagonizes GSK3β binding. In this regard, only non-glycosylated PD-L1 forms a complex with GSK3β and β-TrCP. We also demonstrate that epidermal growth factor (EGF) stabilizes PD-L1 via GSK3β inactivation in basal-like breast cancer. Inhibition of EGF signalling by gefitinib destabilizes PD-L1, enhances antitumour T-cell immunity and therapeutic efficacy of PD-1 blockade in syngeneic mouse models. Together, our results link ubiquitination and glycosylation pathways to the stringent regulation of PD-L1, which could lead to potential therapeutic strategies to enhance cancer immune therapy efficacy. PMID:27572267

  2. Apocynin attenuates cholesterol oxidation product-induced programmed cell death by suppressing NF-κB-mediated cell death process in differentiated PC12 cells.

    PubMed

    Lee, Da Hee; Nam, Yoon Jeong; Lee, Chung Soo

    2015-10-01

    Cholesterol oxidation products are suggested to be involved in neuronal degeneration. Apocynin has demonstrated to have anti-inflammatory and anti-oxidant effects. We assessed the effect of apocynin on the cholesterol oxidation product-induced programmed cell death in neuronal cells using differentiated PC12 cells in relation to NF-κB-mediated cell death process. 7-Ketocholesterol and 25-hydroxycholesterol decreased the levels of Bid and Bcl-2, increased the levels of Bax and p53, and induced loss of the mitochondrial transmembrane potential, release of cytochrome c and activation of caspases (-8, -9 and -3). 7-Ketocholesterol caused an increase in the levels of cytosolic and nuclear NF-κB p65, cytosolic NF-κB p50 and cytosolic phospho-IκB-α, which was inhibited by the addition of 0.5 μM Bay11-7085 (an inhibitor of NF-κB activation). Apocynin attenuated the cholesterol oxidation product-induced changes in the programmed cell death-related protein levels, NF-κB activation, production of reactive oxygen species, and depletion of GSH. The results show that apocynin appears to attenuate the cholesterol oxidation product-induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways that are mediated by NF-κB activation. The preventive effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH.

  3. Exploring diabetes type 1-related stigma

    PubMed Central

    Abdoli, Samereh; Abazari, Parvaneh; Mardanian, Leila

    2013-01-01

    Background: Empowerment of people with diabetes means integrating diabetes with identity. However, others’ stigmatization can influence it. Although diabetes is so prevalent among Iranians, there is little knowledge about diabetes-related stigma in Iran. The present study explored diabetes-related stigma in people living with type 1 diabetes in Isfahan. Materials and Methods: A conventional content analysis was used with in-depth interview with 26 people with and without diabetes from November 2011 to July 2012. Results: A person with type 1 diabetes was stigmatized as a miserable human (always sick and unable, death reminder, and intolerable burden), rejected marriage candidate (busy spouse, high-risk pregnant), and deprived of a normal life [prisoner of (to must), deprived of pleasure]. Although, young adults with diabetes undergo all aspects of the social diabetes-related stigma; in their opinion they were just deprived of a normal life Conclusion: It seems that in Isfahan, diabetes-related stigma is of great importance. In this way, conducting an appropriate intervention is necessary to improve the empowerment process in people with type 1 diabetes in order to reduce the stigma in the context. PMID:23983731

  4. Apoptotic-like programed cell death in fungi: the benefits in filamentous species

    PubMed Central

    Shlezinger, Neta; Goldfinger, Nir; Sharon, Amir

    2012-01-01

    Studies conducted in the early 1990s showed for the first time that Saccharomyces cerevisiae can undergo cell death with hallmarks of animal apoptosis. These findings came as a surprise, since suicide machinery was unexpected in unicellular organisms. Today, apoptosis in yeast is well-documented. Apoptotic death of yeast cells has been described under various conditions and S. cerevisiae homologs of human apoptotic genes have been identified and characterized. These studies also revealed fundamental differences between yeast and animal apoptosis; in S. cerevisiae apoptosis is mainly associated with aging and stress adaptation, unlike animal apoptosis, which is essential for proper development. Further, many apoptosis regulatory genes are either missing, or highly divergent in S. cerevisiae. Therefore, in this review we will use the term apoptosis-like programed cell death (PCD) instead of apoptosis. Despite these significant differences, S. cerevisiae has been instrumental in promoting the study of heterologous apoptotic proteins, particularly from human. Work in fungi other than S. cerevisiae revealed differences in the manifestation of PCD in single cell (yeasts) and multicellular (filamentous) species. Such differences may reflect the higher complexity level of filamentous species, and hence the involvement of PCD in a wider range of processes and life styles. It is also expected that differences might be found in the apoptosis apparatus of yeast and filamentous species. In this review we focus on aspects of PCD that are unique or can be better studied in filamentous species. We will highlight the similarities and differences of the PCD machinery between yeast and filamentous species and show the value of using S. cerevisiae along with filamentous species to study apoptosis. PMID:22891165

  5. Involvement of sphingoid bases in mediating reactive oxygen intermediate production and programmed cell death in Arabidopsis.

    PubMed

    Shi, Lihua; Bielawski, Jacek; Mu, Jinye; Dong, Haili; Teng, Chong; Zhang, Jian; Yang, Xiaohui; Tomishige, Nario; Hanada, Kentaro; Hannun, Yusuf A; Zuo, Jianru

    2007-12-01

    Sphingolipids have been suggested to act as second messengers for an array of cellular signaling activities in plant cells, including stress responses and programmed cell death (PCD). However, the mechanisms underpinning these processes are not well understood. Here, we report that an Arabidopsis mutant, fumonisin B1 resistant 11-1 (fbr 11-1), which fails to generate reactive oxygen intermediates (ROIs), is incapable of initiating PCD when the mutant is challenged by fumonisin B(1) (FB(1)), a specific inhibitor of ceramide synthase. Molecular analysis indicated that FBR11 encodes a long-chain base 1 (LCB1) subunit of serine palmitoyltransferase (SPT), which catalyzes the first rate-limiting step of de novo sphingolipid synthesis. Mass spectrometric analysis of the sphingolipid concentrations revealed that whereas the fbr 11-1 mutation did not affect basal levels of sphingoid bases, the mutant showed attenuated formation of sphingoid bases in response to FB(1). By a direct feeding experiment, we show that the free sphingoid bases dihydrosphingosine, phytosphingosine and sphingosine efficiently induce ROI generation followed by cell death. Conversely, ROI generation and cell death induced by dihydrosphingosine were specifically blocked by its phosphorylated form dihydrosphingosine-1-phosphate in a dose-dependent manner, suggesting that the maintenance of homeostasis between a free sphingoid base and its phosphorylated derivative is critical to determining the cell fate. Because alterations of the sphingolipid level occur prior to the ROI production, we propose that the free sphingoid bases are involved in the control of PCD in Arabidopsis, presumably through the regulation of the ROI level upon receiving different developmental or environmental cues.

  6. Human clusterin gene expression is confined to surviving cells during in vitro programmed cell death.

    PubMed Central

    French, L E; Wohlwend, A; Sappino, A P; Tschopp, J; Schifferli, J A

    1994-01-01

    Clusterin is a serum glycoprotein endowed with cell aggregating, complement inhibitory, and lipid binding properties, and is also considered as a specific marker of dying cells, its expression being increased in various tissues undergoing programmed cell death (PCD). However, no study has so far directly shown that cells expressing clusterin in these tissues are actually apoptotic as defined by morphological and biochemical criteria. We have studied cellular clusterin gene expression in vitro using three different models of PCD: (a) ultraviolet B (UV-B) irradiation of human U937, HeLa, and A431 cell lines, (b) in vitro aging of human peripheral blood neutrophils (PMNs), and (c) dexamethasone-induced cell death of the human lymphoblastoid cell line CEM-C7. In all three models, the classical morphological and biochemical features of PCD observed did not correlate with an increase, but with either a marked decrease or an absence of clusterin gene expression as assessed by Northern blot analysis. In situ hybridization of U937 and A431 cells after UV-B irradiation revealed, in addition, that only morphologically normal cells that are surviving continue to express the clusterin gene. Our results demonstrate that in the human myeloid, lymphoid, and epithelial cell types studied, clusterin gene expression is not a prerequisite to their death by apoptosis. In addition, and most interestingly, in situ hybridization of U937 and A431 cells revealed that only surviving cells express the clusterin gene after the induction of PCD, thus providing novel evidence suggesting that clusterin may be associated with cell survival within tissues regressing as a consequence of PCD. Images PMID:8113419

  7. Apoptotic-like programed cell death in fungi: the benefits in filamentous species.

    PubMed

    Shlezinger, Neta; Goldfinger, Nir; Sharon, Amir

    2012-01-01

    Studies conducted in the early 1990s showed for the first time that Saccharomyces cerevisiae can undergo cell death with hallmarks of animal apoptosis. These findings came as a surprise, since suicide machinery was unexpected in unicellular organisms. Today, apoptosis in yeast is well-documented. Apoptotic death of yeast cells has been described under various conditions and S. cerevisiae homologs of human apoptotic genes have been identified and characterized. These studies also revealed fundamental differences between yeast and animal apoptosis; in S. cerevisiae apoptosis is mainly associated with aging and stress adaptation, unlike animal apoptosis, which is essential for proper development. Further, many apoptosis regulatory genes are either missing, or highly divergent in S. cerevisiae. Therefore, in this review we will use the term apoptosis-like programed cell death (PCD) instead of apoptosis. Despite these significant differences, S. cerevisiae has been instrumental in promoting the study of heterologous apoptotic proteins, particularly from human. Work in fungi other than S. cerevisiae revealed differences in the manifestation of PCD in single cell (yeasts) and multicellular (filamentous) species. Such differences may reflect the higher complexity level of filamentous species, and hence the involvement of PCD in a wider range of processes and life styles. It is also expected that differences might be found in the apoptosis apparatus of yeast and filamentous species. In this review we focus on aspects of PCD that are unique or can be better studied in filamentous species. We will highlight the similarities and differences of the PCD machinery between yeast and filamentous species and show the value of using S. cerevisiae along with filamentous species to study apoptosis. PMID:22891165

  8. Nature of type 1 Supernovae

    NASA Technical Reports Server (NTRS)

    Shklovskiy, I. S.

    1980-01-01

    The nature of type 1 supernovae (SN 1) is discussed through a comparison of observational evidence and theoretical perspectives relating to both type 1 and 2 supernovae. In particular two hypotheses relating to SN 1 phenomenon are examined: the first proposing that SN 1 are components of binary systems in which, at a comparatively late stage of evolution, overflow of the mass occurs; the second considers pre-SN 1 to be recently evolved stars with a mass greater than 1.4 solar mass (white dwarfs). In addition, an explanation of the reduced frequency of flares of SN 1 in spiral galaxies as related to that in elliptical galaxies is presented.

  9. Type 1 Diabetes: Current Perspectives.

    PubMed

    Kozhakhmetova, Aizhan; Gillespie, Kathleen M

    2016-01-01

    Type 1 diabetes, resulting from the autoimmune destruction of insulin producing islet beta cells is caused by genetic and environmental determinants. Recent studies agree that counterintuitively, the major genetic susceptibility factors are decreasing in frequency as the incidence of the condition increases. This suggests a growing role for environmental determinants but these have been difficult to identify and our understanding of gene/environment effects are limited. Individuals "at risk" can be identified accurately through the presence of multiple islet autoantibodies and current efforts in type 1 diabetes research focus on improved biomarkers and strategies to prevent or reverse the condition through immunotherapy. PMID:26659804

  10. Nuclear transfer with apoptotic bovine fibroblasts: can programmed cell death be reprogrammed?

    PubMed

    Miranda, Moyses dos Santos; Bressan, Fabiana Fernandes; De Bem, Tiago Henrique Camara; Merighe, Giovana Krempel Fonseca; Ohashi, Otávio Mitio; King, William Alan; Meirelles, Flavio Viera

    2012-06-01

    Cell death by apoptosis is considered to be irreversible. However, reports have indicated that its reversibility is possible if the cells have not yet reached the "point of no return." In order to add new information about this topic, we used cells at different moments of apoptotic process as nuclear donors in somatic cell nuclear transfer (SCNT) in order to test if programmed cell death can be reversed. Adult bovine fibroblasts were treated with 10 μM of staurosporine (STP) for 3 h and analyzed for phosphatidylserine externalization (Annexin assay) and presence of active caspase-9. Annexin-positive (Anx+) and Caspase-9-positive (Casp-9+) cells were isolated by FACS and immediately transferred into enucleated in vitro matured bovine oocytes. After STP treatment, 89.9% of cells were Anx+ (4.6% in control cells; p<0.01) and 24.9% were Casp-9+ (2.4% in control cells; p<0.01). Fusion and cleavage were not affected by the use apoptotic cells (p>0.05). Also, the use of Anx+ cells did not affect blastocyst production compared to control (26.4% vs. 22.9%, respectively; p>0.05). However, blastocyst formation was affected by the use of Casp-9+ cells (12.3%; p<0.05). These findings contribute to the idea of that apoptosis is reversible only at early stages. Additionally, we hypothesize that the "point of no return" for apoptosis may be located around activation of Caspase-9.

  11. Programmed cell death and adaptation: two different types of abiotic stress response in a unicellular chlorophyte.

    PubMed

    Zuppini, Anna; Gerotto, Caterina; Baldan, Barbara

    2010-06-01

    Eukaryotic microalgae are highly suitable biological indicators of environmental changes because they are exposed to extreme seasonal fluctuations. The biochemical and molecular targets and regulators of key proteins involved in the stress response in microalgae have yet to be elucidated. This study presents morphological and biochemical evidence of programmed cell death (PCD) in a low temperature strain of Chlorella saccharophila induced by exposure to NaCl stress. Morphological characteristics of PCD, including cell shrinkage, detachment of the plasma membrane from the cell wall, nuclear condensation and DNA fragmentation, were observed. Additionally, a significant production of H(2)O(2) and increase in caspase 3-like activity were detected. We demonstrated that singly applied environmental stresses such as warming or salt stress trigger a pathway of PCD. Intriguingly, the prior application of salt stress seems to reduce heat shock-induced cell death significantly, suggesting a combined effect which activates a defense mechanism in algal cells. These results suggest that C. saccharophila can undergo PCD under stress conditions, and that this PCD shares several features with metazoan PCD. Moreover, the simultaneous exposure of this unicellular chlorophyte to different abiotic stresses results in a tolerance mechanism.

  12. Ras pathway signaling accelerates programmed cell death in the pathogenic fungus Candida albicans.

    PubMed

    Phillips, Andrew J; Crowe, Jonathan D; Ramsdale, Mark

    2006-01-17

    A better understanding of the molecular basis of programmed cell death (PCD) in fungi could provide information that is useful in the design of antifungal drugs that combat life-threatening fungal infections. Harsh environmental stresses, such as acetic acid or hydrogen peroxide, have been shown to induce PCD in the pathogenic fungus Candida albicans. In this study, we show that dying cells progress from an apoptotic state to a secondary necrotic state and that the rate at which this change occurs is proportional to the intensity of the stimulus. Also, we found that the temporal response is modulated by Ras-cAMP-PKA signals. Mutations that block Ras-cAMP-PKA signaling (ras1Delta, cdc35Delta, tpk1Delta, and tpk2Delta) suppress or delay the apoptotic response, whereas mutations that stimulate signaling (RAS1(val13) and pde2Delta) accelerate the rate of entry of cells into apoptosis. Pharmacological stimulation or inhibition of Ras signaling reinforces these findings. Transient increases in endogenous cAMP occur under conditions that stimulate apoptosis but not growth arrest. Death-specific changes in the abundance of different isoforms of the PKA regulatory subunit, Bcy1p, are also observed. Activation of Ras signals may regulate PCD of C. albicans, either by inhibiting antiapoptotic functions (such as stress responses) or by activating proapoptotic functions. PMID:16407097

  13. DNA alteration and programmed cell death during ageing of sunflower seed

    PubMed Central

    El-Maarouf-Bouteau, Hayat; Mazuy, Claire; Corbineau, Françoise; Bailly, Christophe

    2011-01-01

    Sunflower (Helianthus annuus L.) seed viability is affected by moisture content (MC) during ageing and is related to accumulation of hydrogen peroxide and changes in energy metabolism. The aim of the present work was to investigate the effect of ageing on DNA alteration events by RAPD (random amplification of polymorphic DNA) analysis and to determine whether loss of seed viability might correspond to a controlled programmed cell death (PCD). Ageing of sunflower seeds was carried out at 35 °C for 7 d at different MCs. The higher the MC, the lower was the seed viability. RAPD analysis showed that DNA alterations occurred during ageing especially in seeds containing a high MC. In addition, PCD, as revealed by DNA fragmentation and TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick-end labelling) assay, was detected in aged seeds at MCs which resulted in ∼50% seed viability. At the cellular level, TUNEL assay and propidium iodide staining showed that cell death concerns all the cells of the embryonic axis. The quantification of the adenylate pool highlights mitochondrial dysfunction in aged seeds containing a high MC. The involvement of oxidative burst, mitochondria dysfunction, and PCD in seed loss of viability is proposed. PMID:21765164

  14. Leaf-shape remodeling: programmed cell death in fistular leaves of Allium fistulosum.

    PubMed

    Ni, Xi-Lu; Su, Hui; Zhou, Ya-fu; Wang, Feng-Hua; Liu, Wen-Zhe

    2015-03-01

    Some species of Allium in Liliaceae have fistular leaves. The fistular lamina of Allium fistulosum undergoes a process from solid to hollow during development. The aims were to reveal the process of fistular leaf formation involved in programmed cell death (PCD) and to compare the cytological events in the execution of cell death to those in the unusual leaf perforations or plant aerenchyma formation. In this study, light and transmission electron microscopy were used to characterize the development of fistular leaves and cytological events. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays and gel electrophoresis were used to determine nuclear DNA cleavage during the PCD. The cavity arises in the leaf blade by degradation of specialized cells, the designated pre-cavity cells, in the center of the leaves. Nuclei of cells within the pre-cavity site become TUNEL-positive, indicating that DNA cleavage is an early event. Gel electrophoresis revealed that DNA internucleosomal cleavage occurred resulting in a characteristic DNA ladder. Ultrastructural analysis of cells at the different stages showed disrupted vacuoles, misshapen nuclei with condensed chromatin, degraded cytoplasm and organelles and emergence of secondary vacuoles. The cell walls degraded last, and residue of degraded cell walls aggregated together. These results revealed that PCD plays a critical role in the development of A. fistulosum fistular leaves. The continuous cavity in A. fistulosum leaves resemble the aerenchyma in the pith of some gramineous plants to improve gas exchange. PMID:25132341

  15. LSD1 and HY5 antagonistically regulate red light induced-programmed cell death in Arabidopsis.

    PubMed

    Chai, Tingting; Zhou, Jun; Liu, Jian; Xing, Da

    2015-01-01

    Programmed cell death (PCD) in plant is triggered by abiotic and biotic stress. Light-dependent PCD is unique to plants. Light-induced PCD also requires reactive oxygen species (ROS) and salicylic acid (SA). In this study, lesion simulating disease1 (LSD1) and elongated hypocotyl 5 (HY5) perform opposite roles to regulate excess red light (RL)-triggered PCD associated with ROS and SA production. Under RL, the lsd1 mutant released more ROS and SA and displayed a stronger cell death rate than the hy5 mutant. It was shown that active LSD1 converted into inactive form by changing the redox status of the plastoquinone pool, and HY5 interacted with phytochrome B (phyB) to promote PCD in response to RL. LSD1 inhibited the enhanced disease susceptibility 1 (EDS1) expression by upregulating SR1, whereas HY5 enhanced the enhanced EDS1 expression by binding to the G-box of the EDS1 promoter. This study suggested that LSD1 and HY5 antagonistically modulated EDS1-dependent ROS and SA signaling; thus, PCD was mediated in response to RL.

  16. Reactive oxygen species do not contribute to ObgE*-mediated programmed cell death

    PubMed Central

    Dewachter, Liselot; Herpels, Pauline; Verstraeten, Natalie; Fauvart, Maarten; Michiels, Jan

    2016-01-01

    Programmed cell death (PCD) in bacteria is considered an important target for developing novel antimicrobials. Development of PCD-specific therapies requires a deeper understanding of what drives this process. We recently discovered a new mode of PCD in Escherichia coli that is triggered by expression of a mutant isoform of the essential ObgE protein, ObgE*. Our previous findings demonstrate that ObgE*-mediated cell death shares key characteristics with apoptosis in eukaryotic cells. It is well-known that reactive oxygen species (ROS) are formed during PCD in eukaryotes and play a pivotal role as signaling molecules in the progression of apoptosis. Therefore, we explored a possible role for ROS in bacterial killing by ObgE*. Using fluorescent probes and genetic reporters, we found that expression of ObgE* induces formation of ROS. Neutralizing ROS by chemical scavenging or by overproduction of ROS-neutralizing enzymes did not influence toxicity of ObgE*. Moreover, expression of ObgE* under anaerobic conditions proved to be as detrimental to bacterial viability as expression under aerobic conditions. In conclusion, ROS are byproducts of ObgE* expression that do not play a role in the execution or progression of ObgE*-mediated PCD. Targeted therapies should therefore look to exploit other aspects of ObgE*-mediated PCD. PMID:27641546

  17. Leaf-shape remodeling: programmed cell death in fistular leaves of Allium fistulosum.

    PubMed

    Ni, Xi-Lu; Su, Hui; Zhou, Ya-fu; Wang, Feng-Hua; Liu, Wen-Zhe

    2015-03-01

    Some species of Allium in Liliaceae have fistular leaves. The fistular lamina of Allium fistulosum undergoes a process from solid to hollow during development. The aims were to reveal the process of fistular leaf formation involved in programmed cell death (PCD) and to compare the cytological events in the execution of cell death to those in the unusual leaf perforations or plant aerenchyma formation. In this study, light and transmission electron microscopy were used to characterize the development of fistular leaves and cytological events. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays and gel electrophoresis were used to determine nuclear DNA cleavage during the PCD. The cavity arises in the leaf blade by degradation of specialized cells, the designated pre-cavity cells, in the center of the leaves. Nuclei of cells within the pre-cavity site become TUNEL-positive, indicating that DNA cleavage is an early event. Gel electrophoresis revealed that DNA internucleosomal cleavage occurred resulting in a characteristic DNA ladder. Ultrastructural analysis of cells at the different stages showed disrupted vacuoles, misshapen nuclei with condensed chromatin, degraded cytoplasm and organelles and emergence of secondary vacuoles. The cell walls degraded last, and residue of degraded cell walls aggregated together. These results revealed that PCD plays a critical role in the development of A. fistulosum fistular leaves. The continuous cavity in A. fistulosum leaves resemble the aerenchyma in the pith of some gramineous plants to improve gas exchange.

  18. Reactive oxygen species do not contribute to ObgE*-mediated programmed cell death.

    PubMed

    Dewachter, Liselot; Herpels, Pauline; Verstraeten, Natalie; Fauvart, Maarten; Michiels, Jan

    2016-01-01

    Programmed cell death (PCD) in bacteria is considered an important target for developing novel antimicrobials. Development of PCD-specific therapies requires a deeper understanding of what drives this process. We recently discovered a new mode of PCD in Escherichia coli that is triggered by expression of a mutant isoform of the essential ObgE protein, ObgE*. Our previous findings demonstrate that ObgE*-mediated cell death shares key characteristics with apoptosis in eukaryotic cells. It is well-known that reactive oxygen species (ROS) are formed during PCD in eukaryotes and play a pivotal role as signaling molecules in the progression of apoptosis. Therefore, we explored a possible role for ROS in bacterial killing by ObgE*. Using fluorescent probes and genetic reporters, we found that expression of ObgE* induces formation of ROS. Neutralizing ROS by chemical scavenging or by overproduction of ROS-neutralizing enzymes did not influence toxicity of ObgE*. Moreover, expression of ObgE* under anaerobic conditions proved to be as detrimental to bacterial viability as expression under aerobic conditions. In conclusion, ROS are byproducts of ObgE* expression that do not play a role in the execution or progression of ObgE*-mediated PCD. Targeted therapies should therefore look to exploit other aspects of ObgE*-mediated PCD. PMID:27641546

  19. On the intrinsic disorder status of the major players in programmed cell death pathways

    PubMed Central

    Uversky, Vladimir N

    2013-01-01

    Earlier computational and bioinformatics analysis of several large protein datasets across 28 species showed that proteins involved in regulation and execution of programmed cell death (PCD) possess substantial amounts of intrinsic disorder. Based on the comprehensive analysis of these datasets by a wide array of modern bioinformatics tools it was concluded that disordered regions of PCD-related proteins are involved in a multitude of biological functions and interactions with various partners, possess numerous posttranslational modification sites, and have specific evolutionary patterns (Peng et al. 2013). This study extends our previous work by providing information on the intrinsic disorder status of some of the major players of the three major PCD pathways: apoptosis, autophagy, and necroptosis. We also present a detailed description of the disorder status and interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathways. PMID:24358900

  20. Evidence of programmed cell death during microsporogenesis in an interspecific Brachiaria (Poaceae: Panicoideae: Paniceae) hybrid.

    PubMed

    Fuzinatto, V A; Pagliarini, M S; Valle, C B

    2007-05-11

    Morphological changes have been investigated during plant programmed cell death (PCD) in the last few years due to the new interest in a possible apoptotic-like phenomenon existing in plants. Although PCD has been reported in several tissues and specialized cells in plants, there have been few reports of its occurrence during microsporogenesis. The present study reports a typical process of PCD during meiosis in an interspecific Brachiaria hybrid leading to male sterility. In this hybrid, some inflorescences initiated meiosis but it was arrested in zygotene/pachytene. From this stage, meiocytes underwent a severe alteration in shape showing substantial membrane blebbing; the cytoplasm became denser at the periphery; the cell nucleus entered a progressive stage of chromatin disintegration, and then the nucleolus disintegrated, and the cytoplasm condensed and shrunk. The oldest flowers of the raceme showed only the callose wall in the anthers showing obvious signs of complete sterility.

  1. Oxidative damage and cell-programmed death induced in Zea mays L. by allelochemical stress.

    PubMed

    Ciniglia, Claudia; Mastrobuoni, Francesco; Scortichini, Marco; Petriccione, Milena

    2015-05-01

    The allelochemical stress on Zea mays was analyzed by using walnut husk washing waters (WHWW), a by-product of Juglans regia post-harvest process, which possesses strong allelopathic potential and phytotoxic effects. Oxidative damage and cell-programmed death were induced by WHWW in roots of maize seedlings. Treatment induced ROS burst, with excess of H2O2 content. Enzymatic activities of catalase were strongly increased during the first hours of exposure. The excess in malonildialdehyde following exposure to WHWW confirmed that oxidative stress severely damaged maize roots. Membrane alteration caused a decrease in NADPH oxidase activity along with DNA damage as confirmed by DNA laddering. The DNA instability was also assessed through sequence-related amplified polymorphism assay, thus suggesting the danger of walnut processing by-product and focusing the attention on the necessity of an efficient treatment of WHWW.

  2. Virus-host arms race at the joint origin of multicellularity and programmed cell death.

    PubMed

    Iranzo, Jaime; Lobkovsky, Alexander E; Wolf, Yuri I; Koonin, Eugene V

    2014-01-01

    Unicellular eukaryotes and most prokaryotes possess distinct mechanisms of programmed cell death (PCD). How an "altruistic" trait, such as PCD, could evolve in unicellular organisms? To address this question, we developed a mathematical model of the virus-host co-evolution that involves interaction between immunity, PCD and cellular aggregation. Analysis of the parameter space of this model shows that under high virus load and imperfect immunity, joint evolution of cell aggregation and PCD is the optimal evolutionary strategy. Given the abundance of viruses in diverse habitats and the wide spread of PCD in most organisms, these findings imply that multiple instances of the emergence of multicellularity and its essential attribute, PCD, could have been driven, at least in part, by the virus-host arms race.

  3. On the intrinsic disorder status of the major players in programmed cell death pathways.

    PubMed

    Uversky, Alexey V; Xue, Bin; Peng, Zhenling; Kurgan, Lukasz; Uversky, Vladimir N

    2013-01-01

    Earlier computational and bioinformatics analysis of several large protein datasets across 28 species showed that proteins involved in regulation and execution of programmed cell death (PCD) possess substantial amounts of intrinsic disorder. Based on the comprehensive analysis of these datasets by a wide array of modern bioinformatics tools it was concluded that disordered regions of PCD-related proteins are involved in a multitude of biological functions and interactions with various partners, possess numerous posttranslational modification sites, and have specific evolutionary patterns (Peng et al. 2013). This study extends our previous work by providing information on the intrinsic disorder status of some of the major players of the three major PCD pathways: apoptosis, autophagy, and necroptosis. We also present a detailed description of the disorder status and interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathways.

  4. Role of peroxynitrite in programmed cell death induced in self-incompatible pollen

    PubMed Central

    Serrano, Irene; Romero-Puertas, Maria C.; Rodríguez Serrano, María; Sandalio, Luisa M.; Olmedilla, Adela

    2012-01-01

    Reactive oxygen species and NO are involved in the signaling pathway of programmed cell death (PCD). Information concerning the role of these molecules in self-incompatible pollination is scarce especially in non-model species studied in vivo. We recently reported that in the olive tree, compatible and self-incompatible pollen have different levels of reactive oxygen and nitrogen species and that PCD is induced in self-incompatible pollen. Levels of O2.- and NO are higher in pollen after self-incompatible pollination than after compatible pollination. The presence of these reactive species was concomitant with the presence of peroxynitrite. Similar results were obtained on pollen-germination experiments both in vivo and in vitro. These data, together with observations made after treating pollinated flowers with scavengers, suggest that peroxynitrite plays a role in PCD induced after self-incompatible pollination and we propose here a model to describe the way in which it might work. PMID:22751302

  5. Early events induced by the toxin deoxynivalenol lead to programmed cell death in Nicotiana tabacum cells.

    PubMed

    Yekkour, Amine; Tran, Daniel; Arbelet-Bonnin, Delphine; Briand, Joël; Mathieu, Florence; Lebrihi, Ahmed; Errakhi, Rafik; Sabaou, Nasserdine; Bouteau, François

    2015-09-01

    Deoxynivalenol (DON) is a mycotoxin affecting animals and plants. This toxin synthesized by Fusarium culmorum and Fusarium graminearum is currently believed to play a decisive role in the fungal phytopathogenesis as a virulence factor. Using cultured cells of Nicotiana tabacum BY2, we showed that DON-induced programmed cell death (PCD) could require transcription and translation processes, in contrast to what was observed in animal cells. DON could induce different cross-linked pathways involving (i) reactive oxygen species (ROS) generation linked, at least partly, to a mitochondrial dysfunction and a transcriptional down-regulation of the alternative oxidase (Aox1) gene and (ii) regulation of ion channel activities participating in cell shrinkage, to achieve PCD.

  6. A Bacterial Inhibitor of Host Programmed Cell Death Defenses is an E3 Ubiquitin Ligase

    SciTech Connect

    Janjusevic,R.; Abramovitch, R.; Martin, G.; Stebbins, C.

    2005-01-01

    The Pseudomonas syringae protein AvrPtoB is translocated into plant cells, where it inhibits immunity-associated programmed cell death (PCD). The structure of a C-terminal domain of AvrPtoB that is essential for anti-PCD activity reveals an unexpected homology to the U-box and RING-finger components of eukaryotic E3 ubiquitin ligases, and we show that AvrPtoB has ubiquitin ligase activity. Mutation of conserved residues involved in the binding of E2 ubiquitin-conjugating enzymes abolishes this activity in vitro, as well as anti-PCD activity in tomato leaves, which dramatically decreases virulence. These results show that Pseudomonas syringae uses a mimic of host E3 ubiquitin ligases to inactivate plant defenses.

  7. Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms.

    PubMed

    Skulachev, V P

    1999-06-01

    The review summarizes the present state of our knowledge concerning alternative functions of mitochondria, namely energy conservation in forms of protonic potential and ATP, thermoregulatory energy dissipation as heat, production of useful substances, decomposition of harmful substances, control of cellular processes. The recent progress in understanding of some mitochondrion-linked pathologies is described. The role of reactive oxygen species in these processes is stressed. Possible mechanisms of programmed death of mitochondrion (mitoptosis), cell (apoptosis) and organism (phenoptosis) are considered. A concept is put forward assuming that mitoptosis is involved in some types of apoptosis whereas apoptosis can be a part of a phenoptotic cascade. It is hypothesized that septic shock, as well as the stress-induced brain and heart ischemic diseases and cancer, exemplify mechanisms of phenoptosis purifying population, community of organisms or kin from dangerous or useless individuals. PMID:10626278

  8. Untangling the Roles of Anti-Apoptosis in Regulating Programmed Cell Death using Humanized Yeast Cells

    PubMed Central

    Clapp, Caitlin; Portt, Liam; Khoury, Chamel; Sheibani, Sara; Eid, Rawan; Greenwood, Matthew; Vali, Hojatollah; Mandato, Craig A.; Greenwood, Michael T.

    2012-01-01

    Genetically programmed cell death (PCD) mechanisms, including apoptosis, are important for the survival of metazoans since it allows, among things, the removal of damaged cells that interfere with normal function. Cell death due to PCD is observed in normal processes such as aging and in a number of pathophysiologies including hypoxia (common causes of heart attacks and strokes) and subsequent tissue reperfusion. Conversely, the loss of normal apoptotic responses is associated with the development of tumors. So far, limited success in preventing unwanted PCD has been reported with current therapeutic approaches despite the fact that inhibitors of key apoptotic inducers such as caspases have been developed. Alternative approaches have focused on mimicking anti-apoptotic processes observed in cells displaying increased resistance to apoptotic stimuli. Hormesis and pre-conditioning are commonly observed cellular strategies where sub-lethal levels of pro-apoptotic stimuli lead to increased resistance to higher or lethal levels of stress. Increased expression of anti-apoptotic sequences is a common mechanism mediating these protective effects. The relevance of the latter observation is exemplified by the observation that transgenic mice overexpressing anti-apoptotic genes show significant reductions in tissue damage following ischemia. Thus strategies aimed at increasing the levels of anti-apoptotic proteins, using gene therapy or cell penetrating recombinant proteins are being evaluated as novel therapeutics to decrease cell death following acute periods of cell death inducing stress. In spite of its functional and therapeutic importance, more is known regarding the processes involved in apoptosis than anti-apoptosis. The genetically tractable yeast Saccharomyces cerevisiae has emerged as an exceptional model to study multiple aspects of PCD including the mitochondrial mediated apoptosis observed in metazoans. To increase our knowledge of the process of anti

  9. alpha-Amylase and programmed cell death in aleurone of ripening wheat grains.

    PubMed

    Mrva, Kolumbina; Wallwork, Meredith; Mares, Daryl J

    2006-01-01

    Late maturity alpha-amylase (LMA) in wheat is a genetic defect that may result in the accumulation of unacceptable levels of high pI alpha-amylase in grain in the absence of germination or weather damage. During germination, gibberellin produced in the embryo triggers expression of alpha-Amy genes, the synthesis of alpha-amylase and, subsequently, cell death in the aleurone. LMA also involves the aleurone and whilst LMA appears to be independent of the embryo there is nevertheless some evidence that gibberellin is involved. The aim of this investigation was to determine whether the increase in alpha-amylase activity in LMA-prone genotypes, like alpha-amylase synthesis by aleurone cells in germinating or GA-challenged grains, is followed by aleurone cell death. Programmed cell death was seen in aleurone layers from developing, ripe and germinated grains using confocal microscopy and fluorescent probes specific for dead or living cells. Small pockets of dying cells were observed distributed at random throughout the aleurone of ripening LMA-affected grains and by harvest-ripeness these cells were clearly dead. The first appearance of dying cells, 35 d post-anthesis, coincided with the later part of the 'window of sensitivity' in grain development in LMA-prone wheat cultivars. No dead or dying cells were present in ripening or fully ripe grains of control cultivars. In germinating grains, dying cells were observed in the aleurone adjacent to the scutellum and, as germination progressed, the number of dead cells increased and the affected area extended further towards the distal end of the grain. Aside from the obvious differences in spatial distribution, dying cells in 20-24 h germinated grains were similar to dying cells in developing LMA-affected grains, consistent with previous measurements of alpha-amylase activity. The increase in high pI alpha-amylase activity in developing grains of LMA-prone cultivars, like alpha-amylase synthesis in germinating grains, is

  10. Developmental Coordination of Gamete Differentiation with Programmed Cell Death in Sporulating Yeast

    PubMed Central

    Eastwood, Michael D.

    2015-01-01

    The gametogenesis program of the budding yeast Saccharomyces cerevisiae, also known as sporulation, employs unusual internal meiotic divisions, after which all four meiotic products differentiate within the parental cell. We showed previously that sporulation is typically accompanied by the destruction of discarded immature meiotic products through their exposure to proteases released from the mother cell vacuole, which undergoes an apparent programmed rupture. Here we demonstrate that vacuolar rupture contributes to de facto programmed cell death (PCD) of the meiotic mother cell itself. Meiotic mother cell PCD is accompanied by an accumulation of depolarized mitochondria, organelle swelling, altered plasma membrane characteristics, and cytoplasmic clearance. To ensure that the gametes survive the destructive consequences of developing within a cell that is executing PCD, we hypothesized that PCD is restrained from occurring until spores have attained a threshold degree of differentiation. Consistent with this hypothesis, gene deletions that perturb all but the most terminal postmeiotic spore developmental stages are associated with altered PCD. In these mutants, meiotic mother cells exhibit a delay in vacuolar rupture and then appear to undergo an alternative form of PCD associated with catastrophic consequences for the underdeveloped spores. Our findings reveal yeast sporulation as a context of bona fide PCD that is developmentally coordinated with gamete differentiation. PMID:26092920

  11. 3,4,5-tricaffeoylquinic acid attenuates proteasome inhibition-mediated programmed cell death in differentiated PC12 cells.

    PubMed

    Nam, Yoon Jeong; Lee, Da Hee; Kim, Yun Jeong; Shin, Yong Kyoo; Sohn, Dong Suep; Lee, Min Sung; Lee, Chung Soo

    2014-08-01

    The dysfunction of the proteasome system is suggested to be implicated in neuronal degeneration. Caffeoylquinic acid derivatives have demonstrated anti-oxidant and anti-inflammatory effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the neuronal cell death induced by proteasome inhibition has not been studied. Therefore, in the respect of cell death process, we assessed the effect of 3,4,5-tricaffeoylquinic acid on the proteasome inhibition-induced programmed cell death using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, and survivin protein levels, an increase in Bax, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), and an increase in the tumor suppressor p53 levels. Treatment with 3,4,5-tricaffeoylquinic acid attenuated the proteasome inhibitor-induced changes in the programmed cell death-related protein levels, formation of reactive oxygen species, GSH depletion and cell death. The results show that 3,4,5-tricaffeoylquinic acid may attenuate the proteasome inhibitor-induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of 3,4,5-tricaffeoylquinic acid appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH.

  12. Viruses in type 1 diabetes.

    PubMed

    Hyöty, Heikki

    2016-07-01

    Environmental factors play an important role in the pathogenesis of type 1 diabetes and can determine if a genetically susceptible individual develops the disease. Increasing evidence suggest that among other exogenous agents certain virus infections can contribute to the beta-cell damaging process. Possible viral etiology of type 1 diabetes has been explored extensively but the final proof for causality is still lacking. Currently, the group of enteroviruses (EVs) is considered as the strongest candidate. These viruses have been found in the pancreas of type 1 diabetic patients, and epidemiological studies have shown more EV infections in diabetic patients than in controls. Prospective studies, such as the Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland, are of fundamental importance in the evaluation viral effects as they can cover all stages of the beta-cell damaging process, including those preceding the initiation of the process. DIPP study has carried out the most comprehensive virological analyses ever done in prospective cohorts. This article summarizes the findings from these analyses and discuss them in the context of the existing other knowledge and the prospects for intervention studies with EV vaccines or antiviral drugs. PMID:27411438

  13. Role of class III phosphatidylinositol 3-kinase during programmed nuclear death of Tetrahymena thermophila.

    PubMed

    Akematsu, Takahiko; Fukuda, Yasuhiro; Attiq, Rizwan; Pearlman, Ronald E

    2014-02-01

    Programmed nuclear death (PND) in the ciliate protozoan Tetrahymena thermophila is a novel type of autophagy that occurs during conjugation, in which only the parental somatic macronucleus is destined to die and is then eliminated from the progeny cytoplasm. Other coexisting nuclei, however, such as new micro- and macronuclei are unaffected. PND starts with condensation in the nucleus followed by apoptotic DNA fragmentation, lysosomal acidification, and final resorption. Because of the peculiarity in the process and the absence of some ATG genes in this organism, the mechanism of PND has remained unclear. In this study, we focus on the role of class III phosphatidylinositol 3-kinase (PtdIns3K, corresponding to yeast Vps34) in order to identify central regulators of PND. We identified the sole Tetrahymena thermophila ortholog (TtVPS34) to yeast Vps34 and human PIK3C3 (the catalytic subunit of PtdIns3K), through phylogenetic analysis, and generated the gene knockdown mutant for functional analysis. Loss of TtVPS34 activity prevents autophagosome formation on the parental macronucleus, and this nucleus escapes from the lysosomal pathway. In turn, DNA fragmentation and final resorption of the nucleus are drastically impaired. These phenotypes are similar to the situation in the ATG8Δ mutants of Tetrahymena, implying an inextricable link between TtVPS34 and TtATG8s in controlling PND as well as general macroautophagy. On the other hand, TtVPS34 does not appear responsible for the nuclear condensation and does not affect the progeny nuclear development. These results demonstrate that TtVPS34 is critically involved in the nuclear degradation events of PND in autophagosome formation rather than with an involvement in commitment to the death program.

  14. ROS-mediated abiotic stress-induced programmed cell death in plants

    PubMed Central

    Petrov, Veselin; Hille, Jacques; Mueller-Roeber, Bernd; Gechev, Tsanko S.

    2015-01-01

    During the course of their ontogenesis plants are continuously exposed to a large variety of abiotic stress factors which can damage tissues and jeopardize the survival of the organism unless properly countered. While animals can simply escape and thus evade stressors, plants as sessile organisms have developed complex strategies to withstand them. When the intensity of a detrimental factor is high, one of the defense programs employed by plants is the induction of programmed cell death (PCD). This is an active, genetically controlled process which is initiated to isolate and remove damaged tissues thereby ensuring the survival of the organism. The mechanism of PCD induction usually includes an increase in the levels of reactive oxygen species (ROS) which are utilized as mediators of the stress signal. Abiotic stress-induced PCD is not only a process of fundamental biological importance, but also of considerable interest to agricultural practice as it has the potential to significantly influence crop yield. Therefore, numerous scientific enterprises have focused on elucidating the mechanisms leading to and controlling PCD in response to adverse conditions in plants. This knowledge may help develop novel strategies to obtain more resilient crop varieties with improved tolerance and enhanced productivity. The aim of the present review is to summarize the recent advances in research on ROS-induced PCD related to abiotic stress and the role of the organelles in the process. PMID:25741354

  15. Inflammation-associated autophagy-related programmed necrotic death of human neutrophils characterized by organelle fusion events.

    PubMed

    Mihalache, Cristina C; Yousefi, Shida; Conus, Sébastien; Villiger, Peter M; Schneider, E Marion; Simon, Hans-Uwe

    2011-06-01

    The most common form of neutrophil death, under both physiological and inflammatory conditions, is apoptosis. In this study, we report a novel form of programmed necrotic cell death, associated with cytoplasmic organelle fusion events, that occurs in neutrophils exposed to GM-CSF and other inflammatory cytokines upon ligation of CD44. Strikingly, this type of neutrophil death requires PI3K activation, a signaling event usually involved in cellular survival pathways. In the death pathway reported in this study, PI3K is required for the generation of reactive oxygen species, which somehow trigger the generation of large cytoplasmic vacuoles, generated by the fusion of CD44-containing endosomes with autophagosomes and secondary, but not primary, granules. Neutrophils demonstrating vacuolization undergo rapid cell death that depends on receptor-interacting protein 1 kinase activity and papain family protease(s), but not caspases, that are most likely activated and released, respectively, during or as a consequence of organelle fusion. Vacuolized neutrophils are present in infectious and autoimmune diseases under in vivo conditions. Moreover, isolated neutrophils from such patients are highly sensitive toward CD44-mediated PI3K activation, reactive oxygen species production, and cell death, suggesting that the newly described autophagy-related form of programmed neutrophil necrosis plays an important role in inflammatory responses.

  16. Environmentally induced programmed cell death in leaf protoplasts of Aponogeton madagascariensis.

    PubMed

    Lord, Christina E N; Gunawardena, Arunika H L A N

    2011-02-01

    Within plant systems, two main forms of programmed cell death (PCD) exist: developmentally regulated and environmentally induced. The lace plant (Aponogeton madagascariensis) naturally undergoes developmentally regulated PCD to form perforations between longitudinal and transverse veins over its leaf surface. Developmental PCD in the lace plant has been well characterized; however, environmental PCD has never before been studied in this plant species. The results presented here portray heat shock (HS) treatment at 55 °C for 20 min as a promising inducer of environmental PCD within lace plant protoplasts originally isolated from non-PCD areas of the plant. HS treatment produces cells displaying many characteristics of developmental PCD, including blebbing of the plasma membrane, increased number of hydrolytic vesicles and transvacuolar strands, nuclear condensation, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive nuclei, as well as increased Brownian motion within the vacuole. Results presented here for the first time provide evidence of chloroplasts in the vacuole of living protoplasts undergoing environmentally induced PCD. Findings suggest that the mitochondria play a critical role in the cell death process. Changes in mitochondrial dynamics were visualized in HS-treated cells, including loss of mitochondrial mobility, reduction in ΔΨ(m), as well as the proximal association with chloroplasts. The role of the mitochondrial permeability transition pore (PTP) was examined by pre-treatment with the PTP agonist cyclosporine A. Overall, HS is depicted as a reliable method to induce PCD within lace plant protoplasts, and proves to be a reliable technique to enable comparisons between environmentally induced and developmentally regulated PCD within one species of plant.

  17. Crosstalks between Myo-Inositol Metabolism, Programmed Cell Death and Basal Immunity in Arabidopsis

    PubMed Central

    Tcherkez, Guillaume; Blanchet, Sophie; Massoud, Kamal; Domenichini, Séverine; Henry, Yves; Soubigou-Taconnat, Ludivine; Lelarge-Trouverie, Caroline; Saindrenan, Patrick; Renou, Jean Pierre; Bergounioux, Catherine

    2009-01-01

    Background Although it is a crucial cellular process required for both normal development and to face stress conditions, the control of programmed cell death in plants is not fully understood. We previously reported the isolation of ATXR5 and ATXR6, two PCNA-binding proteins that could be involved in the regulation of cell cycle or cell death. A yeast two-hybrid screen using ATXR5 as bait captured AtIPS1, an enzyme which catalyses the committed step of myo-inositol (MI) biosynthesis. atips1 mutants form spontaneous lesions on leaves, raising the possibility that MI metabolism may play a role in the control of PCD in plants. In this work, we have characterised atips1 mutants to gain insight regarding the role of MI in PCD regulation. Methodology/Principal Findings - lesion formation in atips1 mutants depends of light intensity, is due to PCD as evidenced by TUNEL labelling of nuclei, and is regulated by phytohormones such as salicylic acid - MI and galactinol are the only metabolites whose accumulation is significantly reduced in the mutant, and supplementation of the mutant with these compounds is sufficient to prevent PCD - the transcriptome profile of the mutant is extremely similar to that of lesion mimic mutants such as cpr5, or wild-type plants infected with pathogens. Conclusion/Significance Taken together, our results provide strong evidence for the role of MI or MI derivatives in the regulation of PCD. Interestingly, there are three isoforms of IPS in Arabidopsis, but AtIPS1 is the only one harbouring a nuclear localisation sequence, suggesting that nuclear pools of MI may play a specific role in PCD regulation and opening new research prospects regarding the role of MI in the prevention of tumorigenesis. Nevertheless, the significance of the interaction between AtIPS1 and ATXR5 remains to be established. PMID:19812700

  18. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo

    PubMed Central

    1995-01-01

    In a number of experimental systems in which lymphocyte depletion was induced by apoptosis-inducing manipulations, no apoptotic morphology and ladder-type DNA fragmentation were detected among freshly isolated peripheral lymphocytes ex vivo. Here we report that one alteration that can be detected among splenocytes stimulated with lymphocyte-depleting doses of dexamethasone (DEX) in vivo is a reduced uptake of 3,3'dihexyloxacarbocyanine iodide (DiOC6[3]), a fluorochrome which incorporates into cells dependent upon their mitochondrial transmembrane potential (delta psi m). In contrast, ex vivo isolated splenocytes still lacked established signs of programmed cell death (PCD):DNA degradation into high or low molecular weight fragments, ultrastructural changes of chromatin arrangement and endoplasmatic reticulum, loss in viability, or accumulation of intracellular peroxides. Moreover, no changes in cell membrane potential could be detected. A reduced delta psi m has been observed in response to different agents inducing lymphoid cell depletion in vivo (superantigen and glucocorticoids [GC]), in mature T and B lymphocytes, as well as their precursors. DEX treatment in vivo, followed by cytofluorometric purification of viable delta psi mlow splenic T cells ex vivo, revealed that this fraction of cells is irreversibly committed to undergoing DNA fragmentation. Immediately after purification neither delta psi mlow, nor delta psi mhigh cells, exhibit detectable DNA fragmentation. However, after short-term culture (37 degrees C, 1 h) delta psi mlow cells show endonucleolysis, followed by cytolysis several hours later. Incubation of delta psi mlow cells in the presence of excess amount of the GC receptor antagonist RU38486 (which displaces DEX from the GC receptor), cytokines that inhibit DEX-induced cell death, or cycloheximide fails to prevent cytolysis. The antioxidant, N- acetylcysteine, as well as linomide, an agent that effectively inhibits DEX or superantigen

  19. Live to die another way: modes of programmed cell death and the signals emanating from dying cells

    PubMed Central

    Fuchs, Yaron; Steller, Hermann

    2015-01-01

    Preface All life ends in death, but perhaps one of life’s grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was virtually synonymous with apoptosis, but recently, alternative PCD mechanisms have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals emanating from dying cells, which can either fuel regeneration or instruct additional killing. Further advances in understanding the physiological role of multiple cell death mechanisms and associated signals will be important to selectively manipulate PCD for therapeutic purposes. PMID:25991373

  20. Macromitophagy, neutral lipids synthesis, and peroxisomal fatty acid oxidation protect yeast from "liponecrosis", a previously unknown form of programmed cell death.

