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Sample records for cadmium-induced necrotic cell

  1. Attenuation of cadmium-induced necrotic cell death by necrostatin-1: Potential necrostatin-1 acting sites

    SciTech Connect

    Hsu, T.-S.; Yang, P.-M.; Tsai, J.-S.; Lin, L.-Y.

    2009-03-01

    Cadmium (Cd) induces necrotic death in Chinese hamster ovary (CHO) K1 cells and we have established the responsible signaling pathway. Reportedly, necrostatin-1 (Nec-1) rescues cells from necrotic death by mediating through the death domain receptor (DR) signaling pathway. We show here that Nec-1 also effectively attenuates necrotic death triggered by Cd. Two other treatments that cause necrotic cell death, one can (z-VAD-fmk/TNF-{alpha} on U937 cells) and the other cannot (etherynic acid (EA) on DLD-1 cells) be rescued by Nec-1, were also studied in parallel for comparison. Results show that Nec-1 is ineffectual in modulating intracellular calcium contents, calpain activity (a downstream protease), or reactive oxygen species production. It can counteract the reduction in mitochondrial membrane potential (MMP) caused by treating CHO K1 or U937 cells with necrosis-inducing agent. However, this effect was not found in EA-treated DLD-1 cells. Notably, Nec-1 elevates NF-{kappa}B activity in the presence or absence of necrosis-inducing agents. Our study shows that, in addition to DR-mediated necrosis, Nec-1 is effective in attenuating Cd-induced necrosis. It rescues cells with reduced MMP implying that mitochondrion is its major acting site.

  2. 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.

  3. Protective effect of quercetin on cadmium-induced oxidative toxicity on germ cells in male mice.

    PubMed

    Bu, Tongliang; Mi, Yuling; Zeng, Weidong; Zhang, Caiqiao

    2011-03-01

    Cadmium is a toxic heavy metal that is widely distributed in the environment. As a critical process, oxidative toxicity mediates the morphological and functional damages in germ cells after cadmium exposure. In this study, the protective effect of quercetin on cadmium-induced oxidative toxicity was investigated in mouse testicular germ cells. After oral administration of cadmium chloride at 4 mg/kg body weight for 2 weeks, damages in spermatozoa occurred in the early stage of spermatogenesis. Cadmium treatment significantly decreased the testicular antioxidant system, including decreases in the glutathione (GSH) level, superoxide dismutase (SOD), and GSH peroxidase (GSH-Px) activities. Moreover, exposure to cadmium resulted in an increase of hydrogen peroxide production and lipid peroxidation in testes. In addition, cadmium provoked germ cell apoptosis by upregulating expression of the proapoptotic proteins Bax and caspase-3 and downregulating expression of the antiapoptotic protein Bcl-XL. However, combined administration of a common flavonoid quercetin at 75 mg/kg body weight significantly attenuated cadmium-induced germ cell apoptosis by suppressing the hydrogen peroxide production and lipid peroxidation in testicular tissue. Simultaneous supplementation of quercetin markedly restored the decrease in GSH level and SOD and GSH-Px activities elicited by cadmium treatment. Additionally, quercetin protected germ cells from cadmium-induced apoptosis by downregulating the expression of Bax and caspase-3 and upregulating Bcl-XL expression. These results indicate that quercetin, due to its antioxidative and antiapoptotic characters, may manifest effective protective action against cadmium-induced oxidative toxicity in mouse testicular germ cells. PMID:21337715

  4. Cadmium induces the activation of cell wall integrity pathway in budding yeast.

    PubMed

    Xiong, Bing; Zhang, Lilin; Xu, Huihui; Yang, Yi; Jiang, Linghuo

    2015-10-01

    MAP kinases are important signaling molecules regulating cell survival, proliferation and differentiation, and can be activated by cadmium stress. In this study, we demonstrate that cadmium induces phosphorylation of the yeast cell wall integrity (CWI) pathway_MAP kinase Slt2, and this cadmium-induced CWI activation is mediated by the cell surface sensor Mid2 through the GEF Rom1, the central regulator Rho1 and Bck1. Nevertheless, cadmium stress does not affect the subcellular localization of Slt2 proteins. In addition, this cadmium-induced CWI activation is independent on the calcium/calcineurin signaling and the high osmolarity glycerol (HOG) signaling pathways in yeast cells. Furthermore, we tested the cadmium sensitivity of 42 paired double-gene deletion mutants between six CWI components and seven components of the HOG pathway. Our results indicate that the CWI pathway is epistatic to the HOG pathway in cadmium sensitivity. However, gene deletion mutations for the Swi4/Swi6 transcription factor complex show synergistic effects with mutations of HOG components in cadmium sensitivity.

  5. Light regulation of cadmium-induced cell death in Arabidopsis

    PubMed Central

    Smith, Sarah J; Wang, Yun; Slabas, Antoni R; Chivasa, Stephen

    2014-01-01

    Cadmium is an environmental pollutant with deleterious effects on both prokaryotic and eukaryotic organisms. In plants, the effects of cadmium toxicity are concentration dependent; lower doses destabilize many physiological processes and inhibit cell growth and multiplication, while higher doses evoke a more severe response that triggers activation of cell death. We recently investigated the effects of light on cadmium toxicity in Arabidopsis using a cell suspension culture system. Although not affecting the inhibitory effects on cell multiplication, we found that light is a powerful regulator of Cd-induced cell death. A very specific proteomic response, which was clearly controlled by light, preceded cell death. Here we discuss the implications of these findings and highlight similarities between the regulation of cell death triggered by Cd and fumonisin B1. We consider how both compounds could be useful tools in dissecting plant cell death signaling. PMID:24398567

  6. Paneth cells and necrotizing enterocolitis.

    PubMed

    Underwood, Mark A

    2012-01-01

    Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Immaturity of the innate immune system of the gut is central to the pathogenesis of NEC. Recent studies suggest a key role for Paneth cells in this disease. Addressing basic questions on the development and function of immature Paneth cells may shed light on the puzzling pathophysiology of NEC. Current animal models of NEC are limited in their capacity to answer these questions.

  7. Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells

    SciTech Connect

    Son, Young-Ok; Wang Xin; Hitron, John Andrew; Zhang Zhuo; Cheng Senping; Budhraja, Amit; Ding Songze; Lee, Jeong-Chae; Shi Xianglin

    2011-09-15

    Cadmium is a toxic heavy metal which is environmentally and occupationally relevant. The mechanisms underlying cadmium-induced autophagy are not yet completely understood. The present study shows that cadmium induces autophagy, as demonstrated by the increase of LC3-II formation and the GFP-LC3 puncta cells. The induction of autophagosomes was directly visualized by electron microscopy in cadmium-exposed skin epidermal cells. Blockage of LKB1 or AMPK by siRNA transfection suppressed cadmium-induced autophagy. Cadmium-induced autophagy was inhibited in dominant-negative AMPK-transfected cells, whereas it was accelerated in cells transfected with the constitutively active form of AMPK. mTOR signaling, a negative regulator of autophagy, was downregulated in cadmium-exposed cells. In addition, cadmium generated reactive oxygen species (ROS) at relatively low levels, and caused poly(ADP-ribose) polymerase-1 (PARP) activation and ATP depletion. Inhibition of PARP by pharmacological inhibitors or its siRNA transfection suppressed ATP reduction and autophagy in cadmium-exposed cells. Furthermore, cadmium-induced autophagy signaling was attenuated by either exogenous addition of catalase and superoxide dismutase, or by overexpression of these enzymes. Consequently, these results suggest that cadmium-mediated ROS generation causes PARP activation and energy depletion, and eventually induces autophagy through the activation of LKB1-AMPK signaling and the down-regulation of mTOR in skin epidermal cells. - Highlights: > Cadmium, a toxic heavy metal, induces autophagic cell death through ROS-dependent activation of the LKB1-AMPK signaling. > Cadmium generates intracellular ROS at low levels and this leads to severe DNA damage and PARP activation, resulting in ATP depletion, which are the upstream events of LKB1-AMPK-mediated autophagy. > This novel finding may contribute to further understanding of cadmium-mediated diseases.

  8. Sensitivity to cadmium-induced genotoxicity in rat testicular cells is associated with minimal expression of the metallothionein gene.

    PubMed

    Shiraishi, N; Hochadel, J F; Coogan, T P; Koropatnick, J; Waalkes, M P

    1995-02-01

    Cadmium is a carcinogenic metal. Although the mechanism of tumor induction is unknown, DNA/metal interactions may be involved. Metallothionein can protect against cadmium toxicity in our previous work it was shown to reduce cadmium genotoxicity in cultured cells. To extend these results, the genotoxicity of cadmium was studied in R2C cells, a rat testicular Leydig cell line. The R2C cells were very sensitive to cadmium-induced single-strand DNA damage (SSD), as measured by alkaline elution. SSD occurred in R2C cells after treatment with 25 and 50 microM CdCl2 for 2 hr. Prior work showed other cells required much higher levels of cadmium (approximately 500 microM) to induce genotoxicity. The genotoxic levels of cadmium (25-50 microM) were not cytotoxic in R2C cells as assessed by a metabolic activity (MTT) assay. Pretreatment of R2C cells with a low cadmium dose (2 microM, 24 hr) had no effect on cadmium-induced SSD, in contrast to prior work in other cells where such pretreatments reduced SSD through metallothionein gene activation. In fact, cadmium or zinc treatments resulted in little or no increase in metallothionein gene expression in R2C cells as determined by Northern blot analysis for metallothionein mRNA using cDNA or oligonucleotide probes and radioimmunoassay for metallothionein protein production. Basal metallothionein mRNA was essentially nondetectable. Induction of a cadmium-binding protein in R2C cells did occur, as determined by Cd-heme assay, but did not induce tolerance to SSD. In vivo, the Leydig cell is a target for cadmium carcinogenicity and its cadmium-binding protein is thought not to be a true metallothionein. These results indicate that R2C cells are sensitive to cadmium-induced genotoxicity and that this sensitivity is associated with minimal expression of the metallothionein gene. PMID:7871536

  9. Selenite suppression of cadmium-induced testicular apoptosis.

    PubMed

    Jones, M M; Xu, C; Ladd, P A

    1997-01-15

    The characteristic apoptotic ladder-like patterns of rat testicular DNA on agarose gel electrophoresis which results from treatment with CdCl2 are suppressed by the administration of Na2SeO3. The examination of testicular tissue using an ELISA programmed cell death detection procedure confirmed this selenite suppression of cadmium-induced apoptosis. The administration of the Na2SeO3 at either 0.5, 1, 2 h prior to or 0.5, 1, 2 h after the administration of the CdCl2 appear to be almost equally effective at suppressing the apoptotic response. These results are in accord with previous studies on the Na2SeO3 suppression of cadmium induced necrotic changes in tissues and suggest that Na2SeO3 interferes with both necrosis and apoptosis. PMID:9020518

  10. Suppression of Kupffer cell function prevents cadmium induced hepatocellular necrosis in the male Sprague-Dawley rat.

    PubMed

    Sauer, J M; Waalkes, M P; Hooser, S B; Kuester, R K; McQueen, C A; Sipes, I G

    1997-08-15

    Exposure of humans to toxic metals and metalloids is a major environmental problem. Many metals, such as cadmium, can be hepatotoxic. However, the mechanisms by which metals cause acute hepatic injury are in many cases unknown. Previous reports suggest a major role for inflammation in acute cadmium induced hepatotoxicity. In initial experiments we found that a non-hepatotoxic dose of cadmium chloride (CdCl2; 2.0 mg/kg, i.v.) markedly increased the clearance rate of colloidal carbon from the blood, which is indicative of enhanced phagocytic activity by Kupffer cells (resident hepatic macrophages). Thus. the objective these studies was to determine the involvement of Kupffer cells in cadmium induced liver injury by inhibiting their function with gadolinium chloride (GdCl3). Male Sprague-Dawley rats were administered GdCl3 (10 mg/kg, i.v.) followed 24 h later by a single dose of CdCl2 (3.0 and 4.0 mg/kg, i.v.). Twenty four hours after CdCl2 administration animals were killed and the degree of liver toxicity was assessed using plasma alanine aminotransferase (ALT), as well as light microscopy. Cadmium chloride administration produced multifocal hepatocellular necrosis and increased plasma ALT activity. Pretreatment with GdCl3 significantly reduced both the morphological changes and hepatic ALT release caused by CdCl2. However, the protection was specific to the liver, and did not alter CdCl2 induced testicular injury, as determined by histopathological damage. In many cases, the inducible cadmium-binding protein, metallothionein (MT) is often an essential aspect of the acquisition of cadmium tolerance in the liver. Although cadmium caused a dramatic induction of hepatic MT (32-fold), GdCl3 caused only a minor increase (2-fold). Combined CdCl2 and GdCl3 treatment did not induce levels to an extent greater than CdCl2 alone. As expected, GdCl3 also caused a slight increase in the amount of cadmium associated with the liver. In cultured hepatocytes isolated from GdCl3

  11. Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling

    SciTech Connect

    Son, Young-Ok; Wang, Lei; Poyil, Pratheeshkumar; Budhraja, Amit; Hitron, J. Andrew; Zhang, Zhuo; Lee, Jeong-Chae; Shi, Xianglin

    2012-10-15

    Cadmium has been widely used in industry and is known to be carcinogenic to humans. Although it is widely accepted that chronic exposure to cadmium increases the incidence of cancer, the mechanisms underlying cadmium-induced carcinogenesis are unclear. The main aim of this study was to investigate the role of reactive oxygen species (ROS) in cadmium-induced carcinogenesis and the signal transduction pathways involved. Chronic exposure of human bronchial epithelial BEAS-2B cells to cadmium induced cell transformation, as evidenced by anchorage-independent growth in soft agar and clonogenic assays. Chronic cadmium treatment also increased the potential of these cells to invade and migrate. Injection of cadmium-stimulated cells into nude mice resulted in the formation of tumors. In contrast, the cadmium-mediated increases in colony formation, cell invasion and migration were prevented by transfection with catalase, superoxide dismutase-1 (SOD1), or SOD2. In particular, chronic cadmium exposure led to activation of signaling cascades involving PI3K, AKT, GSK-3β, and β-catenin and transfection with each of the above antioxidant enzymes markedly inhibited cadmium-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the cadmium-mediated increase in total and active β-catenin proteins and colony formation. Moreover, there was a marked induction of AKT, GSK-3β, β-catenin, and carcinogenic markers in tumor tissues formed in mice after injection with cadmium-stimulated cells. Collectively, our findings suggest a direct involvement of ROS in cadmium-induced carcinogenesis and implicate a role of AKT/GSK-3β/β-catenin signaling in this process. -- Highlights: ► Chronic exposure to cadmium induces carcinogenic properties in BEAS-2B cells. ► ROS involved in cadmium-induced tumorigenicity of BEAS-2B cells. ► Cadmium activates ROS-dependent AKT/GSK-3β/β-catenin-mediated signaling. ► ROS

  12. Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-κB, and AP-1 signaling pathways.

    PubMed

    Khoi, Pham Ngoc; Xia, Yong; Lian, Sen; Kim, Ho Dong; Kim, Do Hyun; Joo, Young Eun; Chay, Kee-Oh; Kim, Kyung Keun; Jung, Young Do

    2014-10-01

    Cadmium exposure has been linked to human cancers, including stomach cancer. In this study, the effects of cadmium on urokinase-type plasminogen activator receptor (uPAR) expression in human gastric cancer cells and the underlying signal transduction pathways were investigated. Cadmium induced uPAR expression in a time- and concentration-dependent manner. Cadmium also induced uPAR promoter activity. Additionally, cadmium induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), and the activation of c-Jun amino terminal kinase (JNK). A specific inhibitor of MEK-1 (PD98059) inhibited cadmium-induced uPAR expression, while JNK and p38 MAPK inhibitors did not. Expression vectors encoding dominant-negative MEK-1 (pMCL-K97M) also prevented cadmium-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift studies showed that sites for the transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1) were involved in cadmium-induced uPAR transcription. Suppression of the cadmium-induced uPAR promoter activity by a mutated-type NF-κB-inducing kinase and I-κB and an AP-1 decoy oligonucleotide confirmed that the activation of NF-κB and AP-1 are essential for cadmium-induced uPAR upregulation. Cells pretreated with cadmium showed markedly enhanced invasiveness and this effect was partially abrogated by uPAR-neutralizing antibodies and by inhibitors of ERK-1/2, NF-κB, and AP-1. These results suggest that cadmium induces uPAR expression via ERK-1/2, NF-κB, and AP-1 signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.

  13. Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro

    SciTech Connect

    Zhang, Huiying; Newman, Donna R.; Bonner, James C.; Sannes, Philip L.

    2012-11-15

    Environmental exposure to cadmium is known to cause damage to alveolar epithelial cells of the lung, impair their capacity to repair, and result in permanent structural alterations. Cell surface heparan sulfate proteoglycans (HSPGs) can modulate cell responses to injury through their interactions with soluble effector molecules. These interactions are often sulfate specific, and the removal of sulfate groups from HS side chains could be expected to influence cellular injury, such as that caused by exposure to cadmium. The goal of this study was to define the role 6-O-sulfate plays in cellular responses to cadmium exposure in two pulmonary epithelial cancer cell lines (H292 and A549) and in normal human primary alveolar type II (hAT2) cells. Sulfate levels were modified by transduced transient over-expression of 6-O-endosulfatase (HSulf-1), a membrane-bound enzyme which specifically removes 6-O-sulfate groups from HSPG side chains. Results showed that cadmium decreased cell viability and activated apoptosis pathways at low concentrations in hAT2 cells but not in the cancer cells. HSulf-1 over-expression, on the contrary, decreased cell viability and activated apoptosis pathways in H292 and A549 cells but not in hAT2 cells. When combined with cadmium, HSulf-1 over-expression further decreased cell viability and exacerbated the activation of apoptosis pathways in the transformed cells but did not add to the toxicity in hAT2 cells. The finding that HSulf-1 sensitizes these cancer cells and intensifies the injury induced by cadmium suggests that 6-O-sulfate groups on HSPGs may play important roles in protection against certain environmental toxicants, such as heavy metals. -- Highlights: ► Primary human lung alveolar type 2 (hAT2) cells and H292 and A549 cells were used. ► Cadmium induced apoptosis in hAT2 cells but not in H292 or A549 cells. ► HSulf-1exacerbates apoptosis induced by cadmium in H292 and A549 but not hAT2 cells.

  14. How are necrotic cells recognized by their predators?

    PubMed

    Li, Zao; Zhou, Zheng

    2016-01-01

    Necrosis is a type of cell death often caused by cell injury and is linked to human diseases including neuron degeneration, stroke, and cancer. Cells undergoing necrosis are engulfed and degraded by engulfing cells, their predators. The mechanisms by which necrotic cells are recognized and removed remain elusive. Here we comment on our recent findings that reveal new molecular mechanisms of necrotic-cell recognition. Through studying the C. elegans touch neurons undergoing excitotoxic necrosis, we identified a receptor/ligand pair that enables engulfing cells to recognize necrotic neurons. The phagocytic receptor CED-1 is activated through interaction with its ligand phosphatidylserine (PS), exposed on the surface of necrotic cells. Furthermore, against the common belief that necrotic cells have ruptured plasma membrane, we found that necrotic C. elegans touch neurons actively present PS on their outer surfaces while maintaining plasma membrane integrity. We further identified 2 mechanisms governing the presentation of PS, one of which is shared with cells undergoing apoptosis, a "cell suicide" event, whereas the other is unique to necrotic neurons. The influx of Ca(2+), a key necrosis-triggering factor, is implicated in activating a neuronal PS-scramblase for PS exposure. We propose that the mechanisms controlling PS-exposure and necrotic-cell recognition by engulfing cells are likely conserved from worms to humans. PMID:27073733

  15. The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells

    SciTech Connect

    Yu Xinyuan; Filardo, Edward J.; Shaikh, Zahir A.

    2010-05-15

    Cadmium (Cd) is a nonessential metal that is dispersed throughout the environment. It is an endocrine-disrupting element which mimics estrogen, binds to estrogen receptor alpha (ERalpha), and promotes cell proliferation in breast cancer cells. We have previously published that Cd promotes activation of the extracellular regulated kinases, erk-1 and -2 in both ER-positive and ER-negative human breast cancer cells, suggesting that this estrogen-like effect of Cd is not associated with the ER. Here, we have investigated whether the newly appreciated transmembrane estrogen receptor, G-protein coupled receptor 30 (GPR30), may be involved in Cd-induced cell proliferation. Towards this end, we compared the effects of Cd in ER-negative human SKBR3 breast cancer cells in which endogenous GPR30 signaling was selectively inhibited using a GPR30 interfering mutant. We found that Cd concentrations from 50 to 500 nM induced a proliferative response in control vector-transfected SKBR3 cells but not in SKBR3 cells stably expressing interfering mutant. Similarly, intracellular cAMP levels increased about 2.4-fold in the vector transfectants but not in cells in which GPR30 was inactivated within 2.5 min after treatment with 500 nM Cd. Furthermore, Cd treatment rapidly activated (within 2.5 min) raf-1, mitogen-activated protein kinase kinase, mek-1, extracellular signal regulated kinases, erk-1/2, ribosomal S6 kinase, rsk, and E-26 like protein kinase, elk, about 4-fold in vector transfectants. In contrast, the activation of these signaling molecules in SKBR3 cells expressing the GPR30 mutant was only about 1.4-fold. These results demonstrate that Cd-induced breast cancer cell proliferation occurs through GPR30-mediated activation in a manner that is similar to that achieved by estrogen in these cells.

  16. Pure White Cell Aplasia and Necrotizing Myositis

    PubMed Central

    Kim, Peter Geon; Suh, Joome; Adelman, Max W.; Oduro, Kwadwo; Williams, Erik; Brunner, Andrew M.; Kuter, David J.

    2016-01-01

    Pure white cell aplasia (PWCA) is a rare hematologic disorder characterized by the absence of neutrophil lineages in the bone marrow with intact megakaryopoiesis and erythropoiesis. PWCA has been associated with autoimmune, drug-induced, and viral exposures. Here, we report a case of a 74-year-old female who presented with severe proximal weakness without pain and was found to have PWCA with nonspecific inflammatory necrotizing myositis and acute liver injury on biopsies. These findings were associated with a recent course of azithromycin and her daily use of a statin. Myositis improved on prednisone but PWCA persisted. With intravenous immunoglobulin and granulocyte-colony stimulating factor therapies, her symptoms and neutrophil counts improved and were sustained for months. PMID:27073704

  17. Cadmium-induced damage to primary cultures of rat Leydig cells.

    PubMed

    Yang, Jian-Ming; Arnush, Marc; Chen, Qiong-Yu; Wu, Xiang-Dong; Pang, Bing; Jiang, Xue-Zhi

    2003-01-01

    The mechanism of testicular toxicity of cadmium is poorly understood. Previous studies focusing on cadmium-related changes in testicular histopathology have implicated testicular blood vessel damage as the main cause of cadmium toxicity. To further explore the toxic effects of cadmium on testis, we isolated and cultured rat Leydig cells, exposed to 10, 20, and 40 microM of cadmium chloride (base doses). After 24 h of exposure, cells and supernatants were harvested to examine cytotoxicity and genotoxicity of cadmium. The results show that both cell viability and concentration of testosterone excretion in primary Leydig cells are significantly lower in cadmium-exposed groups compared to the controls. Changes in testosterone excretion with human chorionic gonadotropin (hCG) stimulation is especially profound. The contents of malondialdehyde (MDA) and the activity of glutathione peroxidase (GSH-Px) in exposed groups are significantly higher than those in the control group, but the activity of superoxide dismutase (SOD) is lower. The number of cells with DNA single strand breaks and the levels of cellular DNA damage in all three exposure groups are significantly higher than in controls. These results indicate that cadmium is directly toxic to primary Leydig cells, and that the decreased percentage of normal cells and the increased level of DNA damage in cadmium-exposed Leydig cells may be responsible for decreased testosterone secretion. PMID:14555193

  18. Cadmium induces NLRP3 inflammasome-dependent pyroptosis in vascular endothelial cells.

    PubMed

    Chen, Haiyan; Lu, Yonghui; Cao, Zhengwang; Ma, Qinlong; Pi, Huifeng; Fang, Yiliang; Yu, Zhengping; Hu, Houxiang; Zhou, Zhou

    2016-03-30

    Cadmium (Cd) is an important and common environmental pollutant that has been linked to cardiovascular diseases, such as atherosclerosis and hypertension. Increasing evidence demonstrates that Cd impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms remain obscure. In human umbilical vein endothelial cells (HUVECs), we observed that Cd treatment led to cell death and the generation of inflammatory cytokines. The Cd-induced cell death was identified as pyroptosis, a novel pro-inflammatory form of cell death depending on caspase-1 activation. In addition, exposure of HUVECs to Cd resulted in NLRP3 inflammasome activation as evidenced by cleavage of caspase-1 and downstream interleukin (IL)-1β production. Moreover, knockdown of NLRP3 by small interfering RNA efficiently suppressed Cd-induced caspase-1 cleavage, IL-1β production and pyroptosis in HUVECs. Additional experiments demonstrated that treatment with Cd significantly increased the levels of mitochondrial reactive oxygen species (mtROS) and intracellular ROS in HUVECs. Accordingly, pre-treatment with mtROS scavenger or total ROS scavenger reduced Cd-induced activation of NLRP3 inflammasome and pyroptotic cell death. Taken together, our data suggest that NLRP3 inflammasome, activated by the generation of mtROS, mediates Cd-induced pyroptosis in HUVECs. Our results provide novel insights into Cd-induced cytotoxicity and the underlying mechanism by which Cd induces endothelial injury.

  19. Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism.

    PubMed

    Brama, Marina; Gnessi, Lucio; Basciani, Sabrina; Cerulli, Nicola; Politi, Laura; Spera, Giovanni; Mariani, Stefania; Cherubini, Sara; Scotto d'Abusco, Anna; Scandurra, Roberto; Migliaccio, Silvia

    2007-01-29

    Breast cancer (BC) is linked to estrogen exposure. Estradiol (E2) stimulates BC cells proliferation by binding the estrogen receptor (ER). Hormone-related cancers have been linked to estrogenic environmental contaminants. Cadmium (Cd) a toxic pollutant, acts as estrogens in BC cells. Purpose of our study was to evaluate whether Cd regulates MCF-7 cell proliferation by activating ERK1/2, Akt and PDGFRalpha kinases. Cd increased cell proliferation and the ER-antagonist ICI 182,780 blunted it. To characterize an ER-dependent mechanism, ERalpha/beta expression was evaluated. Cd decreased ERalpha expression, but not ERbeta. Cd also increased ERK1/2, Akt and PDGFRalpha phosphorylation while ICI blocked it. Since stimulation of phosphorylation was slower than expected, c-fos and c-jun proto-oncogenes, and PDGFA were analyzed. Cd rapidly increased c-jun, c-fos and PDGFA expression. Cells were also co-incubated with the Cd and specific kinases inhibitors, which blocked the Cd-stimulated proliferation. In conclusion, our results indicate that Cd increases BC cell proliferation in vitro by stimulating Akt, ERK1/2 and PDGFRalpha kinases activity likely by activating c-fos, c-jun and PDGFA by an ERalpha-dependent mechanism.

  20. Melatonin alleviates cadmium-induced cellular stress and germ cell apoptosis in testes.

    PubMed

    Ji, Yan-Li; Wang, Hua; Meng, Can; Zhao, Xian-Feng; Zhang, Cheng; Zhang, Ying; Zhao, Mei; Chen, Yuan-Hua; Meng, Xiu-Hong; Xu, De-Xiang

    2012-01-01

    Increasing evidence demonstrates that melatonin has an anti-apoptotic effect in somatic cells. However, whether melatonin can protect against germ cell apoptosis remains obscure. Cadmium (Cd) is a testicular toxicant and induces germ cell apoptosis. In this study, we investigated the effects of melatonin on Cd-evoked germ cell apoptosis in testes. Male ICR mice were intraperitoneally (i.p.) injected with melatonin (5 mg/kg) every 8 hr, beginning at 8 hr before CdCl(2) (2.0 mg/kg, i.p.). As expected, acute Cd exposure resulted in germ cell apoptosis in testes, as determined by terminal dUTP nick-end labeling (TUNEL) staining. Melatonin significantly alleviated Cd-induced testicular germ cell apoptosis. An additional experiment showed that spliced form of XBP-1, the target of the IRE-1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an endoplasmic reticulum (ER) chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly increased testicular eIF2α and JNK phosphorylation, indicating that the unfolded protein response (UPR) pathway was activated by CdCl(2). Interestingly, melatonin almost completely inhibited Cd-induced ER stress and the UPR in testes. In addition, melatonin obviously attenuated Cd-induced heme oxygenase (HO)-1 expression and protein nitration in testes. Taken together, these results suggest that melatonin alleviates Cd-induced cellular stress and germ cell apoptosis in testes. Melatonin may be useful as pharmacological agents to protect against Cd-induced testicular toxicity. PMID:21793897

  1. Ascorbic acid protects against cadmium-induced endoplasmic reticulum stress and germ cell apoptosis in testes.

    PubMed

    Ji, Yan-Li; Wang, Zhen; Wang, Hua; Zhang, Cheng; Zhang, Ying; Zhao, Mei; Chen, Yuan-Hua; Meng, Xiu-Hong; Xu, De-Xiang

    2012-11-01

    Cadmium (Cd) is a testicular toxicant which induces endoplasmic reticulum (ER) stress and germ cell apoptosis in testes. This study investigated the effects of ascorbic acid on Cd-evoked ER stress and germ cell apoptosis in testes. Male mice were intraperitoneally injected with CdCl(2) (2.0 mg/kg). As expected, a single dose of Cd induced testicular germ cell apoptosis. Interestingly, Cd-triggered testicular germ cell apoptosis was almost completely inhibited in mice treated with ascorbic acid. Interestingly, ascorbic acid significantly attenuated Cd-induced upregulation of GRP78 in testes. In addition, ascorbic acid significantly attenuated Cd-triggered testicular IRE1α and eIF2α phosphorylation and XBP-1 activation, indicating that this antioxidant counteracts Cd-induced unfolded protein response (UPR) in testes. Finally, ascorbic acid significantly attenuated Cd-evoked upregulation of CHOP and JNK phosphorylation, two components in ER stress-mediated apoptotic pathway. In conclusion, ascorbic acid protects mice from Cd-triggered germ cell apoptosis via inhibiting ER stress and UPR in testes. PMID:22569276

  2. Proteome profiling of cadmium-induced apoptosis by antibody array analyses in human bronchial epithelial cells

    PubMed Central

    Xu, Yan-Ming; Yu, Fei-Yuan; Yang, Feng; Yao, Yue; Zhou, Yuan; Ching, Yick-Pang; Lau, Andy T. Y.

    2016-01-01

    Protein array technology is a powerful platform for the simultaneous determination of the expression levels of a number of proteins as well as post-translational modifications such as phosphorylation. Here, we screen and report for the first time, the dominant signaling cascades and apoptotic mediators during the course of cadmium (Cd)-induced cytotoxicity in human bronchial epithelial cells (BEAS-2B) by antibody array analyses. Proteins from control and Cd-treated cells were captured on Proteome Profiler™ Arrays for the parallel determination of the relative levels of protein phosphorylation and proteins associated with apoptosis. Our results indicated that the p38 MAPK- and JNK-related signal transduction pathways were dramatically activated by Cd treatment. Cd potently stimulates the phosphorylations of p38α (MAPK14), JNK1/2 (MAPK8/9), and JUN; while the phosphorylations of Akt1, ERK1/2 (MAPK3/1), GSK3β, and mTOR were suppressed. Moreover, there was an induction of proapoptotic protein BAX, release of cytochrome c (CYCS) from mitochondria, activation of caspase-3/9 (CASP3/9); as well as decreased expression of cell cycle checkpoint proteins (TP53, p21, and p27) and several inhibitors of apoptosis proteins (IAPs) [including cIAP-1/2 (BIRC2/3), XIAP (BIRC4), and survivin (BIRC5)]. Pretreatment of cells with the thiol antioxidant glutathione or p38 MAPK/JNK inhibitors before Cd treatment effectively abrogated ROS activation of p38 MAPK/JNK pathways and apoptosis-related proteins. Taken together, our results demonstrate that Cd causes oxidative stress-induced apoptosis; and the p38 MAPK/JNK and mitochondrial pathways are more importantly participated for signal transduction and the induction of apoptosis in Cd-exposed human lung cells. PMID:26716417

  3. Protective effect of boric acid on lead- and cadmium-induced genotoxicity in V79 cells.

    PubMed

    Ustündağ, Aylin; Behm, Claudia; Föllmann, Wolfram; Duydu, Yalçin; Degen, Gisela H

    2014-06-01

    The toxic heavy metals cadmium (Cd) and lead (Pb) are important environmental pollutants which can cause serious damage to human health. As the metal ions (Cd(2+) and Pb(2+)) accumulate in the organism, there is special concern regarding chronic toxicity and damage to the genetic material. Metal-induced genotoxicity has been attributed to indirect mechanisms, such as induction of oxidative stress and interference with DNA repair. Boron is a naturally occurring element and considered to be an essential micronutrient, although the cellular activities of boron compounds remain largely unexplored. The present study has been conducted to evaluate potential protective effects of boric acid (BA) against genotoxicity induced by cadmium chloride (CdCl2) and lead chloride (PbCl2) in V79 cell cultures. Cytotoxicity assays (neutral red uptake and cell titer blue assay) served to determine suitable concentrations for subsequent genotoxicity assays. Chromosomal damage and DNA strand breaks were assessed by micronucleus tests and comet assays. Both PbCl2 and CdCl2 (at 3, 5 and 10 µM) were shown to induce concentration-dependent increases in micronucleus frequencies and DNA strand breaks in V79 cells. BA itself was not cytotoxic (up to 300 µM) and showed no genotoxic effects. Pretreatment of cells with low levels of BA (2.5 and 10 µM) was found to strongly reduce the genotoxic effects of the tested metals. Based on the findings of this in vitro study, it can be suggested that boron provides an efficient protection against the induction of DNA strand breaks and micronuclei by lead and cadmium. Further studies on the underlying mechanisms for the protective effect of boron are needed.

  4. Roles of reactive oxygen species and mitochondria in cadmium-induced injury of liver cells.

    PubMed

    Liu, Tao; He, Wenting; Yan, Chuan; Qi, Yongmei; Zhang, Yingmei

    2011-04-01

    The roles of reactive oxygen species (ROS) and mitochondrial damage in the cadmium (Cd)-induced injury of liver cells were studied by using N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine hydrochloride (ALCAR). After exposure of experimental rats to cadmium (Cd) for 16 h, mitochondrial membrane potential (MMP), ROS production, glutathione peroxidase (GSH-Px) activity, glutathione (GSH) content, malondialdehyde (MDA) content and DNA single-strand break (DNA-SSB) were analyzed. Loss of MMP, increase of ROS production, inhibition of GSH-Px activity, elevation of GSH content, rise of MDA content and DNA-SSB level suggest the participation of ROS and mitochondrion in Cd-induced injury of liver cell. NAC pretreatment attenuated oxidative stress, reversed the decline in GSH-Px activity and reduced GSH and MDA levels significantly. However, Cd-induced loss in MMP was significantly exacerbated by NAC. For another, ALCAR did not perform as well as NAC in terms of reducing ROS production, restoring GSH-Px activity and reducing GSH content. Nevertheless, it significantly improved the recovery of MMP and reduction of MDA content. In addition, conspicuous DNA damage was observed in the samples treated with NAC or ALCAR, indicating Cd could attack DNA through other pathways. These results suggest that oxidative stress or mitochondrial impairment plays a main role in different injuries respectively.

  5. Cadmium induces phosphorylation and stabilization of c-Fos in HK-2 renal proximal tubular cells

    SciTech Connect

    Iwatsuki, Mamiko; Inageda, Kiyoshi; Matsuoka, Masato

    2011-03-15

    We examined the effects of cadmium chloride (CdCl{sub 2}) exposure on the expression and phosphorylation status of members of the Fos family, components of the activator protein-1 transcription factor, in HK-2 human renal proximal tubular cells. Following the exposure to CdCl{sub 2}, the expression of c-fos, fosB, fra-1, and fra-2 increased markedly, with different magnitudes and time courses. The levels of Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) also increased in response to CdCl{sub 2} exposure. Although the elevation of c-fos transcripts was transient, c-Fos protein levels increased progressively with lower electrophoretic mobility, suggesting stabilization of c-Fos through post-translational modifications. Consistently, we observed phosphorylation of c-Fos at Ser362 and Ser374 in HK-2 cells treated with CdCl{sub 2}. Phosphorylated forms of mitogen-activated protein kinases (MAPKs)-including extracellular signal-regulated protein kinase (ERK), c-Jun NH{sub 2}-terminal kinase, and p38-increased after CdCl{sub 2} exposure, whereas treatment with the MAPK/ERK kinase inhibitor U0126 and the p38 inhibitor SB203580 suppressed the accumulation and phosphorylation of c-Fos. We mutated Ser362 to alanine (S362A), Ser374 to alanine (S374A), and both residues to alanines (S362A/S374A) to inhibit potential phosphorylation of c-Fos at these sites. S374A or double S362A/S374A mutations reduced c-Fos level markedly, but S362A mutation did not. On the other hand, S362A/S374A mutations induced a more pronounced reduction in c-Fos DNA-binding activity than S374A mutation. These results suggest that while Ser374 phosphorylation seems to play a role in c-Fos stabilization, phosphorylation at two C-terminal serine residues is required for the transcriptional activation of c-Fos in HK-2 cells treated with CdCl{sub 2}.

  6. In vitro protection by pyruvate against cadmium-induced cytotoxicity in hippocampal HT-22 cells.

    PubMed

    Poteet, Ethan; Winters, Ali; Xie, Luokun; Ryou, Myoung-Gwi; Liu, Ran; Yang, Shao-Hua

    2014-08-01

    Cadmium is a toxic metal with no biological function in higher-order mammals. Humans are exposed to cadmium environmental contamination and the mechanism underlying the cadmium's cytotoxicity is unclear. To better understand this mechanism, we employed murine hippocampal HT-22 cells to test the in vitro effects of cadmium toxicity. Our study indicated that cadmium inhibits both mitochondria oxidative phosphorylation and glycolysis. In turn, this causes depolarization of mitochondrial membrane potential, increase of superoxide production and decrease of ATP generation. Furthermore, we demonstrated that the detrimental action of cadmium in bioenergetics could be mitigated by pyruvate, an intermediate metabolic product. Pyruvate decreased superoxide production, maintained mitochondrial membrane potential, restored glycolysis, mitigated the decrease in cellular ATP and attenuated cadmium cytotoxicity. Our study provides the first evidence that pyruvate might offer promising therapy for cadmium poisoning.

  7. In vitro studies on mangiferin protection against cadmium-induced human renal endothelial damage and cell death via the MAP kinase and NF-κB pathways.

    PubMed

    Rajendran, Peramaiyan; Rengarajan, Thamaraiselvan; Nishigaki, Yutaka; Palaniswami, Rajendran; Nishigaki, Ikuo

    2016-01-01

    The therapeutic effects of the natural antioxidant mangiferin (a xanthonoid and potent oxygen free radical scavenger), which is widely distributed in mango fruit, against CdCl(2)-induced toxicity in human renal glomerulus endothelial cells (HRGEC) were investigated. The viability of HREGCs that were treated with CdCl(2) (25 µ mol) and co-treated with mangiferin (75 µ mol) for 24 h was measured by crystal violet dye. The exposure of human glomerulus renal endothelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal proinflammatory cytokines known to play a significant role in renal inflammation. Proinflammatory cytokine secretion by human renal glomerulus endothelial cells could be the result of cadmium-induced IL-6 secretion via an NF-κB-dependent pathway. However, IL-8 secretion involves the phosphor-JNK phospho-p38 signaling pathway. The results of the current study reveal that mangiferin could prevent both cadmium-induced IL-6 and IL-8 secretion by human glomerulus endothelial cells and be used to prevent renal inflammation. PMID:25798666

  8. A necrotic cell death model in a protist.

    PubMed

    Laporte, C; Kosta, A; Klein, G; Aubry, L; Lam, D; Tresse, E; Luciani, M F; Golstein, P

    2007-02-01

    While necrotic cell death is attracting considerable interest, its molecular bases are still poorly understood. Investigations in simple biological models, taken for instance outside the animal kingdom, may benefit from less interference from other cell death mechanisms and from better experimental accessibility, while providing phylogenetic information. Can necrotic cell death occur outside the animal kingdom? In the protist Dictyostelium, developmental stimuli induced in an autophagy mutant a stereotyped sequence of events characteristic of necrotic cell death. This sequence included swift mitochondrial uncoupling with mitochondrial 2',7'-dichlorofluorescein diacetate fluorescence, ATP depletion and increased oxygen consumption. This was followed by perinuclear clustering of dilated mitochondria. Rapid plasma membrane rupture then occurred, which was evidenced by time-lapse videos and quantified by FACS. Of additional interest, developmental stimuli and classical mitochondrial uncouplers triggered a similar sequence of events, and exogenous glucose delayed plasma membrane rupture in a nonglycolytic manner. The occurrence of necrotic cell death in the protist Dictyostelium (1) provides a very favorable model for further study of this type of cell death, and (2) strongly suggests that the mechanism underlying necrotic cell death was present in an ancestor common to the Amoebozoa protists and to animals and has been conserved in evolution.

  9. Muscarinic M1 receptor partially modulates higher sensitivity to cadmium-induced cell death in primary basal forebrain cholinergic neurons: A cholinesterase variants dependent mechanism.

    PubMed

    Del Pino, Javier; Zeballos, Gabriela; Anadon, María José; Díaz, María Jesús; Moyano, Paula; Díaz, Gloria Gómez; García, Jimena; Lobo, Margarita; Frejo, María Teresa

    2016-06-15

    Cadmium is a toxic compound reported to produce cognitive dysfunctions, though the mechanisms involved are unknown. In a previous work we described how cadmium blocks cholinergic transmission and induces greater cell death in primary cholinergic neurons from the basal forebrain. It also induces cell death in SN56 cholinergic neurons from the basal forebrain through M1R blockage, alterations in the expression of AChE variants and GSK-3β, and an increase in Aβ and total and phosphorylated Tau protein levels. It was observed that the silencing or blockage of M1R altered ChAT activity, GSK-3β, AChE splice variants gene expression, and Aβ and Tau protein formation. Furthermore, AChE-S variants were associated with the same actions modulated by M1R. Accordingly, we hypothesized that cholinergic transmission blockage and higher sensitivity to cadmium-induced cell death of primary basal forebrain cholinergic neurons is mediated by M1R blockage, which triggers this effect through alteration of the expression of AChE variants. To prove this hypothesis, we evaluated, in primary culture from the basal forebrain region, whether M1R silencing induces greater cell death in cholinergic neurons than cadmium does, and whether in SN56 cells M1R mediates the mechanisms described so as to play a part in the cadmium induction of cholinergic transmission blockage and cell death in this cell line through alteration of the expression of AChE variants. Our results prove that M1R silencing by cadmium partially mediates the greater cell death observed on basal forebrain cholinergic neurons. Moreover, all previously described mechanisms for blocking cholinergic transmission and inducing cell death on SN56 cells after cadmium exposure are partially mediated by M1R through the alteration of AChE expression. Thus, our results may explain cognitive dysfunctions observed in cadmium toxicity. PMID:27377441

  10. Primary sterile necrotic cells fail to cross-prime CD8(+) T cells.

    PubMed

    Gamrekelashvili, Jaba; Ormandy, Lars A; Heimesaat, Markus M; Kirschning, Carsten J; Manns, Michael P; Korangy, Firouzeh; Greten, Tim F

    2012-10-01

    Necrotic cells are known to activate the innate immune system and trigger inflammation by releasing damage associated molecular patterns (DAMPs). However, how necrotic cells influence the induction of antigen-specific CD8(+) T cell-mediated adaptive immune responses under sterile conditions, in the absence of pathogen associated molecular patterns (PAMPs), remains poorly understood. Here, we examined antigen-specific CD8(+) T-cell responses to primary sterile necrotic tumor cells both in vitro and in vivo. We found that primary necrotic cells alone fail to generate CD8(+) T cell-dependent immune responses toward cell-associated antigens. We show that necrotic cells trigger CD8(+) T-cell immunity only in the presence of PAMPs or analogs, such as p(dI-dC) and/or unmethylated CpG DNA. The electroporation of tumor cells with these PAMPs prior to necrosis induction triggered antigen-specific CD8(+) T-cell responses through a TLR9/MyD88-dependent pathway. In addition, we found that necrotic cells contain factors that can block the cross-priming of CD8(+) T cells even under non-sterile conditions and can serve as a possible mechanism of immunosuppression. These results suggest that antigen-specific CD8(+) T-cell responses to primary necrotic tumor cells can be induced in the presence of PAMPs and thus have a substantial impact on the development of antitumor vaccination strategies.

  11. Gadolinium chloride pretreatment ameliorates acute cadmium-induced hepatotoxicity.

    PubMed

    Kyriakou, Loukas G; Tzirogiannis, Konstantinos N; Demonakou, Maria D; Kourentzi, Kalliopi T; Mykoniatis, Michael G; Panoutsopoulos, Georgios I

    2013-08-01

    Cadmium is a known industrial and environmental pollutant. It causes hepatotoxicity upon acute administration. Features of cadmium-induced acute hepatoxicity encompass necrosis, apoptosis, peliosis and inflammatory infiltration. Gadolinium chloride (GdCl3) may prevent cadmium-induced hepatotoxicity by suppressing Kupffer cells. The effect of GdCl3 pretreatment on a model of acute cadmium-induced liver injury was investigated. Male Wistar rats 4-5 months old were injected intraperitoneally with normal saline followed by cadmium chloride (CdCl2; 6.5 mg/kg) or GdCl3 (10 mg/kg) followed by CdCl2 (6.5 mg/kg; groups I and II, respectively). Rats of both the groups were killed at 9, 12, 16, 24, 48 and 60 h after cadmium intoxication. Liver sections were analyzed for necrosis, apoptosis, peliosis and mitoses. Liver regeneration was also evaluated by tritiated thymidine incorporation into hepatic DNA. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also determined. Hepatic necrosis, hepatocyte and nonparenchymal cell apoptosis and macroscopic and microscopic types of peliosis hepatis were minimized by gadolinium pretreatment. Serum levels of AST and ALT were also greatly diminished in rats of group II. Tritiated thymidine incorporation into hepatic DNA was increased in gadolinium pretreatment rats. Kupffer cell activation was minimal in both the groups of rats. Gadolinium pretreatment attenuates acute cadmium-induced liver injury in young Wistar rats, with mechanisms other than Kupffer cell elimination.

  12. Hydrogen Sulfide Alleviates Cadmium-Induced Cell Death through Restraining ROS Accumulation in Roots of Brassica rapa L. ssp. pekinensis.

    PubMed

    Zhang, Liping; Pei, Yanxi; Wang, Hongjiao; Jin, Zhuping; Liu, Zhiqiang; Qiao, Zengjie; Fang, Huihui; Zhang, Yanjie

    2015-01-01

    Hydrogen sulfide (H2S) is a cell signal molecule produced endogenously and involved in regulation of tolerance to biotic and abiotic stress in plants. In this work, we used molecular biology, physiology, and histochemical methods to investigate the effects of H2S on cadmium- (Cd-) induced cell death in Chinese cabbage roots. Cd stress stimulated a rapid increase of endogenous H2S in roots. Additionally, root length was closely related to the cell death rate. Pretreatment with sodium hydrosulfide (NaHS), a H2S donor, alleviated the growth inhibition caused by Cd in roots-this effect was more pronounced at 5 μM NaHS. Cd-induced cell death in roots was significantly reduced by 5 μM NaHS treatment. Under Cd stress, activities of the antioxidant enzymes were significantly enhanced in roots. NaHS + Cd treatment made their activities increase further compared with Cd exposure alone. Enhanced antioxidant enzyme activity led to a decline in reactive oxygen species accumulation and lipid peroxidation. In contrast, these effects were reversed by hydroxylamine, a H2S inhibitor. These results suggested that H2S alleviated the cell death caused by Cd via upregulation of antioxidant enzyme activities to remove excessive reactive oxygen species and reduce cell oxidative damage.

  13. Hydrogen Sulfide Alleviates Cadmium-Induced Cell Death through Restraining ROS Accumulation in Roots of Brassica rapa L. ssp. pekinensis

    PubMed Central

    2015-01-01

    Hydrogen sulfide (H2S) is a cell signal molecule produced endogenously and involved in regulation of tolerance to biotic and abiotic stress in plants. In this work, we used molecular biology, physiology, and histochemical methods to investigate the effects of H2S on cadmium- (Cd-) induced cell death in Chinese cabbage roots. Cd stress stimulated a rapid increase of endogenous H2S in roots. Additionally, root length was closely related to the cell death rate. Pretreatment with sodium hydrosulfide (NaHS), a H2S donor, alleviated the growth inhibition caused by Cd in roots—this effect was more pronounced at 5 μM NaHS. Cd-induced cell death in roots was significantly reduced by 5 μM NaHS treatment. Under Cd stress, activities of the antioxidant enzymes were significantly enhanced in roots. NaHS + Cd treatment made their activities increase further compared with Cd exposure alone. Enhanced antioxidant enzyme activity led to a decline in reactive oxygen species accumulation and lipid peroxidation. In contrast, these effects were reversed by hydroxylamine, a H2S inhibitor. These results suggested that H2S alleviated the cell death caused by Cd via upregulation of antioxidant enzyme activities to remove excessive reactive oxygen species and reduce cell oxidative damage. PMID:26078819

  14. Activation of Nrf2 by cadmium and its role in protection against cadmium-induced apoptosis in rat kidney cells

    SciTech Connect

    Chen Jun; Shaikh, Zahir A.

    2009-11-15

    Kidney is the primary target organ in chronic cadmium (Cd) toxicity, and oxidative stress plays an important role in this process. The nuclear transcription factor Nrf2 binds to antioxidant response elements (AREs) and regulates genes involved in protecting cells from oxidative damage. Whether kidney cells respond to Cd by activating Nrf2 is unknown. This study was designed to examine the Cd-induced activation of Nrf2 transcriptional activity in a stable rat kidney cell line, NRK-52E, and to investigate the protection this might offer against apoptosis. The cells were treated with 5-20 muM CdCl{sub 2} for 5 h, followed by a recovery period of up to 24 h. A concentration-dependent increase (up to 2.9-fold) in the level of reactive oxygen species was noted upon termination of 5-h Cd treatment. The Nrf2-ARE binding activity also increased and peaked (6.1-fold) at 10 muM Cd concentration. Time-course study revealed that the binding activity increased at 1 h of Cd treatment and peaked 2 h post Cd treatment. Apoptosis was detected 6 h post treatment with Cd and a concentration- and time-dependent increase in the apoptotic cell population occurred during the next 18 h. Over-expression of Nrf2 by transient transfection conferred resistance against Cd-induced apoptosis. Conversely, suppression of Nrf2 expression by specific siRNA resulted in greater sensitivity of the cells to Cd by decreasing the levels of two antioxidant enzymes, hemeoxygenase-1 and glutamate-cysteine ligase. Taken together, these results suggest that in kidney cells the activation of Nrf2 is an adaptive intracellular response to Cd-induced oxidative stress, and that Nrf2 is protective against Cd-induced apoptosis.

  15. Crosstalk between endoplasmic reticulum stress and mitochondrial pathway mediates cadmium-induced germ cell apoptosis in testes.

    PubMed

    Ji, Yan-Li; Wang, Hua; Zhao, Xian-Feng; Wang, Qun; Zhang, Cheng; Zhang, Ying; Zhao, Mei; Chen, Yuan-Hua; Meng, Xiu-Hong; Xu, De-Xiang

    2011-12-01

    Cadmium (Cd) is associated with male infertility and poor semen quality in humans. Increasing evidence demonstrates that Cd induces testicular germ cell apoptosis in rodent animals. However, the molecular mechanisms of Cd-induced testicular germ cell apoptosis remain poorly understood. In the present study, we investigated the role of endoplasmic reticulum (ER) stress on Cd-evoked germ cell apoptosis in testes. We show that spliced form of XBP-1, the target of the IRE1 pathway, was significantly increased in testes of mice injected with CdCl(2). GRP78, an ER chaperone, and CHOP, a downstream target of the PERK pathway, were upregulated in testes of Cd-treated mice. In addition, acute Cd exposure significantly caused eIF2α and JNK phosphorylation in testes, indicating that the unfolded protein response pathway in testes was activated by Cd. Interestingly, phenylbutyric acid (PBA), an ER chemical chaperone, attenuated Cd-induced ER stress and protected against germ cell apoptosis in testes. In addition, PBA significantly attenuated Cd-evoked release of cytochrome c from mitochondria to cytoplasm in testes. Taken together, these results suggest that crosstalk between ER stress signaling and mitochondrial pathway mediates Cd-induced testicular germ cell apoptosis. PMID:21908765

  16. Intraspecific variability of cadmium tolerance and accumulation, and cadmium-induced cell wall modifications in the metal hyperaccumulator Arabidopsis halleri.