    PubMed

    Sheibani, Sara; Richard, Vincent R; Beach, Adam; Leonov, Anna; Feldman, Rachel; Mattie, Sevan; Khelghatybana, Leila; Piano, Amanda; Greenwood, Michael; Vali, Hojatollah; Titorenko, Vladimir I

    2014-01-01

    We identified a form of cell death called "liponecrosis." It can be elicited by an exposure of the yeast Saccharomyces cerevisiae to exogenous palmitoleic acid (POA). Our data imply that liponecrosis is: (1) a programmed, regulated form of cell death rather than an accidental, unregulated cellular process and (2) an age-related form of cell death. Cells committed to liponecrotic death: (1) do not exhibit features characteristic of apoptotic cell death; (2) do not display plasma membrane rupture, a hallmark of programmed necrotic cell death; (3) akin to cells committed to necrotic cell death, exhibit an increased permeability of the plasma membrane for propidium iodide; (4) do not display excessive cytoplasmic vacuolization, a hallmark of autophagic cell death; (5) akin to cells committed to autophagic death, exhibit a non-selective en masse degradation of cellular organelles and require the cytosolic serine/threonine protein kinase Atg1p for executing the death program; and (6) display a hallmark feature that has not been reported for any of the currently known cell death modalities-namely, an excessive accumulation of lipid droplets where non-esterified fatty acids (including POA) are deposited in the form of neutral lipids. We therefore concluded that liponecrotic cell death subroutine differs from the currently known subroutines of programmed cell death. Our data suggest a hypothesis that liponecrosis is a cell death module dynamically integrated into a so-called programmed cell death network, which also includes the apoptotic, necrotic, and autophagic modules of programmed cell death. Based on our findings, we propose a mechanism underlying liponecrosis. PMID:24196447

  1. Macromitophagy, neutral lipids synthesis, and peroxisomal fatty acid oxidation protect yeast from “liponecrosis”, a previously unknown form of programmed cell death

    PubMed Central

    Sheibani, Sara; Richard, Vincent R; Beach, Adam; Leonov, Anna; Feldman, Rachel; Mattie, Sevan; Khelghatybana, Leila; Piano, Amanda; Greenwood, Michael; Vali, Hojatollah; Titorenko, Vladimir I

    2014-01-01

    We identified a form of cell death called “liponecrosis.” It can be elicited by an exposure of the yeast Saccharomyces cerevisiae to exogenous palmitoleic acid (POA). Our data imply that liponecrosis is: (1) a programmed, regulated form of cell death rather than an accidental, unregulated cellular process and (2) an age-related form of cell death. Cells committed to liponecrotic death: (1) do not exhibit features characteristic of apoptotic cell death; (2) do not display plasma membrane rupture, a hallmark of programmed necrotic cell death; (3) akin to cells committed to necrotic cell death, exhibit an increased permeability of the plasma membrane for propidium iodide; (4) do not display excessive cytoplasmic vacuolization, a hallmark of autophagic cell death; (5) akin to cells committed to autophagic death, exhibit a non-selective en masse degradation of cellular organelles and require the cytosolic serine/threonine protein kinase Atg1p for executing the death program; and (6) display a hallmark feature that has not been reported for any of the currently known cell death modalities—namely, an excessive accumulation of lipid droplets where non-esterified fatty acids (including POA) are deposited in the form of neutral lipids. We therefore concluded that liponecrotic cell death subroutine differs from the currently known subroutines of programmed cell death. Our data suggest a hypothesis that liponecrosis is a cell death module dynamically integrated into a so-called programmed cell death network, which also includes the apoptotic, necrotic, and autophagic modules of programmed cell death. Based on our findings, we propose a mechanism underlying liponecrosis. PMID:24196447

  2. Involvement of phospholipase D-related signal transduction in chemical-induced programmed cell death in tomato cell cultures.

    PubMed

    Iakimova, Elena T; Michaeli, Rina; Woltering, Ernst J

    2013-10-01

    Phospholipase D (PLD) and its product phosphatidic acid (PA) are incorporated in a complex metabolic network in which the individual PLD isoforms are suggested to regulate specific developmental and stress responses, including plant programmed cell death (PCD). Despite the accumulating knowledge, the mechanisms through which PLD/PA operate during PCD are still poorly understood. In this work, the role of PLDα1 in PCD and the associated caspase-like proteolysis, ethylene and hydrogen peroxide (H(2)O(2)) synthesis in tomato suspension cells was studied. Wild-type (WT) and PLDα1-silenced cell lines were exposed to the cell death-inducing chemicals camptothecin (CPT), fumonisin B1 (FB1) and CdSO(4). A range of caspase inhibitors effectively suppressed CPT-induced PCD in WT cells, but failed to alleviate cell death in PLDα1-deficient cells. Compared to WT, in CPT-treated PLDα1 mutant cells, reduced cell death and decreased production of H(2)O(2) were observed. Application of ethylene significantly enhanced CPT-induced cell death both in WT and PLDα1 mutants. Treatments with the PA derivative lyso-phosphatidic acid and mastoparan (agonist of PLD/PLC signalling downstream of G proteins) caused severe cell death. Inhibitors, specific to PLD and PLC, remarkably decreased the chemical-induced cell death. Taken together with our previous findings, the results suggest that PLDα1 contributes to caspase-like-dependent cell death possibly communicated through PA, reactive oxygen species and ethylene. The dead cells expressed morphological features of PCD such as protoplast shrinkage and nucleus compaction. The presented findings reveal novel elements of PLD/PA-mediated cell death response and suggest that PLDα1 is an important factor in chemical-induced PCD signal transduction.

  3. Death duties

    PubMed Central

    Myers, Kathryn A.; Eden, David

    2007-01-01

    PROBLEM BEING ADDRESSED Family physicians are often called upon to pronounce and certify the deaths of patients. Inadequate knowledge of the Coroners Act (in the province of Ontario) and of the correct process of certifying death can make physicians uncomfortable when confronted with these tasks. OBJECTIVE OF PROGRAM To educate family physicians about how to perform the administrative tasks required of them when patients die. PROGRAM DESCRIPTION The program included an educational video, a tutorial outlining the process of death certification, and discussion with a regional coroner about key features of the Coroners Act. In small groups, participants worked through cases of patient deaths in which they were asked to determine whether a coroner needed to be involved, to determine the manner of death, and to complete a mock death certificate for each case. CONCLUSION All participants reported a high level of satisfaction with the workshop and thought the main objective of the program had been achieved. Results of a test given 3 months after the workshop showed substantial improvement in participants’ knowledge of the coroner’s role and of the process of death certification. PMID:17872782

  4. Programmed cell death in the marine cyanobacterium Trichodesmium mediates carbon and nitrogen export.

    PubMed

    Bar-Zeev, Edo; Avishay, Itamar; Bidle, Kay D; Berman-Frank, Ilana

    2013-12-01

    The extent of carbon (C) and nitrogen (N) export to the deep ocean depends upon the efficacy of the biological pump that transports primary production to depth, thereby preventing its recycling in the upper photic zone. The dinitrogen-fixing (diazotrophic) Trichodesmium spp. contributes significantly to oceanic C and N cycling by forming extensive blooms in nutrient-poor tropical and subtropical regions. These massive blooms generally collapse several days after forming, but the cellular mechanism responsible, along with the magnitude of associated C and N export processes, are as yet unknown. Here, we used a custom-made, 2-m high water column to simulate a natural bloom and to specifically test and quantify whether the programmed cell death (PCD) of Trichodesmium mechanistically regulates increased vertical flux of C and N. Our findings demonstrate that extremely rapid development and abrupt, PCD-induced demise (within 2-3 days) of Trichodesmium blooms lead to greatly elevated excretions of transparent exopolymers and a massive downward pulse of particulate organic matter. Our results mechanistically link autocatalytic PCD and bloom collapse to quantitative C and N export fluxes, suggesting that PCD may have an impact on the biological pump efficiency in the oceans.

  5. Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response.

    PubMed

    Choi, Hyo-Kyoung; Choi, Youngsok; Park, Eun Sung; Park, Soo-Yeon; Lee, Seung-Hyun; Seo, Jaesung; Jeong, Mi-Hyeon; Jeong, Jae-Wook; Jeong, Jae-Ho; Lee, Peter C W; Choi, Kyung-Chul; Yoon, Ho-Geun

    2015-01-01

    The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5(WT) in PDCD5(-/-) MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions. PMID:26077467

  6. The N-acetylcysteine-insensitive acetic acid-induced yeast programmed cell death occurs without macroautophagy.

    PubMed

    Antonacci, Lucia; Guaragnella, Nicoletta; Ždralevic, Maša; Passarella, Salvatore; Marra, Ersilia; Giannattasio, Sergio

    2012-12-01

    Programmed cell death can occur through two separate pathways caused by treatment of Saccharomyces cerevisiae with acetic acid (AA-PCD), which differ from one another essentially with respect to their sensitivity to N-acetylcysteine (NAC) and to the role played by cytochrome c and metacaspase YCA1. Moreover, yeast can also undergo macroautophagy which occurs in NAC-insensitive manner. In order to gain some insight into the relationship between AA-PCD and macroautophagy use was made of WT and knock-out cells lacking YCA1 and/or cytochrome c. We show that i. macroautophagy is modulated by YCA1 and by cytochrome c in a negative and positive manner, respectively, ii. the NAC-insensitive AA-PCD and macroautophagy differ from one another and iii. NAC-insensitive AA-PCD pathway takes place essentially without macroautophagy, even if the shift of extracellular pH to acidic values required for AA-PCD to occur leads itself to increased or decreased macroautophagy in YCA1 or cytochrome c-lacking cells. PMID:23072389

  7. Achievements and perspectives in yeast acetic acid-induced programmed cell death pathways.

    PubMed

    Guaragnella, Nicoletta; Antonacci, Lucia; Passarella, Salvatore; Marra, Ersilia; Giannattasio, Sergio

    2011-10-01

    The use of non-mammalian model organisms, including yeast Saccharomyces cerevisiae, can provide new insights into eukaryotic PCD (programmed cell death) pathways. In the present paper, we report recent achievements in the elucidation of the events leading to PCD that occur as a response to yeast treatment with AA (acetic acid). In particular, ROS (reactive oxygen species) generation, cyt c (cytochrome c) release and mitochondrial function and proteolytic activity will be dealt with as they vary along the AA-PCD time course by using both wild-type and mutant yeast cells. Two AA-PCD pathways are described sharing common features, but distinct from one another with respect to the role of ROS and mitochondria, the former in which YCA1 acts upstream of cyt c release and caspase-like activation in a ROS-dependent manner and the latter in which cyt c release does not occur, but caspase-like activity increases, in a ROS-independent manner. PMID:21936848

  8. Ultrastructural observations of programmed cell death during metanephric development in mouse.

    PubMed

    Li, Xiaoming; Guo, Min; Shao, Youzhi

    2013-05-01

    Previous studies revealed apoptosis as an only programmed cell death (PCD) during renal morphogenesis before alternative type of PCD, necroptosis were introduced. Evidences of non-apoptotic PCD during renal development were scarce and needed to be accumulated. The purpose of this study is to investigate whether non-apoptotic PCD is involved in and observe ultrastructural features of apoptotic cells or non-apoptotic PCD during metanephros development. For this purpose, light and transmission electron microscopy were used. The most significant finding to come out of this study was that necroptosis was observed during developing metanephros by electron microscopy. The results also provided another fact that apoptosis and necroptosis constituted the PCD during embryonic development of kidney in mouse. Compared to necroptosis, apoptosis was more predominantly evident throughout whole development period and in every compartment of metanephros except for proximal tubule. However, necroptosis was only exhibited in developing nephrons also except for proximal tubule. In addition, outcomes of PCD were related to morphogenetic features of metanephric development. Efferocytosis for apoptotic cell or bodies took place in each type cell and whole period of developing metanephros. Besides efferocytosis blood flow and urine flux were available to remove the corpses of PCD, especially PCD from developing nephrons. Our findings suggested that both apoptosis and necroptosis play important roles during nephrogenesis and observed three ways to clear the PCD cell: efferocytosis, blood flow, and urine flux.

  9. Programmed Cell Death Occurs Asymmetrically during Abscission in Tomato[C][W][OA

    PubMed Central

    Bar-Dror, Tal; Dermastia, Marina; Kladnik, Aleš; Žnidarič, Magda Tušek; Novak, Maruša Pompe; Meir, Shimon; Burd, Shaul; Philosoph-Hadas, Sonia; Ori, Naomi; Sonego, Lilian; Dickman, Martin B.; Lers, Amnon

    2011-01-01

    Abscission occurs specifically in the abscission zone (AZ) tissue as a natural stage of plant development. Previously, we observed delay of tomato (Solanum lycopersicum) leaf abscission when the LX ribonuclease (LX) was inhibited. The known association between LX expression and programmed cell death (PCD) suggested involvement of PCD in abscission. In this study, hallmarks of PCD were identified in the tomato leaf and flower AZs during the late stage of abscission. These included loss of cell viability, altered nuclear morphology, DNA fragmentation, elevated levels of reactive oxygen species and enzymatic activities, and expression of PCD-associated genes. Overexpression of antiapoptotic proteins resulted in retarded abscission, indicating PCD requirement. PCD, LX, and nuclease gene expression were visualized primarily in the AZ distal tissue, demonstrating an asymmetry between the two AZ sides. Asymmetric expression was observed for genes associated with cell wall hydrolysis, leading to AZ, or associated with ethylene biosynthesis, which induces abscission. These results suggest that different abscission-related processes occur asymmetrically between the AZ proximal and distal sides. Taken together, our findings identify PCD as a key mechanism that occurs asymmetrically during normal progression of abscission and suggest an important role for LX in this PCD process. PMID:22128123

  10. Involvement of TatD nuclease during programmed cell death in the protozoan parasite Trypanosoma brucei.

    PubMed

    Gannavaram, Sreenivas; Debrabant, Alain

    2012-03-01

    In this report, we describe the involvement of TatD nuclease during programmed cell death (PCD) in the human protozoan parasite Trypanosoma brucei. T. brucei TatD nuclease showed intrinsic DNase activity, was localized in the cytoplasm and translocated to the nucleus when cells were treated with inducers previously demonstrated to cause PCD in T. brucei. Overexpression of TatD nuclease resulted in elevated PCD and conversely, loss of TatD expression by RNAi conferred significant resistance to the induction of PCD in T. brucei. Co-immunoprecipitation studies revealed that TatD nuclease interacts with endonucleaseG suggesting that these two nucleases could form a DNA degradation complex in the nucleus. Together, biochemical activity, RNAi and subcellular localization results demonstrate the role of TatD nuclease activity in DNA degradation during PCD in these evolutionarily ancient eukaryotic organisms. Further, in conjunction with endonucleaseG, TatD may represent a critical nuclease in a caspase-independent PCD pathway in trypanosomatid parasites since caspases have not been identified in these organisms.

  11. A novel ligand of calcitonin receptor reveals a potential new sensor that modulates programmed cell death

    PubMed Central

    Furness, SGB; Hare, DL; Kourakis, A; Turnley, AM; Wookey, PJ

    2016-01-01

    We have discovered that the accumulation of an anti-calcitonin receptor (anti-CTR) antibody conjugated to a fluorophore (mAb2C4:AF568) provides a robust signal for cells undergoing apoptotic programmed cell death (PCD). PCD is an absolute requirement for normal development of metazoan organisms. PCD is a hallmark of common diseases such as cardiovascular disease and tissue rejection in graft versus host pathologies, and chemotherapeutics work by increasing PCD. This robust signal or high fluorescent events were verified by confocal microscopy and flow cytometry in several cell lines and a primary culture in which PCD had been induced. In Jurkat cells, GBM-L2 and MG63 cells, the percentage undergoing PCD that were positive for both mAb2C4:AF568 and annexin V ranged between 70 and >90%. In MG63 cells induced for the preapoptotic cell stress response (PACSR), the normal expression of α-tubulin, a key structural component of the cytoskeleton, and accumulation of mAb2C4:AF568 were mutually exclusive. Our data support a model in which CTR is upregulated during PACSR and recycles to the plasma membrane with apoptosis. In cells committed to apoptosis (α-tubulin negative), there is accumulation of the CTR-ligand mAb2C4:AF568 generating a high fluorescent event. The reagent mAb2C4:AF568 effectively identifies a novel event linked to apoptosis. PMID:27777788

  12. Bcl-2 family members inhibit oxidative stress-induced programmed cell death in Saccharomyces cerevisiae.

    PubMed

    Chen, Shao-Rong; Dunigan, David D; Dickman, Martin B

    2003-05-15

    Selected antiapoptotic genes were expressed in baker's yeast (Saccharomyces cerevisiae) to evaluate cytoprotective effects during oxidative stress. When exposed to treatments resulting in the generation of reactive oxygen species (ROS), including H(2)O(2), menadione, or heat shock, wild-type yeast died and exhibited apoptotic-like characteristics, consistent with previous studies. Yeast strains were generated expressing nematode ced-9, human bcl-2, or chicken bcl-xl genes. These transformants tolerated a range of oxidative stresses, did not display features associated with apoptosis, and remained viable under conditions that were lethal to wild-type yeast. Yeast strains expressing a mutant antiapoptotic gene (bcl-2 deltaalpha 5-6), known to be nonfunctional in mammalian cells, were unable to tolerate any of the ROS-generating insults. These data are the first report showing CED-9 has cytoprotective effects against oxidative stress, and add CED-9 to the list of Bcl-2 protein family members that modulate ROS-mediated programmed cell death. In addition, these data indicate that Bcl-2 family members protect wild-type yeast from physiological stresses. Taken together, these data support the concept of the broad evolutionary conservation and functional similarity of the apoptotic processes in eukaryotic organisms.

  13. Inhibition of cathepsin B by caspase-3 inhibitors blocks programmed cell death in Arabidopsis

    PubMed Central

    Ge, Y; Cai, Y-M; Bonneau, L; Rotari, V; Danon, A; McKenzie, E A; McLellan, H; Mach, L; Gallois, P

    2016-01-01

    Programmed cell death (PCD) is used by plants for development and survival to biotic and abiotic stresses. The role of caspases in PCD is well established in animal cells. Over the past 15 years, the importance of caspase-3-like enzymatic activity for plant PCD completion has been widely documented despite the absence of caspase orthologues. In particular, caspase-3 inhibitors blocked nearly all plant PCD tested. Here, we affinity-purified a plant caspase-3-like activity using a biotin-labelled caspase-3 inhibitor and identified Arabidopsis thaliana cathepsin B3 (AtCathB3) by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Consistent with this, recombinant AtCathB3 was found to have caspase-3-like activity and to be inhibited by caspase-3 inhibitors. AtCathepsin B triple-mutant lines showed reduced caspase-3-like enzymatic activity and reduced labelling with activity-based caspase-3 probes. Importantly, AtCathepsin B triple mutants showed a strong reduction in the PCD induced by ultraviolet (UV), oxidative stress (H2O2, methyl viologen) or endoplasmic reticulum stress. Our observations contribute to explain why caspase-3 inhibitors inhibit plant PCD and provide new tools to further plant PCD research. The fact that cathepsin B does regulate PCD in both animal and plant cells suggests that this protease may be part of an ancestral PCD pathway pre-existing the plant/animal divergence that needs further characterisation. PMID:27058316

  14. Intracellular energy depletion triggers programmed cell death during petal senescence in tulip

    PubMed Central

    Azad, A. K.; Ishikawa, Takayuki; Ishikawa, Takahiro; Shibata, H.

    2008-01-01

    Programmed cell death (PCD) in petals provides a model system to study the molecular aspects of organ senescence. In this study, the very early triggering signal for PCD during the senescence process from young green buds to 14-d-old petals of Tulipa gesneriana was determined. The opening and closing movement of petals of intact plants increased for the first 3 d and then gradually decreased. DNA degradation and cytochrome c (Cyt c) release were clearly observed in 6-d-old flowers. Oxidative stress or ethylene production can be excluded as the early signal for petal PCD. In contrast, ATP was dramatically depleted after the first day of flower opening. Sucrose supplementation to cut flowers maintained their ATP levels and the movement ability for a longer time than in those kept in water. The onset of DNA degradation, Cyt c release, and petal senescence was also delayed by sucrose supplementation to cut flowers. These results suggest that intracellular energy depletion, rather than oxidative stress or ethylene production, may be the very early signal to trigger PCD in tulip petals. PMID:18515833

  15. Mod(mdg4) participates in hormonally regulated midgut programmed cell death during metamorphosis.

    PubMed

    Cai, Mei-Juan; Liu, Wen; He, Hong-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2012-12-01

    The insect midgut undergoes programmed cell death (PCD) during metamorphosis, but the molecular basis for this phenomenon has not been demonstrated. We report a mod(mdg4) protein [designated as mod(mdg4)1A] that is involved in hormonally regulated insect midgut PCD, from the lepidopteran Helicoverpa armigera. Mod(mdg4)1A is localized in the larval midgut and is highly expressed during metamorphosis. Knockdown of mod(mdg4)1a by feeding dsRNA to the larvae suppressed midgut PCD and delayed metamorphosis. The mechanism is that mod(mdg4)1a knockdown decreased the transcript levels of genes involved in PCD and metamorphosis, but increased the transcript level of inhibitor of apoptosis survivin. The transcript level of mod(mdg4)1a is independently upregulated by 20-hydroxyecdysone (20E) or juvenile hormone (JH) analog methoprene. Overlapped 20E and methoprene counteractively regulate the transcript level of mod(mdg4)1a. 20E upregulates the mod(mdg4)1a transcript level not through its nuclear receptor EcRB1. Methoprene upregulates the mod(mdg4)1a transcript level through the juvenile hormone candidate receptor Met. These findings indicate that mod(mdg4)1a participates in midgut PCD and metamorphosis by regulating the transcript levels of a network of genes via different pathways under 20E and JH regulation.

  16. Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor.

    PubMed

    Liu, An; Dong, Lei; Wei, Xiao-Li; Yang, Xiao-Hong; Xiao, Jun-Hai; Liu, Zai-Qun

    2016-06-10

    Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery. In addition to some monoclonal antibodies applied to treat cancers clinically, the screening of organic molecules for hindering the interaction of PD-1 with PD-L1 became an efficient strategy in the development of PD-1 inhibitors. We herein applied resorcinol and 3-hydroxythiophenol as the core to link with N,N-dimethylcarbamate and other alkyl-substituted amines to afford 13 amine-appended phenyl dimethylcarbamates (AAPDs). The test for blockading the combination of PD-1 with PD-L1 revealed that abilities of 13 AAPDs were higher than that of sulfamethizole, a successful PD-1 inhibitor. In particular, large hydrophobic substituents at amine moiety or a nitro at resorcinol skeleton enhanced the inhibitory effect of AAPD even higher than that of sulfamethoxypyridazine, another successful PD-1 inhibitor. The present results may provide valuable information for further investigation on synthetic PD-1 inhibitors. PMID:27063329

  17. Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response.

    PubMed

    Choi, Hyo-Kyoung; Choi, Youngsok; Park, Eun Sung; Park, Soo-Yeon; Lee, Seung-Hyun; Seo, Jaesung; Jeong, Mi-Hyeon; Jeong, Jae-Wook; Jeong, Jae-Ho; Lee, Peter C W; Choi, Kyung-Chul; Yoon, Ho-Geun

    2015-06-16

    The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5(WT) in PDCD5(-/-) MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions.

  18. Postnatal Development of Subcallosal Zone Following Suppression of Programmed Cell Death in Bax-deficient Mice.

    PubMed

    Kim, Woon Ryoung; Sun, Woong

    2013-09-01

    Neural stem cells are found in adult mammalian brain regions including the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ). In addition to these two regions, other neurogenic regions are often reported in many species. Recently, the subcallosal zone (SCZ) has been identified as a novel neurogenic region where new neuroblasts are spontaneously generated and then, by Bax-dependent apoptosis, eliminated. However, the development of SCZ in the postnatal brain is not yet fully explored. The present study investigated the precise location and amount of neuroblasts in the developing brain. To estimate the importance of programmed cell death (PCD) for SCZ histogenesis, SCZ development in the Bax-knockout (KO) mouse was examined. Interestingly, an accumulation of extra neurons with synaptic fibers in the SCZ of Bax-KO mice was observed. Indeed, Bax-KO mice exhibited enhanced startle response to loud acoustic stimuli and reduced anxiety level. Considering the prevention of PCD in the SCZ leads to sensory-motor gating dysfunction in the Bax-KO mice, active elimination of SCZ neuroblasts may promote optimal brain function.

  19. Inhibition of cathepsin B by caspase-3 inhibitors blocks programmed cell death in Arabidopsis.

    PubMed

    Ge, Y; Cai, Y-M; Bonneau, L; Rotari, V; Danon, A; McKenzie, E A; McLellan, H; Mach, L; Gallois, P

    2016-09-01

    Programmed cell death (PCD) is used by plants for development and survival to biotic and abiotic stresses. The role of caspases in PCD is well established in animal cells. Over the past 15 years, the importance of caspase-3-like enzymatic activity for plant PCD completion has been widely documented despite the absence of caspase orthologues. In particular, caspase-3 inhibitors blocked nearly all plant PCD tested. Here, we affinity-purified a plant caspase-3-like activity using a biotin-labelled caspase-3 inhibitor and identified Arabidopsis thaliana cathepsin B3 (AtCathB3) by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Consistent with this, recombinant AtCathB3 was found to have caspase-3-like activity and to be inhibited by caspase-3 inhibitors. AtCathepsin B triple-mutant lines showed reduced caspase-3-like enzymatic activity and reduced labelling with activity-based caspase-3 probes. Importantly, AtCathepsin B triple mutants showed a strong reduction in the PCD induced by ultraviolet (UV), oxidative stress (H2O2, methyl viologen) or endoplasmic reticulum stress. Our observations contribute to explain why caspase-3 inhibitors inhibit plant PCD and provide new tools to further plant PCD research. The fact that cathepsin B does regulate PCD in both animal and plant cells suggests that this protease may be part of an ancestral PCD pathway pre-existing the plant/animal divergence that needs further characterisation. PMID:27058316

  20. Transforming growth factor-beta (TGF-beta) and programmed cell death in the vertebrate retina.

    PubMed

    Duenker, Nicole

    2005-01-01

    Programmed cell death (PCD) is a precisely regulated phenomenon essential for the homeostasis of multicellular organisms. Developmental systems, particularly the nervous system, have provided key observations supporting the physiological role of PCD. We have recently shown that transforming growth factor-beta (TGF-beta) plays an important role in mediating ontogenetic PCD in the nervous system. As part of the central nervous system the developing retina serves as an ideal model system for investigating apoptotic processes during neurogenesis in vivo as it is easily accessible experimentally and less complex due to its limited number of different neurons. This review summarizes data indicating a pivotal role of TGF-beta in mediating PCD in the vertebrate retina. The following topics are discussed: expression of TGF-beta isoforms and receptors in the vertebrate retina, the TGF-beta signaling pathway, functions and molecular mechanisms of PCD in the nervous system, TGF-beta-mediated retinal apoptosis in vitro and in vivo, and interactions of TGF-beta with other pro- and anti-apoptotic factors.

  1. Programmed cell death 5 mediates HDAC3 decay to promote genotoxic stress response

    PubMed Central

    Choi, Hyo-Kyoung; Choi, Youngsok; Park, Eun Sung; Park, Soo-Yeon; Lee, Seung-Hyun; Seo, Jaesung; Jeong, Mi-Hyeon; Jeong, Jae-Wook; Jeong, Jae-Ho; Lee, Peter C. W.; Choi, Kyung-Chul; Yoon, Ho-Geun

    2015-01-01

    The inhibition of p53 activity by histone deacetylase 3 (HDAC3) has been reported, but the precise molecular mechanism is unknown. Here we show that programmed cell death 5 (PDCD5) selectively mediates HDAC3 dissociation from p53, which induces HDAC3 cleavage and ubiquitin-dependent proteasomal degradation. Casein kinase 2 alpha phosphorylates PDCD5 at Ser-119 to enhance its stability and importin 13-mediated nuclear translocation of PDCD5. Genetic deletion of PDCD5 abrogates etoposide (ET)-induced p53 stabilization and HDAC3 cleavage, indicating an essential role of PDCD5 in p53 activation. Restoration of PDCD5WT in PDCD5−/− MEFs restores ET-induced HDAC3 cleavage. Reduction of both PDCD5 and p53, but not reduction of either protein alone, significantly enhances in vivo tumorigenicity of AGS gastric cancer cells and correlates with poor prognosis in gastric cancer patients. Our results define a mechanism for p53 activation via PDCD5-dependent HDAC3 decay under genotoxic stress conditions. PMID:26077467

  2. Programmed Cell Death in Flight Muscle Histolysis of the House Cricket

    PubMed Central

    Oliver, Rush H.; Albury, Acchia N.J.; Mousseau, Timothy A.

    2007-01-01

    We have characterized the process of flight muscle histolysis in the female house cricket, Acheta domesticus, through analysis of alterations of tissue wet weight, total protein content, and percent shortening of the dorsal longitudinal flight muscles (DLMs). Our objectives were to (1) define the normal course of histolysis in the cricket, (2) analyze the effects of juvenile hormone (JH) removal and replacement, (3) determine the effects of cycloheximide treatment, and (4) examine patterns of protein expression during histolysis. Our results suggest that flight muscle histolysis in the house cricket is an example of an active, developmentally regulated cell death program induced by an endocrine signal. Initial declines of total protein in DLMs indicated the JH signal that induced histolysis occurred by Day 2 and that histolysis was essentially complete by Day 3. Significant reductions in tissue weight and percent muscle shortening were observed in DLMs from Day 3 crickets. Cervical ligation of Day 1 crickets prevented histolysis but this inhibition could be reversed by continual topical treatments with methoprene (an active JH analog) although ligation of Day 2 crickets did not prevent histolysis. A requirement for active protein expression was demonstrated by analysis of synthesis block by cycloheximide and short-term incorporation of 35S-methionine. Treatment with cycloheximide prevented histolysis. Autofluorographic imaging of DLM proteins separated by electrophoresis revealed apparent coordinated regulation of protein expression. PMID:17118399

  3. Streptomyces natalensis programmed cell death and morphological differentiation are dependent on oxidative stress

    PubMed Central

    Beites, Tiago; Oliveira, Paulo; Rioseras, Beatriz; Pires, Sílvia D. S.; Oliveira, Rute; Tamagnini, Paula; Moradas-Ferreira, Pedro; Manteca, Ángel; Mendes, Marta V.

    2015-01-01

    Streptomyces are aerobic Gram-positive bacteria characterized by a complex life cycle that includes hyphae differentiation and spore formation. Morphological differentiation is triggered by stressful conditions and takes place in a pro-oxidant environment, which sets the basis for an involvement of the oxidative stress response in this cellular process. Characterization of the phenotypic traits of Streptomyces natalensis ΔkatA1 (mono-functional catalase) and ΔcatR (Fur-like repressor of katA1 expression) strains in solid medium revealed that both mutants had an impaired morphological development process. The sub-lethal oxidative stress caused by the absence of KatA1 resulted in the formation of a highly proliferative and undifferentiated vegetative mycelium, whereas de-repression of CatR regulon, from which KatA1 is the only known representative, resulted in the formation of scarce aerial mycelium. Both mutant strains had the transcription of genes associated with aerial mycelium formation and biosynthesis of the hyphae hydrophobic layer down-regulated. The first round of the programmed cell death (PCD) was inhibited in both strains which caused the prevalence of the transient primary mycelium (MI) over secondary mycelium (MII). Our data shows that the first round of PCD and morphological differentiation in S. natalensis is dependent on oxidative stress in the right amount at the right time. PMID:26256439

  4. Intracellular energy depletion triggers programmed cell death during petal senescence in tulip.

    PubMed

    Azad, A K; Ishikawa, Takayuki; Ishikawa, Takahiro; Sawa, Y; Shibata, H

    2008-01-01

    Programmed cell death (PCD) in petals provides a model system to study the molecular aspects of organ senescence. In this study, the very early triggering signal for PCD during the senescence process from young green buds to 14-d-old petals of Tulipa gesneriana was determined. The opening and closing movement of petals of intact plants increased for the first 3 d and then gradually decreased. DNA degradation and cytochrome c (Cyt c) release were clearly observed in 6-d-old flowers. Oxidative stress or ethylene production can be excluded as the early signal for petal PCD. In contrast, ATP was dramatically depleted after the first day of flower opening. Sucrose supplementation to cut flowers maintained their ATP levels and the movement ability for a longer time than in those kept in water. The onset of DNA degradation, Cyt c release, and petal senescence was also delayed by sucrose supplementation to cut flowers. These results suggest that intracellular energy depletion, rather than oxidative stress or ethylene production, may be the very early signal to trigger PCD in tulip petals.

  5. Programmed cell death in the marine cyanobacterium Trichodesmium mediates carbon and nitrogen export

    PubMed Central

    Bar-Zeev, Edo; Avishay, Itamar; Bidle, Kay D; Berman-Frank, Ilana

    2013-01-01

    The extent of carbon (C) and nitrogen (N) export to the deep ocean depends upon the efficacy of the biological pump that transports primary production to depth, thereby preventing its recycling in the upper photic zone. The dinitrogen-fixing (diazotrophic) Trichodesmium spp. contributes significantly to oceanic C and N cycling by forming extensive blooms in nutrient-poor tropical and subtropical regions. These massive blooms generally collapse several days after forming, but the cellular mechanism responsible, along with the magnitude of associated C and N export processes, are as yet unknown. Here, we used a custom-made, 2-m high water column to simulate a natural bloom and to specifically test and quantify whether the programmed cell death (PCD) of Trichodesmium mechanistically regulates increased vertical flux of C and N. Our findings demonstrate that extremely rapid development and abrupt, PCD-induced demise (within 2–3 days) of Trichodesmium blooms lead to greatly elevated excretions of transparent exopolymers and a massive downward pulse of particulate organic matter. Our results mechanistically link autocatalytic PCD and bloom collapse to quantitative C and N export fluxes, suggesting that PCD may have an impact on the biological pump efficiency in the oceans. PMID:23887173

  6. Senescence and programmed cell death in plants: polyamine action mediated by transglutaminase

    PubMed Central

    Del Duca, Stefano; Serafini-Fracassini, Donatella; Cai, Giampiero

    2014-01-01

    Research on polyamines (PAs) in plants laps a long way of about 50 years and many roles have been discovered for these aliphatic cations. PAs regulate cell division, differentiation, organogenesis, reproduction, dormancy-break and senescence, homeostatic adjustments in response to external stimuli and stresses. Nevertheless, the molecular mechanisms of their multiple activities are still matter of research. PAs are present in free and bound forms and interact with several important cell molecules; some of these interactions may occur by covalent linkages catalyzed by transglutaminase (TGase), giving rise to “cationization” or cross-links among specific proteins. Senescence and programmed cell death (PCD) can be delayed by PAs; in order to re-interpret some of these effects and to obtain new insights into their molecular mechanisms, their conjugation has been revised here. The TGase-mediated interactions between proteins and PAs are the main target of this review. After an introduction on the characteristics of this enzyme, on its catalysis and role in PCD in animals, the plant senescence and PCD models in which TGase has been studied, are presented: the corolla of naturally senescing or excised flowers, the leaves senescing, either excised or not, the pollen during self-incompatible pollination, the hypersensitive response and the tuber storage parenchyma during dormancy release. In all the models examined, TGase appears to be involved by a similar molecular mechanism as described during apoptosis in animal cells, even though several substrates are different. Its effect is probably related to the type of PCD, but mostly to the substrate to be modified in order to achieve the specific PCD program. As a cross-linker of PAs and proteins, TGase is an important factor involved in multiple, sometimes controversial, roles of PAs during senescence and PCD. PMID:24778637

  7. Ethylene-Mediated Programmed Cell Death during Maize Endosperm Development of Wild-Type and shrunken2 Genotypes.

    PubMed Central

    Young, T. E.; Gallie, D. R.; DeMason, D. A.

    1997-01-01

    We characterized the progression of programmed cell death during maize (Zea mays L.) endosperm development of starchy (Su; wild-type) and shrunken2 (sh2) genotypes and tested the involve ment of ethylene in mediating this process. Histological and viability staining demonstrated that endosperm cell death was initiated earlier and progressed more rapidly in sh2 endosperm compared with Su endosperm. Internucleosomal DNA fragmentation accompanied endosperm cell death and occurred more extensively in sh2 endosperm. 1-Aminocyclopropane-1-carboxylic acid levels peaked approximately 16 d after pollination (dap) in Su endosperm and gradually decreased during subsequent development, whereas two large 1-aminocyclopropane-1-carboxylic acid peaks were observed in sh2 endosperm, the first between 16 and 20 dap and the second at 36 dap. Ethylene levels were elevated in sh2 kernels compared with Su kernels, with an initial peak 20 dap approximately 3-fold higher than in Su kernels and a second peak 36 dap approximately 5-fold higher than that in Su kernels. Ethylene treatment of Su kernels resulted in earlier and more extensive endosperm cell death and DNA fragmentation. Aminoethoxyvinylglycine treatment of sh2 kernels reduced the extent of DNA fragmentation. We conclude that ethylene is involved in triggering programmed cell death in developing maize endosperm and is responsible for the aberrant phenotype of sh2 kernels. PMID:12223841

  8. AtPDCD5 Plays a Role in Programmed Cell Death after UV-B Exposure in Arabidopsis1[OPEN

    PubMed Central

    Falcone Ferreyra, María Lorena; D’Andrea, Lucio; AbdElgawad, Hamada

    2016-01-01

    DNA damage responses have evolved to sense and react to DNA damage; the induction of DNA repair mechanisms can lead to genomic restoration or, if the damaged DNA cannot be adequately repaired, to the execution of a cell death program. In this work, we investigated the role of an Arabidopsis (Arabidopsis thaliana) protein, AtPDCD5, which is highly similar to the human PDCD5 protein; it is induced by ultraviolet (UV)-B radiation and participates in programmed cell death in the UV-B DNA damage response. Transgenic plants expressing AtPDCD5 fused to GREEN FLUORESCENT PROTEIN indicate that AtPDCD5 is localized both in the nucleus and the cytosol. By use of pdcd5 mutants, we here demonstrate that these plants have an altered antioxidant metabolism and accumulate higher levels of DNA damage after UV-B exposure, similar to levels in ham1ham2 RNA interference transgenic lines with decreased expression of acetyltransferases from the MYST family. By coimmunoprecipitation and pull-down assays, we provide evidence that AtPDCD5 interacts with HAM proteins, suggesting that both proteins participate in the same pathway of DNA damage responses. Plants overexpressing AtPDCD5 show less DNA damage but more cell death in root tips upon UV-B exposure. Finally, we here show that AtPDCD5 also participates in age-induced programmed cell death. Together, the data presented here demonstrate that AtPDCD5 plays an important role during DNA damage responses induced by UV-B radiation in Arabidopsis and also participates in programmed cell death programs. PMID:26884483

  9. AtPDCD5 Plays a Role in Programmed Cell Death after UV-B Exposure in Arabidopsis.

    PubMed

    Falcone Ferreyra, María Lorena; Casadevall, Romina; D'Andrea, Lucio; AbdElgawad, Hamada; Beemster, Gerrit T S; Casati, Paula

    2016-04-01

    DNA damage responses have evolved to sense and react to DNA damage; the induction of DNA repair mechanisms can lead to genomic restoration or, if the damaged DNA cannot be adequately repaired, to the execution of a cell death program. In this work, we investigated the role of an Arabidopsis (Arabidopsis thaliana) protein, AtPDCD5, which is highly similar to the human PDCD5 protein; it is induced by ultraviolet (UV)-B radiation and participates in programmed cell death in the UV-B DNA damage response. Transgenic plants expressing AtPDCD5 fused to GREEN FLUORESCENT PROTEIN indicate that AtPDCD5 is localized both in the nucleus and the cytosol. By use of pdcd5 mutants, we here demonstrate that these plants have an altered antioxidant metabolism and accumulate higher levels of DNA damage after UV-B exposure, similar to levels in ham1ham2 RNA interference transgenic lines with decreased expression of acetyltransferases from the MYST family. By coimmunoprecipitation and pull-down assays, we provide evidence that AtPDCD5 interacts with HAM proteins, suggesting that both proteins participate in the same pathway of DNA damage responses. Plants overexpressing AtPDCD5 show less DNA damage but more cell death in root tips upon UV-B exposure. Finally, we here show that AtPDCD5 also participates in age-induced programmed cell death. Together, the data presented here demonstrate that AtPDCD5 plays an important role during DNA damage responses induced by UV-B radiation in Arabidopsis and also participates in programmed cell death programs.

  10. Genetics Home Reference: otopalatodigital syndrome type 1

    MedlinePlus

    ... Conditions otopalatodigital syndrome type 1 otopalatodigital syndrome type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Otopalatodigital syndrome type 1 is a disorder primarily involving abnormalities in skeletal ...

  11. Genetics Home Reference: optic atrophy type 1

    MedlinePlus

    ... Conditions optic atrophy type 1 optic atrophy type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Optic atrophy type 1 is a condition that affects vision. Individuals with ...

  12. Genetics Home Reference: distal arthrogryposis type 1

    MedlinePlus

    ... Conditions distal arthrogryposis type 1 distal arthrogryposis type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) ...

  13. Role of a Transcriptional Regulator in Programmed Cell Death and Plant Development

    SciTech Connect

    Julie M. Stone

    2008-09-13

    The long-term goal of this research is to understand the role(s) and molecular mechanisms of programmed cell death (PCD) in the controlling plant growth, development and responses to biotic and abiotic stress. We developed a genetic selection scheme to identify A. thaliana FB1-resistant (fbr) mutants as a way to find genes involved in PCD (Stone et al., 2000; Stone et al., 2005; Khan and Stone, 2008). The disrupted gene in fbr6 (AtSPL14) responsible for the FB1-insensitivity and plant architecture phenotypes encodes a plant-specific SBP DNA-binding domain transcriptional regulator (Stone et al., 2005; Liang et al., 2008). This research plan is designed to fill gaps in the knowledge about the role of SPL14 in plant growth and development. The work is being guided by three objectives aimed at determining the pathways in which SPL14 functions to modulate PCD and/or plant development: (1) determine how SPL14 functions in plant development, (2) identify target genes that are directly regulated by SPL14, and (3) identify SPL14 modifications and interacting proteins. We made significant progress during the funding period. Briefly, some major accomplishments are highlighted below: (1) To identify potential AtSPL14 target genes, we identified a consensus DNA binding site for the AtSPL14 SBP DNA-binding domain using systematic evolution of ligands by exponential selection (SELEX) and site-directed mutagenesis (Liang et al., 2008). This consensus binding site was used to analyze Affymetrix microarray gene expression data obtained from wild-type and fbr6 mutant plants to find possible AtSPL14-regulated genes. These candidate AtSPL14-regulated genes are providing new information on the molecular mechanisms linking plant PCD and plant development through modulation of the 26S proteasome. (2) Transgenic plants expressing epitope-tagged versions of AtSPL14 are being used to confirm the AtSPL14 targets (by ChIP-PCR) and further dissect the molecular interactions (Nazarenus, Liang

  14. Mitochondrial Translocation of High Mobility Group Box 1 Facilitates LIM Kinase 2-Mediated Programmed Necrotic Neuronal Death.

    PubMed

    Hyun, Hye-Won; Ko, Ah-Reum; Kang, Tae-Cheon

    2016-01-01

    High mobility group box 1 (HMGB1) acts a signaling molecule regulating a wide range of inflammatory responses in extracellular space. HMGB1 also stabilizes nucleosomal structure and facilitates gene transcription. Under pathophysiological conditions, nuclear HMGB1 is immediately transported to the cytoplasm through chromosome region maintenance 1 (CRM1). Recently, we have reported that up-regulation of LIM kinase 2 (LIMK2) expression induces HMGB1 export from neuronal nuclei during status epilepticus (SE)-induced programmed neuronal necrosis in the rat hippocampus. Thus, we investigated whether HMGB1 involves LIMK2-mediated programmed neuronal necrosis, but such role is not reported. In the present study, SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline, control siRNA, LIMK2 siRNA or leptomycin B (LMB, a CRM1 inhibitor) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining, western blots and immunohistochemical studies. LIMK2 knockdown effectively attenuated SE-induced neuronal death and HMGB1 import into mitochondria accompanied by inhibiting nuclear HMGB1 release and abnormal mitochondrial elongation. LMB alleviated SE-induced neuronal death and nuclear HMGB1 release. However, LMB did not prevent mitochondrial elongation induced by SE, but inhibited the HMGB1 import into mitochondria. The efficacy of LMB was less effective to attenuate SE-induced neuronal death than that of LIMK2 siRNA. These findings indicate that nuclear HMGB1 release and the subsequent mitochondrial import may facilitate and deteriorate programmed necrotic neuronal deaths. The present data suggest that the nuclear HMGB1 release via CRM1 may be a potential therapeutic target for the programmed necrotic neuronal death induced by SE. PMID:27147971

  15. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki

    PubMed Central

    HINO, Shigeo

    2011-01-01

    In late 2010, the nation-wide screening of pregnant women for human T-lymphotropic virus type 1 (HTLV-1) infection was implemented in Japan to prevent milk-borne transmission of HTLV-1. In the late 1970s, recognition of the adult T-cell leukemia (ATL) cluster in Kyushu, Japan, led to the discovery of the first human retrovirus, HTLV-1. In 1980, we started to investigate mother-to-child transmission (MTCT) for explaining the peculiar endemicity of HTLV-1. Retrospective and prospective epidemiological data revealed the MTCT rate at ∼20%. Cell-mediated transmission of HTLV-1 without prenatal infection suggested a possibility of milk-borne transmission. Common marmosets were successfully infected by oral inoculation of HTLV-1 harboring cells. A prefecture-wide intervention study to refrain from breast-feeding by carrier mothers, the ATL Prevention Program Nagasaki, was commenced in July 1987. It revealed a marked reduction of HTLV-1 MTCT by complete bottle-feeding from 20.3% to 2.5%, and a significantly higher risk of short-term breast-feeding (<6 months) than bottle-feeding (7.4% vs. 2.5%, P < 0.001). PMID:21558754

  16. Programmed Cell Death Progresses Differentially in Epidermal and Mesophyll Cells of Lily Petals

    PubMed Central

    Mochizuki-Kawai, Hiroko; Niki, Tomoko; Shibuya, Kenichi; Ichimura, Kazuo

    2015-01-01

    In the petals of some species of flowers, programmed cell death (PCD) begins earlier in mesophyll cells than in epidermal cells. However, PCD progression in each cell type has not been characterized in detail. We separately constructed a time course of biochemical signs and expression patterns of PCD-associated genes in epidermal and mesophyll cells in Lilium cv. Yelloween petals. Before visible signs of senescence could be observed, we found signs of PCD, including DNA degradation and decreased protein content in mesophyll cells only. In these cells, the total proteinase activity increased on the day after anthesis. Within 3 days after anthesis, the protein content decreased by 61.8%, and 22.8% of mesophyll cells was lost. A second peak of proteinase activity was observed on day 6, and the number of mesophyll cells decreased again from days 4 to 7. These biochemical and morphological results suggest that PCD progressed in steps during flower life in the mesophyll cells. PCD began in epidermal cells on day 5, in temporal synchrony with the time course of visible senescence. In the mesophyll cells, the KDEL-tailed cysteine proteinase (LoCYP) and S1/P1 nuclease (LoNUC) genes were upregulated before petal wilting, earlier than in epidermal cells. In contrast, relative to that in the mesophyll cells, the expression of the SAG12 cysteine proteinase homolog (LoSAG12) drastically increased in epidermal cells in the final stage of senescence. These results suggest that multiple PCD-associated genes differentially contribute to the time lag of PCD progression between epidermal and mesophyll cells of lily petals. PMID:26605547

  17. Programmed cell death activated by Rose Bengal in Arabidopsis thaliana cell suspension cultures requires functional chloroplasts

    PubMed Central

    Gutiérrez, Jorge; González-Pérez, Sergio; García-García, Francisco; Daly, Cara T.; Lorenzo, Óscar; Revuelta, José L.; McCabe, Paul F.; Arellano, Juan B.

    2014-01-01

    Light-grown Arabidopsis thaliana cell suspension culture (ACSC) were subjected to mild photooxidative damage with Rose Bengal (RB) with the aim of gaining a better understanding of singlet oxygen-mediated defence responses in plants. Additionally, ACSC were treated with H2O2 at concentrations that induced comparable levels of protein oxidation damage. Under low to medium light conditions, both RB and H2O2 treatments activated transcriptional defence responses and inhibited photosynthetic activity, but they differed in that programmed cell death (PCD) was only observed in cells treated with RB. When dark-grown ACSC were subjected to RB in the light, PCD was suppressed, indicating that the singlet oxygen-mediated signalling pathway in ACSC requires functional chloroplasts. Analysis of up-regulated transcripts in light-grown ACSC, treated with RB in the light, showed that both singlet oxygen-responsive transcripts and transcripts with a key role in hormone-activated PCD (i.e. ethylene and jasmonic acid) were present. A co-regulation analysis proved that ACSC treated with RB exhibited higher correlation with the conditional fluorescence (flu) mutant than with other singlet oxygen-producing mutants or wild-type plants subjected to high light. However, there was no evidence for the up-regulation of EDS1, suggesting that activation of PCD was not associated with the EXECUTER- and EDS1-dependent signalling pathway described in the flu mutant. Indigo Carmine and Methylene Violet, two photosensitizers unable to enter chloroplasts, did not activate transcriptional defence responses in ACSC; however, whether this was due to their location or to their inherently low singlet oxygen quantum efficiencies was not determined. PMID:24723397

  18. Salicylic acid induced cysteine protease activity during programmed cell death in tomato plants.

    PubMed

    Kovács, Judit; Poór, Péter; Szepesi, Ágnes; Tari, Irma

    2016-06-01

    The hypersensitive response (HR), a type of programmed cell death (PCD) during biotic stress is mediated by salicylic acid (SA). The aim of this work was to reveal the role of proteolysis and cysteine proteases in the execution of PCD in response of SA. Tomato plants were treated with sublethal (0.1 mM) and lethal (1 mM) SA concentrations through the root system. Treatment with 1 mM SA increased the electrolyte leakage and proteolytic activity and reduced the total protein content of roots after 6 h, while the proteolytic activity did not change in the leaves and in plants exposed to 0.1 mM SA. The expression of the papain-type cysteine protease SlCYP1, the vacuolar processing enzyme SlVPE1 and the tomato metacaspase SlMCA1 was induced within the first three hours in the leaves and after 0.5 h in the roots in the presence of 1 mM SA but the transcript levels did not increase significantly at sublethal SA. The Bax inhibitor-1 (SlBI-1), an antiapoptotic gene was over-expressed in the roots after SA treatments and it proved to be transient in the presence of sublethal SA. Protease inhibitors, SlPI2 and SlLTC were upregulated in the roots by sublethal SA but their expression remained low at 1 mM SA concentration. It is concluded that in contrast to leaves the SA-induced PCD is associated with increased proteolytic activity in the root tissues resulting from a fast up-regulation of specific cysteine proteases and down-regulation of protease inhibitors. PMID:27165526

  19. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality.

    PubMed

    Saha, Asim; O'Connor, Roddy S; Thangavelu, Govindarajan; Lovitch, Scott B; Dandamudi, Durga Bhavani; Wilson, Caleph B; Vincent, Benjamin G; Tkachev, Victor; Pawlicki, Jan M; Furlan, Scott N; Kean, Leslie S; Aoyama, Kazutoshi; Taylor, Patricia A; Panoskaltsis-Mortari, Angela; Foncea, Rocio; Ranganathan, Parvathi; Devine, Steven M; Burrill, Joel S; Guo, Lili; Sacristan, Catarina; Snyder, Nathaniel W; Blair, Ian A; Milone, Michael C; Dustin, Michael L; Riley, James L; Bernlohr, David A; Murphy, William J; Fife, Brian T; Munn, David H; Miller, Jeffrey S; Serody, Jonathan S; Freeman, Gordon J; Sharpe, Arlene H; Turka, Laurence A; Blazar, Bruce R

    2016-07-01

    Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

  20. Programmed cell death in the larval salivary glands of Apis mellifera (Hymenoptera, Apidae).

    PubMed

    Silva-Zacarin, E C M; Tomaino, G A; Brocheto-Braga, M R; Taboga, S R; De Moraes, R L M Silva

    2007-03-01

    The morphological and histochemical features of degeneration in honeybee (Apis mellifera) salivary glands were investigated in 5th instar larvae and in the pre-pupal period. The distribution and activity patterns of acid phosphatase enzyme were also analysed. As a routine,the larval salivary glands were fixed and processed for light microscopy and transmission electron microscopy.Tissue sections were subsequently stained with haematoxylin -eosin,bromophenol blue,silver,or a variant of the critical electrolyte concentration (CEC) method.Ultrathin sections were contrasted with uranyl acetate and lead citrate.Glands were processed for the histochemical and cytochemical localization of acid phosphatase,as well as biochemical assay to detect its activity pattern. Acid phosphatase activity was histochemically detected in all the salivary glands analysed.The cytochemical results showed acid phosphatase in vesicles, Golgi apparatus and lysosomes during the secretory phase and,additionally, in autophagic structures and luminal secretion during the degenerative phase. These findings were in agreement with the biochemical assay. At the end of the 5th instar, the glandular cells had a vacuolated cytoplasm and pyknotic nuclei, and epithelial cells were shed into the glandular lumen.The transition phase from the 5th instar to the pre-pupal period was characterized by intense vacuolation of the basal cytoplasm and release of parts of the cytoplasm into the lumen by apical blebbing; these blebs contained cytoplasmic RNA, rough endoplasmic reticule and, occasionally, nuclear material. In the pre-pupal phase, the glandular epithelium showed progressive degeneration so that at the end of this phase only nuclei and remnants of the cytoplasm were observed.The nuclei were pyknotic,with peripheral chromatin and blebs. The gland remained in the haemolymph and was recycled during metamorphosis. The programmed cell death in this gland represented a morphological form intermediate between

  1. Programmed cell death (PCD): an essential process of cereal seed development and germination

    PubMed Central

    Domínguez, Fernando; Cejudo, Francisco J.

    2014-01-01

    The life cycle of cereal seeds can be divided into two phases, development and germination, separated by a quiescent period. Seed development and germination require the growth and differentiation of new tissues, but also the ordered disappearance of cells, which takes place by a process of programmed cell death (PCD). For this reason, cereal seeds have become excellent model systems for the study of developmental PCD in plants. At early stages of seed development, maternal tissues such as the nucellus, the pericarp, and the nucellar projections undergo a progressive degeneration by PCD, which allows the remobilization of their cellular contents for nourishing new filial tissues such as the embryo and the endosperm. At a later stage, during seed maturation, the endosperm undergoes PCD, but these cells remain intact in the mature grain and their contents will not be remobilized until germination. Thus, the only tissues that remain alive when seed development is completed are the embryo axis, the scutellum and the aleurone layer. In germinating seeds, both the scutellum and the aleurone layer play essential roles in producing the hydrolytic enzymes for the mobilization of the storage compounds of the starchy endosperm, which serve to support early seedling growth. Once this function is completed, scutellum and aleurone cells undergo PCD; their contents being used to support the growth of the germinated embryo. PCD occurs with tightly controlled spatial-temporal patterns allowing coordinated fluxes of nutrients between the different seed tissues. In this review, we will summarize the current knowledge of the tissues undergoing PCD in developing and germinating cereal seeds, focussing on the biochemical features of the process. The effect of hormones and redox regulation on PCD control will be discussed. PMID:25120551

  2. Programmed cell death (PCD): an essential process of cereal seed development and germination.

    PubMed

    Domínguez, Fernando; Cejudo, Francisco J

    2014-01-01

    The life cycle of cereal seeds can be divided into two phases, development and germination, separated by a quiescent period. Seed development and germination require the growth and differentiation of new tissues, but also the ordered disappearance of cells, which takes place by a process of programmed cell death (PCD). For this reason, cereal seeds have become excellent model systems for the study of developmental PCD in plants. At early stages of seed development, maternal tissues such as the nucellus, the pericarp, and the nucellar projections undergo a progressive degeneration by PCD, which allows the remobilization of their cellular contents for nourishing new filial tissues such as the embryo and the endosperm. At a later stage, during seed maturation, the endosperm undergoes PCD, but these cells remain intact in the mature grain and their contents will not be remobilized until germination. Thus, the only tissues that remain alive when seed development is completed are the embryo axis, the scutellum and the aleurone layer. In germinating seeds, both the scutellum and the aleurone layer play essential roles in producing the hydrolytic enzymes for the mobilization of the storage compounds of the starchy endosperm, which serve to support early seedling growth. Once this function is completed, scutellum and aleurone cells undergo PCD; their contents being used to support the growth of the germinated embryo. PCD occurs with tightly controlled spatial-temporal patterns allowing coordinated fluxes of nutrients between the different seed tissues. In this review, we will summarize the current knowledge of the tissues undergoing PCD in developing and germinating cereal seeds, focussing on the biochemical features of the process. The effect of hormones and redox regulation on PCD control will be discussed.

  3. Programmed cell death activated by Rose Bengal in Arabidopsis thaliana cell suspension cultures requires functional chloroplasts.

    PubMed

    Gutiérrez, Jorge; González-Pérez, Sergio; García-García, Francisco; Daly, Cara T; Lorenzo, Oscar; Revuelta, José L; McCabe, Paul F; Arellano, Juan B

    2014-07-01

    Light-grown Arabidopsis thaliana cell suspension culture (ACSC) were subjected to mild photooxidative damage with Rose Bengal (RB) with the aim of gaining a better understanding of singlet oxygen-mediated defence responses in plants. Additionally, ACSC were treated with H2O2 at concentrations that induced comparable levels of protein oxidation damage. Under low to medium light conditions, both RB and H2O2 treatments activated transcriptional defence responses and inhibited photosynthetic activity, but they differed in that programmed cell death (PCD) was only observed in cells treated with RB. When dark-grown ACSC were subjected to RB in the light, PCD was suppressed, indicating that the singlet oxygen-mediated signalling pathway in ACSC requires functional chloroplasts. Analysis of up-regulated transcripts in light-grown ACSC, treated with RB in the light, showed that both singlet oxygen-responsive transcripts and transcripts with a key role in hormone-activated PCD (i.e. ethylene and jasmonic acid) were present. A co-regulation analysis proved that ACSC treated with RB exhibited higher correlation with the conditional fluorescence (flu) mutant than with other singlet oxygen-producing mutants or wild-type plants subjected to high light. However, there was no evidence for the up-regulation of EDS1, suggesting that activation of PCD was not associated with the EXECUTER- and EDS1-dependent signalling pathway described in the flu mutant. Indigo Carmine and Methylene Violet, two photosensitizers unable to enter chloroplasts, did not activate transcriptional defence responses in ACSC; however, whether this was due to their location or to their inherently low singlet oxygen quantum efficiencies was not determined.

  4. Molecular cloning, expression and characterization of programmed cell death 10 from sheep (Ovis aries).

    PubMed

    Yang, Yong-Jie; Liu, Zeng-Shan; Lu, Shi-Ying; Li, Chuang; Hu, Pan; Li, Yan-Song; Liu, Nan-Nan; Tang, Feng; Xu, Yun-Ming; Zhang, Jun-Hui; Li, Zhao-Hui; Feng, Xiao-Li; Zhou, Yu; Ren, Hong-Lin

    2015-03-01

    Programmed cell death 10 (PDCD10) is a highly conserved adaptor protein. Its mutations result in cerebral cavernous malformations (CCMs). In this study, PDCD10 cDNA from the buffy coat of Small Tail Han sheep (Ovis aries) was cloned from a suppression subtractive hybridization cDNA library, named OaPDCD10. The full-length cDNA of OaPDCD10 was 1343bp with a 639bp open reading frame (ORF) encoding 212 amino acid residues. Tissue distribution of OaPDCD10 mRNA determined that it was ubiquitously expressed in all tested tissue samples, and the highest expression was observed in the heart. The differential expression of OaPDCD10 between infected sheep (challenged with Brucella melitensis) and vaccinated sheep (vaccinated with Brucella suis S2) was also investigated. The results revealed that, compared to the control group, the expression of OaPDCD10 from infected and vaccinated sheep was both significantly up-regulated (p<0.05). Moreover, the expression levels of OaPDCD10 from the vaccinated sheep were significantly higher than the infected sheep (p<0.05) after 30days post-inoculation. The recombinant OaPDCD10 (rOaPDCD10) protein was expressed in Escherichia coli BL21 (DE3), and then purified by affinity chromatography. The rOaPDCD10 protein was demonstrated to induce apoptosis and promote cell proliferation. Our studies are intended to discover potential diagnostic biomarkers of brucellosis to discern infected sheep from vaccinated sheep, and OaPDCD10 could be considered as a potential diagnostic biomarker of brucellosis.

  5. Haem oxygenase delays programmed cell death in wheat aleurone layers by modulation of hydrogen peroxide metabolism.

    PubMed

    Wu, Mingzhu; Huang, Jingjing; Xu, Sheng; Ling, Tengfang; Xie, Yanjie; Shen, Wenbiao

    2011-01-01

    Haem oxygenase-1 (HO-1) confers protection against a variety of oxidant-induced cell and tissue injury in animals and plants. In this report, it is confirmed that programmed cell death (PCD) in wheat aleurone layers is stimulated by GA and prevented by ABA. Meanwhile, HO activity and HO-1 protein expression exhibited lower levels in GA-treated layers, whereas the hydrogen peroxide (H(2)O(2)) content was apparently increased. The pharmacology approach illustrated that scavenging or accumulating H(2)O(2) either delayed or accelerated GA-induced PCD. Furthermore, pretreatment with the HO-1 specific inhibitor, zinc protoporphyrin IX (ZnPPIX), before exposure to GA, not only decreased HO activity but also accelerated GA-induced PCD significantly. The application of the HO-1 inducer, haematin, and the enzymatic reaction product of HO, carbon monoxide (CO) aqueous solution, both of which brought about a noticeable induction of HO expression, substantially prevented GA-induced PCD. These effects were reversed when ZnPPIX was added, suggesting that HO in vivo played a role in delaying PCD. Meanwhile, catalase (CAT) and ascorbate peroxidase (APX) activities or transcripts were enhanced by haematin, CO, or bilirubin (BR), the catalytic by-product of HO. This enhancement resulted in a decrease in H(2)O(2) production and a delay in PCD. In addition, the antioxidants butylated hydroxytoluene (BHT), dithiothreitol (DTT), and ascorbic acid (AsA) were able not only to delay PCD but also to mimic the effects of haematin and CO on HO up-regulation. Overall, the above results suggested that up-regulation of HO expression delays PCD through the down-regulation of H(2)O(2) production.

  6. Photoacoustic spectral analysis to sense programmed erythrocyte cell death (eryptosis) for monitoring cancer response to treatment

    NASA Astrophysics Data System (ADS)

    Fadhel, Muhannad N.; Kibria, Fayruz; Kolios, Michael C.

    2016-03-01

    Many types of cancer therapies target the tumor microenvironment, causing biochemical and morphological changes in tissues. In therapies using ultrasound activated microbubbles, vascular collapse is typically reported. Red blood cells (RBCs) that leak out of the vasculature become exposed to the ceramide that is released from damaged endothelial cells. Ceramide can induce programmed cell death in RBCs (eryptosis), and is characterized by cell shrinkage, membrane blebbing and scrambling. Since the effect of eryptotic cells on generated photoacoustics (PA) signals has not been reported, we investigated the potential PA may have for cancer treatment monitoring by using PA spectral analysis to sense eryptosis. To induce eryptosis, C2-ceramide was added to RBC suspensions and that were incubated for 24 hours at 37°C. A control and ceramide-induced sample was imaged in a vessel phantom using a high frequency PA system (VevoLAZR, 10 - 45 MHz bandwidth) irradiated with multiple wavelengths ranging from 680 to 900 nm. PA spectral parameters were measured and linked to changes in RBCs as it underwent eryptosis. These samples were examined using optical microscopy, a blood gas analyzer and an integrating sphere setup to measure optical properties (wavelengths 600 - 900 nm). The results of the experiment demonstrate how PA spectral analysis can be used to identify eryptosis at a depth of more than 1 cm into the phantom using ultrasound derived the y-intercept and mid bandfit (MBF) parameters at optical wavelengths of 800 - 900 nm. These parameters were correlated to the morphological and biochemical changes that eryptotic RBCs display. The results establish the potential of PA in cancer treatment monitoring through sensing treatment induced eryptosis.

  7. Programmed cell death promotes male sterility in the functional dioecious Opuntia stenopetala (Cactaceae)

    PubMed Central

    Flores-Rentería, Lluvia; Orozco-Arroyo, Gregorio; Cruz-García, Felipe; García-Campusano, Florencia; Alfaro, Isabel; Vázquez-Santana, Sonia

    2013-01-01

    Background and Aims The sexual separation in dioecious species has interested biologists for decades; however, the cellular mechanism leading to unisexuality has been poorly understood. In this study, the cellular changes that lead to male sterility in the functionally dioecious cactus, Opuntia stenopetala, are described. Methods The spatial and temporal patterns of programmed cell death (PCD) were determined in the anthers of male and female flowers using scanning electron microscopy analysis and histological observations, focusing attention on the transition from bisexual to unisexual development. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assays were used as an indicator of DNA fragmentation to corroborate PCD. Key results PCD was detected in anthers of both female and male flowers, but their patterns differed in time and space. Functionally male individuals developed viable pollen, and normal development involved PCD on each layer of the anther wall, which occurred progressively from the inner (tapetum) to the outer layer (epidermis). Conversely, functional female individuals aborted anthers by premature and displaced PCD. In anthers of female flowers, the first signs of PCD, such as a nucleus with irregular shape, fragmented and condensed chromatin, high vacuolization and condensed cytoplasm, occurred at the microspore mother cell stage. Later these features were observed simultaneously in all anther wall layers, connective tissue and filament. Neither pollen formation nor anther dehiscence was detected in female flowers of O. stenopetala due to total anther disruption. Conclusions Temporal and spatial changes in the patterns of PCD are responsible for male sterility of female flowers in O. stenopetala. Male fertility requires the co-ordination of different events, which, when altered, can lead to male sterility and to functionally unisexual individuals. PCD could be a widespread mechanism in the determination of

  8. Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay.

    PubMed

    Ni, Yan G; Yuan, Xiling; Newitt, John A; Peterson, Jon E; Gleason, Carol R; Haulenbeek, Jonathan; Santockyte, Rasa; Lafont, Virginie; Marsilio, Frank; Neely, Robert J; DeSilva, Binodh; Piccoli, Steven P

    2015-07-01

    Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra- and inter-assay imprecision were ≤15%, and the assay bias (percent deviation) was ≤10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD-1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL-2, do not interfere with the assay.

  9. Immunological effects of the anti-programmed death-1 antibody on human peripheral blood mononuclear cells.

    PubMed

    Akiyama, Yasuto; Nonomura, Chizu; Kondou, Ryota; Miyata, Haruo; Ashizawa, Tadashi; Maeda, Chie; Mitsuya, Koichi; Hayashi, Nakamasa; Nakasu, Yoko; Yamaguchi, Ken

    2016-09-01

    Immune checkpoint antibody-mediated blockade has gained attention as a new cancer immunotherapy strategy. Accumulating evidence suggests that this therapy imparts a survival benefit to metastatic melanoma and non-small cell lung cancer patients. A substantial amount of data on immune checkpoint antibodies has been collected from clinical trials; however, the direct effect of the antibodies on human peripheral blood mononuclear cells (PBMCs) has not been exclusively investigated. In this study, we developed an anti-programmed death-1 (PD-1) antibody (with biosimilarity to nivolumab) and examined the effects of the antibody on PBMCs derived from cancer patients. Specifically, we investigated the effects of the anti-PD-1 antibody on proliferation, cytokine production, cytotoxic T lymphocytes (CTL) and regulatory T cells. These investigations yielded several important results. First, the anti-PD-1 antibody had no obvious effect on resting PBMCs; however, high levels of the anti-PD-1 antibody partly stimulated PBMC proliferation when accompanied by an anti-CD3 antibody. Second, the anti-PD-1 antibody restored the growth inhibition of anti-CD3 Ab-stimulated PBMCs mediated by PD-L1. Third, the anti-PD-1 antibody exhibited a moderate inhibitory effect on the induction of myeloid-derived suppressor cells (MDSCs) by anti-CD3 antibody stimulation. Additionally, the presence of the anti-PD-1 antibody promoted antigen-specific CTL induction, which suggests that combining anti-PD-1 antibody and conventional immunotherapy treatments may have beneficial effects. These results indicate that specific cellular immunological mechanisms are partly responsible for the antitumor effect exhibited by the anti-PD-1 antibody against advanced cancers in clinical trials. PMID:27573705

  10. Overexpression of Arabidopsis Ceramide Synthases Differentially Affects Growth, Sphingolipid Metabolism, Programmed Cell Death, and Mycotoxin Resistance.

    PubMed

    Luttgeharm, Kyle D; Chen, Ming; Mehra, Amit; Cahoon, Rebecca E; Markham, Jonathan E; Cahoon, Edgar B

    2015-10-01

    Ceramide synthases catalyze an N-acyltransferase reaction using fatty acyl-coenzyme A (CoA) and long-chain base (LCB) substrates to form the sphingolipid ceramide backbone and are targets for inhibition by the mycotoxin fumonisin B1 (FB1). Arabidopsis (Arabidopsis thaliana) contains three genes encoding ceramide synthases with distinct substrate specificities: LONGEVITY ASSURANCE GENE ONE HOMOLOG1 (LOH1; At3g25540)- and LOH3 (At1g19260)-encoded ceramide synthases use very-long-chain fatty acyl-CoA and trihydroxy LCB substrates, and LOH2 (At3g19260)-encoded ceramide synthase uses palmitoyl-CoA and dihydroxy LCB substrates. In this study, complementary DNAs for each gene were overexpressed to determine the role of individual isoforms in physiology and sphingolipid metabolism. Differences were observed in growth resulting from LOH1 and LOH3 overexpression compared with LOH2 overexpression. LOH1- and LOH3-overexpressing plants had enhanced biomass relative to wild-type plants, due in part to increased cell division, suggesting that enhanced synthesis of very-long-chain fatty acid/trihydroxy LCB ceramides promotes cell division and growth. Conversely, LOH2 overexpression resulted in dwarfing. LOH2 overexpression also resulted in the accumulation of sphingolipids with C16 fatty acid/dihydroxy LCB ceramides, constitutive induction of programmed cell death, and accumulation of salicylic acid, closely mimicking phenotypes observed previously in LCB C-4 hydroxylase mutants defective in trihydroxy LCB synthesis. In addition, LOH2- and LOH3-overexpressing plants acquired increased resistance to FB1, whereas LOH1-overexpressing plants showed no increase in FB1 resistance, compared with wild-type plants, indicating that LOH1 ceramide synthase is most strongly inhibited by FB1. Overall, the findings described here demonstrate that overexpression of Arabidopsis ceramide synthases results in strongly divergent physiological and metabolic phenotypes, some of which have significance

  11. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

    PubMed Central

    O’Connor, Roddy S.; Thangavelu, Govindarajan; Lovitch, Scott B.; Dandamudi, Durga Bhavani; Vincent, Benjamin G.; Tkachev, Victor; Pawlicki, Jan M.; Furlan, Scott N.; Kean, Leslie S.; Aoyama, Kazutoshi; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Foncea, Rocio; Ranganathan, Parvathi; Devine, Steven M.; Burrill, Joel S.; Guo, Lili; Sacristan, Catarina; Snyder, Nathaniel W.; Blair, Ian A.; Milone, Michael C.; Dustin, Michael L.; Riley, James L.; Bernlohr, David A.; Murphy, William J.; Fife, Brian T.; Munn, David H.; Miller, Jeffrey S.; Serody, Jonathan S.; Freeman, Gordon J.; Sharpe, Arlene H.; Turka, Laurence A.

    2016-01-01

    Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD. PMID:27294527

  12. Ricinosomes: an organelle for developmentally regulated programmed cell death in senescing plant tissues

    NASA Astrophysics Data System (ADS)

    Gietl, C.; Schmid, M.

    2001-02-01

    This review describes aspects of programmed cell death (PCD). Present research maps the enzymes involved and explores the signal transduction pathways involved in their synthesis. A special organelle (the ricinosome) has been discovered in the senescing endosperm of germinating castor beans (Ricinus communis) that develops at the beginning of PCD and delivers large amounts of a papain-type cysteine endopeptidase (CysEP) in the final stages of cellular disintegration. Castor beans store oil and proteins in a living endosperm surrounding the cotyledons. These stores are mobilized during germination and transferred into the cotyledons. PCD is initiated after this transfer is complete. The CysEP is synthesized in the lumen of the endoplasmic reticulum (ER) where it is retained by its C-terminal KDEL peptide as a rather inactive pro-enzyme. Large number of ricinosomes bud from the ER at the same time as the nuclear DNA is characteristically fragmented during PCD. The mitochondria, glyoxysomes and ribosomes are degraded in autophagic vacuoles, while the endopeptidase is activated by removal of the propeptide and the KDEL tail and enters the cytosol. The endosperm dries and detaches from the cotyledons. A homologous KDEL-tailed cysteine endopeptidase has been found in several senescing tissues; it has been localized in ricinosomes of withering day-lily petals and dying seed coats. Three genes for a KDEL-tailed cysteine endopeptidase have been identified in Arabidopsis. One is expressed in senescing ovules, the second in the vascular vessels and the third in maturing siliques. These genes open the way to exploring PCD in plants.

  13. Salicylic acid induced cysteine protease activity during programmed cell death in tomato plants.

    PubMed

    Kovács, Judit; Poór, Péter; Szepesi, Ágnes; Tari, Irma

    2016-06-01

    The hypersensitive response (HR), a type of programmed cell death (PCD) during biotic stress is mediated by salicylic acid (SA). The aim of this work was to reveal the role of proteolysis and cysteine proteases in the execution of PCD in response of SA. Tomato plants were treated with sublethal (0.1 mM) and lethal (1 mM) SA concentrations through the root system. Treatment with 1 mM SA increased the electrolyte leakage and proteolytic activity and reduced the total protein content of roots after 6 h, while the proteolytic activity did not change in the leaves and in plants exposed to 0.1 mM SA. The expression of the papain-type cysteine protease SlCYP1, the vacuolar processing enzyme SlVPE1 and the tomato metacaspase SlMCA1 was induced within the first three hours in the leaves and after 0.5 h in the roots in the presence of 1 mM SA but the transcript levels did not increase significantly at sublethal SA. The Bax inhibitor-1 (SlBI-1), an antiapoptotic gene was over-expressed in the roots after SA treatments and it proved to be transient in the presence of sublethal SA. Protease inhibitors, SlPI2 and SlLTC were upregulated in the roots by sublethal SA but their expression remained low at 1 mM SA concentration. It is concluded that in contrast to leaves the SA-induced PCD is associated with increased proteolytic activity in the root tissues resulting from a fast up-regulation of specific cysteine proteases and down-regulation of protease inhibitors.

  14. Programmed death ligand-1 expression and its prognostic role in esophageal squamous cell carcinoma

    PubMed Central

    Kim, Ryul; Keam, Bhumsuk; Kwon, Dohee; Ock, Chan-Young; Kim, Miso; Kim, Tae Min; Kim, Hak Jae; Jeon, Yoon Kyung; Park, In Kyu; Kang, Chang Hyun; Kim, Dong-Wan; Kim, Young Tae; Heo, Dae Seog

    2016-01-01

    AIM To investigate the expression and prognostic role of programmed death ligand-1 (PD-L1) in locally advanced esophageal squamous cell carcinoma (ESCC). METHODS A total of 200 patients with ESCC who underwent radical esophagectomy with standard lymphadenectomy as the initial definitive treatment in Seoul National University Hospital from December 2000 to April 2013 were eligible for this analysis. Tissue microarrays were constructed by collecting tissue cores from surgical specimens, and immunostained with antibodies directed against PD-L1, p16, and c-Met. Medical records were reviewed retrospectively to assess clinical outcomes. Patients were divided into two groups by PD-L1 status, and significant differences in clinicopathologic characteristics between the two groups were assessed. RESULTS Tumor tissues from 67 ESCC patients (33.5%) were PD-L1-positive. Positive p16 expression was observed in 21 specimens (10.5%). The H-score for c-Met expression was ≥ 50 in 42 specimens (21.0%). Although PD-L1-positivity was not significantly correlated with any clinical characteristics including age, sex, smoking/alcoholic history, stage, or differentiation, H-scores for c-Met expression were significantly associated with PD-L1-positivity (OR = 2.34, 95%CI: 1.16-4.72, P = 0.017). PD-L1 expression was not significantly associated with a change in overall survival (P = 0.656). In contrast, the locoregional relapse rate tended to increase (P = 0.134), and the distant metastasis rate was significantly increased (HR = 1.72, 95%CI: 1.01-2.79, P = 0.028) in patients with PD-L1-positive ESCC compared to those with PD-L1-negative ESCC. CONCLUSION PD-L1 expression is positively correlated with c-Met expression in ESCC. PD-L1 may play a critical role in distant failure and progression of ESCC. PMID:27729745

  15. Programmed cell death (PCD): an essential process of cereal seed development and germination.

    PubMed

    Domínguez, Fernando; Cejudo, Francisco J

    2014-01-01

    The life cycle of cereal seeds can be divided into two phases, development and germination, separated by a quiescent period. Seed development and germination require the growth and differentiation of new tissues, but also the ordered disappearance of cells, which takes place by a process of programmed cell death (PCD). For this reason, cereal seeds have become excellent model systems for the study of developmental PCD in plants. At early stages of seed development, maternal tissues such as the nucellus, the pericarp, and the nucellar projections undergo a progressive degeneration by PCD, which allows the remobilization of their cellular contents for nourishing new filial tissues such as the embryo and the endosperm. At a later stage, during seed maturation, the endosperm undergoes PCD, but these cells remain intact in the mature grain and their contents will not be remobilized until germination. Thus, the only tissues that remain alive when seed development is completed are the embryo axis, the scutellum and the aleurone layer. In germinating seeds, both the scutellum and the aleurone layer play essential roles in producing the hydrolytic enzymes for the mobilization of the storage compounds of the starchy endosperm, which serve to support early seedling growth. Once this function is completed, scutellum and aleurone cells undergo PCD; their contents being used to support the growth of the germinated embryo. PCD occurs with tightly controlled spatial-temporal patterns allowing coordinated fluxes of nutrients between the different seed tissues. In this review, we will summarize the current knowledge of the tissues undergoing PCD in developing and germinating cereal seeds, focussing on the biochemical features of the process. The effect of hormones and redox regulation on PCD control will be discussed. PMID:25120551

  16. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas.

    PubMed

    Chong, Lauren C; Twa, David D W; Mottok, Anja; Ben-Neriah, Susana; Woolcock, Bruce W; Zhao, Yongjun; Savage, Kerry J; Marra, Marco A; Scott, David W; Gascoyne, Randy D; Morin, Ryan D; Mungall, Andrew J; Steidl, Christian

    2016-09-01

    Programmed death ligands (PDLs) are immune-regulatory molecules that are frequently affected by chromosomal alterations in B-cell lymphomas. Although PDL copy-number variations are well characterized, a detailed and comprehensive analysis of structural rearrangements (SRs) and associated phenotypic consequences is largely lacking. Here, we used oligonucleotide capture sequencing of 67 formalin-fixed paraffin-embedded tissues derived from primary B-cell lymphomas and 1 cell line to detect and characterize, at base-pair resolution, SRs of the PDL locus (9p24.1; harboring PDL1/CD274 and PDL2/PDCD1LG2). We describe 36 novel PDL SRs, including 17 intrachromosomal events (inversions, duplications, deletions) and 19 translocations involving BZRAP-AS1, CD44, GET4, IL4R, KIAA0226L, MID1, RCC1, PTPN1 and segments of the immunoglobulin loci. Moreover, analysis of the precise chromosomal breakpoints reveals 2 distinct cluster breakpoint regions (CBRs) within either CD274 (CBR1) or PDCD1LG2 (CBR2). To determine the phenotypic consequences of these SRs, we performed immunohistochemistry for CD274 and PDCD1LG2 on primary pretreatment biopsies and found that PDL SRs are significantly associated with PDL protein expression. Finally, stable ectopic expression of wild-type PDCD1LG2 and the PDCD1LG2-IGHV7-81 fusion showed, in coculture, significantly reduced T-cell activation. Taken together, our data demonstrate the complementary utility of fluorescence in situ hybridization and capture sequencing approaches and provide a classification scheme for PDL SRs with implications for future studies using PDL immune-checkpoint inhibitors in B-cell lymphomas.

  17. Puberty and type 1 diabetes

    PubMed Central

    Chowdhury, Subhankar

    2015-01-01

    Various data on type 1 diabetes mellitus (T1DM) have showed that the incidence of T1DM peaks at puberty. However, diabetes control and complications could be adversely affected by the physiological changes of puberty. In early years of insulin therapy, severe growth retardation with pubertal delay, like in Mauriac syndrome, have been reported. Insulin and leptin are metabolic factors, circulating in the periphery, which participate in the hypothalamic control of metabolism and reproduction. Insulin may be an important regulator of leptin in humans. Increased levels of advanced glycation end products suppress activation of the gonadotropin-releasing hormone (GnRH) pulse generator, resulting in pubertal delay. Glycemic control deteriorates during puberty as the lean body mass doubles mainly over a period of 25 years, which increases insulin requirement. There is also an increase in insulin resistance over the period of puberty. In normal individuals, fasting and postprandial insulin concentrations reach a peak in both sexes in mid to late puberty. Puberty, at all stages, has the worst insulin resistance. It has been observed that an excessive GH secretion in T1DM during puberty has significant effects on ketogenesis. Adolescent T1DM tends to decompensate very rapidly and develop ketoacidosis when the late night insulin dose is omitted. Adolescence is a critical developmental phase that presents unique challenges and opportunities to individuals with diabetes, their families and their healthcare providers. PMID:25941652

  18. Type 1 diabetes associated autoimmunity.

    PubMed

    Kahaly, George J; Hansen, Martin P

    2016-07-01

    Diabetes mellitus is increasing in prevalence worldwide. The economic costs are considerable given the cardiovascular complications and co-morbidities that it may entail. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. Genetic background may affect the risk for autoimmune disease and patients with T1D exhibit an increased risk of other autoimmune disorders such as autoimmune thyroid disease, Addison's disease, autoimmune gastritis, coeliac disease and vitiligo. Approximately 20%-25% of patients with T1D have thyroid antibodies, and up to 50% of such patients progress to clinical autoimmune thyroid disease. Approximately 0.5% of diabetic patients have concomitant Addison's disease and 4% have coeliac disease. The prevalence of autoimmune gastritis and pernicious anemia is 5% to 10% and 2.6% to 4%, respectively. Early detection of antibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown disease. Patients and family members should be educated to be able to recognize signs and symptoms of underlying disease.

  19. Coordinated Activation of Programmed Cell Death and Defense Mechanisms in Transgenic Tobacco Plants Expressing a Bacterial Proton Pump.

    PubMed Central

    Mittler, R.; Shulaev, V.; Lam, E.

    1995-01-01

    In plants, programmed cell death is thought to be activated during the hypersensitive response to certain avirulent pathogens and in the course of several differentiation processes. We describe a transgenic model system that mimics the activation of programmed cell death in higher plants. In this system, expression of a bacterial proton pump in transgenic tobacco plants activates a cell death pathway that may be similar to that triggered by recognition of an incompatible pathogen. Thus, spontaneous lesions that resemble hypersensitive response lesions are formed, multiple defense mechanisms are apparently activated, and systemic resistance is induced in the absence of a pathogen. Interestingly, mutation of a single amino acid in the putative channel of this proton pump renders it inactive with respect to lesion formation and induction of resistance to pathogen challenge. This transgenic model system may provide insights into the mechanisms involved in mediating cell death in higher plants. In addition, it may also be used as a general agronomic tool to enhance disease protection. PMID:12242350

  20. A Monoclonal Antibody Specific for the Programmed Death-1 Homolog Prevents Graft Versus Host Disease in Mouse Models1

    PubMed Central

    Flies, Dallas B; Wang, Shengdian; Xu, Haiying; Chen, Lieping

    2011-01-01

    Upon interaction with B7 homolog 1, Programmed Death-1 transmits a critical co-inhibitory signal to T cells to negatively regulate immune responses. By extensively searching the genomic database with the immunoglobulin variable region of PD-1, we identified a homolog and named it Programmed Death-1 homolog (PD-1H). PD-1H is broadly expressed on the cell surface of hematopoietic cells, and could be further upregulated on CD4+ and CD8+ T cells following activation. We have generated a monoclonal antibody against PD-1H, which strikingly prevents acute graft versus host disease (GVHD) in semi- and fully-allogeneic murine models, leading to full chimerism following treatment. GVHD remains a primary hindrance to successful allogeneic hematopoietic cell transplantation therapy for the treatment of hematologic malignancy. Therefore, manipulation of PD-1H function may provide a new modality for controlling T cell responses to allogeneic tissues in transplant medicine. PMID:21768399

  1. Vibrio cholerae Porin OmpU Induces Caspase-independent Programmed Cell Death upon Translocation to the Host Cell Mitochondria.

    PubMed

    Gupta, Shelly; Prasad, G V R Krishna; Mukhopadhaya, Arunika

    2015-12-25

    Porins, a major class of outer membrane proteins in Gram-negative bacteria, primarily act as transport channels. OmpU is one of the major porins of human pathogen, Vibrio cholerae. In the present study, we show that V. cholerae OmpU has the ability to induce target cell death. Although OmpU-mediated cell death shows some characteristics of apoptosis, such as flipping of phosphatidylserine in the membrane as well as cell size shrinkage and increased cell granularity, it does not show the caspase-3 activation and DNA laddering pattern typical of apoptotic cells. Increased release of lactate dehydrogenase in OmpU-treated cells indicates that the OmpU-mediated cell death also has characteristics of necrosis. Further, we show that the mechanism of OmpU-mediated cell death involves major mitochondrial changes in the target cells. We observe that OmpU treatment leads to the disruption of mitochondrial membrane potential, resulting in the release of cytochrome c and apoptosis-inducing factor (AIF). AIF translocates to the host cell nucleus, implying that it has a crucial role in OmpU-mediated cell death. Finally, we observe that OmpU translocates to the target cell mitochondria, where it directly initiates mitochondrial changes leading to mitochondrial membrane permeability transition and AIF release. Partial blocking of AIF release by cyclosporine A in OmpU-treated cells further suggests that OmpU may be inducing the opening of the mitochondrial permeability transition pore. All of these results lead us to the conclusion that OmpU induces cell death in target cells in a programmed manner in which mitochondria play a central role.

  2. Increased programmed death ligand-1 expression predicts poor prognosis in hepatocellular carcinoma patients

    PubMed Central

    Gu, Xiaobin; Gao, Xian-Shu; Xiong, Wei; Guo, Wei; Han, Linjun; Bai, Yun; Peng, Chuan; Cui, Ming; Xie, Mu

    2016-01-01

    Purpose Accumulating studies have investigated the prognostic and clinical significance of programmed death ligand-1 (PD-L1) expression in patients with hepatocellular carcinoma (HCC); however, the results were conflicting and inconclusive. We conducted a meta-analysis to combine controversial data to precisely evaluate this issue. Methods Relevant studies were thoroughly searched on PubMed, Web of Science, and Embase until April 2016. Eligible studies were evaluated by selection criteria. Hazard ratio (HR) with 95% confidence interval (CI) was used to estimate the prognostic role of PD-L1 for overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS). Odds ratio (OR) with 95% CI were selected to assess the relationship between PD-L1 and clinicopathological features of HCC patients. Publication bias was tested using Begg’s funnel plot. Results A total of seven studies published from 2009 to 2016 were included for meta-analysis. The data showed that high PD-L1 expression was correlated to shorter OS (HR =2.09, 95% CI: 1.66–2.64, P<0.001) as well as poor DFS/RFS (HR =2.3, 95% CI: 1.46–3.62, P<0.001). In addition, increased PD-L1 expression was also associated with tumor differentiation (HR =1.51, 95% CI: 1–2.29, P=0.05), vascular invasion (HR =2.16, 95% CI: 1.43–3.27, P<0.001), and α-fetoprotein (AFP; HR =1.46, 95% CI: 1–2.14, P=0.05), but had no association with tumor stage, tumor size, hepatitis history, sex, age, or tumor multiplicity. No publication bias was found for all analyses. Conclusion This meta-analysis revealed that overexpression of PD-L1 was predictive for shortened OS and DFS/RFS in HCC. Furthermore, increased PD-L1 expression was associated with less differentiation, vascular invasion, and AFP elevation. PMID:27536144

  3. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

    PubMed Central

    Berghoff, Anna Sophie; Kiesel, Barbara; Widhalm, Georg; Rajky, Orsolya; Ricken, Gerda; Wöhrer, Adelheid; Dieckmann, Karin; Filipits, Martin; Brandstetter, Anita; Weller, Michael; Kurscheid, Sebastian; Hegi, Monika E.; Zielinski, Christoph C.; Marosi, Christine; Hainfellner, Johannes A.; Preusser, Matthias; Wick, Wolfgang

    2015-01-01

    Background Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. Methods We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Results Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. Conclusion TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma. PMID:25355681

  4. Programmed cell death of the ovarian nurse cells during oogenesis of the ladybird beetle Adalia bipunctata (Coleoptera: Coccinellidae).

    PubMed

    Mpakou, Vassiliki E; Velentzas, Athanassios D; Velentzas, Panagiotis D; Margaritis, Lukas H; Stravopodis, Dimitrios J; Papassideri, Issidora S

    2011-08-01

    Programmed cell death (PCD) is an evolutionary conserved and genetically regulated form of cell death, in which the cell plays an active role in its own demise. It is widely recognized that PCD can be morphologically classified into three major types: type I, known as apoptosis, type II, called autophagy, and type III, specified as cytoplasmic cell death. So far, PCD has been morphologically analyzed in certain model insect species of the meroistic polytrophic ovary-type, but has never been examined before in insects carrying meroistic telotrophic ovaries. In the present study, we attempted to thoroughly describe the three different types (I, II and III) of PCD occurring during oogenesis in the meroistic telotrophic ovary of the Coleoptera species Adalia bipunctata, at different developmental ages of the adult female insects. We reveal that in the ladybird beetle A. bipunctata, the ovarian tropharia undergo age-dependent forms of apoptotic, autophagic and cytoplasmic (paraptotic-like) cell death, which seem to operate in a rather synergistic fashion, in accordance with previous observations in Diptera and Lepidoptera species. Furthermore, we herein demonstrate the occurrence of morphogenetically abnormal ovarioles in A. bipunctata female insects. These atretic ovarioles collapse and die through a PCD-mediated process that is characterized by the combined activation of all three types of PCD. Conclusively, the distinct cell death programs (I, II and III) specifically engaged during oogenesis of A. bipunctata provide strong evidence for the structural and functional conserved nature of PCD during insect evolution among meroistic telotrophic and meroistic polytrophic ovary-type insects.

  5. Gene trapping identifies transiently induced survival genes during programmed cell death

    PubMed Central

    Wempe, Frank; Yang, Ji-Yeon; Hammann, Joanna; Melchner, Harald von

    2001-01-01

    Background The existence of a constitutively expressed machinery for death in individual cells has led to the notion that survival factors repress this machinery and, if such factors are unavailable, cells die by default. In many cells, however, mRNA and protein synthesis inhibitors induce apoptosis, suggesting that in some cases transcriptional activity might actually impede cell death. To identify transcriptional mechanisms that interfere with cell death and survival, we combined gene trap mutagenesis with site-specific recombination (Cre/loxP system) to isolate genes from cells undergoing apoptosis by growth factor deprivation. Results From an integration library consisting of approximately 2 × 106 unique proviral integrations obtained by infecting the interleukin-3 (IL-3)-dependent hematopoietic cell line - FLOXIL3 - with U3Cre gene trap virus, we have isolated 125 individual clones that converted to factor independence upon IL-3 withdrawal. Of 102 cellular sequences adjacent to U3Cre integration sites, 17% belonged to known genes, 11% matched single expressed sequence tags (ESTs) or full cDNAs with unknown function and 72% had no match within the public databases. Most of the known genes recovered in this analysis encoded proteins with survival functions. Conclusions We have shown that hematopoietic cells undergoing apoptosis after withdrawal of IL-3 activate survival genes that impede cell death. This results in reduced apoptosis and improved survival of cells treated with a transient apoptotic stimulus. Thus, apoptosis in hematopoietic cells is the end result of a conflict between death and survival signals, rather than a simple death by default. PMID:11516336

  6. Blood-based signatures in type 1 diabetes.

    PubMed

    Cabrera, Susanne M; Chen, Yi-Guang; Hagopian, William A; Hessner, Martin J

    2016-03-01

    Type 1 diabetes mellitus is one of the most common chronic diseases in childhood. It develops through autoimmune destruction of the pancreatic beta cells and results in lifelong dependence on exogenous insulin. The pathogenesis of type 1 diabetes involves a complex interplay of genetic and environmental factors and has historically been attributed to aberrant adaptive immunity; however, there is increasing evidence for a role of innate inflammation. Over the past decade new methodologies for the analysis of nucleic acid and protein signals have been applied to type 1 diabetes. These studies are providing a new understanding of type 1 diabetes pathogenesis and have the potential to inform the development of new biomarkers for predicting diabetes onset and monitoring therapeutic interventions. In this review we will focus on blood-based signatures in type 1 diabetes, with special attention to both direct transcriptomic analyses of whole blood and immunocyte subsets, as well as plasma/serum-induced transcriptional signatures. Attention will also be given to proteomics, microRNA assays and markers of beta cell death. We will also discuss the results of blood-based profiling in type 1 diabetes within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes. PMID:26699650

  7. Blood-based signatures in type 1 diabetes.

    PubMed

    Cabrera, Susanne M; Chen, Yi-Guang; Hagopian, William A; Hessner, Martin J

    2016-03-01

    Type 1 diabetes mellitus is one of the most common chronic diseases in childhood. It develops through autoimmune destruction of the pancreatic beta cells and results in lifelong dependence on exogenous insulin. The pathogenesis of type 1 diabetes involves a complex interplay of genetic and environmental factors and has historically been attributed to aberrant adaptive immunity; however, there is increasing evidence for a role of innate inflammation. Over the past decade new methodologies for the analysis of nucleic acid and protein signals have been applied to type 1 diabetes. These studies are providing a new understanding of type 1 diabetes pathogenesis and have the potential to inform the development of new biomarkers for predicting diabetes onset and monitoring therapeutic interventions. In this review we will focus on blood-based signatures in type 1 diabetes, with special attention to both direct transcriptomic analyses of whole blood and immunocyte subsets, as well as plasma/serum-induced transcriptional signatures. Attention will also be given to proteomics, microRNA assays and markers of beta cell death. We will also discuss the results of blood-based profiling in type 1 diabetes within the context of the genetic and environmental factors implicated in the natural history of autoimmune diabetes.

  8. Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.

    PubMed

    Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Frey, Blake F; Billeskov, Rolf; Singer, Steven M; Berzofsky, Jay A; Eckmann, Lars; Kagnoff, Martin F

    2016-03-01

    The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.

  9. Type 1 Diabetes: What Is It?

    MedlinePlus

    ... Things to Know About Zika & Pregnancy Type 1 Diabetes: What Is It? KidsHealth > For Parents > Type 1 ... in learning to live with the disease. About Diabetes Diabetes is a disease that affects how the ...

  10. Autoimmune diseases associated with neurofibromatosis type 1.

    PubMed

    Nanda, Arti

    2008-01-01

    Associations of autoimmune diseases with neurofibromatosis type 1 have been rarely described. In the present report, we describe two patients of neurofibromatosis type 1 having an association with vitiligo in one, and alopecia areata and autoimmune thyroiditis in another. The associations of neurofibromatosis type 1 with vitiligo, alopecia areata, and autoimmune thyroiditis have not been reported earlier. Whether these associations reflect a causal relationship with neurofibromatosis type 1 or are coincidental needs to be settled.

  11. A Single-Amino-Acid Substitution in Obg Activates a New Programmed Cell Death Pathway in Escherichia coli

    PubMed Central

    Dewachter, Liselot; Verstraeten, Natalie; Monteyne, Daniel; Kint, Cyrielle Ines; Versées, Wim; Pérez-Morga, David; Fauvart, Maarten

    2015-01-01

    ABSTRACT Programmed cell death (PCD) is an important hallmark of multicellular organisms. Cells self-destruct through a regulated series of events for the benefit of the organism as a whole. The existence of PCD in bacteria has long been controversial due to the widely held belief that only multicellular organisms would profit from this kind of altruistic behavior at the cellular level. However, over the past decade, compelling experimental evidence has established the existence of such pathways in bacteria. Here, we report that expression of a mutant isoform of the essential GTPase ObgE causes rapid loss of viability in Escherichia coli. The physiological changes that occur upon expression of this mutant protein—including loss of membrane potential, chromosome condensation and fragmentation, exposure of phosphatidylserine on the cell surface, and membrane blebbing—point to a PCD mechanism. Importantly, key regulators and executioners of known bacterial PCD pathways were shown not to influence this cell death program. Collectively, our results suggest that the cell death pathway described in this work constitutes a new mode of bacterial PCD. PMID:26695632

  12. Can a single "powerless" mitochondrion in the malaria parasite contribute to parasite programmed cell death in the asexual stages?

    PubMed

    Ch'ng, Jun-Hong; Yeo, Su-Ping; Shyong-Wei Tan, Kevin

    2013-05-01

    The protozoan pathogens responsible for malaria are from the Plasmodium genus, with Plasmodium falciparum and Plasmodium vivax accounting for almost all clinical infections. With recent estimates of mortality exceeding 800,000 annually, malaria continues to take a terrible toll on lives and the early promises of medicine to eradicate the disease have yet to approach realization, in part due to the spread of drug resistant parasites. Recent reports of artemisinin-resistance have prompted renewed efforts to identify novel therapeutic options, and one such pathway being considered for antimalarial exploit is the parasite's programmed cell death (PCD) pathway. In this mini-review, we will discuss the roles of the plasmodium mitochondria in cell death and as a target of antimalarial compounds, taking into account recent data suggesting that PCD pathways involving the mitochondria may be attractive antimalarial targets.

  13. Induction of programmed cell death in aging Prorocentrum donghaiense cells as was evidenced preliminarily by the identification of associated transcripts.

    PubMed

    Zhang, Xiufang; Yang, G; Liu, Y; Yu, W; Pan, K; Li, Ruixiang; Zhu, M

    2006-12-01

    Prorocentrum donghaiense caused large-scale red tides off Chinese coast in recent years. Expressed sequence tag (EST) analysis was carried out for this dinoflagellate in order to identify the genes involved in its proliferation and death. A cDNA library was constructed for P. donghaiense at late exponential growth phase, and 308 groups of EST were generated, which include 36 contigs and 272 singletons. Among 22 groups showed homologies with known genes, 2 matched significantly with caspase and proliferating cell nuclear antigen. Caspase and proliferating cell nuclear antigen are 2 key proteins involved in programmed cell death. Their identification evidenced preliminarily the induction of PCD in aging P. donghaiense. The identified included also calmodulin and protein phosphatase, two proteins involved in diverse cell processes including PCD by binding to or modifying others. PMID:17278709

  14. Role of nitric oxide in actin depolymerization and programmed cell death induced by fusicoccin in sycamore (Acer pseudoplatanus) cultured cells.

    PubMed

    Malerba, Massimo; Contran, Nicla; Tonelli, Mariagrazia; Crosti, Paolo; Cerana, Raffaella

    2008-06-01

    Programmed cell death (PCD) plays a vital role in plant development and is involved in defence mechanisms against biotic and abiotic stresses. Different forms of PCD have been described in plants on the basis of the cell organelle first involved. In sycamore (Acer pseudoplatanus L.) cultured cells, the phytotoxin fusicoccin (FC) induces cell death. However, only a fraction of the dead cells shows the typical hallmarks of animal apoptosis, including cell shrinkage, chromatin condensation, DNA fragmentation and release of cytochrome c from the mitochondrion. In this work, we show that the scavenging of nitric oxide (NO), produced in the presence of FC, by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) and rutin inhibits cell death without affecting DNA fragmentation and cytochrome c release. In addition, we show that FC induces a massive depolymerization of actin filaments that is prevented by the NO scavengers. Finally, the addition of actin-depolymerizing drugs induces PCD in control cells and overcomes the inhibiting effect of cPTIO on FC-induced cell death. Vice versa, the addition of actin-stabilizing drugs to FC-treated cells partially inhibits the phytotoxin-induced PCD. These results suggest that besides an apoptotic-like form of PCD involving the release of cytochrome c, FC induces at least another form of cell death, likely mediated by NO and independent of cytochrome c release, and they make it tempting to speculate that changes in actin cytoskeleton are involved in this form of PCD.