    PubMed

    Meyer, Claire-Lise; Juraniec, Michal; Huguet, Stéphanie; Chaves-Rodriguez, Elena; Salis, Pietro; Isaure, Marie-Pierre; Goormaghtigh, Erik; Verbruggen, Nathalie

    2015-06-01

    Certain molecular mechanisms of Cd tolerance and accumulation have been identified in the model species Arabidopsis halleri, while intraspecific variability of these traits and the mechanisms of shoot detoxification were little addressed. The Cd tolerance and accumulation of metallicolous and non-metallicolous A. halleri populations from different genetic units were tested in controlled conditions. In addition, changes in shoot cell wall composition were investigated using Fourier transform infrared spectroscopy. Indeed, recent works on A. halleri suggest Cd sequestration both inside cells and in the cell wall/apoplast. All A. halleri populations tested were hypertolerant to Cd, and the metallicolous populations were on average the most tolerant. Accumulation was highly variable between and within populations, and populations that were non-accumulators of Cd were identified. The effect of Cd on the cell wall composition was quite similar in the sensitive species A. lyrata and in A. halleri individuals; the pectin/polysaccharide content of cell walls seems to increase after Cd treatment. Nevertheless, the changes induced by Cd were more pronounced in the less tolerant individuals, leading to a correlation between the level of tolerance and the extent of modifications. This work demonstrated that Cd tolerance and accumulation are highly variable traits in A. halleri, suggesting adaptation at the local scale and involvement of various molecular mechanisms. While in non-metallicolous populations drastic modifications of the cell wall occur due to higher Cd toxicity and/or Cd immobilization in this compartment, the increased tolerance of metallicolous populations probably involves other mechanisms such as vacuolar sequestration. PMID:25873677

  17. Autophagy and gap junctional intercellular communication inhibition are involved in cadmium-induced apoptosis in rat liver cells

    SciTech Connect

    Zou, Hui; Zhuo, Liling; Han, Tao; Hu, Di; Yang, Xiaokang; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Liu, Xuezhong; Liu, Zongping

    2015-04-17

    Cadmium (Cd) is known to induce hepatotoxicity, yet the underlying mechanism of how this occurs is not fully understood. In this study, Cd-induced apoptosis was demonstrated in rat liver cells (BRL 3A) with apoptotic nuclear morphological changes and a decrease in cell index (CI) in a time- and concentration-dependent manner. The role of gap junctional intercellular communication (GJIC) and autophagy in Cd-induced apoptosis was investigated. Cd significantly induced GJIC inhibition as well as downregulation of connexin 43 (Cx43). The prototypical gap junction blocker carbenoxolone disodium (CBX) exacerbated the Cd-induced decrease in CI. Cd treatment was also found to cause autophagy, with an increase in mRNA expression of autophagy-related genes Atg-5, Atg-7, Beclin-1, and microtubule-associated protein light chain 3 (LC3) conversion from cytosolic LC3-I to membrane-bound LC3-II. The autophagic inducer rapamycin (RAP) prevented the Cd-induced CI decrease, while the autophagic inhibitor chloroquine (CQ) caused a further reduction in CI. In addition, CBX promoted Cd-induced autophagy, as well as changes in expression of Atg-5, Atg-7, Beclin-1 and LC3. CQ was found to block the Cd-induced decrease in Cx43 and GJIC inhibition, whereas RAP had opposite effect. These results demonstrate that autophagy plays a protective role during Cd-induced apoptosis in BRL 3A cells during 6 h of experiment, while autophagy exacerbates Cd-induced GJIC inhibition which has a negative effect on cellular fate. - Highlights: • GJIC and autophagy is crucial for biological processes. • Cd exposure causes GJIC inhibition and autophagy increase in BRL 3A cells. • Autophagy protects Cd induced BRL 3A cells apoptosis at an early stage. • Autophagy exacerbates Cd-induced GJIC inhibition. • GJIC plays an important role in autophagy induced cell death or survival.

  18. Intraspecific variability of cadmium tolerance and accumulation, and cadmium-induced cell wall modifications in the metal hyperaccumulator Arabidopsis halleri

    PubMed Central

    Meyer, Claire-Lise; Juraniec, Michal; Huguet, Stéphanie; Chaves-Rodriguez, Elena; Salis, Pietro; Isaure, Marie-Pierre; Goormaghtigh, Erik; Verbruggen, Nathalie

    2015-01-01

    Certain molecular mechanisms of Cd tolerance and accumulation have been identified in the model species Arabidopsis halleri, while intraspecific variability of these traits and the mechanisms of shoot detoxification were little addressed. The Cd tolerance and accumulation of metallicolous and non-metallicolous A. halleri populations from different genetic units were tested in controlled conditions. In addition, changes in shoot cell wall composition were investigated using Fourier transform infrared spectroscopy. Indeed, recent works on A. halleri suggest Cd sequestration both inside cells and in the cell wall/apoplast. All A. halleri populations tested were hypertolerant to Cd, and the metallicolous populations were on average the most tolerant. Accumulation was highly variable between and within populations, and populations that were non-accumulators of Cd were identified. The effect of Cd on the cell wall composition was quite similar in the sensitive species A. lyrata and in A. halleri individuals; the pectin/polysaccharide content of cell walls seems to increase after Cd treatment. Nevertheless, the changes induced by Cd were more pronounced in the less tolerant individuals, leading to a correlation between the level of tolerance and the extent of modifications. This work demonstrated that Cd tolerance and accumulation are highly variable traits in A. halleri, suggesting adaptation at the local scale and involvement of various molecular mechanisms. While in non-metallicolous populations drastic modifications of the cell wall occur due to higher Cd toxicity and/or Cd immobilization in this compartment, the increased tolerance of metallicolous populations probably involves other mechanisms such as vacuolar sequestration. PMID:25873677

  19. N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes.

    PubMed

    Ji, Yan-Li; Wang, Hua; Zhang, Cheng; Zhang, Ying; Zhao, Mei; Chen, Yuan-Hua; Xu, De-Xiang

    2013-03-01

    Cadmium (Cd) is a reproductive toxicant that induces germ cell apoptosis in the testes. Previous studies have demonstrated that endoplasmic reticulum (ER) stress is involved in Cd-induced germ cell apoptosis. The aim of the present study was to investigate the effects of N-acetylcysteine (NAC), an antioxidant, on Cd-induced ER stress and germ cell apoptosis in the testes. Male CD-1 mice were intraperitoneally injected with CdCl2 (2.0 mg kg(-1)). As expected, acute Cd exposure induced germ cell apoptosis in the testes, as determined by terminal dUTP nick-end labelling (TUNEL). However, the administration of NAC alleviated Cd-induced germ cell apoptosis in the testes. Further analysis showed that NAC attenuated the Cd-induced upregulation of testicular glucose-regulated protein 78 (GRP78), an important ER molecular chaperone. Moreover, NAC inhibited the Cd-induced phosphorylation of testicular eukaryotic translation initiation factor 2α (eIF2α), a downstream target of the double-stranded RNA-activated kinase-like ER kinase (PERK) pathway. In addition, NAC blocked the Cd-induced activation of testicular X binding protein (XBP)-1, indicating that NAC attenuates the Cd-induced ER stress and the unfolded protein response (UPR). Interestingly, NAC almost completely prevented the Cd-induced elevation of C/EBP homologous protein (CHOP) and phosphorylation of c-Jun N-terminal kinase (JNK), two components of the ER stress-mediated apoptotic pathway. In conclusion, NAC protects against Cd-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in the testes. PMID:23353715

  20. Intraspecific variability of cadmium tolerance and accumulation, and cadmium-induced cell wall modifications in the metal hyperaccumulator Arabidopsis halleri.

    PubMed

    Meyer, Claire-Lise; Juraniec, Michal; Huguet, Stéphanie; Chaves-Rodriguez, Elena; Salis, Pietro; Isaure, Marie-Pierre; Goormaghtigh, Erik; Verbruggen, Nathalie

    2015-06-01

    Certain molecular mechanisms of Cd tolerance and accumulation have been identified in the model species Arabidopsis halleri, while intraspecific variability of these traits and the mechanisms of shoot detoxification were little addressed. The Cd tolerance and accumulation of metallicolous and non-metallicolous A. halleri populations from different genetic units were tested in controlled conditions. In addition, changes in shoot cell wall composition were investigated using Fourier transform infrared spectroscopy. Indeed, recent works on A. halleri suggest Cd sequestration both inside cells and in the cell wall/apoplast. All A. halleri populations tested were hypertolerant to Cd, and the metallicolous populations were on average the most tolerant. Accumulation was highly variable between and within populations, and populations that were non-accumulators of Cd were identified. The effect of Cd on the cell wall composition was quite similar in the sensitive species A. lyrata and in A. halleri individuals; the pectin/polysaccharide content of cell walls seems to increase after Cd treatment. Nevertheless, the changes induced by Cd were more pronounced in the less tolerant individuals, leading to a correlation between the level of tolerance and the extent of modifications. This work demonstrated that Cd tolerance and accumulation are highly variable traits in A. halleri, suggesting adaptation at the local scale and involvement of various molecular mechanisms. While in non-metallicolous populations drastic modifications of the cell wall occur due to higher Cd toxicity and/or Cd immobilization in this compartment, the increased tolerance of metallicolous populations probably involves other mechanisms such as vacuolar sequestration.

  1. Cadmium-induced cell transformation and tumorigenesis are associated with transcriptional activation of c-fos, c-jun, and c-myc proto-oncogenes: role of cellular calcium and reactive oxygen species.

    PubMed

    Joseph, P; Muchnok, T K; Klishis, M L; Roberts, J R; Antonini, J M; Whong, W Z; Ong, T

    2001-06-01

    The molecular mechanisms of carcinogenesis by cadmium were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with cadmium chloride were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in the present study. The proto-oncogenes c-fos and c-jun were overexpressed in 100% (10 out of 10) of the cell lines, while a statistically significant overexpression of c-myc was observed in 40% (4 out of 10) of the cell lines. Analysis of tumor cells stained with fluorescent dyes specific for reactive oxygen species revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by treating the cells with superoxide dismutase, catalase, and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra acetoxy methyl ester (BAPTA/AM), which are scavengers of superoxide anion, hydrogen peroxide, and calcium, respectively. This confirmed that the overexpression of the proto-oncogenes in the tumor cells required elevated intracellular levels of reactive oxygen species and calcium. In addition to the scavengers of reactive oxygen species and calcium, inhibitors specific for transcription (actinomycin D), protein kinase C (RO-31-8220), and MAP kinase (PD 98059) also blocked the cadmium-induced overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/c-3T3 cells to 20 microM cadmium chloride for 1 h caused elevated intracellular levels of superoxide anion, hydrogen peroxide, and calcium, with corresponding increases in the expression levels of c-fos, c-jun, and c-myc. As in the case of the tumor cells, treating the nontransformed cells with the various modulators prior to their exposure to

  2. Peptidases released by necrotic cells control CD8+ T cell cross-priming

    PubMed Central

    Gamrekelashvili, Jaba; Kapanadze, Tamar; Han, Miaojun; Wissing, Josef; Ma, Chi; Jaensch, Lothar; Manns, Michael P.; Armstrong, Todd; Jaffee, Elizabeth; White, Ayla O.; Citrin, Deborah E.; Korangy, Firouzeh; Greten, Tim F.

    2013-01-01

    Cross-priming of CD8+ T cells and generation of effector immune responses is pivotal for tumor immunity as well as for successful anticancer vaccination and therapy. Dead and dying cells produce signals that can influence Ag processing and presentation; however, there is conflicting evidence regarding the immunogenicity of necrotic cell death. We used a mouse model of sterile necrosis, in which mice were injected with sterile primary necrotic cells, to investigate a role of these cells in priming of CD8+ T cells. We discovered a molecular mechanism operating in Ag donor cells that regulates cross-priming of CD8+ T cells during primary sterile necrosis and thereby controls adaptive immune responses. We found that the cellular peptidases dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1), both of which are present in nonimmunogenic necrotic cells, eliminated proteasomal degradation products and blocked Ag cross-presentation. While sterile necrotic tumor cells failed to induce CD8+ T cell responses, their nonimmunogenicity could be reversed in vitro and in vivo by inactivation of DPP-3 and TOP-1. These results indicate that control of cross-priming and thereby immunogenicity of primary sterile necrosis relies on proteasome-dependent oligopeptide generation and functional status of peptidases in Ag donor cells. PMID:24216478

  3. Cadmium transporters in the kidney and cadmium-induced nephrotoxicity.

    PubMed

    Yang, Hong; Shu, Yan

    2015-01-09

    Among the organs in which the environmental pollutant cadmium causes toxicity, the kidney has gained the most attention in recent years. Numerous studies have sought to unravel the exact pathways by which cadmium enters the renal epithelial cells and the mechanisms by which it causes toxicity in the kidney. The purpose of this review is to present the progress made on the mechanisms of cadmium transport in the kidney and the role of transporter proteins in cadmium-induced nephrotoxicity.

  4. Responses of macrophages to the danger signals released from necrotic cells.

    PubMed

    Kimura, Toshifumi; Kobayashi, Shuhei; Hanihara-Tatsuzawa, Fumito; Sayama, Aoi; MaruYama, Takashi; Muta, Tatsushi

    2014-12-01

    The immune system maintains homeostasis by recognizing and responding to cell death caused by various stresses. The immune response is considered to be elicited by 'danger signals' released from necrotic cells. However, the identity of the danger signals remains elusive. In this study, we focused on the expression of chemokines by macrophages stimulated with necrotic cells. In mouse bone-marrow-derived macrophages, the chemokine monocyte chemoattractant protein (MCP)-3 was induced at both the mRNA and protein levels in response to heat-killed murine cells. The induction of MCP-3 was also observed in MyD88-deficient macrophages, indicating that Toll-like receptors and the IL-1 receptor are not involved in this response. Consistent with this observation, the activation of NF-κB was not detected in RAW264.7 macrophages stimulated with necrotic cells. Treatments with proteinase K, DNaseI or RNaseA did not affect the ' STIMULATING ACTIVITY': of necrotic cells. In contrast, treatment with apyrase, which removes phosphates from nucleoside tri- and di-phosphates, abolished the inducing activity. Purified UDP at 30 µM concentration elicited similar induction of MCP-3 in RAW264.7 macrophages. Small interfering RNA-mediated knock-down of the UDP receptor P2Y6 in RAW264.7 cells significantly reduced the induction of MCP-3 in response to necrotic cells, but not its induction by lipopolysaccharide. Furthermore, ectopic expression of the P2Y6 receptor in HEK293 cells conferred responsiveness to necrotic cells. These results suggest that UDP released by necrotic cells plays a critical role as an endogenous danger signal and that P2Y6 is required for the induction of MCP-3 in response to necrotic cells.

  5. Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

    PubMed Central

    Cohen, Aviv; Lerner-Yardeni, Jenny; Meridor, David; Kasher, Roni; Nathan, Ilana; Parola, Abraham H

    2015-01-01

    Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer’s disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide’s antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide’s direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17. PMID:26062019

  6. Humanin Derivatives Inhibit Necrotic Cell Death in Neurons.

    PubMed

    Cohen, Aviv; Lerner-Yardeni, Jenny; Meridor, David; Kasher, Roni; Nathan, Ilana; Parola, Abraham H

    2015-01-01

    Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer's disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide's antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide's direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17.

  7. Humanin Derivatives Inhibit Necrotic Cell Death in Neurons.

    PubMed

    Cohen, Aviv; Lerner-Yardeni, Jenny; Meridor, David; Kasher, Roni; Nathan, Ilana; Parola, Abraham H

    2015-01-01

    Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer's disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide's antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide's direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17. PMID:26062019

  8. Necrotizing sialometaplasia.

    PubMed

    Gavron, J P; Ardito, J A; Curtis, A W

    1981-07-01

    Necrotizing sialometaplasia of salivary gland tissue is a benign, self-limiting disease usually confined to the minor salivary glands. To date only 49 cases have been reported. The clinical and histologic appearance may simulate squamous cell carcinoma, and unnecessary mutilating surgery may be performed if an erroneous diagnosis is made. The otolaryngologist must recognize this disease entity since it heals spontaneously and requires no treatment. Necrotizing sialometaplasia has no known premalignant potential.

  9. A Proteolytic Cascade Controls Lysosome Rupture and Necrotic Cell Death Mediated by Lysosome-Destabilizing Adjuvants

    PubMed Central

    Muehlbauer, Stefan M.; Chandran, Kartik; Diaz-Griffero, Felipe

    2014-01-01

    Recent studies have linked necrotic cell death and proteolysis of inflammatory proteins to the adaptive immune response mediated by the lysosome-destabilizing adjuvants, alum and Leu-Leu-OMe (LLOMe). However, the mechanism by which lysosome-destabilizing agents trigger necrosis and proteolysis of inflammatory proteins is poorly understood. The proteasome is a cellular complex that has been shown to regulate both necrotic cell death and proteolysis of inflammatory proteins. We found that the peptide aldehyde proteasome inhibitors, MG115 and MG132, block lysosome rupture, degradation of inflammatory proteins and necrotic cell death mediated by the lysosome-destabilizing peptide LLOMe. However, non-aldehyde proteasome inhibitors failed to prevent LLOMe-induced cell death suggesting that aldehyde proteasome inhibitors triggered a pleotropic effect. We have previously shown that cathepsin C controls lysosome rupture, necrotic cell death and the adaptive immune response mediated by LLOMe. Using recombinant cathepsin C, we found that aldehyde proteasome inhibitors directly block cathepsin C, which presumably prevents LLOMe toxicity. The cathepsin B inhibitor CA-074-Me also blocks lysosome rupture and necrotic cell death mediated by a wide range of necrosis inducers, including LLOMe. Using cathepsin-deficient cells and recombinant cathepsins, we demonstrate that the cathepsins B and C are not required for the CA-074-Me block of necrotic cell death. Taken together, our findings demonstrate that lysosome-destabilizing adjuvants trigger an early proteolytic cascade, involving cathepsin C and a CA-074-Me-dependent protease. Identification of these early events leading to lysosome rupture will be crucial in our understanding of processes controlling necrotic cell death and immune responses mediated by lysosome-destabilizing adjuvants. PMID:24893007

  10. Nrf2 activation prevents cadmium-induced acute liver injury

    SciTech Connect

    Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D.

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  11. Cell death stages in single apoptotic and necrotic cells monitored by Raman microspectroscopy

    PubMed Central

    Brauchle, Eva; Thude, Sibylle; Brucker, Sara Y.; Schenke-Layland, Katja

    2014-01-01

    Although apoptosis and necrosis have distinct features, the identification and discrimination of apoptotic and necrotic cell death in vitro is challenging. Immunocytological and biochemical assays represent the current gold standard for monitoring cell death pathways; however, these standard assays are invasive, render large numbers of cells and impede continuous monitoring experiments. In this study, both room temperature (RT)-induced apoptosis and heat-triggered necrosis were analyzed in individual Saos-2 and SW-1353 cells by utilizing Raman microspectroscopy. A targeted analysis of defined cell death modalities, including early and late apoptosis as well as necrosis, was facilitated based on the combination of Raman spectroscopy with fluorescence microscopy. Spectral shifts were identified in the two cell lines that reflect biochemical changes specific for either RT-induced apoptosis or heat-mediated necrosis. A supervised classification model specified apoptotic and necrotic cell death based on single cell Raman spectra. To conclude, Raman spectroscopy allows a non-invasive, continuous monitoring of cell death, which may help shedding new light on complex pathophysiological or drug-induced cell death processes. PMID:24732136

  12. Necrotizing sialometaplasia.

    PubMed

    Gavron, J P; Shugar, M A; Rice, D A

    1983-02-01

    Necrotizing sialometaplasia is a benign inflammatory disease of salivary gland origin. Because of its clinical and histologic resemblance to squamous cell carcinoma, this disease must be recognized. The cause is unknown, but it may be related to oral trauma, tobacco use or inadequate blood supply. The lesion heals spontaneously, regardless of therapy, in two to eight weeks.

  13. Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents.

    PubMed

    Brojatsch, Jürgen; Lima, Heriberto; Palliser, Deborah; Jacobson, Lee S; Muehlbauer, Stefan M; Furtado, Raquel; Goldman, David L; Lisanti, Michael P; Chandran, Kartik

    2015-01-01

    Necrotic cell death triggers a range of biological responses including a strong adaptive immune response, yet we know little about the cellular pathways that control necrotic cell death. Inhibitor studies suggest that proteases, and in particular cathepsins, drive necrotic cell death. The cathepsin B-selective inhibitor CA-074-Me blocks all forms of programmed necrosis by an unknown mechanism. We found that cathepsin B deficiency does not prevent induction of pyroptosis and lysosome-mediated necrosis suggesting that CA-074-Me blocks necrotic cell death by targeting cathepsins other than cathepsin B. A single cathepsin, cathepsin C, drives necrotic cell death mediated by the lysosome-destabilizing agent Leu-Leu-OMe (LLOMe). Here we present evidence that cathepsin C-deficiency and CA-074-Me block LLOMe killing in a distinct and cell type-specific fashion. Cathepsin C-deficiency and CA-074-Me block LLOMe killing of all myeloid cells, except for neutrophils. Cathepsin C-deficiency, but not CA-074-Me, blocks LLOMe killing of neutrophils suggesting that CA-074-Me does not target cathepsin C directly, consistent with inhibitor studies using recombinant cathepsin C. Unlike other cathepsins, cathepsin C lacks endoproteolytic activity, and requires activation by other lysosomal proteases, such as cathepsin D. Consistent with this theory, we found that lysosomotropic agents and cathepsin D downregulation by siRNA block LLOMe-mediated necrosis. Our findings indicate that a proteolytic cascade, involving cathepsins C and D, controls LLOMe-mediated necrosis. In contrast, cathepsins C and D were not required for pyroptotic cell death suggesting that distinct cathepsins control pyroptosis and lysosome-mediated necrosis. PMID:25830414

  14. Necrotic cells influence migration and invasion of glioblastoma via NF-κB/AP-1-mediated IL-8 regulation

    PubMed Central

    Ahn, So-Hee; Park, Hyunju; Ahn, Young-Ho; Kim, Sewha; Cho, Min-Sun; Kang, Jihee Lee; Choi, Youn-Hee

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common primary intracranial tumor in adults and has poor prognosis. Diffuse infiltration into normal brain parenchyma, rapid growth, and the presence of necrosis are remarkable hallmarks of GBM. However, the effect of necrotic cells on GBM growth and metastasis is poorly understood at present. In this study, we examined the biological significance of necrotic tissues by exploring the molecular mechanisms underlying the signaling network between necrotic tissues and GBM cells. The migration and invasion of the GBM cell line CRT-MG was significantly enhanced by treatment with necrotic cells, as shown by assays for scratch wound healing and spheroid invasion. Incubation with necrotic cells induced IL-8 secretion in CRT-MG cells in a dose-dependent manner. In human GBM tissues, IL-8 positive cells were mainly distributed in the perinecrotic region, as seen in immunohistochemistry and immunofluorescence analysis. Necrotic cells induced NF-κB and AP-1 activation and their binding to the IL-8 promoter, leading to enhanced IL-8 production and secretion in GBM cells. Our data demonstrate that when GBM cells are exposed to and stimulated by necrotic cells, the migration and invasion of GBM cells are enhanced and facilitated via NF-κB/AP-1 mediated IL-8 upregulation. PMID:27076368

  15. Water-soluble germanium nanoparticles cause necrotic cell death and the damage can be attenuated by blocking the transduction of necrotic signaling pathway.

    PubMed

    Ma, Yu-Hsin; Huang, Chin-Ping; Tsai, Jia-Shiuan; Shen, Mo-Yuan; Li, Yaw-Kuen; Lin, Lih-Yuan

    2011-12-15

    Water-soluble germanium nanoparticles (wsGeNPs) with allyamine-conjugated surfaces were fabricated and emit blue fluorescence under ultraviolet light. The wsGeNP was physically and chemically stable at various experimental conditions. Cytotoxicity of the fabricated wsGeNP was examined. MTT assay demonstrated that wsGeNP possessed high toxicity to cells and clonogenic survival assay further indicated that this effect was not resulted from retarding cell growth. Flow cytometric analysis indicated that wsGeNP did not alter the cell cycle profile but the sub-G1 fraction was absent from treated cells. Results from DNA fragmentation and propidium iodide exclusion assays also suggested that apoptotic cell death did not occur in cells treated with wsGeNP. Addition of a necrosis inhibitor, necrostatin-1, attenuated cell damage and indicated that wsGeNP caused necrotic cell death. Cell signaling leads to necrotic death was investigated. Intracellular calcium and reactive oxygen species (ROS) levels were increased upon wsGeNP treatment. These effects can be abrogated by BAPTA-AM and N-acetyl cysteine respectively, resulting in a reduction in cell damage. In addition, wsGeNP caused a decrease in mitochondrial membrane potential (MMP) which could be recovered by cyclosporine A. The cellular signaling events revealed that wsGeNP increase the cellular calcium level which enhances the production of ROS and leads to a reduction of MMP, consequentially results in necrotic cell death.

  16. Complement activation by necrotic cells in normal plasma environment compares to that by late apoptotic cells and involves predominantly IgM.

    PubMed

    Ciurana, Caroline L F; Zwart, Bas; van Mierlo, Gerard; Hack, C Erik

    2004-09-01

    Necrotic cells are generally considered to stimulate inflammation, whereas apoptotic cells should not. However, apoptotic cells have pro-inflammatory properties since they can activate complement. To what extent this activation compares to that by necrotic cells is not known. We compared complement activation by necrotic cells and apoptotic cells in plasma. Jurkat cells were made apoptotic or necrotic by incubation with etoposide or by heat shock, respectively. Cells incubated in recalcified plasma were tested for C3 and C4 fixation and fluid phase generation of complement activation products. Fixation of C3 and C4 to necrotic cells occurred mainly via the classical pathway, independent from the method of necrosis induction and the cell type. Depletion of IgM from plasma almost completely abrogated complement fixation by necrotic cells, which was restored by supplementation with purified IgM. Complement activation by late apoptotic cells was comparable to that by necrotic cells regarding the extent and dependence on IgM. Moreover, incubation of plasma with necrotic or late apoptotic cells led to the generation of comparable amounts of complement activation products. These results indicate that late apoptotic and necrotic cells employ similar complement activation mechanisms in the plasma environment.

  17. Intracellular Delivery of Synthetic dsRNA to Leukemic Cells Induces Apoptotic and Necrotic Cell Death.

    PubMed

    Mahmud, S M; Mek, K J; Idris, A

    2016-01-01

    The type of tumour cell death dictates the type of adaptive immune response mounted against the tumours. In haematological malignancies such as acute myeloid leukaemia (AML), immune evasion due to the poor immunogenicity of leukemic cells is a major hurdle in generating an effective immune response. Transfection of synthetic dsRNA, poly I:C, into leukemic cells to trigger tumour cell death and enhance immunogenicity of the tumour is a promising immunotherapeutic approach. However, the temporal cell death kinetics of poly I:C-electroporated AML cells has not been thoroughly investigated. Electroporation of U937 cells, a human AML cell line, with a high dose of poly I:C resulted in cytotoxicity as early as 1 h post-transfection. Flow cytometric analysis revealed the temporal switch from early apoptosis to late apoptosis/secondary necrosis in poly I:C-electroporated cells in which the nuclear morphology at later time points was consistent with necrotic cell death. Our brief findings demonstrated the temporal cell death kinetics of dsRNA-transfected leukemic cells. This finding is an important development in the field of dsRNA immunotherapy for leukaemia as understanding the type of cell death elicited by transfected dsRNA will dictate the type of immune response to be directed against leukemic cells. PMID:27187041

  18. Effects of ORP150 on appearance and function of pancreatic beta cells following acute necrotizing pancreatitis.

    PubMed

    Deng, Wen-Hong; Chen, Chen; Wang, Wei-Xing; Yu, Jia; Li, Jin-You; Liu, Lei

    2011-06-15

    Pancreatic beta cells produce and release insulin, which decreases the blood glucose level. Endoplasmic reticulum stress caused pancreatic beta cell dysfunction and death in acute necrotizing pancreatitis (ANP). The 150kD oxygen-regulated protein (ORP150) took part in the process of endoplasmic reticulum stress. This study investigated the effect of ORP150 on appearance and function of pancreatic beta cells in ANP. Acute necrotizing pancreatitis relied on retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct. The severity of ANP was estimated by serum amylase, secretory phospholipase A(2,) and pancreatic histopathology. The changes in appearance and function of pancreatic beta cells were detected by light and electron microscopy and the levels of serum glucose, insulin, and C-peptide. ORP150 expression was studied using western blot and immunohistochemisty assay. The expression of ORP150 mainly appeared on pancreatic beta cells and decreased gradually during the pathogenesis of ANP. The results of light and electron microscopy indicated pancreatic beta cell dysfunction and death, concomitant with elevation of serum glucose, insulin, and C-peptide in ANP. These results imply a probable role of ORP150 in the changes in appearance and function of pancreatic beta cells following acute necrotizing pancreatitis, through the pathway of endoplasmic reticulum stress.

  19. Necrotic and apoptotic cells serve as nuclei for calcification on osteoblastic differentiation of human mesenchymal stem cells in vitro.

    PubMed

    Fujita, Hirofumi; Yamamoto, Masanao; Ogino, Tetsuya; Kobuchi, Hirotsugu; Ohmoto, Naoko; Aoyama, Eriko; Oka, Takashi; Nakanishi, Tohru; Inoue, Keiji; Sasaki, Junzo

    2014-01-01

    A close relationship between cell death and pathological calcification has recently been reported, such as vascular calcification in atherosclerosis. However, the roles of cell death in calcification by osteoblast lineage have not been elucidated in detail. In this study, we investigated whether cell death is involved in the calcification on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hMSC) under osteogenic culture in vitro. Apoptosis and necrosis occurred in an osteogenic culture of hMSC, and cell death preceded calcification. The generation of intracellular reactive oxygen species, chromatin condensation and fragmentation, and caspase-3 activation increased in this culture. A pan-caspase inhibitor (Z-VAD-FMK) and anti-oxidants (Tiron and n-acetylcysteine) inhibited osteogenic culture-induced cell death and calcification. Furthermore, calcification was significantly promoted by the addition of necrotic dead cells or its membrane fraction. Spontaneously dead cells by osteogenic culture and exogenously added necrotic cells were surrounded by calcium deposits. Induction of localized cell death by photodynamic treatment in the osteogenic culture resulted in co-localized calcification. These findings show that necrotic and apoptotic cell deaths were induced in an osteogenic culture of hMSC and indicated that both necrotic and apoptotic cells of osteoblast lineage served as nuclei for calcification on osteoblastic differentiation of hMSC in vitro.

  20. Hydrogen peroxide-induced necrotic cell death in cardiomyocytes is independent of matrix metalloproteinase-2.

    PubMed

    Ali, Mohammad A M; Kandasamy, Arulmozhi D; Fan, Xiaohu; Schulz, Richard

    2013-09-01

    Matrix metalloproteinase-2 (MMP-2) is well known to proteolyse both extracellular and intracellular proteins. Reactive oxygen species activate MMP-2 at both transcriptional and post-translational levels, thus MMP-2 activation is considered an early event in oxidative stress injury. Although hydrogen peroxide is widely used to trigger oxidative stress-induced cell death, the type of cell death (apoptosis vs. necrosis) in cardiomyocytes is still controversial depending on the concentration used and the exposure time. We carefully investigated the mode of cell death in neonatal rat cardiomyocytes induced by different concentrations (50-500 μM) of hydrogen peroxide at various time intervals after exposure and determined whether MMP-2 is implicated in hydrogen peroxide-induced cardiomyocyte death. Treating cardiomyocytes with hydrogen peroxide led to elevated MMP-2 level/activity with maximal effects seen at 200 μM. Hydrogen peroxide caused necrotic cell death by disrupting the plasmalemma as evidenced by the release of lactate dehydrogenase in a concentration- and time-dependent manner as well as the necrotic cleavage of PARP-1. The absence of both caspase-3 cleavage/activation and apoptotic cleavage of PARP-1 illustrated the weak contribution of apoptosis. Pre-treatment with selective MMP inhibitors did not protect against hydrogen peroxide-induced necrosis. In conclusion hydrogen peroxide increases MMP-2 level/activity in cardiomyocytes and induces necrotic cell death, however, the later effect is MMP-2 independent.

  1. Apoptotic, necrotic, or fused tumor cells: an equivalent source of antigen for dendritic cell loading.

    PubMed

    Larmonier, Nicolas; Mérino, Delphine; Nicolas, Alexandra; Cathelin, Dominique; Besson, Angélique; Bateman, Andrew; Solary, Eric; Martin, François; Katsanis, Emmanuel; Bonnotte, Bernard

    2006-09-01

    The identification of the most efficient strategy for tumor antigen loading of dendritic cells (DCs) remains a challenge in cancer immunotherapy protocols. Autologous dead tumor cells have been demonstrated to constitute an acceptable source of multiple tumor-associated antigens (TAA) to pulse DCs. However the optimal approach for inducing cell death that would lead to effective endocytosis and activation of DCs remains controversial. In this study we have induced and defined 3 distinct mechanisms of tumor cell death (apoptosis, necrosis and fusion-mediated cell death), and investigated their differential effects on DCs. Bone marrow-derived DCs demonstrated comparable uptake of primary apoptotic, necrotic, or fused dead tumor cells. Furthermore, the distinct modes of cancer cell death had analogous potential in activating the transcription factors NF-kappaB and STAT1 and in maturing DCs, resulting in an equally effective stimulation of immune T cells. The current study therefore provides further informations on the use of dead whole tumor cells as antigen sources for effective active anti-cancer immunotherapy.

  2. Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways.

    PubMed

    Xu, Chong; Liu, Chunxiao; Liu, Lei; Zhang, Ruijie; Zhang, Hai; Chen, Sujuan; Luo, Yan; Chen, Long; Huang, Shile

    2015-10-01

    Cadmium (Cd), a toxic environmental contaminant, contributes to neurodegeneration. Rapamycin, a macrocyclic lactone, has shown preventive effect on Cd-induced neuronal cell death. However, the underlying mechanism is not fully understood. Here, we show that rapamycin prevented Cd-induced apoptotic cell death in neuronal cells. Coincidently, rapamycin markedly blocked Cd-induced phosphorylation of Akt, S6K1 and 4E-BP1 in the cells. Expression of a rapamycin-resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of Cd-induced cell death, implying that the preventive effect of rapamycin on Cd-induced neurotoxicity is mTOR kinase activity-dependent. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor, rictor or raptor/rictor enhanced rapamycin's blockage of Cd-induced cell death. Furthermore, downregulation of S6K1, ectopic expression of constitutively hypophosphorylated 4E-BP1 or dominant negative Akt, or co-treatment with Akt inhibitor also potentiated the rapamycin's inhibitory effect. The findings indicate that rapamycin prevents Cd-induced neuronal cell death via suppressing both mTORC1 and mTORC2 pathways. Our results highlight that rapamycin may be exploited for the prevention of Cd-induced neurodegenerative disorders.

  3. Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB

    SciTech Connect

    Chen, De-Ju; Xu, Yan-Ming; Du, Ji-Ying; Huang, Dong-Yang; Lau, Andy T.Y.

    2014-02-28

    Highlights: • Normal human bronchial epithelial cells (BEAS-2B) were dosed with cadmium (Cd). • A low level (2 μM) of Cd treatment for 36 h elicited negligible cytotoxicity. • High levels (20 or 30 μM) of Cd treatment for 36 h induced cell death. • High levels of Cd can upregulate the protein levels of eIF5A1 and NF-κB p65. • We suggest that eIF5A1 level is possibly modulated by NF-κB. - Abstract: Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well-known carcinogens. Here, we report that in CdCl{sub 2}-exposed human bronchial epithelial cells (BEAS-2B), the level of p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 μM) of Cd can significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-κB p65. Moreover, there is an enhanced NF-κB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF5A1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF5A1 in Cd cytotoxicity. As eIF5A1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-κB might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF-κB binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-κB binding on eIF5A1 promoter region of Cd-treated BEAS-2B cells. Taken together, our findings suggest for the first time a regulatory mechanism for the pro

  4. Hwanggunchungyitang prevents cadmium-induced ototoxicity through suppression of the activation of caspase-9 and extracellular signal-related kinase in auditory HEI-OC1 cells.

    PubMed

    Kim, Su-Jin; Shin, Bong-Gi; Choi, In-Young; Kim, Dong-Hyun; Kim, Min-Cheol; Myung, Noh-Yil; Moon, Phil-Dong; Lee, Jeong-Han; An, Hyo-Jin; Kim, Na-Hyung; Lee, Joo-Young; So, Hong-Seob; Park, Rae-Kil; Jeong, Hyun-Ja; Um, Jae-Young; Kim, Hyung-Min; Hong, Seung-Heon

    2009-02-01

    Hwanggunchungyitang (HGCYT) is a newly designed herbal drug formula for the purpose of treating auditory diseases. A number of heavy metals have been associated with toxic effects to the peripheral or central auditory system. Cadmium (Cd(2+)) is a heavy metal and a potent carcinogen implicated in tumor development through occupational and environmental exposure. However, the auditory effect of Cd(2+) is not poorly understood. The purpose of the present study was to investigate whether HGCYT prevent the ototoxic effects induced by Cd(2+) in auditory cell line, HEI-OC1. HGCYT inhibited the cell death, reactive oxygen species generation (ROS), activation of caspase-9, and extracellular signal-related kinase (ERK) induced by Cd(2+). In addition, we observed that cochlear hair cells in middle turn were damaged by Cd(2+). However, HGCYT prevented the destruction of hair cell arrays of the rat primary organ of Corti explants in the presence of Cd(2+). These results support the notion that ROS are involved in Cd(2+) ototoxicity and suggest HGCYT therapeutic usefulness, against Cd(2+)-induced activation of caspase-9 and ERK. PMID:19182378

  5. Distinct Modes of Macrophage Recognition for Apoptotic and Necrotic Cells Are Not Specified Exclusively by Phosphatidylserine Exposure

    PubMed Central

    Cocco, Regina E.; Ucker, David S.

    2001-01-01

    The distinction between physiological (apoptotic) and pathological (necrotic) cell deaths reflects mechanistic differences in cellular disintegration and is of functional significance with respect to the outcomes that are triggered by the cell corpses. Mechanistically, apoptotic cells die via an active and ordered pathway; necrotic deaths, conversely, are chaotic and passive. Macrophages and other phagocytic cells recognize and engulf these dead cells. This clearance is believed to reveal an innate immunity, associated with inflammation in cases of pathological but not physiological cell deaths. Using objective and quantitative measures to assess these processes, we find that macrophages bind and engulf native apoptotic and necrotic cells to similar extents and with similar kinetics. However, recognition of these two classes of dying cells occurs via distinct and noncompeting mechanisms. Phosphatidylserine, which is externalized on both apoptotic and necrotic cells, is not a specific ligand for the recognition of either one. The distinct modes of recognition for these different corpses are linked to opposing responses from engulfing macrophages. Necrotic cells, when recognized, enhance proinflammatory responses of activated macrophages, although they are not sufficient to trigger macrophage activation. In marked contrast, apoptotic cells profoundly inhibit phlogistic macrophage responses; this represents a cell-associated, dominant-acting anti-inflammatory signaling activity acquired posttranslationally during the process of physiological cell death. PMID:11294896

  6. Necrotizing myopathy as a paraneoplastic syndrome associated with renal cell carcinoma.

    PubMed

    Naert, E; De Bleecker, J L; Lumen, N; Rottey, S

    2015-02-01

    We report a 49-year-old patient with necrotizing myopathy and a right renal mass. After laparoscopic radical nephrectomy, a remission of myopathy was seen. Pathologic evaluation of the nephrectomy specimen revealed a clear cell renal cell carcinoma. Relapse of myopathy 6 months postoperatively coincided with the diagnosis of the appearance of liver metastatic disease. After initiation of treatment with an mTOR-inhibitor, myopathy became less active requiring smaller amounts of corticosteroids with a complete remission of myopathy after 3 months of systemic treatment for metastatic renal cell cancer.

  7. Complement activation by apoptotic cells occurs predominantly via IgM and is limited to late apoptotic (secondary necrotic) cells.

    PubMed

    Zwart, Bas; Ciurana, Caroline; Rensink, Irma; Manoe, Rishi; Hack, C Erik; Aarden, Lucien A

    2004-03-01

    Apoptotic cells activate complement via various molecular mechanisms. It is not known which of these mechanisms predominate in a physiological environment. Using Jurkat cells as a model, we investigated complement deposition on vital, early and late apoptotic (secondary necrotic) cells in a physiological medium, human plasma, and established the main molecular mechanism involved in this activation. Upon incubation with recalcified plasma, binding of C3 and C4 to early apoptotic cells was similar to background binding on vital cells. In contrast, late apoptotic (secondary necrotic) cells consistently displayed substantial binding of C4 and C3 and low, but detectable, binding of C1q. Binding of C3 and C4 to the apoptotic cells was abolished by EDTA or Mg-EGTA, and also by C1-inhibitor or a monoclonal antibody that inhibits C1q binding, indicating that complement fixation by the apoptotic cells was mainly dependent on the classical pathway. Late apoptotic cells also consistently bound IgM, in which binding significantly correlated with that of C4 and C3. Depletion of plasma for IgM abolished most of the complement fixation by apoptotic cells, which was restored by supplementation with purified IgM. We conclude that complement binding by apoptotic cells in normal human plasma occurs mainly to late apoptotic, secondary necrotic cells, and that the dominant mechanism involves classical pathway activation by IgM.

  8. Research Article Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood-Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice.

    PubMed

    Minutoli, Letteria; Micali, Antonio; Pisani, Antonina; Puzzolo, Domenico; Bitto, Alessandra; Rinaldi, Mariagrazia; Pizzino, Gabriele; Irrera, Natasha; Galfo, Federica; Arena, Salvatore; Pallio, Giovanni; Mecchio, Anna; Germanà, Antonino; Bruschetta, Daniele; Laurà, Rosaria; Magno, Carlo; Marini, Herbert; Squadrito, Francesco; Altavilla, Domenica

    2015-11-01

    Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -β3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-β3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity.

  9. Melatonin antagonizes cadmium-induced neurotoxicity by activating the transcription factor EB-dependent autophagy-lysosome machinery in mouse neuroblastoma cells.

    PubMed

    Li, Min; Pi, Huifeng; Yang, Zhiqi; Reiter, Russel J; Xu, Shangcheng; Chen, Xiaowei; Chen, Chunhai; Zhang, Lei; Yang, Min; Li, Yuming; Guo, Pan; Li, Gaoming; Tu, Manyu; Tian, Li; Xie, Jia; He, Mindi; Lu, Yonghui; Zhong, Min; Zhang, Yanwen; Yu, Zhengping; Zhou, Zhou

    2016-10-01

    Cadmium (Cd), a highly ubiquitous heavy metal, induces neurotoxicity. Melatonin, a major secretory product of the pineal gland, protects against Cd-induced neurotoxicity. However, the mechanism that accounts for this protection remains to be elucidated. Herein, we exposed mouse neuroblastoma cells (Neuro-2a cells) to different concentrations of cadmium chloride (CdCl2 ) (12.5, 25, and 50 μ mol L(-1) ) for 24 hours. We showed that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function, subsequently leading to nerve cell death. In addition, Cd decreases the level of transcription factor EB (TFEB) but induces the nuclear translocation of TFEB, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Moreover, compared to the 50-μ mol L(-1) Cd group, administration of 1 μ mol L(-1) melatonin increased "TFEB-responsive genes" (P<.05) and the levels of lysosomal-associated membrane protein (0.57±0.06 vs 1.00±0.11, P<.05), preserved lysosomal protease activity (0.52±0.01 vs 0.90±0.02, P<.05), maintained the lysosomal pH level (0.50±0.01 vs 0.87±0.05, P<.01), and enhanced autophagosome-lysosome fusion (0.05±0.00 vs 0.21±0.01, P<.01). Notably, melatonin enhanced TFEB expression (0.37±0.04 vs 0.72±0.07, P<.05) and nuclear translocation (2.81±0.08 vs 3.82±0.05, P<.05). Tfeb siRNA blocked the melatonin-mediated elevation in autophagy-lysosome machinery in Cd-induced neurotoxicity (P<.01). Taken together, these results uncover a potent role for TFEB-mediated autophagy in the pathogenesis of Cd-induced neurotoxicity, suggesting that control of the autophagic pathway by melatonin might provide an important clue for exploring potential targets for novel therapeutics of Cd-induced neurotoxicity.

  10. Research Article Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood-Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice.

    PubMed

    Minutoli, Letteria; Micali, Antonio; Pisani, Antonina; Puzzolo, Domenico; Bitto, Alessandra; Rinaldi, Mariagrazia; Pizzino, Gabriele; Irrera, Natasha; Galfo, Federica; Arena, Salvatore; Pallio, Giovanni; Mecchio, Anna; Germanà, Antonino; Bruschetta, Daniele; Laurà, Rosaria; Magno, Carlo; Marini, Herbert; Squadrito, Francesco; Altavilla, Domenica

    2015-11-01

    Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -β3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-β3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity. PMID

  11. Melatonin antagonizes cadmium-induced neurotoxicity by activating the transcription factor EB-dependent autophagy-lysosome machinery in mouse neuroblastoma cells.

    PubMed

    Li, Min; Pi, Huifeng; Yang, Zhiqi; Reiter, Russel J; Xu, Shangcheng; Chen, Xiaowei; Chen, Chunhai; Zhang, Lei; Yang, Min; Li, Yuming; Guo, Pan; Li, Gaoming; Tu, Manyu; Tian, Li; Xie, Jia; He, Mindi; Lu, Yonghui; Zhong, Min; Zhang, Yanwen; Yu, Zhengping; Zhou, Zhou

    2016-10-01

    Cadmium (Cd), a highly ubiquitous heavy metal, induces neurotoxicity. Melatonin, a major secretory product of the pineal gland, protects against Cd-induced neurotoxicity. However, the mechanism that accounts for this protection remains to be elucidated. Herein, we exposed mouse neuroblastoma cells (Neuro-2a cells) to different concentrations of cadmium chloride (CdCl2 ) (12.5, 25, and 50 μ mol L(-1) ) for 24 hours. We showed that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function, subsequently leading to nerve cell death. In addition, Cd decreases the level of transcription factor EB (TFEB) but induces the nuclear translocation of TFEB, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Moreover, compared to the 50-μ mol L(-1) Cd group, administration of 1 μ mol L(-1) melatonin increased "TFEB-responsive genes" (P<.05) and the levels of lysosomal-associated membrane protein (0.57±0.06 vs 1.00±0.11, P<.05), preserved lysosomal protease activity (0.52±0.01 vs 0.90±0.02, P<.05), maintained the lysosomal pH level (0.50±0.01 vs 0.87±0.05, P<.01), and enhanced autophagosome-lysosome fusion (0.05±0.00 vs 0.21±0.01, P<.01). Notably, melatonin enhanced TFEB expression (0.37±0.04 vs 0.72±0.07, P<.05) and nuclear translocation (2.81±0.08 vs 3.82±0.05, P<.05). Tfeb siRNA blocked the melatonin-mediated elevation in autophagy-lysosome machinery in Cd-induced neurotoxicity (P<.01). Taken together, these results uncover a potent role for TFEB-mediated autophagy in the pathogenesis of Cd-induced neurotoxicity, suggesting that control of the autophagic pathway by melatonin might provide an important clue for exploring potential targets for novel therapeutics of Cd-induced neurotoxicity. PMID:27396692

  12. Cadmium-induced activation of stress signaling pathways, disruption of ubiquitin-dependent protein degradation and apoptosis in primary rat Sertoli cell-gonocyte cocultures.

    PubMed

    Yu, Xiaozhong; Hong, Sungwoo; Faustman, Elaine M

    2008-08-01

    Cadmium (Cd) is a ubiquitous environmental pollutant that has been associated with male reproductive toxicity in both humans and animal models. The underlying mechanism of this response, however, is still uncharacterized. To address this issue, we employed a recently developed and optimized three-dimensional primary Sertoli cell-gonocyte coculture system and examined the time- and dose-dependent effects of Cd on morphological alterations, cell viability, activation of stress signaling pathway proteins, and the disruption of the ubiquitin proteasome system (UPS). Our results demonstrated that Cd exposure lead to time- and dose-dependent morphological changes that are associated with the induction of apoptosis. In response to Cd, we also saw a disruption of the UPS as evaluated through the accumulation of high-molecular weight polyubiquitinated proteins (HMW-polyUb) as well as alterations in proteasome activity. Robust activation of cellular stress response, measured through the increased phosphorylation of stress-activated protein kinase/c-jun N-terminal kinase and p38, paralleled the accumulation of HMW-polyUb. In addition, p53, a key regulatory protein, was upregulated and underwent increased ubiquitination in response to Cd. To further characterize the role of the UPS in Cd cellular response, we compared the above changes with two classic proteasomal inhibitors, lactacystin, and MG132. The stress response and the accumulation of HWM-polyUb induced by Cd were consistent with the response seen with MG132 but not with lactacystin. In addition, Cd treatment resulted in a dose- and time-dependent effect on proteasome activity, but the overall Cd-induced proteasomal inhibition was unique as compared to MG132 and lactacystin. Taken together, our studies further characterize Cd-induced in vitro testicular toxicity and highlight the potential role of the UPS in this response. PMID:18463101

  13. Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways.

    PubMed

    Jiang, Jiao Hua; Ge, Guo; Gao, Kai; Pang, Ying; Chai, Rui Chao; Jia, Xi Hua; Kong, Jin Ge; Yu, Albert Cheung-Hoi

    2015-09-01

    Cadmium (Cd), a highly ubiquitous toxic heavy metal, can contaminate the environment, including agricultural soil, water and air, via industrial runoff and other sources of pollution. Cd accumulated in the body via direct exposure or through the food chain results in neurodegeneration and many other diseases. Previous studies on its toxicity in the central nervous system (CNS) focused mainly on neurons. To obtain a more comprehensive understanding of Cd toxicity for the CNS, we investigated how astrocytes respond to acute and chronic Cd exposure and its toxic molecular mechanisms. When primary cultures of cerebral cortical astrocytes incubated with 1-300 μM CdCl2, morphological changes, LDH release and cell death were observed in a time and dose-dependent manner. Further studies demonstrated that acute and chronic Cd treatment phosphorylated JNK, p38 and Akt to different degrees, while ERK1/2 was only phosphorylated under low doses of Cd (10 μM) exposure. Inhibition of JNK and PI3K/Akt, but not of p38, could partially protect astrocyte from cytotoxicity in chronic and acute Cd exposure. Moreover, Cd also induced a strong calcium signal, while BAPTA, a specific intracellular calcium (Ca(2+)) chelator, prevented Cd-induced intracellular increase of calcium levels in astrocytes; inhibited the Cd-induced activation of ERK1/2, JNK, p38 and Akt; and also significantly reduced astrocyte cell death. All of these results suggested that the Cd-Ca(2+)-MAPK and PI3K/Akt signaling pathways were involved in Cd-induced toxicity in astrocytes. This toxicity involvement indicates that these pathways may be exploited as a target for the prevention of Cd-induced neurodegenerative diseases. PMID:26248512

  14. Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa

    PubMed Central

    Murakami, Y; Ikeda, Y; Nakatake, S; Tachibana, T; Fujiwara, K; Yoshida, N; Notomi, S; Nakao, S; Hisatomi, T; Miller, J W; Vavvas, DG; Sonoda, KH; Ishibashi, T

    2015-01-01

    Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP. PMID:27551484

  15. An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death.

    PubMed

    Garcia-Belinchón, Mercè; Sánchez-Osuna, María; Martínez-Escardó, Laura; Granados-Colomina, Carla; Pascual-Guiral, Sònia; Iglesias-Guimarais, Victoria; Casanelles, Elisenda; Ribas, Judit; Yuste, Victor J

    2015-08-21

    Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as "apoptosis-necrosis continuum." To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like cell death. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death. PMID:26124276

  16. An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death*

    PubMed Central

    Garcia-Belinchón, Mercè; Sánchez-Osuna, María; Martínez-Escardó, Laura; Granados-Colomina, Carla; Pascual-Guiral, Sònia; Iglesias-Guimarais, Victoria; Casanelles, Elisenda; Ribas, Judit; Yuste, Victor J.

    2015-01-01

    Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as “apoptosis-necrosis continuum.” To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like cell death. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death. PMID:26124276

  17. Necrotic cell death caused by exposure to graphitic carbon-coated magnetic nanoparticles.

    PubMed

    Kim, Jung-Hee; Sanetuntikul, Jakkid; Shanmugam, Sangaraju; Kim, Eunjoo

    2015-09-01

    We synthesized graphitic carbon-coated magnetic nanoparticles (Fe@C NPs) and evaluated their physicochemical properties and mechanism of cytotoxicity in vitro. The structure of these nanocomposites consisted of an iron core encapsulated by a graphitic-carbon shell. The diameter of these Fe@C NPs was 81 ± 14 nm, and the thickness of the carbon layer encapsulating the core was 7.0 ± 0.5 nm. Inhibition of cell proliferation was induced by exposure to Fe@C NPs at doses above 50 μg mL(-1) . The exposed cells did not show increased activation of apoptosis biomarkers such as PARP, caspase-3, caspase-7, and caspase-9, and apoptosis-specific responses such as DNA laddering and annexin V binding to the cell membranes. In addition, the expression levels of autophagy-specific biomarkers such as ATG5 and LC3 after exposure were not enhanced, either. Instead, we observed increased release of lactate dehydrogenase in the culture media and red-fluorescent cell cytosol stained with ethidium homodimer I after the exposure. These results indicated enhanced cell membrane permeability after exposure to Fe@C NPs, probably caused by necrosis. The analysis of the regulatory molecules of cell cycling and proliferation, ERK, p53, and AKT, implied that cell cycle arrest was initiated and the cells were sensitized to necrosis. This necrotic cell death was also observed in carbon shells from Fe@C NPs obtained by removing the metal core. In conclusion, the graphitic carbon-encapsulated magnetic nanoparticles synthesized by one-pot synthesis induced necrotic cell death to human HEK293 cells, which was caused by graphitic carbon surface encapsulating the metal core.

  18. Necrotizing fasciitis.

    PubMed

    Cherneski, C L; Embil, J M

    2001-07-01

    Necrotizing fasciitis is a devestating condition which has been recognized for several years. In North America a recent increase of cases has led to much media attention and public fear. Necrotizing fasciitis may occur as a consequence of infection with Streptococcus pyogenes or as a result of a polymicrobial synergistic infection caused by aerobic, anaerobic, gram positive and gram negative organisms, often in postoperative patients. Necrotizing fasciitis caused by Streptococcus pyogenes is mediated by superantigens. The management of necrotizing fasciitis requires a high index of suspicion for diagnosis followed by antimicrobial therapy and early surgical intervention. In cases caused by Streptococcus pyogenes with streptococcal toxic shock syndrome, intravenous immunoglobulin may be of benefit.

  19. Induction of transcription factor CEBP homology protein mediates hypoglycaemia-induced necrotic cell death in human neuroblastoma cells.

    PubMed

    Kögel, Donat; Svensson, Birte; Copanaki, Ekaterini; Anguissola, Sergio; Bonner, Caroline; Thurow, Nadia; Gudorf, Daniel; Hetschko, Holger; Müller, Thorsten; Peters, Marion; König, Hans-Georg; Prehn, Jochen H M

    2006-11-01

    Oxygen and glucose deprivation are direct consequences of tissue ischaemia. We explored the interaction of hypoxia and hypoglycaemia on cell survival and gene expression in the absence of glutamatergic signalling using human SH-SY5Y neuroblastoma cells as a model. In agreement with previous investigations in non-neural cells, prolonged hypoxia (0.5% O(2)) failed to induce significant cell death in this system. In contrast, exposure to hypoglycaemia induced significant necrotic cell death (> 80% after 72 h). Interestingly, hypoglycaemia-induced cell death was completely abrogated by simultaneous exposure to hypoxia, suggesting strong cytoprotective effects of hypoxia. Subsequent microarray analysis of the underlying transcriptional responses revealed that the transcription factor CEBP homology protein (CHOP) was strongly induced by hypoglycaemia, and suppressed by simultaneous hypoxia. RNA interference against CHOP significantly protected cells from glucose deprivation-induced cell death. Hypoxia-induced vascular endothelial growth factor (VEGF) activation also protected cells against hypoglycaemia-induced cell death, but VEGF failed to modify hypoglycaemia-induced CHOP induction. Our data suggest that hypoglycaemia-induced necrotic cell death of neuroblastoma cells is an active process mediated via the induction of the transcription factor CHOP, and that hypoxia counteracts this cell death via at least two distinct mechanisms: repression of CHOP and induction of VEGF.

  20. Elisidepsin Interacts Directly with Glycosylceramides in the Plasma Membrane of Tumor Cells to Induce Necrotic Cell Death

    PubMed Central

    Molina-Guijarro, José Manuel; García, Carolina; Macías, Álvaro; García-Fernández, Luis Francisco; Moreno, Cristina; Reyes, Fernando; Martínez-Leal, Juan Fernando; Fernández, Rogelio; Martínez, Valentín; Valenzuela, Carmen; Lillo, M. Pilar; Galmarini, Carlos M.

    2015-01-01

    Plasma membrane integrity is essential for cell life. Any major break on it immediately induces the death of the affected cell. Different molecules were described as disrupting this cell structure and thus showing antitumor activity. We have previously defined that elisidepsin (Irvalec®, PM02734) inserts and self-organizes in the plasma membrane of tumor cells, inducing a rapid loss of membrane integrity, cell permeabilization and necrotic death. Here we show that, in sensitive HCT-116 colorectal cells, all these effects are consequence of the interaction of elisidepsin with glycosylceramides in the cell membrane. Of note, an elisidepsin-resistant subline (HCT-116-Irv) presented reduced levels of glycosylceramides and no accumulation of elisidepsin in the plasma membrane. Consequently, drug treatment did not induce the characteristic necrotic cell death. Furthermore, GM95, a mutant derivative from B16 mouse melanoma cells lacking ceramide glucosyltransferase (UGCG) activity and thus the synthesis of glycosylceramides, was also resistant to elisidepsin. Over-expression of UGCG gene in these deficient cells restored glycosylceramides synthesis, rendering them sensitive to elisidepsin, at a similar level than parental B16 cells. These results indicate that glycosylceramides act as membrane targets of elisidepsin, facilitating its insertion in the plasma membrane and the subsequent membrane permeabilization that leads to drug-induced cell death. They also indicate that cell membrane lipids are a plausible target for antineoplastic therapy. PMID:26474061

  1. Application of hyperthermia in addition to ionizing irradiation fosters necrotic cell death and HMGB1 release of colorectal tumor cells

    SciTech Connect

    Schildkopf, Petra; Frey, Benjamin; Mantel, Frederick; Ott, Oliver J.; Weiss, Eva-Maria; Sieber, Renate; Janko, Christina; Sauer, Rolf; Fietkau, Rainer; Gaipl, Udo S.

    2010-01-01

    Colorectal cancer is the second leading cause of death in developed countries. Tumor therapies should on the one hand aim to stop the proliferation of tumor cells and to kill them, and on the other hand stimulate a specific immune response against residual cancer cells. Dying cells are modulators of the immune system contributing to anti-inflammatory or pro-inflammatory responses, depending on the respective cell death form. The positive therapeutic effects of temperature-controlled hyperthermia (HT), when combined with ionizing irradiation (X-ray), were the origin to examine whether combinations of X-ray with HT can induce immune activating tumor cell death forms, also characterized by the release of the danger signal HMGB1. Human colorectal tumor cells with differing radiosensitivities were treated with combinations of HT (41.5 {sup o}C for 1 h) and X-ray (5 or 10 Gy). Necrotic cell death was prominent after X-ray and could be further increased by HT. Apoptosis remained quite low in HCT 15 and SW480 cells. X-ray and combinations with HT arrested the tumor cells in the radiosensitive G2 cell cycle phase. The amount of released HMGB1 protein was significantly enhanced after combinatorial treatments in comparison to single ones. We conclude that combining X-ray with HT may induce anti-tumor immunity as a result of the predominant induction of inflammatory necrotic tumor cells and the release of HMGB1.

  2. Cold Atmospheric Plasma Induces a Predominantly Necrotic Cell Death via the Microenvironment

    PubMed Central

    Cousty, Sarah; Cambus, Jean-Pierre; Valentin, Alexis

    2015-01-01

    Introduction Cold plasma is a partially ionized gas generated by an electric field at atmospheric pressure that was initially used in medicine for decontamination and sterilization of inert surfaces. There is currently growing interest in using cold plasma for more direct medical applications, mainly due to the possibility of tuning it to obtain selective biological effects in absence of toxicity for surrounding normal tissues,. While the therapeutic potential of cold plasma in chronic wound, blood coagulation, and cancer treatment is beginning to be documented, information on plasma/cell interaction is so far limited and controversial. Methods and Results Using normal primary human fibroblast cultures isolated from oral tissue, we sought to decipher the effects on cell behavior of a proprietary cold plasma device generating guided ionization waves carried by helium. In this model, cold plasma treatment induces a predominantly necrotic cell death. Interestingly, death is not triggered by a direct interaction of the cold plasma with cells, but rather via a transient modification in the microenvironment. We show that modification of the microenvironment redox status suppresses treatment toxicity and protects cells from death. Moreover, necrosis is not accidental and seems to be an active response to an environmental cue, as its execution can be inhibited to rescue cells. Conclusion These observations will need to be taken into account when studying in vitro plasma/cell interaction and may have implications for the design and future evaluation of the efficacy and safety of this new treatment strategy. PMID:26275141

  3. pH-dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205

    PubMed Central

    Cao, Longxing; Shi, Xiangyi; Chang, Haishuang; Zhang, Qinfen; He, Yongning

    2015-01-01

    Dendritic cells play important roles in regulating innate and adaptive immune responses. DEC205 (CD205) is one of the major endocytotic receptors on dendritic cells and has been widely used for vaccine generation against viruses and tumors. However, little is known about its structure and functional mechanism. Here we determine the structure of the human DEC205 ectodomain by cryoelectron microscopy. The structure shows that the 12 extracellular domains form a compact double ring-shaped conformation at acidic pH and become extended at basic pH. Biochemical data indicate that the pH-dependent conformational change of DEC205 is correlated with ligand binding and release. DEC205 only binds to apoptotic and necrotic cells at acidic pH, whereas live cells cannot be recognized by DEC205 at either acidic or basic conditions. These results suggest that DEC205 is an immune receptor that recognizes apoptotic and necrotic cells specifically through a pH-dependent mechanism. PMID:26039988

  4. pH-Dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205.

    PubMed

    Cao, Longxing; Shi, Xiangyi; Chang, Haishuang; Zhang, Qinfen; He, Yongning

    2015-06-01

    Dendritic cells play important roles in regulating innate and adaptive immune responses. DEC205 (CD205) is one of the major endocytotic receptors on dendritic cells and has been widely used for vaccine generation against viruses and tumors. However, little is known about its structure and functional mechanism. Here we determine the structure of the human DEC205 ectodomain by cryoelectron microscopy. The structure shows that the 12 extracellular domains form a compact double ring-shaped conformation at acidic pH and become extended at basic pH. Biochemical data indicate that the pH-dependent conformational change of DEC205 is correlated with ligand binding and release. DEC205 only binds to apoptotic and necrotic cells at acidic pH, whereas live cells cannot be recognized by DEC205 at either acidic or basic conditions. These results suggest that DEC205 is an immune receptor that recognizes apoptotic and necrotic cells specifically through a pH-dependent mechanism.

  5. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia.

    PubMed

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C; Sellati, Timothy J; Harton, Jonathan A

    2016-03-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection. PMID:27015566

  6. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia.

    PubMed

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C; Sellati, Timothy J; Harton, Jonathan A

    2016-03-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection.

  7. An Immature Myeloid/Myeloid-Suppressor Cell Response Associated with Necrotizing Inflammation Mediates Lethal Pulmonary Tularemia

    PubMed Central

    Periasamy, Sivakumar; Avram, Dorina; McCabe, Amanda; MacNamara, Katherine C.; Sellati, Timothy J.; Harton, Jonathan A.

    2016-01-01

    Inhalation of Francisella tularensis (Ft) causes acute and fatal pneumonia. The lung cytokine milieu favors exponential Ft replication, but the mechanisms underlying acute pathogenesis and death remain unknown. Evaluation of the sequential and systemic host immune response in pulmonary tularemia reveals that in contrast to overwhelming bacterial burden or cytokine production, an overt innate cellular response to Ft drives tissue pathology and host mortality. Lethal infection with Ft elicits medullary and extra-medullary myelopoiesis supporting recruitment of large numbers of immature myeloid cells and MDSC to the lungs. These cells fail to mature and die, leading to subsequent necrotic lung damage, loss of pulmonary function, and host death that is partially dependent upon immature Ly6G+ cells. Acceleration of this process may account for the rapid lethality seen with Ft SchuS4. In contrast, during sub-lethal infection with Ft LVS the pulmonary cellular response is characterized by a predominance of mature neutrophils and monocytes required for protection, suggesting a required threshold for lethal bacterial infection. Further, eliciting a mature phagocyte response provides transient, but dramatic, innate protection against Ft SchuS4. This study reveals that the nature of the myeloid cell response may be the primary determinant of host mortality versus survival following Francisella infection. PMID:27015566

  8. Cadmium induced changes in the liver of langurs (Presbytis entellus-entellus dufresne).

    PubMed

    Dixit, V P

    1977-01-01

    1- Cadmium-induced hepatic disturbances in Langurs have been studied following a single low dose administration of the salt (Cd Cl2 4 mg/kg s.c.). 2-Serum transaminases, choelsterol and liver glycogen levels were elevated. Alkaline phosphatase levels were in normal range. The blood sugar was at a low level. 3- Degranulation, vacuolization and distortion of the liver cells and lobules were conspicuous. 4- In conclusion this study would indicate that increased serum enzyme activity and increased plasma choelsterol levels are a manifestation of tissue damage. It would seem plausible to translate these observations in terms of similar infarcts occurring in man. PMID:207645

  9. Phytomedicinal Role of Pithecellobium dulce against CCl4-mediated Hepatic Oxidative Impairments and Necrotic Cell Death

    PubMed Central

    Manna, Prasenjit; Bhattacharyya, Sudip; Das, Joydeep; Ghosh, Jyotirmoy; Sil, Parames C.

    2011-01-01

    Present study investigates the beneficial role of the aqueous extract of the fruits of Pithecellobium dulce (AEPD) against carbon tetrachloride (CCl4)-induced hepatic injury using a murine model. AEPD has been found to possess free radical (DPPH, hydroxyl and superoxide) scavenging activity in cell-free system. CCl4 exposure increased the activities of various serum maker enzymes and intracellular reactive oxygen species (ROS) production. In line with these findings, we also observed that CCl4 intoxication increased the lipid peroxidation and protein carbonylation accompanied by decreased intracellular antioxidant defense, activity of cytochrome P450 and CYP2E1 expression. DNA fragmentation and flow cytometric analyses revealed that CCl4 exposure caused hepatic cell death mainly via the necrotic pathway. Treatment with AEPD both pre- and post-toxin exposure protected the organ from CCl4-induced hepatic damage. Histological findings also support our results. A well-known antioxidant vitamin C was included in this study to compare the antioxidant potency of AEPD. Combining all, results suggest that AEPD protects murine liver against CCl4-induced oxidative impairments probably via its antioxidative property. PMID:21869899

  10. Cadmium induced malformation in eyes of Ambassis commersoni Cuvier

    SciTech Connect

    Pragatheeswaran, V. ); Loganathan, B. ); Natarajan, R. ); Venugopalan, V.K. )

    1989-11-01

    Pathological manifestations in fishes from the polluted environment reflect the deleterious effects of environmental damage to higher animals in the food chain including man. Industrial and mining wastes containing cadmium ions induced several abnormalities and metabolic disorders in aquatic animals. Though cadmium is reported to be toxic to all tissues of animals, cadmium-induced malformations in eyes of fish have not yet been described. During these investigations on acute toxicity of cadmium on the estuarine fish Ambassis commersoni, the authors observed the manifestations of creamy white eyes and protrusion of eye balls, leading to death of the fish. This paper deals with the eye malformation in cadmium-treated estuarine fish, A. commersoni. Cadmium induced behavioral changes and alteration in the glycogen levels in muscle and liver are also described.

  11. Cadmium Induces Retinoic Acid Signaling by Regulating Retinoic Acid Metabolic Gene Expression*

    PubMed Central

    Cui, Yuxia; Freedman, Jonathan H.

    2009-01-01

    The transition metal cadmium is an environmental teratogen. In addition, cadmium and retinoic acid can act synergistically to induce forelimb malformations. The molecular mechanism underlying the teratogenicity of cadmium and the synergistic effect with retinoic acid has not been addressed. An evolutionarily conserved gene, β,β-carotene 15,15′-monooxygenase (BCMO), which is involved in retinoic acid biosynthesis, was studied in both Caenorhabditis elegans and murine Hepa 1–6 cells. In C. elegans, bcmo-1 was expressed in the intestine and was cadmium inducible. Similarly, in Hepa 1–6 cells, Bcmo1 was induced by cadmium. Retinoic acid-mediated signaling increased after 24-h exposures to 5 and 10 μm cadmium in Hepa 1–6 cells. Examination of gene expression demonstrated that the induction of retinoic acid signaling by cadmium may be mediated by overexpression of Bcmo1. Furthermore, cadmium inhibited the expression of Cyp26a1 and Cyp26b1, which are involved in retinoic acid degradation. These results indicate that cadmium-induced teratogenicity may be due to the ability of the metal to increase the levels of retinoic acid by disrupting the expression of retinoic acid-metabolizing genes. PMID:19556237

  12. Necrotizing sialometaplasia.

    PubMed

    Sneige, N; Batsakis, J G

    1992-03-01

    Necrotizing sialometaplasia of salivary tissues is a vascular-based (lobular infarct), benign, and often self-limited disorder. Preponderantly a lesion of palatal salivary glands, it can involve any salivary gland, and it may be mistaken for carcinoma. Adherence to histopathologic criteria should obviate this mistake.

  13. Necrotizing sialometaplasia.

    PubMed

    Lieberman, J; Weinstein, M

    1988-02-01

    A case of necrotizing sialometaplasia in a 29-year-old man is reported. Characterized by large, deep, well-demarcated ulcerations on the hard palate and other areas where salivary gland tissue is found, the condition is benign and resolves spontaneously. The cause is believed to be infarctive.

  14. Cadmium-induced apoptosis and necrosis in human osteoblasts: role of caspases and mitogen-activated protein kinases pathways.

    PubMed

    Brama, M; Politi, L; Santini, P; Migliaccio, S; Scandurra, R

    2012-02-01

    Cadmium is a widespread environmental pollutant which induces severe toxic alterations, including osteomalacia and osteoporosis, likely by estrogen receptor-dependent mechanisms. Indeed, cadmium has been described to act as an endocrine disruptor and its toxicity is exerted both in vivo and in vitro through induction of apoptosis and/or necrosis by not fully clarified intracellular mechanism(s) of action. Aim of the present study was to further investigate the molecular mechanism by which cadmium might alter homeostasis of estrogen target cells, such as osteoblast homeostasis, inducing cell apoptosis and/or necrosis. Human osteoblastic cells (hFOB 1.19) in culture were used as an in vitro model to characterize the intracellular mechanisms induced by this heavy metal. Cells were incubated in the presence/ absence of 10-50 μM cadmium chloride at different times and DNA fragmentation and activation of procaspases- 8 and -3 were induced upon CdCl(2) treatment triggering apoptotic and necrotic pathways. Addition of caspase-8 and -3 inhibitors (Z-IETD-FMK and Z-DQMD-FMK) partially blocked these effects. No activation of procaspase-9 was observed. To determine the role of mitogen-activated protein kinases (MAPK) in these events, we investigated c-jun N-terminal kinase (JNK), p38 and extracellular signal-regulated protein kinase (ERK1/2) phosphorylation which were activated by 10 μM CdCl(2). Chemical inhibitors of JNK, p38, and ERK1/2, SP600125, SB202190, and PD98059, significantly reduced the phosphorylation of the kinases and blunted apoptosis. In contrast, caspase inhibitors did not reduce the cadmium-induced MAPK phosphorylation, suggesting an independent activation of these pathways. In conclusion, at least 2 pathways appear activated by cadmium in osteoblasts: a direct induction of caspase-8 followed by activation of caspase-3 and an indirect induction by phosphorylation of ERK1/2, p38, and JNK MAPK triggering activation of caspase-8 and -3.

  15. Two rare entities in the same palate lesion: hyalinizing-type clear cell carcinoma and necrotizing sialometaplasia.

    PubMed

    Arpaci, Rabia Bozdoğan; Kara, Tuba; Porgali, Canan; Serinsoz, Ebru; Polat, Ayse; Vayisoglu, Yusuf; Ozcan, Cengiz

    2014-05-01

    Hyalinizing clear cell carcinoma is a low-grade malignant epithelial neoplasm of the salivary glands. The tumor has epithelial cells and lacks myoepithelial cells. Necrotizing sialometaplasia is a benign, self-limiting lesion of the salivary glands. The clinical and histologic features mimic those of mucoepidermoid carcinoma or squamous cell carcinoma. The importance of these entities are the rarity of both of them and their potential to be misdiagnosed as other lesions. Pathologists and clinicians should be aware of these entities to prevent misdiagnosis. This is the first clinical report of 2 rare and consecutive different entities of the same location on the hard palate to our knowledge.

  16. Necrotizing fasciitis

    PubMed Central

    Puvanendran, Rukshini; Huey, Jason Chan Meng; Pasupathy, Shanker

    2009-01-01

    Abstract OBJECTIVE To describe the defining characteristics and treatment of necrotizing fasciitis (NF), emphasizng early diagnostic indications. QUALITY OF EVIDENCE PubMed was searched using the terms necrotizing fasciitis and necrotizing soft tissue infections, paired with early diagnosis. Results were limited to human studies in English. Additional articles were obtained from references within articles. Evidence is levels II and III. MAIN MESSAGE Necrotizing fasciitis is classified according to its microbiology (polymicrobial or monomicrobial), anatomy, and depth of infection. Polymicrobial NF mostly occurs in immunocompromised individuals. Monomicrobial NF is less common and affects healthy individuals who often have a history of trauma (usually minor). Patients with NF can present with symptoms of sepsis, systemic toxicity, or evidence of skin inflammation, with pain that is disproportional to the degree of inflammation. However, these are also present in less serious conditions. Hyperacute cases present with sepsis and quickly progress to multiorgan failure, while subacute cases remain indolent, with festering soft-tissue infection. Because the condition is rare with minimal specific signs, it is often misdiagnosed. If NF is suspected, histology of tissue specimens is necessary. Laboratory and radiologic tests can be useful in deciding which patients require surgical consultation. Once NF is diagnosed, next steps include early wound debridement, excision of nonviable tissue, and wide spectrum cover with intravenous antibiotics. CONCLUSION Necrotizing fasciitis is an uncommon disease that results in gross morbidity and mortality if not treated in its early stages. At onset, however, it is difficult to differentiate from other superficial skin conditions such as cellulitis. Family physicians must have a high level of suspicion and low threshold for surgical referral when confronted with cases of pain, fever, and erythema. PMID:19826154

  17. Necrotizing sialometaplasia: a case report.

    PubMed

    Coley-Smith, A; Ellis, S G

    1994-01-01

    Necrotizing sialometaplasia, a benign self-limiting disease of minor salivary glands, may be confused both clinically and histologically with squamous cell carcinoma or a minor salivary gland neoplasm. Its sinister appearance has lead to misdiagnosis and some patients have undergone extensive surgery unnecessarily. This paper describes the salient features of necrotizing sialometaplasia and discusses the management of a patient with the condition.

  18. Necrotizing fasciitis in oro-maxillo-facial area after radiotherapy for squamous cell carcinoma of the soft palate.

    PubMed

    Ormenişan, Alina; Morariu, Silviu Horia; Cotoi, Ovidiu Simion; Vartolomei, Mihai Dorin; Grigoraş, Radu Ionuţ; Mocan, Simona Liliana; Suciu, Mircea

    2015-01-01

    The fascia's and subcutaneous adipose tissue's impairment by mono or polymicrobial infection, which also can involve the skin and the muscles, is rarely seen in oro-maxillo-facial area. The present case report is presenting a case of necrotizing fasciitis in a patient who had a history of an invasive squamous cell carcinoma of the soft palate, with surgical treatment and with radiotherapy. He was admitted in our Clinic with malaise and subsequently developed a toxico-septic shock. Clinical symptoms, serological and bacteriological analysis and histopathological examination confirmed the diagnosis of necrotizing fasciitis (NF). The patient subsequently underwent a series of surgical reconstruction and aesthetic treatments because of the complications that had arised in the meantime. Postoperative evolution was favorable towards complete closure of the defect. The prognosis of this disease is generally reserved, the favorable evolution depending on the possibility of wound sterilization and the surgery is required despite its mutilating effect. PMID:26429184

  19. Necrotizing sialometaplasia of tongue.

    PubMed

    Randhawa, Tanu; Varghese, Ipe; Shameena, Pm; Sudha, S; Nair, Resmi G

    2009-01-01

    Necrotizing sialometaplasia, is a benign inflammatory lesion primarily involving the minor salivary glands of the hard palate. The lesion often presents itself as a deep-seated palatal ulcer with clinical and histological features similar to those of a malignant neoplasm. Here we report a case of necrotizing sialometaplasia in a 40-year-old female, present on the lateral border of the tongue, mimicking squamous cell carcinoma, clinically. A correct diagnosis to avoid mutilant surgical treatments is essential, considering that it is a self-limiting disease.

  20. Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2

    PubMed Central

    Burzynski, Laura C.; Humphry, Melanie; Bennett, Martin R.; Clarke, Murray C. H.

    2015-01-01

    Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection. PMID:26324711

  1. Cadmium induced potassium efflux from Scenedesmus quadricauda

    SciTech Connect

    Reddy, G.N.; Prasad, M.N.V.

    1992-10-01

    Plants, algae and bacteria respond to heavy metal toxicity by inducing different enzymes, ion influx/efflux for ionic balance and synthesize small peptides such as poly({gamma}-glutamyl cysteinyl) glycines called phytochelatins (PCs) mainly consisting of glutamate, cysteine and glycine. These peptides bind metal ions and reduce toxicity. The uptake of metal ions comprises two phases. The first phase consists of a quick and nonspecific binding of the cations to negatively-charged membrane components located at the cell surface. The second phase consists of energy-dependent intracellular uptake of the metal ions. During uptake of Co{sup 2+} by yeast cells, an electroneutral 2:1 exchange with K{sup +} was found. Cd{sup 2+} uptake by yeast also caused loss of cell K{sup +}, however, there was no electroneutral exchange of K{sup +}. The molar ratio of K{sup +} released and Cd{sup 2+} accumulated by yeast in the initial stage of incubation is 22 and seems to be independent of the Cd concentration. Disruption of the cell membrane of part of the cells, according to an all-or-none process, by Cd{sup 2+} may explain the disproportional loss of cell K{sup +} during Cd{sup 2+} uptake. This paper examines the exchange of K{sup +} with Cd{sup 2+} uptake in Scenedesmus quadricauda, and whether it follows an electroneutral 2:1 exchange or an all-or-none process. 11 refs., 2 figs.

  2. Cadmium-induced olfactory dysfunction in rainbow trout: Effects of binary and quaternary metal mixtures.

    PubMed

    Dew, William A; Veldhoen, Nik; Carew, Amanda C; Helbing, Caren C; Pyle, Greg G

    2016-03-01

    A functioning olfactory response is essential for fish to be able to undertake essential behaviors. The majority of work investigating the effects of metals on the olfactory response of fish has focused on single-metal exposures. In this study we exposed rainbow trout to cadmium, copper, nickel, zinc, or a mixture of these four metals at or below the current Canadian Council of Ministers of the Environment guidelines for the protection of aquatic life. Measurement of olfactory acuity using an electro-olfactogram demonstrated that cadmium causes significant impairment of the entire olfactory system, while the other three metals or the mixture of all four metals did not. Binary mixtures with cadmium and each of the other metals demonstrated that nickel and zinc, but not copper, protect against cadmium-induced olfactory dysfunction. Testing was done to determine if the protection from cadmium-induced olfactory dysfunction could be explained by binding competition between cadmium and the other metals at the cell surface, or if the protection could be explained by an up-regulation of an intracellular detoxification pathway, namely metallothionein. This study is the first to measure the effects of binary and quaternary metal mixtures on the olfactory response of fish, something that will aid in future assessments of the effects of metals on the environment. PMID:26775207

  3. Cadmium-induced olfactory dysfunction in rainbow trout: Effects of binary and quaternary metal mixtures.

    PubMed

    Dew, William A; Veldhoen, Nik; Carew, Amanda C; Helbing, Caren C; Pyle, Greg G

    2016-03-01

    A functioning olfactory response is essential for fish to be able to undertake essential behaviors. The majority of work investigating the effects of metals on the olfactory response of fish has focused on single-metal exposures. In this study we exposed rainbow trout to cadmium, copper, nickel, zinc, or a mixture of these four metals at or below the current Canadian Council of Ministers of the Environment guidelines for the protection of aquatic life. Measurement of olfactory acuity using an electro-olfactogram demonstrated that cadmium causes significant impairment of the entire olfactory system, while the other three metals or the mixture of all four metals did not. Binary mixtures with cadmium and each of the other metals demonstrated that nickel and zinc, but not copper, protect against cadmium-induced olfactory dysfunction. Testing was done to determine if the protection from cadmium-induced olfactory dysfunction could be explained by binding competition between cadmium and the other metals at the cell surface, or if the protection could be explained by an up-regulation of an intracellular detoxification pathway, namely metallothionein. This study is the first to measure the effects of binary and quaternary metal mixtures on the olfactory response of fish, something that will aid in future assessments of the effects of metals on the environment.

  4. Target of rapamycin signaling regulates high mobility group protein association to chromatin, which functions to suppress necrotic cell death

    PubMed Central

    2013-01-01

    Background The target of rapamycin complex 1 (TORC1) is an evolutionarily conserved signal transduction pathway activated by environmental nutrients that regulates gene transcription to control cell growth and proliferation. How TORC1 modulates chromatin structure to control gene expression, however, is largely unknown. Because TORC1 is a major transducer of environmental information, defining this process has critical implications for both understanding environmental effects on epigenetic processes and the role of aberrant TORC1 signaling in many diseases, including cancer, diabetes, and cardiovascular disease. Results To elucidate the role of TORC1 signaling in chromatin regulation, we screened a budding yeast histone H3 and H4 mutant library using the selective TORC1 inhibitor rapamycin to identify histone residues functionally connected to TORC1. Intriguingly, we identified histone H3 lysine 37 (H3K37) as a residue that is essential during periods of limited TORC1 activity. An H3K37A mutation resulted in cell death by necrosis when TORC1 signaling was simultaneously impaired. The induction of necrosis was linked to alterations in high mobility group (HMG) protein binding to chromatin. Furthermore, the necrotic phenotype could be recapitulated in wild-type cells by deregulating the model HMG proteins, Hmo1 or Ixr1, thus implicating a direct role for HMG protein deregulation as a stimulus for inducing necrosis. Conclusions This study identifies histone H3 and H4 residues functionally required for TORC1-dependent cell growth and proliferation that are also candidate epigenetic pathways regulated by TORC1 signaling. It also demonstrates a novel role for H3K37 and TORC1 in regulating the binding of select HMG proteins to chromatin and that HMG protein deregulation can initiate a necrotic cell death response. Overall, the results from this study suggest a possible model by which chromatin anchors HMG proteins during periods of limited TORC1 signaling, such as that

  5. The Balance of Apoptotic and Necrotic Cell Death in Mycobacterium tuberculosis Infected Macrophages Is Not Dependent on Bacterial Virulence

    PubMed Central

    Butler, Rachel E.; Brodin, Priscille; Jang, Jichan; Jang, Mi-Seon; Robertson, Brian D.; Gicquel, Brigitte; Stewart, Graham R.

    2012-01-01

    Background An important mechanism of Mycobacterium tuberculosis pathogenesis is the ability to control cell death pathways in infected macrophages: apoptotic cell death is bactericidal, whereas necrotic cell death may facilitate bacterial dissemination and transmission. Methods We examine M.tuberculosis control of spontaneous and chemically induced macrophage cell death using automated confocal fluorescence microscopy, image analysis, flow cytometry, plate-reader based vitality assays, and M.tuberculosis strains including H37Rv, and isogenic virulent and avirulent strains of the Beijing lineage isolate GC1237. Results We show that bacterial virulence influences the dynamics of caspase activation and the total level of cytotoxicity. We show that the powerful ability of M.tuberculosis to inhibit exogenously stimulated apoptosis is abrogated by loss of virulence. However, loss of virulence did not influence the balance of macrophage apoptosis and necrosis – both virulent and avirulent isogenic strains of GC1237 induced predominantly necrotic cell death compared to H37Rv which induced a higher relative level of apoptosis. Conclusions This reveals that macrophage necrosis and apoptosis are independently regulated during M. tuberculosis infection of macrophages. Virulence affects the level of host cell death and ability to inhibit apoptosis but other strain-specific characteristics influence the ultimate mode of host cell death and alter the balance of apoptosis and necrosis. PMID:23118880

  6. Histological Characterization of the Tumorigenic “Peri-Necrotic Niche” Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma

    PubMed Central

    Ishii, Aya; Kimura, Tokuhiro; Sadahiro, Hirokazu; Kawano, Hiroo; Takubo, Keiyo; Suzuki, Michiyasu; Ikeda, Eiji

    2016-01-01

    Background Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically. Methods Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay. Results A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity. Conclusions These data suggest that the “peri-necrotic niche” harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas. PMID:26799577

  7. Use of yeast cell wall extract as a tool to reduce the impact of necrotic enteritis in broilers.

    PubMed

    M'Sadeq, Shawkat A; Wu, Shu-Biao; Choct, Mingan; Forder, Rebecca; Swick, Robert A

    2015-05-01

    The use of a yeast cell wall extract derived from Saccharomyces cerevisiae (Actigen(®)) has been proposed as an alternative to in-feed antibiotics. This experiment was conducted to investigate the efficacy of yeast cell extract as an alternative to zinc bacitracin or salinomycin using a necrotic enteritis challenge model. A feeding study was conducted using 480-day-old male Ross 308 chicks assigned to 48 floor pens. A 2 × 4 factorial arrangement of treatments was employed. The factors were: challenge (- or +) and feed additive (control, zinc bacitracin at 100/50 mg/kg, yeast cell wall extract at 400/800/200 mg/kg, or salinomycin at 60 mg/kg in starter, grower, and finisher, respectively). Diets based on wheat, sorghum, soybean meal, meat and bone meal, and canola meal were formulated according to the Ross 308 nutrient specifications. Birds were challenged using a previously established protocol (attenuated Eimeria spp oocysts) on d 9 and 10(8) to 10(9) Clostridium perfringens (type A strain EHE-NE18) on d 14 and 15). Challenged and unchallenged birds were partitioned to avoid cross contamination. Challenged birds had lower weight gain, feed intake and livability compared to unchallenged birds on d 24 and d 35 (P < 0.05). Birds given zinc bacitracin, yeast cell wall extract, or salinomycin had improved weight gain and livability when compared to control birds given no additives. Challenge × additive interactions were observed for feed intake and weight gain on d 24 and d 35 (P < 0.01). The additives all had a greater positive impact on feed intake, weight gain, and livability in challenged than unchallenged birds. All challenged birds showed higher necrotic enteritis lesion scores in the small intestine sections when compared to unchallenged birds (P < 0.01). Birds fed yeast cell wall extract exhibited increased villus height, decreased crypt depth, and increased villus:crypt ratio when challenged. Yeast cell wall extract, zinc bacitracin, and salinomycin were

  8. Cytotoxicity of silica nanoparticles through exocytosis of von Willebrand factor and necrotic cell death in primary human endothelial cells.

    PubMed

    Bauer, Alexander T; Strozyk, Elwira A; Gorzelanny, Christian; Westerhausen, Christoph; Desch, Anna; Schneider, Matthias F; Schneider, Stefan W

    2011-11-01

    Nanoparticle-induced endothelial cell (EC) dysfunction, due to the induction of inflammation and/or the activation of the coagulation system, is associated with pulmonary and ischemic cardiovascular diseases. Although it is contigent on several mechanisms, involving formation of reactive oxygen species and inflammatory cytokines such as interleukin (IL)-6 and 8, the involvement of the coagulation system is not well understood. The results of toxicity assays using the tetrazolium reduction (MTT) and lactate dehydrogenase (LDH) release showed that silica NP-induced cytotoxicity depends on the size and the dose of applied NP. Moreover, propidium iodide (PI) stainings and caspase 3/7 assays identified increased necrosis in ECs. Exposing human umbilical vein endothelial cells (HUVECs) to SiO(2) NP with diameters of 304 nm and 310 nm led to significant increase of Weibel-Palade body (WPB) exocytosis, associated with the release of von Willebrand factor (VWF) and the formation of ultralarge fibers (ULVWF). High resolution microscopy techniques revealed that internalization and perinuclear localization of perylene-labeled NP with a size of 310 nm affect not only viability, but also cell migration and proliferation. In conclusion, our data indicate that NP-induced activation and dysfunction of ECs is reflected by release of VWF and necrotic cell death.

  9. Inorganic mercury causes pancreatic beta-cell death via the oxidative stress-induced apoptotic and necrotic pathways

    SciTech Connect

    Chen Yawen; Huang Chunfa; Yang Chingyao; Yen Chengchieh; Tsai Kehsung; Liu Shinghwa

    2010-03-15

    Mercury is a well-known highly toxic metal. In this study, we characterize and investigate the cytotoxicity and its possible mechanisms of inorganic mercury in pancreatic beta-cells. Mercury chloride (HgCl{sub 2}) dose-dependently decreased the function of insulin secretion and cell viability in pancreatic beta-cell-derived HIT-T15 cells and isolated mouse pancreatic islets. HgCl{sub 2} significantly increased ROS formation in HIT-T15 cells. Antioxidant N-acetylcysteine effectively reversed HgCl{sub 2}-induced insulin secretion dysfunction in HIT-T15 cells and isolated mouse pancreatic islets. Moreover, HgCl{sub 2} increased sub-G1 hypodiploids and annexin-V binding in HIT-T15 cells, indicating that HgCl{sub 2} possessed ability in apoptosis induction. HgCl{sub 2} also displayed several features of mitochondria-dependent apoptotic signals including disruption of the mitochondrial membrane potential, increase of mitochondrial cytochrome c release and activations of poly (ADP-ribose) polymerase (PARP) and caspase 3. Exposure of HIT-T15 cells to HgCl{sub 2} could significantly increase both apoptotic and necrotic cell populations by acridine orange/ethidium bromide dual staining. Meanwhile, HgCl{sub 2} could also trigger the depletion of intracellular ATP levels and increase the LDH release from HIT-T15 cells. These HgCl{sub 2}-induced cell death-related signals could be significantly reversed by N-acetylcysteine. The intracellular mercury levels were markedly elevated in HgCl{sub 2}-treated HIT-T15 cells. Taken together, these results suggest that HgCl{sub 2}-induced oxidative stress causes pancreatic beta-cell dysfunction and cytotoxicity involved the co-existence of apoptotic and necrotic cell death.

  10. Cadmium induces histone H3 lysine methylation by inhibiting histone demethylase activity.

    PubMed

    Xiao, Chunlian; Liu, Yin; Xie, Chengfeng; Tu, Wei; Xia, Yujie; Costa, Max; Zhou, Xue

    2015-05-01

    Cadmium is an established human lung carcinogen with weak mutagenicity. However, the mechanisms underlying cadmium-induced carcinogenesis remain obscure. It has been suggested that epigenetic mechanisms may play a role in cadmium-induced carcinogenesis. In this study, we investigated the effects of cadmium on histone methylation and histone demethylases, and the role of histone methylation in transformation of immortalized normal human bronchial epithelial (BEAS-2B) cells. Exposure to 0.625, 1.25, 2.5, and 5.0 μM of cadmium for 6, 24, and 48 h increased global trimethylated histone H3 on lysine 4 (H3K4me3) and dimethylated histone H3 on lysine 9 (H3K9me2) in BEAS-2B cells compared with untreated cells, and most of these changes remained after the removal of cadmium (P < .05 or P < .01 for most modifications). Meanwhile, cadmium inhibited the activities of histone H3 on lysine 4 (H3K4) and histone H3 on lysine 9 (H3K9) demethylases which were detected by histone demethylation assay. However, there was no significant change in the protein levels of the H3K4 demethylase lysine-specific demethylase 5A (KDM5A) and the H3K9 demethylase lysine-specific demethylase 3A (KDM3A). Interestingly, during transformation of BEAS-2B cells by 20 weeks of exposure to 2.0 μM cadmium as assessed by anchorage-independent growth in soft agar, global H3K4me3, and H3K9me2 were significantly increased at 4 weeks (P < .05 or P < .01), whereas no significant change was observed at 8, 12, 16, and 20 weeks compared with control. Our study suggests that cadmium increases global H3K4me3 and H3K9me2 by inhibiting the activities of histone demethylases, and aberrant histone methylation that occurs early (48 h) and at 4 weeks is associated with cadmium-induced transformation of BEAS-2B cells at the early stage. PMID:25673502

  11. Necrotizing sialometaplasia.

    PubMed

    Nilsen, R; Bernhoft, C H; Gilhuus-Moe, O

    1978-12-01

    Two cases of necrotizing sialometaplasia are reported together with a review of the literature. This self-limiting benign lesion is easily confused with malignant tumors. The lesions are characterized histologically by an extensive necrosis of the salivary gland tissue together with squamous metaplasia of the ducts. The present report of two females who had intense pain in the initial phase differs from previous reports concerning age and symptoms. The importance of rather extensive biopsy specimens is stressed. Antibiotic treatment appears to be insignificant. A clinical history of allergy and a dominance of eosinophilic granulocytes in the inflammatory exudate in both cases may indicate an allergic etiology.

  12. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells.

    PubMed

    Okuhira, Keiichiro; Demizu, Yosuke; Hattori, Takayuki; Ohoka, Nobumichi; Shibata, Norihito; Nishimaki-Mogami, Tomoko; Okuda, Haruhiro; Kurihara, Masaaki; Naito, Mikihiko

    2013-11-01

    Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed a series of hybrid small molecules named SNIPER (Specific and Non-genetic IAP-dependent Protein ERaser) that induces degradation of target proteins via ubiquitin-proteasome system. Here we report the activities of SNIPER(ER) that targets estrogen receptor alpha (ERα) for degradation. SNIPER(ER) induced degradation of ERα and inhibited estrogen-dependent expression of pS2 gene in an estrogen-dependent breast cancer cell line MCF-7. A proteasome inhibitor MG132 and siRNA-mediated downregulation of cIAP1 abrogated the SNIPER(ER)-induced ERα degradation, suggesting that the ERα is degraded by proteasome subsequent to cIAP1-mediated ubiquitylation. Intriguingly, after the ERα degradation, the SNIPER(ER)-treated MCF-7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, a marker of necrosis, from the cells. Following the ERα degradation, reactive oxygen species (ROS) was produced in the SNIPER(ER)-treated MCF-7 cells, and an anti-oxidant N-acetylcysteine inhibited the necrotic cell death. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα-positive breast cancers.

  13. Necrotizing soft tissue infection

    MedlinePlus

    Necrotizing fasciitis; Fasciitis - necrotizing; Flesh-eating bacteria; Soft tissue gangrene; Gangrene - soft tissue ... Many different types of bacteria can cause this infection. A very severe and usually deadly form of necrotizing soft tissue infection is due to the ...

  14. Glycine reduces cadmium-induced teratogenic damage in mice.

    PubMed

    Paniagua-Castro, Norma; Escalona-Cardoso, Gerardo; Chamorro-Cevallos, Germán

    2007-01-01

    The effect of glycine in preventing cadmium (Cd) teratogenicity in mice was studied. Cadmium chloride (CdCl2) was administered subcutaneously at 1, 2 or 4 mg/kg doses on gestation days (GD) 7, 8 and 9. Glycine was given ad libitum (in the drinking water) from GD0 through GD18 (the day when animals were killed), as a 1% and 2% drinking water solution. Cd and nucleic acid concentrations in embryos were determined. The most common finding seen after CdCl2 4 mg/kg exposure was exencephaly. The incidence of this malformation was significantly reduced in mice receiving 2% glycine while fetal Cd significantly decreased as compared to cadmium-treated positive control animals. Increased nucleic acid levels were seen in the same embryos. In glycine non-supplemented mice given CdCl2 4 mg/kg, embryonic lipid peroxidation proved to be increased. In conclusion, lipid peroxidation was associated with cadmium-induced teratogenicity, and glycine inhibited the cadmium-induced effect by inhibiting placental transport of cadmium. However, further detailed studies are needed to establish the mechanism(s) of action.

  15. 3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines

    SciTech Connect

    Qin, J.-Z.; Xin, H.; Nickoloff, B.J.

    2010-05-28

    Clinicians successfully utilize high uptake of radiolabeled glucose via PET scanning to localize metastases in melanoma patients. To take advantage of this altered metabolome, 3-bromopyruvate (BrPA) was used to overcome the notorious resistance of melanoma to cell death. Using four melanoma cell lines, BrPA triggered caspase independent necrosis in two lines, whilst the other two lines were resistant to killing. Mechanistically, sensitive cells differed from resistant cells by; constitutively lower levels of glutathione, reduction of glutathione by BrPA only in sensitive cells; increased superoxide anion reactive oxygen species, loss of outer mitochondrial membrane permeability, and rapid ATP depletion. Sensitive cell killing was blocked by N-acetylcysteine or glutathione. When glutathione levels were reduced in resistant cell lines, they became sensitive to killing by BrPA. Taken together, these results identify a metabolic-based Achilles' heel in melanoma cells to be exploited by use of BrPA. Future pre-clinical and clinical trials are warranted to translate these results into improved patient care for individuals suffering from metastatic melanoma.

  16. Complement-mediated muscle cell lysis: a possible mechanism of myonecrosis in anti-SRP associated necrotizing myopathy (ASANM).

    PubMed

    Rojana-udomsart, Arada; Mitrpant, Chalermchai; Bundell, Christine; Price, Loren; Luo, Yue-Bei; Fabian, Victoria; Wilton, Steve D; Hollingsworth, Peter; Mastaglia, Frank L

    2013-11-15

    The mechanism of necrotizing myopathy associated with antibodies to signal recognition particle (SRP) remains unclear. We investigated the effect of anti-SRP+serum and complement on cell viability in myoblast cultures. Cell viability was only slightly reduced by incubation with anti-SRP+serum compared with control serum. However, the addition of fresh complement resulted in a marked reduction in cell survival. Surface immunostaining for SRP, C3c and C5b-9 was demonstrated in cultures pre-incubated with anti-SRP+serum and complement, and in muscle biopsies from patients with myopathy. These findings provide further support for a complement-dependent antibody-mediated mechanism in anti-SRP associated myopathy.

  17. Exogenous NAD(+) decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy.

    PubMed

    Zhu, Ying; Zhao, Ke-Ke; Tong, Yao; Zhou, Ya-Li; Wang, Yi-Xiao; Zhao, Pei-Quan; Wang, Zhao-Yang

    2016-05-31

    Increased oxidative stress, which can lead to the retinal pigment epithelium (RPE) cell death by inducing ATP depletion and DNA repair, is believed to be a prominent pathology in age-related macular degeneration (AMD). In the present study, we showed that and 0.1 mM nicotinamide adenine dinucleotide (NAD(+)) administration significantly blocked RPE cell death induced by 300 μM H2O2. Further investigation showed that H2O2 resulted in increased intracellular ROS level, activation of PARP-1 and subsequently necrotic death of RPE cells. Exogenous NAD(+) administration significantly decreased intracellular and intranuclear ROS levels in H2O2-treated RPE cells. In addition, NAD(+) administration to H2O2-treated RPE cells inhibited the activation of PARP-1 and protected the RPE cells against necrotic death. Moreover, exogenous NAD(+) administration up-regulated autophagy in the H2O2-treated RPE cells. Inhibition of autophagy by LY294002 blocked the decrease of intracellular and intranuclear ROS level. Besides, inhibition of autophagy by LY294002 abolished the protection of exogenous NAD(+) against H2O2-induced cell necrotic death. Taken together, our findings indicate that that exogenous NAD(+) administration suppresses H2O2-induced oxidative stress and protects RPE cells against PARP-1 mediated necrotic death through the up-regulation of autophagy. The results suggest that exogenous NAD(+) administration might be potential value for the treatment of AMD.

  18. Exogenous NAD+ decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy

    PubMed Central

    Zhu, Ying; Zhao, Ke-ke; Tong, Yao; Zhou, Ya-li; Wang, Yi-xiao; Zhao, Pei-quan; Wang, Zhao-yang

    2016-01-01

    Increased oxidative stress, which can lead to the retinal pigment epithelium (RPE) cell death by inducing ATP depletion and DNA repair, is believed to be a prominent pathology in age-related macular degeneration (AMD). In the present study, we showed that and 0.1 mM nicotinamide adenine dinucleotide (NAD+) administration significantly blocked RPE cell death induced by 300 μM H2O2. Further investigation showed that H2O2 resulted in increased intracellular ROS level, activation of PARP-1 and subsequently necrotic death of RPE cells. Exogenous NAD+ administration significantly decreased intracellular and intranuclear ROS levels in H2O2-treated RPE cells. In addition, NAD+ administration to H2O2-treated RPE cells inhibited the activation of PARP-1 and protected the RPE cells against necrotic death. Moreover, exogenous NAD+ administration up-regulated autophagy in the H2O2-treated RPE cells. Inhibition of autophagy by LY294002 blocked the decrease of intracellular and intranuclear ROS level. Besides, inhibition of autophagy by LY294002 abolished the protection of exogenous NAD+ against H2O2-induced cell necrotic death. Taken together, our findings indicate that that exogenous NAD+ administration suppresses H2O2-induced oxidative stress and protects RPE cells against PARP-1 mediated necrotic death through the up-regulation of autophagy. The results suggest that exogenous NAD+ administration might be potential value for the treatment of AMD. PMID:27240523

  19. Melatonin Improves Mitochondrial Function by Promoting MT1/SIRT1/PGC-1 Alpha-Dependent Mitochondrial Biogenesis in Cadmium-Induced Hepatotoxicity In Vitro

    PubMed Central

    Guo, Pan; Pi, Huifeng; Xu, Shangcheng; Zhang, Lei; Li, Yuming; Li, Min; Cao, Zhengwang; Tian, Li; Xie, Jia; Li, Renyan; He, Mindi; Lu, Yonghui; Liu, Chuan; Duan, Weixia; Yu, Zhengping; Zhou, Zhou

    2014-01-01

    Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10μM) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity. PMID:25159133

  20. Logistic regression analysis of cadmium-induced renal abnormalities

    SciTech Connect

    Ellis, K.J.; Yuen, K.; Cohn, S.H.

    1986-02-01

    Cases of renal dysfunction associated with cadium exposure have been reported in Belgium, Great Britian, Japan, United States, and Sweden. Indirect estimates of body burden were often based on the measurement of environmental exposure conditions or on tissue concentrations in urine, blood, saliva, or hair clippings. More recently, however, the direct in vivo assessment of liver and kidney cadmium burden in humans has provided additional data. Sufficient data on humans does exist, however, to make reasonable estimates of the increased risk for cadmium-induced renal dysfunction. In the present paper, a linear logistic regression model has been developed on the basis of liver and kidney cadmium burden. These relationships are discussed with respect to the concept of a critical concentration for the renal cortex. 14 refs., 3 figs., 2 tabs.

  1. Effect of Physalis peruviana L. on cadmium-induced testicular toxicity in rats.

    PubMed

    Othman, Mohamed S; Nada, Ahmed; Zaki, Hassan S; Abdel Moneim, Ahmed E

    2014-06-01

    Cadmium (Cd) stimulates the production of reactive oxygen species and causes tissue damage. We investigated here the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced testes toxicity in rats. Twenty-eight Wistar albino rats were used. They were divided into four groups (n=7). Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg body weight (bwt) of cadmium chloride for 5 days. Group 3 was orally treated with 200 mg/kg bwt of methanolic extract of physalis (MEPh). Group 4 was pretreated with MEPh before cadmium for 5 days. Changes in body and testes weights were determined. Oxidative stress markers, antioxidant enzymes, and testosterone level were measured. Histopathological changes of testes were examined, and the immunohistochemical staining for the proapoptotic (caspase-3) protein was performed. The injection of cadmium caused a significant decrease in body weight, while a significant increase in testes weight and testes weight index was observed. Pretreatment with MEPh was associated with significant reduction in the toxic effects of Cd as shown by reduced testicular levels of malondialdehyde, nitric oxide, and caspase-3 expression and increased glutathione content, and the activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and testosterone were also increased. Testicular histopathology showed that Cd produced an extensive germ cell apoptosis, and the pretreatment of MEPh in Cd-treated rats significantly reduced Cd-induced testicular damage. On the basis of the above results, it can be hypothesized that P. peruviana L. has a protective effect against cadmium-induced testicular oxidative stress and apoptosis in the rat. PMID:24728876

  2. Irradiation of necrotic cancer cells, employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma

    PubMed Central

    Vandenberk, Lien; Garg, Abhishek D.; Verschuere, Tina; Koks, Carolien; Belmans, Jochen; Beullens, Monique; Agostinis, Patrizia; De Vleeschouwer, Steven; Van Gool, Stefaan W.

    2016-01-01

    ABSTRACT Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins — a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines. PMID:27057467

  3. [Necrotizing autoimmune myopathies].