  15. A Novel Function for Arabidopsis CYCLASE1 in Programmed Cell Death Revealed by Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Analysis of Extracellular Matrix Proteins.

    PubMed

    Smith, Sarah J; Kroon, Johan T M; Simon, William J; Slabas, Antoni R; Chivasa, Stephen

    2015-06-01

    Programmed cell death is essential for plant development and stress adaptation. A detailed understanding of the signal transduction pathways that regulate plant programmed cell death requires identification of the underpinning protein networks. Here, we have used a protagonist and antagonist of programmed cell death triggered by fumonisin B1 as probes to identify key cell death regulatory proteins in Arabidopsis. Our hypothesis was that changes in the abundance of cell death-regulatory proteins induced by the protagonist should be blocked or attenuated by concurrent treatment with the antagonist. We focused on proteins present in the mobile phase of the extracellular matrix on the basis that they are important for cell-cell communications during growth and stress-adaptive responses. Salicylic acid, a plant hormone that promotes programmed cell death, and exogenous ATP, which can block fumonisin B1-induced cell death, were used to treat Arabidopsis cell suspension cultures prior to isobaric-tagged relative and absolute quantitation analysis of secreted proteins. A total of 33 proteins, whose response to salicylic acid was suppressed by ATP, were identified as putative cell death-regulatory proteins. Among these was CYCLASE1, which was selected for further analysis using reverse genetics. Plants in which CYCLASE1 gene expression was knocked out by insertion of a transfer-DNA sequence manifested dramatically increased cell death when exposed to fumonisin B1 or a bacterial pathogen that triggers the defensive hypersensitive cell death. Although pathogen inoculation altered CYCLASE1 gene expression, multiplication of bacterial pathogens was indistinguishable between wild type and CYCLASE1 knockout plants. However, remarkably severe chlorosis symptoms developed on gene knockout plants in response to inoculation with either a virulent bacterial pathogen or a disabled mutant that is incapable of causing disease in wild type plants. These results show that CYCLASE1, which

  16. The HET-S/s Prion Motif in the Control of Programmed Cell Death.

    PubMed

    Riek, Roland; Saupe, Sven J

    2016-01-01

    The [Het-s] prion of the fungus Podospora anserina is a well-studied model system to elucidate the action of prions and beyond. The [Het-s] prion works as an activation trigger of a cell death execution protein termed HET-S. Amyloid transconformation of the prion-forming region of HET-S induces activation of its pore-forming cell death execution HeLo domain. The prion motif functions in a signal transduction process by which a nucleotide-binding oligomerization domain (NOD)-like receptor termed NWD2 controls the HET-S cell death effector. This prion motif thus corresponds to a functional amyloid motif, allowing a conformational crosstalk between homologous motif domains in signal transduction processes that appears to be widespread from the fungal to the mammalian animal kingdoms. This review aims to establish a structure-activity relationship of the HET-S/s prion system and sets it in the context of its wider biological significance. PMID:27352624

  17. Type 1 diabetes in India: Overall insights

    PubMed Central

    Das, Ashok Kumar

    2015-01-01

    Type 1 diabetes mellitus (T1DM) is also on increase like type 2 diabetes, even though not in the same proportion, but still with a trend of 3–5% increase/year. India has three new cases of T1DM/100,000 children of 0–14 years. Three sets of prevalence data shows 17.93 cases/100,000 children in Karnataka, 3.2 cases/100,000 children in Chennai, and 10.2 cases/100,000 children in Karnal (Haryana). T1DM may be autoimmune or idiopathic in nature and is present in 9% cases of insulin deficiency. T1DM is primarily caused by genetic factors, environmental factors, and disorder of the immune regulatory mechanism. A combination of all these three factors causes autoimmune disease, which may ultimately result in the destruction of pancreatic beta cells leading to hyperglycemia, ketoacidosis and potentially death, if not treated with insulin. Prediabetes is the phase before the onset of T1DM, which provides a window of opportunity for early intervention. All available interventions including steroids, immunosuppressants, and cyclosporins can be possibly applied during the prediabetes phase. The treatment goals for T1DM are simple and include maintaining near normal blood glucose levels and avoiding long-term complications, which is a constant juggle between insulin and maintaining an appropriate lifestyle. The Indian Council of Medical Research funded Registry of People with diabetes in India with young age at onset (YDR) was started in the year 2006 with 10 collaborating centres across India. This registry is focusing on to provide an overview of diabetes in the young. PMID:25941645

  18. Developmental Block and Programmed Cell Death in Bos indicus Embryos: Effects of Protein Supplementation Source and Developmental Kinetics

    PubMed Central

    Garcia, Sheila Merlo; Marinho, Luciana Simões Rafagnin; Lunardelli, Paula Alvares; Seneda, Marcelo Marcondes; Meirelles, Flávio Vieira

    2015-01-01

    The aims of this study were to determine if the protein source of the medium influences zebu embryo development and if developmental kinetics, developmental block and programmed cell death are related. The culture medium was supplemented with either fetal calf serum or bovine serum albumin. The embryos were classified as Fast (n = 1,235) or Slow (n = 485) based on the time required to reach the fourth cell cycle (48 h and 90 h post insemination - hpi -, respectively). The Slow group was further separated into two groups: those presenting exactly 4 cells at 48 hpi (Slow/4 cells) and those that reached the fourth cell cycle at 90 hpi (Slow). Blastocyst quality, DNA fragmentation, mitochondrial membrane potential and signs of apoptosis or necrosis were evaluated. The Slow group had higher incidence of developmental block than the Fast group. The embryos supplemented with fetal calf serum had lower quality. DNA fragmentation and mitochondrial membrane potential were absent in embryos at 48 hpi but present at 90 hpi. Early signs of apoptosis were more frequent in the Slow and Slow/4 cell groups than in the Fast group. We concluded that fetal calf serum reduces blastocyst development and quality, but the mechanism appears to be independent of DNA fragmentation. The apoptotic cells detected at 48 hpi reveal a possible mechanism of programmed cell death activation prior to genome activation. The apoptotic cells observed in the slow-developing embryos suggested a relationship between programmed cell death and embryonic developmental kinetics in zebu in vitro-produced embryos. PMID:25760989

  19. Developmental block and programmed cell death in Bos indicus embryos: effects of protein supplementation source and developmental kinetics.

    PubMed

    Garcia, Sheila Merlo; Marinho, Luciana Simões Rafagnin; Lunardelli, Paula Alvares; Seneda, Marcelo Marcondes; Meirelles, Flávio Vieira

    2015-01-01

    The aims of this study were to determine if the protein source of the medium influences zebu embryo development and if developmental kinetics, developmental block and programmed cell death are related. The culture medium was supplemented with either fetal calf serum or bovine serum albumin. The embryos were classified as Fast (n = 1,235) or Slow (n = 485) based on the time required to reach the fourth cell cycle (48 h and 90 h post insemination - hpi -, respectively). The Slow group was further separated into two groups: those presenting exactly 4 cells at 48 hpi (Slow/4 cells) and those that reached the fourth cell cycle at 90 hpi (Slow). Blastocyst quality, DNA fragmentation, mitochondrial membrane potential and signs of apoptosis or necrosis were evaluated. The Slow group had higher incidence of developmental block than the Fast group. The embryos supplemented with fetal calf serum had lower quality. DNA fragmentation and mitochondrial membrane potential were absent in embryos at 48 hpi but present at 90 hpi. Early signs of apoptosis were more frequent in the Slow and Slow/4 cell groups than in the Fast group. We concluded that fetal calf serum reduces blastocyst development and quality, but the mechanism appears to be independent of DNA fragmentation. The apoptotic cells detected at 48 hpi reveal a possible mechanism of programmed cell death activation prior to genome activation. The apoptotic cells observed in the slow-developing embryos suggested a relationship between programmed cell death and embryonic developmental kinetics in zebu in vitro-produced embryos. PMID:25760989

  20. [Complex heterogeneity phenotypes and genotypes of glutaric aciduria type 1].

    PubMed

    Wang, Qiao; Yang, Yan-Ling

    2016-05-01

    Glutaric aciduria type 1 is a rare autosomal recessive disorder. GCDH gene mutations cause glutaryl-CoA dehydrogenase deficiency and accumulation of glutaric acid and 3-hydroxyglutaric acid, resulting in damage of striatum and other brain nucleus and neurodegeneration. Patients with glutaric aciduria type 1 present with complex heterogeneous phenotypes and genotypes. The symptoms are extremely variable. The ages of the clinical onset of the patients range from the fetus period to adulthood. The patients with mild glutaric aciduria type 1 are almost asymptomatic before onset, however, severe glutaric aciduria type 1 may cause death or disability due to acute encephalopathy. Acute metabolic crisis in patients with underlying glutaric aciduria type 1 is often triggered by febrile illnesses, trauma, hunger, high-protein foods and vaccination during a vulnerable period of brain development in infancy or early childhood. The early-onset patients usually have a poor prognosis. Urinary organic acids analysis, blood acylcarnitines analysis and GCDH study are important for the diagnosis of this disorder. Neonatal screening is essential for the early diagnosis and the improvement of prognosis. PMID:27165598

  1. Programmed cell death in vegetative development: apoptosis during the colonial life cycle of the ascidian Botryllus schlosseri.

    PubMed

    Tiozzo, S; Ballarin, L; Burighel, P; Zaniolo, G

    2006-06-01

    Programmed cell death (PCD) by apoptosis is a physiological mechanism by which cells are eliminated during embryonic and post-embryonic stages of animal life cycle. During asexual reproduction, the zooids of colonial ascidians originate from an assorted cell population instead of a single zygote, so that we assume that regulation of the equilibrium among proliferation, differentiation and cell death may follow different pathways in comparison to the embryonic development. Here we investigate the presence of apoptotic events throughout the blastogenetic life cycle of the colonial ascidian Botryllus schlosseri, by means of terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) coupled with histochemical and electron microscopy techniques. The occurrence of low levels of morphogenetic cell death suggests that, in contrast to what happens during sexual development (embryogenesis and metamorphosis), apoptosis does not play a pivotal role during asexual propagation in botryllid ascidian. Nevertheless, PCD emerges as a key force to regulate homeostasis in adult zooids and to shape and modulate the growth of the whole colony.

  2. Death Valley Lower Carbonate Aquifer Monitoring Program Wells Down gradient of the Proposed Yucca Mountain Nuclear Waste Repository

    SciTech Connect

    Inyo County

    2006-07-26

    Inyo County has participated in oversight activities associated with the Yucca Mountain Nuclear Waste Repository since 1987. The overall goal of these studies are the evaluation of far-field issues related to potential transport, by ground water, or radionuclides into Inyo County, including Death Valley, and the evaluation of a connection between the Lower Carbonate Aquifer (LCA) and the biosphere. Our oversight and completed Cooperative Agreement research, and a number of other investigators research indicate that there is groundwater flow between the alluvial and carbonate aquifers both at Yucca Mountain and in Inyo County. In addition to the potential of radionuclide transport through the LCA, Czarnecki (1997), with the US Geological Survey, research indicate potential radionuclide transport through the shallower Tertiary-age aquifer materials with ultimate discharge into the Franklin Lake Playa in Inyo County. The specific purpose of this Cooperative Agreement drilling program was to acquire geological, subsurface geology, and hydrologic data to: (1) establish the existence of inter-basin flow between the Amargosa Basin and Death Valley Basin; (2) characterize groundwater flow paths in the LCA through Southern Funeral Mountain Range, and (3) Evaluation the hydraulic connection between the Yucca Mountain repository and the major springs in Death Valley through the LCA.

  3. RAD51 plays a crucial role in halting cell death program induced by ionizing radiation in bovine oocytes.

    PubMed

    Kujjo, Loro L; Ronningen, Reg; Ross, Pablo; Pereira, Ricardo J G; Rodriguez, Ramon; Beyhan, Zeki; Goissis, Marcelo D; Baumann, Thomas; Kagawa, Wataru; Camsari, Cagri; Smith, George W; Kurumizaka, Hitoshi; Yokoyama, Shigeyuki; Cibelli, Jose B; Perez, Gloria I

    2012-03-01

    Reproductive health of humans and animals exposed to daily irradiants from solar/cosmic particles remains largely understudied. We evaluated the sensitivities of bovine and mouse oocytes to bombardment by krypton-78 (1 Gy) or ultraviolet B (UV-B; 100 microjoules). Mouse oocytes responded to irradiation by undergoing massive activation of caspases, rapid loss of energy without cytochrome-c release, and subsequent necrotic death. In contrast, bovine oocytes became positive for annexin-V, exhibited cytochrome-c release, and displayed mild activation of caspases and downstream DNAses but with the absence of a complete cell death program; therefore, cytoplasmic fragmentation was never observed. However, massive cytoplasmic fragmentation and increased DNA damage were induced experimentally by both inhibiting RAD51 and increasing caspase 3 activity before irradiation. Microinjection of recombinant human RAD51 prior to irradiation markedly decreased both cytoplasmic fragmentation and DNA damage in both bovine and mouse oocytes. RAD51 response to damaged DNA occurred faster in bovine oocytes than in mouse oocytes. Therefore, we conclude that upon exposure to irradiation, bovine oocytes create a physiologically indeterminate state of partial cell death, attributed to rapid induction of DNA repair and low activation of caspases. The persistence of these damaged cells may represent an adaptive mechanism with potential implications for livestock productivity and long-term health risks associated with human activity in space. PMID:22190703

  4. RAD51 plays a crucial role in halting cell death program induced by ionizing radiation in bovine oocytes.

    PubMed

    Kujjo, Loro L; Ronningen, Reg; Ross, Pablo; Pereira, Ricardo J G; Rodriguez, Ramon; Beyhan, Zeki; Goissis, Marcelo D; Baumann, Thomas; Kagawa, Wataru; Camsari, Cagri; Smith, George W; Kurumizaka, Hitoshi; Yokoyama, Shigeyuki; Cibelli, Jose B; Perez, Gloria I

    2012-03-01

    Reproductive health of humans and animals exposed to daily irradiants from solar/cosmic particles remains largely understudied. We evaluated the sensitivities of bovine and mouse oocytes to bombardment by krypton-78 (1 Gy) or ultraviolet B (UV-B; 100 microjoules). Mouse oocytes responded to irradiation by undergoing massive activation of caspases, rapid loss of energy without cytochrome-c release, and subsequent necrotic death. In contrast, bovine oocytes became positive for annexin-V, exhibited cytochrome-c release, and displayed mild activation of caspases and downstream DNAses but with the absence of a complete cell death program; therefore, cytoplasmic fragmentation was never observed. However, massive cytoplasmic fragmentation and increased DNA damage were induced experimentally by both inhibiting RAD51 and increasing caspase 3 activity before irradiation. Microinjection of recombinant human RAD51 prior to irradiation markedly decreased both cytoplasmic fragmentation and DNA damage in both bovine and mouse oocytes. RAD51 response to damaged DNA occurred faster in bovine oocytes than in mouse oocytes. Therefore, we conclude that upon exposure to irradiation, bovine oocytes create a physiologically indeterminate state of partial cell death, attributed to rapid induction of DNA repair and low activation of caspases. The persistence of these damaged cells may represent an adaptive mechanism with potential implications for livestock productivity and long-term health risks associated with human activity in space.

  5. Chloroplasts of Arabidopsis are the source and a primary target of a plant-specific programmed cell death signaling pathway.

    PubMed

    Kim, Chanhong; Meskauskiene, Rasa; Zhang, Shengrui; Lee, Keun Pyo; Lakshmanan Ashok, Munusamy; Blajecka, Karolina; Herrfurth, Cornelia; Feussner, Ivo; Apel, Klaus

    2012-07-01

    Enhanced levels of singlet oxygen ((1)O(2)) in chloroplasts trigger programmed cell death. The impact of (1)O(2) production in chloroplasts was monitored first in the conditional fluorescent (flu) mutant of Arabidopsis thaliana that accumulates (1)O(2) upon a dark/light shift. The onset of (1)O(2) production is rapidly followed by a loss of chloroplast integrity that precedes the rupture of the central vacuole and the final collapse of the cell. Inactivation of the two plastid proteins EXECUTER (EX1) and EX2 in the flu mutant abrogates these responses, indicating that disintegration of chloroplasts is due to EX-dependent signaling rather than (1)O(2) directly. In flu seedlings, (1)O(2)-mediated cell death signaling operates as a default pathway that results in seedlings committing suicide. By contrast, EX-dependent signaling in the wild type induces the formation of microlesions without decreasing the viability of seedlings. (1)O(2)-mediated and EX-dependent loss of plastid integrity and cell death in these plants occurs only in cells containing fully developed chloroplasts. Our findings support an as yet unreported signaling role of (1)O(2) in the wild type exposed to mild light stress that invokes photoinhibition of photosystem II without causing photooxidative damage of the plant.

  6. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death

    PubMed Central

    1995-01-01

    Programmed cell death (PCD) is a physiological process commonly defined by alterations in nuclear morphology (apoptosis) and/or characteristic stepwise degradation of chromosomal DNA occurring before cytolysis. However, determined characteristics of PCD such as loss in mitochondrial reductase activity or cytolysis can be induced in enucleated cells, indicating cytoplasmic PCD control. Here we report a sequential disregulation of mitochondrial function that precedes cell shrinkage and nuclear fragmentation. A first cyclosporin A-inhibitable step of ongoing PCD is characterized by a reduction of mitochondrial transmembrane potential, as determined by specific fluorochromes (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine++ + iodide; 3,3'dihexyloxacarbocyanine iodide). Cytofluorometrically purified cells with reduced mitochondrial transmembrane potential are initially incapable of oxidizing hydroethidine (HE) into ethidium. Upon short-term in vitro culture, such cells acquire the capacity of HE oxidation, thus revealing a second step of PCD marked by mitochondrial generation of reactive oxygen species (ROS). This step can be selectively inhibited by rotenone and ruthenium red yet is not affected by cyclosporin A. Finally, cells reduce their volume, a step that is delayed by radical scavengers, indicating the implication of ROS in the apoptotic process. This sequence of alterations accompanying early PCD is found in very different models of apoptosis induction: glucocorticoid-induced death of lymphocytes, activation-induced PCD of T cell hybridomas, and tumor necrosis factor-induced death of U937 cells. Transfection with the antiapoptotic protooncogene Bcl-2 simultaneously inhibits mitochondrial alterations and apoptotic cell death triggered by steroids or ceramide. In vivo injection of fluorochromes such as 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolcarbocyanine iodide; 3,3'dihexyloxacarbocyanine iodide; or HE allows for the detection of

  7. Enhanced recovery program for hip and knee replacement reduces death rate

    PubMed Central

    2011-01-01

    Background and purpose Multimodal techniques can aid early rehabilitation and discharge of patients following primary joint replacement. We hypothesized that this not only reduces the economic burden of joint replacement by reducing length of stay, but also helps in reduction of early complications. Patients and methods We evaluated 4,500 consecutive unselected total hip replacements and total knee replacements regarding length of hospital stay, mortality, and perioperative complications. The first 3,000 underwent a traditional protocol while the other 1,500 underwent an enhanced recovery protocol involving behavioral, pharmacological, and procedural modifications. Results There was a reduction in 30-day death rate (0.5% to 0.1%, p = 0.02) and 90-day death rate (0.8% to 0.2%, p = 0.01). The median length of stay decreased from 6 days to 3 days (p < 0.001), resulting in a saving of 5,418 bed days. Requirement for blood transfusion was reduced (23% to 9.8%, p < 0.001). There was a trend of a reduced rate of 30-day myocardial infarction (0.8% to 0.5%. p = 0 .2) and stroke (0.5% to 0.2%, p = 0.2). The 60-day deep vein thrombosis figures (0.8% to 0.6%, p = 0.5) and pulmonary embolism figures (1.2% to 1.1%, p = 0.9) were similar. Re-admission rate remained unchanged during the period of the study (4.7% to 4.8%, p = 0.8). Interpretation This large observational study of unselected consecutive hip and knee arthroplasty patients shows a substantial reduction in death rate, reduced length of stay, and reduced transfusion requirements after the introduction of a multimodal enhanced recovery protocol. PMID:21895500

  8. No life without death.

    PubMed

    Krammer, Peter H; Kamiński, Marcin; Kiessling, Michael; Gülow, Karsten

    2007-01-01

    Apoptosis-programed cell death-is the most common form of death in the body. Once apoptosis is induced, proper execution of the cell death program requires the coordinated activation and execution of multiple molecular processes. Here, we describe the pathways and the basic components of the death-inducing machinery. Since apoptosis is a key regulator of tissue homeostasis, an imbalance of apoptosis results in severe diseases like cancer, autoimmunity, and AIDS.

  9. Supporting patients with type 1 diabetes.

    PubMed

    Phillips, Anne

    Type 1 diabetes is an autoimmune condition that is mediated by genetic, immunologic and environmental factors. Its prevalence is further complicated by increasing obesity levels, and this can make diagnosis complicated. Health professionals play a key role in enablement and optimising person-centred care approaches to educate and augment the essential skills required for successful self-management of this lifelong condition. This article reflects on the physiology and aetiology of type 1 diabetes and prevalence and considers recent guidance from the National Institute for Health and Care Excellence for adults with type 1 diabetes (NG17) and for children and young people with type 1 and type 2 diabetes (NG18).

  10. The longitudinal time course of QTc in early infancy. Preliminary results of a prospective sudden infant death syndrome surveillance program.

    PubMed

    Schaffer, M S; Trippel, D L; Buckles, D S; Young, R H; Dolan, P L; Gillette, P C

    1991-03-01

    Eleven hundred one healthy neonates in Charleston County, SC, were enrolled in a prospective, serial measurement sudden infant death syndrome/QT surveillance program. Automated computer-enhanced ECGs were recorded at 1 day of age in the hospital nursery and again at 1 week and 1, 2, and 3 months in the participant's home. At 1 year, the families were contacted by phone or mail and questioned as to the health of the child. Validation studies demonstrated the computer-enhanced ECGs to be 96% accurate, whereas traditional ECG recording and measurement was 94% accurate. No systematic differences in the QTc according to race and sex were observed. There were parallel longitudinal time courses for each race and sex group with a significant (P less than .001) shortening of the QTc at 1 week. There was no evidence of tracking of the QTc during the first 3 months of life. In conclusion, (1) automated, enhanced ECG QTc intervals are superior to traditional electrocardiography while retaining the advantages of automation; (2) there is a significant shortening of the QTc during the first month of life; and (3) a home follow-up sudden infant death syndrome surveillance program is feasible and produces accurate, reliable information.

  11. Programmed cell death in castor bean endosperm is associated with the accumulation and release of a cysteine endopeptidase from ricinosomes.

    PubMed

    Schmid, M; Simpson, D; Gietl, C

    1999-11-23

    The cells of the endosperm of castor bean seeds (Ricinus communis) undergo programmed cell death during germination, after their oil and protein reserves have been mobilized. Nuclear DNA fragmentation first was observed at day 3 in the endosperm cells immediately adjacent to the cotyledons and progressed across to the outermost cell layers by day 5. We also detected the accumulation of small organelles known as ricinosomes, by using an antibody against a cysteine endoprotease. By the time the nuclear DNA was susceptible to heavy label by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, the ricinosomes had released into the cytoplasm their content of cysteine endoprotease, which became activated because of the cleavage of its propeptide. The cysteine endoprotease is distinguished by a C-terminal KDEL sequence, although it is not retained in the lumen of the endoplasmic reticulum and is a marker for ricinosomes. Homologous proteases are found in the senescing tissues of other plants, including the petals of the daylily. Ricinosomes were identified in this tissue by electron microscopy and immunocytochemistry. It seems that ricinosomes are not unique to Ricinus and play an important role in the degradation of plant cell contents during programmed cell death. PMID:10570215

  12. Plasmonic Imaging of Human Oral Cancer Cell Communities During Programmed Cell Death by Nuclear Targeting Silver Nanoparticles

    PubMed Central

    Austin, Lauren A.; Kang, Bin; Yen, Chun-Wan; El-Sayed, Mostafa A.

    2016-01-01

    Plasmonic nanoparticles (NPs) have become a useful platform in the biomedical field due to their potential use in disease diagnosis and treatment. Recently, it has been reported that plasmonic NPs conjugated to nuclear-targeting peptides cause DNA damage and apoptotic populations in cancer cells. In the present work, we utilized the plasmonic scattering property and the ability of nuclear-targeted silver nanoparticles (NLS/RGD-AgNPs) to induce programmed cell death in order to image in real-time the behavior of human oral squamous carcinoma (HSC-3) cell communities during and after the induction of apoptosis. Plasmonic live-cell imaging (movie) revealed that HSC-3 cells behave as non-professional phagocytes. The induction of apoptosis in some cells led to the attraction and their subsequent engulfment by the neighboring cells. Attraction to apoptotic cells resulted in clustering of cellular community. The live-cell imaging movies also revealed that as the initial concentration of NLS/RGD-AgNPs increases, the rate of self-killing increases and the degree of attraction and clustering decreases. These results are discussed in terms of the proposed mechanism of cells undergoing programmed cell death. PMID:21981727

  13. Med13p prevents mitochondrial fission and programmed cell death in yeast through nuclear retention of cyclin C.

    PubMed

    Khakhina, Svetlana; Cooper, Katrina F; Strich, Randy

    2014-09-15

    The yeast cyclin C-Cdk8 kinase forms a complex with Med13p to repress the transcription of genes involved in the stress response and meiosis. In response to oxidative stress, cyclin C displays nuclear to cytoplasmic relocalization that triggers mitochondrial fission and promotes programmed cell death. In this report, we demonstrate that Med13p mediates cyclin C nuclear retention in unstressed cells. Deleting MED13 allows aberrant cytoplasmic cyclin C localization and extensive mitochondrial fragmentation. Loss of Med13p function resulted in mitochondrial dysfunction and hypersensitivity to oxidative stress-induced programmed cell death that were dependent on cyclin C. The regulatory system controlling cyclin C-Med13p interaction is complex. First, a previous study found that cyclin C phosphorylation by the stress-activated MAP kinase Slt2p is required for nuclear to cytoplasmic translocation. This study found that cyclin C-Med13p association is impaired when the Slt2p target residue is substituted with a phosphomimetic amino acid. The second step involves Med13p destruction mediated by the 26S proteasome and cyclin C-Cdk8p kinase activity. In conclusion, Med13p maintains mitochondrial structure, function, and normal oxidative stress sensitivity through cyclin C nuclear retention. Releasing cyclin C from the nucleus involves both its phosphorylation by Slt2p coupled with Med13p destruction.

  14. Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death.

    PubMed

    Awasthi, Yogesh C; Sharma, Rajendra; Sharma, Abha; Yadav, Sushma; Singhal, Sharad S; Chaudhary, Pankaj; Awasthi, Sanjay

    2008-07-15

    Within the last two decades, 4-hydroxynonenal has emerged as an important second messenger involved in the regulation of various cellular processes. Our recent studies suggest that HNE can induce apoptosis in various cells through the death receptor Fas (CD95)-mediated extrinsic pathway as well as through the p53-dependent intrinsic pathway. Interestingly, through its interaction with the nuclear protein Daxx, HNE can self-limit its apoptotic role by translocating Daxx to cytoplasm where it binds to Fas and inhibits Fas-mediated apoptosis. In this paper, after briefly describing recent studies on various biological activities of HNE, based on its interactions with Fas, Daxx, and p53, we speculate on possible mechanisms through which HNE may affect a multitude of cellular processes and draw a parallel between signaling roles of H(2)O(2) and HNE.

  15. Type 1 diabetes: The Bangladesh perspective.

    PubMed

    Azad, Kishwar

    2015-04-01

    Diabetes mellitus (DM) is a common endocrine disorder among children and adolescents in Bangladesh. The latest International Diabetes Federation atlas estimated the incidence of type 1 DM (T1DM) in Bangladesh as 4.2 new cases of T1DM/100,000 children (0-14 years)/year, in 2013. Diabetes, being a lifelong disease, places a huge burden on the economy of the most densely populated, and resource-poor country of the world. The Diabetic Association of Bangladesh (BADAS), the largest of its kind in the world, provides comprehensive care to the biggest number of diabetics at any one centre and is engaged in advocacy. Although sounding grandiose, it's aims that 'no diabetic shall die untreated, unfed or unemployed, even if poor' is pursued with a passion. Recently BADAS has been supported in its endeavor for children and adolescents by two programmes; viz the Changing Diabetes in Children program (a joint initiative of BADAS, the World Diabetes Foundation and Novo Nordisk), and the Life for a Child Programme (LFAC) supported by the IDF. Numerous studies from the prosperous countries have demonstrated the incidence of T1DM is increasing. Data from the CDiC clinic at BIRDEM shows a rising trend in patients presenting with classical T1DM. In addition, the pattern of DM is changing.

  16. Transcription factor NFAT1 controls allergic contact hypersensitivity through regulation of activation induced cell death program

    PubMed Central

    Kwon, Ho-Keun; Kim, Gi-Cheon; Hwang, Ji Sun; Kim, Young; Chae, Chang-Suk; Nam, Jong Hee; Jun, Chang-Duk; Rudra, Dipayan; Surh, Charles D.; Im, Sin-Hyeog

    2016-01-01

    Allergic contact hypersensitivity (CHS) is an inflammatory skin disease mediated by allergen specific T cells. In this study, we investigated the role of transcription factor NFAT1 in the pathogenesis of contact hypersensitivity. NFAT1 knock out (KO) mice spontaneously developed CHS-like skin inflammation in old age. Healthy young NFAT1 KO mice displayed enhanced susceptibility to hapten-induced CHS. Both CD4+ and CD8+ T cells from NFAT1 KO mice displayed hyper-activated properties and produced significantly enhanced levels of inflammatory T helper 1(Th1)/Th17 type cytokines. NFAT1 KO T cells were more resistant to activation induced cell death (AICD), and regulatory T cells derived from these mice showed a partial defect in their suppressor activity. NFAT1 KO T cells displayed a reduced expression of apoptosis associated BCL-2/BH3 family members. Ectopic expression of NFAT1 restored the AICD defect in NFAT1 KO T cells and increased AICD in normal T cells. Recipient Rag2−/− mice transferred with NFAT1 KO T cells showed more severe CHS sensitivity due to a defect in activation induced hapten-reactive T cell apoptosis. Collectively, our results suggest the NFAT1 plays a pivotal role as a genetic switch in CD4+/CD8+ T cell tolerance by regulating AICD process in the T cell mediated skin inflammation. PMID:26777750

  17. In vivo programmed cell death of Entamoeba histolytica trophozoites in a hamster model of amoebic liver abscess.

    PubMed

    Villalba-Magdaleno, José D'Artagnan; Pérez-Ishiwara, Guillermo; Serrano-Luna, Jesús; Tsutsumi, Víctor; Shibayama, Mineko

    2011-05-01

    Entamoeba histolytica trophozoites can induce host cell apoptosis, which correlates with the virulence of the parasite. This phenomenon has been seen during the resolution of an inflammatory response and the survival of the parasites. Other studies have shown that E. histolytica trophozoites undergo programmed cell death (PCD) in vitro, but how this process occurs within the mammalian host cell remains unclear. Here, we studied the PCD of E. histolytica trophozoites as part of an in vivo event related to the inflammatory reaction and the host-parasite interaction. Morphological study of amoebic liver abscesses showed only a few E. histolytica trophozoites with peroxidase-positive nuclei identified by terminal deoxynucleotidyltransferase enzyme-mediated dUTP nick end labelling (TUNEL). To better understand PCD following the interaction between amoebae and inflammatory cells, we designed a novel in vivo model using a dialysis bag containing E. histolytica trophozoites, which was surgically placed inside the peritoneal cavity of a hamster and left to interact with the host's exudate components. Amoebae collected from bags were then examined by TUNEL assay, fluorescence-activated cell sorting (FACS) and transmission electron microscopy. Nuclear condensation and DNA fragmentation of E. histolytica trophozoites were observed after exposure to peritoneal exudates, which were mainly composed of neutrophils and macrophages. Our results suggest that production of nitric oxide by inflammatory cells could be involved in PCD of trophozoites. In this modified in vivo system, PCD appears to play a prominent role in the host-parasite interaction and parasite cell death.

  18. Entamoeba histolytica P-glycoprotein (EhPgp) inhibition, induce trophozoite acidification and enhance programmed cell death.

    PubMed

    Medel Flores, Olivia; Gómez García, Consuelo; Sánchez Monroy, Virgina; Villalba Magadaleno, José D'Artagnan; Nader García, Elvira; Pérez Ishiwara, D Guillermo

    2013-11-01

    Programmed cell death (PCD) is induced in Entamoeba histolytica by a variety of stimuli in vitro and in vivo. In mammals, intracellular acidification serves as a global switch for inactivating cellular processes and initiates molecular mechanisms implicated in the destruction of the genome. In contrast, intracellular alkalinization produced by P-glycoprotein overexpression in multidrug-resistant cells has been related to apoptosis resistance. Our previous studies showed that overexpression of E. histolytica P-glycoprotein (PGP) altered chloride-dependent currents and triggered trophozoite swelling, the reverse process of cell shrinkage produced during PCD. Here we showed that antisense inhibition of PGP expression produced a synchronous death of trophozoites and the enhancement of biochemical and morphological characteristics of PCD induced by G418. The nucleus was contracted, and the nuclear membrane was disrupted. Moreover, chromatin was extensively fragmented. Ca(2+) concentration was increased, while the intracellular pH (ipH) was acidified. In contrast, PGP overexpression prevented intracellular acidification and circumvented the apoptotic effect of G418.

  19. The plant metacaspase AtMC1 in pathogen-triggered programmed cell death and aging: functional linkage with autophagy

    PubMed Central

    Coll, N S; Smidler, A; Puigvert, M; Popa, C; Valls, M; Dangl, J L

    2014-01-01

    Autophagy is a major nutrient recycling mechanism in plants. However, its functional connection with programmed cell death (PCD) is a topic of active debate and remains not well understood. Our previous studies established the plant metacaspase AtMC1 as a positive regulator of pathogen-triggered PCD. Here, we explored the linkage between plant autophagy and AtMC1 function in the context of pathogen-triggered PCD and aging. We observed that autophagy acts as a positive regulator of pathogen-triggered PCD in a parallel pathway to AtMC1. In addition, we unveiled an additional, pro-survival homeostatic function of AtMC1 in aging plants that acts in parallel to a similar pro-survival function of autophagy. This novel pro-survival role of AtMC1 may be functionally related to its prodomain-mediated aggregate localization and potential clearance, in agreement with recent findings using the single budding yeast metacaspase YCA1. We propose a unifying model whereby autophagy and AtMC1 are part of parallel pathways, both positively regulating HR cell death in young plants, when these functions are not masked by the cumulative stresses of aging, and negatively regulating senescence in older plants. PMID:24786830

  20. A program of cell death and extracellular matrix degradation is activated in the amnion before the onset of labor.

    PubMed Central

    Lei, H; Furth, E E; Kalluri, R; Chiou, T; Tilly, K I; Tilly, J L; Elkon, K B; Jeffrey, J J; Strauss, J F

    1996-01-01

    Fetal membranes usually rupture during the process of labor. Premature fetal membrane rupture occurs not infrequently and is associated with significant fetal and maternal morbidity. The mechanisms of normal and pathologic fetal membrane rupture are not well understood. We have examined structural and biochemical changes in the rat amnion as labor approaches in order to characterize this process in normal pregnancy. Here we report that before the onset of active labor the amnion epithelial cells undergo apoptotic cell death which encompasses degradation of 28S ribosomal subunit RNA and associated P proteins and fragmentation of nuclear DNA. Concurrent with these cellular changes, the amnion type I collagen matrix is degraded with the accumulation of three-quarter length type I collagen fragments in extraembryonic fluid, characteristic of the cleavage of fibrillar collagen by interstitial collagenase. Western blot and immunohistochemical analyses confirmed that interstitial collagenase protein appears in association with the loss of amnion type I collagen. We conclude that amnion epithelial cells undergo a process of programmed cell death associated with orchestrated extracellular matrix degradation which begins before the onset of active labor. Thus, fetal membrane rupture is likely to be the result of biochemical changes as well as physical forces. PMID:8903315

  1. Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells

    PubMed Central

    Monetti, Emanuela; Kadono, Takashi; Bouteau, François

    2014-01-01

    Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca2+ concentration ([Ca2+]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2·–) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2·– generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca2+]cyt increase and singlet oxygen production, do not seem to be involved in PCD. PMID:24420571

  2. Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells.

    PubMed

    Monetti, Emanuela; Kadono, Takashi; Tran, Daniel; Azzarello, Elisa; Arbelet-Bonnin, Delphine; Biligui, Bernadette; Briand, Joël; Kawano, Tomonori; Mancuso, Stefano; Bouteau, François

    2014-03-01

    Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca(2+) concentration ([Ca(2+)]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2·(-)) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2·(-) generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca(2+)]cyt increase and singlet oxygen production, do not seem to be involved in PCD.

  3. Structure of the CED-4-CED-9 Complex Provides Insights into Programmed Cell Death in Caenorhabditis elegans

    SciTech Connect

    Yan,N.; Chai, J.; Lee, E.; Gu, L.; Liu, Q.; He, J.; Wu, J.; Kokel, D.; Li, H.; et al.

    2005-01-01

    Interplay among four genes-egl-1, ced-9, ced-4 and ced-3-controls the onset of programmed cell death in the nematode Caenorhabditis elegans. Activation of the cell-killing protease CED-3 requires CED-4. However, CED-4 is constitutively inhibited by CED-9 until its release by EGL-1. Here we report the crystal structure of the CED-4-CED-9 complex at 2.6 Angstrom resolution, and a complete reconstitution of the CED-3 activation pathway using homogeneous proteins of CED-4, CED-9 and EGL-1. One molecule of CED-9 binds to an asymmetric dimer of CED-4, but specifically recognizes only one of the two CED-4 molecules. This specific interaction prevents CED-4 from activating CED-3. EGL-1 binding induces pronounced conformational changes in CED-9 that result in the dissociation of the CED-4 dimer from CED-9. The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. Together, our studies provide important insights into the regulation of cell death activation in C. elegans.

  4. Comparison of NaCl-induced programmed cell death in the obligate halophyte Cakile maritima and the glycophyte Arabidopsis thaliana.

    PubMed

    Ben Hamed-Laouti, Ibtissem; Arbelet-Bonnin, Delphine; De Bont, Linda; Biligui, Bernadette; Gakière, Bertrand; Abdelly, Chedly; Ben Hamed, Karim; Bouteau, François

    2016-06-01

    Salinity represents one of the most important constraints that adversely affect plants growth and productivity. In this study, we aimed at determining possible differences between salt tolerant and salt sensitive species in early salt stress response. To this purpose, we subjected suspension-cultured cells from the halophyte Cakile maritima and the glycophyte Arabidopsis thaliana, two Brassicaceae, to salt stress and compared their behavior. In both species we could observe a time and dose dependent programmed cell death requiring an active metabolism, a dysfunction of mitochondria and caspase-like activation although C. maritima cells appeared less sensitive than A. thaliana cells. This capacity to mitigate salt stress could be due to a higher ascorbate pool that could allow C. maritima reducing the oxidative stress generated in response to NaCl. It further appeared that a higher number of C. maritima cultured cells when compared to A. thaliana could efficiently manage the Na(+) accumulation into the cytoplasm through non selective cation channels allowing also reducing the ROS generation and the subsequent cell death. PMID:27095399

  5. Dehydroascorbate: a possible surveillance molecule of oxidative stress and programmed cell death in the green alga Chlamydomonas reinhardtii.

    PubMed

    Murik, Omer; Elboher, Ahinoam; Kaplan, Aaron

    2014-04-01

    Chlamydomonas reinhardtii tolerates relatively high H2 O2 levels that induce an array of antioxidant activities. However, rather than rendering the cells more resistant to oxidative stress, the cells become far more sensitive to an additional H2 O2 dose. If H2 O2 is provided 1.5-9 h after an initial dose, it induces programmed cell death (PCD) in the wild-type, but not in the dum1 mutant impaired in the mitochondrial respiratory complex III. This mutant does not exhibit a secondary oxidative burst 4-5 h after the inducing H2 O2 , nor does it activate metacaspase-1 after the second H2 O2 treatment. The intracellular dehydroascorbate level, a product of ascorbate peroxidase, increases under conditions leading to PCD. The addition of dehydroascorbate induces PCD in the wild-type and dum1 cultures, but higher levels are required in dum1 cells, where it is metabolized faster. The application of dehydroascorbate induces the expression of metacaspase-2, which is much stronger than the expression of metacaspase-1. The presence or absence of oxidative stress, in addition to the rise in internal dehydroascorbate, may determine which metacaspase is activated during Chlamydomonas PCD. Cell death is strongly affected by the timing of H2 O2 or dehydroascorbate admission to synchronously grown cultures, suggesting that the cell cycle phase may distinguish cells that perish from those that do not. PMID:24345283

  6. Environmental risk factors for type 1 diabetes.

    PubMed

    Rewers, Marian; Ludvigsson, Johnny

    2016-06-01

    The incidence of type 1 diabetes has risen considerably in the past 30 years due to changes in the environment that have been only partially identified. In this Series paper, we critically discuss candidate triggers of islet autoimmunity and factors thought to promote progression from autoimmunity to overt type 1 diabetes. We revisit previously proposed hypotheses to explain the growth in the incidence of type 1 diabetes in light of current data. Finally, we suggest a unified model in which immune tolerance to β cells can be broken by several environmental exposures that induce generation of hybrid peptides acting as neoautoantigens. PMID:27302273

  7. Calcium and reactive oxygen species in regulation of the mitochondrial permeability transition and of programmed cell death in yeast.

    PubMed

    Carraro, Michela; Bernardi, Paolo

    2016-08-01

    Mitochondria-dependent programmed cell death (PCD) in yeast shares many features with the intrinsic apoptotic pathway of mammals. With many stimuli, increased cytosolic [Ca(2+)] and ROS generation are the triggering signals that lead to mitochondrial permeabilization and release of proapoptotic factors, which initiates yeast PCD. While in mammals the permeability transition pore (PTP), a high-conductance inner membrane channel activated by increased matrix Ca(2+) and oxidative stress, is recognized as part of this signaling cascade, whether a similar process occurs in yeast is still debated. The potential role of the PTP in yeast PCD has generally been overlooked because yeast mitochondria lack the Ca(2+) uniporter, which in mammals allows rapid equilibration of cytosolic Ca(2+) with the matrix. In this short review we discuss the nature of the yeast permeability transition and reevaluate its potential role in the effector phase of yeast PCD triggered by Ca(2+) and oxidative stress. PMID:26995056

  8. Mechanistic study of programmed cell death of root border cells of cucumber (Cucumber sativus L.) induced by copper.

    PubMed

    Sun, Lijuan; Song, Jie; Peng, Cheng; Xu, Chen; Yuan, Xiaofeng; Shi, Jiyan

    2015-12-01

    Programmed cell death (PCD) in root border cells (RBCs) induced by Copper (Cu) has been little studied. This study explored whether Cu induced PCD in RBCs of cucumber or not and investigated the possible mechanisms. The results showed that the percentage of apoptotic and necrotic RBCs increased with increasing concentration of Cu treatment. A quick burst of ROS in RBCs was detected, while mitochondrial membrane potential (ΔΨm) decreased sharply with Cu treatment. Caspase-3 like protease activity showed a tendency of increase with Cu treatment. The potential of Cu to induce PCD in RBCs of cucumber was first proved. Our results showed that ROS generation and mitochondrial membrane potential loss played important roles in Cu-induced caspase-3-like activation and PCD in RBCs of cucumber, which provided new insight into the signaling cascades that modulate Cu phytotoxicity mechanism.

  9. Reactive oxygen species burst induced by aluminum stress triggers mitochondria-dependent programmed cell death in peanut root tip cells.

    PubMed

    Huang, Wenjing; Yang, Xudong; Yao, Shaochang; LwinOo, Thet; He, Huyi; Wang, Aiqin; Li, Chuangzhen; He, Longfei

    2014-09-01

    Recent studies had certified that aluminum (Al) induced ROS production and programmed cell death (PCD) in higher plants. The relationship between ROS production and PCD occurrence under Al stress is uncovered. The results showed that root elongation inhibition and PCD occurrence was induced by 100 μM AlCl3. Al stress induced ROS burst, up-regulated Rboh and COX gene expression, increased mitochondrial permeability transition pore (MPTP) opening, decreased inner mitochondrial membrane potential (ΔΨm), released cytochrome c from mitochondria to cytoplasm, activated caspase 3-like protease activity. Exogenous H2O2 aggravated the changes caused by Al and accelerated PCD occurrence, but ROS scavenger CAT and AsA reversed the changes caused by Al and inhibited PCD production. A potential cascade of cellular events during Al induced PCD via mitochondria dependent pathway and the mechanism of ROS on regulating PCD induced by Al is proposed.

  10. Aerosol delivery of programmed cell death protein 4 using polysorbitol-based gene delivery system for lung cancer therapy.

    PubMed

    Kim, You-Kyoung; Xing, Lei; Chen, Bao-An; Xu, Fengguo; Jiang, Hu-Lin; Zhang, Can

    2014-11-01

    The development of a safe and effective gene delivery system is the most challenging obstacle to the broad application of gene therapy in the clinic. In this study, we report the development of a polysorbitol-based gene delivery system as an alternative gene carrier for lung cancer therapy. The copolymer was prepared by a Michael addition reaction between sorbitol diacrylate (SD) and spermine (SPE); the SD-SPE copolymer effectively condenses with DNA on the nanoscale and protects it from nucleases. SD-SPE/DNA complexes showed excellent transfection with low toxicity both in vitro and in vivo, and aerosol delivery of SD-SPE complexes with programmed cell death protein 4 DNA significantly suppressed lung tumorigenesis in K-ras(LA1) lung cancer model mice. These results demonstrate that SD-SPE has great potential as a gene delivery system based on its excellent biocompatibility and high gene delivery efficiency for lung cancer gene therapy. PMID:24983766

  11. Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types

    PubMed Central

    Scognamiglio, Giosuè; De Chiara, Anna; Di Bonito, Maurizio; Tatangelo, Fabiana; Losito, Nunzia Simona; Anniciello, Annamaria; De Cecio, Rossella; D’Alterio, Crescenzo; Scala, Stefania; Cantile, Monica; Botti, Gerardo

    2016-01-01

    In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to correlate with a poor prognosis of patients with several types of cancer. However, recent reports have revealed that the immunohistochemical (IHC) expression of the PD-L1 in tumor cells is not uniform for the use of different antibodies clones, with variable specificity, often doubtful topographical localization, and with a score not uniquely defined. The purpose of this study was to analyze the IHC expression of PD-L1 on a large series of several human tumors to correctly define its staining in different tumor tissues. PMID:27213372

  12. Spontaneous programmed cell death (PCD) process of lymphocytes of FIV-infected cats: pharmacological modulation in vitro.

    PubMed

    Guiot, A L; Rigal, D; Chappuis, G

    1997-03-01

    We previously reported that unstimulated lymphocytes in culture from FIV-infected cats undergo spontaneous apoptosis in vitro as indicated by internucleosomal DNA fragmentation and hypodiploid DNA content of nuclei. Unlike what is reported in HIV-infected individuals, we observed that cell death of cat lymphocytes was inhibited by activation. Spontaneous apoptosis was reduced by the addition of cat serum, interleukins [interleukin (IL)1, Il2, IL6 and interferon-gamma (IFN gamma)] and after activation by phorbol ester [phorbol myristyl acetate (PMA)], superantigens [staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin A (SEA)], and to a lesser extent by mitogens such as Concanavalin A and pokeweed mitogen, IN contrast, apoptosis of lymphocytes from FIV-infected, but not from control cats was increased in the presence of calcium ionophore (ionomycin). In this study, we studied the spontaneous programmed cell death (PCD)-inducing pathways, and the mechanisms of action of PMA, SEB and SEA. Spontaneous lymphocyte apoptosis of FIV-infected cats was inhibited by cycloheximide, ZnSO4 and N-acetyl-cystein. The preventive effect of SEB and SEA was inhibited by actinomycin, but not by inhibitors of kinases. Calyculin, an inhibitor of phosphatase, had no effect either on spontaneous apoptosis, or on the action of PMA, SEB and SEA. Ionomycin-induced apoptosis was found sensitive to PMA and cytokines. In FIV-infected cats, these data suggest that the mature lymphocytes appear programmed to die by apoptosis, unless rescued by specific agents, such as protein kinase C activators or growth factors, and that spontaneous PCD seems to be dependent of de nove protein synthesis (see effect of cycloheximide). The effects of PMA, SEB and SEA are probably mediated by de novo proteins which for PMA, undergo a phosphorylation involving serine-threonine and/or tyrosine groups. Our data suggest a clear difference between lymphocytes from FIV-infected cats and lymphocytes from HIV

  13. A matrix metalloproteinase gene is expressed at the boundary of senescence and programmed cell death in cucumber.

    PubMed

    Delorme, V G; McCabe, P F; Kim, D J; Leaver, C J

    2000-07-01

    Cell-cell and extracellular cell matrix (ECM) interactions provide cells with information essential for controlling morphogenesis, cell-fate specification, and cell death. In animals, one of the major groups of enzymes that degrade the ECM is the matrix metalloproteinases (MMPs). Here, we report the characterization of the cucumber (Cucumis sativus L. cv Marketmore) Cs1-MMP gene encoding such an enzyme likely to play a role in plant ECM degradation. Cs1-MMP has all the hallmark motif characteristics of animal MMPs and is a pre-pro-enzyme having a signal peptide, propeptide, and zinc-binding catalytic domains. Cs1-MMP also displays functional similarities with animal MMPs. For example, it has a collagenase-like activity that can cleave synthetic peptides and type-I collagen, a major component of animal ECM. Cs1-MMP activity is completely inhibited by a hydroxamate-based inhibitor that binds at the active site of MMPs in a stereospecific manner. The Cs1-MMP gene is expressed de novo at the end stage of developmental senescence, prior to the appearance of DNA laddering in cucumber cotyledons leaf discs and male flowers. As the steady-state level of Cs1-MMP mRNA peaks late in senescence and the pro-enzyme must undergo maturation and activation, the protease is probably not involved in nutrient remobilization during senescence but may have another function. The physiological substrates for Cs1-MMP remain to be determined, but the enzyme represents a good candidate for plant ECM degradation and may be involved in programmed cell death (PCD). Our results suggest that PCD occurs only at the culmination of the senescence program or that the processes are distinct with PCD being triggered at the end of senescence.