    PubMed

    Petiot, P; Choumert, A; Hamelin, L; Devic, P; Streichenberger, N

    2013-01-01

    Necrotizing autoimmune myopathies are included in the spectrum of inflammatory myopathies, together with polymyosis, dermatopolymyosis and inclusion body myositis, despite the characteristic feature of marked muscular necrosis without inflammatory infiltrates. The clinical presentation is highly variable, often similar to the other inflammatory myopathies. The most common finding is nevertheless the severe form with rhabdomyolysis. The creatine kinase level is elevated (around 10,000IU/l) and electromyography shows myopathic changes with increased spontaneous activities reflecting the importance of the muscular necrosis. Muscle biopsy is required for diagnosis, revealing active necrosis of the muscle fibers without inflammatory invasion by CDA+ or CD8+ T-cells. Deposition of a microvascular membrane attack complex (C5b9) is often noted, whereas the upregulation of MHC class 1 is rarely detected. Signs of endomysial microangiopathy are frequently reported. Necrotizing autoimmune myopathies can be associated with antisignal recognition particle (SRP) antibodies or more rarely with the usual inflammatory myopathy antibodies. Paraneoplasic forms are described but remain exceptional. Lastly, necrotizing autoimmune myopathies, sometimes associated with statin therapy, have been recently described. They are linked with an antibody directed against 3-hydroxy-3-methyglutaryl-coenzyme A. Treatment is based on corticosteroid therapy, immunosuppressive drugs or intravenous immunoglobulins. Response is variable, depending on the clinical form. PMID:23999024

  4. Label-free electrical discrimination of cells at normal, apoptotic and necrotic status with a microfluidic device.

    PubMed

    Gou, Hong-Lei; Zhang, Xian-Bo; Bao, Ning; Xu, Jing-Juan; Xia, Xing-Hua; Chen, Hong-Yuan

    2011-08-19

    As a label-free alternative of conventional flow cytometry, chip-based impedance measurement for single cell analysis has attracted increasing attentions in recent years. In this paper, we designed a T-shape microchannel and fabricated a pair of gold electrodes located horizontally on each side of the microchannel using a transfer printing method. Instant electric signals of flowing-through single cells were then detected by connecting the electrodes to a Keithley resistance and capacitance measurement system. Experimental results based on the simultaneous measurement of resistance and capacitance demonstrated that HL-60 and SMMC-7721 cells could be differentiated effectively. Moreover, SMMC-7721 cells at normal, apoptotic and necrotic status can also be discriminated in the flow. We discussed the possible mechanism for the discrimination of cell size and cell status by electrical analysis, and it is believed that the improvement of detection with our design results from more uniform distribution of the electric field. This microfluidic design may potentially become a promising approach for the label-free cell sorting and screening.

  5. Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis

    PubMed Central

    Penn, Alexander H.; Altshuler, Angelina E.; Small, James W.; Taylor, Sharon F.; Dobkins, Karen R.; Schmid-Schönbein, Geert W.

    2012-01-01

    Background Premature infants fed formula are more likely to develop necrotizing enterocolitis (NEC) than if fed breast milk, but the mechanisms of intestinal necrosis in NEC and protection by breast milk are unknown. We hypothesized that after lipase digestion, formula, but not fresh breast milk, contains levels of unbound free fatty acids (FFAs) that are cytotoxic to intestinal cells. Methods We digested multiple term and preterm infant formulas or human milk with pancreatic lipase, proteases (trypsin and chymotrypsin), lipase + proteases, or luminal fluid from a rat small intestine and tested FFA levels and cytotoxicity in vitro on intestinal epithelial cells, endothelial cells, and neutrophils. Results Lipase digestion of formula, but not milk, caused significant death of neutrophils (ranging from 47–99% with formulas vs. 6% with milk) with similar results in endothelial and epithelial cells. FFAs were significantly elevated in digested formula versus milk and death from formula was significantly decreased with lipase inhibitor pretreatment, or treatments to bind FFAs. Protease digestion significantly increased FFA binding capacity of formula and milk but only enough to decrease cytotoxicity from milk. Conclusion FFA-induced cytotoxicity may contribute to the pathogenesis of NEC. PMID:23007028

  6. Prolyl isomerase Pin1 regulates cadmium-induced autophagy via ubiquitin-mediated post-translational stabilization of phospho-Ser GSK3αβ in human hepatocellular carcinoma cells.

    PubMed

    So, Keum-Young; Oh, Seon-Hee

    2015-12-01

    Accumulating evidence suggests that prolyl-isomerase (Pin1) is an important regulator of apoptosis. In the present study, Pin1 was shown to negatively regulate the stabilization of glycogen synthase kinase (GSK) 3αβ serine phosphorylation by inhibiting ubiquitin (Ub)-proteasome degradation, and to induce autophagy following cadmium (Cd) exposure. Cd-induced autophagy in human hepatoma (HepG2) cells has been demonstrated by green fluorescent protein (GFP)-LC3B plasmid DNA transfection, and LC3-II conversion by autophagy inhibitors. Atg5 silencing inhibited Cd-induced apoptosis, indicating that autophagy is involved in cell death. Exposing HepG2 cells to Cd (≤6 μM) initially increased p-Ser GSK3αβ, but then resulted in a gradual decrease, which correlated with polyubiquitinated protein levels, which is indicative of protein degradation. However, high Cd concentrations lead to p-Ser GSK3αβ and polyubiquitinated protein accumulation, indicating proteasome impairment. Cd-induced p-Ser GSK3αβ was enhanced by proteasome inhibition (MG132) and ubiquitin deficiency (cyclohexamide), but no ubiquitination of p-Ser GSK3αβ or GSK3αβ was detected. Cd exposure resulted in p-Ser GSK3αβ redistribution from the nucleus into the cytosol, and this along with autophagy, was inhibited by leptomycin B. Cd concentrations <6 μM did not alter Pin1; however, Cd≥6 μM decreased Pin1. Pin1 overexpression decreased Cd-induced p-Ser GSK3αβ, autophagy, and polyubiquitinated protein levels, while its inhibition reversed the effects. Silencing and overexpression of GSK3αβ had no effect on Cd-induced Pin1 levels. Immunoprecipitation studies showed that Pin1 and p-Ser GSK3αβ interact. Collectively, Pin1 protects cells by inhibiting p-Ser GSK3αβ, and Pin1 decrease upregulates p-Ser GSK3αβ, through the inhibition of Ub-mediated proteasome degradation, and stimulates cell death via autophagy.

  7. Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION.

    PubMed

    Burzynski, Laura C; Humphry, Melanie; Bennett, Martin R; Clarke, Murray C H

    2015-10-01

    Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection.

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

    PubMed

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

    2008-01-01

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

  9. Legionella pneumophila induces cathepsin B-dependent necrotic cell death with releasing high mobility group box1 in macrophages

    PubMed Central

    2010-01-01

    Background Legionella pneumophila (LPN) can cause a lethal infectious disease with a marked inflammatory response in humans. However, the mechanism of this severe inflammation remains poorly understood. Since necrosis is known to induce inflammation, we investigated whether LPN induces necrosis in macrophages. We also analyzed the involvement of lysosomal cathepsin B in LPN-induced cell death. Methods The human monocytic cell line THP-1 was infected with LPN, NUL1 strain. MG132-treated cells were used as apoptotic control cells. After infection, the type of cell death was analyzed by using microscopy, LDH release and flow cytometry. As a proinflammatory mediator, high-mobility group box 1 (HMGB-1), was measured. Cathepsin B activity was also measured and the inhibitory effects of cathepsin B on LPN-induced cell death were analyzed. Results THP-1 cells after treatment with high dose of LPN showed necrotic features with releasing HMGB-1. This necrosis and the HMGB-1 release were inhibited by a specific lysosomal cathepsin B inhibitor and were characterized by a rapid and high activation of cathepsin B that was not observed in apoptotic control cells. The necrosis was also accompanied by cathepsin B-dependent poly(ADP-ribose) polymerase (PARP) cleavage. Conclusions We demonstrate here that L. pneumophila rapidly induces cathepsin B-dependent necrosis in a dose-dependent manner and releases a proinflammatory mediator, HMGB-1, from macrophages. This report describes a novel aspect of the pathogenesis of Legionnaires' disease and provides a possible therapeutic target for the regulation of inflammation. PMID:21092200

  10. The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing

    PubMed Central

    Mao, Y; Tamura, T; Yuki, Y; Abe, D; Tamada, Y; Imoto, S; Tanaka, H; Homma, H; Tagawa, K; Miyano, S; Okazawa, H

    2016-01-01

    In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein–protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis. PMID:27124581

  11. The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing.

    PubMed

    Mao, Y; Tamura, T; Yuki, Y; Abe, D; Tamada, Y; Imoto, S; Tanaka, H; Homma, H; Tagawa, K; Miyano, S; Okazawa, H

    2016-01-01

    In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis. PMID:27124581

  12. Cytotoxic Necrotizing Factor Type 1 of Uropathogenic Escherichia coli Kills Cultured Human Uroepithelial 5637 Cells by an Apoptotic Mechanism

    PubMed Central

    Mills, Melody; Meysick, Karen C.; O'Brien, Alison D.

    2000-01-01

    Pathogenic Escherichia coli associated with urinary tract infections (UTIs) in otherwise healthy individuals frequently produce cytotoxic necrotizing factor type 1 (CNF1), a member of the family of bacterial toxins that target the Rho family of small GTP-binding proteins. To gain insight into the function of CNF1 in the development of E. coli-mediated UTIs, we examined the effects of CNF1 intoxication on a panel of human cell lines derived from physiologically relevant sites (bladder, ureters, and kidneys). We identified one uroepithelial cell line that exhibited a distinctly different CNF1 intoxication phenotype from the prototypic one of multinucleation without cell death that is seen when HEp-2 or other epithelial cells are treated with CNF1. The 5637 bladder cell line detached from the growth surface within 72 h of CNF1 intoxication, a finding that suggested frank cytotoxicity. To determine the basis for the unexpected toxic effect of CNF1 on 5637 cells, we compared the degree of toxin binding, actin fiber formation, and Rho modification with those CNF1-induced events in HEp-2 cells. We found no apparent difference in the amount of CNF1 bound to 5637 cells and HEp-2 cells. Moreover, CNF1 modified Rho, in vivo and in vitro, in both cell types. In contrast, one of the classic responses to CNF1 in HEp-2 and other epithelial cell lines, the formation of actin stress fibers, was markedly absent in 5637 cells. Indeed, actin stress fiber induction by CNF1 did not occur in any of the other human bladder cell lines that we tested (J82, SV-HUC-1, or T24). Furthermore, the appearance of lamellipodia and filopodia in 5637 cells suggested that CNF1 activated the Cdc42 and Rac proteins. Finally, apoptosis was observed in CNF1-intoxicated 5637 cells. If our results with 5637 cells reflect the interaction of CNF1 with the transitional uroepithelium in the human bladder, then CNF1 may be involved in the exfoliative process that occurs in that organ after infection with

  13. UVA-induced apoptosis studied by the new apo/necro-Comet-assay which distinguishes viable, apoptotic and necrotic cells.

    PubMed

    Morley, N; Rapp, A; Dittmar, H; Salter, L; Gould, D; Greulich, K O; Curnow, A

    2006-03-01

    An adaptation of the Comet-assay was developed which enables the discrimination of viable, apoptotic and necrotic single cells by use of the common Annexin-V staining and a dye exclusion test on the cells already embedded in agarose gel on glass slides. Membrane integrity (Ethidium-Homodimer exclusion), cellular esterase activity (Calcein blue-AM) as well as translocation of phosphadidyl-serine (Annexin-V) were analysed using these stains. The advantage of the 'apo/necro-Comet-assay' is that the viability status of individual cells can be determined and correlated with the DNA fragmentation pattern (comet) formed by the same cells. Hence, DNA damage can be assessed and correlated with viable cells or cells undergoing early, mid- or late stage apoptosis or necrosis as identified by the staining pattern. The staining was verified using heat and etoposide-induced apoptosis. This technique, among others, was used to study whether apoptotic fragmentation interferes with repair kinetics measured with the comet assay following UVA exposure (doses up to 1,280 kJ/m(2)) in the cultured human keratinocytes (HaCaT). Therefore, a time course of apoptotic events (phosphatidyl translocation and TUNEL fragmentation) was established and correlated to the DNA fragmentation in the comet-assay. Apoptotic cells were detected more than 8 h later. The combined three-colour staining method with the comet assay showed that there was no significant interference of DNA repair by apoptotic fragmentation processes since DNA repair was almost completed before the onset of apoptotic fragmentation. The apo/necro-Comet-assay reduces the general problem of false-positive results in genotoxicity tests using the Comet-assay.

  14. Nrf2/p62 Signaling in Apoptosis Resistance and Its Role in Cadmium-induced Carcinogenesis*

    PubMed Central

    Son, Young-Ok; Pratheeshkumar, Poyil; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Zhang, Zhuo; Shi, Xianglin

    2014-01-01

    The cadmium-transformed human lung bronchial epithelial BEAS-2B cells exhibit a property of apoptosis resistance as compared with normal non-transformed BEAS-2B cells. The level of basal reactive oxygen species (ROS) is extremely low in transformed cells in correlation with elevated expressions of both antioxidant enzymes (catalase, SOD1, and SOD2) and antiapoptotic proteins (Bcl-2/Bcl-xL). Moreover, Nrf2 and p62 are highly expressed in these transformed cells. The knockdown of Nrf2 or p62 by siRNA enhances ROS levels and cadmium-induced apoptosis. The binding activities of Nrf2 on the antioxidant response element promoter regions of p62/Bcl-2/Bcl-xL were dramatically increased in the cadmium-exposed transformed cells. Cadmium exposure increased the formation of LC3-II and the frequency of GFP-LC3 punctal cells in non-transformed BEAS-2B cells, whereas these increases are not shown in transformed cells, an indication of autophagy deficiency of transformed cells. Furthermore, the expression levels of Nrf2 and p62 are dramatically increased during chronic long term exposure to cadmium in the BEAS-2B cells as well as antiapoptotic proteins and antioxidant enzymes. These proteins are overexpressed in the tumor tissues derived from xenograft mouse models. Moreover, the colony growth is significantly attenuated in the transformed cells by siRNA transfection specific for Nrf2 or p62. Taken together, this study demonstrates that cadmium-transformed cells have acquired autophagy deficiency, leading to constitutive p62 and Nrf2 overexpression. These overexpressions up-regulate the antioxidant proteins catalase and SOD and the antiapoptotic proteins Bcl-2 and Bcl-xL. The final consequences are decrease in ROS generation, apoptotic resistance, and increased cell survival, proliferation, and tumorigenesis. PMID:25157103

  15. Cadmium-induced ultrastructural changes in Euglena cells

    SciTech Connect

    Duret, S.; Bonaly, J.; Bariaud, A.; Vannereau, A.; Mestre, J.C.

    1986-02-01

    The ultrastructure of Euglena gracilis grown in the presence of Cd showed only numerous myelin-like structures in mitochondria, chloroplasts altered in shape, and thylakoid arrangement and increase of osmiophilic plastoglobuli. These alterations indicate that respiratory processes are the initial target of Cd toxicity.

  16. Smad7 inhibits autocrine expression of TGF-β2 in intestinal epithelial cells in baboon necrotizing enterocolitis.

    PubMed

    Namachivayam, Kopperuncholan; Blanco, Cynthia L; MohanKumar, Krishnan; Jagadeeswaran, Ramasamy; Vasquez, Margarita; McGill-Vargas, Lisa; Garzon, Steven A; Jain, Sunil K; Gill, Ravinder K; Freitag, Nancy E; Weitkamp, Jörn-Hendrik; Seidner, Steven R; Maheshwari, Akhil

    2013-01-15

    Preterm infants may be at risk of necrotizing enterocolitis (NEC) due to deficiency of transforming growth factor-β 2 (TGF-β(2)) in the developing intestine. We hypothesized that low epithelial TGF-β(2) expression in preterm intestine and during NEC results from diminished autocrine induction of TGF-β(2) in these cells. Premature baboons delivered at 67% gestation were treated per current norms for human preterm infants. NEC was diagnosed by clinical and radiological findings. Inflammatory cytokines, TGF-β(2), Smad7, Ski, and strawberry notch N (SnoN)/Ski-like oncoprotein (SKIL) was measured using quantitative reverse transcriptase-polymerase chain reaction, immunoblots, and immunohistochemistry. Smad7 effects were examined in transfected IEC6 intestinal epithelial cells in vitro. Findings were validated in archived human tissue samples of NEC. NEC was recorded in seven premature baboons. Consistent with existing human data, premature baboon intestine expressed less TGF-β(2) than term intestine. TGF-β(2) expression was regulated in epithelial cells in an autocrine fashion, which was interrupted in the premature intestine and during NEC due to increased expression of Smad7. LPS increased Smad7 binding to the TGF-β(2) promoter and was associated with dimethylation of the lysine H3K9, a marker of transcriptional silencing, on the nucleosome of TGF-β(2). Increased Smad7 expression in preterm intestine was correlated with the deficiency of SnoN/SKIL, a repressor of the Smad7 promoter. Smad7 inhibits autocrine expression of TGF-β(2) in intestinal epithelial cells in the normal premature intestine and during NEC. Increased Smad7 expression in the developing intestine may be due to a developmental deficiency of the SnoN/SKIL oncoprotein.

  17. Smad7 Interrupts TGF-β Signaling in Intestinal Macrophages and Promotes Inflammatory Activation of these Cells during Necrotizing Enterocolitis

    PubMed Central

    MohanKumar, Krishnan; Namachivayam, Kopperuncholan; Chapalamadugu, Kalyan; Garzon, Steven A.; Premkumar, Muralidhar H.; Tipparaju, Srinivas; Maheshwari, Akhil

    2015-01-01

    Background Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. Based on our recent findings of increased Smad7 expression in surgically-resected bowel affected by NEC, we hypothesized that NEC macrophages undergo inflammatory activation because increased Smad7 expression renders these cells resistant to normal, gut-specific, transforming growth factor (TGF)-β-mediated suppression of inflammatory pathways. Methods We used surgically-resected human NEC tissue, murine models of NEC-like injury, bone marrow-derived and intestinal macrophages, and RAW264.7 cells. Smad7 and IκB kinase-beta (IKK-β) were measured by quantitative polymerase chain reaction (qPCR), Western blots, and immunohistochemistry. Promoter activation was confirmed in luciferase reporter and chromatin immunoprecipitation assays. Results NEC macrophages showed increased Smad7 expression, particularly in areas with severe tissue damage and high bacterial load. LPS-induced Smad7 expression suppressed TGF-β signaling and augmented NF-κB activation and cytokine production in macrophages. Smad7-mediated NF-κB activated was likely mediated via increased expression of IKK-β, which, further increased Smad7 expression in a feed-forward loop. We show that Smad7 induced IKK-β expression through direct binding to the IKK-β promoter and its transcriptional activation. Conclusions Smad7 expression in NEC macrophages interrupts TGF-β signaling and promotes NF-κB-mediated inflammatory signaling in these cells through increased expression of IKK-β. PMID:26859364

  18. Seed dormancy breaking diterpenoids, including novel brassicicenes J and K, from fungus Alternaria brassicicola, and their necrotic/apoptotic activities in HL-60 cells.

    PubMed

    Kenmoku, Hiromichi; Takeue, Sayaka; Oogushi, Megumi; Yagi, Yasuyuki; Sassa, Takeshi; Toyota, Masao; Asakawa, Yoshinori

    2014-03-01

    To find new metabolites similar to cotylenins and fusicoccins from the fungus Alternaria brassicicola, screening tests were carried out using the lettuce seed dormancy breaking assay. Activity-guided fractionation of the EtOAc extract from the culture using the assay afforded the isolation of two novel fusicoccane diterpenoids named brassicicenes J (1) and K (2), along with three known brassicicenes A (3), B (4), and F (5). Their structures were elucidated from extensive NMR spectral data and by comparison of these with those reported in the literature. Brassicicenes (1-5) exhibited weak to moderate seed dormancy breaking activities against lettuce seeds in the presence of abscisic acid. In addition, the necrotic/apoptotic activities of the brassicicenes (1-5), fusicoccin A (6) and cotylenin A (7) were evaluated by determining their cytotoxicity, cell viability and caspase-3/7 activation on the HL-60 cell line. Brassicicene K (2) exhibited similar cytostatic profiles to that of cotylenin A (7), and brassicicenes J (1), A (3), B (4), and F (5) exhibited necrotic activity. This is the first report of the seed dormancy breaking activity of brassicicenes in plants, and of necrotic/apoptotic activity in mammalian cells. PMID:24689212

  19. Identification of cadmium-induced Agaricus blazei genes through suppression subtractive hybridization.

    PubMed

    Wang, Liling; Li, Haibo; Wei, Hailong; Wu, Xueqian; Ke, Leqin

    2014-01-01

    Cadmium (Cd) is one of the most serious environmental pollutants. Filamentous fungi are very promising organisms for controlling and reducing the amount of heavy metals released by human and industrial activities. However, the molecular mechanisms involved in Cd accumulation and tolerance of filamentous fungi are not fully understood. Agaricus blazei Murrill, an edible mushroom with medicinal properties, demonstrates high tolerance for heavy metals, especially Cd. To investigate the molecular mechanisms underlying the response of A. blazei after Cd exposure, we constructed a forward subtractive library that represents cadmium-induced genes in A. blazei under 4 ppm Cd stress for 14 days using suppression subtractive hybridization combined with mirror orientation selection. Differential screening allowed us to identify 39 upregulated genes, 26 of which are involved in metabolism, protein fate, cellular transport, transport facilitation and transport routes, cell rescue, defense and virulence, transcription, and the action of proteins with a binding function, and 13 are encoding hypothetical proteins with unknown functions. Induction of six A. blazei genes after Cd exposure was further confirmed by RT-qPCR. The cDNAs isolated in this study contribute to our understanding of genes involved in the biochemical pathways that participate in the response of filamentous fungi to Cd exposure.

  20. Effect of atenolol on cadmium-induced testicular toxicity in male rats.

    PubMed

    Biswas, N M; Sen Gupta, R; Chattopadhyay, A; Choudhury, G R; Sarkar, M

    2001-01-01

    Cadmium-induced stress adversely affects testicular activity and causes sympathetic stimulation. To investigate the effect of atenolol, a beta-adrenergic receptor blocker, on testicular androgen synthesis after cadmium treatment, adult Sprague-Dawley strain male rats were given a single sc dose of cadmium chloride 0.45 mg/kg BW. Animals were killed on day 3 after treatment. Adrenal weight, adrenal delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) activity, serum corticosterone, and brain noradrenaline were increased significantly while testicular delta 5-3 beta-HSD and 17 beta-HSD activities, serum testosterone, and accessory sex organs weight were decreased. Oral coadministration of atenolol at a dose of 2.0 mg/kg body weight for 3 days resulted in complete protection of adrenal delta 5-3 beta-HSD, testicular delta 5-3 beta-HSD, and 17 beta-HSD activities, adrenal weight, serum corticosterone, and serum testosterone when compared with cadmium-only group and there were no significant differences in these parameters from the vehicle control values. Simultaneous administration of cadmium and atenolol also protected brain noradrenaline content and reduced the rise of testicular cadmium concentration. All the parameters were similar to control levels in rats treated with atenolol alone. We conclude that atenolol may protect testicular androgen synthesis by inhibiting the action of noradrenaline on testicular Leydig cells and adrenocortical hyperactivity in cadmium-treated rats. PMID:11738523

  1. Mutational analysis of the RNA-binding domain of the Prunus necrotic ringspot virus (PNRSV) movement protein reveals its requirement for cell-to-cell movement

    SciTech Connect

    Carmen Herranz, Ma; Mingarro, Ismael; Pallas, Vicente . E-mail: vpallas@ibmcp.upv.es

    2005-08-15

    The movement protein (MP) of Prunus necrotic ringspot virus (PNRSV) is required for cell-to-cell movement. MP subcellular localization studies using a GFP fusion protein revealed highly punctate structures between neighboring cells, believed to represent plasmodesmata. Deletion of the RNA-binding domain (RBD) of PNRSV MP abolishes the cell-to-cell movement. A mutational analysis on this RBD was performed in order to identify in vivo the features that govern viral transport. Loss of positive charges prevented the cell-to-cell movement even though all mutants showed a similar accumulation level in protoplasts to those observed with the wild-type (wt) MP. Synthetic peptides representing the mutants and wild-type RBDs were used to study RNA-binding affinities by EMSA assays being approximately 20-fold lower in the mutants. Circular dichroism analyses revealed that the secondary structure of the peptides was not significantly affected by mutations. The involvement of the affinity changes between the viral RNA and the MP in the viral cell-to-cell movement is discussed.

  2. Cobalt triggers necrotic cell death and atrophy in skeletal C2C12 myotubes

    SciTech Connect

    Rovetta, Francesca; Stacchiotti, Alessandra; Faggi, Fiorella; Catalani, Simona; Apostoli, Pietro; Fanzani, Alessandro; Aleo, Maria Francesca

    2013-09-01

    Severe poisoning has recently been diagnosed in humans having hip implants composed of cobalt–chrome alloys due to the release of particulate wear debris on polyethylene and ceramic implants which stimulates macrophagic infiltration and destroys bone and soft tissue, leading to neurological, sensorial and muscular impairments. Consistent with this premise, in this study, we focused on the mechanisms underlying the toxicity of Co(II) ions on skeletal muscle using mouse skeletal C2C12 myotubes as an in vitro model. As detected using propidium iodide incorporation, increasing CoCl{sub 2} doses (from 5 to 200 μM) affected the viability of C2C12 myotubes, mainly by cell necrosis, which was attenuated by necrostatin-1, an inhibitor of the necroptotic branch of the death domain receptor signaling pathway. On the other hand, apoptosis was hardly detectable as supported by the lack of caspase-3 and -8 activation, the latter resulting in only faint activation after exposure to higher CoCl{sub 2} doses for prolonged time points. Furthermore, CoCl{sub 2} treatment resulted in atrophy of the C2C12 myotubes which was characterized by the increased expression of HSP25 and GRP94 stress proteins and other typical 'pro-atrophic molecular hallmarks, such as early activation of the NF-kB pathway and down-regulation of AKT phosphorylation, followed by the activation of the proteasome and autophagy systems. Overall, these results suggested that cobalt may impact skeletal muscle homeostasis as an inducer of cell necrosis and myofiber atrophy. - Highlights: • The effects of cobalt on muscle myofibers in vitro were investigated. • Cobalt treatment mainly causes cell necrosis in skeletal C2C12 myotubes. • Cobalt impacts the PI3K/AKT and NFkB pathways and induces cell stress markers. • Cobalt induces atrophy of C2C12 myotubes through the activation of proteasome and autophagy systems. • Co treatment triggers NF-kB and PI3K/AKT pathways in C2C12 myotubes.

  3. Allele-specific recognition by LILRB3 and LILRA6 of a cytokeratin 8 - associated ligand on necrotic glandular epithelial cells

    PubMed Central

    López-Álvarez, María R.; Jahnke, Martin; Russell, Alasdair I.; Radjabova, Valeria; Trowsdale, Alice R.Z.; Trowsdale, John

    2016-01-01

    The LILRs are a family of receptors that regulate the activities of myelomonocytic cells. We found that specific allelic variants of two related members of the LILR family, LILRB3 and LILRA6, interact with a ligand exposed on necrotic glandular epithelial cells. The extracellular domains of LILRB3 and LILRA6 are very similar and their genes are highly polymorphic. A commonly occurring allele, LILRB3*12, displayed particularly strong binding of these necrotic cells and further screening of the products of LILRB3 alleles identified motifs that correlated with binding. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12, identified cytokeratins 8, 18 and 19. Purified proteins obtained from epithelial cell lysates, using anti-cytokeratin 8 antibodies, were able to activate LILRB3*12 reporter cells. Knock-down of cytokeratin 8 in epithelial cells abrogated expression of the LILRB3 ligand, while staining with recombinant LILRB3*12 showed co-localisation with cytokeratin 8 and 18 in permeabilised breast cancer cells. Necrosis is a common feature of tumours. The finding of a necrosis-associated ligand for these two receptors raises the possibility of a novel interaction that alters immune responses within the tumour microenvironment. Since LILRB3 and LILRA6 genes are highly polymorphic the interaction may influence an individual's immune response to tumours. PMID:26769854

  4. At the core of survival: autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury.

    PubMed

    Loos, B; Genade, S; Ellis, B; Lochner, A; Engelbrecht, A-M

    2011-06-10

    Ischemic cell injury leads to cell death. Three main morphologies have been described: apoptosis, cell death with autophagy and necrosis. Their inherent dynamic nature, a point of no return (PONR) and molecular overlap have been stressed. The relationship between a defined cell death type and the severity of injury remains unclear. The functional role of autophagy and its effects on cell death onset is largely unknown. In this study we report a differential induction of cell death, which is dependent on the severity and duration of an ischemic insult. We show that mild ischemia leads to the induction of autophagy and apoptosis, while moderate or severe ischemia induces both apoptotic and necrotic cell death without increased autophagy. The autophagic response during mild injury was associated with an ATP surge. Real-time imaging and Fluorescence Resonance Energy Transfer (FRET) revealed that increased autophagy delays the PONR of both apoptosis and necrosis significantly. Blocking autophagy shifted PONR to an earlier point in time. Our results suggest that autophagic activity directly alters intracellular metabolic parameters, responsible for maintaining mitochondrial membrane potential and cellular membrane integrity. A similar treatment also improved functional recovery in the perfused rat heart. Taken together, we demonstrate a novel finding: autophagy is implicated only in mild injury and positions the PONR in cell death. PMID:21420401

  5. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition.

    PubMed

    Kaiser, William J; Daley-Bauer, Lisa P; Thapa, Roshan J; Mandal, Pratyusha; Berger, Scott B; Huang, Chunzi; Sundararajan, Aarthi; Guo, Hongyan; Roback, Linda; Speck, Samuel H; Bertin, John; Gough, Peter J; Balachandran, Siddharth; Mocarski, Edward S

    2014-05-27

    The pronecrotic kinase, receptor interacting protein (RIP1, also called RIPK1) mediates programmed necrosis and, together with its partner, RIP3 (RIPK3), drives midgestational death of caspase 8 (Casp8)-deficient embryos. RIP1 controls a second vital step in mammalian development immediately after birth, the mechanism of which remains unresolved. Rip1(-/-) mice display perinatal lethality, accompanied by gross immune system abnormalities. Here we show that RIP1 K45A (kinase dead) knockin mice develop normally into adulthood, indicating that development does not require RIP1 kinase activity. In the face of complete RIP1 deficiency, cells develop sensitivity to RIP3-mixed lineage kinase domain-like-mediated necroptosis as well as to Casp8-mediated apoptosis activated by diverse innate immune stimuli (e.g., TNF, IFN, double-stranded RNA). When either RIP3 or Casp8 is disrupted in combination with RIP1, the resulting double knockout mice exhibit slightly prolonged survival over RIP1-deficient animals. Surprisingly, triple knockout mice with combined RIP1, RIP3, and Casp8 deficiency develop into viable and fertile adults, with the capacity to produce normal levels of myeloid and lymphoid lineage cells. Despite the combined deficiency, these mice sustain a functional immune system that responds robustly to viral challenge. A single allele of Rip3 is tolerated in Rip1(-/-)Casp8(-/-)Rip3(+/-) mice, contrasting the need to eliminate both alleles of either Rip1 or Rip3 to rescue midgestational death of Casp8-deficient mice. These observations reveal a vital kinase-independent role for RIP1 in preventing pronecrotic as well as proapoptotic signaling events associated with life-threatening innate immune activation at the time of mammalian parturition.

  6. GENETIC BACKGROUND BUT NOT METALLOTHIONEIN PHENOTYPE DICTATES SENSITIVITY TO CADMIUM-INDUCED TESTICULAR INJURY IN MICE

    EPA Science Inventory

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to
    Cadmium-Induced Testicular Injury in Mice

    Jie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2
    and Curtis D. Klaassen1

    ABSTRACT

    Parenteral administrati...

  7. Statin-associated necrotizing autoimmune myopathy.

    PubMed

    Fernandes, Geórgea Hermogenes; Zanoteli, Edmar; Shinjo, Samuel Katsuyuki

    2014-09-01

    Necrotizing autoimmune myopathy (NAM) is a severe adverse effect of statins. We report a 66-year-old Caucasian female who had progressive proximal muscle weakness after treatment with statins. Results of a muscle biopsy showed necrotizing myopathy with minimal inflammatory cell infiltrate and increased major histocompatibility class I antigen expression in muscle fibers. The clinical and laboratory parameters improved significantly with immunosuppressive treatment. Although it is a rare event, statin-induced NAM should be included as a differential diagnosis of myopathies.

  8. Necrotizing sialometaplasia. Report of a case.

    PubMed

    Myers, E N; Bankaci, M; Barnes, E L

    1975-10-01

    Necrotizing sialometaplasia occurred in a 46-year-old woman. This is an uncommon benign disease that typically begins with an ulcerated lesion on the hard palate and surrounding tissues. Clinical and microscopic findings show obvious similarity with a malignant neoplasm. Necrotizing sialometapiasis is a benign minor salivary gland disease. It is important since it may easily be confused with squamous cell carcinoma and mucoepidermoid carcinoma.

  9. The effects of continuous testosterone exposure on spontaneous and cadmium-induced tumors in the male Fischer (F344/NCr) rat: loss of testicular response.

    PubMed

    Waalkes, M P; Rehm, S; Devor, D E

    1997-01-01

    In the rodent testes, cadmium induces severe necrosis followed by chronic degeneration. Cadmium is also an effective testicular tumorigen, and a single dose produces a high incidence of Leydig cell tumors. The mechanism of tumor formation is unknown, but pituitary feedback, i.e., increased luteinizing hormone (LH) production due to low circulating androgen, has been implicated in causation of proliferative lesions within degenerate, hypofunctioning testes. Thus, the effects of androgen replacement on the testicular toxicity of cadmium in Fischer (F344/NCr) rats was studied. Groups (n = 50) of 10-week-old rats either received testosterone implants that approximate normal circulating levels in castrated rats or were left untreated. After 2 weeks of stabilization, rats were given either 20 micromol CdCl2/kg, s.c., weekly for the next 5 weeks (total dose 100 micromol/kg) or saline for a total of four treatment groups (control, testosterone alone, testosterone + cadmium, or cadmium alone). Portions of each group were killed either 10 weeks after initiation of cadmium exposure (n = 10), for assessment of endocrine function, or over the next 2 years (n = 40), for assessment of testicular neoplastic lesions. At 10 weeks, cadmium reduced circulating testosterone in nonimplanted rats by nearly 80% and induced a marked weight loss of the testes (>70%) and sex accessory glands (reflected in a 50% reduction in prostate mass). Testosterone implantation restored circulating testosterone levels in cadmium-treated rats and prevented Cd-induced weight loss of the sex accessory glands but not of the testes. Over 2 years, cadmium alone induced a >84% incidence of Leydig cell neoplasia and a >97% incidence of chronic degeneration, both significant increases over control rates (60 and 0%, respectively). Testosterone implantation abolished both cadmium-induced and spontaneously occurring Leydig cell tumors but had no effect on cadmium-induced chronic testicular degeneration. Thus cadmium-induced

  10. Irvalec Inserts into the Plasma Membrane Causing Rapid Loss of Integrity and Necrotic Cell Death in Tumor Cells

    PubMed Central

    Molina-Guijarro, José M.; Macías, Álvaro; García, Carolina; Muñoz, Eva; García-Fernández, Luis F.; David, Miren; Núñez, Lucía; Martínez-Leal, Juan F.; Moneo, Victoria; Cuevas, Carmen; Lillo, M. Pilar; Villalobos Jorge, Carlos; Valenzuela, Carmen; Galmarini, Carlos M.

    2011-01-01

    Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca2+ influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn2+. Using fluorescent derivatives of Irvalec it was demonstrated that the compound rapidly interacts with the plasma membrane of tumor cells promoting lipid bilayer restructuration. Also, FRET experiments demonstrated that Irvalec molecules localize in the cell membrane close enough to each other as to suggest that the compound could self-organize, forming supramolecular structures that likely trigger cell death by necrosis through the disruption of membrane integrity. PMID:21556352

  11. Necrotizing soft tissue infections

    PubMed Central

    Urschel, J.

    1999-01-01

    Necrotizing soft tissue infections are a group of highly lethal infections that typically occur after trauma or surgery. Many individual infectious entities have been described, but they all have similar pathophysiologies, clinical features, and treatment approaches. The essentials of successful treatment include early diagnosis, aggressive surgical debridement, antibiotics, and supportive intensive treatment unit care. The two commonest pitfalls in management are failure of early diagnosis and inadequate surgical debridement. These life-threatening infections are often mistaken for cellulitis or innocent wound infections, and this is responsible for diagnostic delay. Tissue gas is not a universal finding in necrotizing soft tissue infections. This misconception also contributes to diagnostic errors. Incision and drainage is an inappropriate surgical strategy for necrotizing soft tissue infections; excisional debridement is needed. Hyperbaric oxygen therapy may be useful, but it is not as important as aggressive surgical therapy. Despite advances in antibiotic therapy and intensive treatment unit medicine, the mortality of necrotizing soft tissue infections is still high. This article emphasizes common treatment principles for all of these infections, and reviews some of the more important individual necrotizing soft tissue infectious entities.


Keywords: fasciitis; gas gangrene; clostridium infections; streptococcal infections; necrosis; debridement; surgical infections; soft tissue infections PMID:10621873

  12. Necrotic Myocardial Cells Release Damage-Associated Molecular Patterns That Provoke Fibroblast Activation In Vitro and Trigger Myocardial Inflammation and Fibrosis In Vivo

    PubMed Central

    Zhang, Weili; Lavine, Kory J; Epelman, Slava; Evans, Sarah A; Weinheimer, Carla J; Barger, Philip M; Mann, Douglas L

    2015-01-01

    Background Tissue injury triggers inflammatory responses that promote tissue fibrosis; however, the mechanisms that couple tissue injury, inflammation, and fibroblast activation are not known. Given that dying cells release proinflammatory “damage-associated molecular patterns” (DAMPs), we asked whether proteins released by necrotic myocardial cells (NMCs) were sufficient to activate fibroblasts in vitro by examining fibroblast activation after stimulation with proteins released by necrotic myocardial tissue, as well as in vivo by injecting proteins released by necrotic myocardial tissue into the hearts of mice and determining the extent of myocardial inflammation and fibrosis at 72 hours. Methods and Results The freeze–thaw technique was used to induce myocardial necrosis in freshly excised mouse hearts. Supernatants from NMCs contained multiple DAMPs, including high mobility group box-1 (HMGB1), galectin-3, S100β, S100A8, S100A9, and interleukin-1α. NMCs provoked a significant increase in fibroblast proliferation, α–smooth muscle actin activation, and collagen 1A1 and 3A1 mRNA expression and significantly increased fibroblast motility in a cell-wounding assay in a Toll-like receptor 4 (TLR4)- and receptor for advanced glycation end products–dependent manner. NMC stimulation resulted in a significant 3- to 4-fold activation of Akt and Erk, whereas pretreatment with Akt (A6730) and Erk (U0126) inhibitors decreased NMC-induced fibroblast proliferation dose-dependently. The effects of NMCs on cell proliferation and collagen gene expression were mimicked by several recombinant DAMPs, including HMGB1 and galectin-3. Moreover, immunodepletion of HMGB1 in NMC supernatants abrogated NMC-induced cell proliferation. Finally, injection of NMC supernatants or recombinant HMGB1 into the heart provoked increased myocardial inflammation and fibrosis in wild-type mice but not in TLR4-deficient mice. Conclusions These studies constitute the initial demonstration that

  13. Protective effect of hemin against cadmium-induced testicular damage in rats.

    PubMed

    Fouad, Amr A; Qureshi, Habib A; Al-Sultan, Ali Ibrahim; Yacoubi, Mohamed T; Ali, Abdellah Abusrie

    2009-03-29

    The protective effect of hemin, the heme oxygenase-1 inducer, was investigated in rats with cadmium induced-testicular injury, in which oxidative stress and inflammation play a major role. Testicular damage was induced by a single i.p. injection of cadmium chloride (2mg/kg). Hemin was given for three consecutive days (40 micromol/kg/day, s.c.), starting 1 day before cadmium administration. Hemin treatment significantly increased serum testosterone level that was reduced by cadmium. Hemin compensated deficits in the antioxidant defense mechanisms (reduced glutathione, and catalase and superoxide dismutase activities), and suppressed lipid peroxidation in testicular tissue resulted from cadmium administration. Also, hemin attenuated the cadmium-induced elevations in testicular tumor necrosis factor-alpha and nitric oxide levels, and caspase-3 activity. Additionally, hemin ameliorated cadmium-induced testicular tissue damage observed by light and electron microscopic examinations. The protective effect afforded by hemin was abolished by prior administration of zinc protoporphyrin-IX, the heme oxygenase-1 inhibitor. It was concluded that hemin, through its antioxidant, anti-inflammatory and antiapoptotic effects, represents a potential therapeutic option to protect the testicular tissue from the detrimental effects of cadmium. PMID:19150641

  14. FK506, a calcineurin inhibitor, prevents cadmium-induced testicular toxicity in mice.

    PubMed

    Martin, Lisa Joy; Chen, Haiyan; Liao, Xiaoyan; Allayee, Hooman; Shih, Diana Mouhan; Lee, Grace Sangeun; Hovland, David Norman; Robbins, Wendie Anne; Carnes, Kay; Hess, Rex Allen; Lusis, Aldons Jake; Collins, Michael David

    2007-12-01

    Cadmium, a ubiquitous environmental contaminant, damages several major organs in humans and other mammals. The molecular mechanisms for damage are not known. At high doses (5 mg/kg cadmium chloride or higher), testicular damage in mice, rats, and other rodents includes interstitial edema, hemorrhage, and changes in the seminiferous tubules affecting spermatogenesis. Necrosis is evident by 48 h. The goal of this study was to fine map and identify the cdm gene, a gene that when mutated prevents cadmium-induced testicular toxicity in mouse strains with a mutation in this gene. A serine-threonine phosphatase, calcineurin (CN), subunit A, alpha isoform (Ppp3ca), was one of the seven candidates in the cdm region that was narrowed from 5.6 to 2.0 Mb on mouse chromosome 3. An inhibitor of CN, the immunosuppressant, FK506, prevented cadmium-induced testicular damage in five pathological categories, including vascular endothelial and seminiferous epithelial endpoints. Inductively coupled plasma-mass spectrometry revealed that FK506 protected without lowering the amount of cadmium in the testes. Ppp3ca(-/-) mice were investigated but were found to exhibit endogenous testicular abnormalities, making them an inappropriate model for determining whether the inactivation of the Ppp3ca gene would afford protection from cadmium-induced testicular toxicity. The protection afforded by FK506, found by the current study, indicated that CN is likely to be important in the mechanism of cadmium toxicity in the testis and possibly other organs. PMID:17785681

  15. Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver

    SciTech Connect

    Patel, Nirav; Joseph, Cecil; Corcoran, George B.; Ray, Sidhartha D.

    2010-06-01

    The emergence of silymarin (SMN) as a natural remedy for liver diseases, coupled with its entry into NIH clinical trial, signifies its hepatoprotective potential. SMN is noted for its ability to interfere with apoptotic signaling while acting as an antioxidant. This in vivo study was designed to explore the hepatotoxic potential of Doxorubicin (Dox), the well-known cardiotoxin, and in particular whether pre-exposures to SMN can prevent hepatotoxicity by reducing Dox-induced free radical mediated oxidative stress, by modulating expression of apoptotic signaling proteins like Bcl-xL, and by minimizing liver cell death occurring by apoptosis or necrosis. Groups of male ICR mice included Control, Dox alone, SMN alone, and Dox with SMN pre/co-treatment. Control and Dox groups received saline i.p. for 14 days. SMN was administered p.o. for 14 days at 16 mg/kg/day. An approximate LD{sub 50} dose of Dox, 60 mg/kg, was administered i.p. on day 12 to animals receiving saline or SMN. Animals were euthanized 48 h later. Dox alone induced frank liver injury (> 50-fold increase in serum ALT) and oxidative stress (> 20-fold increase in malondialdehyde [MDA]), as well as direct damage to DNA (> 15-fold increase in DNA fragmentation). Coincident genomic damage and oxidative stress influenced genomic stability, reflected in increased PARP activity and p53 expression. Decreases in Bcl-xL protein coupled with enhanced accumulation of cytochrome c in the cytosol accompanied elevated indexes of apoptotic and necrotic cell death. Significantly, SMN exposure reduced Dox hepatotoxicity and associated apoptotic and necrotic cell death. The effects of SMN on Dox were broad, including the ability to modulate changes in both Bcl-xL and p53 expression. In animals treated with SMN, tissue Bcl-xL expression exceeded control values after Dox treatment. Taken together, these results demonstrated that SMN (i) reduced, delayed onset, or prevented toxic effects of Dox which are typically associated

  16. Protective effect of Guaraná (Paullinia cupana var. sorbilis) pre-treatment on cadmium-induced damages in adult Wistar testis.

    PubMed

    Leite, Rodrigo Paula; Wada, Ronaldo Seichi; Monteiro, Juliana Castro; Predes, Fabrícia Souza; Dolder, Heidi

    2011-06-01

    Guaraná (Paullinia cupana) is an Amazonian plant. Its antioxidant potential was demonstrated to be due to the high polyphenol concentration. On the other hand, one of the mechanisms underlying cadmium-induced cellular damage is free radical mediated, resulting in increased oxidative processes. This study investigated P. cupana's potential to attenuate cadmium-induced damages in Wistar rat testis. Adult male Wistar rats were either pre-treated with 2 mg/g body weight (BW) of powdered P. cupana seed during 56 days and/or injected with cadmium chloride at a dose of 1.15 mg/kg BW. After cadmium exposition (48 h), testes samples were evaluated by histological and stereological analyses. Both groups exposed to cadmium presented evident morphological alterations relative to control animals. A few rodents showed massive cell death in the seminiferous epithelium and intertubular space, indicating that some animals are more sensitive to cadmium. Despite the alterations observed in both groups, pre-treatment with P. cupana was effective in attenuating morphological changes in Leydig cells, as well as reducing inflammatory response, relative to animals exclusively exposed to the metal. Animals treated only with P. cupana presented a significant increase in plasma testosterone levels and a significant increase in volumetric proportions of seminiferous tubules, which are indicative of spermatogenic stimulation.

  17. [Necrotizing fasciitis after varicella].

    PubMed

    Gonçalves, E; Furtado, F; Estrada, J; Vale, M C; Pinto, M; Santos, M; Moura, G; Vasconcelos, C

    2001-01-01

    Necrotizing fasciitis is a rare and severe infection characterised by extremely rapid progressive involvement of the superficial fascias and deep dermal layers of the skin, with resultant vasculitis and necrosis. The authors present three clinical cases of necrotizing fasciitis; all three patients previously had varicella rash, rapid progressive spreading erythema with severe pain and toxic shock syndrome. Two patients had positive cultures of b-haemolytic streptococcus. Early stage differential diagnosis with celulitis, aggressive antibiotic treatment and pediatric intensive care support are essential. However, the main therapy is early extensive surgical approach involving all indurate areas, down to and including the muscle fascia.

  18. Increased Nuclear Thioredoxin-1 Potentiates Cadmium-Induced Cytotoxicity

    PubMed Central

    Jones, Dean P.

    2013-01-01

    Cadmium (Cd) is a widely dispersed environmental agent that causes oxidative toxicity through mechanisms that are sensitive to thioredoxin-1 (Trx1). Trx1 is a cytoplasmic protein that translocates to nuclei during oxidative stress. Recent research shows that interaction of Trx1 with actin plays a critical role in cell survival and that increased nuclear Trx-1 potentiates proinflammatory signaling and death in cell and mouse models. These observations indicate that oxidative toxicity caused by low-dose Cd could involve disruption of actin-Trx1 interaction, nuclear Trx1 translocation, and potentiation of proinflammatory cell death mechanisms. In this study, we investigated the role of nuclei-localized Trx1 in Cd-induced inflammation and cytotoxicity using in vitro and in vivo models. The results show that Cd stimulated nuclear translocation of Trx1 and p65 of NF-κB. Elevation of Trx1 in nuclei in in vitro cells and kidney of transgenic mice potentiated Cd-stimulated NF-κB activation and cell death. Cd-stimulated Trx1 nuclear translocation and NF-κB activation were inhibited by cytochalasin D, an inhibitor of actin polymerization, suggesting that actin regulates Trx1 nuclear translocation and NF-κB activation by Cd. A nuclear-targeted dominant negative form of Trx1 blocked Cd-stimulated NF-κB activation and decreased cell death. Addition of zinc, known to antagonize Cd toxicity by increasing metallothionein, had no effect on Cd-stimulated nuclear translocation of Trx1 and NF-κB activation. Taken together, the results show that nuclear translocation and accumulation of redox-active Trx1 in nuclei play an important role in Cd-induced inflammation and cell death. PMID:22961094

  19. Influence of combined antioxidants against cadmium induced testicular damage.

    PubMed

    Koyuturk, Meral; Yanardag, Refiye; Bolkent, Sehnaz; Tunali, Sevim

    2006-05-01

    Acute effects of cadmium (Cd) and combined antioxidants were evaluated in Sprague-Dawley rat testes. The rats were subdivided into four groups. Cadmium chloride (2mg/kgday) injected intraperitoneally during 8 days. Vitamin C (250mg/kgday), vitamin E (250mg/kgday) and sodium selenate (0.25mg/kgday) were pretreated by gavage in both of control and cadmium injected rats. Testis lipid peroxidation and glutathione levels were determined by spectrophotometrically. In Cd treated rats, lipid peroxidation levels were increased and glutathione levels were decreased and combined antioxidants treatment was effective in preventing of lipid peroxidation and normalizing glutathione. In Cd treated animals, the degenerative changes were observed, but not observed in the administrated rats with Cd and antioxidants under the light microscope. Proliferating cell nuclear antigen, metallothionein and caspase-3 activities were evaluated by immunohistochemically. Proliferation activity was not seen in the spermatogonial cells of cadmium treated testis. Treatment with antioxidants in cadmium administrated testis leads to pronounced increase in proliferation activity. Cytoplasmic caspase-3 activity was determined in the spermatogenic cells but not spermatogonia in treatment of antioxidants with Cd. In control and treated with antioxidants animals, metallothionein expressions were localized in the cells of seminiferous tubules, although the expression only was observed in the interstitial cells of cadmium treated rats. Results demonstrated beneficial effects of combined vitamin C, vitamin E and selenium treatment in Cd toxicity. PMID:21783663

  20. Cadmium-induced oxidative stress in Saccharomyces cerevisiae.

    PubMed

    Muthukumar, Kannan; Nachiappan, Vasanthi

    2010-12-01

    The present study was undertaken to determine the effect of cadmium (Cd) on the antioxidant status of the yeast Saccharomyces cerevisiae. S. cerevisiae serves as a good eukaryotic model system for the study of the molecular mechanisms of oxidative stress. We investigated the adaptative response of S. cerevisiae exposed to Cd. Yeast cells could tolerate up to 100 microM Cd and an inhibition in the growth and viability was observed. Exposure of yeast cells to Cd showed an increase in malondialdehyde and glutathione. The activities of catalase, superoxide dismutase and glutathione peroxidase were also high in Cd-exposed cells. The incorporation of Cd led to significant increase in iron, zinc and inversely the calcium, copper levels were reduced. The results suggest that antioxidants were increased and are involved in the protection against macromolecular damage during oxidative stress; presumably, these enzymes are essential for counteracting the pro-oxidant effects of Cd. PMID:21355423

  1. Piscidin-1, an antimicrobial peptide from fish (hybrid striped bass morone saxatilis x M. chrysops), induces apoptotic and necrotic activity in HT1080 cells.

    PubMed

    Lin, Heng-Ju; Huang, Tsui-Chin; Muthusamy, Sasikala; Lee, Jheng-Fong; Duann, Yeh-Fang; Lin, Cheng-Hui

    2012-05-01

    Piscidin-1, a 22-residue cationic peptide isolated from mast cells of a hybrid striped bass, has potent antimicrobial activities against both gram-positive and -negative bacteria. To date, there is no report of its antitumor activity on any tumor cell lines. In this study, we examined the antitumor activity of a synthetic piscidin-1 peptide against several human cancer cell lines using an MTS assay and soft-agar colony-formation assay. We found that a low dose of piscidin induces both apoptosis and necrosis in HT1080 cells, as shown by annexin-V/propidium iodide and acridine orange/ethidium bromide staining, and triggers a necrotic cell death pathway in a short period with high-dose treatment. The destruction of cell membranes by piscidin-1 was demonstrated by transmission electron microscopy. Furthermore, piscidin-1 also inhibits the migration of HT1080 cells in a dose-dependent manner. This study provides the first evidence of the anticancer activity of the antimicrobial peptide, piscidin-1, with potential implications for the treatment of cancer. PMID:22559967

  2. Piscidin-1, an antimicrobial peptide from fish (hybrid striped bass morone saxatilis x M. chrysops), induces apoptotic and necrotic activity in HT1080 cells.

    PubMed

    Lin, Heng-Ju; Huang, Tsui-Chin; Muthusamy, Sasikala; Lee, Jheng-Fong; Duann, Yeh-Fang; Lin, Cheng-Hui

    2012-05-01

    Piscidin-1, a 22-residue cationic peptide isolated from mast cells of a hybrid striped bass, has potent antimicrobial activities against both gram-positive and -negative bacteria. To date, there is no report of its antitumor activity on any tumor cell lines. In this study, we examined the antitumor activity of a synthetic piscidin-1 peptide against several human cancer cell lines using an MTS assay and soft-agar colony-formation assay. We found that a low dose of piscidin induces both apoptosis and necrosis in HT1080 cells, as shown by annexin-V/propidium iodide and acridine orange/ethidium bromide staining, and triggers a necrotic cell death pathway in a short period with high-dose treatment. The destruction of cell membranes by piscidin-1 was demonstrated by transmission electron microscopy. Furthermore, piscidin-1 also inhibits the migration of HT1080 cells in a dose-dependent manner. This study provides the first evidence of the anticancer activity of the antimicrobial peptide, piscidin-1, with potential implications for the treatment of cancer.

  3. Cadmium induces alterations in the human spinal cord morphogenesis.

    PubMed

    Sarchielli, Erica; Pacini, Stefania; Morucci, Gabriele; Punzi, Tiziana; Marini, Mirca; Vannelli, Gabriella B; Gulisano, Massimo

    2012-02-01

    The effects of cadmium on the central nervous system are still relatively poorly understood and its role in neurodegenerative diseases has been debated. In our research, cultured explants from 25 human foetal spinal cords (10-11 weeks gestational age) were incubated with 10 and 100 μM cadmium chloride (CdCl(2)) for 24 h. After treatment, an immunohistochemical study [for Sglial fibrillary acidic protein (GFAP) and choline acetyltransferase (ChAT)], a Western blot analysis (for GFAP, β-Tubulin III, nerve growth factor receptor, Caspase 8 and poly (ADP-ribose) polymerase), and a terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) assay (for detection of apoptotic bodies) were performed. The treatment with CdCl(2) induced a significant and dose-dependent change in the ratio motor neurons/glial cells in the ventral horns of human foetal spinal cord. The decrease of the choline acetyltransferase-positive cells (motor neurons) and the reduction of β Tubulin III indicate that CdCl(2) specifically affects motor neurons of the ventral horns. While the number of motor neurons decreased for the activation of apoptotic pathways (as shown by the increased expression of Caspase 8, nerve growth factor receptor, and poly (ADP-ribose) polymerase), glial cells, both in the subependymal zone and in the gray matter of the ventral horns, increased (as shown by the increase of GFAP expression). These results provide the evidence that during human spinal cord development, CdCl(2) may affect the fate of neural and glial cells thus, being potentially involved in the etiopathogenesis of neurodegenerative diseases.

  4. Paneth cell ablation in the presence of Klebsiella pneumoniae induces necrotizing enterocolitis (NEC)-like injury in the small intestine of immature mice

    PubMed Central

    Zhang, Chunxian; Sherman, Michael P.; Prince, Lawrence S.; Bader, David; Weitkamp, Jörn-Hendrik; Slaughter, James C.; McElroy, Steven J.

    2012-01-01

    SUMMARY Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Normally, Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and proinflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae, we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology that is consistent with other currently used animal models, but this technique is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment. PMID:22328592

  5. [Necrotizing sialometaplasia of the hard palate].

    PubMed

    Topstad, T K; Olofsson, J; Myking, A

    1991-11-30

    Necrotizing sialometaplasia is a benign, self-healing disease of salivary gland tissue and is usually confined to the minor salivary glands of the hard palate. It has clinical and histological features that simulate malignancies such as mucoepidermoid and squamous cell carcinomas. Wrong diagnosis has led to unnecessary mutilating surgical procedures. The etiology of the disease is unknown, but an ischaemic process is considered most likely. We describe two patients with necrotizing sialometaplasia, one with midline and one with bilateral symmetrical affection of the hard palate.

  6. Brain most susceptible to cadmium induced oxidative stress in mice.

    PubMed

    Agnihotri, Sandeep K; Agrawal, Usha; Ghosh, Ilora

    2015-04-01

    Accumulated evidence over the years indicate that cadmium (Cd) may be a possible etiological factor for neurodegenerative diseases. This may possibly be linked to excessive generation of free radicals that damages the organs in the body depending on their defence mechanism. Since Cd is a toxic agent that affect several cell types, the aim of this study was to shed light on the effect of Cd and its consequences on different organs of the mice body. To test the hypothesis of concentration dependent Reactive Oxygen Species (ROS) generation and DNA damage, observations were done in the serum of 4-5 weeks old male Swiss albino mice by treating with cadmium chloride (CdCl2) in drinking water for 30 days. The expression of Bcl-2-associated X protein (Bax) an apoptotic marker protein was two times higher in brain compared to liver at an exposure level of 0.5mgL(-1) CdCl2. Furthermore the correlation and linkage data analysis of antioxidant defence system revealed a rapid alteration in the brain, compared to any other organs considered in this study. We report that even at low dose of Cd, it impaired the brain due to lipid peroxidase sensitivity which favoured the Cd-induced oxidative injury in the brain.

  7. Necrotizing sialometaplasia affecting the minor labial glands.

    PubMed

    Matilla, A; Flores, T; Nogales, F F; Galera, H

    1979-02-01

    A case of necrotizing sialometaplasia of the lower lip, a previously unreported location for this lesion, is presented. In the past, other cases of this benign process occuring in this site may have been confused with squamous-cell or mucoepidermoid carcinoma. In order to arrive at the correct diagnosis, an ample biopsy of the lesion is mandatory.

  8. Advantage of Guaraná (Paullinia cupana Mart.) supplementation on cadmium-induced damages in testis of adult Wistar rats.

    PubMed

    Leite, Rodrigo P; Predes, Fabrícia S; Monteiro, Juliana C; Freitas, Karine M; Wada, Ronaldo S; Dolder, Heidi

    2013-01-01

    Paullinia cupana is an Amazonian bush whose seeds have long been used in folk medicine. However, most of the therapeutic properties attributed to this plant are broad and nonspecific, although an antioxidant activity has been reported.  On the other hand, cadmium is a heavy metal known for increasing free radicals, hence resulting in cellular oxidative damages. This study was designed to evaluate whether Paullinia cupana is able to reduce cadmium-induced morphological impairment in Wistar rat testis. Adult male Wistar rats 110 days old were ip injected with cadmium (1.15 mg/kg BW [body weight]) and subsequently treated with P. cupana during 56 days.  Furthermore, groups receiving either P. cupana extract or cadmium are mentioned. After the treatment period, testis samples were subjected to histological and stereological analyses. Moderate to severe testicular impairments were shown by the animals exposed to cadmium. However, the animals supplemented with P. cupana after cadmium exposure showed a significant decrease in the proportion of damaged seminiferous tubules. Also, P. cupana supplementation was effective in maintaining the number of Leydig cells per testis in the animals exposed to cadmium. In conclusion, P. cupana supplementation was partially efficient in preventing cadmium from damaging the testis of adult Wistar rats. PMID:22659242

  9. Advantage of Guaraná (Paullinia cupana Mart.) supplementation on cadmium-induced damages in testis of adult Wistar rats.

    PubMed

    Leite, Rodrigo P; Predes, Fabrícia S; Monteiro, Juliana C; Freitas, Karine M; Wada, Ronaldo S; Dolder, Heidi

    2013-01-01

    Paullinia cupana is an Amazonian bush whose seeds have long been used in folk medicine. However, most of the therapeutic properties attributed to this plant are broad and nonspecific, although an antioxidant activity has been reported.  On the other hand, cadmium is a heavy metal known for increasing free radicals, hence resulting in cellular oxidative damages. This study was designed to evaluate whether Paullinia cupana is able to reduce cadmium-induced morphological impairment in Wistar rat testis. Adult male Wistar rats 110 days old were ip injected with cadmium (1.15 mg/kg BW [body weight]) and subsequently treated with P. cupana during 56 days.  Furthermore, groups receiving either P. cupana extract or cadmium are mentioned. After the treatment period, testis samples were subjected to histological and stereological analyses. Moderate to severe testicular impairments were shown by the animals exposed to cadmium. However, the animals supplemented with P. cupana after cadmium exposure showed a significant decrease in the proportion of damaged seminiferous tubules. Also, P. cupana supplementation was effective in maintaining the number of Leydig cells per testis in the animals exposed to cadmium. In conclusion, P. cupana supplementation was partially efficient in preventing cadmium from damaging the testis of adult Wistar rats.

  10. Influence of naringin on cadmium-induced genomic damage in human lymphocytes in vitro.

    PubMed

    Yilmaz, Dilek; Aydemir, Nilufer Cinkilic; Vatan, Ozgür; Tüzün, Ece; Bilaloglu, Rahmi

    2012-03-01

    Cadmium is an important toxic environmental heavy metal. Generally, occupational and environmental exposures to cadmium result from heavy metal mining, metallurgy and industrial use and the manufacturing of nickel-cadmium batteries, pigments and plastic stabilizers. Cadmium induces oxidative stress and alters the antioxidant system, resulting in oxidative DNA damage and lipid peroxidation. The effect of naringin, a grapefruit flavonone, on cadmium-induced genomic damage was studied by using an in vitro system to test for chromosomal aberrations and sister chromatid exchanges. Cadmium significantly increased the total chromosomal aberrations in human lymphocytes at concentrations of 20 and 40 μM, and although naringin alone did not induce any chromosomal aberrations, it decreased those induced by cadmium. The mitotic index was not affected by either cadmium or naringin. Cadmium also induced a significant number of sister chromatid exchanges, but naringin alone did not induce sister chromatid exchanges and was unable to decrease the frequency of sister chromatid exchanges induced by cadmium. Replicative index analysis revealed that naringin and cadmium did not significantly alter replicative index frequencies. In this study, we show that plant-based flavonoids, such as naringin, may reduce the genomic damage induced by cadmium and may protect the cellular environments from free radical damage by its possible antioxidative potential. PMID:21636685

  11. Fenugreek seed powder mitigates cadmium-induced testicular damage and hepatotoxicity in male rats.

    PubMed

    Arafa, Manar Hamed; Mohammad, Nanies Sameeh; Atteia, Hebatallah Husseini

    2014-09-01

    Cadmium is a potential environmental and industrial pollutant affecting human tissues and organs including liver and testes. The protective role of fenugreek seed powder (FSP) was investigated in male rats subjected to cadmium-induced testicular injury and hepatic dysfunction. Testicular damage and hepatotoxicity were induced by oral administration of cadmium chloride (5 mg/kg body weight, once a day) for 7 weeks. FSP was given at 5% w/w in chow diet for 8 weeks, starting 1 week before cadmium administration. FSP intake significantly increased serum testosterone level and testis weight that were reduced by cadmium. FSP also compensated deficits in hepatic and testicular antioxidant defense system, interleukin-4 and nitric oxide levels, reduced serum liver function enzyme activities and suppressed lipid peroxidation in hepatic and testicular tissues resulted from cadmium administration. Additionally, FSP attenuated the cadmium-induced elevations in hepatic and testicular tumor necrosis factor-α and transforming growth factor-beta1 levels as well as cadmium deposition and hydroxyproline content. The protective effect afforded by FSP was mainly due its antioxidant, antifibrotic and anti-inflammatory effects. In conclusion, the results of the present work indicated that FSP may represent a promising medicinal herb to protect hepatic and testicular tissues from the detrimental effects of cadmium. PMID:24813645

  12. Necrotizing sialometaplasia in the mouth floor secondary to reconstructive surgery for tongue carcinoma.

    PubMed

    Matsumoto, T; Kuwabara, N; Shiotsu, H; Fukuda, Y; Yanai, A; Ichikawa, G

    1991-09-01

    Necrotizing sialometaplasia is a benign inflammatory process, which histologically can mimic squamous cell carcinoma. A 63-year-old man underwent left hemiglossectomy involving transplantation of a myocutaneous flap for squamous cell carcinoma of the tongue. One month after the operation, necrotizing sialometaplasia occurred in the minor salivary gland tissue of the mouth floor, compressed by the necrotic flap. This case is very unusual because of the occurrence of necrotizing sialometaplasia in the floor of the mouth. The etiology of the lesion was considered to be ischemia secondary to compression by the necrotic myocutaneous flap.

  13. Necrotizing enterocolitis: controversies and challenges

    PubMed Central

    Zani, Augusto; Pierro, Agostino

    2015-01-01

    Necrotizing enterocolitis is a devastating intestinal disease that affects ~5% of preterm neonates. Despite advancements in neonatal care, mortality remains high (30–50%) and controversy still persists with regards to the most appropriate management of neonates with necrotizing enterocolitis. Herein, we review some controversial aspects regarding the epidemiology, imaging, medical and surgical management of necrotizing enterocolitis and we describe new emerging strategies for prevention and treatment. PMID:26918125

  14. The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death.

    PubMed

    Chen, Hsiu-Min; Zhu, Ben-Zhan; Chen, Rong-Jane; Wang, Bour-Jr; Wang, Ying-Jan

    2014-01-01

    Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms. PMID:24586814

  15. Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris*

    PubMed Central

    Fernandez-Castaneda, Anthony; Arandjelovic, Sanja; Stiles, Travis L.; Schlobach, Ryan K.; Mowen, Kerri A.; Gonias, Steven L.; Gaultier, Alban

    2013-01-01

    In the central nervous system (CNS), fast neuronal signals are facilitated by the oligodendrocyte-produced myelin sheath. Oligodendrocyte turnover or injury generates myelin debris that is usually promptly cleared by phagocytic cells. Failure to remove dying oligodendrocytes leads to accumulation of degraded myelin, which, if recognized by the immune system, may contribute to the development of autoimmunity in diseases such as multiple sclerosis. We recently identified low density lipoprotein receptor-related protein-1 (LRP1) as a novel phagocytic receptor for myelin debris. Here, we report characterization of the LRP1 interactome in CNS myelin. Fusion proteins were designed corresponding to the extracellular ligand-binding domains of LRP1. LRP1 partners were isolated by affinity purification and characterized by mass spectrometry. We report that LRP1 binds intracellular proteins via its extracellular domain and functions as a receptor for necrotic cells. Peptidyl arginine deiminase-2 and cyclic nucleotide phosphodiesterase are novel LRP1 ligands identified in our screen, which interact with full-length LRP1. Furthermore, the extracellular domain of LRP1 is a target of peptidyl arginine deiminase-2-mediated deimination in vitro. We propose that LRP1 functions as a receptor for endocytosis of intracellular components released during cellular damage and necrosis. PMID:23264627

  16. Pathogenesis of Necrotizing Enterocolitis

    PubMed Central

    Tanner, Scott M.; Berryhill, Taylor F.; Ellenburg, James L.; Jilling, Tamas; Cleveland, Dava S.; Lorenz, Robin G.; Martin, Colin A.

    2016-01-01

    Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants. The pathophysiology is likely secondary to innate immune responses to intestinal microbiota by the premature infant's intestinal tract, leading to inflammation and injury. This review provides an updated summary of the components of the innate immune system involved in NEC pathogenesis. In addition, we evaluate the animal models that have been used to study NEC with regard to the involvement of innate immune factors and histopathological changes as compared to those seen in infants with NEC. Finally, we discuss new approaches to studying NEC, including mathematical models of intestinal injury and the use of humanized mice. PMID:25447054

  17. [Acute necrotizing enteritis].

    PubMed

    Marincaş, M; Bratucu, E; Straja, D; Daha, C; Boru, C

    2003-01-01

    The authors present a retrospective clinical study done on a 13-pacients basis diagnosed during surgery with acute necrotizing enteritis. This study follows the complexity of pathogenic factors and the difficulties one confronts with when establishing a diagnosis since the clinical manifestations are non-specifical and shows the contribution of laboratory data to an earliest possible diagnosis. Both medical and surgical treatment are analyzed depending on the results achieved with an attempt to determine a therapeutic approach as beneficial as possible, aiming at making clear either enterectomy or a conservatory surgical decision should be made. Mortality rate under such therapeutical approach was 38%.

  18. Cadmium-induced glutathionylation of actin occurs through a ROS-independent mechanism: Implications for cytoskeletal integrity

    SciTech Connect

    Choong, Grace; Liu, Ying; Xiao, Weiqun; Templeton, Douglas M.

    2013-10-15

    Cadmium disrupts the actin cytoskeleton in rat mesangial cells, and we have previously shown that this involves a complex interplay involving activation of kinase signaling, protein translocation, and disruption of focal adhesions. Here we investigate the role that glutathionylation of actin plays in Cd{sup 2+}-associated cytoskeletal reorganization. Low concentrations of Cd{sup 2+} (0.5–2 μM) caused an increase in actin glutathionylation by 6 h, whereas at higher concentrations glutathionylation remained at basal levels. Although oxidation with diamide increased glutathionylation, reactive oxygen species (ROS) were not involved in the Cd{sup 2+}-dependent effect, as only Cd{sup 2+} concentrations above 2 μM were sufficient to increase ROS. However, low [Cd{sup 2+}] increased total glutathione levels without affecting the ratio of reduced/oxidized glutathione, and inhibition of glutathione synthesis suppressed actin glutathionylation. Cadmium increased the activity of the enzyme glutaredoxin, which influences the equilibrium between glutathionylated and deglutathionylated proteins and thus may influence levels of glutathionylated actin. Together these observations show that cadmium-dependent effects on actin glutathionylation are affected by glutathione metabolism and not by direct effects of ROS on thiol chemistry. In vitro polymerization assays with glutathionylated actin show a decreased rate of polymerization. In contrast, immunofluorescence of cytoskeletal structure in intact cells suggests that increases in actin glutathionylation accompanying increased glutathione levels occurring under low Cd{sup 2+} exposure are protective in vivo, with cytoskeletal disruption ensuing only when higher Cd{sup 2+} concentrations increase ROS levels and prevent an increase in actin–glutathione conjugates. - Highlights: • Cadmium disrupts the actin cytoskeleton in mesangial cells. • Cadmium induces glutathionylation of actin at low concentrations.

  19. [Necrotizing sialometaplasia of the nasal cavity].

    PubMed

    Deubel, M; Meister, F; Podvinec, M; Stamm, B

    1994-11-01

    In the present paper we report two cases of "necrotizing sialometaplasia" in uncommon locations. The relevant literature is reviewed. Necrotizing sialometaplasia is self-limiting and is characterized by necrosis and squamous pseudohypertrophy. Typically occurring in the minor salivary glands of the oral mucosa, our cases appear to be the sixth and seventh cases of involvement of the nasal cavity reported in the literature. Owing to the similarity of histological findings, the term "sialometaplasia" is also used for this disorder. This rare disease is a benign process but may be misdiagnosed as mucoepidermoid or squamous cell carcinoma. Therefore, the possibility of this disease in the nose should again be presented. Both of our cases show that with a histological examination considering defined morphological findings, the diagnosis of necrotizing sialometaplasia can be verified and a diagnosis of a carcinoma can be excluded. Especially with regard to radical and possibly unnecessary invasive therapeutic procedures we emphasize the importance of considering "necrotizing sialometaplasia" as part of the differential diagnosis of nasal lesions.

  20. Cadmium-induced ultramorphological and physiological changes in leaves of two transgenic cotton cultivars and their wild relative.

    PubMed

    Daud, M K; Variath, M T; Ali, Shafaqat; Najeeb, U; Jamil, Muhammad; Hayat, Y; Dawood, M; Khan, Muhammad Imran; Zaffar, M; Cheema, Sardar Alam; Tong, X H; Zhu, Shuijin

    2009-09-15

    The present study describes cadmium-induced alterations in the leaves as well as at the whole plant level in two transgenic cotton cultivars (BR001 and GK30) and their wild relative (Coker 312) using both ultramorphological and physiological indices. With elevated levels of Cd (i.e. 10, 100, 1000 microM), the mean lengths of root, stem and leaf and leaf width as well as their fresh and dry biomasses linearly decreased over their respective controls. Moreover, root, stem and leaf water absorption capacities progressively stimulated, which were high in leaves followed by roots and stems. BR001 accumulated more cadmium followed by GK30 and Coker 312. Root and shoot cadmium uptakes were significantly and directly correlated with each other as well as with leaf, stem and root water absorption capacities. The ultrastructural modifications in leaf mesophyll cells were triggered with increase in Cd stress regime. They were more obvious in BR001 followed by GK30 and Coker 312. Changes in morphology of chloroplast, increase in number and size of starch grains as well as increase in number of plastoglobuli were the noticed qualitative effects of Cd on photosynthetic organ. Cd in the form of electron dense granules could be seen inside the vacuoles and attached to the cell walls in all these cultivars. From the present experiment, it can be well established that both apoplastic and symplastic bindings are involved in Cd detoxification in these cultivars. Absence of tonoplast invagination reveals that Cd toxic levels did not cause water stress in any cultivars. Additionally, these cultivars possess differential capabilities towards Cd accumulation and its sequestration.

  1. Deamidation of Cdc42 and Rac by Escherichia coli Cytotoxic Necrotizing Factor 1: Activation of c-Jun N-Terminal Kinase in HeLa Cells

    PubMed Central

    Lerm, M.; Selzer, J.; Hoffmeyer, A.; Rapp, U. R.; Aktories, K.; Schmidt, G.

    1999-01-01

    Recently, Escherichia coli cytotoxic necrotizing factor 1 (CNF1) was shown to activate the low-molecular-mass GTPase RhoA by deamidation of Gln63, thereby inhibiting intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities (G. Schmidt, P. Sehr, M. Wilm, J. Selzer, M. Mann, and K. Aktories, Nature 387:725–729, 1997; G. Flatau, E. Lemichez, M. Gauthier, P. Chardin, S. Paris, C. Fiorentini, and P. Boquet, Nature 387:729–733, 1997). Here we report that in addition to RhoA, Cdc42 and Rac also are targets for CNF1 in vitro and in intact cells. Treatment of HeLa cells with CNF1 induced a transient formation of microspikes and formation of membrane ruffles. CNF1 caused a transient 10- to 50-fold increase in the activity of the c-Jun N-terminal kinase. Tryptic peptides of Cdc42 obtained from CNF1-treated cells by immunoprecipitation exhibited an increase in mass of 1 Da compared to control peptides, indicating the deamidation of glutamine 61 by the toxin. The same increase in mass was observed with the respective peptides obtained from CNF1-modified recombinant Cdc42 and Rac1. Modification of recombinant Cdc42 and Rac1 by CNF1 inhibited intrinsic and GAP-stimulated GTPase activities and retarded binding of 2′(3′)-O-(N-methylanthraniloyl)GDP. The data suggest that recombinant as well as cellular Cdc42 and Rac are substrates for CNF1. PMID:9916051

  2. Induction and Determination of Apoptotic and Necrotic Cell Death by Cadmium Chloride in Testis Tissue of Mouse

    PubMed Central

    Niknafs, Behrooz; Salehnia, Mojdeh; Kamkar, Mahmood

    2015-01-01

    Background Cadmium chloride which is potentially toxic is currently used in industry. The toxic effects of cadmium on testes have been reported to range from apoptosis to necrosis, with different effects on fertility. This research aimed to study the effect of different doses of cadmium on testicular tissues at acute stage by light and electron microscopy. Methods Cadmium chloride was injected into mature Balb/c mice intraperitoneally in 7 doses. Five mice were studied in each group. After 48 hr, the testes were extracted and prepared for light microscopy. Then two concentrations (15 and 25 µM/kg) of them were selected for electron microscopic study based on histological changes. The cellular changes of luminal epithelium of seminiferous tubules were studied under an electron microscope. Histological and ultrastructural changes were reported. Results The absence of sperm in the tubules was observed at 20 µM/kg concentration. At 25 µM/kg, histological destruction and epithelial damages were observed. Histological changes were not remarkable at 5 and 10 µM/kg. However, ultrastructural changes of seminiferous tubules at 20 µM/kg included spermatogonial cell death. At 25 µM/kg, vacuolation of Sertoli cells and death of spermatids as well as spermatocytes were observed. Cell death in the tubules was limited to germ cells. However, Sertoli cells exhibited architectural alterations without any cell death. Conclusion Both apoptosis and necrosis occurred in testicular tissue by exposure to cadmium in a concentration-dependent manner. Gonadal cells were sensitive to cadmium administration. Supportive cells such as Sertoli cells in seminiferous tubules did not exhibit sensitivity to cadmium. PMID:25717432

  3. Cross-linking of cellular proteins by tissue transglutaminase during necrotic cell death: a mechanism for maintaining tissue integrity.

    PubMed

    Nicholas, Ben; Smethurst, Peter; Verderio, Elisabetta; Jones, Richard; Griffin, Martin

    2003-04-15

    Tissue transglutaminase (tTG) is a Ca(2+)-dependent enzyme which cross-links proteins via epsilon(gamma-glutamyl)lysine bridges. There is increasing evidence that tTG is involved in wound repair and tissue stabilization, as well as in physiological mechanisms leading to cell death. To investigate the role of this enzyme in tissue wounding leading to loss of Ca(2+) homoeostasis, we initially used a model involving electroporation to reproduce cell wounding under controlled conditions. Two cell models were used whereby tTG expression is regulated either by antisense silencing in ECV 304 cells or by using transfected Swiss 3T3 cells in which tTG expression is under the control of the tet regulatory system. Using these cells, loss of Ca(2+) homoeostasis following electroporation led to a tTG-dependent formation of highly cross-linked proteinaceous shells from intracellular proteins. Formation of these structures is dependent on elevated intracellular Ca(2+), but it is independent of intracellular proteases and is near maximal after only 20 min post-wounding. Using labelled primary amines as an indicator of tTG activity within these 'wounded cells', we demonstrate that tTG modifies a wide range of proteins that are present in both the perinuclear and intranuclear spaces. The demonstration of entrapped DNA within these shell structures, which showed limited fragmentation, provides evidence that the high degree of transglutaminase cross-linking results in the prevention of DNA release, which may serve to dampen any subsequent inflammatory response. Comparable observations were shown when monolayers of cells were mechanically wounded by scratching. In this second model of cell wounding, redistribution of tTG activity to the extracellular matrix was also demonstrated, an effect which may serve to stabilize tissues post-trauma, and thus contribute to the maintenance of tissue integrity. PMID:12533191

  4. Cross-linking of cellular proteins by tissue transglutaminase during necrotic cell death: a mechanism for maintaining tissue integrity.

    PubMed

    Nicholas, Ben; Smethurst, Peter; Verderio, Elisabetta; Jones, Richard; Griffin, Martin

    2003-04-15

    Tissue transglutaminase (tTG) is a Ca(2+)-dependent enzyme which cross-links proteins via epsilon(gamma-glutamyl)lysine bridges. There is increasing evidence that tTG is involved in wound repair and tissue stabilization, as well as in physiological mechanisms leading to cell death. To investigate the role of this enzyme in tissue wounding leading to loss of Ca(2+) homoeostasis, we initially used a model involving electroporation to reproduce cell wounding under controlled conditions. Two cell models were used whereby tTG expression is regulated either by antisense silencing in ECV 304 cells or by using transfected Swiss 3T3 cells in which tTG expression is under the control of the tet regulatory system. Using these cells, loss of Ca(2+) homoeostasis following electroporation led to a tTG-dependent formation of highly cross-linked proteinaceous shells from intracellular proteins. Formation of these structures is dependent on elevated intracellular Ca(2+), but it is independent of intracellular proteases and is near maximal after only 20 min post-wounding. Using labelled primary amines as an indicator of tTG activity within these 'wounded cells', we demonstrate that tTG modifies a wide range of proteins that are present in both the perinuclear and intranuclear spaces. The demonstration of entrapped DNA within these shell structures, which showed limited fragmentation, provides evidence that the high degree of transglutaminase cross-linking results in the prevention of DNA release, which may serve to dampen any subsequent inflammatory response. Comparable observations were shown when monolayers of cells were mechanically wounded by scratching. In this second model of cell wounding, redistribution of tTG activity to the extracellular matrix was also demonstrated, an effect which may serve to stabilize tissues post-trauma, and thus contribute to the maintenance of tissue integrity.

  5. PCR-cloning of cadmium-inducible peptides in the barnacle, Megabalanus volcano.

    PubMed

    Togi, Akiko; Kamino, Kei; Shizuri, Yoshikazu

    2002-04-01

    A 340 bp DNA fragment was amplified from barnacle (Megabalanus volcano) cDNA by polymerase chain reaction using primers designed based on the amino acid sequences of barnacle cadmium-inducible peptides CdlP1 and CdlP2. The whole sequence was determined by rapid amplification of cDNA ends method. The cDNA contained an open reading frame encoding 71 amino acid residues and the sequences for CdlP1 and CdlP2 were found to be located in the center of this coding region. Although CdlP1 and CdlP2 had been detected only in the cadmium-exposed barnacles, their mRNA was present both in cadmium-exposed barnacles and in unexposed barnacles. These results suggest that posttranslational proteolytic processing may be induced in the presence of cadmium.

  6. Aqueous extract of Monodora myristica ameliorates cadmium-induced hepatotoxicity in male rats.

    PubMed

    Oyinloye, Babatunji Emmanuel; Adenowo, Abiola Fatimah; Osunsanmi, Foluso Oluwagbemiga; Ogunyinka, Bolajoko Idiat; Nwozo, Sarah Onyenibe; Kappo, Abidemi Paul

    2016-01-01

    In recent years, indigenous medicinal plants exhibiting diverse biological activities have been explored in the amelioration of hepatotoxicity. This study investigates the protective effect of Monodora myristica (MM) on cadmium-induced liver damage in experimental animals. Male Wistar albino rats were maintained on 200 mg/L cadmium: Cd (Cd as CdCl2) in the animals' main drinking water to induce hepatotoxicity. Added to this, the animals received aqueous extracts of MM at a dose of 200 or 400 and 20 mg/kg bw of Livolin forte (LF) for 21 days. At the end of the experiment, levels of serum enzyme biomarkers (alanine transaminase, alkaline phosphatase and aspartate transaminase) as well as total cholesterol (TC), triacylglyceride (TG) and malondialdehyde were significantly raised in the cadmium treated groups. Conversely, cadmium treatment elicited noticeable decrease in hepatic enzymatic and non-enzymatic antioxidants (reduced glutathione: GSH, catalase: CAT, superoxide dismutase: SOD). Co-treatment with MM at varying doses as well as LF considerably decreased the elevated levels of the serum biomarkers as well as TC, TG and malondialdehyde in the cadmium-treated groups in a dose dependant manner. Additionally, MM exhibited reversal potential on cadmium-toxicity at the tested doses as its administration was accompanied by a pronounced increase in GSH, SOD, and CAT levels. Histopathological results were parallel to these findings. These results demonstrates that aqueous extracts of MM is effective in the amelioration of hepatic damages arising from cadmium-induced toxicity, indicating that the antioxidant bio-constituents of MM play an important role in the prevention of liver toxicity possibly by inhibiting bioaccumulation of free radicals in animal models. PMID:27330907

  7. Management of necrotizing pancreatitis

    PubMed Central

    Slavin, John; Ghaneh, Paula; Sutton, Robert; Hartley, Mark; Rowlands, Peter; Garvey, Conall; Hughes, Mark; Neoptolemos, John

    2001-01-01

    Infection complicating pancreatic necrosis leads to persisting sepsis, multiple organ dysfunction syndrome and accounts for about half the deaths that occur following acute pancreatitis. Severe cases due to gallstones require urgent endoscopic sphincterotomy. Patients with pancreatic necrosis should be followed with serial contrast enhanced computed tomography (CE-CT) and if infection is suspected fine needle aspiration of the necrotic area for bacteriology (FNAB) should be undertaken. Treatment of sterile necrosis should initially be non-operative. In the presence of infection necrosectomy is indicated. Although traditionally this has been by open surgery, minimally invasive procedures are a promising new alternative. There are many unresolved issues in the management of pancreatic necrosis. These include, the use of antibiotic prophylaxis, the precise indications for and frequency of repeat CE-CT and FNAB, and the role of enteral feeding. PMID:11819813

  8. Identifying statin-associated autoimmune necrotizing myopathy.

    PubMed

    Albayda, Jemima; Christopher-Stine, Lisa

    2014-12-01

    Statins up-regulate expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the major target of autoantibodies in statin-associated immune-mediated necrotizing myopathy. As muscle cells regenerate, they express high levels of HMGCR, which may sustain the immune response even after statin therapy is stopped. Awareness of this entity will help physicians who prescribe statins to take action to limit the associated morbidity.

  9. Necrotizing sialometaplasia (adenometaplasia) of the trachea.

    PubMed

    Romagosa, V; Bella, M R; Truchero, C; Moya, J

    1992-09-01

    Necrotizing sialometaplasia is a benign condition first described in minor salivary glands of the soft palate with morphological changes which can be misinterpreted as squamous-cell carcinoma. Similar lesions have been subsequently reported in other locations including major salivary glands, lip, breast and skin (the term syringometaplasia has been applied for the latter). We report three cases of such a process involving submucosal glands in the trachea following prolonged translaryngeal intubation.

  10. Necrotizing sialometaplasia. A condition simulating malignancy.

    PubMed

    Raugi, G J; Kessler, S

    1979-03-01

    Necrotizing sialometaplasia occurred in a 55-year-old woman. The ulcerated lesion on the hard palate was treated conservatively and resolved spontaneously in about three months. The histology of the lesion consisted of coagulative necrosis of the salivary gland lobules and prominent squamous metaplasia within adjacent viable lobules. Since this benign lesion has frequently been mistaken for mucoepidermoid carcinoma or squamous cell carcinoma, recognition of it may spare the patient a radical surgical procedure.

  11. [Necrotizing sialometaplasia. Report of a case].

    PubMed

    Rapisarda, F; Ficarra, G

    1999-06-01

    Necrotizing sialometaplasia is a benign lesion of the minor and major salivary glands. It occurs with a palatal swelling which rapidly becomes a deep ulcer. Histopathological aspects include ulceration of the surface epithelium, squamous metaplasia and acinar necrosis. In general no treatment is necessary and the lesion heals spontaneously in 4-10 weeks. This condition must be distinguished from more serious diseases such as squamous cell carcinoma and mucoepidermoid carcinoma.

  12. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

    PubMed Central

    Chen, Xin; Li, Wenjuan; Ren, Junming; Huang, Deli; He, Wan-ting; Song, Yunlong; Yang, Chao; Li, Wanyun; Zheng, Xinru; Chen, Pengda; Han, Jiahuai

    2014-01-01

    Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain (HBD*) triggers necroptosis. Notably, forcing together the N-terminal domain (ND) but not the C-terminal kinase domain of MLKL causes necroptosis. Further deletion analysis showed that the four-α-helix bundle of MLKL (1-130 amino acids) is sufficient to trigger necroptosis. Both the HBD*-mediated and TNF-induced complexes of MLKL(ND) or MLKL are tetramers, and translocation of these complexes to lipid rafts of the plasma membrane precedes cell death. The homo-oligomerization is required for MLKL translocation and the signal sequence for plasma membrane location is located in the junction of the first and second α-helices of MLKL. The plasma membrane translocation of MLKL or MLKL(ND) leads to sodium influx, and depletion of sodium from the cell culture medium inhibits necroptosis. All of the above phenomena were not seen in apoptosis. Thus, the MLKL oligomerization leads to translocation of MLKL to lipid rafts of plasma membrane, and the plasma membrane MLKL complex acts either by itself or via other proteins to increase the sodium influx, which increases osmotic pressure, eventually leading to membrane rupture. PMID:24366341

  13. Necrotizing sialometaplasia: a diagnostic dilemma.

    PubMed

    Madala, Jayakiran; Guttikonda, Venkateswara Rao; Korlepara, Rajani; Yeluri, Sivaranjani

    2014-09-01

    Necrotizing sialometaplasia is a benign self-limiting lesion of both major and minor salivary glands although more commonly the latter. The clinical and histological similarity between this entity and a malignant lesion implies a risk of unnecessary radical treatment. We report a case of necrotizing sialometaplasia in middle aged women presenting as a non-ulcerated swelling. This case illustrates the need for careful analysis of a biopsy specimen for a correct diagnosis.

  14. Protective effect of an aphrodisiac herb Tribulus terrestris Linn on cadmium-induced testicular damage

    PubMed Central

    Rajendar, B.; Bharavi, K.; Rao, G. S.; Kishore, P.V.S; Kumar, P. Ravi; Kumar, C.S.V Satish; Patel, T. Pankaj

    2011-01-01

    Aim: The aim of the present study was to investigate whether Tribulus terrestris Linn (TT) could protect the cadmium (Cd)-induced testicular tissue peroxidation in rats and to explore the underlying mechanism of the same. Materials and Methods: In vitro and in vivo studies were conducted to know the protective effect of ethanolic extract of TT (eTT) in Cd toxicity. In in vitro studies, total antioxidant and ferrous metal ion chelating activity of TT was studied. In vivo studies were conducted in rats. A total of 40 Wistar strain adult male rats were divided into four groups. Group 1 served as control, while group 2 to 4 received CdCl2 (3 mg/kg b. wt. s/c once a week). In addition to Cd, group 3 and 4 rats also received eTT (5 mg/kg b.wt. daily as oral gavage) and α-tocopherol (75 mg/kg daily by oral gavage), respectively. At the end of 6th week, all the rats were sacrificed and the separated testes were weighted and processed for estimation of tissue peroxidation markers, antioxidant markers, functional markers, and Cd concentration. The testes were also subjected to histopathological screening. Results: In in vitro studies, the percentage of metal ion chelating activity of 50 μg/ml of eTT and α-tocopherol were 2.76 and 9.39, respectively, and the antioxidant capacity of eTT was equivalent to 0.063 μg of α-tocopherol/μg of eTT. In in vivo studies, administration of Cd significantly reduced the absolute and relative testicular weight, antioxidant markers such as superoxide dismutase and glutathione, and functional markers such as LDH and ALP, along with significant increase in peroxidation markers such as malondialdehyde and protein carbonyls in testicular tissue. Testes of Cd only-treated group showed histological insults like necrotic changes in seminiferous tubules and interstitium, shrunken tubules with desquamated basal lamina, vacuolization and destruction of sertoli cells, and degenerating Leydig cells. This group also had higher Cd levels in testicular

  15. Characterizing multiple metal ion binding sites within a ribozyme by cadmium-induced EPR silencing

    PubMed Central

    Kisseleva, Natalia; Kraut, Stefanie; Jäschke, Andres; Schiemann, Olav

    2007-01-01

    In ribozyme catalysis, metal ions are generally known to make structural and∕or mechanistic contributions. The catalytic activity of a previously described Diels-Alderase ribozyme was found to depend on the concentration of divalent metal ions, and crystallographic data revealed multiple binding sites. Here, we elucidate the interactions of this ribozyme with divalent metal ions in solution using electron paramagnetic resonance (EPR) spectroscopy. Manganese ion titrations revealed five high-affinity Mn2+ binding sites with an upper Kd of 0.6±0.2 μM. In order to characterize each binding site individually, EPR-silent Cd2+ ions were used to saturate the other binding sites. This cadmium-induced EPR silencing showed that the Mn2+ binding sites possess different affinities. In addition, these binding sites could be assigned to three different types, including innersphere, outersphere, and a Mn2+ dimer. Based on simulations, the Mn2+-Mn2+ distance within the dimer was found to be ∼6 Å, which is in good agreement with crystallographic data. The EPR-spectroscopic characterization reveals no structural changes upon addition of a Diels-Alder product, supporting the concept of a preorganized catalytic pocket in the Diels-Alder ribozyme and the structural role of these ions. PMID:19404418

  16. Ethylene signalling is mediating the early cadmium-induced oxidative challenge in Arabidopsis thaliana.

    PubMed

    Schellingen, Kerim; Van Der Straeten, Dominique; Remans, Tony; Vangronsveld, Jaco; Keunen, Els; Cuypers, Ann

    2015-10-01

    Cadmium (Cd) induces the generation of reactive oxygen species (ROS) and stimulates ethylene biosynthesis. The phytohormone ethylene is a regulator of many developmental and physiological plant processes as well as stress responses. Previous research indicated various links between ethylene signalling and oxidative stress. Our results support a correlation between the Cd-induced oxidative challenge and ethylene signalling in Arabidopsis thaliana leaves. The effects of 24 or 72 h exposure to 5 μM Cd on plant growth and several oxidative stress-related parameters were compared between wild-type (WT) and ethylene insensitive mutants (etr1-1, ein2-1, ein3-1). Cadmium-induced responses observed in WT plants were mainly affected in etr1-1 and ein2-1 mutants, of which the growth was less inhibited by Cd exposure as compared to WT and ein3-1 mutants. Both etr1-1 and ein2-1 showed a delayed response in the glutathione (GSH) metabolism, including GSH levels and transcript levels of GSH synthesising and recycling enzymes. Furthermore, the expression of different oxidative stress marker genes was significantly lower in Cd-exposed ein2-1 mutants, evidencing that ethylene signalling is involved in early responses to Cd stress. A model for the cross-talk between ethylene signalling and oxidative stress is proposed. PMID:26398798

  17. Influence of arbuscular mycorrhizal colonisation on cadmium induced Medicago truncatula root isoflavonoid accumulation.

    PubMed

    Aloui, Achref; Dumas-Gaudot, Eliane; Daher, Zeina; van Tuinen, Diederik; Aschi-Smit, Samira; Morandi, Dominique

    2012-11-01

    Cadmium is a serious environmental pollution threats to the planet. Its accumulation in plants affects many cellular functions, resulting in growth and development inhibition, whose mechanisms are not fully understood. However, some fungi forming arbuscular mycorrhizal symbiosis with the majority of plant species have the capacity to buffer the deleterious effect of this heavy metal. In the present work we investigated the capacity of Rhizophagus irregularis (syn. Glomus irregularis) to alleviate cadmium stress in Medicago truncatula. In spite of a reduction in all mycorrhizal parameters, plants colonized for 21 days by R. irregularis and treated by 2 mg kg⁻¹ cadmium displayed less growth inhibition in comparison to plants grown without cadmium. Cadmium strongly increased the accumulation of some isoflavonoids and their derivates: formononetin, malonylononin, medicarpin 3-O-β-(6'-malonylglucoside), medicarpin and coumestrol. Interestingly, in plants colonized by R. irregularis we noticed a strong reduction of the cadmium-induced accumulation of root isoflavonoids, a part for medicarpin and coumestrol. Moreover, transcripts of chalcone reductase, a protein that we reported previously as being down-regulated in R. irregularis-colonized M. truncatula roots, revealed a similar expression pattern with a strong increase in response to cadmium and a reduced expression in cadmium-treated mycorrhizal roots.

  18. γ-Oryzanol protects against acute cadmium-induced oxidative damage in mice testes.

    PubMed

    Spiazzi, Cristiano C; Manfredini, Vanusa; Barcellos da Silva, Fabiana E; Flores, Erico M M; Izaguirry, Aryele P; Vargas, Laura M; Soares, Melina B; Santos, Francielli W

    2013-05-01

    Cadmium is a non-essential heavy metal that is present at low levels mainly in food and water and also in cigar smoke. The present study evaluated the testicular damage caused by acute cadmium exposure and verified the protective role of γ-oryzanol (ORY). Mice were administrated with a single dose of 2.5mg/kg of CdCl2, and then treated with ORY (50mM in canola oil, 5mL/kg). Testes were removed after 24h and tested for lipid peroxidation (TBARS), protein carbonylation, DNA breakage, ascorbic acid, cadmium and non-proteic thiols contents, and for the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and δ-aminolevulic acid dehydratase (δ-ALA-D). Cadmium presented a significant alteration in all parameters, except GPx and CAT activities. Therapy reduced in a slight degree cadmium concentration in testes (around 23%). ORY restored SOD and GST activities as well as TBARS production to the control levels. Furthermore, ORY partially recovered δ-ALA-D activity inhibited by cadmium. This study provides the first evidence on the therapeutic properties of ORY in protecting against cadmium-induced testicular toxicity. PMID:23395783

  19. Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats.

    PubMed

    Fouad, Amr A; Jresat, Iyad

    2013-04-01

    The possible protective effect of captopril, an angiotensin-converting enzyme inhibitor, vs. telmisartan, an angiotensin II-receptor antagonist, was investigated in rats with testicular injury induced by a single i.p. injection of cadmium chloride (2 mg/kg). Captopril (60 mg/kg/day, p.o.) and telmisartan (10 mg/kg/day, p.o.) were given for five consecutive days, starting 3 days before cadmium administration. Both agents significantly increased serum testosterone level, which was reduced by cadmium, suppressed lipid peroxidation, restored the depleted reduced glutathione, decreased the elevations of nitric oxide, tumor necrosis factor-α, and cadmium ion levels, and attenuated the reductions of selenium and zinc ions in testicular tissue resulted from cadmium administration. Immunohistochemical analysis revealed that both captopril and telmisartan significantly reduced the cadmium-induced expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand, and caspase-3 in testicular tissue. The differences between the results obtained with captopril and telmisartan were insignificant, suggesting that both drugs equally protected the testicular tissue from the detrimental effects of cadmium. PMID:21819444

  20. Hydrogen sulfide modulates cadmium-induced physiological and biochemical responses to alleviate cadmium toxicity in rice.

    PubMed

    Mostofa, Mohammad Golam; Rahman, Anisur; Ansary, Md Mesbah Uddin; Watanabe, Ayaka; Fujita, Masayuki; Tran, Lam-Son Phan

    2015-09-11

    We investigated the physiological and biochemical mechanisms by which H2S mitigates the cadmium stress in rice. Results revealed that cadmium exposure resulted in growth inhibition and biomass reduction, which is correlated with the increased uptake of cadmium and depletion of the photosynthetic pigments, leaf water contents, essential minerals, water-soluble proteins, and enzymatic and non-enzymatic antioxidants. Excessive cadmium also potentiated its toxicity by inducing oxidative stress, as evidenced by increased levels of superoxide, hydrogen peroxide, methylglyoxal and malondialdehyde. However, elevating endogenous H2S level improved physiological and biochemical attributes, which was clearly observed in the growth and phenotypes of H2S-treated rice plants under cadmium stress. H2S reduced cadmium-induced oxidative stress, particularly by enhancing redox status and the activities of reactive oxygen species and methylglyoxal detoxifying enzymes. Notably, H2S maintained cadmium and mineral homeostases in roots and leaves of cadmium-stressed plants. By contrast, adding H2S-scavenger hypotaurine abolished the beneficial effect of H2S, further strengthening the clear role of H2S in alleviating cadmium toxicity in rice. Collectively, our findings provide an insight into H2S-induced protective mechanisms of rice exposed to cadmium stress, thus proposing H2S as a potential candidate for managing toxicity of cadmium, and perhaps other heavy metals, in rice and other crops.

  1. Hydrogen sulfide modulates cadmium-induced physiological and biochemical responses to alleviate cadmium toxicity in rice

    PubMed Central

    Mostofa, Mohammad Golam; Rahman, Anisur; Ansary, Md. Mesbah Uddin; Watanabe, Ayaka; Fujita, Masayuki; Phan Tran, Lam-Son

    2015-01-01

    We investigated the physiological and biochemical mechanisms by which H2S mitigates the cadmium stress in rice. Results revealed that cadmium exposure resulted in growth inhibition and biomass reduction, which is correlated with the increased uptake of cadmium and depletion of the photosynthetic pigments, leaf water contents, essential minerals, water-soluble proteins, and enzymatic and non-enzymatic antioxidants. Excessive cadmium also potentiated its toxicity by inducing oxidative stress, as evidenced by increased levels of superoxide, hydrogen peroxide, methylglyoxal and malondialdehyde. However, elevating endogenous H2S level improved physiological and biochemical attributes, which was clearly observed in the growth and phenotypes of H2S-treated rice plants under cadmium stress. H2S reduced cadmium-induced oxidative stress, particularly by enhancing redox status and the activities of reactive oxygen species and methylglyoxal detoxifying enzymes. Notably, H2S maintained cadmium and mineral homeostases in roots and leaves of cadmium-stressed plants. By contrast, adding H2S-scavenger hypotaurine abolished the beneficial effect of H2S, further strengthening the clear role of H2S in alleviating cadmium toxicity in rice. Collectively, our findings provide an insight into H2S-induced protective mechanisms of rice exposed to cadmium stress, thus proposing H2S as a potential candidate for managing toxicity of cadmium, and perhaps other heavy metals, in rice and other crops. PMID:26361343

  2. Ethylene signalling is mediating the early cadmium-induced oxidative challenge in Arabidopsis thaliana.

    PubMed

    Schellingen, Kerim; Van Der Straeten, Dominique; Remans, Tony; Vangronsveld, Jaco; Keunen, Els; Cuypers, Ann

    2015-10-01

    Cadmium (Cd) induces the generation of reactive oxygen species (ROS) and stimulates ethylene biosynthesis. The phytohormone ethylene is a regulator of many developmental and physiological plant processes as well as stress responses. Previous research indicated various links between ethylene signalling and oxidative stress. Our results support a correlation between the Cd-induced oxidative challenge and ethylene signalling in Arabidopsis thaliana leaves. The effects of 24 or 72 h exposure to 5 μM Cd on plant growth and several oxidative stress-related parameters were compared between wild-type (WT) and ethylene insensitive mutants (etr1-1, ein2-1, ein3-1). Cadmium-induced responses observed in WT plants were mainly affected in etr1-1 and ein2-1 mutants, of which the growth was less inhibited by Cd exposure as compared to WT and ein3-1 mutants. Both etr1-1 and ein2-1 showed a delayed response in the glutathione (GSH) metabolism, including GSH levels and transcript levels of GSH synthesising and recycling enzymes. Furthermore, the expression of different oxidative stress marker genes was significantly lower in Cd-exposed ein2-1 mutants, evidencing that ethylene signalling is involved in early responses to Cd stress. A model for the cross-talk between ethylene signalling and oxidative stress is proposed.

  3. Application of path analysis to urinary findings of cadmium-induced renal dysfunction.

    PubMed

    Abe, T; Kobayashi, E; Okubo, Y; Suwazono, Y; Kido, T; Shaikh, Z A; Nogawa, K

    2001-01-01

    In order to identify some causal relations among various urinary indices of cadmium-induced renal dysfunction, such as glucose, total protein, amino nitrogen, beta 2-microglobulin (beta 2-m), metallothionein (MT), and cadmium (Cd), we applied path analysis method to previous epidemiological studies targeting the residents of the Cd-polluted Kakehashi River basin of Ishikawa Prefecture, Japan. We obtained a diagram-termed path model, representing some causal relations among the above urinary indices. It shows that urinary Cd is located at the beginning point in the diagram, and Cd-induced renal dysfunction develops in the following order: Cd exposure-->increase of beta 2-m and/or MT excretion-->increase of amino-N and/or total protein excretion-->increase of glucose excretion. It was proved mathematically, that in the case of both males and females, increased excretions of beta 2-m and/or MT were the most sensitive urinary indices of the early stage of chronic Cd-induced renal dysfunction.

  4. Insights into cadmium induced physiological and ultra-structural disorders in Juncus effusus L. and its remediation through exogenous citric acid.

    PubMed

    Najeeb, Ullah; Jilani, Ghulam; Ali, Shafaqat; Sarwar, Muhammad; Xu, Ling; Zhou, Weijun

    2011-02-15

    This study appraised cadmium (Cd) toxicity stress in wetland plant Juncus effusus, and explored its potential for Cd phytoextraction through chelators (citric acid and EDTA). Cadmium altered morphological and physiological attributes of J. effusus as reflected by growth retardation. Citric acid in the presence of 100 μM Cd significantly countered Cd toxicity by improving plant growth. Elevated Cd concentrations reduced translocation factor that was increased under application of both chelators. Citric acid enhanced Cd accumulation, while EDTA reduced its uptake. Cadmium induced oxidative stress modified the antioxidative enzyme activity. Both levels of citric acid (2.5 and 5.0 mM) and lower EDTA concentration (2.5 mM) helped plants to overcome oxidative stress by enhancing their antioxidative enzyme activities. Cadmium damaged the root cells through cytoplasmic shrinkage and metal deposition. Citric acid restored structure and shape of root cells and eliminated plasmolysis; whereas, EDTA exhibited no positive effect on it. Shoot cells remained unaffected under Cd treatment alone or with citric acid except for chloroplast swelling. Only EDTA promoted starch accumulation in chloroplast reflecting its negative impact on cellular structure. It concludes that Cd and EDTA induce structural and morphological damage in J. effusus; while, citric acid ameliorates Cd toxicity stress. PMID:21159423

  5. Insights into cadmium induced physiological and ultra-structural disorders in Juncus effusus L. and its remediation through exogenous citric acid.