  14. Streptolysin S Promotes Programmed Cell Death and Enhances Inflammatory Signaling in Epithelial Keratinocytes during Group A Streptococcus Infection

    PubMed Central

    Flaherty, Rebecca A.; Puricelli, Jessica M.; Higashi, Dustin L.; Park, Claudia J.

    2015-01-01

    Streptococcus pyogenes, or group A Streptococcus (GAS), is a pathogen that causes a multitude of human diseases from pharyngitis to severe infections such as toxic shock syndrome and necrotizing fasciitis. One of the primary virulence factors produced by GAS is the peptide toxin streptolysin S (SLS). In addition to its well-recognized role as a cytolysin, recent evidence has indicated that SLS may influence host cell signaling pathways at sublytic concentrations during infection. We employed an antibody array-based approach to comprehensively identify global host cell changes in human epithelial keratinocytes in response to the SLS toxin. We identified key SLS-dependent host responses, including the initiation of specific programmed cell death and inflammatory cascades with concomitant downregulation of Akt-mediated cytoprotection. Significant signaling responses identified by our array analysis were confirmed using biochemical and protein identification methods. To further demonstrate that the observed SLS-dependent host signaling changes were mediated primarily by the secreted toxin, we designed a Transwell infection system in which direct bacterial attachment to host cells was prevented, while secreted factors were allowed access to host cells. The results using this approach were consistent with our direct infection studies and reveal that SLS is a bacterial toxin that does not require bacterial attachment to host cells for activity. In light of these findings, we propose that the production of SLS by GAS during skin infection promotes invasive outcomes by triggering programmed cell death and inflammatory cascades in host cells to breach the keratinocyte barrier for dissemination into deeper tissues. PMID:26238711

  15. Alpha-toxin induces programmed cell death of human T cells, B cells, and monocytes during USA300 infection.

    PubMed

    Nygaard, Tyler K; Pallister, Kyler B; DuMont, Ashley L; DeWald, Mark; Watkins, Robert L; Pallister, Erik Q; Malone, Cheryl; Griffith, Shannon; Horswill, Alexander R; Torres, Victor J; Voyich, Jovanka M

    2012-01-01

    This investigation examines the influence of alpha-toxin (Hla) during USA300 infection of human leukocytes. Survival of an USA300 isogenic deletion mutant of hla (USA300Δhla) in human blood was comparable to the parental wild-type strain and polymorphonuclear leukocyte (PMN) plasma membrane permeability caused by USA300 did not require Hla. Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) following infection by USA300, USA300Δhla, and USA300Δhla transformed with a plasmid over-expressing Hla (USA300Δhla Comp) demonstrated this toxin plays a significant role inducing plasma membrane permeability of CD14(+), CD3(+), and CD19(+) PBMCs. Rapid plasma membrane permeability independent of Hla was observed for PMNs, CD14(+) and CD19(+) PBMCs following intoxication with USA300 supernatant while the majority of CD3(+) PBMC plasma membrane permeability induced by USA300 required Hla. Addition of recombinant Hla to USA300Δhla supernatant rescued CD3(+) and CD19(+) PBMC plasma membrane permeability generated by USA300 supernatant. An observed delay in plasma membrane permeability caused by Hla in conjunction with Annexin V binding and ApoBrdU Tunel assays examining PBMCs intoxicated with recombinant Hla or infected with USA300, USA300Δhla, USA300Δhla Comp, and USA300ΔsaeR/S suggest Hla induces programmed cell death of monocytes, B cells, and T cells that results in plasma membrane permeability. Together these findings underscore the importance of Hla during S. aureus infection of human tissue and specifically demonstrate Hla activity during USA300 infection triggers programmed cell death of human monocytes, T cells and B cells that leads to plasma membrane permeability.

  16. A Matrix Metalloproteinase Gene Is Expressed at the Boundary of Senescence and Programmed Cell Death in Cucumber1

    PubMed Central

    Delorme, Valérie G.R.; McCabe, Paul F.; Kim, Dae-Jae; Leaver, Christopher J.

    2000-01-01

    Cell-cell and extracellular cell matrix (ECM) interactions provide cells with information essential for controlling morphogenesis, cell-fate specification, and cell death. In animals, one of the major groups of enzymes that degrade the ECM is the matrix metalloproteinases (MMPs). Here, we report the characterization of the cucumber (Cucumis sativus L. cv Marketmore) Cs1-MMP gene encoding such an enzyme likely to play a role in plant ECM degradation. Cs1-MMP has all the hallmark motif characteristics of animal MMPs and is a pre-pro-enzyme having a signal peptide, propeptide, and zinc-binding catalytic domains. Cs1-MMP also displays functional similarities with animal MMPs. For example, it has a collagenase-like activity that can cleave synthetic peptides and type-I collagen, a major component of animal ECM. Cs1-MMP activity is completely inhibited by a hydroxamate-based inhibitor that binds at the active site of MMPs in a stereospecific manner. The Cs1-MMP gene is expressed de novo at the end stage of developmental senescence, prior to the appearance of DNA laddering in cucumber cotyledons leaf discs and male flowers. As the steady-state level of Cs1-MMP mRNA peaks late in senescence and the pro-enzyme must undergo maturation and activation, the protease is probably not involved in nutrient remobilization during senescence but may have another function. The physiological substrates for Cs1-MMP remain to be determined, but the enzyme represents a good candidate for plant ECM degradation and may be involved in programmed cell death (PCD). Our results suggest that PCD occurs only at the culmination of the senescence program or that the processes are distinct with PCD being triggered at the end of senescence. PMID:10889240

  17. Filamentation protects Candida albicans from amphotericin B-induced programmed cell death via a mechanism involving the yeast metacaspase, MCA1

    PubMed Central

    Laprade, David J.; Brown, Melissa S.; McCarthy, Morgan L.; Ritch, James J.; Austriaco, Nicanor

    2016-01-01

    The budding yeast Candida albicans is one of the most significant fungal pathogens worldwide. It proliferates in two distinct cell types: blastopores and filaments. Only cells that are able to transform from one cell type into the other are virulent in mouse disease models. Programmed cell death is a controlled form of cell suicide that occurs when C. albicans cells are exposed to fungicidal drugs like amphotericin B and caspofungin, and to other stressful conditions. We now provide evidence that suggests that programmed cell death is cell-type specific in yeast: Filamentous C. albicans cells are more resistant to amphotericin B- and caspofungin-induced programmed cell death than their blastospore counterparts. Finally, our genetic data suggests that this phenomenon is mediated by a protective mechanism involving the yeast metacaspase, MCA1. PMID:27683660

  18. Filamentation protects Candida albicans from amphotericin B-induced programmed cell death via a mechanism involving the yeast metacaspase, MCA1

    PubMed Central

    Laprade, David J.; Brown, Melissa S.; McCarthy, Morgan L.; Ritch, James J.; Austriaco, Nicanor

    2016-01-01

    The budding yeast Candida albicans is one of the most significant fungal pathogens worldwide. It proliferates in two distinct cell types: blastopores and filaments. Only cells that are able to transform from one cell type into the other are virulent in mouse disease models. Programmed cell death is a controlled form of cell suicide that occurs when C. albicans cells are exposed to fungicidal drugs like amphotericin B and caspofungin, and to other stressful conditions. We now provide evidence that suggests that programmed cell death is cell-type specific in yeast: Filamentous C. albicans cells are more resistant to amphotericin B- and caspofungin-induced programmed cell death than their blastospore counterparts. Finally, our genetic data suggests that this phenomenon is mediated by a protective mechanism involving the yeast metacaspase, MCA1.

  19. Comparison between the effects of fusicoccin, Tunicamycin, and Brefeldin A on programmed cell death of cultured sycamore (Acer pseudoplatanus L.) cells.

    PubMed

    Malerba, M; Cerana, R; Crosti, P

    2004-10-01

    Programmed cell death occurs in plants during several developmental processes and during the expression of resistance to pathogen attack (i.e., the hypersensitive response). An unsolved question of plant programmed cell death is whether a unique signaling pathway or different, possibly convergent pathways exist. This problem was addressed in cultured sycamore (Acer pseudoplatanus L.) cells by comparing the effects of fusicoccin, Tunicamycin and Brefeldin A, inducers of programmed cell death with well-defined molecular and cellular targets, on some of the parameters involved in the regulation of this process. In addition to cell death, the inducers are able to stimulate the production of H2O2, the leakage of cytochrome c from mitochondria, the accumulation of cytosolic 14-3-3 proteins, and changes at the endoplasmic reticulum level, such as accumulation of the molecular chaperone binding protein and modifications in the organelle architecture. Interestingly, no additive effect on any of these parameters is observed when fusicoccin is administered in combination with Tunicamycin or Brefeldin A. Thus, these inducers seem to utilize the same or largely coincident pathways to induce programmed cell death and involvement of the endoplasmic reticulum, in addition to that of mitochondria, appears to be a common step.

  20. A Jekyll and Hyde Profile: Type 1 Interferon Signaling Plays a Prominent Role in the Initiation and Maintenance of a Persistent Virus Infection

    PubMed Central

    Oldstone, Michael B. A.

    2015-01-01

    The hallmarks of persistent viral infections are exhaustion of virus-specific T cells, elevated production of interleukin 10 (IL-10) and programmed death-1 (PD-1) the dominant negative regulators of the immune system and disruption of secondary lymphoid tissues. Within the first 12–24 hours after mice are infected with lymphocytic choriomeningitis virus (LCMV) clone 13, which is used as a model of persistent virus infection, we note generation of high titers of type 1 interferon. Blockade of type 1 interferon significantly lessens IL-10 and PD-1/PD-L1, allows normal secondary lymphoid architecture and re-establishes antiviral T-cell function, thus eradicating the virus and clearing the infection. Hence, type 1 interferon is a master reostat for establishing persistent viral infection. PMID:26116728

  1. Type 1 Diabetes in Young Adulthood

    PubMed Central

    Monaghan, Maureen; Helgeson, Vicki; Wiebe, Deborah

    2015-01-01

    Type 1 diabetes has traditionally been studied as a chronic illness of childhood. However, young adulthood is a critical time for the development and integration of lifelong diabetes management skills, and research is starting to identify unique challenges faced by youth with diabetes as they age into adulthood. Most young adults experience multiple transitions during this unstable developmental period, including changes in lifestyle (e.g., education, occupation, living situation), changes in health care, and shifting relationships with family members, friends, and intimate others. Young adults with type 1 diabetes must navigate these transitions while also assuming increasing responsibility for their diabetes care and overall health. Despite these critical health and psychosocial concerns, there is a notable lack of evidence-based clinical services and supports for young adults with type 1 diabetes. We review relevant evolving concerns for young adults with type 1 diabetes, including lifestyle considerations, health care transitions, psychosocial needs, and changes in supportive networks, and how type 1 diabetes impacts and is impacted by these key developmental considerations. Specific avenues for intervention and future research are offered. PMID:25901502

  2. Type 1 diabetes in young adulthood.

    PubMed

    Monaghan, Maureen; Helgeson, Vicki; Wiebe, Deborah

    2015-01-01

    Type 1 diabetes has traditionally been studied as a chronic illness of childhood. However, young adulthood is a critical time for the development and integration of lifelong diabetes management skills, and research is starting to identify unique challenges faced by youth with diabetes as they age into adulthood. Most young adults experience multiple transitions during this unstable developmental period, including changes in lifestyle (e.g., education, occupation, living situation), changes in health care, and shifting relationships with family members, friends, and intimate others. Young adults with type 1 diabetes must navigate these transitions while also assuming increasing responsibility for their diabetes care and overall health. Despite these critical health and psychosocial concerns, there is a notable lack of evidence-based clinical services and supports for young adults with type 1 diabetes. We review relevant evolving concerns for young adults with type 1 diabetes, including lifestyle considerations, health care transitions, psychosocial needs, and changes in supportive networks, and how type 1 diabetes impacts and is impacted by these key developmental considerations. Specific avenues for intervention and future research are offered. PMID:25901502

  3. A lysigenic programmed cell death-dependent process shapes schizogenously formed aerenchyma in the stems of the waterweed Egeria densa

    PubMed Central

    Bartoli, G.; Forino, L. M. C.; Durante, M.; Tagliasacchi, A. M.

    2015-01-01

    Background and Aims Plant adaptation to submergence can include the formation of prominent aerenchyma to facilitate gas exchange. The aim of this study was to characterize the differentiation of the constitutive aerenchyma in the stem of the aquatic macrophyte Egeria densa (Hydrocharitaceae) and to verify if any form of cell death might be involved. Methods Plants were collected from a pool in a botanical garden. Aerenchyma differentiation and apoptotic hallmarks were investigated by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay coupled with genomic DNA extraction and gel electrophoresis (DNA laddering assay). Cell viability and the occurrence of peroxides and nitric oxide (NO) were determined histochemically using specific fluorogenic probes. Key Results Aerenchyma differentiation started from a hexagonally packed pre-aerenchymatic tissue and, following a basipetal and centripetal developmental pattern, produced a honeycomb arrangement. After an early schizogenous differentiation process, a late lysigenous programmed cell death- (PCD) dependent mechanism occurred. This was characterized by a number of typical apoptotic hallmarks, including DNA fragmentation, chromatin condensation, apoptotic-like bodies, partial cell wall lysis and plasmolysis. In addition, local increases in H2O2 and NO were observed and quantified. Conclusions The differentiation of cortical aerenchyma in the stem of E. densa is a complex process, consisting of a combination of an early schizogenous differentiation mechanism and a late lysigenous PCD-dependent process. The PCD remodels the architecture of the gas spaces previously formed schizogenously, and also results in a reduction of O2-consuming cells and in recycling of material derived from the lysigenic dismantling of the cells. PMID:26002256

  4. Turning up the heat: heat stress induces markers of programmed cell death in Plasmodium falciparum in vitro

    PubMed Central

    Engelbrecht, D; Coetzer, T L

    2013-01-01

    Malaria is characterised by cyclical febrile episodes that result from the rupture of mature schizont-infected erythrocytes releasing merozoites. In patients infected with Plasmodium falciparum, fever may reach peak temperatures as high as 41 °C. Febrile episodes typically have a deleterious effect on parasites and probably benefit the host by aiding parasite clearance; however, the parasite may also gain advantage from limiting its burden on the host and prolonging infection to ensure development and transmission of slow-maturing gametocytes. Programmed cell death (PCD) may provide the parasite with a mechanism of self-limitation, although the occurrence and phenotype of PCD in the erythrocytic stages remain controversial due to conflicting data. This study aimed to characterise the cell death phenotype of P. falciparum in response to in vitro heat stress. A variety of biochemical markers of PCD, including DNA fragmentation, mitochondrial dysregulation and phosphatidylserine externalisation, as well as morphological studies of Giemsa-stained thin smears and real-time microscopy were utilised to characterise the phenotype. Heat stress decreased P. falciparum growth and development in vitro. Late-stage parasites were more susceptible, although early stages were more affected than expected. Early-stage parasites exposed to 41 °C exhibited markers of an apoptosis-like PCD phenotype, including DNA fragmentation and mitochondrial depolarisation. Heat-stressed late-stage parasites showed no significant DNA fragmentation or mitochondrial dysregulation; however, cytoplasmic vacuolisation was suggestive of an autophagy-like form of PCD. Our results therefore showed that biochemical and morphological markers of PCD varied with intra-erythrocytic parasite development and that P. falciparum exhibited facets of both apoptosis- and autophagy-like phenotypes after exposure to febrile temperatures, which may reflect a unique PCD phenotype. PMID:24357802

  5. New Arabidopsis thaliana Cytochrome c Partners: A Look Into the Elusive Role of Cytochrome c in Programmed Cell Death in Plants*

    PubMed Central

    Martínez-Fábregas, Jonathan; Díaz-Moreno, Irene; González-Arzola, Katiuska; Janocha, Simon; Navarro, José A.; Hervás, Manuel; Bernhardt, Rita; Díaz-Quintana, Antonio; De la Rosa, Miguel Á.

    2013-01-01

    Programmed cell death is an event displayed by many different organisms along the evolutionary scale. In plants, programmed cell death is necessary for development and the hypersensitive response to stress or pathogenic infection. A common feature in programmed cell death across organisms is the translocation of cytochrome c from mitochondria to the cytosol. To better understand the role of cytochrome c in the onset of programmed cell death in plants, a proteomic approach was developed based on affinity chromatography and using Arabidopsis thaliana cytochrome c as bait. Using this approach, ten putative new cytochrome c partners were identified. Of these putative partners and as indicated by bimolecular fluorescence complementation, nine of them bind the heme protein in plant protoplasts and human cells as a heterologous system. The in vitro interaction between cytochrome c and such soluble cytochrome c-targets was further corroborated using surface plasmon resonance. Taken together, the results obtained in the study indicate that Arabidopsis thaliana cytochrome c interacts with several distinct proteins involved in protein folding, translational regulation, cell death, oxidative stress, DNA damage, energetic metabolism, and mRNA metabolism. Interestingly, some of these novel Arabidopsis thaliana cytochrome c-targets are closely related to those for Homo sapiens cytochrome c (Martínez-Fábregas et al., unpublished). These results indicate that the evolutionarily well-conserved cytosolic cytochrome c, appearing in organisms from plants to mammals, interacts with a wide range of targets on programmed cell death. The data have been deposited to the ProteomeXchange with identifier PXD000280. PMID:24019145

  6. Should Type 1 diabetics fast in Ramadan.

    PubMed

    Mohsin, Fauzia; Azad, Kishwar; Zabeen, Bedowra; Tayyeb, Samin; Baki, Abdul; Nahar, Nazmun

    2015-05-01

    Fasting during the holy month of Ramadan is obligatory for all healthy adult and adolescent Muslims from the age of 12 years. This involves abstaining from eating or drinking from early dawn (Suhur/Sehri) till sunset (Iftar).Fasting is not meant to create excessive hardships or impart any adverse effect to the Muslim individual. As such, Islam has exempted certain categories of people from fasting including young children, travelers, the sick, the elderly,and pregnant and lactating women. According to expert opinion, people with type 1 diabetes who fast during Ramadan are at very high risk of metabolic deterioration. However, some recent studies have demonstrated that individuals with type 1 diabetes who are otherwise healthy and stable, can fast during Ramadan provided they comply with the Ramadan focused management plan and are under close professional supervision. This article discusses how to assess, counsel, monitor and manage people with type 1 diabetes who wish to fast during Ramadan.

  7. Programmed hepatocytes cell death associated with FLIP downregulation in response to extracellular preS1/2.

    PubMed

    Rojas, Masyelly D; Peterson, Darrell L; Barboza, Luisa; Terán-Ángel, Guillermo; Labastida-Moreno, Cesar A; Berrueta, Lisbeth; Salmen, Siham

    2014-03-01

    Chronic hepatitis B virus (HBV) infection involves liver damage resulting in continuous cell injury and death. During HBV infection, hepatocytes exhibit changes in death receptor expression and in their susceptibility to death. These changes are observed not only in infected cells but also in bystander cells. Because excess viral surface protein (HBsAg) is secreted in large amounts as soluble particles containing preS proteins, the role of soluble preS1/2 in hepatocyte (HepG2) death modulation is an important issue to be explored. An increase of cell death induced by preS1/2 was observed. Also, cell death was associated with the down-regulation of FLIP and activation of caspase 8, caspase 9, and BID. Additionally, hepatocytes exhibited a sensitization to death mediated by the Fas receptor. These results, may contribute to understanding the role of envelope proteins (preS1/2) in the pathogenesis of HBV infection.

  8. Histology of Type 1 Diabetes Pancreas.

    PubMed

    Willcox, Abby; Gillespie, Kathleen M

    2016-01-01

    The islets of Langerhans play a critical role in glucose homeostasis. Islets are predominantly composed of insulin-secreting beta cells and glucagon-secreting alpha cells. In type 1 diabetes, the beta cells are destroyed by autoimmune destruction of insulin producing beta cells resulting in hyperglycemia. This is a gradual process, taking from several months to decades. Much of the beta cell destruction takes place during a silent, asymptomatic phase. Type 1 diabetes becomes clinically evident upon destruction of approximately 70-80 % of beta cell mass. Studying the decline in beta cell mass and the cells which are responsible for their demise is difficult as pancreatic biopsies are not feasible in patients with type 1 diabetes. The relative size of islets and their dispersed location throughout the pancreas means in vivo imaging of human islets is currently not manageable. At present, there are no validated biomarkers which accurately track the decline in beta cell mass in individuals who are at risk of developing, or have already developed, type 1 diabetes. Therefore, studies of pancreatic tissue retrieved at autopsy from donors with type 1 diabetes, or donors with high risk markers of type 1 diabetes such as circulating islet-associated autoantibodies, is currently the best method for studying beta cells and the associated inflammatory milieu in situ. In recent years, concerted efforts have been made to source such tissues for histological studies, enabling great insights to be made into the relationship between islets and the inflammatory insult to which they are subjected. This article describes in detail, a robust immunohistochemical method which can be utilized to study both recent, and archival human pancreatic tissue, in order to examine islet endocrine cells and the surrounding immune cells. PMID:26801316

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

    PubMed

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

    2016-01-01

    Modern methods of industrial poultry and egg production systems involve stressful practices that stimulate Escherichia coli (E. coli) activity causing endotoxic shock. This investigation was conducted to evaluate the expression of pro-inflammatory cytokines and cell death program genes and DNA damage induced by E. coli in the brain and liver tissues of laying hens. A total of two hundred and ten H&N brown layer hens with 20 week age, were used in this research. First, preliminary experiments were designed (60 hens in total) to establish the optimal exposure dose of E. coli and to determine the nearest time of notable response to be used in the remainder studies of this research. At 35-wk of age, 150 hens were randomly assigned into 2 groups with 3 replicates of 25 birds each; the first group was injected in the brachial wing vein with 107 E. coli colony/hen, while the second group was injected with saline and served as a control. The body temperature and plasma corticosterone concentration were measured 3 hr after injection. Specimens of liver and brain were obtained from each group and the gene expression of p38 mitogen-activated protein kinase, interlukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), Bax, and caspase-3 genes were measured by quantitative real-time PCR. DNA damage in the brain and liver tissues were also measured by comet assay. Hens treated with E. coli showed significant (P<0.05) increase of body temperature and plasma corticosterone (42.6°C and 14.5 ng/ml, respectively) compared to the control group (41.1°C and 5.5 ng/ml, respectively). Additional remarkable over-inflammation gene expression of p38, IL-1β and TNF-α.genes were also detected in the brain (2.2-fold, 2.0-fold and 3.3-fold, respectively) and the liver (2.1-fold, 1.9-fold and 3.0-fold, respectively) tissues of the infected chickens. It is also important to note that hens injected with E. coli showed an increase in DNA damage in the brain and liver cells (P<0.05). These

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

    PubMed Central

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

    2016-01-01

    Modern methods of industrial poultry and egg production systems involve stressful practices that stimulate Escherichia coli (E. coli) activity causing endotoxic shock. This investigation was conducted to evaluate the expression of pro-inflammatory cytokines and cell death program genes and DNA damage induced by E. coli in the brain and liver tissues of laying hens. A total of two hundred and ten H&N brown layer hens with 20 week age, were used in this research. First, preliminary experiments were designed (60 hens in total) to establish the optimal exposure dose of E. coli and to determine the nearest time of notable response to be used in the remainder studies of this research. At 35-wk of age, 150 hens were randomly assigned into 2 groups with 3 replicates of 25 birds each; the first group was injected in the brachial wing vein with 107 E. coli colony/hen, while the second group was injected with saline and served as a control. The body temperature and plasma corticosterone concentration were measured 3 hr after injection. Specimens of liver and brain were obtained from each group and the gene expression of p38 mitogen-activated protein kinase, interlukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), Bax, and caspase-3 genes were measured by quantitative real-time PCR. DNA damage in the brain and liver tissues were also measured by comet assay. Hens treated with E. coli showed significant (P<0.05) increase of body temperature and plasma corticosterone (42.6°C and 14.5 ng/ml, respectively) compared to the control group (41.1°C and 5.5 ng/ml, respectively). Additional remarkable over-inflammation gene expression of p38, IL-1β and TNF-α.genes were also detected in the brain (2.2-fold, 2.0-fold and 3.3-fold, respectively) and the liver (2.1-fold, 1.9-fold and 3.0-fold, respectively) tissues of the infected chickens. It is also important to note that hens injected with E. coli showed an increase in DNA damage in the brain and liver cells (P<0.05). These

  11. Programmed Death Ligand-1 Immunohistochemistry--A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society.

    PubMed

    Sholl, Lynette M; Aisner, Dara L; Allen, Timothy Craig; Beasley, Mary Beth; Borczuk, Alain C; Cagle, Philip T; Capelozzi, Vera; Dacic, Sanja; Hariri, Lida; Kerr, Keith M; Lantuejoul, Sylvie; Mino-Kenudson, Mari; Raparia, Kirtee; Rekhtman, Natasha; Roy-Chowdhuri, Sinchita; Thunnissen, Eric; Tsao, Ming Sound; Yatabe, Yasushi

    2016-04-01

    The binding of programmed death ligand-1 and ligand-2 (PD-L1 and PD-L2) to PD-1 blocks T-cell-mediated immune response to tumor. Antibodies that target programmed death receptor-1 (PD-1) will block the ligand-receptor interface, thereby allowing T cells to attack the tumor and increase antitumor immune response. In clinical trials, PD-1 inhibitors have been associated with an approximately 20% overall response rate in unselected patients with non-small cell lung cancer, with sustained tumor response in a subset of patients treated by these immune checkpoint inhibitors. Facing a proliferation of PD-L1 immunohistochemistry clones, staining platforms, and scoring criteria, the pathologist must decide on the feasibility of introducing a newly approved companion diagnostic assay that may require purchase not only of a specific antibody kit but of a particular staining platform. Given the likely reality that clinical practice may, in the near future, demand access to 4 different PD-L1 antibodies coupled with different immunohistochemistry platforms, laboratories will be challenged with deciding among this variety of testing methods, each with its own potential benefits. Another immediate challenge to PD-L1 testing in lung cancer patients is that of access to adequate tumor tissue, given that non-small cell lung cancer samples are often extremely limited in size. With PD-L1 testing it has become clear that the historically used US regulatory approach of one assay-one drug will not be sustainable. One evolving concept is that of complementary diagnostics, a novel regulatory pathway initiated by the US Food and Drug Administration, which is distinct from companion diagnostics in that it may present additional flexibility. Although pathologists need to face the practical reality that oncologists will be asking regularly for the PD-L1 immunohistochemistry status of their patients' tumors, we should also keep in mind that there may be room for improvement of biomarkers for

  12. Tyrosinemia Type 1: A case report

    PubMed Central

    Nassar, Carmen

    2011-01-01

    Tyrosinemia type 1 is an inherited metabolic disorder attributable to deficiency of fumarylacetoacetate hydrolase enzyme. Here we report an eight month-old male Saudi infant who presented with jaundice, fever, and disturbed level of consciousness accompanied by abdominal distension, hepatomegaly and ascites with features suggestive of rickets. The diagnosis of tyrosinemia typ 1was confirmed based on clinical and biochemical findings. PMID:27493308

  13. Genetics Home Reference: neurofibromatosis type 1

    MedlinePlus

    ... of neurofibromatosis type 1. Semin Pediatr Neurol. 2006 Mar;13(1):8-20. Review. Citation on PubMed ... PubMed Rose VM. Neurocutaneous syndromes. Mo Med. 2004 Mar-Apr;101(2):112-6. Review. Citation on ...

  14. Genetics Home Reference: pseudohypoaldosteronism type 1

    MedlinePlus

    ... hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996 Mar;12(3):248-53. Citation on PubMed Chen ... sgk. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2514-9. Citation on PubMed ...

  15. Experimental Reproduction of Type 1B Chondrules

    NASA Technical Reports Server (NTRS)

    Lofgren, G. E.; Le, L.

    2002-01-01

    We have replicated type 1B chondrule textures and compositions with crystallization experiments in which UOC material was melted at 1400 deg.C and cooled at 5-1000 deg.C/hr using graphite crucibles in evacuated silica tubes to provide a reducing environment. Additional information is contained in the original extended abstract.

  16. Disruption of the vacuolar calcium-ATPases in arabidopsis results in the activation of a salicylic acid-dependent programmed cell death pathway

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Calcium (Ca2+) signals regulate many aspects of plant development, including the Hypersensitive Response (HR) that triggers a programmed cell death response to protect a plant from a pathogen. A transient increase in cytosolic Ca2+ ([Ca2+]cyt ) results from Ca2+ entry from the apoplast or release fr...

  17. Tomato 14-3-3 protein 7 (TFT7) positively regulates immunity-associated programmed cell death by enhancing accumulation and signaling ability of MAPKKKalpha

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Programmed cell death (PCD) is triggered when Pto, a serine-threonine protein kinase recognizes either the AvrPto or AvrPtoB effector from Pseudomonas syringae pv. tomato. This PCD requires MAPKKKalpha as a positive regulator in tomato and Nicotiana benthamiana. To examine how PCD-eliciting activi...

  18. ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes

    PubMed Central

    Brozzi, Flora

    2016-01-01

    Components of the unfolded protein response (UPR) modulate beta cell inflammation and death in early type 1 diabetes (T1D). The UPR is a mechanism by which cells react to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). It aims to restore cellular homeostasis, but in case of chronic or overwhelming ER stress the persistent activation of the UPR triggers apoptosis, contributing to the loss of beta cells in both T1D and type 2 diabetes. It remains to be determined how and why the transition from ‘physiological’ to ‘pathological’ UPR takes place. A key component of the UPR is the ER transmembrane protein IRE1α (inositol-requiring enzyme 1α). IRE1α activity is modulated by both intra-ER signals and by the formation of protein complexes at its cytosolic domain. The amplitude and duration of IRE1α signaling is critical for the transition between the adaptive and cell death programs, with particular relevance for the activation of the pro-apoptotic c-Jun N-terminal kinase (JNK) in beta cells. In the present review we discuss the available information on IRE1α-regulating proteins in beta cells and their downstream targets, and the important differences observed between cytokine-induced UPR in human and rodent beta cells. PMID:26899404

  19. Cytochrome c Trp65Ser substitution results in inhibition of acetic acid-induced programmed cell death in Saccharomyces cerevisiae.

    PubMed

    Guaragnella, Nicoletta; Passarella, Salvatore; Marra, Ersilia; Giannattasio, Sergio

    2011-11-01

    To gain further insight into the role of cytochrome c (cyt c) in yeast programmed cell death induced by acetic acid (AA-PCD), comparison was made between wild type and two mutant cells, one lacking cyt c and the other (W65Scyc1) expressing a mutant iso-1-cyt c in a form unable to reduce cyt c oxidase, with respect to occurrence of AA-PCD, cyt c release, ROS production and caspase-like activity. We show that in W65Scyc1 cells: i. no release of mutant cyt c occurs with inhibition of W65Scyc1 cell AA-PCD shown to be independent on impairment of electron flow, ii. there is a decrease in ROS production and an increase in caspase-like activity. We conclude that cyt c release does not depend on cyt c function as an electron carrier and that when still associated to the mitochondrial membrane, cyt c in its reduced form has a role in AA-PCD, by regulating ROS production and caspase-like activity. PMID:21907312

  20. Expression of programmed cell death protein 4 (PDCD4) and miR-21 in urothelial carcinoma

    SciTech Connect

    Fischer, Nicolas; Goeke, Friederike; Splittstoesser, Vera; Lankat-Buttgereit, Brigitte; Mueller, Stefan C.; Ellinger, Joerg

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer The tumor suppressor gene PDCD4 is down-regulated in many tumorous entities. Black-Right-Pointing-Pointer We investigate the impact of PDCD4 and its regulating factor miR-21 in urothelial carcinoma. Black-Right-Pointing-Pointer We confirm PDCD4 as a tumor suppressor gene and it could be a diagnostic marker for this tumor. -- Abstract: Background: We investigated the role of the programmed cell death 4 (PDCD4) tumor suppressor gene in specimens of transitional cell carcinoma and of healthy individuals. Methods: PDCD4 immunohistochemical expression was investigated in 294 cases in histologically proven transitional cell carcinoma in different tumorous stages (28 controls, 122 non-muscle invasive urothelial carcinoma, stages Tis-T1, 119 invasive transitional cell carcinoma stages T2-T4 and 25 metastases). MiR-21 expression, an important PDCD4 regulator, was assessed with real-time PCR analysis and showed inverse correlation to tissue PDCD4 expression. Results: Nuclear and cytoplasmatic PDCD4 immunostaining decreased significantly with histopathological progression of the tumor (p < 0001). Controls showed strong nuclear and cytoplasmatic immunohistochemical staining. MiR-21 up regulation in tissue corresponded to PDCD4 suppression. Conclusions: These data support a decisive role for PDCD4 down regulation in transitional cell carcinoma and confirm miR-21 as a negative regulator for PDCD4. Additionally, PDCD4 immunohistochemical staining turns out to be a possible diagnostic marker for transitional cell carcinoma.

  1. Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis.

    PubMed

    Pritchett, T L; McCall, K

    2012-06-01

    Amino-acid starvation leads to an inhibition of cellular proliferation and the induction of programmed cell death (PCD) in the Drosophila ovary. Disruption of insulin signaling has been shown to inhibit the progression of oogenesis, but it is unclear whether this phenotype mimics starvation. Here, we investigate whether the insulin-mediated phosphoinositide kinase-3 pathway regulates PCD in mid oogenesis. We reasoned that under well-fed conditions, disruption of positive components of the insulin signaling pathway within the germline would mimic starvation and produce degenerating egg chambers. Surprisingly, mutants did not mimic starvation but instead produced many abnormal egg chambers in which the somatic follicle cells disappeared and the germline persisted. These abnormal egg chambers did not show an induction of caspases and lysosomes like that observed in wild-type (WT) degenerating egg chambers. Egg chambers from insulin signaling mutants were resistant to starvation-induced PCD, indicating that a complete block in insulin-signaling prevents the proper response to starvation. However, target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. These results suggest that inhibition of the insulin signaling pathway is not sufficient to regulate starvation-induced PCD in mid oogenesis. Furthermore, starvation-induced PCD is regulated by Tor signaling converging with the canonical insulin signaling pathway.

  2. The TUNEL assay suggests mandibular regression by programmed cell death during presoldier differentiation in the nasute termite Nasutitermes takasagoensis

    NASA Astrophysics Data System (ADS)

    Toga, Kouhei; Yoda, Shinichi; Maekawa, Kiyoto

    2011-09-01

    Termite soldiers are the most specialized caste of social insects in terms of their morphology and function. Soldier development requires increased juvenile hormone (JH) titer and the two molts via a presoldier stage. These molts are accompanied by dramatic morphological changes, including the exaggeration and regression of certain organs. Soldiers of the most apical termitid subfamily Nasutitermitinae possess not only a horn-like frontal tube, called the nasus, for the projection of defensive chemicals from the frontal gland reservoir but also regressed mandibles. Although candidate genes regulating soldier mandibular growth were reported in a relatively basal termite species, the regulatory mechanisms of mandibular regression remain unknown. To clarify these mechanisms, we performed morphological and histological examinations of the mandibles during soldier differentiation in Nasutitermes takasagoensis. Mandibular size reduced dramatically during soldier differentiation, and mandibular regression occurred just prior to the presoldier molt. Spotted TUNEL signals were observed in regressing mandibles of presoldiers, suggesting that the regression involved programmed cell death. Because soldiers of N. takasagoensis possess exaggerated organs (nasus and frontal gland), the present results suggest that JH-dependent regressive mechanisms exist in the mandibles without interfering with the formation of the exaggerated organs.

  3. Programmed cell death in barley aleurone cells is not directly stimulated by reactive oxygen species produced in response to gibberellin.

    PubMed

    Aoki, Nozomi; Ishibashi, Yushi; Kai, Kyohei; Tomokiyo, Reisa; Yuasa, Takashi; Iwaya-Inoue, Mari

    2014-05-01

    The cereal aleurone layer is a secretory tissue that produces enzymes to hydrolyze the starchy endosperm during germination. We recently demonstrated that reactive oxygen species (ROS), produced in response to gibberellins (GA), promoted GAMyb expression, which induces α-amylase expression in barley aleurone cells. On the other hand, ROS levels increase during programmed cell death (PCD) in barley aleurone cells, and GAMyb is involved in PCD of these cells. In this study, we investigated whether the ROS produced in response to GA regulate PCD directly by using mutants of Slender1 (SLN1), a DELLA protein that negatively regulates GA signaling. The wild-type, the sln1c mutant (which exhibits gibberellin-type signaling even in the absence of GA), and the Sln1d mutant (which is gibberellin-insensitive with respect to α-amylase production) all produced ROS in response to GA, suggesting that ROS production in aleurone cells in response to GA is independent of GA signaling through this DELLA protein. Exogenous GA promoted PCD in the wild-type. PCD in sln1c was induced even without exogenous GA (and so without induction of ROS), whereas PCD in Sln1d was not induced in the presence of exogenous GA, even though the ROS content increased significantly in response to GA. These results suggest that PCD in barley aleurone cells is not directly stimulated by ROS produced in response to GA but is regulated by GA signaling through DELLA protein.

  4. Programmed cell death 4 in bacterially-challenged Apostichopus japonicus: Molecular cloning, expression analysis and functional characterization.

    PubMed

    Lv, Zhimeng; Li, Chenghua; Shao, Yina; Zhang, Weiwei; Wang, Zhenhui; Wang, Haihong

    2016-07-01

    Programmed cell death 4 (PDCD4) plays a crucial role in modulating cellular signals, mainly via TOLL cascades during the immune response. In the present study, a novel PDCD4 homologue gene (denoted as AjPDCD4) was cloned from the sea cucumber Apostichopus japonicus using RACE. The full-length AjPDCD4 cDNA comprised a 366bp 5'-UTR, a 418bp 3'-UTR, and a 1353bp open reading frame encoding a 450 amino acid residue protein with two typical MA3 domains. Phylogenetic analysis revealed that AjPDCD4 belonged to the invertebrate PDCD4 family. Spatial expression analysis indicated that AjPDCD4 mRNA transcripts are expressed at a high level in the tentacles and at a low level in muscle compared with coelomocytes. Vibrio splendidus challenge and LPS exposure could both significantly down-regulate AjPDCD4 mRNA expression. More importantly, we found that ultraviolet (UV)-induced ROS production and DNA damage were greatly repressed in AjPDCD4-knockdown coelomocytes. Meanwhile, the expression levels of the NF-kappa B homologue, p105, were synchronously up-regulated in the same conditions. All of these results indicated that AjPDCD4 is involved in modulating DNA damage and ROS production in sea cucumber, perhaps by affecting the TLR pathway. PMID:27262523

  5. Aluminum-induced programmed cell death promoted by AhSAG, a senescence-associated gene in Arachis hypoganea L.

    PubMed

    Zhan, Jie; He, Hu-Yi; Wang, Tian-Ju; Wang, Ai-Qin; Li, Chuang-Zhen; He, Long-Fei

    2013-09-01

    Programmed cell death (PCD) is a foundational cellular process in plant development and elimination of damaged cells under environmental stresses. In this study, Al induced PCD in two peanut (Arachis hypoganea L.) cultivars Zhonghua 2 (Al-sensitive) and 99-1507 (Al-tolerant) using DNA ladder, TUNEL detection and electron microscopy. The concentration of Al-induced PCD was lower in Zhonghua 2 than in 99-1507. AhSAG, a senescence-associated gene was isolated from cDNA library of Al-stressed peanut with PCD. Open reading frame (ORF) of AhSAG was 474bp, encoding a SAG protein composed of 157 amino acids. Compared to the control and the antisense transgenic tobacco plants, the fast development and blossom of the sense transgenic plants happened to promote senescence. The ability of Al tolerance in sense transgenic tobacco was lower than in antisense transgenic tobacco according to root elongation and Al content analysis. The expression of AhSAG-GFP was higher in sense transgenic tobacco than in antisense transgenic tobacco. Altogether, these results indicated that there was a negative relationship between Al-induced PCD and Al-resistance in peanut, and the AhSAG could induce or promote the occurrence of PCD in plants. PMID:23849118

  6. Crystal Structure of the Complex Between Programmed Death-1 (PD-1) and its Ligand PD-L2

    SciTech Connect

    Lazar-Molnar,E.; Yan, Q.; Cao, E.; Ramagopal, U.; Nathenson, S.; Almo, S.

    2008-01-01

    Programmed death-1 (PD-1) is a member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. The high-resolution crystal structure of the complex formed by the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 inhibitory complexes. Furthermore, our structure also provides insights into the association between PD-1 and PD-L1 and highlights differences in the interfaces formed by the two PD-1 ligands (PD-Ls) Mutagenesis studies confirmed the details of the proposed PD-1/PD-L binding interfaces and allowed for the design of a mutant PD-1 receptor with enhanced affinity. These studies define spatial and organizational constraints that control the localization and signaling of PD-1/PD-L complexes within the immunological synapse and provide a basis for manipulating the PD-1 pathways for immunotherapy.

  7. Programmed cell death 4 and BCR-ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

    PubMed Central

    Zhang, Xia; Liu, Riming; Huang, Baohua; Zhang, Xiaolu; Yu, Weijuan; Bao, Cuixia; Li, Jie; Sun, Chengming

    2016-01-01

    Programmed cell death 4 (PDCD4) is a tumor suppressor that inhibits carcinogenesis, tumor progression and invasion by preventing gene transcription and translation. Downregulation of PDCD4 expression has been identified in multiple types of human cancer, however, to date, the function of PDCD4 in leukemia has not been investigated. In the present study, PDCD4 mRNA and protein expression was investigated in 50 patients exhibiting various phases of chronic myeloid leukemia (CML) and 20 healthy individuals by reverse transcription-quantitative polymerase chain reaction and western blot analysis. PDCD4 expression and cell proliferation was also investigated following treatment with the tyrosine kinase inhibitor, imatinib, in K562 cells. The results demonstrated that PDCD4 mRNA and protein expression was decreased in all CML samples when compared with healthy controls, who expressed high levels of PDCD4 mRNA and protein. No significant differences in PDCD4 expression were identified between chronic phase, accelerated phase and blast phase CML patients. In addition, PDCD4 expression was negatively correlated with BCR-ABL gene expression (r=−0.6716; P<0.001). Furthermore, K562 cells treated with imatinib exhibited significantly enhanced PDCD4 expression. These results indicate that downregulation of PDCD4 expression may exhibit a critical function in the progression and malignant proliferation of human CML.

  8. Thioredoxin-2 Modulates Neuronal Programmed Cell Death in the Embryonic Chick Spinal Cord in Basal and Target-Deprived Conditions

    PubMed Central

    Pirson, Marc; Debrulle, Stéphanie; Clippe, André; Clotman, Frédéric; Knoops, Bernard

    2015-01-01

    Thioredoxin-2 (Trx2) is a mitochondrial protein using a dithiol active site to reduce protein disulfides. In addition to the cytoprotective function of this enzyme, several studies have highlighted the implication of Trx2 in cellular signaling events. In particular, growing evidence points to such roles of redox enzymes in developmental processes taking place in the central nervous system. Here, we investigate the potential implication of Trx2 in embryonic development of chick spinal cord. To this end, we first studied the distribution of the enzyme in this tissue and report strong expression of Trx2 in chick embryo post-mitotic neurons at E4.5 and in motor neurons at E6.5. Using in ovo electroporation, we go on to highlight a cytoprotective effect of Trx2 on the programmed cell death (PCD) of neurons during spinal cord development and in a novel cultured spinal cord explant model. These findings suggest an implication of Trx2 in the modulation of developmental PCD of neurons during embryonic development of the spinal cord, possibly through redox regulation mechanisms. PMID:26540198

  9. Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor

    PubMed Central

    1995-01-01

    Positive selection of T cells is a complex developmental process generating long-lived, functionally mature CD4+CD8- and CD4-CD8+ cells from short-lived, immature CD4+CD8+ precursors. The process is initiated in the thymus by interaction of the alpha beta TCR with molecules encoded by the MHC, occurs without cell division, and involves rescue from programmed cell death (PCD), as well as induction of differentiation and maturation of selected precursors. It is unclear whether development of small, positively selected CD4+CD8+ thymocytes (characterized by up-regulated levels of TCR and CD69 molecules) depends on further interactions with MHC molecules and, if so, whether such interactions are required for survival, for maturation, or for both. The involvement of the TCR and/or CD4/CD8 coreceptors in transmitting additional signals is also unknown. We have examined these questions by analyzing survival and differentiation of early (CD4+CD8+TCRhi) and later (CD4-CD8+TCRhi) postselection stages of thymocytes from normal and bcl-2 transgenic mice expressing transgenic, class I MHC-restricted TCR, upon intrathymic transfer into recipients that lacked ligands either for both the TCR and CD8 coreceptor, or for the TCR only. The results provide direct evidence that induction of differentiation of CD4+CD8+ thymocytes by recognition of MHC molecules does not rescue them from PCD and is insufficient to activate the entire maturation program. Both processes require continual engagement of the TCR by positively selecting MHC molecules that, at least in the case of class I MHC-restricted CD4-CD8+ T cells, cannot be substituted by the engagement of coreceptor alone. PMID:7759993

  10. Fragile X Mental Retardation Protein is Required for Programmed Cell Death and Clearance of Developmentally-Transient Peptidergic Neurons

    PubMed Central

    Gatto, Cheryl L.; Broadie, Kendal

    2011-01-01

    Fragile X syndrome (FXS), caused by loss of fragile X mental retardation 1 (FMR1) gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 product (FMRP) is an RNA-binding protein best established to function in activity-dependent modulation of synaptic connections. In the Drosophila FXS disease model, loss of functionally-conserved dFMRP causes synaptic overgrowth and overelaboration in pigment dispersing factor (PDF) peptidergic neurons in the adult brain. Here, we identify a very different component of PDF neuron misregulation in dfmr1 mutants: the aberrant retention of normally developmentally-transient PDF tritocerebral (PDF-TRI) neurons. In wild-type animals, PDF-TRI neurons in the central brain undergo programmed cell death and complete, processive clearance within days of eclosion. In the absence of dFMRP, a defective apoptotic program leads to constitutive maintenance of these peptidergic neurons. We tested whether this apoptotic defect is circuit-specific by examining crustacean cardioactive peptide (CCAP) and bursicon circuits, which are similarly developmentally-transient and normally eliminated immediately post-eclosion. In dfmr1 null mutants, CCAP/bursicon neurons also exhibit significantly delayed clearance dynamics, but are subsequently eliminated from the nervous system, in contrast to the fully persistent PDF-TRI neurons. Thus, the requirement of dFMRP for the retention of transitory peptidergic neurons shows evident circuit specificity. The novel defect of impaired apoptosis and aberrant neuron persistence in the Drosophila FXS model suggests an entirely new level of “pruning” dysfunction may contribute to the FXS disease state. PMID:21596027

  11. Mouse embryonic stem cells undergo charontosis, a novel programmed cell death pathway dependent upon cathepsins, p53, and EndoG, in response to etoposide treatment.

    PubMed

    Tichy, Elisia D; Stephan, Zachary A; Osterburg, Andrew; Noel, Greg; Stambrook, Peter J

    2013-05-01

    Embryonic stem cells (ESCs) are hypersensitive to many DNA damaging agents and can rapidly undergo cell death or cell differentiation following exposure. Treatment of mouse ESCs (mESCs) with etoposide (ETO), a topoisomerase II poison, followed by a recovery period resulted in massive cell death with characteristics of a programmed cell death pathway (PCD). While cell death was both caspase- and necroptosis-independent, it was partially dependent on the activity of lysosomal proteases. A role for autophagy in the cell death process was eliminated, suggesting that ETO induces a novel PCD pathway in mESCs. Inhibition of p53 either as a transcription factor by pifithrin α or in its mitochondrial role by pifithrin μ significantly reduced ESC death levels. Finally, EndoG was newly identified as a protease participating in the DNA fragmentation observed during ETO-induced PCD. We coined the term charontosis after Charon, the ferryman of the dead in Greek mythology, to refer to the PCD signaling events induced by ETO in mESCs. PMID:23500643

  12. Death imagery and death anxiety.

    PubMed

    McDonald, R T; Hilgendorf, W A

    1986-01-01

    This study investigated the relationship between positive/negative death imagery and death anxiety. Subjects were 179 undergraduate students at a large, private, midwestern university. Results reveal that on five measures of death anxiety the subjects with low death anxiety scores had significantly more positive death images than did those with high death anxiety scores. The few subjects who imagined death to be young (N = 14) had a significantly more positive image of death than those who perceived it to be an old person. Death was seen as male by 92% of the male respondents and 74% of the female respondents. Significant differences in death imagery and death anxiety were found between subjects enrolled in an introductory psychology course and those enrolled in a thanatology course. No sex differences in death anxiety or positive/negative death imagery were found.

  13. Ultrastructural Evidence for a Dual Function of the Phloem and Programmed Cell Death in the Floral Nectary of Digitalis purpurea

    PubMed Central

    Gaffal, Karl Peter; Friedrichs, Gudrun Johanna; El-Gammal, Stefan

    2007-01-01

    Background and Aims The floral nectary of Digitalis purpurea is a transitory organ with stomatal exudation of nectar. In this type of nectary, the nectar is thought to be transported to the exterior via intercellular ducts that traverse the nectariferous tissue. The latter is also traversed by a ramified system of phloem strands from which prenectar sugar is most probably unloaded. The aims of this study were to provide some of the basic information needed to evaluate the possible mechanism involved in nectar secretion and to discover the fate of the nectary. Methods The ultrastructure of the nectary was investigated at different stages of development by analysis of a series of ultrathin (7 × 10−8 m) sections 7 × 10−7 m apart from one another. Proportions of the cells typical of the nectary were documented by 3D-reconstruction and morphometry. Key Results The phloem consisted of variably shaped sieve elements and companion cells which, as a rule, were more voluminous than the sieve elements. Direct contact between the phloem strands and intercellular ducts was observed. In contrast to the phloem, which remained structurally intact beyond the secretory phase, the nectariferous tissue exhibited degenerative changes reminiscent of programmed cell death (PCD), which started as early as the onset of secretion and progressed in a cascade-like fashion until final cell death occurred in the exhausted nectary. Hallmarks of PCD were: increased vacuolation; increase in electron opacity of individual cells; progressive incorporation of plasmatic components into the vacuole reminiscent of autophagy; degradation of plastids starting with hydrolysis of starch; deformation of the nucleus and gradual disappearance of chromatin; loss of tonoplast integrity and subsequent autolysis of the rest of cellular debris. Degeneration of the cells occurred against a background of increasing cell size. Conclusions The cytological and anatomical evidence presented here, and calculations

  14. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants.

    PubMed

    Chowdhury, Subrata; Veyhl, Joe; Jessa, Fatima; Polyakova, Olena; Alenzi, Ahmed; MacMillan, Christina; Ralhan, Ranju; Walfish, Paul G

    2016-05-31

    Programmed death-ligand 1(PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1 directed cancer immunotherapy. We analyzed PD-L1 expression in papillary thyroid carcinoma (PTC) and its variants and determined its prognostic potential to predict clinical outcome in these patients. This study was conducted at an academic oncology hospital which is a prime referral centre for thyroid diseases. Immunohistochemical subcellular localization (IHC) analyses of PD-L1 protein was retrospectively performed on 251 archived formalin fixed and paraffin embedded (FFPE) surgical tissues (66 benign thyroid nodules and 185 PTCs) using a rabbit monoclonal anti-PD-L1 antibody (E1L3N, Cell Signaling Technology) and detected using VECTASTAIN rapid protocol with diaminobenzidine (DAB) as the chromogen. The clinical-pathological factors and disease outcome over 190 months were assessed; immunohistochemical subcellular localization of PD-L1 was correlated with disease free survival (DFS) using Kaplan Meier survival and Cox multivariate regression analysis. Increased PD-L1 immunostaining was predominantly localized in cytoplasm and occasionally in plasma membrane of tumor cells. Among all combined stages of PTC, patients with increased PD-L1 membrane or cytoplasmic positivity had significantly shorter median DFS (36 months and 49 months respectively) as compared to those with PD-L1 negative tumors (DFS, both 186 months with p < 0.001 and p < 0.01 respectively). Comparison of PD-L1+ and PD-L1- patients with matched staging showed increased cytoplasmic positivity in all four stages of PTC that correlated with a greater risk of recurrence and a poor prognosis, but increased membrane positivity significantly correlated with a greater risk of metastasis or death only in Stage IV patients. In conclusion, PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease free survival supporting its potential application as

  15. Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia.

    PubMed

    Yang, Wen; Song, Yan; Lu, Yun-Long; Sun, Jun-Zhong; Wang, Hong-Wei

    2013-08-01

    Impaired local cellular immunity contributes to the pathogenesis of persistent high-risk human papillomavirus (HR-HPV) infection and related cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms remain unclear. Recently, the programmed death 1/programmed death 1 ligand (PD-1/PD-L1; CD279/CD274) pathway was demonstrated to play a critical role in attenuating T-cell responses and promoting T-cell tolerance during chronic viral infections. In this study, we examined the expression of PD-1 and PD-L1 on cervical T cells and dendritic cells (DCs), respectively, from 40 women who were HR-HPV-negative (-) or HR-HPV-positive (+) with CIN grades 0, I and II-III. We also measured interferon-γ, interleukin-12 (IL-12) and IL-10 in cervical exudates. The most common HPV type was HPV 16, followed by HPV 18, 33, 51 and 58. PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, was associated with HR-HPV positivity and increased in parallel with increasing CIN grade. The opposite pattern was observed for CD80 and CD86 expression on DCs, which decreased in HR-HPV+ patients in parallel with increasing CIN grade. Similarly, reduced levels of the T helper type 1 cytokines interferon-γ and IL-12 and increased levels of the T helper type 2 cytokine IL-10 in cervical exudates correlated with HR-HPV positivity and CIN grade. Our results suggest that up-regulation of the inhibitory PD-1/PD-L1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to the progression of HR-HPV-related CIN. These results may aid in the development of PD-1/PD-L1 pathway-based strategies for immunotherapy of HR-HPV-related CIN.

  16. [Epidemiology of type 1 diabetes in children].

    PubMed

    Barat, Pascal

    2016-01-01

    Type 1 diabetes is by far the most common in children. In 2004, its incidence was 13 to 14 new cases per 100 000 children each year and is progressing every year by more than 3%. This increase in incidence is affecting younger children. More than one quarter of children diagnosed in France are under the age of 5. The disease is still, in more than 40% of cases, first diagnosed as a result of an episode of ketoacidosis.

  17. Writer's cramp in spinocerebellar ataxia Type 1

    PubMed Central

    Khwaja, Geeta Anjum; Srivastava, Abhilekh; Ghuge, Vijay Vishwanath; Chaudhry, Neera

    2016-01-01

    Dystonia can be encountered in a small subset of patients with spinocerebellar ataxia (SCA), but task specific dystonia is extremely rare. We report a case of a 48-year-old male with confirmed SCA Type 1 (SCA1) with mild progressive cerebellar ataxia and a prominent and disabling Writer's cramp. This case highlights the ever-expanding phenotypic heterogeneity of the SCA's in general and SCA1 in particular. PMID:27695243

  18. Goldenhar syndrome and hereditary tyrosinemia type 1.

    PubMed

    Al-Sayed, Moeen A; Asmari, Ali M; Rashed, Mohammed S

    2002-12-01

    We report a case of Goldenhar syndrome and hereditary tyrosinemia type 1 (HTT1), to our knowledge an association not previously described. This case further increases the diversity of observations and clinical descriptions of patients with this complex syndrome. We discuss pathogenetic aspects, and demonstrate further evidence of the effectiveness of 2-(2-nitro-4-trifluoromethyl benzoyl)-1,3-cyclohexanedione in the treatment of HTT1.

  19. Writer's cramp in spinocerebellar ataxia Type 1

    PubMed Central

    Khwaja, Geeta Anjum; Srivastava, Abhilekh; Ghuge, Vijay Vishwanath; Chaudhry, Neera

    2016-01-01

    Dystonia can be encountered in a small subset of patients with spinocerebellar ataxia (SCA), but task specific dystonia is extremely rare. We report a case of a 48-year-old male with confirmed SCA Type 1 (SCA1) with mild progressive cerebellar ataxia and a prominent and disabling Writer's cramp. This case highlights the ever-expanding phenotypic heterogeneity of the SCA's in general and SCA1 in particular.

  20. Type 1 diabetes and cardiovascular disease

    PubMed Central

    2013-01-01

    The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements. PMID:24165454

  1. Type 1 diabetes and cardiovascular disease.

    PubMed

    Schnell, Oliver; Cappuccio, Francesco; Genovese, Stefano; Standl, Eberhard; Valensi, Paul; Ceriello, Antonio

    2013-01-01

    The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements. PMID:24165454

  2. Cardiovascular disease risk in young people with type 1 diabetes.

    PubMed

    Snell-Bergeon, Janet K; Nadeau, Kristen

    2012-08-01

    Cardiovascular disease (CVD) is the most frequent cause of death in people with type 1 diabetes (T1D), despite modern advances in glycemic control and CVD risk factor modification. CVD risk identification is essential in this high-risk population, yet remains poorly understood. This review discusses the risk factors for CVD in young people with T1D, including hyperglycemia, traditional CVD risk factors (dyslipidemia, smoking, physical activity, hypertension), as well as novel risk factors such as insulin resistance, inflammation, and hypoglycemia. We present evidence that adverse changes in cardiovascular function, arterial compliance, and atherosclerosis are present even during adolescence in people with T1D, highlighting the need for earlier intervention. The methods for investigating cardiovascular risk are discussed and reviewed. Finally, we discuss the observational studies and clinical trials which have thus far attempted to elucidate the best targets for early intervention in order to reduce the burden of CVD in people with T1D. PMID:22528676

  3. Cardiovascular disease risk in young people with type 1 diabetes.

    PubMed

    Snell-Bergeon, Janet K; Nadeau, Kristen

    2012-08-01

    Cardiovascular disease (CVD) is the most frequent cause of death in people with type 1 diabetes (T1D), despite modern advances in glycemic control and CVD risk factor modification. CVD risk identification is essential in this high-risk population, yet remains poorly understood. This review discusses the risk factors for CVD in young people with T1D, including hyperglycemia, traditional CVD risk factors (dyslipidemia, smoking, physical activity, hypertension), as well as novel risk factors such as insulin resistance, inflammation, and hypoglycemia. We present evidence that adverse changes in cardiovascular function, arterial compliance, and atherosclerosis are present even during adolescence in people with T1D, highlighting the need for earlier intervention. The methods for investigating cardiovascular risk are discussed and reviewed. Finally, we discuss the observational studies and clinical trials which have thus far attempted to elucidate the best targets for early intervention in order to reduce the burden of CVD in people with T1D.

  4. Programmed cell death in kiwifruit stigmatic arms and its relationship to the effective pollination period and the progamic phase

    PubMed Central

    Ferradás, Yolanda; López, Marián; Rey, Manuel; González, Ma Victoria

    2014-01-01

    Background and Aims Kiwifruit is a crop with a highly successful reproductive performance, which is impaired by the short effective pollination period of female flowers. This study investigates whether the degenerative processes observed in both pollinated and non-pollinated flowers after anthesis may be considered to be programmed cell death (PCD). Methods Features of PCD in kiwifruit, Actinidia chinensis var. deliciosa, were studied in both non-pollinated and pollinated stigmatic arms using transmission electron microscopy, DAPI (4′,6-diamidino-2-phenylindole) staining, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assays, DNA gel electrophoresis and caspase-like activity assays. Key Results In the secretory tissues of the stigmatic arms, cell organelles disintegrated sequentially while progressive vacuolization was detected. At the same time, chromatin condensation, nuclear deformation, and DNA fragmentation and degradation were observed. These features were detected in both non-pollinated and pollinated stigmatic arms; they were evident in the stigmas of pollinated flowers by the second day after anthesis but only by 4 d after anthesis in non-pollinated flowers. In addition, in pollinated stigmatic arms, these features were first initiated in the stigma and gradually progressed through the style, consistent with pollen tube growth. This timing of events was also observed in both non-pollinated and pollinated stigmatic arms for caspase-3-like activity. Conclusions The data provide evidence to support the hypothesis that PCD processes occurring in the secretory tissue of non-pollinated kiwifruit stigmatic arms could be the origin for the observed short effective pollination period. The results obtained in the secretory tissue of pollinated kiwifruit stigmatic arms upon pollination support the idea that PCD might be accelerated by pollination, pointing to the involvement of PCD during the progamic phase. PMID:24782437

  5. Hypoxic stress triggers a programmed cell death pathway to induce vascular cavity formation in Pisum sativum roots.

    PubMed

    Sarkar, Purbasha; Gladish, Daniel K

    2012-12-01

    Flooding at warm temperatures induces hypoxic stress in Pisum sativum seedling roots. In response, some undifferentiated cells in the primary root vascular cylinder start degenerating and form a longitudinal vascular cavity. Changes in cellular morphology and cell wall ultrastructure detected previously in the late stages of cavity formation suggest possible involvement of programmed cell death (PCD). In this study, cytological events occurring in the early stages of cavity formation were investigated. Systematic DNA fragmentation, a feature of many PCD pathways, was detected in the cavity-forming roots after 3 h of flooding in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and in isolated total DNA by gel electrophoresis. High molecular weight DNA fragments of about 20-30 kb were detected by pulse-field gel electrophoresis, but no low-molecular weight internucleosomal DNA fragments were detected by conventional gel electrophoresis. Release of mitochondrial cytochrome c protein into the cytosol, an integral part of mitochondria-dependent PCD pathways, was detected in the cavity-forming roots within 2 h of flooding by fluorescence microscopy of immunolabeled cytochrome c in situ and in isolated mitochondrial and cytosolic protein fractions by western blotting. DNA fragmentation and cytochrome c release remained confined to the undifferentiated cells in center of the root vascular cylinders, even after 24 h of flooding, while outer vascular cylinder cells and cortical cells maintained cellular integrity and normal activity. These findings confirm that hypoxia-induced vascular cavity formation in P. sativum roots involves PCD, and provides a chronological model of cytological events involved in this rare and understudied PCD system.

  6. Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells.

    PubMed

    Coombs, Melanie R Power; Harrison, Megan E; Hoskin, David W

    2016-10-01

    Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells. IFN-β-induced expression of PD-L1 by MDA-MB-468 cells was also inhibited by apigenin. In addition, luteolin, the major metabolite of apigenin, inhibited IFN-γ-induced PD-L1 expression by MDA-MB-468 cells. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 and 4T1 cells was associated with reduced phosphorylation of STAT1, which was early and transient at Tyr701 and sustained at Ser727. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 cells also increased proliferation and interleukin-2 synthesis by PD-1-expressing Jurkat T cells that were co-cultured with MDA-MB-468 cells. Apigenin therefore has the potential to increase the vulnerability of BC cells to T cell-mediated anti-tumor immune responses. PMID:27378243

  7. Unveiling Interactions among Mitochondria, Caspase-Like Proteases, and the Actin Cytoskeleton during Plant Programmed Cell Death (PCD)

    PubMed Central

    Lord, Christina E. N.; Dauphinee, Adrian N.; Watts, Rebecca L.; Gunawardena, Arunika H. L. A. N.

    2013-01-01

    Aponogeton madagascariensis produces perforations over its leaf surface via programmed cell death (PCD). PCD begins between longitudinal and transverse veins at the center of spaces regarded as areoles, and continues outward, stopping several cells from these veins. The gradient of PCD that exists within a single areole of leaves in an early stage of development was used as a model to investigate cellular dynamics during PCD. Mitochondria have interactions with a family of proteases known as caspases, and the actin cytoskeleton during metazoan PCD; less is known regarding these interactions during plant PCD. This study employed the actin stain Alexa Fluor 488 phalloidin, the actin depolymerizer Latrunculin B (Lat B), a synthetic caspase peptide substrate and corresponding specific inhibitors, as well as the mitochondrial pore inhibitor cyclosporine A (CsA) to analyze the role of these cellular constituents during PCD. Results depicted that YVADase (caspase-1) activity is higher during the very early stages of perforation formation, followed by the bundling and subsequent breakdown of actin. Actin depolymerization using Lat B caused no change in YVADase activity. In vivo inhibition of YVADase activity prevented PCD and actin breakdown, therefore substantiating actin as a likely substrate for caspase-like proteases (CLPs). The mitochondrial pore inhibitor CsA significantly decreased YVADase activity, and prevented both PCD and actin breakdown; therefore suggesting the mitochondria as a possible trigger for CLPs during PCD in the lace plant. To our knowledge, this is the first in vivo study using either caspase-1 inhibitor (Ac-YVAD-CMK) or CsA, following which the actin cytoskeleton was examined. Overall, our findings suggest the mitochondria as a possible upstream activator of YVADase activity and implicate these proteases as potential initiators of actin breakdown during perforation formation via PCD in the lace plant. PMID:23483897

  8. Presence of base excision repair enzymes in the wheat aleurone and their activation in cells undergoing programmed cell death.

    PubMed

    Bissenbaev, Amangeldy K; Ishchenko, Alexander A; Taipakova, Sabira M; Saparbaev, Murat K

    2011-10-01

    Cereal aleurone cells are specialized endosperm cells that produce enzymes to hydrolyze the starchy endosperm during germination. Aleurone cells can undergo programmed cell death (PCD) when incubated in the presence of gibberellic acid (GA) in contrast to abscisic acid (ABA) which inhibits the process. The progression of PCD in aleurone layer cells of wheat grain is accompanied by an increase in deoxyribonuclease (DNase) activities and the internucleosomal degradation of nuclear DNA. Reactive oxygen species (ROS) are increased during PCD in the aleurone cells owing to the β-oxidation of triglycerides and inhibition of the antioxidant enzymes possibly leading to extensive oxidative damage to DNA. ROS generate mainly non-bulky DNA base lesions which are removed in the base excision repair (BER) pathway, initiated by the DNA glycosylases. At present, very little is known about oxidative DNA damage repair in cereals. Here, we study DNA repair in the cell-free extracts of wheat aleurone layer incubated or not with phytohormones. We show, for the first time, the presence of 8-oxoguanine-DNA and ethenoadenine-DNA glycosylase activities in wheat aleurone cells. Interestingly, the DNA glycosylase and AP endonuclease activities are strongly induced in the presence of GA. Based on these data we propose that GA in addition to activation of nuclear DNases also induces the DNA repair activities which remove oxidized DNA bases in the BER pathway. Potential roles of the wheat DNA glycosylases in GA-induced oligonucleosomal fragmentation of DNA and metabolic activation of aleurone layer cells via repair of transcribed regions are discussed.

  9. Ectopic Expression of BnaC.CP20.1 Results in Premature Tapetal Programmed Cell Death in Arabidopsis.

    PubMed

    Song, Liping; Zhou, Zhengfu; Tang, Shan; Zhang, Zhiqiang; Xia, Shengqian; Qin, Maomao; Li, Bao; Wen, Jing; Yi, Bin; Shen, Jinxiong; Ma, Chaozhi; Fu, Tingdong; Tu, Jinxing

    2016-09-01

    Tapetal programmed cell death (PCD) is essential in pollen grain development, and cysteine proteases are ubiquitous enzymes participating in plant PCD. Although the major papain-like cysteine proteases (PLCPs) have been investigated, the exact functions of many PLCPs are still poorly understood in PCD. Here, we identified a PLCP gene, BnaC.CP20.1, which was closely related to XP_013596648.1 from Brassica oleracea. Quantitative real-time PCR analysis revealed that BnaC.CP20.1 expression was down-regulated in male-sterile lines in oilseed rape, suggesting a connection between this gene and male sterility. BnaC.CP20.1 is especially active in the tapetum and microspores in Brassica napus from the uninucleate stage until formation of mature pollen grains during anther development. On expression of BnaC.CP20.1 prior to the tetrad stage, BnA9::BnaC.CP20.1 transgenic lines in Arabidopsis thaliana showed a male-sterile phenotype with shortened siliques containing fewer or no seeds by self-crossing. Scanning electron microscopy indicated that the reticulate exine was defective in aborted microspores. Callose degradation was delayed and microspores were not released from the tetrad in a timely fashion. Additionally, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay indicated that BnaC.CP20.1 ectopic expression led to premature tapetal PCD. Transmission electron microscopy analyses further demonstrated that the pollen abortion was due to the absence of tectum connections to the bacula in the transgenic anthers. These findings suggest that timely expression of BnaC.CP20.1 is necessary for tapetal degeneration and pollen wall formation. PMID:27388342

  10. Epigenetic Changes are Associated with Programmed Cell Death Induced by Heat Stress in Seedling Leaves of Zea mays.

    PubMed

    Wang, Pu; Zhao, Lin; Hou, Haoli; Zhang, Hao; Huang, Yan; Wang, Yapei; Li, Hui; Gao, Fei; Yan, Shihan; Li, Lijia

    2015-05-01

    Histone modification plays a crucial role in regulation of chromatin architecture and function, responding to adverse external stimuli. However, little is known about a possible relationship between epigenetic modification and programmed cell death (PCD) in response to environmental stress. Here, we found that heat stress induced PCD in maize seedling leaves which was characterized by chromatin DNA laddering and DNA strand breaks detected by a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) test. The activities of the reactive oxygen species (ROS)-related enzymes superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) were progressively increased over time in the heat-treated seedlings. However, the concentration of H2O2 remained at relatively lower levels, while the concentration of superoxide anion ([Formula: see text]) was increased, accompanied by the occurrence of higher ion leakage rates after heat treatment. The total acetylation levels of histones H3K9, H4K5 and H3 were significantly increased, whereas the di-methylation level of histone H3K4 was unchanged and the di-methylation level of histone H3K9 was decreased in the seedling leaves exposed to heat stress compared with the control seedlings, accompanied by increased nucleolus size indicative of chromatin decondensation. Furthermore, treatment of seedlings with trichostatin A (TSA), which always results in genomic histone hyperacetylation, caused an increase in the [Formula: see text] level within the cells. The results suggested that heat stress persistently induced [Formula: see text], leading to PCD in association with histone modification changes in the maize leaves.

  11. Overexpression of Arabidopsis Ceramide Synthases Differentially Affects Growth, Sphingolipid Metabolism, Programmed Cell Death, and Mycotoxin Resistance1[OPEN

    PubMed Central

    Luttgeharm, Kyle D.; Chen, Ming; Mehra, Amit; Cahoon, Rebecca E.; Markham, Jonathan E.; Cahoon, Edgar B.

    2015-01-01

    Ceramide synthases catalyze an N-acyltransferase reaction using fatty acyl-coenzyme A (CoA) and long-chain base (LCB) substrates to form the sphingolipid ceramide backbone and are targets for inhibition by the mycotoxin fumonisin B1 (FB1). Arabidopsis (Arabidopsis thaliana) contains three genes encoding ceramide synthases with distinct substrate specificities: LONGEVITY ASSURANCE GENE ONE HOMOLOG1 (LOH1; At3g25540)- and LOH3 (At1g19260)-encoded ceramide synthases use very-long-chain fatty acyl-CoA and trihydroxy LCB substrates, and LOH2 (At3g19260)-encoded ceramide synthase uses palmitoyl-CoA and dihydroxy LCB substrates. In this study, complementary DNAs for each gene were overexpressed to determine the role of individual isoforms in physiology and sphingolipid metabolism. Differences were observed in growth resulting from LOH1 and LOH3 overexpression compared with LOH2 overexpression. LOH1- and LOH3-overexpressing plants had enhanced biomass relative to wild-type plants, due in part to increased cell division, suggesting that enhanced synthesis of very-long-chain fatty acid/trihydroxy LCB ceramides promotes cell division and growth. Conversely, LOH2 overexpression resulted in dwarfing. LOH2 overexpression also resulted in the accumulation of sphingolipids with C16 fatty acid/dihydroxy LCB ceramides, constitutive induction of programmed cell death, and accumulation of salicylic acid, closely mimicking phenotypes observed previously in LCB C-4 hydroxylase mutants defective in trihydroxy LCB synthesis. In addition, LOH2- and LOH3-overexpressing plants acquired increased resistance to FB1, whereas LOH1-overexpressing plants showed no increase in FB1 resistance, compared with wild-type plants, indicating that LOH1 ceramide synthase is most strongly inhibited by FB1. Overall, the findings described here demonstrate that overexpression of Arabidopsis ceramide synthases results in strongly divergent physiological and metabolic phenotypes, some of which have significance

  12. The Hydrogen Sulfide Donor NaHS Delays Programmed Cell Death in Barley Aleurone Layers by Acting as an Antioxidant.

    PubMed

    Zhang, Ying-Xin; Hu, Kang-Di; Lv, Kai; Li, Yan-Hong; Hu, Lan-Ying; Zhang, Xi-Qi; Ruan, Long; Liu, Yong-Sheng; Zhang, Hua

    2015-01-01

    H2S is a signaling molecule in plants and animals. Here we investigated the effects of H2S on programmed cell death (PCD) in barley (Hordeum vulgare L.) aleurone layers. The H2S donor NaHS significantly delayed PCD in aleurone layers isolated from imbibed embryoless barley grain. NaHS at 0.25 mM effectively reduced the accumulation of superoxide anion (·O2 (-)), hydrogen peroxide (H2O2), and malondialdehyde (MDA), promoted the activity of superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX), and decreased those of lipoxygenase (LOX) in isolated aleurone layers. Quantitative-PCR showed that NaHS treatment of aleurone tissue led to enhanced transcript levels of the antioxidant genes HvSOD1, HvAPX, HvCAT1, and HvCAT2 and repressed transcript levels of HvLOX (lipoxygenase gene) and of two cysteine protease genes HvEPA and HvCP3-31. NaHS treatment in gibberellic acid- (GA-) treated aleurone layers also delayed the PCD process, reduced the content of ·O2 (-), and increased POD activity while decreasing LOX activity. Furthermore, α-amylase secretion in barley aleurone layers was enhanced by NaHS treatment regardless of the presence or absence of GA. These data imply that H2S acted as an antioxidant in delaying PCD and enhances α-amylase secretion regardless of the presence of GA in barley aleurone layers.

  13. Anti-Programmed Cell Death (PD)-1 Immunotherapy for Malignant Tumor: A Systematic Review and Meta-Analysis.

    PubMed

    Chen, Ran; Peng, Pei-Chun; Wen, Bin; Li, Fu-Ying; Xie, Sheng; Chen, Guozhong; Lu, Jiefu; Peng, Zhuoyu; Tang, Shao-Bo; Liang, Yu-Mei; Deng, Xin

    2016-02-01

    This systematic review and meta-analysis evaluated anti-programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti-PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti-PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti-PD-1 therapy can be recommended for routine clinical use. PMID:26947879

  14. Programmed Death Ligand 1 Promotes Early-Life Chlamydia Respiratory Infection-Induced Severe Allergic Airway Disease.

    PubMed

    Starkey, Malcolm R; Nguyen, Duc H; Brown, Alexandra C; Essilfie, Ama-Tawiah; Kim, Richard Y; Yagita, Hideo; Horvat, Jay C; Hansbro, Philip M

    2016-04-01

    Chlamydia infections are frequent causes of respiratory illness, particularly pneumonia in infants, and are linked to permanent reductions in lung function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. In the current study, we investigated the role of programmed death (PD)-1 and its ligands PD-L1 and PD-L2 in promoting early-life Chlamydia respiratory infection, and infection-induced airway hyperresponsiveness (AHR) and severe allergic airway disease in later life. Infection increased PD-1 and PD-L1, but not PD-L2, mRNA expression in the lung. Flow cytometric analysis of whole lung homogenates identified monocytes, dendritic cells, CD4(+), and CD8(+) T cells as major sources of PD-1 and PD-L1. Inhibition of PD-1 and PD-L1, but not PD-L2, during infection ablated infection-induced AHR in later life. Given that PD-L1 was the most highly up-regulated and its targeting prevented infection-induced AHR, subsequent analyses focused on this ligand. Inhibition of PD-L1 had no effect on Chlamydia load but suppressed infection-induced pulmonary inflammation. Infection decreased the levels of the IL-13 decoy receptor in the lung, which were restored to baseline levels by inhibition of PD-L1. Finally, inhibition of PD-L1 during infection prevented subsequent infection-induced severe allergic airways disease in later life by decreasing IL-13 levels, Gob-5 expression, mucus production, and AHR. Thus, early-life Chlamydia respiratory infection-induced PD-L1 promotes severe inflammation during infection, permanent reductions in lung function, and the development of more severe allergic airway disease in later life.

  15. Self-incompatibility-induced programmed cell death in field poppy pollen involves dramatic acidification of the incompatible pollen tube cytosol.

    PubMed

    Wilkins, Katie A; Bosch, Maurice; Haque, Tamanna; Teng, Nianjun; Poulter, Natalie S; Franklin-Tong, Vernonica E

    2015-03-01

    Self-incompatibility (SI) is an important genetically controlled mechanism to prevent inbreeding in higher plants. SI involves highly specific interactions during pollination, resulting in the rejection of incompatible (self) pollen. Programmed cell death (PCD) is an important mechanism for destroying cells in a precisely regulated manner. SI in field poppy (Papaver rhoeas) triggers PCD in incompatible pollen. During SI-induced PCD, we previously observed a major acidification of the pollen cytosol. Here, we present measurements of temporal alterations in cytosolic pH ([pH]cyt); they were surprisingly rapid, reaching pH 6.4 within 10 min of SI induction and stabilizing by 60 min at pH 5.5. By manipulating the [pH]cyt of the pollen tubes in vivo, we show that [pH]cyt acidification is an integral and essential event for SI-induced PCD. Here, we provide evidence showing the physiological relevance of the cytosolic acidification and identify key targets of this major physiological alteration. A small drop in [pH]cyt inhibits the activity of a soluble inorganic pyrophosphatase required for pollen tube growth. We also show that [pH]cyt acidification is necessary and sufficient for triggering several key hallmark features of the SI PCD signaling pathway, notably activation of a DEVDase/caspase-3-like activity and formation of SI-induced punctate actin foci. Importantly, the actin binding proteins Cyclase-Associated Protein and Actin-Depolymerizing Factor are identified as key downstream targets. Thus, we have shown the biological relevance of an extreme but physiologically relevant alteration in [pH]cyt and its effect on several components in the context of SI-induced events and PCD.

  16. Ectopic Expression of BnaC.CP20.1 Results in Premature Tapetal Programmed Cell Death in Arabidopsis.

    PubMed

    Song, Liping; Zhou, Zhengfu; Tang, Shan; Zhang, Zhiqiang; Xia, Shengqian; Qin, Maomao; Li, Bao; Wen, Jing; Yi, Bin; Shen, Jinxiong; Ma, Chaozhi; Fu, Tingdong; Tu, Jinxing

    2016-09-01

    Tapetal programmed cell death (PCD) is essential in pollen grain development, and cysteine proteases are ubiquitous enzymes participating in plant PCD. Although the major papain-like cysteine proteases (PLCPs) have been investigated, the exact functions of many PLCPs are still poorly understood in PCD. Here, we identified a PLCP gene, BnaC.CP20.1, which was closely related to XP_013596648.1 from Brassica oleracea. Quantitative real-time PCR analysis revealed that BnaC.CP20.1 expression was down-regulated in male-sterile lines in oilseed rape, suggesting a connection between this gene and male sterility. BnaC.CP20.1 is especially active in the tapetum and microspores in Brassica napus from the uninucleate stage until formation of mature pollen grains during anther development. On expression of BnaC.CP20.1 prior to the tetrad stage, BnA9::BnaC.CP20.1 transgenic lines in Arabidopsis thaliana showed a male-sterile phenotype with shortened siliques containing fewer or no seeds by self-crossing. Scanning electron microscopy indicated that the reticulate exine was defective in aborted microspores. Callose degradation was delayed and microspores were not released from the tetrad in a timely fashion. Additionally, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay indicated that BnaC.CP20.1 ectopic expression led to premature tapetal PCD. Transmission electron microscopy analyses further demonstrated that the pollen abortion was due to the absence of tectum connections to the bacula in the transgenic anthers. These findings suggest that timely expression of BnaC.CP20.1 is necessary for tapetal degeneration and pollen wall formation.

  17. Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma.

    PubMed

    Xie, Qian-Kun; Zhao, Yu-Jie; Pan, Tao; Lyu, Ning; Mu, Lu-Wen; Li, Shao-Long; Shi, Mu-De; Zhang, Zhen-Feng; Zhou, Peng-Hui; Zhao, Ming

    2016-07-01

    It is well known that the aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impairs antitumor immunity. To date, in hepatocellular carcinoma (HCC), the relationship between PD-L1 expression and host-tumor immunity is not well defined. Here, the expression levels of PD-L1 and CD8(+) T cell infiltration were analyzed by immunohistochemistry (IHC) in formalin fixed paraffin embedded (FFPE) specimens from 167 HCC patients undergoing resection. A significant positive association was found between PD-L1 expression and the presence of CD8(+) T cell (p < 0.0001). Moreover, constitutive PD-L1 protein expression was not detected by western blot in HepG2, Hep3B, and 7402 HCC cancer cell lines; but co-cultured these cell lines with INFγ, a cytokine produced by activated CD8(+) T cells, remarkably upregulated PD-L1 expression. In fresh frozen HCC specimens, INFγ was found to be significantly correlated with PD-L1 and CD8(+) gene expression, as evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). These findings indicate that increased PD-L1 level may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity. Both increased intratumoral PD-L1 and CD8(+) were significantly associated with superior DFS (CD8(+): p = 0.03; PD-L1: p = 0.023) and OS (CD8(+): p = 0.001 and PD-L1: p = 0.059), but PD-L1 expression was not independently prognostic. In conclusions, PD-L1 upregulation is mainly induced by activated CD8(+) cytotoxic T cells pre-existing in HCC milieu rather than be constitutively expressed by the tumor cells, and it is a favorable prognostic factor for HCC. PMID:27622038

  18. Downregulation of Programmed Cell Death 4 by Inflammatory Conditions Contributes to the Generation of the Tumor Promoting Microenvironment

    PubMed Central

    Yasuda, Michiko; Schmid, Tobias; Rübsamen, Daniela; Colburn, Nancy H.; Irie, Kazuhiro; Murakami, Akira

    2012-01-01

    Ample evidence has shown key roles of inflammation in tumor promotion and carcinogenesis, and tumor-associated macrophages are known to promote tumor growth and dissemination. Programmed cell death 4 (Pdcd4) is a novel tumor suppressor, and although various studies have revealed that the functions and expression mechanisms of Pdcd4 in tumor promotion, those in regard to inflammation remain unclear. In the present study, we examined whether inflammatory stimuli regulate Pdcd4 expression. 12-O-tetradecanoylphorbol 13-acetate (TPA) suppressed expression of pdcd4 mRNA in human monocytic cell lines (U937, THP-1). Similarly, the bacterial endotoxin lipopolysaccharide (LPS) downregulated pdcd4 level in mouse RAW264.7 and peritoneal macrophages. Furthermore, conditioned medium from LPS-stimulated RAW264.7 macrophages suppressed pdcd4 mRNA in RAW264.7 macrophages, and findings obtained with recombinant tumor necrosis factor-α (TNF-α) and TNF-α-specific siRNA suggested that TNF-α partly mediates LPS-triggered Pdcd4 downregulation via an autocrine mechanism. Specific inhibitors of phosphoinositide-3-kinase (PI3K) and c-jun N-terminus kinase (JNK) restored LPS-abolished pdcd4 mRNA. Consistently, in MCF7 mammary carcinoma cells, conditioned medium from TPA-differentiated/activated U937 cells suppressed pdcd4 mRNA. Additionally, knockdown of pdcd4 in RAW264.7 macrophages using siRNA significantly enhanced LPS-induced TNF-α protein production, and interferon-γ, CC chemokine ligand (Ccl) 1, Ccl20, and interleukin-10 mRNA expression. These results suggest that Pdcd4 suppresses the induction of these inflammatory mediators. Taken together, loss of Pdcd4 in macrophages may be a critical step in establishing the inflammatory environment while that in tumor cells contributes to tumor progression. PMID:20607724

  19. Programmed Death-1 and Its Ligand Are Novel Immunotolerant Molecules Expressed on Leukemic B Cells in Chronic Lymphocytic Leukemia

    PubMed Central

    Mertens, Daniel; Tomczak, Waldemar; Wlasiuk, Paulina; Kosior, Kamila; Piechnik, Agnieszka; Bojarska-Junak, Agnieszka; Dmoszynska, Anna; Giannopoulos, Krzysztof

    2012-01-01

    Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies. PMID:22532845

  20. Hypothesis: increase of the ratio singlet oxygen plus superoxide radical to hydrogen peroxide changes stress defense response to programmed leaf death

    PubMed Central

    Sabater, Bartolomé; Martín, Mercedes

    2013-01-01

    The level of reactive oxygen species (ROS) increases under different stresses and, by destroying cellular components, may cause cell death. In addition, ROS are part of the complex network of transduction signals that induce defense reactions against stress or, alternatively, trigger programmed cell death, and key questions are the levels of each ROS that, respectively determine defense and death responses of the cell. The answer to those questions is difficult because there are several patterns of cell death that frequently appear mixed and are hardly distinguishable. Moreover, although considerable progresses have been achieved in the determination of the levels of specific ROS, critical questions remain on the ROS level in specific cell compartments. By considering chloroplasts as the main source of ROS in photosynthetic tissues at light, a comparison of the levels in stress and senescence of the chloroplastic activities involved in the generation and scavenging of ROS suggests plausible differences in the levels of specific ROS between stress defense and death. In effect, the three activities of the chlororespiratory chain increase similarly in stress defense response. However, in senescence, superoxide dismutase (SOD), that converts superoxide anion radical (O2∙−) to hydrogen peroxide (H2O2,) decreases, while the thylakoid Ndh complex, that favors the generation of singlet oxygen (1O2) and O2∙−, and peroxidase (PX), that consumes H2O2, increase. The obvious inference is that, in respect to defense response, the ratio (1O2 plus O2∙−)/H2O2 is increased in the senescence previous to cell death. We hypothesize that the different ROS ratios, probably through changes in the jasmonic acid/H2O2 ratio, could determine the activation of the defense network or the death network response of the cell. PMID:24324479

  1. Islet neogenesis: a potential therapeutic tool in type 1 diabetes.

    PubMed

    Lipsett, Mark; Aikin, Reid; Castellarin, Mauro; Hanley, Stephen; Jamal, Al-Maleek; Laganiere, Simon; Rosenberg, Lawrence

    2006-01-01

    Current therapies for type 1 diabetes, including fastidious blood glucose monitoring and multiple daily insulin injections, are not sufficient to prevent complications of the disease. Though pancreas and possibly islet transplantation can prevent the progression of complications, the scarcity of donor organs limits widespread application of these approaches. Understanding the mechanisms of beta-cell mass expansion as well as the means to exploit these pathways has enabled researchers to develop new strategies to expand and maintain islet cell mass. Potential new therapeutic avenues include ex vivo islet expansion and improved viability of islets prior to implantation, as well as the endogenous expansion of beta-cell mass within the diabetic patient. Islet neogenesis, through stem cell activation and/or transdifferentiation of mature fully differentiated cells, has been proposed as a means of beta-cell mass expansion. Finally, any successful new therapy for type 1 diabetes via beta-cell mass expansion will require prevention of beta-cell death and maintenance of long-term endocrine function. PMID:16216541

  2. Islet neogenesis: a potential therapeutic tool in type 1 diabetes.

    PubMed

    Lipsett, Mark; Aikin, Reid; Hanley, Stephen; Al-Maleek, Jamal; Laganiere, Simon; Rosenburg, Lawrence

    2006-01-01

    Current therapies for type 1 diabetes, including fastidious blood glucose monitoring and multiple daily insulin injections, are not sufficient to prevent complications of the disease. Though pancreas and possibly islet transplantation can prevent the progression of complications, the scarcity of donor organs limits widespread application of these approaches. Understanding the mechanisms of beta-cell mass expansion as well as the means to exploit these pathways has enabled researchers to develop new strategies to expand and maintain islet cell mass. Potential new therapeutic avenues include ex vivo islet expansion and improved viability of islets prior to implantation, as well as the endogenous expansion of beta-cell mass within the diabetic patient. Islet neogenesis, through stem cell activation and/or transdifferentiation of mature fully differentiated cells, has been proposed as a means of beta-cell mass expansion. Finally, any successful new therapy for type 1 diabetes via beta-cell mass expansion will require prevention of beta-cell death and maintenance of long-term endocrine function. PMID:16607698

  3. Type 1 diabetes pathogenesis – Prevention???

    PubMed Central

    Krishna, C. S. Muralidhara; Srikanta, S.

    2015-01-01

    Pathogenesis of type 1 diabetes is multi-faceted, including, autoimmunity, genetics and environment. Autoimmunity directed against pancreatic islet cells results in slowly progressive selective beta-cell destruction (“Primary autoimmune insulitis”), culminating over years in clinically manifested insulin-dependent diabetes mellitus (IDDM). Circulating serum autoantibodies directed against the endocrine cells of the islets of Langerhans (Islet cell autoantibodies - ICAb) are an important hallmark of this disease. Assays for islet cell autoantibodies have facilitated the investigation and understanding of several facets in the pathogenesis of autoimmune diabetes. Their applications have extended into clinical practice and have opened new avenues for early preclinical prediction and preventive prophylaxis in IDDM/type 1 DM. Recently, surprisingly, differences in insulin content between T1DM islets, as well as, ‘patchy’ or ‘lobular’ destruction of islets have been described. These unique pathobiological phenomena, suggest that beta cell destruction may not always be inexorable and inevitably complete/total, and thus raise hopes for possible therapeutic interruption of beta cell autoimmunity – destruction and cure of type 1 diabetes. “Recurrent or secondary autoimmune insulitis” refers to the rapid reappearance of islet cell autoantibodies post pancreas transplant, and selective islet beta cell destruction in the grafted pancreas [never forgetting or “anamnestic” beta cell destructive memory], in the absence of any graft pancreas rejection [monozygotic twin to twin transplantation]. The one definite environmental factor is congenital rubella, because of which a subset of children subsequently develop type 1 diabetes. The putative predisposing factors are viruses, gluten and cow's milk. The putative protective factors include gut flora, helminths, viral infections, and Vitamin D. Prevention of T1DM can include: Primary prevention strategies before

  4. Real life with type 1 diabetes mellitus.

    PubMed

    Yagnik, Deepak

    2015-04-01

    Type 1 diabetes mellitus (T1DM) is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. Those affected by this disorder have a challenging life, both in terms of health and social adjustments. Various "alternative medicines" are offered to them in an effort to cure. Research has shown that good control over diabetes can be maintained through regular self-monitoring of blood glucose and frequent checking of diabetic complications. Here, I describe a female with T1DM and her journey with the disorder.

  5. Real life with type 1 diabetes mellitus

    PubMed Central

    Yagnik, Deepak

    2015-01-01

    Type 1 diabetes mellitus (T1DM) is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. Those affected by this disorder have a challenging life, both in terms of health and social adjustments. Various “alternative medicines” are offered to them in an effort to cure. Research has shown that good control over diabetes can be maintained through regular self-monitoring of blood glucose and frequent checking of diabetic complications. Here, I describe a female with T1DM and her journey with the disorder. PMID:25941661

  6. Enzymes That Scavenge Reactive Oxygen Species Are Down-Regulated Prior to Gibberellic Acid-Induced Programmed Cell Death in Barley Aleurone1

    PubMed Central

    Fath, Angelika; Bethke, Paul C.; Jones, Russell L.

    2001-01-01

    Gibberellins (GAs) initiate a series of events that culminate in programmed cell death, whereas abscisic acid (ABA) prevents this process. Reactive oxygen species (ROS) are key elements in aleurone programmed cell death. Incubation of barley (Hordeum vulgare) aleurone layers in H2O2 causes rapid death of all cells in GA- but not ABA-treated layers. Sensitivity to H2O2 in GA-treated aleurone cells results from a decreased ability to metabolize ROS. The amounts and activities of ROS scavenging enzymes, including catalase (CAT), ascorbate peroxidase, and superoxide dismutase are strongly down-regulated in aleurone layers treated with GA. CAT activity, protein, and Cat2 mRNA decline rapidly following exposure of aleurone layers to GA. In ABA-treated layers, on the other hand, the amount and activity of CAT and Cat2 mRNA increases. Incubation in ABA maintains high amounts of ascorbate peroxidase and superoxide dismutase, whereas GA brings about a rapid reduction in the amounts of these enzymes. These data imply that GA-treated cells loose their ability to scavenge ROS and that this loss ultimately results in oxidative damage and cell death. ABA-treated cells, on the other hand, maintain their ability to scavenge ROS and remain viable. PMID:11351079

  7. Genetic risk factors for type 1 diabetes.

    PubMed

    Pociot, Flemming; Lernmark, Åke

    2016-06-01

    Type 1 diabetes is diagnosed at the end of a prodrome of β-cell autoimmunity. The disease is most likely triggered at an early age by autoantibodies primarily directed against insulin or glutamic acid decarboxylase, or both, but rarely against islet antigen-2. After the initial appearance of one of these autoantibody biomarkers, a second, third, or fourth autoantibody against either islet antigen-2 or the ZnT8 transporter might also appear. The larger the number of β-cell autoantibody types, the greater the risk of rapid progression to clinical onset of diabetes. This association does not necessarily mean that the β-cell autoantibodies are pathogenic, but rather that they represent reproducible biomarkers of the pathogenesis. The primary risk factor for β-cell autoimmunity is genetic, mainly occurring in individuals with either HLA-DR3-DQ2 or HLA-DR4-DQ8 haplotypes, or both, but a trigger from the environment is generally needed. The pathogenesis can be divided into three stages: 1, appearance of β-cell autoimmunity, normoglycaemia, and no symptoms; 2, β-cell autoimmunity, dysglycaemia, and no symptoms; and 3, β-cell autoimmunity, dysglycaemia, and symptoms of diabetes. The genetic association with each one of the three stages can differ. Type 1 diabetes could serve as a disease model for organ-specific autoimmune disorders such as coeliac disease, thyroiditis, and Addison's disease, which show similar early markers of a prolonged disease process before clinical diagnosis. PMID:27302272

  8. Genetics Home Reference: autoimmune polyglandular syndrome, type 1

    MedlinePlus

    ... polyglandular syndrome, type 1 autoimmune polyglandular syndrome, type 1 Enable Javascript to view the expand/collapse boxes. ... All Close All Description Autoimmune polyglandular syndrome, type 1 is an inherited condition that affects many of ...

  9. Genetics Home Reference: leukocyte adhesion deficiency type 1

    MedlinePlus

    ... adhesion deficiency type 1 leukocyte adhesion deficiency type 1 Enable Javascript to view the expand/collapse boxes. ... All Close All Description Leukocyte adhesion deficiency type 1 is a disorder that causes the immune system ...

  10. Genetics Home Reference: medullary cystic kidney disease type 1

    MedlinePlus

    ... disease type 1 medullary cystic kidney disease type 1 Enable Javascript to view the expand/collapse boxes. ... Close All Description Medullary cystic kidney disease type 1 (MCKD1) is an inherited condition that affects the ...

  11. Genetics Home Reference: congenital bile acid synthesis defect type 1

    MedlinePlus

    ... bile acid synthesis defect type 1 congenital bile acid synthesis defect type 1 Enable Javascript to view ... PDF Open All Close All Description Congenital bile acid synthesis defect type 1 is a disorder characterized ...

  12. 39 CFR 3010.13 - Proceedings for Type 1-A and Type 1-B rate adjustment filings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 39 Postal Service 1 2012-07-01 2012-07-01 false Proceedings for Type 1-A and Type 1-B rate... (Type 1-A and 1-B Rate Adjustments) § 3010.13 Proceedings for Type 1-A and Type 1-B rate adjustment... pursuant to appropriate action by the Governors. (e) If planned rate adjustments are found...

  13. 17beta-estradiol attenuates programmed cell death in cortical pericontusional zone following traumatic brain injury via upregulation of ERalpha and inhibition of caspase-3 activation.

    PubMed

    Li, Li-Zhuo; Bao, Yi-Jun; Zhao, Min

    2011-01-01

    Pericontusional zone (PCZ) of traumatic cerebral contusion is a target of pharmacological intervention. It is well studied that 17beta-estradiol has a protective role in ischemic brain injury, but its role in brain protection of traumatic brain damage deserves further investigation, especially in pericontusional zone. Here we show that 17beta-estradiol enhances the protein expression and mRNA induction of estrogen alpha receptor (ERalpha) and prevents from programmed cell death in cortical pericontusional zone. ERalpha specific antagonist blocks this protective effect of 17beta-estradiol. Caspase-3 activation occurs in cortical pericontusional zone of the oil-treated injured rat brain and its activation is inhibited by 17beta-estradiol treatment. Additionally, ERalpha specific antagonist reverses this inhibition. Pan-caspase inhibitor also protect cortical pericontusional zone from programmed cell death. Our present study indicates 17beta-estradiol protects from programmed cell death in cortical pericontusional zone via enhancement of ERalpha and decrease of caspase-3 activation.

  14. Pseudomonas Type III effector AvrPto suppresses the programmed cell death induced by two nonhost pathogens in Nicotiana benthamiana and tomato.

    PubMed

    Kang, Li; Tang, Xiaoyan; Mysore, Kirankumar S

    2004-12-01

    Many gram-negative bacterial pathogens rely on a type III secretion system to deliver a number of effector proteins into the host cell. Though a number of these effectors have been shown to contribute to bacterial pathogenicity, their functions remain elusive. Here we report that AvrPto, an effector known for its ability to interact with Pto and induce Pto-mediated disease resistance, inhibited the hypersensitive response (HR) induced by nonhost pathogen interactions. Pseudomonas syringae pv. tomato T1 causes an HR-like cell death on Nicotiana benthamiana. This rapid cell death was delayed significantly in plants inoculated with P. syringae pv. tomato expressing avrPto. In addition, P. syringae pv. tabaci expressing avrPto suppressed nonhost HR on tomato prf3 and ptoS lines. Transient expression of avrPto in both N. benthamiana and tomato prf3 plants also was able to suppress nonhost HR. Interestingly, AvrPto failed to suppress cell death caused by other elicitors and nonhost pathogens. AvrPto also failed to suppress cell death caused by certain gene-for-gene disease resistance interactions. Experiments with avrPto mutants revealed several residues important for the suppression effects. AvrPto mutants G2A, G99V, P146L, and a 12-amino-acid C-terminal deletion mutant partially lost the suppression ability, whereas S94P and 196T enhanced suppression of cell death in N. benthamiana. These results, together with other discoveries, demonstrated that suppression of host-programmed cell death may serve as one of the strategies bacterial pathoens use for successful invasion. PMID:15597738

  15. High Specificity in Circulating Tumor Cell Identification Is Required for Accurate Evaluation of Programmed Death-Ligand 1

    PubMed Central

    Schultz, Zachery D.; Warrick, Jay W.; Guckenberger, David J.; Pezzi, Hannah M.; Sperger, Jamie M.; Heninger, Erika; Saeed, Anwaar; Leal, Ticiana; Mattox, Kara; Traynor, Anne M.; Campbell, Toby C.; Berry, Scott M.; Beebe, David J.; Lang, Joshua M.

    2016-01-01

    Background Expression of programmed-death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) is typically evaluated through invasive biopsies; however, recent advances in the identification of circulating tumor cells (CTCs) may be a less invasive method to assay tumor cells for these purposes. These liquid biopsies rely on accurate identification of CTCs from the diverse populations in the blood, where some tumor cells share characteristics with normal blood cells. While many blood cells can be excluded by their high expression of CD45, neutrophils and other immature myeloid subsets have low to absent expression of CD45 and also express PD-L1. Furthermore, cytokeratin is typically used to identify CTCs, but neutrophils may stain non-specifically for intracellular antibodies, including cytokeratin, thus preventing accurate evaluation of PD-L1 expression on tumor cells. This holds even greater significance when evaluating PD-L1 in epithelial cell adhesion molecule (EpCAM) positive and EpCAM negative CTCs (as in epithelial-mesenchymal transition (EMT)). Methods To evaluate the impact of CTC misidentification on PD-L1 evaluation, we utilized CD11b to identify myeloid cells. CTCs were isolated from patients with metastatic NSCLC using EpCAM, MUC1 or Vimentin capture antibodies and exclusion-based sample preparation (ESP) technology. Results Large populations of CD11b+CD45lo cells were identified in buffy coats and stained non-specifically for intracellular antibodies including cytokeratin. The amount of CD11b+ cells misidentified as CTCs varied among patients; accounting for 33–100% of traditionally identified CTCs. Cells captured with vimentin had a higher frequency of CD11b+ cells at 41%, compared to 20% and 18% with MUC1 or EpCAM, respectively. Cells misidentified as CTCs ultimately skewed PD-L1 expression to varying degrees across patient samples. Conclusions Interfering myeloid populations can be differentiated from true CTCs with additional staining criteria

  16. Programmed Death-1 Antibody Blocks Therapeutic Effects of T-Regulatory Cells in Cockroach Antigen-Induced Allergic Asthma

    PubMed Central

    McGee, Halvor S.; Yagita, Hideo; Shao, Zhifei; Agrawal, Devendra K.