    PubMed

    Najeeb, Ullah; Jilani, Ghulam; Ali, Shafaqat; Sarwar, Muhammad; Xu, Ling; Zhou, Weijun

    2011-02-15

    This study appraised cadmium (Cd) toxicity stress in wetland plant Juncus effusus, and explored its potential for Cd phytoextraction through chelators (citric acid and EDTA). Cadmium altered morphological and physiological attributes of J. effusus as reflected by growth retardation. Citric acid in the presence of 100 μM Cd significantly countered Cd toxicity by improving plant growth. Elevated Cd concentrations reduced translocation factor that was increased under application of both chelators. Citric acid enhanced Cd accumulation, while EDTA reduced its uptake. Cadmium induced oxidative stress modified the antioxidative enzyme activity. Both levels of citric acid (2.5 and 5.0 mM) and lower EDTA concentration (2.5 mM) helped plants to overcome oxidative stress by enhancing their antioxidative enzyme activities. Cadmium damaged the root cells through cytoplasmic shrinkage and metal deposition. Citric acid restored structure and shape of root cells and eliminated plasmolysis; whereas, EDTA exhibited no positive effect on it. Shoot cells remained unaffected under Cd treatment alone or with citric acid except for chloroplast swelling. Only EDTA promoted starch accumulation in chloroplast reflecting its negative impact on cellular structure. It concludes that Cd and EDTA induce structural and morphological damage in J. effusus; while, citric acid ameliorates Cd toxicity stress.

  6. Necrotizing sialometaplasia involving the nasal cavity.

    PubMed

    Maisel, R H; Johnston, W H; Anderson, H A; Cantrell, R W

    1977-03-01

    Necrotizing sialometaplasia is a disease process which affects minor salivary glands. It may clinically and microscopically resemble squamous cell or mucoepidermoid carcinoma but is histologically benign. Thirteen patients with this process occurring on the hard palate have been reported in the past two years. We describe two cases in the nasal cavity and propose that compromise of the blood supply contributed to the occurrence of these lesions. This apparently benign lesion may represent nonspecific reaction of salivary and mucous glands to ischemic injury and must be distinguished from carcinoma.

  7. Protective role of pectin against cadmium-induced testicular toxicity and oxidative stress in rats.

    PubMed

    Koriem, Khaled M M; Fathi, Gamal E; Salem, Huda A; Akram, Nabil H; Gamil, Sofie A

    2013-05-01

    Cadmium has been classified as an environmental pollutant and human carcinogen. Pectin is a family of complex polysaccharides that function as hydrating agents and cementing materials for the cellulosic network. The aim of this study was to evaluate the protective role of pectin against cadmium-induced testicular toxicity and oxidative stress in rats. Forty male Wistar rats were divided into five equal groups. Groups 1 and 2 were injected intraperitoneally (i.p.) saline (1 mg/kg) and pectin (50 mg/kg), respectively, two days/weeks over three weeks period. Groups 3-5 were injected i.p. with 1 mg/kg cadmium two days/week while groups 4 and 5 co-administrated i.p. with 25 and 50 mg/kg pectin, respectively, three days/week over three weeks period. The results of the present work revealed that cadmium-exposed rats showed decrease in serum testosterone, dehydroepiandrosterone sulfate and lactate dehydrogenase. Testicular cholesterol, total protein, glucose-6-phosphate dehydrogenase, 3β-hydroxysteroid dehydrogenase, superoxide dismutase, glutathione peroxidase, catalase, glutathione S-transferase and reduced glutathione levels were also decreased while testicular malondialdehyde level was increased after cadmium injection. On the other hand, serum luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin and γ-glutamyl transpeptidase were increased after cadmium exposure. Cadmium also induced sperms loss. Co-administration of pectin with cadmium restores all the above parameters and sperms to the normal levels where pectin at higher dose was more effective than lower one. These results were supported by histochemical investigations. In conclusion, pectin can counteract the testicular toxicity and oxidative stress induced by cadmium and the effect was dose-dependent. PMID:23193971

  8. Necrotizing fasciitis and myositis: a case report.

    PubMed

    Razi-Syed, S; Jafri, S Z

    1994-01-01

    Necrotizing fasciitis is a relatively rare, potentially life-threatening infection involving the subcutaneous tissues. We report a case of group A streptococcal necrotizing fasciitis/myositis in which CT played an important role in differential diagnosis.

  9. Programmed Cell Death in the Leaves of the Arabidopsis Spontaneous Necrotic Spots (sns-D) Mutant Correlates with Increased Expression of the Eukaryotic Translation Initiation Factor eIF4B2

    PubMed Central

    Gaussand, Gwénaël M. D. J.-M.; Jia, Qi; van der Graaff, Eric; Lamers, Gerda E. M.; Fransz, Paul F.; Hooykaas, Paul J. J.; de Pater, Sylvia

    2011-01-01

    From a pool of transgenic Arabidopsis (Arabidopsis thaliana) plants harboring an activator T-DNA construct, one mutant was identified that developed spontaneous necrotic spots (sns-D) on the rosette leaves under aseptic conditions. The sns-D mutation is dominant and homozygous plants are embryo lethal. The mutant produced smaller rosettes with a different number of stomata than the wild-type. DNA fragmentation in the nuclei of cells in the necrotic spots and a significant increase of caspase-3 and caspase-6 like activities in sns-D leaf extracts indicated that the sns-D mutation caused programmed cell death (PCD). The integration of the activator T-DNA caused an increase of the expression level of At1g13020, which encodes the eukaryotic translation initiation factor eIF4B2. The expression level of eIF4B2 was positively correlated with the severity of sns-D mutant phenotype. Overexpression of the eIF4B2 cDNA mimicked phenotypic traits of the sns-D mutant indicating that the sns-D mutant phenotype is indeed caused by activation tagging of eIF4B2. Thus, incorrect regulation of translation initiation may result in PCD. PMID:22639576

  10. Hypernatraemic dehydration and necrotizing enterocolitis.

    PubMed

    Clarke, A J; Sibert, J R

    1985-01-01

    Severe hypernatraemic dehydration developed over the first twelve days of life in a breastfed infant girl. Upon oral rehydration with formula milk, no acute neurological problems arose, but she subsequently developed necrotizing enterocolitis. Intravenous rehydration may be preferred to the oral route in such infants.

  11. Prevention of neonatal necrotizing enterocolitis.

    PubMed

    Carrion, V; Egan, E A

    1990-10-01

    Small premature infants are often hypochlorhydric, and frequently their stomachs are colonized by enteric, gram-negative bacteria. We tested a hypothesis that gastric pH affected the colonization of the stomach with enteric bacteria and that this colonization was causally related to the risk or severity of necrotizing enterocolitis. A prospective, double-blind study was conducted that compared a group of infants supplemented with 0.01-0.02 ml of 1 N HCl/ml of milk to a group with a similar supplement of water. Gastric pH, gastric enteric bacteria counts, and the incidence and severity of necrotizing enterocolitis were monitored. The median gastric pH of the HCl-supplemented group was lower (3.0) than controls (4.0) throughout the study (p less than 0.001). The gastric enteric bacterial colonization rate and the quantitative bacterial counts were strongly correlated with gastric pH over 4 (p less than 0.001). Somatic growth rates in infants in the HCl-supplemented group were equal to, or exceeded, those in the control group. There was 1 case of necrotizing enterocolitis among the 34 infants in the HCl-supplemented group and 8 cases among the 34 in the control group (p = 0.02). It appears that acidifying the feedings of small premature infants to a pH low enough to inhibit bacterial proliferation in the stomach significantly lowers the risk of necrotizing enterocolitis.

  12. Growth of Necrotic Cores in Vulnerable Plaque

    NASA Astrophysics Data System (ADS)

    Fok, Pak-Wing

    2011-03-01

    Plaques are fatty deposits that grow mainly in arteries and develop as a result of a chronic inflammatory response. Plaques are called vulnerable when they are prone to mechanical rupture. Vulnerable Plaques (VPs) are characterized by lipid-rich, necrotic cores that are heavily infiltrated with macrophages. The rupture of VPs releases thrombogenic agents into the bloodstream, usually resulting in myocardial infarctions. We propose a quantitative model to predict the development of a plaque's necrotic core. By solving coupled reaction-diffusion equations for macrophages and dead cells, we explore the joint effects of hypoxic cell death and chemo-attraction to Ox-LDL, a molecule that is strongly linked to atherosclerosis. Our model predicts cores that have approximately the right size and shape. Normal mode analysis and subsequent calculation of the smallest eigenvalues allow us to compute the times required for the system to reach its steady state. This study allows us to make quantitative predictions for how quickly vulnerable plaques develop and how their growth depends on system parameters such as chemotactic coefficients and cell death rates.

  13. Necrotizing sialometaplasia: review of the literature and report of nonulcerative case.

    PubMed

    Birkholz, H; Minton, G A; Yuen, Y L

    1979-08-01

    A review of the literature and a report of a case of necrotizing sialometaplasia of the hard palate is presented. Because necrotizing sialometaplasia may be misdiagnosed as squamous cell carcinoma or mucoepidermoid carcinoma, it is important that the clinician and pathologist take the necessary precautions to prevent any further mutilative surgery for this benign disease entity.

  14. Necrotizing sialometaplasia: literature review and presentation of five cases.

    PubMed

    Grillon, G L; Lally, E T

    1981-10-01

    Necrotizing sialometaplasia is a benign, ulcerative, inflammatory process of the minor salivary glands, primarily found in the hard palate. It is often mistaken clinically and histologically for a malignant tumor (that is, mucoepidermoid or squamous cell carcinoma). The lesion heals spontaneously in six to 12 weeks. It occurs primarily in persons between the ages of 40 and 60 and has been reported more frequently in men than women. In necrotizing sialometaplasia the squamous metaplasia and tissue necrosis is confined to the existing ductal and lobular pattern of the salivary glands, a unique characteristic that aids in diagnosis. Five additional cases are presented.

  15. Necrotizing sialometaplasia masquerading as residual cancer of the lip.

    PubMed

    Granick, M S; Solomon, M P; Benedetto, A V; Hannegan, M W; Sohn, M

    1988-08-01

    Necrotizing sialometaplasia is a benign disorder that histologically can mimic carcinoma. It is thought to develop as a result of ischemia or adjacent tissue injury. A patient is described who underwent a Mohs' micrographical fresh-tissue excision of one-third of the upper lip for basal cell carcinoma. By the time she was ready for reconstruction, a marked eczematous reaction developed to a polymyxin neomycin preparation (Neosporin ointment) at the wound edges. Reexcision of the wound margins before a flap reconstruction revealed necrotizing sialometaplasia on histopathological examination. This incidental finding fortunately was not mistaken for residual tumor. To prevent over-diagnosis and over-treatment of presumed malignancies, an awareness of necrotizing sialometaplasia is essential for all surgeons operating on mucosal surfaces in the head and neck.

  16. [Infectious complications in necrotizing pancreatitis].

    PubMed

    Werner, J; Büchler, M W

    2007-10-01

    Patients with CT evidence of more than 50 % necrosis, or an increased CRP or procalcitonin are at risk of developing severe pancreatitis and septic complications and should be monitored in an intensive care unit. ERCP and sphincterotomy are indicated in patients with biliary pancreatitis and impacted gall stones, biliary sepsis, or obstructive jaundice. In septic patients with necrotizing pancreatitis, a FNA should be performed for differentiation of sterile and infected pancreatic necrosis. Adequate volume resuscitation and analgesic treatment are the most important treatment of acute pancreatitis. Antibiotic prophylaxis reduces septic complications in severe necrotizing pancreatitis and should be started early. Surgical therapy is indicated in patients with infected pancreatic necrosis. The surgical technique of choice is open necrosectomy with postoperative closed lavage of the lesser sac.

  17. Necrotizing sialometaplasia of the nasopharynx.

    PubMed

    Merwin, G E; Duckert, L G; Pollak, K

    1979-01-01

    Necrotizing sialometaplasia is an uncommon salivary gland disease originally described by Abrams et al in 1973. The disease may occur wherever salivary gland tissue is found. Theories on the etiology of this disorder have been advanced, but never definitely determined. Treatment consists of adequate biopsy and observation until healing occurs at six to eight weeks. While the disease is considered benign, its similarity to more aggressive neoplasms can be both disturbing and misleading to the patient and the clinician. Such a case of necrotizing sialometaplasia of the nasopharynx is presented to demonstrate the clinical and histological similarity of this disease to carcinoma. In this case, the patient first presented with a neck mass which could easily have been mistaken for a regional metastasis. The current literature is reviewed.

  18. Protective effects of ginger toward cadmium-induced testes and kidney lipid peroxidation and hematological impairment in albino rats.

    PubMed

    Onwuka, Frank C; Erhabor, Osaro; Eteng, M U; Umoh, I B

    2011-01-01

    This study was carried out to investigate the effect of oral dietary supplementation with ginger on cadmium-induced toxic effects on biochemical, hematological, and pathophysiological indices of albino rats. The effect of cadmium and cadmium/ginger treatment on lipid peroxidation was measured by malondialdehyde (MDA) levels in testes and kidney; serum activities of alkaline phosphatase (ALP), acid phosphatase (ACP), and prostatic acid phosphatase (PAP) enzyme were investigated alongside hematological indices. The results showed that cadmium induces a significant increase in both testicular and kidney MDA, whereas cadmium/ginger treatment produced a significant reversal of the effect of lipid peroxidation (P=.004). Cadmium treatment induced 75%, 78%, and 22% increases in activities of ACP, PAP, and ALP, respectively, whereas the cadmium/ginger-treated group reversed these values for enzyme activities (P=.001). Results of organ weight and hematological indices analysis in the cadmium-treated rats showed a decrease in organ weight and distortion of the hemopoietic features, whereas the cadmium/ginger-treated rats showed an improvement in organ weight and hematological indices (P=.04 and .001, respectively). The reversal of the toxic effects of cadmium in the cadmium/ginger-treated albino rats heralds the antioxidant potency of ginger toward cadmium toxicity-associated oxidative stress. PMID:21476888

  19. Necrotizing fasciitis in Crohn's disease.

    PubMed

    Panter, S J; Bramble, M G; Bell, J R

    2001-04-01

    We report a case of a 34-year-old woman, presenting initially with anaemia followed by sacro-iliac pain, and subsequently found to have necrotizing fasciitis complicating Crohn's disease where the organisms were introduced via a fistulous tract. It is perhaps surprising that this is not a more common complication of fistulating Crohn's disease, but we believe this is the first case report of this particular complication. PMID:11338075

  20. Dysregulation of nectin-2 in the testicular cells: an explanation of cadmium-induced male infertility.

    PubMed

    Zhang, Xu; Lui, Wing-Yee

    2014-09-01

    Nectin-2, a junction molecule, is found at the basal and apical ectoplasmic specializations (ES) for the formation of the blood-testis barrier (BTB) (constituted by tight junctions and basal ES) and Sertoli-spermatid adhesion. Loss of nectin-2 causes male infertility, suggesting nectin-2-based ES is crucial for spermatogenesis. Cadmium (Cd) has been known to induce severe testicular injury. Recent evidence has shown that the basal ES at the BTB and apical ES are the targets of Cd, suggesting that unique junction protein at the ES may explain why testis is more susceptible than other tissues. Since nectin-2 is expressed exclusively at the ES, it is highly possible that nectin-2 is the direct target of Cd. In this study, we investigate if nectin-2 is the target protein of Cd toxicity and the mechanism on how Cd down-regulates nectin-2 to achieve ES disruption. Our results revealed that Cd suppresses nectin-2 at transcriptional and post-translational levels. Inhibitor and shRNA knockdown have shown that Cd induces nectin-2 protein degradation via clathrin-dependent endocytosis. Immunofluorescence staining and endocytosis assays further confirmed that nectin-2 internalization is promoted upon Cd treatment. Besides, Cd directly represses nectin-2 transcription. EMSA and ChIP assays showed that Cd inhibits the binding of positive regulators to nectin-2 promoter. siRNA and overexpression analyses have demonstrated that Cd reduces the expression and binding affinity of positive regulators for transcription. Taken together, nectin-2 is the direct molecular target of Cd and its disruptive effects are mediated via direct repressing nectin-2 transcription and endocytosis of nectin-2 for degradation. PMID:25046863

  1. Necrotizing sialometaplasia: frequency of histologic misdiagnosis.

    PubMed

    Mesa, M L; Gertler, R S; Schneider, L C

    1984-01-01

    Necrotizing sialometaplasia is said to mimic carcinoma, both clinically and histologically. A review of approximately 10,000 oral biopsy specimens revealed only three cases of necrotizing sialometaplasia, all of which had been misdiagnosed as other benign entities. While this suggests that necrotizing sialometaplasia represents only 0.03 percent of biopsied oral lesions, it does not deal with the frequency of cases of this condition which heal spontaneously without being biopsied.

  2. Necrotizing sialometaplasia of the nasal cavity.

    PubMed

    Chen, K T

    1982-01-01

    A case of necrotizing sialometaplasia involving the mucous membrane of a nasal turbinate is described. Necrotizing sialometaplasia is a benign, self-limited process characterized by necrosis and squamous metaplasia of the salivary or mucous glands. Typically, the lesion manifests as an ulcer of the hard palate. Nonulcerated lesions and involvement of sites other than the hard palate have also been reported. This case appears to be the second reported case of involvement of the nasal cavity by necrotizing sialometaplasia.

  3. Antioxidants, cadmium-induced toxicity, serum biochemical and the histological abnormalities of the kidney and testes of the male Wistar rats.

    PubMed

    Obianime, A W; Roberts, I I

    2009-12-01

    The effect of different doses of cadmium [CD] on some biochemical, hormonal and histopathological parameters of the liver, kidney and testes of the Wistar rate were investigated. Cadmium in the dose range 0-40 mg/kg while causing a time-and dose-dependent decrease of the basal serum levels of alkaline phosphatase [ALP] also caused a dose-dependent increase in the serum concentration of the acid and prostatic acid phosphatases. The value of the ALP changed from 148.7+/-1.0 IU/L in the control to 53.7+/-0.098 at 40 mg/kg of cadmium. While the ACP and ACPT changed from 32.6+/-0.72 and 7 Units in the control to 54 and 17 units respectively at 40 mg/kg of CD. Furthermore cadmium also caused positively correlated dose-and time-dependent destruction of the histology of the liver, kidney and testes. These were characterized by vascular congestion, vacuolation, destruction of the seminal epithelial layers, focal necrosis of nucleus, oedema of the seminal epithelia layers, focal necrosis of nucleus, oedema of the seminiferous tubules and reduction of spermatogenesis. CD also caused granular and eosinophilic cytoplasm, enlargement of sinusoids with kupffer cells, haemorrhage and apoptosis of cells. Finally pre-treatment with vitamin C [0.0015/kg], vitamin E [1.51/g] and selenium [0.25 mg] which on their own had little or no effects on the serum basal phosphatases, hormonal and histological stability caused a reversal of the cadmium-induced biochemical, hormonal and histological toxicities of the liver, kidney and testes. These results may be explained by the oxidational/antioxidational properties of these xenobiotics and their mechanisms of actions.

  4. Disseminated histoplasmosis and necrotizing vasculitis.

    PubMed Central

    Small, P.; Levitt, P.

    1976-01-01

    A 74-year-old man with congestive heart failure was found to have Histoplasma capsulatum in a lesion of the right nasal septum. His initial treatment with amphotericin B was inadequate because of severe intolerance to the drug. Three months after initial presentation H. capsulatum was detected in his blood and bone marrow. Slightly elevated purpuric lesions on the arms, lower legs and trunk showed the typical features of necrotizing vasculitis. Cutaneous anergy was reversed after treatment with transfer factor. Skin involvement in disseminated histoplasmosis is unusual and there are no previous reports of vasculitis associated with this infection. Images FIG. 1 FIG. 2 PMID:1253047

  5. Cutaneous necrotizing vasculitis. Relation to systemic disease.

    PubMed

    Lotti, T M; Comacchi, C; Ghersetich, I

    1999-01-01

    Cutaneous necrotizing vasculitis (CNV) is a complex multisystem disease generally involving the skin and mucous membranes, often accompanied by renal, gastrointestinal, pericardial, neurological, and articular signs and symptoms. CNV may be idiopatical or occur in association with a drug, infection, or underlying disease. CNV has been shown in patients with chronic infections (viral, bacterial, protozoa, helminthic), serum sickness, a variety of collagen vascular diseases (systemic lupus erythematous, Sjögren's syndrome, rheumatoid arthritis, Behçet's disease) hyperglobulinemic states, cryoglobulinemia, bowel bypass syndrome, ulcerative colitis, cystic fibrosis, primary biliary cirrhosis and HIV infection. Association with malignancies is not frequent. Lymphoproliferative disorders (Hodgkin's disease, mycosis fungoides, lymphosarcoma, adult T-cell leukemia, multiple mieloma) and solid tumors (lung cancer, colon carcinoma, renal, prostate, head and neck cancer and breast cancer) may be associated with CNV. Whenever possible, treatment is directed at the elimination of the cause. In other cases after adequate laboratory screening local and systemic therapy are recommended. PMID:10599332

  6. Necrotizing granulomatous inflammation of the glans penis.

    PubMed

    Christodoulidou, Michelle; Bunker, Christopher B; Trevisan, Giorgia; Muneer, Asif

    2016-01-01

    We describe the case of a 73-year-old man who presented with a 10-month history of an ulcerating lesion on the glans penis. Initially this was thought to be an invasive squamous cell carcinoma but a biopsy showed histological features consistent with necrotizing granulomatous inflammation. Extensive serological, immunological and microbiological tests only showed a positive antinuclear and perinuclear antineutrophil cytoplasmic antibodies indicating a possible autoimmune aetiology but an underlying systemic cause was not identified. Treatment with oral corticosteroids limited the inflammatory process but due to the gross destruction of the glans penis, he still required a glansectomy and split-skin graft reconstruction from which he recovered well. Although this patient ultimately required surgery for this rare presentation, this case highlights the differential diagnosis of penile ulceration (that transcends neoplasia) and the importance of performing and interpreting penile biopsies before undertaking potentially mutilating definitive surgery. PMID:27558192

  7. Smad8 is expressed in the anterior necrotic zone: evidence for a role of bone morphogenetic proteins/SMAD signaling in the activation of a molecular cascade that culminates in cell death.

    PubMed

    Abarca-Buis, René F; Bustamante, Marcia; Cuervo, Rodrigo; Aguilar-Fernández-de-Lara, Dante; Chimal-Monroy, Jesús

    2011-08-01

    Bone morphogenetic proteins (BMPs) play a crucial role in programmed cell death (PCD), a biological process required for the sculpturing of the embryonic limbs. However, it is unknown if BMP signaling directly promotes cell death, or if it induces a molecular cascade that culminates in cell death. Given that Smad8, which encodes one component of BMP signaling, is expressed during the regression of interdigital tissue and responds to BMPs, we presumed that it may be expressed in other cell death areas during chick limb development such as the anterior and posterior necrotic zones (ANZ and PNZ). The present study found that the Smad8 expression pattern in the anterior mesoderm of the hindlimb is very similar to that observed in limbs stained to detect cell death. Also, BMPs and retinoic acid, which act as apoptosis-promoting factors, induced expression of Smad8 before the onset of cell death, while sonic hedgehog protein, acting as a survival factor, inhibited Smad8 expression in the ANZ. However, although there was correlation between Smad8 expression patterns and PCD in the ANZ, phosphorylated forms of SMAD1/5/8 and TUNEL staining did not co-localize in dying cells. Interestingly, a short pulse of BMP was sufficient to trigger cell death. On the other hand, most dying cells were located in the avascular region, while many cells expressing Smad8 were located in the vascular region of the ANZ. These results suggest that BMPs mediated by SMAD signaling activate a molecular cascade that culminates in PCD.

  8. Necrotizing sialometaplasia involving the mucous glands of the nasal cavity.

    PubMed

    Johnston, W H

    1977-09-01

    Necrotizing sialometaplasia was found in maxillary sinus mucous glands of an 83 year old woman who had undergone a radical maxillectomy for basal cell carcinoma 10 days earlier. Previously recognized as an ulcerating lesion involving salivary glands in the oral cavity, this benign reactive process may also occur in the mucous glands of the nasal cavity and sinuses and can simulate squamous cell or mucoepidermoid carcinoma. Ischemia appears to be pathogenetic.

  9. Pyoderma Gangrenosum Simulating Necrotizing Fasciitis

    PubMed Central

    de Souza, Erik Friedrich Alex; da Silva, Guilherme Almeida Rosa; dos Santos, Gustavo Randow; Motta, Heloisa Loureiro de Sá Neves; Cardoso, Pedro Afonso Nogueira Moisés; de Azevedo, Marcelo Costa Velho Mendes; Pires, Karina Lebeis; Motta, Rogerio Neves; Silva, Walter de Araujo Eyer; Ferry, Fernando Raphael de Almeida; Pinto, Jorge Francisco da Cunha

    2015-01-01

    Pyoderma gangrenosum received this name due to the notion that this disease was related to infections caused by bacteria in the genus Streptococcus. In contrast to this initial assumption, today the disease is thought to have an autoimmune origin. Necrotizing fasciitis was first mentioned around the fifth century AD, being referred to as a complication of erysipelas. It is a disease characterized by severe, rapidly progressing soft tissue infection, which causes necrosis of the subcutaneous tissue and the fascia. On the third day of hospitalization after antecubital venipuncture, a 59-year-old woman presented an erythematous and painful pustular lesion that quickly evolved into extensive ulceration circumvented by an erythematous halo and accompanied by toxemia. One of the proposed etiologies was necrotizing fasciitis. The microbiological results were all negative, while the histopathological analysis showed epidermal necrosis and inflammatory infiltrate composed predominantly of dermal neutrophils. Pyoderma gangrenosum was considered as a diagnosis. After 30 days, the patient was discharged with oral prednisone (60 mg/day), and the patient had complete healing of the initial injury in less than two months. This case was an unexpected event in the course of the hospitalization which was diagnosed as pyoderma gangrenosum associated with myelodysplastic syndrome. PMID:26783395

  10. Cadmium-induced bone effect is not mediated via low serum 1,25-dihydroxy vitamin D

    SciTech Connect

    Engstroem, Annette; Skerving, Staffan; Lidfeldt, Jonas; Burgaz, Ann; Lundh, Thomas; Samsioe, Goeran; Vahter, Marie; Akesson, Agneta

    2009-02-15

    Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH){sub 2}D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 {mu}g/L) or high (0.66-2.1 {mu}g/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH){sub 2}D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH){sub 2}D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH){sub 2}D. Hence, decreased circulating levels of 1,25(OH){sub 2}D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone.

  11. Necrotic seminoma of the testis: establishing the diagnosis with Masson trichrome stain and immunostains.

    PubMed

    Florentine, Barbara D; Roscher, Arno A; Garrett, Jerry; Warner, Nancy E

    2002-02-01

    We describe an infarcted mass in the testis containing "ghost" cells suspicious for neoplasm. The entire lesion was necrotic. A Masson trichrome stain greatly improved nuclear and cytologic detail, confirming the suspicion of neoplasm. Placental alkaline phosphatase revealed specific membrane staining of the neoplastic cells and established a diagnosis of seminoma. Masson trichrome plus selected immunostains offer a promising approach to the diagnosis of certain necrotic neoplasms.

  12. Necrotizing Fasciltis Case Presentation and Literature Review.

    PubMed

    Christensen, Louis; Evans, Heath; Cundick, David; McShane, Matt; Penna, Kevin; Sadoff, Rory

    2015-01-01

    Necrotizing fasciitis is a rare, rapidly progressing in- fection with significant morbidity and high mortality rates. Rarely does necrotizing fasciitis appear in the head and neck region; rather, it usually affects the limbs and abdomen of patients. This article presents our institution's experience with the disease and pro- vides a discussion of proposed treatment options.

  13. Vesicular, ulcerative, and necrotic dermatitis of reptiles.

    PubMed

    Maas, Adolf K

    2013-09-01

    Vesicular, ulcerative, and necrotic dermatologic conditions are common in captive reptiles. Although these conditions have distinct differences histologically, they are commonly sequelae to each other. This article examines the anatomy and physiology of reptile skin; discusses reported causes of vesicular, ulcerative, and necrotic dermatologic conditions; and reviews various management options.

  14. Statin induced necrotizing autoimmune myopathy.

    PubMed

    Babu, Suma; Li, Yuebing

    2015-04-15

    Statin induced necrotizing autoimmune myopathy (SINAM) is a recently characterized entity belonging to the spectrum of statin myotoxicity. It is a more severe form, and is usually associated with significant proximal muscle weakness, strikingly elevated creatine kinase levels and persistent symptoms despite statin discontinuation. The characteristic pathological finding is a marked muscle fiber necrosis with minimal or no inflammation on muscle biopsy. SINAM is an autoimmune disorder associated with an antibody against 3-hydroxy-3-methyglutaryl-coenzyme A reductase (HMGCR), and the antibody titer is a useful marker for assessing treatment response. However, anti-HMGCR positive myopathies are also caused by unknown etiologies other than statin exposure, especially in the younger population. SINAM should be promptly recognized as immunosuppressive therapy can improve its clinical outcome significantly. Further research is needed to elucidate its pathogenesis and provide evidence based guidelines for management.

  15. What next in necrotizing enterocolitis?

    PubMed

    Yurdakök, Murat

    2008-01-01

    Necrotizing enterocolitis (NEC) is a devastating disease of premature infants, with a mortality rate of 10-50%. It is uncommon in term infants and in premature infants who have not yet been fed. Most commonly NEC develops suddenly in a preterm infant who was otherwise well, with initial symptoms of abdominal distention, bilious or bloody emesis or gastric aspirates, hematochezia, and pneumatosis intestinalis, and sometimes progresses quickly to include bowel perforation, acidosis, shock, and death. Trigger factors (i.e. perinatal hypoxia, mild infection or formula feeding) cause focal mild intestinal mucosal injury. In the presence of proliferation of commensal bacteria, local breakdown of mucosal barrier may cause entry of bacterial products (e.g. lipopolysaccharides, platelet-activating factor). Endothelial platelet-activating factor and/or tumor necrotizing factor and/or direct stimulating effects of polymorphonuclear leukocytes cause proinflammatory cascade and focal necrosis, which increase the entry of large amounts of bacterial toxins, and then severe NEC, sepsis, and shock develop. Therapies for the prevention of NEC that appear to have some benefit are breastfeeding and antenatal steroids, and probably probiotics. Enteral immunoglobulin, polyunsaturated fatty acids, and arginine or glutamine supplementation are therapies for the prevention of NEC that do not appear to be of benefit. Enteral erythropoietin and enteral granulocyte colony-stimulating factor are promising novel therapies. Treatment options are limited to gut rest, parenteral nutrition, broad-spectrum antibiotics, and surgical interventions for enteral perforation. Two commonly used methods for NEC with intestinal perforation are laparotomy or primary peritoneal drainage ("patch, drain and wait"); however, the preferred method is controversial.

  16. Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G0/G1 Arrest followed by Necrotic Cell Death in Leishmania donovani.

    PubMed

    Zahir, Abdul Abduz; Chauhan, Indira Singh; Bagavan, Asokan; Kamaraj, Chinnaperumal; Elango, Gandhi; Shankar, Jai; Arjaria, Nidhi; Roopan, Selvaraj Mohana; Rahuman, Abdul Abdul; Singh, Neeloo

    2015-08-01

    The aim of the present study was to synthesize silver (Ag) and titanium dioxide (TiO2) nanoparticles (NPs) using green synthesis from aqueous leaf extract of Euphorbia prostrata as antileishmanial agents and to explore the underlying molecular mechanism of induced cell death. In vitro antileishmanial activity of synthesized NPs was tested against promastigotes of Leishmania donovani by alamarBlue and propidium iodide uptake assays. Antileishmanial activity of synthesized NPs on intracellular amastigotes was assessed by Giemsa staining. The leishmanicidal effect of synthesized Ag NPs was further confirmed by DNA fragmentation assay and by cell cycle progression and transmission electron microscopy (TEM) of the treated parasites. TEM analysis of the synthesized Ag NPs showed a spherical shape with an average size of 12.82 ± 2.50 nm, and in comparison to synthesized TiO2 NPs, synthesized Ag NPs were found to be most active against Leishmania parasites after 24 h exposure, with 50% inhibitory concentrations (IC50) of 14.94 μg/ml and 3.89 μg/ml in promastigotes and intracellular amastigotes, respectively. A significant increase in G0/G1 phase of the cell cycle with a subsequent decrease in S (synthesis) and G2/M phases compared to controls was observed. The growth-inhibitory effect of synthesized Ag NPs was attributed to increased length of S phase. A decreased reactive oxygen species level was also observed, which could be responsible for the caspase-independent shift from apoptosis (G0/G1 arrest) to massive necrosis. High-molecular-weight DNA fragmentation as a positive consequence of necrotic cell death was also visualized. We also report that the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by synthesized Ag NPs. The green-synthesized Ag NPs may provide promising leads for the development of cost-effective and safer alternative treatment against visceral leishmaniasis. PMID:26033724

  17. Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G0/G1 Arrest followed by Necrotic Cell Death in Leishmania donovani.

    PubMed

    Zahir, Abdul Abduz; Chauhan, Indira Singh; Bagavan, Asokan; Kamaraj, Chinnaperumal; Elango, Gandhi; Shankar, Jai; Arjaria, Nidhi; Roopan, Selvaraj Mohana; Rahuman, Abdul Abdul; Singh, Neeloo

    2015-08-01

    The aim of the present study was to synthesize silver (Ag) and titanium dioxide (TiO2) nanoparticles (NPs) using green synthesis from aqueous leaf extract of Euphorbia prostrata as antileishmanial agents and to explore the underlying molecular mechanism of induced cell death. In vitro antileishmanial activity of synthesized NPs was tested against promastigotes of Leishmania donovani by alamarBlue and propidium iodide uptake assays. Antileishmanial activity of synthesized NPs on intracellular amastigotes was assessed by Giemsa staining. The leishmanicidal effect of synthesized Ag NPs was further confirmed by DNA fragmentation assay and by cell cycle progression and transmission electron microscopy (TEM) of the treated parasites. TEM analysis of the synthesized Ag NPs showed a spherical shape with an average size of 12.82 ± 2.50 nm, and in comparison to synthesized TiO2 NPs, synthesized Ag NPs were found to be most active against Leishmania parasites after 24 h exposure, with 50% inhibitory concentrations (IC50) of 14.94 μg/ml and 3.89 μg/ml in promastigotes and intracellular amastigotes, respectively. A significant increase in G0/G1 phase of the cell cycle with a subsequent decrease in S (synthesis) and G2/M phases compared to controls was observed. The growth-inhibitory effect of synthesized Ag NPs was attributed to increased length of S phase. A decreased reactive oxygen species level was also observed, which could be responsible for the caspase-independent shift from apoptosis (G0/G1 arrest) to massive necrosis. High-molecular-weight DNA fragmentation as a positive consequence of necrotic cell death was also visualized. We also report that the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by synthesized Ag NPs. The green-synthesized Ag NPs may provide promising leads for the development of cost-effective and safer alternative treatment against visceral leishmaniasis.

  18. Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G0/G1 Arrest followed by Necrotic Cell Death in Leishmania donovani

    PubMed Central

    Zahir, Abdul Abduz; Chauhan, Indira Singh; Bagavan, Asokan; Kamaraj, Chinnaperumal; Elango, Gandhi; Shankar, Jai; Arjaria, Nidhi; Roopan, Selvaraj Mohana

    2015-01-01

    The aim of the present study was to synthesize silver (Ag) and titanium dioxide (TiO2) nanoparticles (NPs) using green synthesis from aqueous leaf extract of Euphorbia prostrata as antileishmanial agents and to explore the underlying molecular mechanism of induced cell death. In vitro antileishmanial activity of synthesized NPs was tested against promastigotes of Leishmania donovani by alamarBlue and propidium iodide uptake assays. Antileishmanial activity of synthesized NPs on intracellular amastigotes was assessed by Giemsa staining. The leishmanicidal effect of synthesized Ag NPs was further confirmed by DNA fragmentation assay and by cell cycle progression and transmission electron microscopy (TEM) of the treated parasites. TEM analysis of the synthesized Ag NPs showed a spherical shape with an average size of 12.82 ± 2.50 nm, and in comparison to synthesized TiO2 NPs, synthesized Ag NPs were found to be most active against Leishmania parasites after 24 h exposure, with 50% inhibitory concentrations (IC50) of 14.94 μg/ml and 3.89 μg/ml in promastigotes and intracellular amastigotes, respectively. A significant increase in G0/G1 phase of the cell cycle with a subsequent decrease in S (synthesis) and G2/M phases compared to controls was observed. The growth-inhibitory effect of synthesized Ag NPs was attributed to increased length of S phase. A decreased reactive oxygen species level was also observed, which could be responsible for the caspase-independent shift from apoptosis (G0/G1 arrest) to massive necrosis. High-molecular-weight DNA fragmentation as a positive consequence of necrotic cell death was also visualized. We also report that the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by synthesized Ag NPs. The green-synthesized Ag NPs may provide promising leads for the development of cost-effective and safer alternative treatment against visceral leishmaniasis. PMID:26033724

  19. Grape juice concentrate protects reproductive parameters of male rats against cadmium-induced damage: a chronic assay.

    PubMed

    Pires, Vanessa Cardoso; Gollücke, Andréa Pittelli Boiago; Ribeiro, Daniel Araki; Lungato, Lisandro; D'Almeida, Vânia; Aguiar, Odair

    2013-12-14

    The aim of the present study was to investigate the effects of long-term grape juice concentrate (GJC) consumption, in two dosages, on the reproductive parameters of cadmium-exposed male rats. The effects of the concentrate on body mass gain, plasma testosterone levels, reproductive organ weights, daily sperm production, sperm morphology, testis histopathological and histomorphometrical parameters, and testicular antioxidant markers were investigated. Wistar rats (n 54) were distributed into six groups: CdCl2; cadmium and grape juice I (1·18 g/kg per d); cadmium and grape juice II (2·36 g/kg per d); grape juice I (1·18 g/kg per d); grape juice II (2·36 g/kg per d); control. A single dose of CdCl2 (1·2 mg/kg body weight (BW)) was injected intraperitoneally and the grape juice was administered orally for 56 d. The results indicated that cadmium changed all reproductive and antioxidant parameters. At dosage I (1·18 g/kg BW), GJC consumption did not show the effects against cadmium-induced damages. In contrast, at dosage II (2·36 g/kg BW), the GJC improved the gonadosomatic index (P= 0·003), serum testosterone levels (P= 0·001), the relative weight of epididymis (P= 0·013) and ventral prostate (P= 0·052), the percentage of normal sperm (P= 0·001), and histopathological and histomorphometrical parameters. In addition, at this dosage, normalisation of the enzymatic activity of superoxide dismutase (P= 0·001) and of testicular levels of glutathione (P= 0·03) were observed. The parameters of the non-exposed rats did not depict significant alterations. In conclusion, the product was able to act as a protector of reproductive function against cadmium-induced damage. Such a property was expressed in a dose-dependent manner as the more effective dose was dosage II. The GJC acted possibly by antioxidant mechanisms. PMID:23656754

  20. Defect of zinc transporter ZRT1 ameliorates cadmium induced lipid accumulation in Saccharomyces cerevisiae.

    PubMed

    Rajakumar, Selvaraj; Ravi, Chidambaram; Nachiappan, Vasanthi

    2016-04-01

    Cadmium (Cd) is a non-essential divalent heavy metal that enters the cells by utilizing the transport pathways of the essential metals, like zinc (Zn), in Saccharomyces cerevisiae. This work focuses on Cd accumulation and its impact on deletion of Zn transporters Zrt1p and Zrt2p and lipid homeostasis. Cd exposure reduces the Zn levels in the mutant strains, and the effect was higher in zrt2Δ cells. Upon Cd exposure, the wild-type and zrt2Δ cells follow a similar pattern, but an opposite pattern was observed in zrt1Δ cells. The Cd influx and ROS levels were high in both wild-type cells and zrt2Δ cells but significantly reduced in zrt1Δ cells. Cd exposure led to accumulation of triacylglycerol and lipid droplets in wild-type cells and zrt2Δ cells but these levels were decreased in zrt1Δ cells. Hence, these studies suggest that the zrt1Δ cells provide resistance towards Cd and aid in the maintenance of lipid homeostasis in yeast cells. PMID:26999708

  1. A mesenteric hernia complicated with a triple necrotic volvulus.

    PubMed

    Tassinari, Davide; Santoro, Stefano; Bernardi, Filippo; Lima, Mario

    2012-09-24

    A 6-year-old girl was admitted to the paediatric emergency department with colicky abdominal pain. She had a significant medical history, with four previous admissions due to recurrent abdominal pain in the past year. On examination the abdomen was soft, there was no rebound tenderness and Rovsing's sign was negative. Her blood tests revealed a raised white cells count, although her C reactive protein was within the normal range. Abdominal x-ray revealed small bowel obstruction. During her assessment the patient rapidly deteriorated and seemed to go into shock. Her clinical state in addition to the radiological findings meant that she was taken to theatre for surgical exploration. This showed a triple volvulus with necrotic bowel loops that had herniated through a mesenteric defect. The necrotic bowel was subsequently resected.

  2. [Risk factors of necrotizing enterocolitis].

    PubMed

    Tapia-Rombo, C A; Velasco-Lavín, M R; Nieto-Caldelas, A

    1993-09-01

    The purpose of the present study is to compare risk factors of necrotizing enterocolitis (NEC) between two group: group A, newborns with the disease and group B, newborns with other diseases different from NEC, in order to know if these risk factors are more frequent or not in the first group. We assessed the clinical records of all the patients hospitalized in the Neonatal Intensive Care Unit and Neonatology Service of the La Raza General Hospital between 1987 and 1991 with the diagnosis of NEC. They were compared with 65 clinical records chosen at random of patients hospitalized in the same Unit with other diagnosis at the same time, and who were discharged by improvement or deceased. In all of them were look for known risk factors for NEC generally accepted such as: prematurity, neonatal asphyxia, poliglobulia, cyanotic congenital heart disease, patent ductus arteriosus, respiratory distress syndrome, catheterization of umbilical vessels, early feeding of elevated formula increases, exchange exchange transfusion, hypoxic ischemic encephalopathy, infection, etc. Just 25 records of the possible 50 with the diagnosis of NEC full filled inclusion criteria. There were no statistically significant difference in weight, sex, mortality and known risk factors of NEC between both groups. Were concluded that NEC is a disease of unknown etiology that should be studied more thoroughly. The known risk factors must be avoided because the patient susceptibility probably play an important role. PMID:8373546

  3. Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cells.

    PubMed

    Rowson-Hodel, Ashley R; Berg, Anastasia L; Wald, Jessica H; Hatakeyama, Jason; VanderVorst, Kacey; Curiel, Daniel A; Leon, Leonardo J; Sweeney, Colleen; Carraway, Kermit L

    2016-05-28

    Anticancer chemotherapeutics often rely on induction of apoptosis in rapidly dividing cells. While these treatment strategies are generally effective in debulking the primary tumor, post-therapeutic recurrence and metastasis are pervasive concerns with potentially devastating consequences. We demonstrate that the amiloride derivative 5-(N,N-hexamethylene) amiloride (HMA) harbors cytotoxic properties particularly attractive for a novel class of therapeutic agent. HMA is potently and specifically cytotoxic toward breast cancer cells, with remarkable selectivity for transformed cells relative to non-transformed or primary cells. Nonetheless, HMA is similarly cytotoxic to breast cancer cells irrespective of their molecular profile, proliferative status, or species of origin, suggesting that it engages a cell death mechanism common to all breast tumor subtypes. We observed that HMA induces a novel form of caspase- and autophagy-independent programmed necrosis relying on the orchestration of mitochondrial and lysosomal pro-death mechanisms, where its cytotoxicity was attenuated with ROS-scavengers or lysosomal cathepsin inhibition. Overall, our findings suggest HMA may efficiently target the heterogeneous populations of cancer cells known to reside within a single breast tumor by induction of a ROS- and lysosome-mediated form of programmed necrosis.

  4. Fatal necrotizing fasciitis due to Vibrio damsela.

    PubMed

    Yuen, K Y; Ma, L; Wong, S S; Ng, W F

    1993-01-01

    A patient who succumbed to fulminant necrotizing fasciitis due to Vibrio damsela after injury by a rabbitfish is described. Despite the absence of any known underlying illness, he did not respond to appropriate antibiotic therapy and radical surgical intervention. This represents the first documented case of necrotizing fasciitis due to this organism, and is also the first reported case in Southeast Asia inflicted by rabbitfish.

  5. Necrotizing sialometaplasia: an early, nonulcerative presentation.

    PubMed

    Santis, H R; Kabani, S P; Roderiques, A; Driscoll, J M

    1982-04-01

    Necrotizing sialometaplasia usually presents as a painless, deeply excavating ulcer and is considered in the differential diagnosis of large palatal ulcers along with mucoepidermoid carcinoma and adenoid cystic carcinoma. This case is presented to illustrate that the early signs and symptoms of necrotizing sialometaplasia may be swelling with a purulent exudate, diffuse, vague pain, and numbness. It also demonstrates the rapidity with which initial signs of healing become apparent. This latter clinically suggests a benign process.

  6. Cadmium-Induced Proteome Remodeling Regulated by Spc1/Sty1 and Zip1 in Fission Yeast

    PubMed Central

    Russell, Paul

    2012-01-01

    Stress-activated protein kinases and transcription factors are crucial for surviving exposure to cadmium and other environmental toxicants, but their effects on the proteome remain largely unexplored. In this study, isobaric tag for relative and absolute quantitation reveals that cadmium stress triggers rapid proteome remodeling in the fission yeast Schizosaccharomyces pombe. Spc1/Sty1, a mitogen/stress-activated protein kinase homologous to human p38 and Saccharomyces cerevisiae Hog1, controls many of these changes, including enzymes of the oxidative phase of the pentose phosphate pathway and trehalose metabolism. Genetic studies indicate that control of carbohydrate metabolism by Spc1 is required for cadmium tolerance. The bZIP transcription factor Zip1, which is functionally related to human Nrf2 and S. cerevisiae Met4, has a smaller effect on cadmium-induced proteome remodeling, but it is required for production of key proteins involved in sulfur metabolism, which are essential for cadmium resistance. These studies reveal how Spc1 and Zip1 independently reshape the proteome to modulate cellular defense mechanisms against the toxic effects of cadmium. PMID:22610605

  7. Protective effects of kolaviron and quercetin on cadmium-induced testicular damage and endocrine pathology in rats.

    PubMed

    Farombi, E O; Adedara, I A; Akinrinde, S A; Ojo, O O; Eboh, A S

    2012-08-01

    This study evaluated the effects of kolaviron, a biflavonoid from Garcinia kola seed, and quercetin on cadmium-induced reproductive toxicity in rats. Adult male rats were administered with either cadmium (15 mg kg(-1)) alone or in combination with kolaviron (200 mg kg(-1)) or quercetin (10 mg kg(-1)) daily for 5 days. Cadmium-treated rats showed (P < 0.05) decrease in the body weight gain, testis and epididymis weights. However, upon co-administration of kolaviron or quercetin, these changes were significantly reversed in cadmium-treated rats. Also, administration of kolaviron or quercetin significantly prevented cadmium-mediated decrease in sperm motility and epididymal sperm concentration and reversed the increased level of sperm abnormality to near control. In testes and sperm, cadmium treatment resulted in significant decrease in the activities of superoxide dismutase, catalase and glutathione peroxidase, whereas it increased glutathione S-transferase activity as well as hydrogen peroxide and malondialdehyde levels. While plasma levels of triiodothyronine and tetraiodothyronine remained unaffected, the levels of testosterone, luteinising hormone and follicle stimulating hormone were decreased in cadmium-treated rats. Cadmium treatment caused mild congestion of interstitial vessels and oedema in the testes. Taken together, kolaviron and quercetin inhibited the adverse effects of cadmium on the antioxidant enzymes, markers of oxidative stress, endocrine and testicular structure in rats. PMID:22356231

  8. Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats

    PubMed Central

    Milton Prabu, S.; Muthumani, M.; Shagirtha, K.

    2012-01-01

    The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats. PMID:23961183

  9. Refining the mouse chromosomal location of Cdm, the major gene associated with susceptibility to cadmium-induced testicular necrosis.

    PubMed

    Dalton, T P; Miller, M L; Wu, X; Menon, A; Cianciolo, E; McKinnon, R A; Smith, P W; Robinson, L J; Nebert, D W

    2000-03-01

    Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC 'Category I' human carcinogen. Cd++ can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, named Cdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing the Cdm gene from more than 24 cM to 0.64 cM (estimated 40-80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6J (B6, resistant) and DBA/2J (D2, sensitive) inbred mice, and determined that the Cdm gene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouse Cdm gene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity. PMID:10762002

  10. Cadmium Induces Apoptosis in Freshwater Crab Sinopotamon henanense through Activating Calcium Signal Transduction Pathway

    PubMed Central

    Wang, Jinxiang; Zhang, Pingping; Liu, Na; Wang, Qian; Luo, Jixian; Wang, Lan

    2015-01-01

    Calcium ion (Ca2+) is one of the key intracellular signals, which is implicated in the regulation of cell functions such as impregnation, cell proliferation, differentiation and death. Cadmium (Cd) is a toxic environmental pollutant that can disturb cell functions and even lead to cell death. Recently, we have found that Cd induced apoptosis in gill cells of the freshwater crab Sinopotamon henanense via caspase activation. In the present study, we further investigated the role of calcium signaling in the Cd-induced apoptosis in the animals. Our data showed that Cd triggered gill cell apoptosis which is evidenced by apoptotic DNA fragmentation, activations of caspases-3, -8 and -9 and the presence of apoptotic morphological features. Moreover, Cd elevated the intracellular concentration of Ca2+, the protein concentration of calmodulin (CaM) and the activity of Ca2+-ATPase in the gill cells of the crabs. Pretreatment of the animals with ethylene glycol-bis-(b-aminoethyl ether)-N,N,N’,N’-tetraacetic acid (EGTA), Ca2+ chelator, inhibited Cd-induced activation of caspases-3, -8 and -9 as well as blocked the Cd-triggered apoptotic DNA fragmentation. The apoptotic morphological features were no longer observed in gill cells pretreated with the Ca2+ signaling inhibitors before Cd treatment. Our results indicate that Cd evokes gill cell apoptosis through activating Ca2+-CaM signaling transduction pathway. PMID:26714174

  11. The chemopreventive effects of aged garlic extract against cadmium-induced toxicity.

    PubMed

    Lawal, Akeem O; Ellis, Elizabeth M

    2011-09-01

    Garlic has been reported in many previous studies as a potent chemopreventive agent. The protective effect of garlic has been ascribed to the presence of organosulphur compounds (OSC). In this study, the efficacy of aged garlic extract (AGE) compared to diallyl disulfide (DADS) in protecting against toxicity induced by cadmium (Cd) in 1321N1 and HEK293 cells was investigated. The involvement of the transcription factor Nrf2 in this protection was also examined. The results show that AGE significantly prevented loss of cell viability in Cd-treated 1321N1 and HEK293 cells. In comparison DADS had no significant effect in protecting HEK293 cells but did protect 1321N1 cells. AGE significantly reduced Cd-induced TBARS production and LDH leakage in the two cell lines, and AGE and DADS both increased GSH levels in Cd-treated cell lines. Pre-treatment of cells with AGE or DADS increased expression of the protective enzyme NAD(P)H:quinone oxidoreductase (NQO1), and this was associated with the accumulation of the transcription factor Nrf2. These results show that AGE and DADS have beneficial effects against Cd-induced toxicity, and this protection appears to be mediated via induction of cytoprotective enzymes in an Nrf2-dependent manner. This indicates the potential for using AGE as a chemoprevention strategy for Cd toxicity. PMID:21843808

  12. A novel class of autoantigens of anti-neutrophil cytoplasmic antibodies in necrotizing and crescentic glomerulonephritis: the lysosomal membrane glycoprotein h-lamp-2 in neutrophil granulocytes and a related membrane protein in glomerular endothelial cells

    PubMed Central

    1995-01-01

    Necrotizing and crescentic glomerulonephritis (NCGN) is frequently associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA). It is established that ANCA are specific for soluble enzymes of granules of polymorphonuclear neutrophil granulocytes (PMN), such as myeloperoxidase (MPO) or protease 3 (PR3). The purpose of this study was to identify membrane proteins of PMNs, and/or glomerular cells, as additional autoantigenic ANCA targets. When membrane protein fractions were prepared from PMNs and isolated human glomeruli, and immunoblotted with ANCA sera of NCGN patients, two bands with apparent molecular masses of 170 and 80-110 kD (gp170/80-110) were labeled in PMNs, and a 130-kD glycoprotein (gp130) in glomeruli. Gp130 was purified, and monoclonal and rabbit antibodies (Abs) were produced which showed the same double specificity as the patient's ANCA. Using these probes, evidence was provided that gp170/80-110 is identical with human lysosomal-associated membrane protein 2 (h-lamp-2), because both proteins were immunologically cross-reactive and screening of a cDNA expression library from human promyelocytic leukemia cells with anti- gp130 Ab yielded a clone derived from h-lamp-2. Gp170/80-110 was localized primarily in granule membranes of resting PMNs, and was translocated to the cell surfaces by activation with FMLP. By contrast, gp130 was localized in the surface membranes of endothelial cells of human glomerular and renal interstitial capillaries, rather than in lysosomes, as found for h-lamp-2. Potential clinical relevance of autoantibodies to gp170/80-110 and gp130 was assessed in a preliminary trial, in which ANCA sera of patients (n = 16) with NCGN were probed with purified or recombinant antigens. Specific reactivity was detected in approximately 90% of cases with active phases of NCGN, and frequently also in combination with autoantibodies specific for PR3 or MPO. Collectively, these data provide evidence that h-lamp-2 in PMNs and a

  13. Cadmium induced changes in subcellular glutathione contents within glandular trichomes of Cucurbita pepo L.

    PubMed

    Kolb, Dagmar; Müller, Maria; Zellnig, Günther; Zechmann, Bernd

    2010-07-01

    Plants cope with cadmium (Cd) stress by complexation with phytochelatins (Pc), metallothioneins and glutathione and sequestration within vacuoles. Especially glutathione was found to play a major role in Cd detoxification as Cd shows a high binding affinity towards thiols and as glutathione is a precursor for Pc synthesis. In the present study, we have used an immunohistochemical approach combined with computer-supported transmission electron microscopy in order to measure changes in the subcellular distribution of glutathione during Cd-stress in mesophyll cells and cells of different glandular trichomes (long and short stalked) of Cucurbita pepo L. subsp. pepo var. styriaca GREB: . Even though no ultrastructural alterations were observed in leaf and glandular trichome cells after the treatment of plants with 50 microM cadmium chloride (CdCl(2)) for 48 h, all cells showed a large decrease in glutathione contents. The strongest decrease was found in nuclei and the cytosol (up to 76%) in glandular trichomes which are considered as a major side of Cd accumulation in leaves. The ratio of glutathione between the cytosol and nuclei and the other cell compartments was strongly decreased only in glandular trichomes (more than 50%) indicating that glutathione in these two cell compartments is especially important for the detoxification of Cd in glandular trichomes. Additionally, these data indicate that large amounts of Cd are withdrawn from nuclei during Cd exposure. The present study gives a detailed insight into the compartment-specific importance of glutathione during Cd exposure in mesophyll cells and glandular trichomes of C. pepo L. plants.