    2010-01-01

    We recently reported that the adoptive transfer of T-regulatory cells (Tregs) isolated from lung and spleen tissue of green fluorescent protein–transgenic mice reversed airway hyperresponsiveness and airway inflammation. Because Programmed Death-1 (PD-1) is a pivotal receptor regulating effector T-cell activation by Tregs, we evaluated whether PD-1 is involved in the therapeutic effect of naturally occurring Tregs (NTregs) and inducible Tregs (iTregs) in cockroach (CRA)-sensitized and challenged mice. The CD4+CD25+ NTregs and CD4+CD25− iTregs isolated from the lungs and spleens of BALB/c mice were adoptively transferred into CRA-sensitized and CRA-challenged mice with and without anti–PD-1 antibody (100 μg/mice). The CD4+CD25+ T cells in the lung were phenotyped after adoptive transfer. Concentrations of IL-4, IL-5, IL-10, IFN-γ, and IL-13 in bronchoalveolar lavage fluid (BALF) were measured using ELISA. The NTregs and iTregs from either lung or spleen tissue reversed airway hyperresponsiveness for at least 4 wk. However, the therapeutic effect was blocked by administering the anti–PD-1 antibody. The administration of Tregs-recipient mice with anti–PD-1 antibody significantly decreased cytotoxic T-lymphocyte antigen-4 expression, with low concentrations of Forkhead-winged transcriptional factor box 3 (Foxp3) mRNA transcripts in lung CD4+CD25+ T cells. These mice had substantially higher concentrations of BALF IL-4, IL-5, and IL-13, but significantly decreased levels of BALF IL-10. Adoptive therapy recipients without the anti–PD-1 antibody exhibited high levels of CTLA-4 expression and Foxp3 transcripts in lung CD4+CD25+ T cells, with a significant decrease in BALF IL-4, IL-5, and IL-13 concentrations and a substantial increase in BALF IL-10 concentrations. These data suggest that the reversal of airway hyperresponsiveness and airway inflammation by Tregs is mediated in part by PD-1, because other costimulatory molecules (e.g., inducible costimulatory

  17. Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4

    PubMed Central

    Chen, B.; Huang, S.G.; Ju, L.; Li, M.; Nie, F.F.; Zhang, Y.; Zhang, Y.H.; Chen, X.; Gao, F.

    2016-01-01

    This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4) tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration (IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions were tested. NP cells from IDD patients were collected and divided into blank control group, negative control group (transfected with miR-21 negative sequences), miR-21 inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group (transfected with miR-21 mimics) and PDCD4 siRNA group (transfected with PDCD4 siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA were respectively elevated and decreased (both P<0.05). The miR-21 expressions were positively correlated with Pfirrmann grades, but negatively correlated with PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9 mRNA expressions, and p-c-Jun protein expressions were significantly lower, while PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05). These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the proliferation of human degenerated NP cells by targeting PDCD4, increasing phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of IDD. PMID:27240294

  18. Virus infections and type 1 diabetes risk.

    PubMed

    Roivainen, Merja; Klingel, Karin

    2010-10-01

    Common intestinal infections caused by human enteroviruses (HEVs) are considered major environmental factors predisposing to type 1 diabetes (T1D). In spite of the active research of the field, the HEV-induced pathogenetic processes are poorly understood. Recently, after the first documented report on HEV infections in the pancreatic islets of deceased T1D patients, several groups became interested in the issue and studied valuable human material, the autopsy pancreases of diabetic and/or autoantibody-positive patients for HEV infections. In this review, the data on HEV infections in human pancreatic islets are discussed with special reference to the methods used. Likewise, mechanisms that could increase viral access to the pancreas are reviewed and discussed.

  19. Microcephalic osteodysplastic primordial dwarfism type 1.

    PubMed

    Ferrell, Steven; Johnson, Aaron; Pearson, Waylon

    2016-01-01

    Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is an uncommon cause of microcephaly and intrauterine growth retardation in a newborn. Early identifying features include but are not limited to sloping forehead, micrognathia, sparse hair, including of eyebrows and short limbs. Immediate radiological findings may include partial or complete agenesis of the corpus callosum, interhemispheric cyst and shallow acetabula leading to dislocation. Genetic testing displaying a mutation in RNU4ATAC gene is necessary for definitive diagnosis. Early identification is important as MOPD1 is an autosomal recessive condition and could present in subsequent pregnancies. The purpose of this case is to both identify and describe some common physical findings related to MOPD1. We present a case of MOPD1 in a girl born to non-consanguineous parents that was distinct for subglottic stenosis and laryngeal cleft. PMID:27312855

  20. NK Cells and Type 1 Diabetes

    PubMed Central

    Rodacki, Melanie; Milech, Adolpho; de Oliveira, José Egídio Paulo

    2006-01-01

    Type 1 diabetes (T1D) is characterized by an immuno-mediated progressive destruction of the pancreatic β cells. Due to the ability of NK cells to kill target cells as well as to interact with antigen-presenting and T cells, it has been suggested that they could be involved in one or multiple steps of the immune-mediated attack that leads to T1D. Abnormalities in the frequency and activity of NK cells have been described both in animal models and patients with T1D. Some of these alterations are linked to its onset while others seem to be a consequence of the disease. Here, we discuss the main characteristics of NK cells and review the studies that investigated the role of NK cells in T1D, both in mouse models and humans. PMID:17162353

  1. The intestinal microbiome in type 1 diabetes

    PubMed Central

    Dunne, J L; Triplett, E W; Gevers, D; Xavier, R; Insel, R; Danska, J; Atkinson, M A

    2014-01-01

    Few concepts in recent years have garnered more disease research attention than that of the intestinal (i.e. ‘gut’) microbiome. This emerging interest has included investigations of the microbiome's role in the pathogenesis of a variety of autoimmune disorders, including type 1 diabetes (T1D). Indeed, a growing number of recent studies of patients with T1D or at varying levels of risk for this disease, as well as in animal models of the disorder, lend increasing support to the notion that alterations in the microbiome precede T1D onset. Herein, we review these investigations, examining the mechanisms by which the microbiome may influence T1D development and explore how multi-disciplinary analysis of the microbiome and the host immune response may provide novel biomarkers and therapeutic options for prevention of T1D. PMID:24628412

  2. Lipoatrophy in Children With Type 1 Diabetes

    PubMed Central

    Kordonouri, Olga; Biester, Torben; Schnell, Kerstin; Hartmann, Reinhard; Tsioli, Christiana; Fath, Maryam; Datz, Nicolin; Danne, Thomas

    2014-01-01

    Objectives: The objectives were to evaluate the current prevalence of lipoatrophy at insulin injection sites in young patients with type 1 diabetes. Methods: Standardized examination of insulin injection sites in all 678 patients with type 1 diabetes treated in 2013 in our outpatient clinic were conducted. In case of lipoatrophy photo documentation and standardized interview with parents and patients were performed. Methods: We identified a total of 16 patients (43.8% male) with lipoatrophy (overall prevalence 2.4%). The current mean age (±SD) of the affected patients was 14.4 ± 3.9 years, age and diabetes duration at onset of lipoatrophy were 11.5 ± 3.8 years and 5.4 ± 3.6 years, respectively. All patients were using analogs at the onset of lipoatrophy. In all, 14 of 16 patients (87.5%) were on insulin pump compared with 52% without lipoatrophy (P = .0018). The use of steel needle and Teflon catheter was equal between the pump patients. Concomitant autoimmune diseases were present in 37.5% of the patients (thyroiditis: n = 3, thyroiditis and celiac disease: n = 2, celiac disease: n = 1) compared with 15.0% in those without lipoatrophy (P = .0128). Conclusions: Lipoatrophy was present in young patients treated with modern insulins and pumps; however, the prevalence was relatively low as expected with the use of modern insulins. Our data may support the hypothesis that a constant mechanical element such as a subcutaneous catheter may trigger the development of lipoatrophy, particularly in those patients with more than 1 autoimmune disease. PMID:25411060

  3. Cot Deaths.

    ERIC Educational Resources Information Center

    Tyrrell, Shelagh

    1985-01-01

    Addresses the tragedy of crib deaths, giving particular attention to causes, prevention, and medical research on Sudden Infant Death Syndrome (SIDS). Gives anecdotal accounts of coping strategies used by parents and families of SIDS infants. (DT)

  4. Is the risk and nature of CVD the same in type 1 and type 2 diabetes?

    PubMed

    Duca, Lindsey; Sippl, Rachel; Snell-Bergeon, Janet K

    2013-06-01

    The incidence of both type 1 and type 2 diabetes is increasing globally, most likely explained by environmental changes, such as changing exposures to foods, viruses, and toxins, and by increasing obesity. While cardiovascular disease (CVD) mortality has been declining recently, this global epidemic of diabetes threatens to stall this trend. CVD is the leading cause of death in both type 1 and type 2 diabetes, with at least a two- to fourfold increased risk in patients with diabetes. In this review, the risk factors for CVD are discussed in the context of type 1 and type 2 diabetes. While traditional risk factors such as dyslipidemia, hypertension, and obesity are greater in type 2 patients than in type 1 diabetes, they explain only about half of the increased CVD risk. The role for diabetes-specific risk factors, including hyperglycemia and kidney complications, is discussed in the context of new study findings. PMID:23519720

  5. Impact of the Family Health Program on the quality of vital information and reduction of child unattended deaths in Brazil: an ecological longitudinal study

    PubMed Central

    2010-01-01

    Background Vital information, despite of being an important public health instrument for planning and evaluation, in most of the developing countries have still low quality and coverage. Brazil has recently implemented the Family Health Program (PSF), one of the largest comprehensive primary health care programs in the world, which demonstrated effectiveness on the reduction of infant mortality. In the present study we evaluate the impact of the PSF on mortality rates related to the quality of vital information: the under-five mortality rate due to ill-defined causes and unattended death. Methods Data on mortality rates and PSF coverage was obtained for the total 5,507 Brazilian municipalities from 2000 to 2006. A multivariate regression analysis of panel data was carried out with a negative binomial response by using fixed effects models that control for relevant covariates. Results A statistically significant negative association was observed between PSF coverage levels, classified in none (0%, the reference category), low (<30.0%), intermediate (≥ 30.0% and <70.0%) and high (≥ 70.0%), and all analysed mortalities rates, with a reduction of 17% (Rate Ratio [RR]: 0.83; 95% confidence interval [CI]: 0.79 - 0.88), 35% (RR: 0.65; 95% CI: 0.61-0.68) and 50% (RR: 0.50; 95% CI: 0.47-0.53) on under-five mortality due to ill-defined causes, respectively. In the mortality rate for unattended death the reduction was even greater, reaching 60% (RR: 0.40; 95% CI: 0.37-0.44) in the municipalities with the highest PSF coverage. The PSF effect on unattended deaths was slightly stronger in municipalities with a higher human development index. Conclusions The PSF, a primary health care program developed mostly in rural and deprived areas, had an important role on reducing the unattended deaths and improving the quality of vital information in Brazil. PMID:20587036

  6. [A diagnostic program for estimating the time of death using microcalculators MK-61 and B3-34].

    PubMed

    Shved, E F; Novikov, P I; Vlasov, A Iu

    1989-01-01

    The programme design is based on the process of changes in dead body temperature. Specific features of the process of changes in temperature values of a dead body are characterized by a parameter which involves process sample obtained by temperature measurements in diagnostical area of a cadaver at the accident scene during 1 hour. Programme provides for estimation of postmortem interval within the first 60 h after death occurrence. Diagnostical deviations don't exceed +/- 3% as compared to the real time of death.

  7. Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor.

    PubMed

    Zhou, Huan; Xu, Minying; Gao, Ya; Deng, Zhigang; Cao, Hanwei; Zhang, Wenqing; Wang, Qiao; Zhang, Bing; Song, Gang; Zhan, Yanyan; Hu, Tianhui

    2014-03-16

    Matrine, a clinical drug in China, has been used to treat viral hepatitis, cardiac arrhythmia and skin inflammations. Matrine also exhibits chemotherapeutic potential through its ability to trigger cancer cell death. However, the mechanisms involved are still largely unknown. The objective of this study was to investigate the major determinant for the cell death induced by matrine in human hepatocellular carcinoma. We use human hepatocellular carcinoma cell line HepG2 and human hepatocellular carcinoma xenograft in nude mice as models to study the action of matrine in hepatocellular cancers. We found that caspase-dependent and -independent Program Cell Death (PCD) occurred in matrine-treated HepG2 cells, accompanied by the decreasing of mitochondrial transmembrane potential and the increasing ROS production. Further studies showed that AIF released from the mitochondria to the nucleus, and silencing of AIF reduced the caspase-independent PCD induced by matrine. What's more, AIF nuclear translocation, and the subsequent cell death as well, was prevented by Bid inhibitor BI-6C9, Bid-targeted siRNA and ROS scavenger Tiron. In the in vivo study, matrine significantly attenuated tumor growth with AIF release from mitochondria into nucleus in nude mice. These data imply that matrine potently induce caspase-independent PCD in HepG2 cells through Bid-mediated AIF translocation.

  8. Immunogenetics of type 1 diabetes mellitus.

    PubMed

    Morran, Michael P; Vonberg, Andrew; Khadra, Anmar; Pietropaolo, Massimo

    2015-04-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (i.e. HLA), and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations. A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immune-mediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped

  9. Immunogenetics of Type 1 Diabetes Mellitus

    PubMed Central

    Morran, Michael P.; Vonberg, Andrew; Khadra, Anmar; Pietropaolo, Massimo

    2015-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects, (i.e. HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations. A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immune-mediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped

  10. Apoptosis: A Functional Paradigm for Programmed Plant Cell Death Induced by a Host-Selective Phytotoxin and Invoked during Development.

    PubMed Central

    Wang, H; Li, J; Bostock, RM; Gilchrist, DG

    1996-01-01

    The host-selective AAL toxins secreted by Alternaria alternata f sp lycopersici are primary chemical determinants in the Alternaria stem canker disease of tomato. The AAL toxins are members of a new class of sphinganine analog mycotoxins that cause cell death in both animals and plants. Here, we report detection of stereotypic hallmarks of apoptosis during cell death induced by these toxins in tomato. DNA ladders were observed during cell death in toxin-treated tomato protoplasts and leaflets. The intensity of the DNA ladders was enhanced by Ca2+ and inhibited by Zn2+. The progressive delineation of fragmented DNA into distinct bodies, coincident with the appearance of DNA ladders, also was observed during death of toxin-treated tomato protoplasts. In situ analysis of cells dying during development in both onion root caps and tomato leaf tracheary elements revealed DNA fragmentation localized to the dying cells as well as the additional formation of apoptotic-like bodies in sloughing root cap cells. We conclude that the fundamental elements of apoptosis, as characterized in animals, are conserved in plants. The apoptotic process may be expressed during some developmental transitions and is the functional process by which symptomatic lesions are formed in the Alternaria stem canker disease of tomato. Sphinganine analog mycotoxins may be used to characterize further signaling pathways leading to apoptosis in plants. PMID:12239387

  11. Multiple Domain Associations within the Arabidopsis Immune Receptor RPP1 Regulate the Activation of Programmed Cell Death

    PubMed Central

    Schreiber, Karl J.; Bentham, Adam; Williams, Simon J.; Kobe, Bostjan; Staskawicz, Brian J.

    2016-01-01

    Upon recognition of pathogen virulence effectors, plant nucleotide-binding leucine-rich repeat (NLR) proteins induce defense responses including localized host cell death. In an effort to understand the molecular mechanisms leading to this response, we examined the Arabidopsis thaliana NLR protein RECOGNITION OF PERONOSPORA PARASITICA1 (RPP1), which recognizes the Hyaloperonospora arabidopsidis effector ARABIDOPSIS THALIANA RECOGNIZED1 (ATR1). Expression of the N-terminus of RPP1, including the Toll/interleukin-1 receptor (TIR) domain (“N-TIR”), elicited an effector-independent cell death response, and we used allelic variation in TIR domain sequences to define the key residues that contribute to this phenotype. Further biochemical characterization indicated that cell death induction was correlated with N-TIR domain self-association. In addition, we demonstrated that the nucleotide-binding (NB)-ARC1 region of RPP1 self-associates and plays a critical role in cell death activation, likely by facilitating TIR:TIR interactions. Structural homology modeling of the NB subdomain allowed us to identify a putative oligomerization interface that was shown to influence NB-ARC1 self-association. Significantly, full-length RPP1 exhibited effector-dependent oligomerization and, although mutations at the NB-ARC1 oligomerization interface eliminated cell death induction, RPP1 self-association was unaffected, suggesting that additional regions contribute to oligomerization. Indeed, the leucine-rich repeat domain of RPP1 also self-associates, indicating that multiple interaction interfaces exist within activated RPP1 oligomers. Finally, we observed numerous intramolecular interactions that likely function to negatively regulate RPP1, and present a model describing the transition to an active NLR protein. PMID:27427964

  12. [NARCOLEPSY WITH CATAPLEXY: TYPE 1 NARCOLEPSY].

    PubMed

    Dauvilliers, Yves; Lopez, Régis

    2016-06-01

    Narcolepsy with cataplexy or narcolepsy type 1 in a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden less of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and weight gain. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin-1/orexin-A levels (values below 110 pg/mL) in the cerebrospinal fluid was highly specific for narcolepsy with cataplexy and was included in the recent diagnostic criteria for narcolepsy. The deficiency of the hypocretin system is well-established in human narcoleptics with a reduction of cerebrospinal fluid hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process in most probable acting on a highly genetic background with environmental factors such as streptococcal infections, and H1N1 AS03-adjuvanted vaccine named Pandemrix. PMID:27538328

  13. Equatorial Staphyloma Associated with Neurofibromatosis Type 1

    PubMed Central

    Shimada, Yoshiaki; Horiguchi, Masayuki

    2016-01-01

    We report a case of a 38-year-old man who presented with a recently self-detected lump under his left eyebrow. Previous ophthalmological history was unremarkable except for unilateral high myopia (left eye) since childhood. The appearance of the left eye was seemingly normal; however, with the top lid pulled up on downward gaze, a dark brown bulge emerged. The bulge was 10 × 7 mm and approximately 4 mm in height, and was covered by the extended superior rectus muscle. The diagnosis of equatorial staphyloma was made after coronal T1-weighted magnetic resonance imaging of the orbit revealed the dilatation of the vitreous cavity. Ocular movements were fully maintained and visual acuity was largely spared: 20/15 in the right eye without correction and 20/25 in the left eye with −10.00 spheres and −4.00 × 80 degrees cylinders. His past and family histories were unremarkable; however, small neurofibromas and café au lait spots all over his body led to the diagnosis of neurofibromatosis type 1 (NF1). From this case, similar to previous reports, we suggest that manifestations of NF1 are extremely variable and unpredictable. PMID:27721788

  14. Type 1 reaction center of photosynthetic heliobacteria.

    PubMed

    Oh-oka, Hirozo

    2007-01-01

    The reaction center (RC) of heliobacteria contains iron-sulfur centers as terminal electron acceptors, analogous to those of green sulfur bacteria as well as photosystem I in cyanobacteria and higher plants. Therefore, they all belong to the so-called type 1 RCs, in contrast to the type 2 RCs of purple bacteria and photosystem II containing quinone molecules. Although the architecture of the heliobacterial RC as a protein complex is still unknown, it forms a homodimer made up of two identical PshA core proteins, where two symmetrical electron transfer pathways along the C2 axis are assumed to be equally functional. Electrons are considered to be transferred from membrane-bound cytochrome c (PetJ) to a special pair P800, a chlorophyll a-like molecule A0, (a quinone molecule A1) and a [4Fe-4S] center Fx and, finally, to 2[4Fe-4S] centers FA/FB. No definite evidence has been obtained for the presence of functional quinone acceptor A1. An additional interesting point is that the electron transfer reaction from cytochrome c to P800 proceeds in a collisional mode. It is highly dependent on the temperature, ion strength and/or viscosity in a reaction medium, suggesting that a heme-binding moiety fluctuates in an aqueous phase with its amino-terminus anchored to membranes. PMID:16842023

  15. Outpatient Management of Pediatric Type 1 Diabetes

    PubMed Central

    Cogen, Fran R.

    2015-01-01

    The incidence of both type 1 and type 2 diabetes (T1DM and T2DM) continues to rise within the pediatric population. However, T1DM remains the most prevalent form diagnosed in children. It is critical that health-care professionals understand the types of diabetes diagnosed in pediatrics, especially the distinguishing features between T1DM and T2DM, to ensure proper treatment. Similar to all individuals with T1DM, lifelong administration of exogenous insulin is necessary for survival. However, children have very distinct needs and challenges compared to those in the adult diabetes population. Accordingly, treatment, goals, and age-appropriate requirements must be individually addressed. The main objectives for the treatment of pediatric T1DM include maintaining glucose levels as close to normal as possible, avoiding acute complications, and preventing long-term complications. In addition, unique to pediatrics, facilitating normal growth and development is important to comprehensive care. To achieve these goals, a careful balance of insulin therapy, medical nutrition therapy, and exercise or activity is necessary. Pharmacological treatment options consist of various insulin products aimed at mimicking prior endogenous insulin secretion while minimizing adverse effects. This review focuses on the management of pediatric T1DM in the outpatient environment, highlighting pharmacotherapy management strategies. PMID:26472948

  16. Recent advances in type 1 diabetes.

    PubMed

    Kyi, Mervyn; Wentworth, John M; Nankervis, Alison J; Fourlanos, Spiros; Colman, Peter G

    2015-10-01

    Type 1 diabetes (T1D) is caused by an autoimmune attack on pancreatic beta cells that leads to insulin deficiency. The incidence of T1D in Australia has doubled over the past 20 years. T1D treatment focuses on physiological insulin replacement, aiming for near-normal blood glucose levels. Hypoglycaemia is a significant cause of morbidity and mortality in T1D. Optimal T1D management is complex, and is enhanced by empowering individuals in all aspects of managing diabetes. New technologies, including insulin pumps, continuous glucose monitors and sensor-augmented pumps, can assist people achieve better glycaemic control and reduce the risk of severe hypoglycaemia. Women with T1D can achieve significantly better outcomes during pregnancy and for their infants by planning for their pregnancy and by intensive glycaemic control. Several trials are underway that seek to identify the determinants of autoimmunity and to develop therapies that prevent T1D in at-risk individuals. Pancreatic and islet cell transplants are proven therapies, but are only offered to individuals with diabetes and renal failure (pancreas) or severe hypoglycaemia unawareness (islet cell transplants). Although T1D is still associated with considerable premature mortality, recent findings show that a significant improvement in life expectancy has occurred. PMID:26424063

  17. Celiac disease in type 1 diabetes mellitus

    PubMed Central

    2012-01-01

    Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients. PMID:22449104

  18. Cannabinoid receptor type-1: breaking the dogmas

    PubMed Central

    Busquets Garcia, Arnau; Soria-Gomez, Edgar; Bellocchio, Luigi; Marsicano, Giovanni

    2016-01-01

    The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile. PMID:27239293

  19. Helminth Infection and Type 1 Diabetes

    PubMed Central

    Zaccone, Paola; Hall, Samuel W.

    2012-01-01

    The increasing incidence of type 1 diabetes (T1D) and autoimmune diseases in industrialized countries cannot be exclusively explained by genetic factors. Human epidemiological studies and animal experimental data provide accumulating evidence for the role of environmental factors, such as infections, in the regulation of allergy and autoimmune diseases. The hygiene hypothesis has formally provided a rationale for these observations, suggesting that our co-evolution with pathogens has contributed to the shaping of the present-day human immune system. Therefore, improved sanitation, together with infection control, has removed immunoregulatory mechanisms on which our immune system may depend. Helminths are multicellular organisms that have developed a wide range of strategies to manipulate the host immune system to survive and complete their reproductive cycles successfully. Immunity to helminths involves profound changes in both the innate and adaptive immune compartments, which can have a protective effect in inflammation and autoimmunity. Recently, helminth-derived antigens and molecules have been tested in vitro and in vivo to explore possible applications in the treatment of inflammatory and autoimmune diseases, including T1D. This exciting approach presents numerous challenges that will need to be addressed before it can reach safe clinical application. This review outlines basic insight into the ability of helminths to modulate the onset and progression of T1D, and frames some of the challenges that helminth-derived therapies may face in the context of clinical translation. PMID:23804266

  20. The streetlight effect in type 1 diabetes.

    PubMed

    Battaglia, Manuela; Atkinson, Mark A

    2015-04-01

    In the nearly 100 years since the discovery of therapeutic insulin, significant research efforts have been directed at finding the underlying cause of type 1 diabetes (T1D) and developing a "cure" for the disease. While progress has clearly been made toward each of these goals, neither vision has been fulfilled. With increasing pressure from both public and private funders of diabetes research, growing impatience of those with T1D at the lack of practical discoveries, increased competition for research funds, uncertainties on the reproducibility of published scientific data, and questions regarding the value of animal models, the current research environment has become extraordinarily difficult to traverse from the perspective of investigators. As a result, there is an increasing pressure toward performance of what might be considered "safe" research, where the aim is to affirm existing dogmas rather than to pioneer efforts involving unconventional thought. Psychologists refer to this practice as "observational bias" while cartoonists label the process the "streetlight effect." In this Perspective, we consider notions in T1D research that should be subject to bold question and provide additional concepts, many somewhat orphan to research efforts, whose investigation could lead to a means for truly identifying the cause of and a cure for T1D.

  1. [Latest overview of type 1 diabetes mellitus].

    PubMed

    Miura, Junnosuke; Uchigata, Yasuko

    2008-07-01

    Type 1 diabetes mellitus (T1DM) was defined as a heterogeneous disorder characterized by severe beta-cell loss. The subtype 1A is characterized by abnormal autoimmue-mediated response and 1B is idiopathic etiology, and most of patients with T1DM are classified in 1A. There are three subtypes characterized by onset, fulminant, acute onset and slowly progressive in T1DM. Among these three subtypes, there are differences in genetic etiology, pathogenesis and prevalence of autoantibodies. Glutamic acid decarboxylase-65 (GAD65), insulinoma-associated antigen-2 (IA-2) and insulin are major autoantigens in T1DM and autoantibodies for former two are frequently used for clinical diagnosis. Also novel autoantibodies for T1DM have been found and clinical characteristics of the patients with each antibody will be made clearer. There have been eager efforts to develop immunotherapies to prevent islet destruction and to cure the disorder with islet transplantation, and new treatment with inhaled insulin regimen. Continuous glucose monitoring system(CGMS) has been established to make clearer the daily profile of blood glucose of the patients and to improve the metabolic control. Most efficient treatment for T1DM is a still insulin injection. However, the development of new medical devices and novel treatment rather than insulin injection has been done and the progression will promise improved prognosis of vascular complications.

  2. Combination immunotherapies for type 1 diabetes mellitus.

    PubMed

    Pozzilli, Paolo; Maddaloni, Ernesto; Buzzetti, Raffaella

    2015-05-01

    Immunotherapies for type 1 diabetes mellitus (T1DM) have been the focus of intense basic and clinical research over the past few decades. Restoring β-cell function is the ultimate goal of intervention trials that target the immune system in T1DM. In an attempt to achieve this aim, different combination therapies have been proposed over the past few years that are based on treatments tackling the various mechanisms involved in the destruction of β cells. The results of clinical trials have not matched expectations based on the positive results from preclinical studies. The heterogeneity of T1DM might explain the negative results obtained, but previous trials have not addressed this issue. However, novel promising combination therapies are being developed, including those that couple immunomodulators with drugs that stimulate β-cell regeneration in order to restore normoglycaemia. This strategy is an encouraging one to pursue the goal of finding a cure for T1DM. This Review summarizes the available data about combination immunotherapies in T1DM, particularly addressing their clinical importance. The available data supporting the use of registered drugs, such as proton pump inhibitors and incretin-based agents, that have been shown to induce β-cell regeneration will also be discussed.

  3. [Management of craniofacial type 1 neurofibromatosis].

    PubMed

    Bachelet, J T; Combemale, P; Devic, C; Foray, N; Jouanneau, E; Breton, P

    2015-09-01

    Type I neurofibromatosis (NF) is the most common autosomal dominant disease. It concerns one in 3000 births, the penetrance is close to 100% and 50% of new cases are de novo mutations (17q11.2 chromosome 17 location). Cranio-maxillofacial region is concerned in 10% of the cases, in different forms: molluscum neurofibroma, plexiform neurofibroma, cranio-orbital neurofibroma, parotido-jugal neurofibroma, cervical neurofibroma. These lesions have different prognosis depending on the craniofacial localization: ocular functional risk, upper airway compressive risk, nerve compression risk, aesthetic and social impact. The maxillofacial surgeon in charge of patients with type I NF should follow the patient from the diagnosis and organize the different surgical times in order to take care about the different issues: vital, functional and aesthetic. We describe the treatment of facial localizations of type 1 NF as it is done at the University Hospital of Lyon and at the Rhône-Alpes-Auvergne neurofibromatosis reference center. PMID:26194627

  4. Type 1 diabetes guidelines: Are they enough?

    PubMed

    Zargar, Abdul Hamid

    2015-04-01

    The discovery of insulin by Banting and Best in 1922 changed the landscape of type 1 diabetes mellitus (T1DM). Guidelines on T1DM should be evidence based and should emphasize comprehensive risk management. Guidelines would improve awareness amongst governments, state health care providers and the general public about the serious long-term implications of poorly managed diabetes and of the essential resources needed for optimal care. T1DM requires lifelong daily medication, regular control as well as access to facilities to manage acute and chronic complications. American Diabetes Association 2014 guidelines recommends annual nephropathy screening for albumin levels; random spot urine sample for albumin-to-creatinine ratio at start of puberty or age ≥10 years, whichever is earlier, once the child has had diabetes for 5 years. Hypertension should be screened for in T1DM patients by measuring blood pressure at each routine visit. Dyslipidemia in T1DM patients is important and patients should be screened if there is a family history of hypercholesterolemia or a cardiovascular event before the age of 55 years exists or if family history is unknown. Retinopathy is another important complication of diabetes and patients should be subjected to an initial dilated and comprehensive eye examination. Basic diabetes training should be provided for school staff, and they should be assigned with responsibilities for the care of diabetic children. Self-management should be allowed at all school settings for students. PMID:25941640

  5. Type 1 diabetes: A predictable disease

    PubMed Central

    Simmons, Kimber M; Michels, Aaron W

    2015-01-01

    Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of insulin producing beta cells and reliance on exogenous insulin for survival. T1D is one of the most common chronic diseases in childhood and the incidence is increasing, especially in children less than 5 years of age. In individuals with a genetic predisposition, an unidentified trigger initiates an abnormal immune response and the development of islet autoantibodies directed against proteins in insulin producing beta cells. There are currently four biochemical islet autoantibodies measured in the serum directed against insulin, glutamic decarboxylase, islet antigen 2, and zinc transporter 8. Development of islet autoantibodies occurs before clinical diagnosis of T1D, making T1D a predictable disease in an individual with 2 or more autoantibodies. Screening for islet autoantibodies is still predominantly done through research studies, but efforts are underway to screen the general population. The benefits of screening for islet autoantibodies include decreasing the incidence of diabetic ketoacidosis that can be life threatening, initiating insulin therapy sooner in the disease process, and evaluating safe and specific therapies in large randomized clinical intervention trials to delay or prevent progression to diabetes onset. PMID:25897349

  6. Chapter 1: Epidemiology of Type 1 Diabetes

    PubMed Central

    Maahs, David M; West, Nancy A; Lawrence, Jean M.; Mayer-Davis, Elizabeth J

    2010-01-01

    Synopsis This chapter describes the epidemiology of type 1 diabetes mellitus (T1D) around the world and across the lifespan. Epidemiologic patterns of T1D by demographic, geographic, biologic, cultural and other factors in populations are presented to gain insight about the etiology, natural history, risks, and complications of T1D. Data from large epidemiologic studies worldwide indicate that the incidence of T1D has been increasing by 2–5% worldwide and that the prevalence of T1D is approximately 1 in 300 in the US by 18 years of age. Research on risk factors for T1D is an active area of research to identify genetic and environmental triggers that could potentially be targeted for intervention. While significant advances have been made in the clinical care of T1D with resultant improvements in quality of life and clinical outcomes, much more needs to be done to improve care of, and ultimately find a cure for T1D. Epidemiologic studies have an important on-going role to investigate the complex causes, clinical care, prevention, and cure of T1D. PMID:20723815

  7. DPL-1 DP, LIN-35 Rb and EFL-1 E2F act with the MCD-1 zinc-finger protein to promote programmed cell death in Caenorhabditis elegans.

    PubMed

    Reddien, Peter W; Andersen, Erik C; Huang, Michael C; Horvitz, H Robert

    2007-04-01

    The genes egl-1, ced-9, ced-4, and ced-3 play major roles in programmed cell death in Caenorhabditis elegans. To identify genes that have more subtle activities, we sought mutations that confer strong cell-death defects in a genetically sensitized mutant background. Specifically, we screened for mutations that enhance the cell-death defects caused by a partial loss-of-function allele of the ced-3 caspase gene. We identified mutations in two genes not previously known to affect cell death, dpl-1 and mcd-1 (modifier of cell death). dpl-1 encodes the C. elegans homolog of DP, the human E2F-heterodimerization partner. By testing genes known to interact with dpl-1, we identified roles in cell death for four additional genes: efl-1 E2F, lin-35 Rb, lin-37 Mip40, and lin-52 dLin52. mcd-1 encodes a novel protein that contains one zinc finger and that is synthetically required with lin-35 Rb for animal viability. dpl-1 and mcd-1 act with efl-1 E2F and lin-35 Rb to promote programmed cell death and do so by regulating the killing process rather than by affecting the decision between survival and death. We propose that the DPL-1 DP, MCD-1 zinc finger, EFL-1 E2F, LIN-35 Rb, LIN-37 Mip40, and LIN-52 dLin52 proteins act together in transcriptional regulation to promote programmed cell death.

  8. Wheat zinc finger protein TaLSD1, a negative regulator of programmed cell death, is involved in wheat resistance against stripe rust fungus.

    PubMed

    Guo, Jun; Bai, Pengfei; Yang, Qian; Liu, Furong; Wang, Xiaodong; Huang, Lili; Kang, Zhensheng

    2013-10-01

    Genetic characterization of the Arabidopsis lesion simulating disease 1 (lsd1) mutant, a lesion mimic mutant (LMM), has revealed the essential role of AtLSD1 in the negative regulation of cell death and disease resistance. The three zinc-finger motifs found in AtLSD1 revealed a novel plant-specific gene family, whose members are significantly related to programmed cell death (PCD). In this study, we characterized a functional homologue to AtLSD1, TaLSD1, in the wheat-stripe rust fungus pathosystem. The expression of TaLSD1 was differentially induced during incompatible and compatible interactions between wheat and Puccinia striiformis f. sp. tritici (Pst) and was up-regulated by oxidative stress generated by methyl viologen (MV). TaLSD1 was found to be predominately localized in the nucleus of onion epidermal cell. Transient overexpression assays in Nicotiana benthamiana demonstrated that TaLSD1 partially inhibited programmed cell death triggered by a mouse Bax protein, whereas expression of TaLSD1 alone had no influence on the phenotype of tobacco. Knocking down the expression of TaLSD1 through virus-induced gene silencing (VIGS) increased wheat resistance against Pst accompanied by an enhanced hypersensitive response (HR), an increase in PR1 gene expression and a reduction in Pst hyphal growth. Our results suggest that TaLSD1 functions negatively in regulating the plant hypersensitive cell death and is involved in disease resistance of wheat against the stripe rust pathogen.

  9. Mining for Dust in Type 1 Quasars

    NASA Astrophysics Data System (ADS)

    Krawczyk, Coleman M.; Richards, Gordon T.; Gallagher, S. C.; Leighly, Karen M.; Hewett, Paul C.; Ross, Nicholas P.; Hall, P. B.

    2015-06-01

    We explore the extinction/reddening of ˜35,000 uniformly selected quasars with 0\\lt z≤slant 5.3 in order to better understand their intrinsic optical/ultraviolet (UV) spectral energy distributions. Using rest-frame optical-UV photometry taken from the Sloan Digital Sky Survey’s (SDSS) 7th data release, cross-matched to WISE in the mid-infrared, 2MASS and UKIDSS in the near-infrared, and GALEX in the UV, we isolate outliers in the color distribution and find them well described by an SMC-like reddening law. A hierarchical Bayesian model with a Markov Chain Monte Carlo sampling method was used to find distributions of power law indices and E(B-V) consistent with both the broad absorption line (BAL) and non-BAL samples. We find that, of the ugriz color-selected type 1 quasars in SDSS, 2.5% (13%) of the non-BAL (BAL) sample are consistent with E(B-V)\\gt 0.1 and 0.1% (1.3%) with E(B-V)\\gt 0.2. Simulations show both populations of quasars are intrinsically bluer than the mean composite, with a mean spectral index ({{α }λ }) of -1.79 (-1.83). The emission and absorption-line properties of both samples reveal that quasars with intrinsically red continua have narrower Balmer lines and stronger high-ionization emission lines, the latter indicating a harder continuum in the extreme-UV and the former pointing to differences in black hole mass and/or orientation.

  10. Management of Type 1 Diabetes in Pregnancy.

    PubMed

    Feldman, Anna Z; Brown, Florence M

    2016-08-01

    Women with type 1 diabetes (T1DM) have unique needs during the preconception, pregnancy, and postpartum periods. Preconception counseling is essential for women with T1DM to minimize pregnancy risks. The goals of preconception care should be tight glycemic control with a hemoglobin A1c (A1C) < 7 % and as close to 6 % as possible, without significant hypoglycemia. This will lower risks of congenital malformations, preeclampsia, and perinatal mortality. The safety of medications should be assessed prior to conception. Optimal control of retinopathy, hypertension, and nephropathy should be achieved. During pregnancy, the goal A1C is near-normal at <6 %, without excessive hypoglycemia. There is no clear evidence that continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI) is superior in achieving the desired tight glycemic control of T1DM during pregnancy. Data regarding continuous glucose monitoring (CGM) in pregnant women with T1DM is conflicting regarding improved glycemic control. However, a recent CGM study does provide some distinct patterns of glucose levels associated with large for gestational age infants. Frequent eye exams during pregnancy are essential due to risk of progression of retinopathy during pregnancy. Chronic hypertension treatment goals are systolic blood pressure 110-129 mmHg and diastolic blood pressure 65-79 mmHg. Labor and delivery target plasma glucose levels are 80-110 mg/dl, and an insulin drip is recommended to achieve these targets during active labor. Postpartum, insulin doses must be reduced and glucoses closely monitored in women with T1DM because of the enhanced insulin sensitivity after delivery. Breastfeeding is recommended and should be highly encouraged due to maternal benefits including increased insulin sensitivity and weight loss and infant and childhood benefits including reduced prevalence of overweight. In this article, we discuss the care of pregnant patients with T1DM. PMID

  11. Innate inflammation in type 1 diabetes.

    PubMed

    Cabrera, Susanne M; Henschel, Angela M; Hessner, Martin J

    2016-01-01

    Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay between genetic and environmental factors and has historically been attributed to adaptive immunity, although there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible biobreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyperpermeability, or viral exposures. Special focus is put on the temporal measurement of plasma-induced transcriptional signatures of recent-onset T1D patients and their siblings as well as in the biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy may be improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.

  12. Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment

    SciTech Connect

    Jakubowicz-Gil, Joanna; Langner, Ewa; Bądziul, Dorota; Wertel, Iwona; Rzeski, Wojciech

    2013-12-15

    The aim of the present study was to investigate whether silencing of Hsp27 or Hsp72 expression in glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cells increases their sensitivity to programmed cell death induction upon temozolomide and/or quercetin treatment. Transfection with specific siRNA was performed for the Hsp gene silencing. As revealed by microscopic observation and flow cytometry, the inhibition of Hsp expression was correlated with severe apoptosis induction upon the drug treatment studied. No signs of autophagy were detected. This was correlated with a decreased mitochondrial membrane potential, increased level of cytochrome c in the cytoplasm, and activation of caspase 3 and caspase 9. All these results suggest that the apoptotic signal was mediated by an internal pathway. Additionally, in a large percentage of cells treated with temozolomide, with or without quercetin, granules within the ER system were found, which was accompanied by an increased level of caspase 12 expression. This might be correlated with ER stress. Quercetin and temozolomide also changed the shape of nuclei from circular to “croissant like” in both transfected cell lines. Our results indicate that blocking of Hsp27 and Hsp72 expression makes T98G cells and MOGGCCM cells extremely vulnerable to apoptosis induction upon temozolomide and quercetin treatment and that programmed cell death is initiated by an internal signal. - Highlights: • Hsps gene silencing induced severe apoptosis upon temozolomide–quercetin treatment • Apoptosis in transfected glioma cells was initiated by internal signal • Programmed cell death was preceded by ER stress • Temozolomide–quercetin treatment changed nuclei shape in transfected glioma cells.

  13. Equid Herpesvirus Type 1 Activates Platelets

    PubMed Central

    Stokol, Tracy; Yeo, Wee Ming; Burnett, Deborah; DeAngelis, Nicole; Huang, Teng; Osterrieder, Nikolaus; Catalfamo, James

    2015-01-01

    Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in

  14. Equid herpesvirus type 1 activates platelets.

    PubMed

    Stokol, Tracy; Yeo, Wee Ming; Burnett, Deborah; DeAngelis, Nicole; Huang, Teng; Osterrieder, Nikolaus; Catalfamo, James

    2015-01-01

    Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in

  15. Markers for Risk of Type 1 Diabetes in Relatives of Alsacian Patients With Type 1 Diabetes

    PubMed Central

    Sapin, Remi; Pinget, Michel; Belcourt, Alain

    2002-01-01

    Background: The cytotoxic T lymphocyteassociated antigen 4 gene (CTLA-4) encode the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. The receptor protein is a specific T lymphocyte surface antigen that is detected on cells only after antigen presentation. Thus, CTLA-4 is directly involved in both immune and autoimmune responses and may be involved in the pathogenesis of multiple T cell-mediated autoimmune disorders. There is polymorphism at position 49 in exon 1 of the CTLA-4 gene, providing an A-G exchange. Moreover, we assessed the CTLA-4 49 (Thr/Ala) polymorphism in diabetic patients and first-degree relatives as compared to control subjects. Research design and methods: Three loci (HLA-DQB1, DQA1 and CTLA-4) were analysed in 62 type 1 diabetic patients, 72 firstdegree relatives and 84 nondiabetic control subjects by means of PCR-RFLP. Results: A significant enrichment in DQB1 alleles encoding for an amino acid different from Asp in position 57 (NA) and DQA1 alleles encoding for Arg in position 52 was observed in diabetic subjects and first-degree relatives as compared to controls. The genotype and allele frequencies of these polymorphisms in type 1 diabetic patients and firstdegree relatives differed significantly from those of controls (p< 0.001 and 0.05 respectively). CTLA-49 Ala alleles frequencies were 75.8% in type 1 diabetic patients and 68.1% in first-degree relatives in comparison to 35.7% in control subjects. The Ala/Ala genotype conferred a relative risk of 18.8 (p < 0.001). Conclusion: The CTLA-4 49 Ala allele confers an increased risk of type 1 diabetes, independent of age and HLA-DQ genetic markers. PMID:11900275

  16. Ion channels involved in cell volume regulation: effects on migration, proliferation, and programmed cell death in non adherent EAT cells and adherent ELA cells.

    PubMed

    Hoffmann, Else Kay

    2011-01-01

    This mini review outlines studies of cell volume regulation in two closely related mammalian cell lines: nonadherent Ehrlich ascites tumour cells (EATC) and adherent Ehrlich Lettre ascites (ELA) cells. Focus is on the regulatory volume decrease (RVD) that occurs after cell swelling, the volume regulatory ion channels involved, and the mechanisms (cellular signalling pathways) that regulate these channels. Finally, I shall also briefly review current investigations in these two cell lines that focuses on how changes in cell volume can regulate cell functions such as cell migration, proliferation, and programmed cell death.

  17. Autophagy Induction by Histone Deacetylase Inhibitors Inhibits HIV Type 1*

    PubMed Central

    Campbell, Grant R.; Bruckman, Rachel S.; Chu, Yen-Lin; Spector, Stephen A.

    2015-01-01

    Histone deacetylase inhibitors (HDACi) are being evaluated in a “shock-and-kill” therapeutic approach to reverse human immunodeficiency virus type-1 (HIV) latency from CD4+ T cells. Using this approach, HDACi have induced HIV RNA synthesis in latently infected cells from some patients. The hope is that the increase in viral production will lead to killing of the infected cell either by the virus itself or by the patient's immune system, a “sterilizing cure.” Although administered within the context of combination antiretroviral therapy, the infection of bystander cells remains a concern. In this study, we investigated the effect of HDACi (belinostat, givinostat, panobinostat, romidepsin, and vorinostat) on the productive infection of macrophages. We demonstrate that the HDACi tested do not alter the initial susceptibility of macrophages to HIV infection. However, we demonstrate that HDACi decrease HIV release from macrophages in a dose-dependent manner (belinostat < givinostat < vorinostat < panobinostat < romidepsin) via degradation of intracellular HIV through the canonical autophagy pathway. This mechanism involves unc-51-like autophagy-activating kinase 1 (ULK1) and the inhibition of the mammalian target of rapamycin and requires the formation of autophagosomes and their maturation into autolysosomes in the absence of increased cell death. These data provide further evidence in support of a role for autophagy in the control of HIV infection and suggest that careful consideration of off-target effects will be essential if HDACi are to be a component of a multipronged approach to eliminate latently infected cells. PMID:25540204

  18. Expression of the antiapoptotic baculovirus p35 gene in tomato blocks programmed cell death and provides broad-spectrum resistance to disease

    PubMed Central

    Lincoln, James E.; Richael, Craig; Overduin, Bert; Smith, Kathy; Bostock, Richard; Gilchrist, David G.

    2002-01-01

    The sphinganine analog mycotoxin, AAL-toxin, induces a death process in plant and animal cells that shows apoptotic morphology. In nature, the AAL-toxin is the primary determinant of the Alternaria stem canker disease of tomato, thus linking apoptosis to this disease caused by Alternaria alternata f. sp. lycopersici. The product of the baculovirus p35 gene is a specific inhibitor of a class of cysteine proteases termed caspases, and naturally functions in infected insects. Transgenic tomato plants bearing the p35 gene were protected against AAL-toxin-induced death and pathogen infection. Resistance to the toxin and pathogen co-segregated with the expression of the p35 gene through the T3 generation, as did resistance to A. alternata, Colletotrichum coccodes, and Pseudomonas syringae pv. tomato. The p35 gene, stably transformed into tomato roots by Agrobacterium rhizogenes, protected roots against a 30-fold greater concentration of AAL-toxin than control roots tolerated. Transgenic expression of a p35 binding site mutant (DQMD to DRIL), inactive against animal caspases-3, did not protect against AAL-toxin. These results indicate that plants possess a protease with substrate-site specificity that is functionally equivalent to certain animal caspases. A biological conclusion is that diverse plant pathogens co-opt apoptosis during infection, and that transgenic modification of pathways regulating programmed cell death in plants is a potential strategy for engineering broad-spectrum disease resistance in plants. PMID:12403830

  19. The NFĸB pathway inhibitors Bay 11-7082 and parthenolide induce programmed cell death in anucleated Erythrocytes.

    PubMed

    Ghashghaeinia, Mehrdad; Toulany, Mahmoud; Saki, Mohammad; Bobbala, Diwakar; Fehrenbacher, Birgit; Rupec, Rudolf; Rodemann, H Peter; Ghoreschi, Kamran; Röcken, Martin; Schaller, Martin; Lang, Florian; Wieder, Thomas

    2011-01-01

    The preclinical compounds Bay 11-7082 and parthenolide trigger apoptosis, an effect contributing to their antiinflammatory action. The substances interfere with the activation and nuclear translocation of nuclear factor NFκB, by inhibiting NFκB directly (parthenolide) or by interfering with the inactivation of the NFκB inhibitory protein IκB-α (Bay 11-7082). Beyond that, the substances may be effective in part by nongenomic effects. Similar to apoptosis of nucleated cells, erythrocytes may undergo apoptosis-like cell death (eryptosis) characterized by cell membrane scrambling with phosphatidylserine exposure, and cell shrinkage. Thus, erythrocytes allow the study of nongenomic mechanisms contributing to suicidal cell death, e.g. Ca(2+) leakage or glutathione depletion. The present study utilized Western blotting to search for NFκB and IκB-α expression in erythrocytes, FACS analysis to determine cytosolic Ca(2+) (Fluo3 fluorescence), phosphatidylserine exposure (annexin V binding), and cell volume (forward scatter), as well as an enzymatic method to determine glutathione levels. As a result, both NFκB and IκB-α are expressed in erythrocytes. Targeting the NFκB pathway by Bay 11-7082 (IC(50) ≈ 10 μM) and parthenolide (IC(50) ≈ 30 μM) triggered suicidal erythrocyte death as shown by annexin V binding and decrease of forward scatter. Bay 11-7082 treatment further increased intracellular Ca(2+) and led to depletion of reduced glutathione. The effects of Bay 11-7082 and parthenolide on annexin V binding could be fully reversed by the antioxidant N-acetylcysteine. In conclusion, the pharmacological inhibitors of NFκB, Bay 11-7082 and parthenolide, interfere with the survival of erythrocytes involving mechanisms other than disruption of NFκB-dependent gene expression.