  14. Role of autophagy in cadmium-induced apoptosis of primary rat osteoblasts

    PubMed Central

    Liu, Wei; Dai, Nannan; Wang, Yi; Xu, Chao; Zhao, Hongyan; Xia, Pengpeng; Gu, Jianhong; Liu, Xuezhong; Bian, Jianchun; Yuan, Yan; Zhu, Jiaqiao; Liu, Zongping

    2016-01-01

    Cadmium (Cd) is a common environmental pollutant that can damage many organs and the fetus. We previously reported that Cd induced apoptosis in primary rat osteoblasts (OBs). OB apoptosis induced by Cd will eventually lead to osteoporosis. In this study, a novel pharmacotherapeutic approach was investigated involving the regulation of autophagy to prevent Cd osteoporosis. The results showed that Cd treatment induced apoptosis in OBs, as demonstrated by the ratio of Bax/Bcl-2, activation of poly (ADP-ribose) polymerase (PARP) and nuclear condensation. In addition, cells treated with Cd were observed to undergo autophagic cell death by monitoring the induction of the beclin 1, autophagy gene 5 (Atg5) and the expression of microtubule-associated protein 1 light chain 3 (LC3). The results indicated that promotion of apoptotic cell death by Cd is accompanied by induction of autophagy in OBs. Interestingly, Cd-mediated apoptotic cell death was suppressed by pretreatment with the autophagy activator rapamycin (RAP) and potentiated by the autophagy inhibitor chloroquine (CQ) or small interfering RNA against beclin 1. These findings suggest that the autophagic response plays a protective role that impedes eventual cell death. Activation of autophagy could therefore be an adjunctive strategy for treatment of Cd-induced osteoporosis. PMID:26852917

  15. Effects of alpha-tocopherol on cadmium-induced toxicity in rat testis and spermatogenesis.

    PubMed

    Yang, Hoe Saeng; Han, Dong Keun; Kim, Jung Ran; Sim, Jae Chul

    2006-06-01

    Cadmium is known to exert toxic effects on multiple organs, including the testes. To determine if alpha-tocopherol, an antioxidant, could protect testicular tissues and spermatogenesis from the toxic effects of cadmium, six-week old male Sprague-Dawley rats were randomized to receive cadmium at doses of 0 (control), 1, 2, 4 or 8 mg/kg by the intraperitoneal route (Group A) or alpha-tocopherol for 5 days before being challenged with cadmium (Group B) in an identical dose-dependent manner. When both groups received cadmium at 1 mg/kg, there were no changes in testicular histology relative to controls. When Group A received cadmium at 2 mg/kg, undifferentiated spermatids and dead Sertoli cells increased in the seminiferous tubules while interstitial cells decreased and inflammatory cells increased in the interstitial tissues. On flow cytometric analysis, the numbers of elongated spermatids (M1) and round spermatids (M2) decreased while 2c stage cells (M3, diploid) increased. In contrast, when Group B received cadmium at 2 mg/kg, the histological insults were reduced and the distribution of the germ cell population remained comparable to controls. However, alpha-tocopherol had no protective effects with higher cadmium doses of 4 and 8 mg/kg. These findings indicate that alpha-tocopherol treatment can protect testicular tissue and preserve spermatogenesis from the detrimental effects of cadmium but its effectiveness is dependent on the dose of cadmium exposed. PMID:16778387

  16. Role of autophagy in cadmium-induced apoptosis of primary rat osteoblasts.

    PubMed

    Liu, Wei; Dai, Nannan; Wang, Yi; Xu, Chao; Zhao, Hongyan; Xia, Pengpeng; Gu, Jianhong; Liu, Xuezhong; Bian, Jianchun; Yuan, Yan; Zhu, Jiaqiao; Liu, Zongping

    2016-01-01

    Cadmium (Cd) is a common environmental pollutant that can damage many organs and the fetus. We previously reported that Cd induced apoptosis in primary rat osteoblasts (OBs). OB apoptosis induced by Cd will eventually lead to osteoporosis. In this study, a novel pharmacotherapeutic approach was investigated involving the regulation of autophagy to prevent Cd osteoporosis. The results showed that Cd treatment induced apoptosis in OBs, as demonstrated by the ratio of Bax/Bcl-2, activation of poly (ADP-ribose) polymerase (PARP) and nuclear condensation. In addition, cells treated with Cd were observed to undergo autophagic cell death by monitoring the induction of the beclin 1, autophagy gene 5 (Atg5) and the expression of microtubule-associated protein 1 light chain 3 (LC3). The results indicated that promotion of apoptotic cell death by Cd is accompanied by induction of autophagy in OBs. Interestingly, Cd-mediated apoptotic cell death was suppressed by pretreatment with the autophagy activator rapamycin (RAP) and potentiated by the autophagy inhibitor chloroquine (CQ) or small interfering RNA against beclin 1. These findings suggest that the autophagic response plays a protective role that impedes eventual cell death. Activation of autophagy could therefore be an adjunctive strategy for treatment of Cd-induced osteoporosis. PMID:26852917

  17. Cadmium-induced oxidative stress and apoptosis in the testes of frog Rana limnocharis.

    PubMed

    Zhang, Hangjun; Cai, Chenchen; Shi, Cailei; Cao, Hui; Han, Ziliu; Jia, Xiuying

    2012-10-15

    This study explored the genetic damage induced by cadmium exposure in the testes of Rana limnocharis. Healthy adult frogs were exposed to 2.5, 5, 7.5, or 10 mg/L of cadmium solution for 14 days. The results showed that exposure to these concentrations increased the levels of reactive oxygen species and malondialdehyde content in the testes, clearly indicating a dose-effect relationship. Moreover, the same dosages of Cd(2+) solution increased glutathione (reduced) content, with the values being significantly different from those observed in the control group (P<0.01). The comet assay results demonstrated that the DNA damage rate, tail length, and tail moment of samples obtained from frogs exposed to 2.5-7.5 mg/L of cadmium solution significantly increased compared with those of samples obtained from the control group (P<0.01). These findings suggest that cadmium can induce free radical generation, followed by lipid peroxidation and DNA damage. Ultrastructural observation revealed vacuoles in the spermatogenic cells, cell dispersion, incomplete cell structures, and deformed nucleoli. Moreover, cadmium exposure induced significant down-regulation of Bcl-2 expression and up-regulation of Bax and caspase-3 expressions. Taken together, these data indicate that cadmium can induce testicular cell apoptosis in R. limnocharis. Exploring the effects of cadmium on the mechanism of reproductive toxicity in amphibians will help provide a scientific basis accounting for the global population decline in amphibian species. PMID:22728207

  18. Cervical Necrotizing Fasciitis Caused by Dental Extraction

    PubMed Central

    Figueiredo, Eugênia; Álvares, Pâmella; Silva, Luciano; Silva, Leorik; Caubi, Antônio; Silveira, Marcia; Sobral, Ana Paula

    2016-01-01

    Cervical necrotizing fasciitis is an unusual infection characterized by necrosis of the subcutaneous tissue and fascial layers. Risk factors for the development of necrotizing fasciitis include diabetes mellitus, chronic renal disease, peripheral vascular disease, malnutrition, advanced age, obesity, alcohol abuse, intravenous drug use, surgery, and ischemic ulcers. This report presents a case of necrotizing fasciitis in the cervical area caused by dental extraction in a 73-year-old woman. Cervical necrotizing fasciitis in geriatric patient is rare, and even when establishing the diagnosis and having it timely treated, the patient can suffer irreversible damage or even death. Clinical manifestations in the head and neck usually have an acute onset characterized by severe pain, swelling, redness, erythema, presence of necrotic tissue, and in severe cases obstruction of the upper airways. Therefore, the presentation of this clinical case can serve as guidance to dentists as a precaution to maintain an aseptic chain and be aware of the clinical condition of older patients and the systemic conditions that may increase the risk of infections. PMID:27375905

  19. Cervical Necrotizing Fasciitis Caused by Dental Extraction.

    PubMed

    Arruda, José Alcides; Figueiredo, Eugênia; Álvares, Pâmella; Silva, Luciano; Silva, Leorik; Caubi, Antônio; Silveira, Marcia; Sobral, Ana Paula

    2016-01-01

    Cervical necrotizing fasciitis is an unusual infection characterized by necrosis of the subcutaneous tissue and fascial layers. Risk factors for the development of necrotizing fasciitis include diabetes mellitus, chronic renal disease, peripheral vascular disease, malnutrition, advanced age, obesity, alcohol abuse, intravenous drug use, surgery, and ischemic ulcers. This report presents a case of necrotizing fasciitis in the cervical area caused by dental extraction in a 73-year-old woman. Cervical necrotizing fasciitis in geriatric patient is rare, and even when establishing the diagnosis and having it timely treated, the patient can suffer irreversible damage or even death. Clinical manifestations in the head and neck usually have an acute onset characterized by severe pain, swelling, redness, erythema, presence of necrotic tissue, and in severe cases obstruction of the upper airways. Therefore, the presentation of this clinical case can serve as guidance to dentists as a precaution to maintain an aseptic chain and be aware of the clinical condition of older patients and the systemic conditions that may increase the risk of infections. PMID:27375905

  20. Cadmium-induced ethylene production and responses in Arabidopsis thaliana rely on ACS2 and ACS6 gene expression

    PubMed Central

    2014-01-01

    Background Anthropogenic activities cause metal pollution worldwide. Plants can absorb and accumulate these metals through their root system, inducing stress as a result of excess metal concentrations inside the plant. Ethylene is a regulator of multiple plant processes, and is affected by many biotic and abiotic stresses. Increased ethylene levels have been observed after exposure to excess metals but it remains unclear how the increased ethylene levels are achieved at the molecular level. In this study, the effects of cadmium (Cd) exposure on the production of ethylene and its precursor 1-aminocyclopropane-1-carboxylic acid (ACC), and on the expression of the ACC Synthase (ACS) and ACC Oxidase (ACO) multigene families were investigated in Arabidopsis thaliana. Results Increased ethylene release after Cd exposure was directly measurable in a system using rockwool-cultivated plants; enhanced levels of the ethylene precursor ACC together with higher mRNA levels of ethylene responsive genes: ACO2, ETR2 and ERF1 also indicated increased ethylene production in hydroponic culture. Regarding underlying mechanisms, it was found that the transcript levels of ACO2 and ACO4, the most abundantly expressed members of the ACO multigene family, were increased upon Cd exposure. ACC synthesis is the rate-limiting step in ethylene biosynthesis, and transcript levels of both ACS2 and ACS6 showed the highest increase and became the most abundant isoforms after Cd exposure, suggesting their importance in the Cd-induced increase of ethylene production. Conclusions Cadmium induced the biosynthesis of ACC and ethylene in Arabidopsis thaliana plants mainly via the increased expression of ACS2 and ACS6. This was confirmed in the acs2-1acs6-1 double knockout mutants, which showed a decreased ethylene production, positively affecting leaf biomass and resulting in a delayed induction of ethylene responsive gene expressions without significant differences in Cd contents between wild-type and

  1. Efficacy of 2,3-dimercapto-1-propanesulfonic acid (DMPS) and diphenyl diselenide on cadmium induced testicular damage in mice.

    PubMed

    Santos, Francielli W; Zeni, Gilson; Rocha, Joao B T; do Nascimento, Paulo C; Marques, Marieli S; Nogueira, Cristina W

    2005-12-01

    The deleterious effect of acute cadmium-intoxication in mice testes was evaluated. Animals received a single dose of CdCl2 (2.5 or 5 mg/kg, intraperitoneally) and a number of toxicological parameters in mice testes were examined, such as delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, hemoglobin and ascorbic acid contents. Furthermore, the parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were also determined. Thus, a possible protective effect of 2,3-dimercapto-1-propane-sulfonic acid (DMPS) and diphenyl diselenide (PhSe)2 were studied. The results demonstrated an inhibition of delta-ALA-D activity, a reduction of ascorbic acid and an increase of lipid peroxidation induced by cadmium, indicating testes damage. Furthermore, we observed an increase of plasma LDH, AST and ALT activities. DMPS (400 mol/kg) and (PhSe)2 (100 micromol/kg) partially protected from the inhibitory effect of 2.5 mg/kg CdCl2 on delta-ALA-D and from the increase of TBARS (thiobarbituric acid reactive species) levels. (PhSe)2 therapy was effective in ameliorate ascorbic acid content when the cadmium dose was 2.5 mg/kg. Treatment with DMPS and (PhSe)2, individually or combined, was inefficient in reducing cadmium-induced plasma LDH and ALT activity increase. The use of combined therapy (DMPS plus (PhSe)2) proved to be efficient in decreasing cadmium levels in testes and in ameliorating plasma AST activity from animals that received the highest dose of cadmium. PMID:16000234

  2. Apparent quiescence of the metallothionein gene in the rat ventral prostate: association with cadmium-induced prostate tumors in rats.

    PubMed

    Coogan, T P; Shiraishi, N; Waalkes, M P

    1994-09-01

    Several chronic studies in rats indicating that cadmium exposure can induce tumors of the ventral prostate have recently been completed in our laboratory. In one such study, a single dose of cadmium, s.c., increased prostatic tumor incidence only at doses below 5.0 mumol/kg, the approximate threshold for cadmium-induced testicular damage. In a further study, prostatic tumors were elevated with higher doses of cadmium (30 mumol/kg, s.c.) if testicular damage was prevented by zinc pretreatment. Most recently, we found that dietary cadmium (25 to 200 micrograms/g) also can increase prostatic neoplastic lesions, but these were reduced by zinc-deficient diets. Thus it appears that cadmium produces prostatic tumors only if testicular function is maintained. Furthermore, we find that metallothionein (MT), a protein associated with cadmium tolerance, may be deficient in the rat prostate, and the prostatic MT gene, at least in the ventral lobe, is unresponsive to metal stimuli. In liver, MT gene expression, as assessed by MT-1 mRNA, was quite apparent in control tissue and was induced in a dose-dependent manner 24 hr following cadmium exposure (1 to 10 mumol/kg, s.c.). However, in the ventral prostate very low constitutive levels of MT-1 mRNA were detected and increases did not occur with cadmium exposure. Cadmium concentrations in the ventral prostate were in excess of those that cause significant induction in the liver. In sharp contrast to the gene in the ventral prostate, in the dorsal prostate the MT gene was quite active. The dorsal prostate is not susceptible to cadmium carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7843088

  3. The influence of water pH on the genesis of cadmium-induced cancer in a rat model.

    PubMed

    Alborghetti Nai, Gisele; Soria Golghetto, Gisele Maria; Soriano Estrella, Mariani Paulino; Di Santi Teixeira, Larissa; do Carmo Moura, Felipe; Bremer Neto, Hermann; Santos Parizi, José Luiz

    2015-01-01

    Cadmium is a heavy metal that is widely used in industry and can cause tumours in multiple organs. The purpose of our study was to investigate the effect of water pH in the genesis of cadmium-induced cancer. We divided 98 male Wistar rats into 7 groups: group A - 15 rats that received cadmium chloride (CdCl₂- 400 mg/L) in their drinking water at a neutral pH of 7.0; group B - 15 rats that received CdCl₂(400 mg/L) in their drinking water at an acidic pH of 5.0; group C - 15 rats that received CdCl₂(400 mg/L) in their drinking water at a basic pH of 8.0; group D - 15 rats that received water at an acidic pH of 5.0; group E - 15 rats that received water at a basic pH of 8.0; group F - 15 rats that received water at a neutral pH of 7.0; and group G - 8 rats that were subcutaneously injected with a single dose of cyclophosphamide (50 mg/kg). Groups A through F were euthanised 6 months after the start of the experiment and group G was euthanised 24 hours after cyclophosphamide injection. We collected the liver, kidneys, pancreas, prostate, seminal vesicles and testes for histopathological analysis and the bone marrow for micronuclei testing. In all of the groups, neither neoplastic lesions nor an increase in micronuclei (p>0.05) were observed in the liver, kidney, pancreas, seminal vesicles and testes. We found that animals exposed to cadmium had grade one prostatic intraepithelial neoplasia, but this was found more frequently in animals from group B (p<0.05). The acidic pH increased the formation of pre-neoplastic lesions in the prostate glands of cadmium-exposed animals.

  4. Cadmium-Induced Pathologies: Where Is the Oxidative Balance Lost (or Not)?

    PubMed Central

    Nair, Ambily Ravindran; DeGheselle, Olivier; Smeets, Karen; Van Kerkhove, Emmy; Cuypers, Ann

    2013-01-01

    Over the years, anthropogenic factors have led to cadmium (Cd) accumulation in the environment causing various health problems in humans. Although Cd is not a Fenton-like metal, it induces oxidative stress in various animal models via indirect mechanisms. The degree of Cd-induced oxidative stress depends on the dose, duration and frequency of Cd exposure. Also the presence or absence of serum in experimental conditions, type of cells and their antioxidant capacity, as well as the speciation of Cd are important determinants. At the cellular level, the Cd-induced oxidative stress either leads to oxidative damage or activates signal transduction pathways to initiate defence responses. This balance is important on how different organ systems respond to Cd stress and ultimately define the pathological outcome. In this review, we highlight the Cd-induced oxidant/antioxidant status as well as the damage versus signalling scenario in relation to Cd toxicity. Emphasis is addressed to Cd-induced pathologies of major target organs, including a section on cell proliferation and carcinogenesis. Furthermore, attention is paid to Cd-induced oxidative stress in undifferentiated stem cells, which can provide information for future therapies in preventing Cd-induced pathologies. PMID:23507750

  5. Cadmium induces cadmium-tolerant gene expression in the filamentous fungus Trichoderma harzianum.

    PubMed

    Cacciola, Santa O; Puglisi, Ivana; Faedda, Roberto; Sanzaro, Vincenzo; Pane, Antonella; Lo Piero, Angela R; Evoli, Maria; Petrone, Goffredo

    2015-11-01

    The filamentous fungus Trichoderma harzianum, strain IMI 393899, was able to grow in the presence of the heavy metals cadmium and mercury. The main objective of this research was to study the molecular mechanisms underlying the tolerance of the fungus T. harzianum to cadmium. The suppression subtractive hybridization (SSH) method was used for the characterization of the genes of T. harzianum implicated in cadmium tolerance compared with those expressed in the response to the stress induced by mercury. Finally, the effects of cadmium exposure were also validated by measuring the expression levels of the putative genes coding for a glucose transporter, a plasma membrane ATPase, a Cd(2+)/Zn(2+) transporter protein and a two-component system sensor histidine kinase YcbA, by real-time-PCR. By using the aforementioned SSH strategy, it was possible to identify 108 differentially expressed genes of the strain IMI 393899 of T. harzianum grown in a mineral substrate with the addition of cadmium. The expressed sequence tags identified by SSH technique were encoding different genes that may be involved in different biological processes, including those associated to primary and secondary metabolism, intracellular transport, transcription factors, cell defence, signal transduction, DNA metabolism, cell growth and protein synthesis. Finally, the results show that in the mechanism of tolerance to cadmium a possible signal transduction pathway could activate a Cd(2+)/Zn(2+) transporter protein and/or a plasma membrane ATPase that could be involved in the compartmentalization of cadmium inside the cell. PMID:26349455

  6. Cadmium induces cadmium-tolerant gene expression in the filamentous fungus Trichoderma harzianum.

    PubMed

    Cacciola, Santa O; Puglisi, Ivana; Faedda, Roberto; Sanzaro, Vincenzo; Pane, Antonella; Lo Piero, Angela R; Evoli, Maria; Petrone, Goffredo

    2015-11-01

    The filamentous fungus Trichoderma harzianum, strain IMI 393899, was able to grow in the presence of the heavy metals cadmium and mercury. The main objective of this research was to study the molecular mechanisms underlying the tolerance of the fungus T. harzianum to cadmium. The suppression subtractive hybridization (SSH) method was used for the characterization of the genes of T. harzianum implicated in cadmium tolerance compared with those expressed in the response to the stress induced by mercury. Finally, the effects of cadmium exposure were also validated by measuring the expression levels of the putative genes coding for a glucose transporter, a plasma membrane ATPase, a Cd(2+)/Zn(2+) transporter protein and a two-component system sensor histidine kinase YcbA, by real-time-PCR. By using the aforementioned SSH strategy, it was possible to identify 108 differentially expressed genes of the strain IMI 393899 of T. harzianum grown in a mineral substrate with the addition of cadmium. The expressed sequence tags identified by SSH technique were encoding different genes that may be involved in different biological processes, including those associated to primary and secondary metabolism, intracellular transport, transcription factors, cell defence, signal transduction, DNA metabolism, cell growth and protein synthesis. Finally, the results show that in the mechanism of tolerance to cadmium a possible signal transduction pathway could activate a Cd(2+)/Zn(2+) transporter protein and/or a plasma membrane ATPase that could be involved in the compartmentalization of cadmium inside the cell.

  7. Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures.

    PubMed

    Wang, Tao; Wang, Qiwen; Song, Ruilong; Zhang, Yajing; Zhang, Kangbao; Yuan, Yan; Bian, Jianchun; Liu, Xuezhong; Gu, Jianhong; Liu, Zongping

    2015-12-01

    Cadmium (Cd) induces significant oxidative damage in cells. Recently, it was reported that autophagy could be induced by Cd in neurons. However, little is known about the role of reactive oxygen species (ROS) during Cd-induced autophagy. In our study, we examined the cross-talk between ROS and autophagy by using N-acetyl cysteine (NAC, an antioxidant) and chloroquine (CQ, a pharmacological inhibitor of autophagy) in a primary rat neuronal cell cultures. We observed accumulation of acidic vesicular organelles and the increased expression of endogenous protein light chain 3 (LC3) in Cd-treated neurons, revealing that Cd induced a high level of autophagy. Moreover, increased levels of ROS were observed in neurons treated with Cd, showing that ROS accumulation was closely associated with neuron's exposure to Cd. Furthermore, we found that autophagy was inhibited by using CQ and/or NAC with further aggravation of mitochondrial damage, lactate dehydrogenase (LDH) leakage and hypoploid apoptotic cell number in Cd-treated neurons. These results proved that autophagy has a cytoprotective role during Cd-induced toxicity in neurons, and it can prevent the oxidative damage. These findings may enable the development of novel therapeutic strategies for neurological diseases.

  8. Necrotizing sialometaplasia of palate: a case report.

    PubMed

    Garcia, N G; Oliveira, D T; Faustino, S E S; Azevedo, A L R

    2012-01-01

    Background. Necrotizing sialometaplasia (NS) is an uncommon benign reactive necrotizing inflammatory process involving minor salivary gland that often mimics malignancy both clinically and histopathologically. Case Report. We report the case of a healthy 26-year-old man with a painless swelling in the hard palate near the middle raphe, asymptomatic, well limited, and raised edges. The patient was submitted to incisional biopsy and histopathological examination. The histological diagnosis was necrotizing sialometaplasia. Discussion. The clinical and histological similarity between this entity and a malignant lesion implies a risk of unnecessary or mistreatment. Therefore, clinicians and pathologists should be aware of this lesion as to avoid errors in the diagnosis and treatment of this benign pathologic condition.

  9. Cadmium exposure activates the ERK signaling pathway leading to altered osteoblast gene expression and apoptotic death in Saos-2 cells

    PubMed Central

    Arbon, Kate S.; Christensen, Cody M.; Harvey, Wendy A.; Heggland, Sara J.

    2012-01-01

    Recent reports of cadmium in electronic waste and jewelry have increased public awareness regarding this toxic metal. Human exposure to cadmium is associated with the development of osteoporosis. We previously reported cadmium induces apoptosis in human tumor-derived Saos-2 osteoblasts. In this study, we examine the extracellular signal-regulated protein kinase (ERK) and protein kinase C (PKC) pathways in cadmium-induced apoptosis and altered osteoblast gene expression. Saos-2 osteoblasts were cultured in the presence or absence of 10 μM CdCl2 for 2–72 hours. We detected significant ERK activation in response to CdCl2 and pretreatment with the ERK inhibitor PD98059 attenuated cadmium-induced apoptosis. However, PKCα activation was not observed after exposure to CdCl2 and pretreatment with the PKC inhibitor, Calphostin C, was unable to rescue cells from cadmium-induced apoptosis. Gene expression studies were conducted using qPCR. Cells exposed to CdCl2 exhibited a significant decrease in the bone-forming genes osteopontin (OPN) and alkaline phosphatase (ALP) mRNA. In contrast, SOST, whose protein product inhibits bone formation, significantly increased in response to CdCl2. Pretreatment with PD98059 had a recovery effect on cadmium-induced changes in gene expression. This research demonstrates cadmium can directly inhibit osteoblasts via ERK signaling pathway and identifies SOST as a target for cadmium-induced osteotoxicity. PMID:22019892

  10. Hydrogen sulfide alleviates cadmium-induced morpho-physiological and ultrastructural changes in Brassica napus.

    PubMed

    Ali, Basharat; Gill, Rafaqat A; Yang, Su; Gill, Muhammad B; Ali, Shafaqat; Rafiq, Muhammad T; Zhou, Weijun

    2014-12-01

    In the present study, role of hydrogen sulfide (H2S) in alleviating cadmium (Cd) induced stress in oilseed rape (Brassica napus L.) was studied under greenhouse conditions. Plants were grown hydroponically under three levels (0, 100, and 500µM) of Cd and three levels (0, 100 and 200µM) of H2S donor, sodium hydrosulfide (NaHS). Results showed that application of H2S significantly improved the plant growth, root morphology, chlorophyll contents, elements uptake and photosynthetic activity in B. napus plants under Cd stress. Moreover, addition of H2S reduced the Cd concentration in the leaves and roots of B. napus plants under Cd-toxicity. Exogenously applied H2S decreased the production of malondialdehyde and reactive oxygen species in the leaves and roots by improving the enzymatic antioxidant activities under Cd stress conditions. The microscopic examination indicated that application of exogenous H2S improved the cell structures and enabled a clean mesophyll cell having a well developed chloroplast with thylakoid membranes, and a number of mitochondria could be observed in the micrographs. A number of modifications could be found in root tip cell i.e. mature mitochondria, long endoplasmic reticulum and golgibodies under combined application of H2S and Cd. On the basis of these findings, it can be concluded that application of exogenous H2S has a protective role on plant growth, photosynthetic parameters, elements uptake, antioxidants enzyme activities and ultrastructural changes in B. napus under high Cd stress conditions.

  11. Cadmium induces vascular permeability via activation of the p38 MAPK pathway

    SciTech Connect

    Dong, Fengyun; Guo, Fang; Li, Liqun; Guo, Ling; Hou, Yinglong; Hao, Enkui; Yan, Suhua; Allen, Thaddeus D.; Liu, Ju

    2014-07-18

    Highlights: • Low-dose cadmium (Cd) induces vascular hyper-permeability. • p38 MAPK mediates Cd-induced disruption of endothelial cell barrier function. • SB203850 inhibits Cd-induced membrane dissociation of VE-cadherin and β-catenin. • SB203850 reduces Cd-induced expression and secretion of TNF-α. - Abstract: The vasculature of various organs is a targeted by the environmental toxin, cadmium (Cd). However, mechanisms leading to pathological conditions are poorly understood. In the present study, we examined the effect of cadmium chloride (CdCl{sub 2}) on human umbilical vein endothelial cells (HUVECs). At 4 μM, CdCl{sub 2} induced a hyper-permeability defect in HUVECs, but not the inhibition of cell growth up to 24 h. This effect of CdCl{sub 2} was dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. The p38 MAPK inhibitor SB203850 suppressed the CdCl{sub 2}-induced alteration in trans-endothelial electrical resistance in HUVEC monolayers, a model measurement of vascular endothelial barrier integrity. SB203850 also inhibited the Cd-induced membrane dissociation of vascular endothelial (VE) cadherin and β-catenin, the important components of the adherens junctional complex. In addition, SB203850 reduces the Cd-induced expression and secretion of tumor necrosis factor α (TNF-α). Taken together, our findings suggest that Cd induces vascular hyper-permeability and disruption of endothelial barrier integrity through stimulation of p38 MAPK signaling.

  12. Cadmium induces hypodermal periderm formation in the roots of the monocotyledonous medicinal plant Merwilla plumbea

    PubMed Central

    Lux, Alexander; Vaculík, Marek; Martinka, Michal; Lišková, Desana; Kulkarni, Manoj G.; Stirk, Wendy A.; Van Staden, Johannes

    2011-01-01

    Background and Aims Merwilla plumbea is an important African medicinal plant. As the plants grow in soils contaminated with metals from mining activities, the danger of human intoxication exists. An experiment with plants exposed to cadmium (Cd) was performed to investigate the response of M. plumbea to this heavy metal, its uptake and translocation to plant organs and reaction of root tissues. Methods Plants grown from seeds were cultivated in controlled conditions. Hydroponic cultivation is not suitable for this species as roots do not tolerate aquatic conditions, and additional stress by Cd treatment results in total root growth inhibition and death. After cultivation in perlite the plants exposed to 1 and 5 mg Cd L−1 in half-strength Hoagland's solution were compared with control plants. Growth parameters were evaluated, Cd content was determined by inductively coupled plasma mass spectroscopy (ICP-MS) and root structure was investigated using various staining procedures, including the fluorescent stain Fluorol yellow 088 to detect suberin deposition in cell walls. Key Results The plants exposed to Cd were significantly reduced in growth. Most of the Cd taken up by plants after 4 weeks cultivation was retained in roots, and only a small amount was translocated to bulbs and leaves. In reaction to higher Cd concentrations, roots developed a hypodermal periderm close to the root tip. Cells produced by cork cambium impregnate their cell walls by suberin. Conclusions It is suggested that the hypodermal periderm is developed in young root parts in reaction to Cd toxicity to protect the root from radial uptake of Cd ions. Secondary meristems are usually not present in monocotyledonous species. Another interpretation explaining formation of protective suberized layers as a result of periclinal divisions of the hypodermis is discussed. This process may represent an as yet unknown defence reaction of roots when exposed to elemental stress. PMID:21118841

  13. The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation

    SciTech Connect

    Song, Changcheng Xiao Zhen; Nagashima, Kunio; Li, Chou-Chi H.; Lockett, Stephen J.; Dai Renming; Cho, Edward H.; Conrads, Thomas P.; Veenstra, Timothy D.; Colburn, Nancy H.; Wang Qing; Wang Jiming

    2008-05-01

    Cadmium (Cd{sup 2+}) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd{sup 2+} is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded proteins in the lesions. Here, we report that Cd{sup 2+} directly induces the formation of protein inclusion bodies in cells. The protein inclusion body is an aggresome, a major organelle for collecting ubiquitinated or misfolded proteins. Our results show that aggresomes are enriched in the detergent-insoluble fraction of Cd{sup 2+}-treated cell lysates. Proteomic analysis identified 145 proteins in the aggresome-enriched fractions. One of the proteins is the highly conserved valosin-containing protein (VCP), which has been shown to colocalize with aggresomes and bind ubiquitinated proteins through its N domain (1-200). Our subsequent examination of VCP's role in the formation of aggresomes induced by Cd{sup 2+} indicates that the C-terminal tail (no. 780-806) of VCP interacts with histone deacetylase HDAC6, a mediator for aggresome formation, suggesting that VCP participates in transporting ubiquitinated proteins to aggresomes. This function of VCP is impaired by inhibition of the deacetylase activity of HDAC6 or by over-expression of VCP mutants that do not bind ubiquitinated proteins or HDAC6. Our results indicate that Cd{sup 2+} induces the formation of protein inclusion bodies by promoting the accumulation of ubiquitinated proteins in aggresomes through VCP and HDAC6. Our delineation of the role of VCP in regulating cell responses to ubiquitinated proteins has important implications for understanding Cd{sup 2+} toxicity and associated diseases.

  14. Cadmium-induced changes in the membrane of human erythrocytes and molecular models.

    PubMed

    Suwalsky, M; Villena, F; Norris, B; Cuevas, F; Sotomayor, C P

    2004-06-01

    The structural effects of cadmium on cell membranes were studied through the interaction of Cd(2+) ions with human erythrocytes and their isolated unsealed membranes (IUM). Studies were carried out by scanning electron microscopy and fluorescence spectroscopy, respectively. Cd(2+) induced shape changes in erythrocytes, which took the form of echinocytes. According to the bilayer couple hypothesis, this result meant that Cd(2+) ions located in the outer monolayer of the erythrocyte membrane. Fluorescence spectroscopy measurements in IUM indicated a disordering effect at both the polar headgroup and the acyl chain packing arrangements of the membrane phospholipid bilayer. Cd(2+) ions also interacted with molecular models of the erythrocyte membrane consisting in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representing classes of phospholipids located in the outer and inner monolayers the erythrocyte membrane, respectively. X-ray diffraction indicated that Cd(2+) ions induced structural perturbation of the polar headgroup and of the hydrophobic acyl regions of DMPC, while the effects of cadmium on DMPE bilayers were much milder. This conclusion is supported by fluorescence spectroscopy measurements on DMPC large unilamellar vesicles (LUV). All these findings point to the important role of phospholipid bilayers in the interaction of cadmium on cell membranes. PMID:15149816

  15. Cadmium induced oxidative damage and apoptosis in the hepatopancreas of Meretrix meretrix.

    PubMed

    Xia, Liping; Chen, Sihan; Dahms, Hans-Uwe; Ying, Xueping; Peng, Xue

    2016-07-01

    Even trace amounts of cadmium (Cd), a non-essential metal, are known to be toxic to aquatic organisms. Here we investigated the relationship between cadmium ion (Cd(2+)) exposure and oxidative damage and apoptosis in the hepatopancreas of the clam Meretrix meretrix. Clams were exposed to different concentrations of Cd(2+) (0, 1.5, 3, 6 and 12 mg L(-1)) for 5 days. We monitored both antioxidant enzyme activity, including that of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and levels of malondialdehyde (MDA), glutathione (GSH) and glutathione disulfide (GSSG). Apoptosis of hepatopancreatic cells was detected by DNA laddering and AO/EB double fluorescent staining. The results show that the rate of apoptotis, MDA levels, and caspase-3 activity, increased with Cd(2+) concentration, whereas GPx activity and the ratio of GSH/GSSG, decreased. SOD and CAT enzyme activity first increased, then decreased, with increasing Cd(2+) concentration; peak activity of these enzymes was recorded in the 3 mg L(-1) Cd(2+)-treatment group. These results show that Cd-induced oxidative damage can both induce, and aggravate, apoptosis in the hepatopancreatic cells of clams, even at Cd(2+) concentrations far below the semi-lethal dose for adult clams. The observed changes in caspase-3 activity enhanced significantly at lower Cd(2+) concentrations, indicating that caspase-3 is a suitable biomarker for heavy metal pollution, especially cadmium pollution, in marine organisms. PMID:27038477

  16. Protective effect of grape seed extract against cadmium-induced testicular dysfunction

    PubMed Central

    ALKHEDAIDE, ADEL; ALSHEHRI, ZAFER SAAD; SABRY, AYMAN; ABDEL-GHAFFAR, TULIP; SOLIMAN, MOHAMED MOHAMED; ATTIA, HOSSAM

    2016-01-01

    Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)-induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2–4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi-quantitative RT-PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B-cell lymphoma 2-associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co-treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B-cell lymphoma 2-associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side-chain cleavage enzyme, cytochrome P450 17A1, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, androgen receptor, steroidogenic acute regulatory

  17. Protective effect of grape seed extract against cadmium-induced testicular dysfunction.

    PubMed

    Alkhedaide, Adel; Alshehri, Zafer Saad; Sabry, Ayman; Abdel-Ghaffar, Tulip; Soliman, Mohamed Mohamed; Attia, Hossam

    2016-04-01

    Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)‑induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2‑4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi‑quantitative RT‑PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B‑cell lymphoma 2‑associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co‑treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B‑cell lymphoma 2‑associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side‑chain cleavage enzyme, cytochrome P450 17A1, 3β‑hydroxysteroid dehydrogenase (3β‑HSD), 17β‑HSD, androgen receptor

  18. Protective effects of different antioxidants against cadmium induced oxidative damage in rat testis and prostate tissues.

    PubMed

    Jahan, Sarwat; Zahra, Asia; Irum, Umaira; Iftikhar, Natasha; Ullah, Hizb

    2014-08-01

    The present study was performed to determine the effects of different antioxidants on testicular histopathology and oxidative damage induced by cadmium (Cd) in rat testis and prostate. Twenty five rats were equally divided into five groups (n = 5/group). The control group was injected subcutaneously with saline while the Cd alone treated group received a subcutaneous injection of 0.2 mg/kg CdCl(2). Other groups were treated with sulphoraphane (25 µg/rat), vitamin E (75 mg/kg), and Ficus Religiosa plant extract (100 mg/kg) orally along with subcutaneous injections of 0.2 mg/kg CdCl(2) for fifteen days. Oxidative damage in the testicular and prostate tissues were assessed by the estimation of catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and glutathione reductase (GSR) activity. Lipid peroxidation (TBARS), protein estimation, and histomorphology were also assessed. Cadmium exposure caused a significant decrease in antioxidant enzymes like CAT, POD, SOD, GSR, protein concentrations, and a marked increase in TBARS activity in rat testis and prostate. Histological examination of adult male rat testes showed a disruption in the arrangement of seminiferous tubules along with a reduction in the number of germ cells, Leydig cells, tunica albuginea thickness, diameter of seminiferous tubules, and height of germinal epithelium. Co-treatment with vitamin E, sulphoraphane, and Ficus religiosa were found to be effective in reversing Cd induced toxicity, representing potential therapeutic options to protect the reproductive tissues from the detrimental effects of Cd toxicity. PMID:24758558

  19. Necrotizing hepatitis in pet birds associated with Pseudomonas fluorescens.

    PubMed

    Jackson, M K; Phillips, S N

    1996-01-01

    Six pet birds, from a flock of 100 birds of various species, died within a 2-day period. Drinking water had recently been changed from potable water to irrigation water. Three birds submitted for necropsy had hepatic necrosis with numerous gram-negative rodshaped bacteria present in necrotic areas and Kuppfer cells. Pseudomonas fluorescens was isolated in pure culture from the livers of all three birds and from other organs. This is the first report of naturally occurring disease in which P. fluorescens was the sole etiologic agent identified. PMID:8790902

  20. Ribosomal genes as early targets of cadmium-induced toxicity in Chironomus riparius larvae.

    PubMed

    Planelló, R; Martínez-Guitarte, J L; Morcillo, G

    2007-02-01

    Cadmium is a widespread environmental pollutant that causes severe impacts in organisms. Although the effects of cadmium on aquatic insects have been studied in terms of their toxicity and changes in developmental parameters, little is known about its molecular and genetic effects. We have investigated the alterations in the pattern of gene expression provoked by acute exposure to cadmium in Chironomus riparius Mg. (Diptera, Chironomidae), a sentinel organism widely used in aquatic toxicity testing. The early cytotoxic effects were evaluated using immunocytochemistry and specific fluorescent probes in fourth instar larvae after 12 h of 10 mM cadmium treatments; under these conditions no significant effect on larvae mortality was detected until after 36 h of exposure. The changes in the pattern of gene expression were analysed by means of DNA/RNA hybrid antibodies in the polytene chromosomes from salivary gland cells. A decrease in the activity of the nucleolus is especially remarkable, accompanied by a significant reduction in size and the modification in nucleolar architecture, as shown by FISH. The inhibition of rDNA transcription was further evaluated by Northern blot analysis, which showed a marked decrease in the level of preribosomal rRNA (54% 45S 12 h). However, the BR genes, whose products are the giant polypeptides that constitute the silk-like secretion for constructing housing tubes, remain active. Simultaneously, decondensation and activation take place at some chromosomal regions, especially at the centromeres. The changes observed in the pattern of gene expression do not resemble those found after heat shock or other cell stressors. These data provide the first evidence that cadmium interacts with ribosomal genes and results in a drastic impairment of the functional activity of the nucleolus, an essential organelle for cellular survival. Therefore, the depletion of ribosomes would be a long-term effect of Cd-induced cellular damage. These findings may

  1. Cadmium-induced accumulation of putrescine in oat and bean leaves

    NASA Technical Reports Server (NTRS)

    Weinstein, L. H.; Kaur-Sawhney, R.; Rajam, M. V.; Wettlaufer, S. H.; Galston, A. W.

    1986-01-01

    The effects of Cd2+ on putrescine (Put), spermidine (Spd), and spermine (Spm) titers were studied in oat and bean leaves. Treatment with Cd2+ for up to 16 hours in the light or dark resulted in a large increase in Put titer, but had little or no effect on Spd or Spm. The activity of arginine decarboxylase (ADC) followed the pattern of Put accumulation, and experiments with alpha-difluoromethylarginine established that ADC was the enzyme responsible for Put increase. Concentrations of Cd2+ as low as 10 micromolar increased Put titer in oat segments. In bean leaves, there was a Cd(2+)-induced accumulation of Put in the free and soluble conjugated fractions, but not in the insoluble fraction. This suggests a rapid exchange between Put that exists in the free form and Put found in acid soluble conjugate forms. It is concluded that Cd2+ can act like certain other stresses (K+ and Mg2+ deficiency, excess NH4+, low pH, salinity, osmotic stress, wilting) to induce substantial increases in Put in plant cells.

  2. Arsenic- and cadmium-induced toxicogenomic response in mouse embryos undergoing neurulation

    SciTech Connect

    Robinson, Joshua F.; Yu, Xiaozhong; Moreira, Estefania G.; Hong, Sungwoo; Faustman, Elaine M.

    2011-01-15

    Arsenic (As) and cadmium (Cd) are well-characterized teratogens in animal models inducing embryotoxicity and neural tube defects (NTDs) when exposed during neurulation. Toxicological research is needed to resolve the specific biological processes and associated molecular pathways underlying metal-induced toxicity during this timeframe in gestational development. In this study, we investigated the dose-dependent effects of As and Cd on gene expression in C57BL/6J mouse embryos exposed in utero during neurulation (GD8) to identify significantly altered genes and corresponding biological processes associated with embryotoxicity. We quantitatively examined the toxicogenomic dose-response relationship at the gene level. Our results suggest that As and Cd induce dose-dependent gene expression alterations representing shared (cell cycle, response to UV, glutathione metabolism, RNA processing) and unique (alcohol/sugar metabolism) biological processes, which serve as robust indicators of metal-induced developmental toxicity and indicate underlying embryotoxic effects. Our observations also correlate well with previously identified impacts of As and Cd on specific genes associated with metal-induced toxicity (Cdkn1a, Mt1). In summary, we have identified in a quantitative manner As and Cd induced dose-dependent effects on gene expression in mouse embryos during a peak window of sensitivity to embryotoxicity and NTDs in the sensitive C57BL/6J strain.

  3. Mechanistic insight into cadmium-induced inactivation of the Bloom protein

    PubMed Central

    Qin, Wei; Bazeille, Nicolas; Henry, Etienne; Zhang, Bo; Deprez, Eric; Xi, Xu-Guang

    2016-01-01

    Cadmium is a toxic metal that inactivates DNA-repair proteins via multiple mechanisms, including zinc substitution. In this study, we investigated the effect of Cd2+ on the Bloom protein (BLM), a DNA-repair helicase carrying a zinc-binding domain (ZBD) and playing a critical role to ensure genomic stability. One characteristics of BLM-deficient cells is the elevated rate of sister chromatid exchanges, a phenomenon that is also induced by Cd2+. Here, we show that Cd2+ strongly inhibits both ATPase and helicase activities of BLM. Cd2+ primarily prevents BLM-DNA interaction via its binding to sulfhydryl groups of solvent-exposed cysteine residues and, concomitantly, promotes the formation of large BLM multimers/aggregates. In contrast to previously described Cd2+ effects on other zinc-containing DNA-repair proteins, the ZBD appears to play a minor role in the Cd2+-mediated inhibition. While the Cd2+-dependent formation of inactive multimers and the defect of DNA-binding were fully reversible upon addition of EDTA, the inhibition of the DNA unwinding activity was not counteracted by EDTA, indicating another mechanism of inhibition by Cd2+ relative to the targeting of a catalytic residue. Altogether, our results provide new clues for understanding the mechanism behind the ZBD-independent inactivation of BLM by Cd2+ leading to accumulation of DNA double-strand breaks. PMID:27194376

  4. N-acetylcysteine protects against cadmium-induced oxidative stress in rat hepatocytes

    PubMed Central

    Wang, Jicang; Zhu, Huali; Liu, Xuezhong

    2014-01-01

    Cadmium (Cd) is a well-known hepatotoxic environmental pollutant. We used rat hepatocytes as a model to study oxidative damage induced by Cd, effects on the antioxidant systems, and the role of N-acetylcysteine (NAC) in protecting cells against Cd toxicity. Hepatocytes were incubated for 12 and 24 h with Cd (2.5, 5, 10 µM). Results showed that Cd can induce cytotoxicity: 10 µM resulted in 36.2% mortality after 12 h and 47.8% after 24 h. Lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase activities increased. Additionally, reactive oxygen species (ROS) generation increased in Cd-treated hepatocytes along with malondialdehyde levels. Glutathione concentrations significantly decreased after treatment with Cd for 12 h but increased after 24 h of Cd exposure. In contrast, glutathione peroxidase activity significantly increased after treatment with Cd for 12 h but decreased after 24 h. superoxide dismutase and catalase activities increased at 12 h and 24 h. glutathione S-transferase and glutathione reductase activities decreased, but not significantly. Rat hepatocytes incubated with NAC and Cd simultaneously had significantly increased viability and decreased Cd-induced ROS generation. Our results suggested that Cd induces ROS generation that leads to oxidative stress. Moreover, NAC protects rat hepatocytes from cytotoxicity associated with Cd. PMID:25234327

  5. Lead and cadmium induced alterations of cellular functions in leaves of Alocasia macrorrhiza L. Schott.

    PubMed

    Liu, Nan; Lin, Zhi-Fang; Lin, Gui-Zhu; Song, Li-Ying; Chen, Shao-Wei; Mo, Hui; Peng, Chang-Lian

    2010-09-01

    Alocasia macrorrhiza is a fast growing and propagating herbaceous species commonly found in South China. To determine its physiological responses to Pb and Cd stresses, the biochemical, histochemical and cytochemical changes under PbAC2 and CdCl2 phytotoxicity were detected using leaf discs as an experimental model. After leaf discs were infiltrated in different concentrations of PbAC2 and CdCl2 solutions (0, 50, 100, 150, 200 microM) for 72 h, the formation of reactive oxygen species (H2O2 and O2-) in plant tissue were found to be exaggerated together with elevated OH concentration and cell death. Changes in chlorophyll fluorescence (Fv/Fm, PhiPSII, qP and NPQ) imaging colours/areas of leaf discs indicated decreased photosystem II functions by both heavy metal treatments and positive reactions of antioxidants under Pb2+ stress. Results showed that fluorescent detection of hydroxylated terephthlate using terephthalic acid as OH trap is a simple, yet valuable and specific method for monitoring OH generation in plant tissue under heavy metal stresses. As compared with Cd2+, Pb2+ was found to be less toxic, indicating that A. macrorrhiza tissue might have a potential tolerance to Pb.

  6. Cadmium-Induced Accumulation of Putrescine in Oat and Bean Leaves 1

    PubMed Central

    Weinstein, Leonard H.; Kaur-Sawhney, Ravindar; Rajam, M. Venkat; Wettlaufer, Scott H.; Galston, Arthur W.

    1986-01-01

    The effects of Cd2+ on putrescine (Put), spermidine (Spd), and spermine (Spm) titers were studied in oat and bean leaves. Treatment with Cd2+ for up to 16 hours in the light or dark resulted in a large increase in Put titer, but had little or no effect on Spd or Spm. The activity of arginine decarboxylase (ADC) followed the pattern of Put accumulation, and experiments with α-difluoromethylarginine established that ADC was the enzyme responsible for Put increase. Concentrations of Cd2+ as low as 10 micromolar increased Put titer in oat segments. In bean leaves, there was a Cd2+-induced accumulation of Put in the free and soluble conjugated fractions, but not in the insoluble fraction. This suggests a rapid exchange between Put that exists in the free form and Put found in acid soluble conjugated forms. It is concluded that Cd2+ can act like certain other stresses (K+ and Mg2+ deficiency, excess NH4+, low pH, salinity, osmotic stress, wilting) to induce substantial increases in Put in plant cells. PMID:11539091

  7. Calcium alleviates cadmium-induced inhibition on root growth by maintaining auxin homeostasis in Arabidopsis seedlings.

    PubMed

    Li, Ping; Zhao, Chengzhou; Zhang, Yongqiang; Wang, Xiaomin; Wang, Xiaoyu; Wang, Jianfeng; Wang, Feng; Bi, Yurong

    2016-01-01

    Cadmium (Cd) toxicity has been widely studied in different plant species. However, the mechanism involved in its toxicity and the cell response to Cd has not been well established. In the present study, we investigated the possible mechanism of calcium (Ca) in protecting Arabidopsis from Cd toxicity. The results showed that 50 μM Cd significantly inhibited the seedling growth and decreased the chlorophyll content in Arabidopsis. Specifically, the primary root (PR) length was decreased but the lateral root (LR) number was increased under Cd stress. Furthermore, Cd enhanced the hydrogen peroxide (H2O2) content and lipid peroxidation as indicated by malondialdehyde (MDA) accumulation. Cd also altered the level and the distribution of auxin in PR tips (as evidenced by DR5::GUS and PIN:GFP reporter expression) and the expression of several putative auxin biosynthetic, catabolic, and transport pathway-related genes. Application of 3 mM Ca alleviated the inhibition of Cd on the root growth. Ca application not only led to reducing oxidative injuries but also restoring the normal auxin transport and distribution in Arabidopsis root under Cd stress. Taken together, these results suggest that Ca alleviates the root growth inhibition caused by Cd through maintaining auxin homeostasis in Arabidopsis seedlings.

  8. Cadmium-induced physiological response and antioxidant enzyme changes in the novel cadmium accumulator, Tagetes patula.

    PubMed

    Liu, Yu-Ting; Chen, Zueng-Sang; Hong, Chwan-Yang

    2011-05-30

    The accumulation and effect of cadmium (Cd) on the growth and enzymatic activities changes of antioxidants in Tagetes patula, French marigold, were investigated to reveal the physiological mechanisms corresponding to its Cd tolerance and accumulation. Hydroponically grown T. patula plants were treated with different concentrations of Cd (0, 10, 25, 50 μM Cd Cl(2)) at various regime of times. T. patula accumulated Cd to a maximum of 450 mg Cd kg(-1) dry weight (DW) in shoot and 3500 mg Cd kg(-1) DW in root after 14 days' exposure at 10 and 50 μM Cd Cl(2), respectively. The translocation factors of Cd were greater than 1 in plants exposed to 10 μM Cd Cl(2). Toxic effects were gradually observed with increasing Cd concentration (25 and 50 μM) accompanied with the reduction of biomass, chlorophyll content, decrease of cell viability and the increase level of lipid peroxidation. In leaves of T. patula, the activities of ascorbate peroxidase (APX), glutathione reductase (GR) and superoxide dismutase (SOD) were induced by Cd. However, in roots, activities of APX, GR, SOD and catalase (CAT) were significantly reduced by 25 and 50 μM Cd treatment but not 10 μM Cd. In-gel zymography analysis revealed that Cd induced the enzymatic activities of APX, MnSOD, CuZnSOD and different isozymes of GR in leaves. These results indicate that T. patula is a novel Cd accumulator and able to tolerate with Cd-induced toxicity by activation of its antioxidative defense system. PMID:21458916

  9. Modulation of cadmium induced alterations in murine thymocytes by piperine: oxidative stress, apoptosis, phenotyping and blastogenesis.