  20. Vascular endothelial dysfunction and nutritional compounds in early type 1 diabetes.

    PubMed

    Hoffman, Robert P

    2014-05-01

    Cardiovascular disease is the major cause of death in patients with type 1 diabetes. Vascular endothelial dysfunction is an early pathophysiological precursor of cardiovascular disease. There is extensive evidence that hyperglycemia causes acute perturbations in endothelial function likely due to increases in oxidative damage. Interestingly, oscillating hyperglycemia may cause more damage than persistent hyperglycemia. Many, but not all, studies indicate that vascular endothelial dysfunction occurs early in the course of type 1 diabetes and is present even in adolescents. Ascorbic acid has been shown to diminish the acute effects of hyperglycemia on endothelial function in type 1 diabetes and in conjunction with euglycemia to restore endothelial function to normal values in adults with well-controlled diabetes. In vitro and in vivo animal evidence suggests potential benefit from two other small molecule antioxidants, nicotinamide and taurine. Early studies suggested that folate supplementation may improve endothelial function in adolescents with type 1 diabetes but this has not been confirmed by more recent studies. Epidemiological evidence suggests a possible role for vitamin D therapy although intervention studies in type 2 diabetes have yielded varying results and have not been done in type 1 diabetes. Further exploration of these and other compounds is clearly appropriate if we are to reduce cardiovascular risk in type 1 diabetes.

  1. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    MedlinePlus

    ... Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/collapse boxes. ... Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by progressive problems ...

  2. FEATURE A, TYPE 1 PILLBOX, SOUTH SIDE, REST MOSTLY COVERED ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    FEATURE A, TYPE 1 PILLBOX, SOUTH SIDE, REST MOSTLY COVERED BY VEGETATION AND SAND, VIEW FACING NORTHEAST. - Naval Air Station Barbers Point, Shore Pillbox Complex-Type 1 Pillbox, Along shoreline, seaward of Coral Sea Road, Ewa, Honolulu County, HI

  3. FEATURE B, TYPE 1 PILLBOX, SOUTH AND WEST SIDES, VIEW ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    FEATURE B, TYPE 1 PILLBOX, SOUTH AND WEST SIDES, VIEW FACING NORTH-NORTHEAST. - Naval Air Station Barbers Point, Shore Pillbox Complex-Type 1 Pillbox, Along shoreline, seaward of Coral Sea Road, Ewa, Honolulu County, HI

  4. Cell acidification in apoptosis: granulocyte colony-stimulating factor delays programmed cell death in neutrophils by up-regulating the vacuolar H(+)-ATPase.

    PubMed Central

    Gottlieb, R A; Giesing, H A; Zhu, J Y; Engler, R L; Babior, B M

    1995-01-01

    Neutrophils in tissue culture spontaneously undergo programmed cell death (apoptosis), a process characterized by well-defined morphological alterations affecting the cell nucleus. We found that these morphological changes were preceded by intracellular acidification and that acidification and the apoptotic changes in nuclear morphology were both delayed by granulocyte colony-stimulating factor (G-CSF). Among the agents that defend neutrophils against intracellular acidification is a vacuolar H(+)-ATPase that pumps protons out of the cytosol. When this proton pump was inhibited by bafilomycin A1, G-CSF no longer protected the neutrophils against apoptosis. We conclude that G-CSF delays apoptosis in neutrophils by up-regulating the cells' vacuolar H(+)-ATPase and that intracellular acidification is an early event in the apoptosis program. Images Fig. 1 Fig. 2 PMID:7541139

  5. Transcriptome-Wide Mapping of Pea Seed Ageing Reveals a Pivotal Role for Genes Related to Oxidative Stress and Programmed Cell Death

    PubMed Central

    Colville, Louise; Lorenzo, Oscar; Graeber, Kai; Küster, Helge; Leubner-Metzger, Gerhard; Kranner, Ilse

    2013-01-01

    Understanding of seed ageing, which leads to viability loss during storage, is vital for ex situ plant conservation and agriculture alike. Yet the potential for regulation at the transcriptional level has not been fully investigated. Here, we studied the relationship between seed viability, gene expression and glutathione redox status during artificial ageing of pea (Pisum sativum) seeds. Transcriptome-wide analysis using microarrays was complemented with qRT-PCR analysis of selected genes and a multilevel analysis of the antioxidant glutathione. Partial degradation of DNA and RNA occurred from the onset of artificial ageing at 60% RH and 50°C, and transcriptome profiling showed that the expression of genes associated with programmed cell death, oxidative stress and protein ubiquitination were altered prior to any sign of viability loss. After 25 days of ageing viability started to decline in conjunction with progressively oxidising cellular conditions, as indicated by a shift of the glutathione redox state towards more positive values (>−190 mV). The unravelling of the molecular basis of seed ageing revealed that transcriptome reprogramming is a key component of the ageing process, which influences the progression of programmed cell death and decline in antioxidant capacity that ultimately lead to seed viability loss. PMID:24205239

  6. Soluble Programmed Death 1 (PD-1) Is Decreased in Patients With Immune Thrombocytopenia (ITP): Potential Involvement of PD-1 Pathway in ITP Immunopathogenesis.

    PubMed

    Birtas Atesoglu, Elif; Tarkun, Pinar; Demirsoy, Esra Terzi; Geduk, Ayfer; Mehtap, Ozgur; Batman, Adnan; Kaya, Fatih; Cekmen, Mustafa Baki; Gulbas, Zafer; Hacıhanefioglu, Abdullah

    2016-04-01

    Immune thrombocytopenia (ITP) is an autoimmune disease characterized by dysregulation of T cells. Programmed death (PD) 1 and programmed death 1 ligand 1 (PD-L1) are cosignaling molecules, and the major role of the PD-1 pathway is the inhibition of self-reactive T cells and to protect against autoimmune diseases. We measured levels of serum soluble PD 1 (sPD-1) and serum soluble PD-L1 (sPD-L1) in 67 patients with ITP (24 newly diagnosed ITP [ndITP], 43 chronic ITP [cITP]) and 21 healthy controls (HCs). We determined decreased serum sPD-1 levels both in patients with ndITP and in patients with cITP when compared to HC. Moreover, there was a positive correlation between sPD-1 levels and platelet counts. The sPD-L1 levels were decreased in patients with ndITP when compared to patients with cITP. This is the first study investigating PD-1 signaling pathway in ITP. Decreased sPD-1 levels may have a role in ITP pathogenesis as without the inhibitory regulation of PD-1, sustained activation of T cells may cause inflammatory responses which is the case in ITP.

  7. DEATH CONCERN AND DEATH OBSESSION IN IRANIAN NURSES.

    PubMed

    Dadfar, Mahboubeh; Lester, David

    2015-06-01

    The goal of the present study was to examine whether nurses had increased death concern and death obsession compared to non-nursing staff. A Death Concern Scale and a Death Obsession Scale, translated into Persian, were administered to 56 female Iranian nurses (55% in their 30s) and compared to 56 female hospital staff members (45% in their 30s). The two groups did not differ significantly in their scores on either scale. It is, therefore, recommended that death education programs in hospitals be given to all staff, nursing and non-nursing.

  8. Ultrastructural changes and programmed cell death of trophocytes in the gonad of Isohypsibius granulifer granulifer Thulin, 1928 (Tardigrada, Eutardigrada, Isohypsibiidae).

    PubMed

    Poprawa, Izabela; Hyra, Marta; Kszuk-Jendrysik, Michalina; Rost-Roszkowska, Magdalena Maria

    2015-03-01

    The studies on the fates of the trophocytes, the apoptosis and autophagy in the gonad of Isohypsibius granulifer granulifer have been described using transmission electron microscope, light and fluorescent microscopes. The results presented here are the first that are connected with the cell death of nurse cells in the gonad of tardigrades. However, here we complete the results presented by Węglarska (1987). The reproductive system of I. g. granulifer contains a single sack-like hermaphroditic gonad and a single gonoduct. The gonad is composed of three parts: a germarium filled with proliferating germ cells (oogonia); a vitellarium that has clusters of female germ cells (the region of oocytes development); and a male part filled with male germ cells in which the sperm cells develop. The trophocytes (nurse cells) show distinct alterations during all of the stages of oogenesis: previtello-, vitello- and choriogenesis. During previtellogenesis the female germ cells situated in the vitellarium are connected by cytoplasmic bridges, and form clusters of cells. No ultrastructural differences appear among the germ cells in a cluster during this stage of oogenesis. In early vitellogenesis, the cells in each cluster start to grow and numerous organelles gradually accumulate in their cytoplasm. However, at the beginning of the middle of vitellogenesis, one cell in each cluster starts to grow in order to differentiate into oocyte, while the remaining cells are trophocytes. Eventually, the cytoplasmic bridges between the oocyte and trophocytes disappear. Autophagosomes also appear in the cytoplasm of nurse cells together with many degenerating organelles. The cytoplasm starts to shrink, which causes the degeneration of the cytoplasmic bridges between trophocytes. Apoptosis begins when the cytoplasm of these cells is full of autophagosomes/autolysosomes and causes their death.

  9. Ultrastructural changes and programmed cell death of trophocytes in the gonad of Isohypsibius granulifer granulifer Thulin, 1928 (Tardigrada, Eutardigrada, Isohypsibiidae).

    PubMed

    Poprawa, Izabela; Hyra, Marta; Kszuk-Jendrysik, Michalina; Rost-Roszkowska, Magdalena Maria

    2015-03-01

    The studies on the fates of the trophocytes, the apoptosis and autophagy in the gonad of Isohypsibius granulifer granulifer have been described using transmission electron microscope, light and fluorescent microscopes. The results presented here are the first that are connected with the cell death of nurse cells in the gonad of tardigrades. However, here we complete the results presented by Węglarska (1987). The reproductive system of I. g. granulifer contains a single sack-like hermaphroditic gonad and a single gonoduct. The gonad is composed of three parts: a germarium filled with proliferating germ cells (oogonia); a vitellarium that has clusters of female germ cells (the region of oocytes development); and a male part filled with male germ cells in which the sperm cells develop. The trophocytes (nurse cells) show distinct alterations during all of the stages of oogenesis: previtello-, vitello- and choriogenesis. During previtellogenesis the female germ cells situated in the vitellarium are connected by cytoplasmic bridges, and form clusters of cells. No ultrastructural differences appear among the germ cells in a cluster during this stage of oogenesis. In early vitellogenesis, the cells in each cluster start to grow and numerous organelles gradually accumulate in their cytoplasm. However, at the beginning of the middle of vitellogenesis, one cell in each cluster starts to grow in order to differentiate into oocyte, while the remaining cells are trophocytes. Eventually, the cytoplasmic bridges between the oocyte and trophocytes disappear. Autophagosomes also appear in the cytoplasm of nurse cells together with many degenerating organelles. The cytoplasm starts to shrink, which causes the degeneration of the cytoplasmic bridges between trophocytes. Apoptosis begins when the cytoplasm of these cells is full of autophagosomes/autolysosomes and causes their death. PMID:25543879

  10. Neonatal Death

    MedlinePlus

    ... story First Candle Centering Corporation The Compassionate Friends Star Legacy Foundation Last reviewed: November, 2015 Neonatal death ... story First Candle Centering Corporation The Compassionate Friends Star Legacy Foundation Last reviewed: November, 2015 Complications & Loss ...

  11. Early risk stratification in pediatric type 1 diabetes.

    PubMed

    Broe, Rebecca

    2015-03-01

    of early glycemic control. Identifying high-risk patients at a very early stage is not only desired for prevention of diabetic retinopathy - neuropathy and nephropathy similarly remain frequent in type 1 diabetes. Early risk stratification will allow for timely implementation of effective interventions and for individualized screening and diabetes care. The second and third studies of this thesis provide the longest prospective studies to date on both retinal vessel calibers and retinal fractal dimensions and their predictive value on diabetic microvascular complications. Semi-automated computer software has been developed to measure smaller changes in the retinal vessels on retinal photographs. Two of the first parameters to be reliably estimated by these programs were retinal vessel calibers and retinal vascular fractal dimensions (a quantitative measure on vascular complexity). There is very limited knowledge on their predictive value on diabetic complications thus far. In the second and third study, a consistent relation between narrower retinal arteriolar calibers, wider retinal venular calibers, lower fractal dimensions and the 16-year incidences of diabetic neuropathy, nephropathy and proliferative retinopathy was found. This has never been shown before. The results on vessel analyzes provides indications of a common pathogenic pathway for diabetic microvascular complications and therefore a possibility of universal risk estimation for development of neuropathy, nephropathy and retinopathy in type 1 diabetes. PMID:25703648

  12. Early risk stratification in pediatric type 1 diabetes.

    PubMed

    Broe, Rebecca

    2015-03-01

    of early glycemic control. Identifying high-risk patients at a very early stage is not only desired for prevention of diabetic retinopathy - neuropathy and nephropathy similarly remain frequent in type 1 diabetes. Early risk stratification will allow for timely implementation of effective interventions and for individualized screening and diabetes care. The second and third studies of this thesis provide the longest prospective studies to date on both retinal vessel calibers and retinal fractal dimensions and their predictive value on diabetic microvascular complications. Semi-automated computer software has been developed to measure smaller changes in the retinal vessels on retinal photographs. Two of the first parameters to be reliably estimated by these programs were retinal vessel calibers and retinal vascular fractal dimensions (a quantitative measure on vascular complexity). There is very limited knowledge on their predictive value on diabetic complications thus far. In the second and third study, a consistent relation between narrower retinal arteriolar calibers, wider retinal venular calibers, lower fractal dimensions and the 16-year incidences of diabetic neuropathy, nephropathy and proliferative retinopathy was found. This has never been shown before. The results on vessel analyzes provides indications of a common pathogenic pathway for diabetic microvascular complications and therefore a possibility of universal risk estimation for development of neuropathy, nephropathy and retinopathy in type 1 diabetes.

  13. Pregnancy and pregnancy outcome in hepatitis C type 1b.

    PubMed

    Jabeen, T; Cannon, B; Hogan, J; Crowley, M; Devereux, C; Fanning, L; Kenny-Walsh, E; Shanahan, F; Whelton, M J

    2000-09-01

    A large cohort of rhesus-negative women in Ireland were inadvertently infected with hepatitis C virus following exposure to contaminated anti-D immunoglobulin in 1977-8. This major iatrogenic episode was discovered in 1994. We studied 36 women who had been infected after their first pregnancy, and compared them to an age- and parity-matched control group of rhesus-positive women. The presence of hepatitis C antibody was confirmed in all 36 by enzyme-linked immunosorbent assay and by recombinant immunoblot assay, while 26 (72%) of the cohort were HCV-RNA-positive (type 1b) on PCR testing. In the 20 years post-infection, all members of the study group had at least one pregnancy, and mean parity was 3.5. They had a total of 100 pregnancies and 85 of these went to term. There were four premature births, one being a twin pregnancy, and 11 spontaneous miscarriages. One miscarriage occurred in the pregnancy following HCV infection. There were two neonatal deaths due to severe congenital abnormalities in the PCR-positive women. Of the children born to HCV-RNA positive mothers, only one (2.3%) tested positive for the virus. Significant portal fibrosis on liver biopsy was confined to HCV-RNA-positive mothers apart from one single exception in the antibody-positive HCV-RNA-negative group. Comparison with the control group showed no increase in spontaneous miscarriage rate, and no significant difference in obstetric complications; birth weights were similar for the two groups.

  14. Type 1 collagenopathy presenting with a Russell-Silver phenotype.

    PubMed

    Parker, Michael J; Deshpande, Charulata; Rankin, Julia; Wilson, Louise C; Balasubramanian, Meena; Hall, Christine M; Wagner, Bart E; Pollitt, Rebecca; Dalton, Ann; Bishop, Nicholas J

    2011-06-01

    Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. It exhibits a broad spectrum of clinical severity, ranging from multiple fractures in utero and perinatal death, to normal adult stature and low fracture incidence. Extra-skeletal features of OI include blue sclera, hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta. The proα1(I) and proα2(I) chains of collagen 1 are encoded by the COL1A1 and COL1A2 genes, respectively; quantitative or qualitative defects in type I collagen synthesis usually manifest as types of OI or some sub-types of EDS. The majority of patients (about 90%) with a clinical diagnosis of OI have a mutation in the COL1A1 or COL1A2 genes, which shows an autosomal dominant pattern of inheritance. Six other genes, CRTAP, LEPRE1, FKBP10, PP1B, SP7/Osterix (OSX), and SERPINH1, are associated with autosomal recessive forms of OI. However, other, rare phenotypes have also been described. There are many differential diagnoses of the short, syndromic child, including chromosomal, single gene, and multifactorial causes. However, one condition of particular relevance in the context of this report is the Russell-Silver syndrome (RSS). As originally described, the RSS is a very specific condition. However, it has subsequently become an umbrella term for a heterogeneous group of conditions presenting with short stature and triangular shape to the face. A significant proportion of these are now believed to be due to imprinting defects at 11p15. However, the cause in many cases remains unknown. We describe two cases with a phenotypic overlap between OI and RSS who both have COL1A1 mutations. Thus, a type 1 collagenopathy should be considered in the differential diagnosis of syndromic short stature.

  15. Progress and challenges for treating Type 1 diabetes.

    PubMed

    Garyu, Justin W; Meffre, Eric; Cotsapas, Chris; Herold, Kevan C

    2016-07-01

    It has been more than 30 years since the initial trials of Cyclosporin A to treat patients with new onset Type 1 diabetes (T1D). Since that time, there have been insights into genetic predisposition to the disease, the failures of immune tolerance, and mechanisms that cause the immune mediated β cell destruction. The genetic loci associated affect lymphocyte development and tolerance mechanisms. Discoveries related to the roles of specific immune responses gene such as the major histocompatibility complex, PTPN22, CTLA-4, IL-2RA, as well as the mechanisms of antigen presentation in the thymus have suggested ways in which autoreactivity may follow changes in the functions of these genes that are associated with risk. Antigens that are recognized by the immune system in patients with T1D have been identified. With this information, insights into the novel cellular mechanisms leading to the initiation and orchestration of β cell killing have been developed such as the presentation of unique antigens within the islets. Clinical trials have been performed, some of which have shown efficacy in improving β cell function but none have been able to permanently prevent loss of insulin secretion. The reasons for the lack of long term success are not clear but may include the heterogeneity of the immune response and in individual responses to immune therapies, recurrence of autoimmunity after the initial effects of the therapies, or even intrinsic mechanisms of β cell death that proceeds independently of immune attack after initiation of the disease. In this review, we cover developments that have led to new therapeutics and characteristics of patients who may show the most benefits from therapies. We also identify areas of incomplete understanding that might be addressed to develop more effective therapeutic strategies. PMID:27210268

  16. Pediatric Type 1 Diabetes: Reducing Admission Rates for Diabetes Ketoacidosis

    PubMed Central

    Choi, Steven; Rinke, Michael L.; Vandervoot, Kathy; Heptulla, Rubina A.

    2016-01-01

    Background: Diabetes ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus (T1DM). Reducing DKA admissions in children with T1DM requires a coordinated, comprehensive management plan. We aimed to decrease DKA admissions, 30-day readmissions, and length of stay (LOS) for DKA admissions. Methods: A multipronged intervention was designed in 2011 to reach all patients: (1) increase insulin pump use and basal-bolus regimen versus sliding scales, (2) transform educational program, (3) increased access to medical providers, and (4) support for patients and families. A before-after study was conducted comparing performance outcomes in years 2007-2010 (preintervention) to 2012-2014 (postintervention) using administrative data and Wilcoxon rank sum and Fischer exact tests. Results: DKA admissions decreased by 44% postintervention (16.7 vs 9.3 per 100 followed patient-years; P = .006), unique patient 30-day readmissions decreased from 20% to 5% postintervention (P = .001), and median LOS significantly decreased postintervention (P < .0001). Although not an original goal of the study, median hemoglobin A1C of a subset of the population transitioned from sliding scale decreased, 10.3% to 8.9% (P < .02). Conclusions: When clinical and widespread program interventions were used, significant reductions in DKA hospitalizations, 30-day readmissions, and LOS occurred for pediatric T1DM. Continuous performance improvement efforts are needed for improving DKA outcomes. PMID:27749721

  17. Plant programmed cell death caused by an autoactive form of Prf is suppressed by co-expression of the Prf LRR domain.

    PubMed

    Du, Xinran; Miao, Min; Ma, Xinrong; Liu, Yongsheng; Kuhl, Joseph C; Martin, Gregory B; Xiao, Fangming

    2012-09-01

    In tomato, the NBARC-LRR resistance (R) protein Prf acts in concert with the Pto or Fen kinase to determine immunity against Pseudomonas syringae pv. tomato (Pst). Prf-mediated defense signaling is initiated by the recognition of two sequence-unrelated Pst-secreted effector proteins, AvrPto and AvrPtoB, by tomato Pto or Fen. Prf detects these interactions and activates signaling leading to host defense responses including localized programmed cell death (PCD) that is associated with the arrest of Pst growth. We found that Prf variants with single amino acid substitutions at D1416 in the IHD motif (isoleucine-histidine-aspartic acid) in the NBARC domain cause effector-independent PCD when transiently expressed in leaves of Nicotiana benthamiana, suggesting D1416 plays an important role in activation of Prf. The N-terminal region of Prf (NPrf) and the LRR domain are required for this autoactive Prf cell death signaling but dispensable for accumulation of the Prf(D1416V) protein. Significantly, co-expression of the Prf LRR but not NPrf, with Prf(D1416V), AvrPto/Pto, AvrPtoB/Pto, an autoactive form of Pto (Pto(Y207D)), or Fen completely suppresses PCD. However, the Prf LRR does not interfere with PCD caused by Rpi-blb1(D475V), a distinct R protein-mediated PCD signaling event, or that caused by overexpression of MAPKKKα, a protein acting downstream of Prf. Furthermore, we found the Prf(D1416V) protein is unable to accumulate in plant cells when co-expressed with the Prf LRR domain, likely explaining the cell death suppression. The mechanism for the LRR-induced degradation of Prf(D1416V) is unknown but may involve interference in the intramolecular interactions of Prf or to binding of the unattached LRR to other host proteins that are needed for Prf stability.

  18. Beclin-1-independent autophagy mediates programmed cancer cell death through interplays with endoplasmic reticulum and/or mitochondria in colbat chloride-induced hypoxia.

    PubMed

    Sun, Lei; Liu, Ning; Liu, Shan-Shan; Xia, Wu-Yan; Liu, Meng-Yao; Li, Lin-Feng; Gao, Jian-Xin

    2015-01-01

    Autophagy has dual functions in cell survival and death. However, the effects of autophagy on cancer cell survival or death remain controversial. In this study, we show that Autophagy can mediate programmed cell death (PCD) of cancer cells in responding to cobalt chloride (CoCl2)-induced hypoxia in a Beclin-1-independent but autophagy protein 5 (ATG5)-dependent manner. Although ATG5 is not directly induced by CoCl2, its constitutive expression is essential for CoCl2-induced PCD. The ATG5-mediated autophagic PCD requires interplays with endoplasmic reticulum (ER) and/or mitochondria. In this process, ATG5 plays a central role in regulating ER stress protein CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) and mitochondrial protein second mitochondria derived activator of caspases (Smac). Two pathways for autophagic PCD in cancer cells responding to hypoxia have been identified: ATG5/CHOP/Smac pathway and ATG5/Smac pathway, which are probably dependent on the context of cell lines. The former is more potent than the latter for the induction of PCD at the early stage of hypoxia, although the ultimate efficiency of both pathways is comparable. In addition, both pathways may require ATG5-mediated conversion of LC3-I into LC3-II. Therefore, we have defined two autophagy-mediated pathways for the PCD of cancer cells in hypoxia, which are dependent on ATG5, interplayed with ER and mitochondria and tightly regulated by hypoxic status. The findings provide a new evidence that autophagy may inhibit tumor cell proliferation through trigger of PCD, facilitating the development of novel anti-cancer drugs. PMID:26609472

  19. The root hair assay facilitates the use of genetic and pharmacological tools in order to dissect multiple signalling pathways that lead to programmed cell death.

    PubMed

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  20. The Root Hair Assay Facilitates the Use of Genetic and Pharmacological Tools in Order to Dissect Multiple Signalling Pathways That Lead to Programmed Cell Death

    PubMed Central

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F.

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  1. Programmed Cell Death Induced by (−)-8,9-Dehydroneopeltolide in Human Promyelocytic Leukemia HL-60 Cells under Energy Stress Conditions

    PubMed Central

    Fuwa, Haruhiko; Sato, Mizuho; Sasaki, Makoto

    2014-01-01

    (+)-Neopeltolide is a marine macrolide natural product that exhibits potent antiproliferative activity against several human cancer cell lines. Previous study has established that this natural product primarily targets the complex III of the mitochondrial electron transport chain. However, the biochemical mode-of-actions of neopeltolide have not been investigated in detail. Here we report that (−)-8,9-dehydroneopeltolide (8,9-DNP), a more accessible synthetic analogue, shows potent cytotoxicity against human promyelocytic leukemia HL-60 cells preferentially under energy stress conditions. Nuclear morphology analysis, as well as DNA ladder assay, indicated that 8,9-DNP induced significant nuclear condensation/fragmentation and DNA fragmentation, and these events could be suppressed by preincubating the cells with a pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). Immunoblot analysis demonstrated the release of cytochrome c from the mitochondria and the cleavage of full-length caspase-3 and poly(ADP-ribose) polymerase (PARP). These results indicated that 8,9-DNP induced caspase-dependent apoptotic programmed cell death under energy stress conditions. It was also found that 8,9-DNP induced non-apoptotic cell death in the presence/absence of zVAD under energy stress conditions. Immunoblot analysis showed the intracytosolic release of apoptosis-inducing factor (AIF), although it did not further translocate to the nucleus. It appears most likely that, in the presence of zVAD, 8,9-DNP triggered necrotic cell death as a result of severe intracellular ATP depletion. PMID:25419998

  2. Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus-induced immune deficiency.

    PubMed Central

    Razvi, E S; Welsh, R M

    1993-01-01

    Acute viral infections induce immune deficiencies, as shown by unresponsiveness to mitogens and unrelated antigens. T lymphocytes isolated from mice acutely infected with lymphocytic choriomeningitis virus (LCMV) were found in this study to undergo activation-induced apoptosis upon signalling through the T-cell receptor (TcR)-CD3 complex. Kinetic studies demonstrated that this sensitivity to apoptosis directly correlated with the induction of immune deficiency, as measured by impaired proliferation in response to anti-CD3 antibody or to concanavalin A. Cell cycling in interleukin-2 (IL-2) alone stimulated proliferation of LCMV-induced T cells without inducing apoptosis, but preculturing of T cells from acutely infected mice in IL-2 accelerated apoptosis upon subsequent TcR-CD3 cross-linking. T lymphocytes isolated from mice after the acute infection were less responsive to IL-2, but those T cells, presumably memory T cells, responding to IL-2 were primed in each case to die a rapid apoptotic death upon TcR-CD3 cross-linking. These results indicate that virus infection-induced unresponsiveness to T-cell mitogens is due to apoptosis of the activated lymphocytes and suggest that the sensitization of memory cells by IL-2 induced during infection will cause them to die upon antigen recognition, thereby impairing specific responses to nonviral antigens. Images PMID:8371341

  3. Hexamethylene bisacetamide induces programmed cell death (apoptosis) and down-regulates BCL-2 expression in human myeloma cells.

    PubMed

    Siegel, D S; Zhang, X; Feinman, R; Teitz, T; Zelenetz, A; Richon, V M; Rifkind, R A; Marks, P A; Michaeli, J

    1998-01-01

    Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of monoclonal Ig-secreting plasma cells with low proliferative activity. It is postulated that inhibition of physiologic cell death is an underlying factor in the pathophysiology of MM. The development of chemoresistance is a common feature in patients with MM. In the present studies, hexamethylene bisacetamide (HMBA), a hybrid polar compound that is a potent inducer of terminal differentiation of various transformed cells, is shown to inhibit the growth of several human myeloma cell lines (ARP-1, U266, and RPMI 8226), including doxorubicin-resistant RPMI 8226 variants that overexpress the multidrug-resistance gene, MDR-1, and its product, p-glycoprotein. In addition to growth arrest and suppression of clonogenicity, HMBA induces apoptosis both in freshly isolated human myeloma cells and in cell lines, as determined by morphologic alterations, cell cycle distribution and endonucleosomal DNA fragmentation. Further, HMBA decreases BCL-2 protein expression in myeloma cells within 12-48 hr. Overexpression of BCL-2 protein in ARP-1 cells confers resistance to HMBA-induced apoptosis. Taken together, these data suggest that HMBA is a potent inducer of apoptosis in human myeloma cells, which may act through suppressing the anti-apoptotic function of the bcl-2 gene. HMBA, and related hybrid polar compounds, may prove useful in the management of this presently incurable disease.

  4. Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1

    PubMed Central

    Hatanaka, Yusuke; Watase, Kei; Wada, Keiji; Nagai, Yoshitaka

    2015-01-01

    Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1154Q/2Q mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1154Q/2Q mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1154Q/2Q mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1154Q/2Q mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1. PMID:26531852

  5. Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1.

    PubMed

    Hatanaka, Yusuke; Watase, Kei; Wada, Keiji; Nagai, Yoshitaka

    2015-11-04

    Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1(154Q/2Q) mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1(154Q/2Q) mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1(154Q/2Q) mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1(154Q/2Q) mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1.

  6. Type 1 Diabetes--Reaping the Rewards of a Targeted Research Investment.

    PubMed

    Fradkin, Judith E; Wallace, Julie A; Akolkar, Beena; Rodgers, Griffin P

    2016-02-01

    The Diabetes Control and Complications Trial (DCCT) precipitated a major research effort to develop new approaches to achieve near-normal glycemic control in real-world settings in people with type 1 diabetes. Toward that end, a unique funding stream from the U.S. Congress-the Special Statutory Funding Program for Type 1 Diabetes Research-has provided nearly $2.5 billion for research into the prevention, cure, and treatment of type 1 diabetes since 1998. This funding generated a targeted, sustained investment in type 1 diabetes research with six specific goals: identifying new therapeutic targets through the understanding of disease etiology and pathogenesis, preventing or reversing the disease, developing cell replacement therapy, improving management and care, preventing or reducing the complications, and attracting new talent and applying new technologies to type 1 diabetes research. This Perspective describes exciting results that have emerged from the investment and further advances on the horizon, including artificial pancreas technologies, new therapies for diabetic retinopathy, and breakthroughs in laboratory production of β-cells. The recent program extension enables us to build on this foundation and pursue key new initiatives to harness emerging technologies and develop the next generation of type 1 diabetes researchers. PMID:26798117

  7. Type 1 Diabetes--Reaping the Rewards of a Targeted Research Investment.

    PubMed

    Fradkin, Judith E; Wallace, Julie A; Akolkar, Beena; Rodgers, Griffin P

    2016-02-01

    The Diabetes Control and Complications Trial (DCCT) precipitated a major research effort to develop new approaches to achieve near-normal glycemic control in real-world settings in people with type 1 diabetes. Toward that end, a unique funding stream from the U.S. Congress-the Special Statutory Funding Program for Type 1 Diabetes Research-has provided nearly $2.5 billion for research into the prevention, cure, and treatment of type 1 diabetes since 1998. This funding generated a targeted, sustained investment in type 1 diabetes research with six specific goals: identifying new therapeutic targets through the understanding of disease etiology and pathogenesis, preventing or reversing the disease, developing cell replacement therapy, improving management and care, preventing or reducing the complications, and attracting new talent and applying new technologies to type 1 diabetes research. This Perspective describes exciting results that have emerged from the investment and further advances on the horizon, including artificial pancreas technologies, new therapies for diabetic retinopathy, and breakthroughs in laboratory production of β-cells. The recent program extension enables us to build on this foundation and pursue key new initiatives to harness emerging technologies and develop the next generation of type 1 diabetes researchers.

  8. Lesion simulating disease 1 and enhanced disease susceptibility 1 differentially regulate UV-C-induced photooxidative stress signalling and programmed cell death in Arabidopsis thaliana.

    PubMed

    Wituszyńska, Weronika; Szechyńska-Hebda, Magdalena; Sobczak, Mirosław; Rusaczonek, Anna; Kozłowska-Makulska, Anna; Witoń, Damian; Karpiński, Stanisław

    2015-02-01

    As obligate photoautotrophs, plants are inevitably exposed to ultraviolet (UV) radiation. Because of stratospheric ozone depletion, UV has become more and more dangerous to the biosphere. Therefore, it is important to understand UV perception and signal transduction in plants. In the present study, we show that lesion simulating disease 1 (LSD1) and enhanced disease susceptibility 1 (EDS1) are antagonistic regulators of UV-C-induced programmed cell death (PCD) in Arabidopsis thaliana. This regulatory dependence is manifested by a complex deregulation of photosynthesis, reactive oxygen species homeostasis, antioxidative enzyme activity and UV-responsive genes expression. We also prove that a UV-C radiation episode triggers apoptotic-like morphological changes within the mesophyll cells. Interestingly, chloroplasts are the first organelles that show features of UV-C-induced damage, which may indicate their primary role in PCD development. Moreover, we show that Arabidopsis Bax inhibitor 1 (AtBI1), which has been described as a negative regulator of plant PCD, is involved in LSD1-dependent cell death in response to UV-C. Our results imply that LSD1 and EDS1 regulate processes extinguishing excessive energy, reactive oxygen species formation and subsequent PCD in response to different stresses related to impaired electron transport.

  9. Hijacking of the jasmonate pathway by the mycotoxin fumonisin B1 (FB1) to initiate programmed cell death in Arabidopsis is modulated by RGLG3 and RGLG4

    PubMed Central

    Zhang, Xu; Wu, Qian; Cui, Shao; Ren, Jiao; Qian, Wanqiang; Yang, Yang; He, Shanping; Chu, Jinfang; Sun, Xiaohong; Yan, Cunyu; Yu, Xiangchun; An, Chengcai

    2015-01-01

    The mycotoxin fumonisin B1 (FB1) is a strong inducer of programmed cell death (PCD) in plants, but its underlying mechanism remains unclear. Here, we describe two ubiquitin ligases, RING DOMAIN LIGASE3 (RGLG3) and RGLG4, which control FB1-triggered PCD by modulating the jasmonate (JA) signalling pathway in Arabidopsis thaliana. RGLG3 and RGLG4 transcription was sensitive to FB1. Arabidopsis FB1 sensitivity was suppressed by loss of function of RGLG3 and RGLG4 and was increased by their overexpression. Thus RGLG3 and RGLG4 have coordinated and positive roles in FB1-elicited PCD. Mutated JA perception by coi1 disrupted the RGLG3- and RGLG4-related response to FB1 and interfered with their roles in cell death. Although FB1 induced JA-responsive defence genes, it repressed growth-related, as well as JA biosynthesis-related, genes. Consistently, FB1 application reduced JA content in wild-type plants. Furthermore, exogenously applied salicylic acid additively suppressed JA signalling with FB1 treatment, suggesting that FB1-induced salicylic acid inhibits the JA pathway during this process. All of these effects were attenuated in rglg3 rglg4 plants. Altogether, these data suggest that the JA pathway is hijacked by the toxin FB1 to elicit PCD, which is coordinated by Arabidopsis RGLG3 and RGLG4. PMID:25788731

  10. Lesion simulating disease 1 and enhanced disease susceptibility 1 differentially regulate UV-C-induced photooxidative stress signalling and programmed cell death in Arabidopsis thaliana.

    PubMed

    Wituszyńska, Weronika; Szechyńska-Hebda, Magdalena; Sobczak, Mirosław; Rusaczonek, Anna; Kozłowska-Makulska, Anna; Witoń, Damian; Karpiński, Stanisław

    2015-02-01

    As obligate photoautotrophs, plants are inevitably exposed to ultraviolet (UV) radiation. Because of stratospheric ozone depletion, UV has become more and more dangerous to the biosphere. Therefore, it is important to understand UV perception and signal transduction in plants. In the present study, we show that lesion simulating disease 1 (LSD1) and enhanced disease susceptibility 1 (EDS1) are antagonistic regulators of UV-C-induced programmed cell death (PCD) in Arabidopsis thaliana. This regulatory dependence is manifested by a complex deregulation of photosynthesis, reactive oxygen species homeostasis, antioxidative enzyme activity and UV-responsive genes expression. We also prove that a UV-C radiation episode triggers apoptotic-like morphological changes within the mesophyll cells. Interestingly, chloroplasts are the first organelles that show features of UV-C-induced damage, which may indicate their primary role in PCD development. Moreover, we show that Arabidopsis Bax inhibitor 1 (AtBI1), which has been described as a negative regulator of plant PCD, is involved in LSD1-dependent cell death in response to UV-C. Our results imply that LSD1 and EDS1 regulate processes extinguishing excessive energy, reactive oxygen species formation and subsequent PCD in response to different stresses related to impaired electron transport. PMID:24471507

  11. T lymphocytes bearing the gamma delta T cell receptor are susceptible to steroid-induced programmed cell death.

    PubMed

    Spinozzi, F; Agea, E; Bistoni, O; Travetti, A; Migliorati, G; Moraca, R; Nicoletti, I; Riccardi, C; Paoletti, F P; Vaccaro, R

    1995-05-01

    The mechanisms by which glucocorticoids suppress immune responses have not yet been clearly defined. In steroid-sensitive pathological conditions, an increase in gamma delta T cells can occur in certain untreated systemic autoimmune disorders and seems to be a peristent feature in most cases of systemic lupus erythematosus (SLE). Our previously published data demonstrated that immunosuppressive therapy normalized this expanded SLE T cell subset in parallel with clinical remission of the symptoms. To establish how corticosteroid treatment determines the disappearance of peripheral blood gamma delta T lymphocytes, circulating alpha beta and gamma delta T lymphocytes from seven SLE subjects with active disease and seven healthy individuals were cultured in the presence or absence of 10(-7) M Dexamethasone (DEX). Cell suspensions were then analysed for DNA fragmentation, characteristic of apoptotic cell death, by a new cytofluorimetric method. Conventional agarose-gel electrophoresis on the same T cell populations was carried out for comparison. Regular follow-ups for 6 months revealed in vivo steroid treatment determined a dramatic fall in SLE blood gamma delta T cells, and in vitro experiments seem to indicate that DEX-triggered apoptotic signals are confined to the double negative (CD4-CD8-) gamma delta T cell subpopulation which disappears after in vivo immunosuppressive therapy. Clinical and pathological remission of some autoimmune diseases is often obtained by corticosteroids. Our results offer new insights on the mechanisms through these hormones exert their potent inhibitory activities on immune system cells postulated to play a role in the generation of autoimmune responses. PMID:7725070

  12. Kupffer cells potentiate liver sinusoidal endothelial cell injury in sepsis by ligating programmed cell death ligand-1

    PubMed Central

    Hutchins, Noelle A.; Wang, Fei; Wang, Yvonne; Chung, Chun-Shiang; Ayala, Alfred

    2013-01-01

    PD-1 and PD-L1 have been reported to provide peripheral tolerance by inhibiting TCR-mediated activation. We have reported that PD-L1−/− animals are protected from sepsis-induced mortality and immune suppression. Whereas studies indicate that LSECs normally express PD-L1, which is also thought to maintain local immune liver tolerance by ligating the receptor PD-1 on T lymphocytes, the role of PD-L1 in the septic liver remains unknown. Thus, we hypothesized initially that PD-L1 expression on LSECs protects them from sepsis-induced injury. We noted that the increased vascular permeability and pSTAT3 protein expression in whole liver from septic animals were attenuated in the absence of PD-L1. Isolated LSECs taken from septic animals, which exhibited increased cell death, declining cell numbers, reduced cellular proliferation, and VEGFR2 expression (an angiogenesis marker), also showed improved cell numbers, proliferation, and percent VEGFR2+ levels in the absence of PD-L1. We also observed that sepsis induced an increase of liver F4/80+PD-1+-expressing KCs and increased PD-L1 expression on LSECs. Interestingly, PD-L1 expression levels on LSECs decreased when PD-1+-expressing KCs were depleted with clodronate liposomes. Contrary to our original hypothesis, we document here that increased interactions between PD-1+ KCs and PD-L1+ LSECs appear to lead to the decline of normal endothelial function—essential to sustain vascular integrity and prevent ALF. Importantly, we uncover an underappreciated pathological aspect of PD-1:PD-L1 ligation during inflammation that is independent of its normal, immune-suppressive activity. PMID:23766529

  13. Development of salinity tolerance in rice by constitutive-overexpression of genes involved in the regulation of programmed cell death

    PubMed Central

    Hoang, Thi M. L.; Moghaddam, Lalehvash; Williams, Brett; Khanna, Harjeet; Dale, James; Mundree, Sagadevan G.

    2015-01-01

    Environmental factors contribute to over 70% of crop yield losses worldwide. Of these drought and salinity are the most significant causes of crop yield reduction. Rice is an important staple crop that feeds more than half of the world’s population. However among the agronomically important cereals rice is the most sensitive to salinity. In the present study we show that exogenous expression of anti-apoptotic genes from diverse origins, AtBAG4 (Arabidopsis), Hsp70 (Citrus tristeza virus) and p35 (Baculovirus), significantly improves salinity tolerance in rice at the whole plant level. Physiological, biochemical and agronomical analyses of transgenic rice expressing each of the anti-apoptotic genes subjected to salinity treatment demonstrated traits associated with tolerant varieties including, improved photosynthesis, membrane integrity, ion and ROS maintenance systems, growth rate, and yield components. Moreover, FTIR analysis showed that the chemical composition of salinity-treated transgenic plants is reminiscent of non-treated, unstressed controls. In contrast, wild type and vector control plants displayed hallmark features of stress, including pectin degradation upon subjection to salinity treatment. Interestingly, despite their diverse origins, transgenic plants expressing the anti-apoptotic genes assessed in this study displayed similar physiological and biochemical characteristics during salinity treatment thus providing further evidence that cell death pathways are conserved across broad evolutionary kingdoms. Our results reveal that anti-apoptotic genes facilitate maintenance of metabolic activity at the whole plant level to create favorable conditions for cellular survival. It is these conditions that are crucial and conducive to the plants ability to tolerate/adapt to extreme environments. PMID:25870602

  14. Impact of neurofibromatosis type 1 on school performance.

    PubMed

    Krab, Lianne C; Aarsen, Femke K; de Goede-Bolder, Arja; Catsman-Berrevoets, Coriene E; Arts, Willem F; Moll, Henriette A; Elgersma, Ype

    2008-09-01

    School functioning of 86 Dutch neurofibromatosis type 1 children (7-17 years) using teacher questionnaires was analyzed to determine the impact of neurofibromatosis type 1 on school performance. In all, 75% of the neurofibromatosis type 1 children performed more than 1 standard deviation below grade peers in at least one of the domains of spelling, mathematics, technical reading or comprehensive reading. Furthermore, neurofibromatosis type 1 children had a 4-fold increased risk for attending special education and a 6-fold increased risk for receiving remedial teaching for learning, behavior, speech, or motor problems. Children without apparent learning disabilities still frequently displayed neuropsychological deficits. Only 10% of the children did not show any school-functioning problems. Finally, it was found that the clinical severity of neurofibromatosis type 1 correlated with the cognitive deficits. Taken together, it was shown that neurofibromatosis type 1 has profound impact on school performance. Awareness of these problems may facilitate timely recognition and appropriate support. PMID:18827266

  15. The Effect of Ursolic Acid on Leishmania (Leishmania) amazonensis Is Related to Programed Cell Death and Presents Therapeutic Potential in Experimental Cutaneous Leishmaniasis

    PubMed Central

    Yamamoto, Eduardo S.; Campos, Bruno L. S.; Jesus, Jéssica A.; Laurenti, Márcia D.; Ribeiro, Susan P.; Kallás, Esper G.; Rafael-Fernandes, Mariana; Santos-Gomes, Gabriela; Silva, Marcelo S.; Sessa, Deborah P.; Lago, João H. G.; Levy, Débora; Passero, Luiz F. D.

    2015-01-01

    Among neglected tropical diseases, leishmaniasis is one of the most important ones, affecting more than 12 million people worldwide. The available treatments are not well tolerated, and present diverse side effects, justifying the search for new therapeutic compounds. In the present study, the activity of ursolic acid (UA) and oleanolic acid (OA) were assayed in experimental cutaneous leishmaniasis (in vitro and in vivo). Promastigote forms of L. amazonensis were incubated with OA and UA for 24h, and effective concentration 50% (EC50) was estimated. Ultraestructural alterations in Leishmania amazonensis promastigotes after UA treatment were evaluated by transmission electron microscopy, and the possible mode of action was assayed through Annexin V and propidium iodide staining, caspase 3/7 activity, DNA fragmentation and transmembrane mitochondrial potential. The UA potential was evaluated in intracellular amastigotes, and its therapeutic potential was evaluated in L. amazonensis infected BALB/c mice. UA eliminated L. amazonensis promastigotes with an EC50 of 6.4 μg/mL, comparable with miltefosine, while OA presented only a marginal effect on promastigote forms at 100 μg/mL. The possible mechanism by which promastigotes were eliminated by UA was programmed cell death, independent of caspase 3/7, but it was highly dependent on mitochondria activity. UA was not toxic for peritoneal macrophages from BALB/c mice, and it was able to eliminate intracellular amastigotes, associated with nitric oxide (NO) production. OA did not eliminate amastigotes nor trigger NO. L. amazonensis infected BALB/c mice submitted to UA treatment presented lesser lesion size and parasitism compared to control. This study showed, for the first time, that UA eliminate promastigote forms through a mechanism associated with programed cell death, and importantly, was effective in vivo. Therefore, UA can be considered an interesting candidate for future tests as a prototype drug for the treatment

  16. Predicting major outcomes in type 1 diabetes: a model development and validation study

    PubMed Central

    Soedamah-Muthu, Sabita S.; Vergouwe, Yvonne; Costacou, Tina; Miller, Rachel G.; Zgibor, Janice; Chaturvedi, Nish; Snell-Bergeon, Janet K.; Maahs, David M.; Rewers, Marian; Forsblom, Carol; Harjutsalo, Valma; Groop, Per-Henrik; Fuller, John H.; Moons, Karel G.M.; Orchard, Trevor J.

    2015-01-01

    Aims/hypothesis Type 1 diabetes is associated with a higher risk of major vascular complications and death. A reliable method that predicts these outcomes early in the disease process would be helpful in risk classification. We therefore developed such a prognostic model and quantified its performance in independent cohorts. Methods Data were analysed of 1,973 participants with type 1 diabetes who were followed for seven years in the EURODIAB Prospective Complications Study. Strong prognostic factors of major outcomes were combined in a Weibull regression model. The model performance was tested in three different prospective cohorts: Pittsburgh Epidemiology of Diabetes Complications study (EDC, n=554), Finnish Diabetic Nephropathy study (FinnDiane, n=2,999) and Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n=580). Major outcomes included major coronary heart disease, stroke, end-stage renal failure, amputations, blindness and all-cause death. Results 95 EURODIAB patients with type 1 diabetes developed major outcomes during follow-up. Prognostic factors were age, glycated haemoglobin, waist-hip ratio, albumin/creatinine ratio, and HDL cholesterol. A high risk group could be identified with 15% risk after 3-years of follow-up, 24% after 5-years and 32% after 7-years. The discriminative ability of the model was adequate with a C-statistic of 0.74. Discrimination was similar or even better in the independent cohorts: EDC, C-statistic = 0.79; FinnDiane, 0.82; and CACTI, 0.73. Conclusions/Interpretation Our prognostic model that uses easily accessible clinical features can discriminate between type 1 diabetes patients with good and poor prognosis. Such a prognostic model may be helpful in clinical practice and for risk stratification in clinical trials. PMID:25186291

  17. Expression of Programmed Death Receptor Ligand 1 with High Tumor-Infiltrating Lymphocytes Is Associated with Better Prognosis in Breast Cancer

    PubMed Central

    Bae, Sang Byung; Cho, Hyun Deuk; Oh, Mee-Hye; Lee, Ji-Hye; Jang, Si-Hyong; Hong, Soon Auck; Cho, Junhun; Kim, Sung Yong; Han, Sun Wook; Lee, Jong Eun; Kim, Han Jo

    2016-01-01

    Purpose The interaction of programmed death receptor 1 (PD-1) and its ligand, programmed death receptor ligand 1 (PD-L1), negatively regulates immune responses. This study aimed to clarify PD-L1 expression levels in breast cancer through immunohistochemistry (IHC) and to evaluate associations between these findings and clinicopathologic variables, including prognosis. Methods PD-L1 expression was analyzed using IHC on tissue microarrays of 465 invasive breast carcinomas. Results High PD-L1 expression was demonstrated in 63 of 465 tumors (13.5%). High PD-L1 expression was significantly associated with high histologic grade (p<0.001), negative lymph nodes (p=0.011), early pathologic stage (p=0.025), high tumor-infiltrating lymphocyte (TIL) (p<0.001) counts, negative estrogen receptor (p<0.001) and progesterone receptor (p=0.002) expression, positive human epidermal growth factor receptor 2 (HER2) (p=0.003), cytokeratin 5/6 (p=0.011), epidermal growth factor receptor (p<0.001), and p53 (p<0.001) expression, and high Ki-67 proliferating index (p<0.001). Based on intrinsic subtypes, high PD-L1 expression and high TIL counts were significantly associated with the HER2 and triple-negative basal type (p<0.001). PD-L1 expression was significantly associated with better disease-free survival (DFS) (p=0.041) and overall survival (OS) (p=0.026) in the univariate analysis, but not in the multivariate analysis. Higher TIL levels was an independent prognostic factor for decreased disease progression (hazard ratio [HR], 2.389; 95% confidence interval [CI], 1.284–4.445; p=0.006) and overall death (HR, 3.666; 95% CI, 1.561–8.607; p=0.003). Conclusion PD-L1 protein expression in breast cancer is associated with better DFS and OS, but is not an independent prognostic factor. High PD-L1 expression was significantly associated with high TIL levels. This finding has important implications for antibody therapies targeting the PD-1/PD-L1 signaling mechanism in breast cancer. PMID

  18. Synaptic protein dysregulation in myotonic dystrophy type 1

    PubMed Central

    Hernández-Hernández, Oscar; Sicot, Géraldine; Dinca, Diana M.; Huguet, Aline; Nicole, Annie; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-01-01

    The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program. PMID:25003003

  19. Type 1 Diabetes Genetic Risk Score: a novel tool to discriminate monogenic and type 1 diabetes

    PubMed Central

    Patel, K A; Oram, R A; Flanagan, S E; De Franco, E; Colclough, K;