    PubMed

    Pathak, Neelima; Khandelwal, Shashi

    2006-08-14

    Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use in Indian medicine. It is known to exhibit a variety of biological activities which include anti-pyretic, anti-inflammatory, anti-depressant, hepatoprotective and antitumor. Its immunomodulatory role has so far been limited to humoral response. The influence of piperine on murine thymocytes, immunocompromised by cadmium has been reported by us in this investigation. The various biochemical parameters such as oxidative stress markers (ROS and GSH), Bcl-2 protein expression, mitochondrial membrane potential, caspase-3 activity, DNA damage, blastogenesis and T lymphocyte phenotypes were determined. Cadmium (25 microM) induced apoptosis earliest at 6 h. Alterations in ROS and GSH preceded mitochondrial membrane depolarization and caspase-3 activation followed by apoptosis. The phenotypic changes occurred at 18 h and blastogenesis at 72 h. Various conc. of piperine (1, 10 and 50 microg/ml) when added along with Cd (25 microM) from 1.5 to 72 h, caused a dose and time dependent amelioration in all the cellular events mentioned above. Modulation of oxidative stress has earlier been reported to reduce Cd induced apoptosis in murine lymphocytes. Inhibition of the ROS production and replenishment of GSH by piperine, may in part be responsible for the suppression of downstream cascade of events, i.e. apoptosis, blastogenesis and T lymphocyte phenotyping. The study clearly demonstrated the anti-oxidative, anti-apoptotic, and restorative ability against cell proliferative mitogenic response and phenotypic alterations by piperine, suggesting its therapeutic usefulness in immunocompromised conditions. PMID:16780805

  10. Cadmium-induced teratogenicity: Association with ROS-mediated endoplasmic reticulum stress in placenta

    SciTech Connect

    Wang, Zhen; Wang, Hua; Xu, Zhong Mei; Ji, Yan-Li; Chen, Yuan-Hua; Zhang, Zhi-Hui; Zhang, Cheng; Meng, Xiu-Hong; Zhao, Mei; Xu, De-Xiang

    2012-03-01

    The placenta is essential for sustaining the growth of the fetus. An increased endoplasmic reticulum (ER) stress has been associated with the impaired placental and fetal development. Cadmium (Cd) is a potent teratogen that caused fetal malformation and growth restriction. The present study investigated the effects of maternal Cd exposure on placental and fetal development. The pregnant mice were intraperitoneally injected with CdCl{sub 2} (4.5 mg/kg) on gestational day 9. As expected, maternal Cd exposure during early limb development significantly increased the incidences of forelimb ectrodactyly in fetuses. An obvious impairment in the labyrinth, a highly developed tissue of blood vessels, was observed in placenta of mice treated with CdCl{sub 2}. In addition, maternal Cd exposure markedly repressed cell proliferation and increased apoptosis in placenta. An additional experiment showed that maternal Cd exposure significantly upregulated the expression of GRP78, an ER chaperone. Moreover, maternal Cd exposure induced the phosphorylation of placental eIF2α, a downstream molecule of PERK signaling. In addition, maternal Cd exposure significantly increased the level of placental CHOP, another target of PERK signaling, indicating that the unfolded protein response (UPR) signaling was activated in placenta of mice treated with CdCl{sub 2}. Interestingly, alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, significantly alleviated Cd-induced placental ER stress and UPR. Taken together, these results suggest that reactive oxygen species (ROS)-mediated ER stress might be involved in Cd-induced impairment on placental and fetal development. Antioxidants may be used as pharmacological agents to protect against Cd-induced fetal malformation and growth restriction. -- Highlights: ► Cd induces fetal malformation and growth restriction. ► Cd induced placental ER stress and UPR. ► PBN alleviates Cd-induced ER stress and UPR in placenta. ► ROS-mediated ER

  11. [Necrotizing fasciitis of the head and neck].

    PubMed

    Gajda, Mieczysław; Holzhausen, Hans-Jürgen; Gudziol, Silke; Hauptmann, Steffen; Bloching, Marc

    2005-01-01

    Necrotizing fasciitis (NF) is a potentially lethal soft tissue infection characterized by cutaneous necrosis, suppurative fasciitis, vascular thrombosis and extreme systemic toxicity. It is a rare entity in the head and neck region, but occur most frequently in patients with diabetes and chronic alcoholism. Mostly involved are immunodeficient patients with banal infections of the upper aerodigestive tract, small traumas, but also after surgical procedures. Necrotizing fasciitis is an infection caused by aerobic or anaerobic microorganisms. A strong complication is a streptococcus-associated-toxic shock-syndrome which should be prevented because it is often associated with letal outcome. Septicemia and systemic toxic effects may lead to death within as short a time as 2 to 4 days. Necrotizing fasciitis is often misdiagnosed or the diagnosis is delayed with a mortality rate of approximately 30-70%. Once identified, treatment consists of antimicrobial therapy and surgical debridement followed at a later date with reconstructive surgery. We present a fatal case of craniofacial necrotizing fasciitis (NF) in a 63-year-old diabetic and chronic alcoholic man and discuss it's pathophysiology, clinical manifestations and the best therapeutic choice for this disease. A review of the literature with the clinical presentations, bacteriology diagnosis and treatment was presented.

  12. Necrotizing granulomatous inflammation of the liver.

    PubMed

    Chou, Chung Kuao; Chou, Shih-Cheng

    2016-09-01

    A 73-year-old patient with necrotizing granulomatous inflammation of the liver is presented. The computed tomography demonstrated 2 hypodense tumors with progressive enhancement in the liver. They became nearly isodense to the normal hepatic parenchyma on the delayed phase. PMID:27594940

  13. [Necrotizing fasciitis of the head and neck].

    PubMed

    Gajda, Mieczysław; Holzhausen, Hans-Jürgen; Gudziol, Silke; Hauptmann, Steffen; Bloching, Marc

    2005-01-01

    Necrotizing fasciitis (NF) is a potentially lethal soft tissue infection characterized by cutaneous necrosis, suppurative fasciitis, vascular thrombosis and extreme systemic toxicity. It is a rare entity in the head and neck region, but occur most frequently in patients with diabetes and chronic alcoholism. Mostly involved are immunodeficient patients with banal infections of the upper aerodigestive tract, small traumas, but also after surgical procedures. Necrotizing fasciitis is an infection caused by aerobic or anaerobic microorganisms. A strong complication is a streptococcus-associated-toxic shock-syndrome which should be prevented because it is often associated with letal outcome. Septicemia and systemic toxic effects may lead to death within as short a time as 2 to 4 days. Necrotizing fasciitis is often misdiagnosed or the diagnosis is delayed with a mortality rate of approximately 30-70%. Once identified, treatment consists of antimicrobial therapy and surgical debridement followed at a later date with reconstructive surgery. We present a fatal case of craniofacial necrotizing fasciitis (NF) in a 63-year-old diabetic and chronic alcoholic man and discuss it's pathophysiology, clinical manifestations and the best therapeutic choice for this disease. A review of the literature with the clinical presentations, bacteriology diagnosis and treatment was presented. PMID:16521446

  14. [Face necrotizing fasciitis following spinocellular epithelioma excision].

    PubMed

    Gindre, S; Dellamonica, J; Couadau, E; Carles, M; Vandenbos, F; Delgiudice, P; Grimaud, D; Ichai, C

    2005-06-01

    Necrotizing fasciitis is a bacterial dermo-hypodermitis with superficial aponevrosis necrosis due to Streptococcus pyogenes. Head and neck region are some rare localization of this infection especially after surgery. We report herein a case of a face necrotizing fasciitis following minor face surgery. A 86 year-old Caucasian male without any antecedents, nor treatment, has been operated for a fronthead spinocellular epithelioma under local anesthesia. Twelve hours later, a severe pain localized to the face occurred, with sleeplessness, followed up with a face orbitary oedema and fever. Twenty-four hours later, an intravenous antibiotherapy was therefore started and surgical treatment was performed as soon as the diagnosis of necrotizing fasciitis was considered. An important inflammatory oedema was noticed, associated to a large necrotic softening of the face, the eyelid and the neck sub-cutaneous tissues. Then, the patient has been transferred in intensive care unit because multi-organ failure clinical and biological signs occurred. Pre-operatory bacteriological samples culture identified Streptococcus pyogenes. Repeated surgical explorations and debridement (excision, cleaning, draining and bandages recovery) were performed daily as needed until all the necrotic tissue was all eradicated. The antibiotherapy was prescribed to totalised 15 days. Our report underlines the importance of an early recognition of the diagnosis of soft tissue infection, because early surgical treatment has a better prognosis and antibiotic treatment alone is inefficient for the recovery. Alert is delivered by the local signs quickly followed up by skin changes. Anti-inflammatory therapy must be avoid in case of any soft tissue infection sign: they may increase the lesions, hide alarm signs and delay surgical treatment.

  15. [Face necrotizing fasciitis following spinocellular epithelioma excision].

    PubMed

    Gindre, S; Dellamonica, J; Couadau, E; Carles, M; Vandenbos, F; Delgiudice, P; Grimaud, D; Ichai, C

    2005-06-01

    Necrotizing fasciitis is a bacterial dermo-hypodermitis with superficial aponevrosis necrosis due to Streptococcus pyogenes. Head and neck region are some rare localization of this infection especially after surgery. We report herein a case of a face necrotizing fasciitis following minor face surgery. A 86 year-old Caucasian male without any antecedents, nor treatment, has been operated for a fronthead spinocellular epithelioma under local anesthesia. Twelve hours later, a severe pain localized to the face occurred, with sleeplessness, followed up with a face orbitary oedema and fever. Twenty-four hours later, an intravenous antibiotherapy was therefore started and surgical treatment was performed as soon as the diagnosis of necrotizing fasciitis was considered. An important inflammatory oedema was noticed, associated to a large necrotic softening of the face, the eyelid and the neck sub-cutaneous tissues. Then, the patient has been transferred in intensive care unit because multi-organ failure clinical and biological signs occurred. Pre-operatory bacteriological samples culture identified Streptococcus pyogenes. Repeated surgical explorations and debridement (excision, cleaning, draining and bandages recovery) were performed daily as needed until all the necrotic tissue was all eradicated. The antibiotherapy was prescribed to totalised 15 days. Our report underlines the importance of an early recognition of the diagnosis of soft tissue infection, because early surgical treatment has a better prognosis and antibiotic treatment alone is inefficient for the recovery. Alert is delivered by the local signs quickly followed up by skin changes. Anti-inflammatory therapy must be avoid in case of any soft tissue infection sign: they may increase the lesions, hide alarm signs and delay surgical treatment. PMID:15963844

  16. Detecting necrotic neurons with fluoro-jade stain.

    PubMed

    Krinke, G J; Classen, W; Vidotto, N; Suter, E; Würmlin, C H

    2001-10-01

    Fluoro-jade, a novel stain for detection of neuropathic lesions by fluorescence microscopy, was validated on the models of toxic neuropathy induced with 3-acetylpyridine (3-AP) or with acrylamide (ACR). Groups of male and female albino rats of Wistar strain were either exposed to a single administration of 80 mg/kg i.p. 3-AP followed 5 hours later by 300 mg/kg of nicotinamide i.p. and examined at days 3 and 15, or to 15 daily doses of 30 mg/kg p.o. ACR and examined at day 15. Following in-life behavioral observations and measurements, the rats were fixed by perfusion with formalin. Additional animals treated with same dose of 3-AP and nicotinamide were submitted to purposeful autolysis for 4 or 16 hours before immersion fixation with formalin on test day 3. In-life observations showed in 3-AP-treated animals signs of severe general toxicity, sensorimotor dysfunction and decreased motor activity starting shortly after the treatment and persisting throughout the observation period. ACR-treated rats started to develop abnormal gait on test day 8 and by day 15 developed reduced grip strength, increased landing footsplay and decreased motor activity. Fluoro-jade, applied to paraffin sections of the nervous system, detected selectively and sensitively the necrotic neurons in the brain, especially those in the inferior olivary nucleus of animals treated with 3-AP, at test day 3, as well as the necrotic Purkinje cells in the cerebellum of ACR-treated animals at test day 15. Chromatolytic neurons in the dorsal root ganglia of ACR-treated animals did not stain positively, indicating that this kind of reversible neuronal remodeling is not detectable using fluoro-jade. Necrotic neurons were still stained by fluoro-jade after 4 hour autolysis, but following 16 hour autolysis the results became false negative. There was no false positive fluorescence in fresh or autolytic tissues, except that emitted by red blood cells in unperfused specimens. The study confirmed the validity of

  17. Cadmium-induced osteomalacia.

    PubMed Central

    Blainey, J D; Adams, R G; Brewer, D B; Harvey, T C

    1980-01-01

    The detailed study of a battery plate maker, who had worked with cadmium for 36 years, showed that proteinuria, typical of renal tubular dysfunction, had been observed for 25 years and during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment. Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death. Previously unreported changes were present in the bones, especially the lumbar vertebrae which were probably more the result of gross bone deformity than cadmium deposition. The mechanism of development of the severe acquired Fanconi syndrome was thought to be a combination of dietary calcium and vitamin D deficiency and impaired calcium absorption from abnormal vitamin D synthesis, related to the cadmium deposition in the renal tubules, which also caused the defect in renal tubular reabsorption. Images PMID:7426480

  18. Expression of anti-SRP19 antibody in muscle tissues from patients with autoimmune necrotizing myopathy.

    PubMed

    Wang, Q; Duan, F; Liu, P; Wang, P F; Wang, M X

    2016-01-01

    This study aimed to investigate the role of anti-SRP19 antibody in muscle tissues of patients with autoimmune necrotizing myopathy. Immunohistochemistry staining was used to determine the expression of anti-SRP19 antibodies in muscle tissues of autoimmune necrotizing myopathy patients. Results demonstrated that anti-SRP19 antibody was expressed in 71.4% (20/28) of muscle tissue specimens from patients with autoimmune necrotizing myopathy. Anti-SRP19 antibody expression was mainly localized in cytoplasm of necrotic muscle fibers surrounding the small blood vessels and interstitial cells. There were no significant differences in the age, course of disease, muscle, and creatine kinase levels between patients with positive or negative expression of anti-SRP19 antibodies. The expression levels of anti-SRP19, serum anti-nuclear antibodies, as well as anti-Ro-52, anti- SSA, anti-Sm, and anti-Jo-1 antibodies were not significantly different among groups. This study demonstrates that anti-SRP19 antibody is highly expressed in muscle tissues of patients with autoimmune necrotizing myopathy, and suggests that this protein may be involved in the origin and progression of the disease. PMID:27525944

  19. Necrotizing fasciitis in a young patient with acute myeloid leukemia – a diagnostic challenge

    PubMed Central

    2014-01-01

    Background Necrotizing fasciitis is characterized by a fulminant destruction of the soft tissue with an alarmingly high mortality rate. One of the main reasons for the continued high mortality is due to the challenge to punctual recognize and diagnose this disease, as specific cutaneous signs can vary or even be missing early in its evolution – especially in case of simultaneous first manifestation of an acute leukemia. Case presentation An untypical case of necrotizing fasciitis disease in a young patient with the first diagnosis of acute myeloid leukemia is presented. After her induction chemotherapy the only presenting clinical sign was fever in the presence of severe neutropenia without an evident infectious focus. After a few days a painless confluent, erythematous, pustular skin rash with a central necrosis on lateral thigh appeared. Escherichia coli was isolated from blood cultures. Surgical debridement was performed and showed subcutaneous tissue, fascia and underlying muscle around the site of initial cutaneous manifestation with typical necrosis on exploration. But, initially taken skin biopsy did not show any typical histopathological findings like bacteria or inflammatory cells confirming necrotizing fasciitis. Nevertheless, the intraoperative findings were impressive and highly indicative for a necrotizing soft tissue infection, so that the patient was treated according to clinical guidelines with extensive recurrent surgical debridement, broad-spectrum antibiotics and intensive care therapy. After recovering from NF, she successfully underwent further chemotherapy and stem cell transplantation. Conclusion The presented case highlights the risk of potential misinterpretation, delayed diagnosis and treatment of necrotizing fasciitis in patients presenting with an untypical clinical and histopathological manifestation of necrotizing fasciitis as a result of severe neutropenia following chemotherapy for acute myeloid leukemia. PMID:25002906

  20. Contact lens-associated nocardial necrotizing scleritis.

    PubMed

    Rush, Ryan B

    2013-08-01

    A 52 year-old, contact lens-wearing man presented with progressive right eye pain and redness for one month. He had been evaluated and treated for necrotizing scleritis by multiple eye care specialists prior to presentation. He underwent a complete systemic work-up for both autoimmune and infectious causes of scleritis, including a culture. The culture revealed heavy growth of Nocardia asteroides complexes. The patient was treated with topical amikacin and oral Bactrim. Following several weeks of antibiotic treatment, the patient's infection resolved completely, and his visual acuity returned to baseline status. Nocardia is a rare but potentially devastating cause of necrotizing scleritis that may affect contact lens wearers without an associated keratitis. Prompt recognition and early treatment with appropriate antimicrobial agents are critical to achieve a favorable outcome. PMID:23908577

  1. [Necrotizing enterocolitis. Pathogenesis and iatrogenic factors].

    PubMed

    Obladen, M

    1986-08-01

    Following clinical observations, measurements of osmolarity of liquid drugs, and determination of blood loss due to sampling in very low birthweight infants, the following hypothesis on iatrogenic factors contributing to the pathogenesis of necrotizing enterocolitis is proposed: Due to diagnostic blood sampling during intensive care, premature infants may become severely anemic. Therefore their intestinal perfusion is reduced, causing hypoxia and hypoperfusion in the submucosa. Especially in infants with oral feeding and hyperosmolar medication, mechanical factors, hyperosmolarity and infection can affect the mucosa from the luminal side. Simultaneous hypoperfusion and hyperosmolar load may contribute to the pathogenesis of necrotizing enterocolitis. This hypothesis, which needs experimental verification, explains the different incidence of the disease in different hospitals.

  2. Necrotizing Fasciitis: An Emergency Medicine Simulation Scenario

    PubMed Central

    Galust, Henrik; Oliverio, Matthew H; Giorgio, Daniel J; Espinal, Alexis M

    2016-01-01

    Necrotizing fasciitis (NF) is a rare and rapidly progressing life-threatening infectious process. By progressing through a simulation involving a patient with NF and participating in a post-scenario debriefing, learners will gain the necessary skills and knowledge to properly diagnose and manage patients with NF. Learners are taught to initiate appropriate and timely treatment and to advocate on behalf of their patient after inappropriate pushback from consultants to improve outcomes. PMID:27733963

  3. Neonatal necrotizing enterocolitis: a focus on.

    PubMed

    Pellegrini, M; Lagrasta, N; Garcìa Garcìa, C; Campos Serna, J; Zicari, E; Marzocca, G

    2002-01-01

    Necrotizing enterocolitis (NEC) is a multifactorial worldwide problem, representing the most frequent gastrointestinal emergency in neonates. Extremely common in preterm infants, it is also registered in fullterm low birth weight neonates. Despite extensive research, its etiopathogenesis is not completely understood and this neonatal disease remains associated with high morbidity and mortality rates. This review proposes an interdisciplinary focus on recent developments in NEC etiopathogenesis, diagnosis and management. PMID:12608653

  4. Necrotizing sialometaplasia: literature review and case reports.

    PubMed

    Imbery, T A; Edwards, P A

    1996-07-01

    The authors describe necrotizing sialometaplasia, a benign inflammatory lesion primarily involving the minor salivary glands of the hard palate. The lesion presents itself as a deep-seated palatal ulcer with clinical and histologic features mimicking those of a malignant neoplasm. The lesion is believed to be the result of vascular ischemia initiated by trauma. An incisional biopsy is required to confirm the diagnosis, and the lesion heals by secondary intention within four to 10 weeks.

  5. [Descendending necrotizing mediastinitis single center experience].

    PubMed

    Kovacić, Ivan; Kovacić, Marijan

    2014-01-01

    The descending necrotizing mediastinitis is a rare but life-threatening inflammation, and occurs as a complication of deep inflammation of the neck. The mortality rate is still high by 40% despite the use of a variety of potent antimicrobial drugs. We describe 7 patients with the descending necrotizing mediastinitis treated in our hospital during the last 12 years. The primary site of infection in 5 patients were tonsils and pharynx, and in the other two patients odontogenic inflammation of the lower molars. Most of the patients belonged to the risk groups (diabetes mellitus, alcoholism), the average age of 60.4 years. After the diagnosis with computed tomography (CT), we surgically intervened in all patients. Deep neck infections are treated with aggressive surgical cervicotomy and high quality mediastinal drainage was performed with transcervical approach in all patients. Perioperative tracheotomy (n=3) was performed for the upper airway edema and postoperative tracheostomy for extended intubation (n = 1).Only in one case, we subsequently conducted a secondary surgical procedure, lateral thoracotomy because of pleural decortication. All patients were successfully cured with an average length of hospitalization was 24.6 days. For successful treatment of the descending necrotizing mediastinitis diagnosis must be set as early as possible and with the use of computed tomography scanning. Treatment requires the simultaneous application of potent antimicrobial drugs, aggressive surgical debridement of the neck and high-quality drainage of the mediastinum, which can be achieved through the transcervical approach.

  6. A rare case of necrotic thymoma*

    PubMed Central

    DE PALMA, A.; PAGLIARULO, V.; LORUSSO, M.; VERARDO, L.; DI GENNARO, F.; GENUALDO, M.; QUERCIA, R.; MONTRONE, T.; GENTILE, A.; LOIZZI, M.

    2014-01-01

    Summary The Authors report the case of a patient who underwent resection of a huge anterior mediastinal mass, revealing to be a necrotic thymoma. The patient had been previously submitted to surgical biopsies of the mass yielding non-diagnostic results due to extensive necrosis. A sternotomy was then performed to resect the mediastinal mass originating from the thymus, en-bloc with the mediastinal fat and the apparently infiltrated lung. Histopathology showed a possible cyst/thymoma in massive necrosis, not further definable; revision by a specialized experienced pathologist (J. Rosai) confirmed total mass necrosis and no lung infiltration, thus orientating diagnosis towards a necrotic thymoma and excluding a lymphoblastic lymphoma, with similar histopathological features but more frequent in children or characterized by neoplastic infiltration of surrounding lung. Total body computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/CT, show neither local recurrence, nor distant metastases two years after surgery. In case of anterior mediastinal mass with difficult histopathological diagnosis due to massive necrosis, the hypothesis of a necrotic thymoma should be considered. After radical removal prognosis is generally favourable and no adjuvant treatment is required. PMID:24690340

  7. Epidemiology of acute necrotizing ulcerative gingivitis.

    PubMed

    Melnick, S L; Roseman, J M; Engel, D; Cogen, R B

    1988-01-01

    In the last 60 years, there have been approximately 50 studies of various suspected risk factors associated with acute necrotizing ulcerative gingivitis. Two thirds of these studies have been either surveys or case reports; nearly all the rest have been case-control studies. There have been only a few longitudinal and population-based studies, most of which were in high-risk populations. The findings of many studies pertain to gingivitis in general rather than in acute necrotizing ulcerative gingivitis in particular; the findings of other studies are based on small numbers or solely on case histories without the inclusion of control subjects. There are comparisons between the epidemiology of acute necrotizing ulcerative gingivitis as it occurs in military populations and the epidemiology of meningococcal meningitis (98-103). Both diseases have been reported in closed communities such as in young recruits away from home and in new surroundings. A temporal trend upward in disease frequency was described for both infections during World War II. Both infections appear to be characterized by low communicability, with no documented transmission by fomites or vectors. Furthermore, active disease in both cases is associated with markedly increased numbers of normally indigenous flora: B. intermedius in the case of acute necrotizing ulcerative gingivitis and Neisseria meningococcus in the case of epidemic meningococcal meningitis. Risk factors associated with both diseases include crowding, physical fatigue, increased stress, low socioeconomic status, and failure of host defense mechanisms. In general, there is potential for longitudinal studies of young people such as new military recruits and college students who are undergoing the transition from dependence to independence. It is intriguing that these young adults are suddenly at increased risk of this disease in late adolescence when they should be at peak fitness and, just as suddenly, at decreased risk after their

  8. The Tuberculosis Necrotizing Toxin kills macrophages by hydrolyzing NAD

    PubMed Central

    Sun, Jim; Siroy, Axel; Lokareddy, Ravi K.; Speer, Alexander; Doornbos, Kathryn S.; Cingolani, Gino; Niederweis, Michael

    2015-01-01

    Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb utilizes the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT) that induces necrosis by an unknown mechanism. Here we show that TNT gains access to the cytosol of Mtb-infected macrophages, where it hydrolyzes the essential co-enzyme nicotinamide adenine dinucleotide (NAD+). Expression or injection of a non-catalytic TNT mutant showed no cytotoxicity in macrophages or zebrafish zygotes, respectively, demonstrating that the NAD+-glycohydrolase activity is required for TNT-induced cell death. To prevent self-poisoning, Mtb produces an immunity factor for TNT (IFT) that binds TNT and inhibits its activity. The crystal structure of the TNT-IFT complex revealed a novel NAD+-glycohydrolase fold of TNT, which constitutes the founding member of a toxin family wide-spread in pathogenic microorganisms. PMID:26237511

  9. Necrotizing sialometaplasia of the palate. Ulcerative or necrotizing stage of leukokeratosis nicotina palati?

    PubMed

    Philipsen, H P; Petersen, J K; Simonsen, B H

    1976-12-01

    A typical case of the recently described tumor-suspect lesion, necrotizing sialometaplasia (NS) of the palate, in a 54-year old Caucasian male is presented. Results of complete blood- and urinanalysis including serum electrophoresis and labial salivary gland biopsy strongly pointed at a local etiologic factor. Previous statements that the disease represents a new entity are questioned. The present authors favor the idea that NS is the necrotizing (ulcerative) or terminal stage of leukokeratosis nicotina palati (nicotinic stomatitis). It is of particular importance that this lesion is not diagnosed as a malignancy, as it heals spontaneously and uneventfully.

  10. DESCENDING NECROTIZING MEDIASTINITIS SECONDARY TO RETROPHARYNGEAL ABSCESS.

    PubMed

    Kovacić, Marijan; Kovacić, Ivan; Dželalija, Boris

    2015-12-01

    Descending necrotizing mediastinitis secondary to a nontraumatic retropharyngeal abscess is very rare. This form of mediastinitis in the era of potent antibiotics often ends up with lethal outcome. It usually occurs in immunocompromised patients and requires intensive multidisciplinary treatment approach. We report a case of nontraumatic retropharyngeal abscess complicated by descending necrotizing mediastinitis in a 70-year-old man with insulin dependent diabetes mellitus. The patient was admitted to our hospital after clinical and radiological diagnosis of retropharyngeal abscess. During treatment for retropharyngeal abscess with antibiotic therapy and transoral incision, the patient showed mild clinical improvement but his condition suddenly aggravated on day 4 of hospital stay. He had high fever, chest pain with tachypnea, tachycardia, hypotension, and showed signs of occasional disorientation. Emergency computed tomography (CT) scan of the neck and thorax showed inflammation in the retropharyngeal space, as well as thickening of the upper posterior mediastinum fascia with the presence of air. Emergency surgery including cervicotomy and drainage of the retropharyngeal space and posterior mediastinum was performed. The patient promptly recovered with improvement of the clinical status and laboratory findings. After 16 days of treatment he was discharged from the hospital in good condition. Descending necrotizing mediastinitis can be a serious and life threatening complication of deep neck infection if the diagnosis is not quickly established. Besides inevitable application of antimicrobial drugs, good drainage of the mediastinum is necessary. We believe that transcervical approach can achieve high-quality drainage of the upper mediastinum, especially if it is done timely as in this case. Its efficacy can be verified by intensive monitoring of the patient clinical condition, by CT scan of the thorax, and by laboratory tests. In the case of inefficacy of this type

  11. DESCENDING NECROTIZING MEDIASTINITIS SECONDARY TO RETROPHARYNGEAL ABSCESS.

    PubMed

    Kovacić, Marijan; Kovacić, Ivan; Dželalija, Boris

    2015-12-01

    Descending necrotizing mediastinitis secondary to a nontraumatic retropharyngeal abscess is very rare. This form of mediastinitis in the era of potent antibiotics often ends up with lethal outcome. It usually occurs in immunocompromised patients and requires intensive multidisciplinary treatment approach. We report a case of nontraumatic retropharyngeal abscess complicated by descending necrotizing mediastinitis in a 70-year-old man with insulin dependent diabetes mellitus. The patient was admitted to our hospital after clinical and radiological diagnosis of retropharyngeal abscess. During treatment for retropharyngeal abscess with antibiotic therapy and transoral incision, the patient showed mild clinical improvement but his condition suddenly aggravated on day 4 of hospital stay. He had high fever, chest pain with tachypnea, tachycardia, hypotension, and showed signs of occasional disorientation. Emergency computed tomography (CT) scan of the neck and thorax showed inflammation in the retropharyngeal space, as well as thickening of the upper posterior mediastinum fascia with the presence of air. Emergency surgery including cervicotomy and drainage of the retropharyngeal space and posterior mediastinum was performed. The patient promptly recovered with improvement of the clinical status and laboratory findings. After 16 days of treatment he was discharged from the hospital in good condition. Descending necrotizing mediastinitis can be a serious and life threatening complication of deep neck infection if the diagnosis is not quickly established. Besides inevitable application of antimicrobial drugs, good drainage of the mediastinum is necessary. We believe that transcervical approach can achieve high-quality drainage of the upper mediastinum, especially if it is done timely as in this case. Its efficacy can be verified by intensive monitoring of the patient clinical condition, by CT scan of the thorax, and by laboratory tests. In the case of inefficacy of this type

  12. [Necrotizing enterocolitis in the preterm infant: etiopathogenic considerations].

    PubMed

    Pellegrini, Michele; Lagrasta, Nancy; Campos Serna, Javier; Garcìa Garcìa, Covadonga; Marzocca, Giuseppe

    2004-01-01

    Necrotizing enterocolitis (NE) represents the most frequent gastrointestinal emergency encountered in neonatal intensive care units. This necrotic-inflammatory bowel disease affects primarily premature patients and it is recorded as an important cause of neonatal morbidity and mortality. The NE aetiology seems to be multifactorial: prematurity, enteral feeding, hypoxia and micro-organisms toxicity are registered as the most important risk factors, able to trigger the phlogistic and necrotic way at the basis of necrotizing enterocolitis. Despite the NE first report was in the past century, the correct pathogenic sequence of this neonatal disease is still hypothetical. PMID:15303550

  13. Necrotizing fasciitis caused by Aeromonas caviae.

    PubMed

    Kumar, Simit; Mukhopadhyay, Prabir; Chatterjee, Mitali; Bandyopadhyay, Manas K; Bandyopadhyay, Maitreyi; Ghosh, Tapashi; Samaddar, Debopriyo

    2012-10-01

    Aeromonads are rarely associated with human intestinal and extra-intestinal diseases and syndromes, ranging from relatively mild illnesses such as acute gastroenteritis to life-threatening conditions, including septicemia, necrotizing fasciitis, and myonecrosis. Among the aeromonas species known to cause human infection, Aeromonas caviae has been associated with septicemia and only one reported case of human soft tissue infection. Most of the infections due to aeromonas occur in immunocompromised patients. Herein we describe a successfully treated case of post-traumatic skin and soft-tissue infections due to A. caviae in an otherwise immunocompetent individual.

  14. Carpal tunnel release complicated by necrotizing fasciitis.

    PubMed

    Greco, R J; Curtsinger, L J

    1993-06-01

    We report a 31-year-old diabetic woman who underwent carpal tunnel release for median nerve compression followed by a laparoscopic tubal ligation. The procedure was complicated by a severe postoperative necrotizing fasciitis infection of the carpal tunnel release incision. This has not been previously reported. The wound was poorly responsive to antibiotic therapy and serial wound debridements. Control of the woman's infection required total excision of the palmar skin and fascia. Complicating factors in this case included the woman's long history of insulin-dependent diabetes and a concomitant clean-contaminated procedure.

  15. Necrotizing Soft Tissue Infections: Surgeon's Prospective

    PubMed Central

    Mishra, Shashi Prakash; Gupta, Sanjeev Kumar

    2013-01-01

    Necrotizing soft tissue infections (NSTIs) are fulminant infections of any layer of the soft tissue compartment associated with widespread necrosis and systemic toxicity. Delay in diagnosing and treating these infections increases the risk of mortality. Early and aggressive surgical debridement with support for the failing organs significantly improves the survival. Although there are different forms of NSTIs like Fournier's gangrene or clostridial myonecrosis, the most important fact is that they share common pathophysiology and principles of treatment. The current paper summarizes the pathophysiology, clinical features, the diagnostic workup required and the treatment principles to manage these cases. PMID:24455410

  16. The surgical management of necrotizing enterocolitis.

    PubMed

    Kastenberg, Zachary J; Sylvester, Karl G

    2013-03-01

    Necrotizing enterocolitis (NEC), a common cause of neonatal morbidity and mortality, is strongly associated with prematurity and typically occurs following initiation of enteral feeds. Mild NEC is adequately treated by cessation of enteral feeding, empiric antibiotics, and supportive care. Approximately 50% of affected infants will develop progressive intestinal necrosis requiring urgent operation. Several surgical techniques have been described, but there is no clear survival benefit for any single operative approach. While debate continues regarding the optimal surgical management for infants with severe NEC, future progress will likely depend on the development of improved diagnostic tools and preventive therapies. PMID:23415269

  17. Necrotic enteritis predisposing factors in broiler chickens.

    PubMed

    Moore, Robert J

    2016-06-01

    Necrotic enteritis in chickens develops as a result of infection with pathogenic strains of Clostridium perfringens and the presence of predisposing factors. Predisposing factors include elements that directly change the physical properties of the gut, either damaging the epithelial surface, inducing mucus production, or changing gut transit times; factors that disrupt the gut microbiota; and factors that alter the immune status of birds. In the past research into necrotic enteritis predisposing factors was directed by the simple hypothesis that low-level colonization of C. perfringens commonly occurred within the gut of healthy chickens and the predisposing factors lead to a proliferation of those bacteria to produce disease. More recently, with an increasing understanding of the major virulence factors of C. perfringens and the application of molecular techniques to define different clades of C. perfringens strains, it has become clear that the C. perfringens isolates commonly found in healthy chickens are generally not strains that have the potential to cause disease. Therefore, we need to re-evaluate hypotheses regarding the development of disease, the origin of disease causing isolates of C. perfringens, and the importance of interactions with other C. perfringens strains and with predisposing factors. Many predisposing factors that affect the physical and immunological characteristics of the gastrointestinal tract may also change the resident microbiota. Research directed towards defining the relative importance of each of these different actions of predisposing factors will improve the understanding of disease pathogenesis and may allow refinement of experiment disease models. PMID:26926926

  18. Necrotic enteritis predisposing factors in broiler chickens.

    PubMed

    Moore, Robert J

    2016-06-01

    Necrotic enteritis in chickens develops as a result of infection with pathogenic strains of Clostridium perfringens and the presence of predisposing factors. Predisposing factors include elements that directly change the physical properties of the gut, either damaging the epithelial surface, inducing mucus production, or changing gut transit times; factors that disrupt the gut microbiota; and factors that alter the immune status of birds. In the past research into necrotic enteritis predisposing factors was directed by the simple hypothesis that low-level colonization of C. perfringens commonly occurred within the gut of healthy chickens and the predisposing factors lead to a proliferation of those bacteria to produce disease. More recently, with an increasing understanding of the major virulence factors of C. perfringens and the application of molecular techniques to define different clades of C. perfringens strains, it has become clear that the C. perfringens isolates commonly found in healthy chickens are generally not strains that have the potential to cause disease. Therefore, we need to re-evaluate hypotheses regarding the development of disease, the origin of disease causing isolates of C. perfringens, and the importance of interactions with other C. perfringens strains and with predisposing factors. Many predisposing factors that affect the physical and immunological characteristics of the gastrointestinal tract may also change the resident microbiota. Research directed towards defining the relative importance of each of these different actions of predisposing factors will improve the understanding of disease pathogenesis and may allow refinement of experiment disease models.

  19. Altered accumulation and subcellular disposition of testicular cadmium in inbred mice resistant to cadmium-induced testicular necrosis

    SciTech Connect

    Chellman, G.J.

    1985-01-01

    Rodent testis is one of the most sensitive mammalian tissues to the toxic effects of acutely administered Cd. However, numerous inbred mouse strains are resistant to Cd-induced testicular damage, even at lethal Cd doses; the mechanism of this resistance has not been determined. Therefore, testes of mice susceptible (129/J) or resistant (A/J) to Cd-induced damage were examined for possible differences in the accumulation and subcellular disposition of Cd. Twenty-four hours after subcutaneous injection of mice with 30 ..mu..moles CdCl/sub 2//kg, 129/J testes showed extensive interstitial hemorrhage and seminiferous tubule necrosis, while A/J testes appeared histologically normal. Testicular Cd accumulation was 5-6 times less in A/J mice than in 129/J mice at all time points examined. Chromatography of testicular cytosol on Sephadex G-75 Superfine revealed four Cd-binding peaks. Both 15 min and 6 hr after dosing, A/J testes had 14% more of the total tissue Cd bound to the 14,500 MW protein (Cd-BP III), compared to 129/J testes, Cd-BP III behaved like metallothionein during gel filtration and ion exchange chromatography. Additional mice were injected i.v. with 10 (129/J) or 45 (A/J) ..mu..moles CdCl/sub 2//kg to achieve equal testicular Cd concentrations (approx. 4 nmoles Cd/g testis). Twenty-four hours later, 129/J testes were necrotic while A/J testes showed no microscopic evidence of damage. Therefore, resistance of A/J testes to Cd is not determined solely by decreased Cd accumulation, but is associated with increased binding of testicular Cd to Cd-BP III.

  20. Case 11: large, infected, necrotic mixed-aetiology leg ulcer.

    PubMed

    Price, Juliet; Boulton, Zoe

    2016-03-01

    This painful and malodorous ulcer was covered with 40% necrotic tissue. Combined use of octenilin Wound gel and Wound Irrigation Solution gently debrided the necrotic tissue, and helped reduce the pain and malodour. Within 6 weeks, the wound was covered with granulation tissue. PMID:26949855

  1. Case 9: heavily exuding, malodorous, necrotic pressure ulcer.

    PubMed

    Simon, Deborah

    2016-03-01

    In this case, the necrotic tissue was so hard it was not possible to categorise the ulcer. Octenilin products were able to debride the necrotic tissue, so that the wound depth could be determined. After 4 weeks, the wound was covered with granulation tissue, improving the patient's quality of life.

  2. Regulatory and necrotic volume increase in boar spermatozoa.

    PubMed

    Petrunkina, A M; Jebe, E; Töpfer-Petersen, E

    2005-08-01

    subsequent volume decrease. RVI was inhibited by the vanadate. Hypertonic stress did not result in an increase in early apoptotic cells, but produced a shift toward late necrotic cells. Substitution of sodium and chloride by choline and sulfate resulted in decreased isotonic volume of sperm treated with lavendustin. Tyrosine phosphorylation levels were reduced after 20 min under hypertonic conditions. It was concluded that RVI is regulated via a protein tyrosine kinase-dependent pathway, and that dephosphorylation occurs when volume regulation is required. The necrotic volume increase (NVI) is associated with the accumulation of sodium and chloride following uncontrolled opening of the channels. The ability to regulate volume after exposure to hypertonic conditions is important for sperm functionality and can have practical applications in spermatological diagnostics and cryopreservation. PMID:15744775

  3. Necrotizing enterocolitis in premature infants and newborns.

    PubMed

    Mϋller, M J; Paul, T; Seeliger, S

    2016-09-16

    Necrotizing enterocolitis (NEC) is the most common acquired disease of the gastrointestinal tract (GIT) in premature infants and newborns. It is defined as an ulcerative inflammation of the intestinal wall. The clinical signs of incipient NEC are often very discrete, and range from localized intestinal symptoms to generalized signs of sepsis. NEC is classified depending on its severity into disease states according to the modified Bell's Classification. Treatment of NEC ranges, depending on its severity, from a conservative therapeutic approach to surgery with resection of the affected parts of the intestine. Mortality is considerably high in extremely small preterm infants reaching up to 42% of the affected children. Measures such as breastfeeding or alternatively nutrition with pasteurized human donor milk from a milk bank, administration of probiotics, avoidance of histamine type II receptor antagonists, and restrictive antibiotic treatment should be considered early on for prevention of NEC. PMID:27589549

  4. Cervical Necrotizing Fasciitis Caused by Dental Infection

    PubMed Central

    Song, Chi-Woong; Yoon, Hyun-Joong; Jung, Da-Woon; Lee, Sang-Hwa

    2014-01-01

    Necrotizing fasciitis (NF) is defined as rapidly progressive necrosis of subcutaneous fat and fascia. Although NF of the face is rare, its mortality rate is nearly 30%. It usually originates from dental infection and can lead to involvement of the neck, mediastinum, and chest wall. Complications resulting from pre-existing systemic diseases can increase the mortality rate. Known complication factors for NF include diabetes, malnutrition, advanced age, peripheral vascular disease, renal failure, and obesity. Here, we report a case of NF originating from dental infection in an 88-year-old woman already diagnosed with hypertension, thoracic aortic aneurysm, and renal diseases. Such conditions limited adequate surgical and antibiotic treatment. However, interdisciplinary treatment involving multiple departments was implemented with good results. PMID:27489813

  5. Epizootic necrotic enteritis in wild geese.

    PubMed

    Wobeser, G; Rainnie, D J

    1987-07-01

    Outbreaks of a disease characterized by severe necrotic enteritis occurred among Canada geese (Branta canadensis), lesser snow geese (Anser caerulescens), Ross' geese (A. rossi), and white-fronted geese (A. albifrons) on lakes in Saskatchewan and Manitoba during the autumn of 1983, 1984 and 1985. Ducks using the lakes were apparently not affected. Lesions in the geese closely resembled those described in enteritides in other species associated with the proliferation of Clostridium perfringens in the small intestine. Clostridium perfringens was present in large numbers in the affected areas of the intestine of the geese; other pathogens were not identified. It is hypothesized that an abrupt change in diet as geese begin to feed on grain disrupts the intestinal microflora, allowing C. perfringens to proliferate in the upper small intestine. Toxins produced by the bacteria then cause mucosal necrosis. Protease-inhibitory substances in some grains might also have a role in the disease. PMID:3625893

  6. In situ detection of Mycobacterium tuberculosis transcripts in human lung granulomas reveals differential gene expression in necrotic lesions.

    PubMed

    Fenhalls, Gael; Stevens, Liesel; Moses, Lorraine; Bezuidenhout, Juanita; Betts, Joanna C; Helden Pv, Paul van; Lukey, Pauline T; Duncan, Ken

    2002-11-01

    We have used RNA-RNA in situ hybridization to detect the expression of several Mycobacterium tuberculosis genes in tuberculous granulomas in lung tissue sections from tuberculosis patients. The M. tuberculosis genes chosen fall into two classes. Four genes (icl, narX, and Rv2557 and Rv2558) have been implicated in the persistence of the bacterium in the host, and two genes (iniB and kasA) are upregulated in response to isoniazid exposure. Both necrotic and nonnecrotic granulomas were identified in all of the patients. Necrotic granulomas were divided into three zones: an outer lymphocyte cuff containing lymphocytes and macrophages, a transition zone consisting of necrotic material interspersed with macrophages, and a central acellular necrotic region. Transcripts of all of the genes studied were found in nonnecrotic granulomas and in the lymphocyte cuff of necrotic granulomas. Mycobacterial gene expression was associated with CD68-positive myeloid cells. Rv2557 and/or its homologue Rv2558, kasA, and iniB were expressed within the transition zone of necrotic granulomas, whereas icl and narX transcripts were absent from this area. There was no evidence of transcription of any of the genes examined in the central necrotic region, although mycobacterial DNA was present. The differential expression of genes within granulomas demonstrates that M. tuberculosis exists in a variety of metabolic states and may be indicative of the response to different microenvironments. These observations confirm that genes identified in models of persistence or in response to drug treatment in vitro are expressed in the human host. PMID:12379712

  7. Vaccination with recombinant NetB toxin partially protects broiler chickens from necrotic enteritis.

    PubMed

    Keyburn, Anthony L; Portela, Ricardo W; Sproat, Kathy; Ford, Mark E; Bannam, Trudi L; Yan, Xuxia; Rood, Julian I; Moore, Robert J

    2013-07-16

    NetB toxin from Clostridium perfringens is a major virulence factor in necrotic enteritis in poultry. In this study the efficacy of NetB as a vaccine antigen to protect chickens from necrotic enteritis was examined. Broiler chickens were immunized subcutaneously with purified recombinant NetB (rNetB), formalin treated bacterin and cell free toxoid with or without rNetB supplementation. Intestinal lesion scores and NetB antibody levels were measured to determine protection after mild oral gavage, moderate in-feed and heavy in-feed challenges with virulent C. perfringens isolates. Birds immunized with rNetB were significantly protected against necrotic enteritis when challenged with a mild oral dose of virulent bacteria, but were not protected when a more robust challenge was used. Bacterin and cell free toxoid without rNetB supplementation did not protect birds from moderate and severe in-feed challenge. Only birds immunized with bacterin and cell free toxoid supplemented with rNetB showed significant protection against moderate and severe in-feed challenge, with the later giving the greatest protection. Higher NetB antibody titres were observed in birds immunized with rNetB compared to those vaccinated with bacterin or toxoid, suggesting that the in vitro levels of NetB produced by virulent C. perfringens isolates are too low to induce the development of a strong immune response. These results suggest that vaccination with NetB alone may not be sufficient to protect birds from necrotic enteritis in the field, but that in combination with other cellular or cell-free antigens it can significantly protect chickens from disease.

  8. Necrotizing fasciitis of the nose complicated with cavernous sinus thrombosis.

    PubMed

    Swaminath, D; Narayanan, R; Orellana-Barrios, M A; Temple, B

    2014-01-01

    Necrotizing fasciitis is a rapidly progressive life threatening bacterial infection of the skin, the subcutaneous tissue, and the fascia. We present a case of necrotizing fasciitis involving the nose complicated by cavernous sinus thrombosis. Few cases of septic cavernous sinus thrombosis have been reported to be caused by cellulitis of the face but necrotizing fasciitis of the nose is rare. It is very important to recognize the early signs of cavernous thrombosis. Treatment for septic cavernous sinus thrombosis is controversial but early use of empirical antibiotics is imperative. PMID:24876978

  9. A Case of Necrotizing Epiglottitis Due to Nontoxigenic Corynebacterium diphtheriae.

    PubMed

    Lake, Jessica A; Ehrhardt, Matthew J; Suchi, Mariko; Chun, Robert H; Willoughby, Rodney E

    2015-07-01

    Diphtheria is a rare cause of infection in highly vaccinated populations and may not be recognized by modern clinicians. Infections by nontoxigenic Corynebacterium diphtheriae are emerging. We report the first case of necrotizing epiglottitis secondary to nontoxigenic C diphtheriae. A fully vaccinated child developed fever, poor oral intake, and sore throat and was found to have necrotizing epiglottitis. Necrotizing epiglottitis predominantly occurs in the immunocompromised host. Laboratory evaluation revealed pancytopenia, and bone marrow biopsy was diagnostic for acute lymphoblastic leukemia. Clinicians should be aware of aggressive infections that identify immunocompromised patients. This case highlights the features of a reemerging pathogen, C diphtheriae.

  10. Polymicrobial abdominal wall necrotizing fasciitis after cesarean section.

    PubMed

    DeMuro, Jp; Hanna, Af; Chalas, E; Cunha, Ba

    2012-09-01

    We report a case of a previously healthy woman after an uneventful caesarean section who developed polymicrobial necrotizing fasciitis. She was given a non-steroidal anti-inflamatory drug (NSAID) after her delivery. Her post-delivery course was complicated by septic shock, and required multiple debridements before abdominal reconstruction. This case describes the increased risk of necrotizing fasciitis with NSAID use. Unusual were the organisms causing the polymicrobial necrotizing fasciitis: Staphylococcus aureus, Enterobacter agglomerans, Acinetobacter baumannii, and two strains of Enterobacter cloacae.

  11. The use of maggots in head and neck necrotizing fasciitis.

    PubMed

    Dunn, Christopher; Raghavan, Ullas; Pfleiderer, A G

    2002-01-01

    Historically maggots have been used to clean necrotic war wounds. With the ready availability of sterile maggots, they are being used increasingly in surgical practice. Although maggots have most frequently been employed in the management of necrotic wounds and ulcers involving the lower limb, we have identified a particularly useful application in the head and neck and describe a case in which maggots played a significant part in the successful treatment of a florid necrotizing cervical fasciitis in a patient, who was unfit for repeated surgical debridement.

  12. Statin-induced necrotizing myositis – A discrete autoimmune entity within the “statin-induced myopathy spectrum”

    PubMed Central

    Hamann, Philip; Cooper, Robert; McHugh, Neil; Chinoy, Hector

    2015-01-01

    Statin-induced necrotizing myositis is increasingly being recognised as part of the “statin-induced myopathy spectrum”. As in other immune-mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum creatine kinase elevations and histological evidence of myonecrosis, and with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the enzyme target of statin therapies), and with HLA-DRB1*11. This article summarises the clinical presentation, investigations and management of this rare, but serious complication of statin therapy. PMID:23851103

  13. Predictors of Monomicrobial Necrotizing Soft Tissue Infections

    PubMed Central

    Guidry, Christopher A.; Horn, Christopher B.; Gilsdorf, Daniel; Davies, Stephen W.; Dietch, Zachary C.; Sawyer, Robert G.

    2015-01-01

    Abstract Background: Broad-spectrum antibiotic therapy is critical in the management of necrotizing soft tissue infections (NSTI) in the emergency setting. Clindamycin often is included empirically to cover monomicrobial gram-positive pathogens but probably is of little value for polymicrobial infections and is associated with significant side effects, including the induction of Clostridium difficile colitis. However, there have been no studies predicting monomicrobial infections prior to obtaining cultures. The purpose of this study was to identify independent predictors of monomicrobial NSTI where the use of clindamycin would be most beneficial. We hypothesized that monomicrobial infections are characterized by involvement of the upper extremities and fewer co-morbid diseases. Methods: We reviewed all cases of potential NSTI occurring between 1996 and 2013 in a single tertiary-care center. The infection was diagnosed by the finding of rapidly progressing necrotic fascia during debridement with positive cultures of tissue. Univariable analysis was performed using the Student t-, Wilcoxon rank sum, χ2, and Fisher exact tests as appropriate. Multivariable logistic regression was used to identify independent variables associated with outcomes. Results: A group of 151 patients with confirmed NSTI with complete data was used. Of the monomicrobial infections, 61.8% were caused by Group A streptococci, 20.1% by Staphylococcus aureus, and 12.7% by Escherichia coli. Of the polymicrobial infections, E. coli was involved 13.7% of the time, followed by Candida spp. at 12.9%, and Bacteroides fragilis at 11.3%. On univariable analysis, immunosuppression, upper extremity infection, and elevated serum sodium concentration were associated with monomicrobial infection, whereas morbid obesity and a perineal infection site were associated with polymicrobial infection. On multivariable analysis, the strongest predictor of monomicrobial infection was immunosuppression (odds ratio [OR

  14. Transfusion-related necrotizing enterocolitis: a conceptual framework.

    PubMed

    Marin, Terri; Strickland, Ora L

    2013-06-01

    Necrotizing enterocolitis (NEC) is a disease primarily of prematurity characterized by partial or entire gut necrosis and is associated with significant mortality and morbidity. Recent studies report that approximately 25% to 35% of very low-birth-weight infants less than 1500 g receiving packed red blood cell transfusions develop temporally associated NEC, known as transfusion-related NEC (TR-NEC). Although there are many known risk factors for NEC, this article focuses on 3 contributing factors: packed red blood cell transfusions, enteral feedings, and gastrointestinal immaturity. Previous data suggest that these factors may interact to affect neonatal intestinal tissue oxygenation, which may lead to tissue ischemia, resulting in intestinal injury. This article presents a conceptual framework that combines current theoretical perspectives for TR-NEC, and reviews previous research examining related variables and how their interaction may increase the risk for TR-NEC development. In addition, incorporation of the proposed framework to guide future research and nursing care in this area is discussed.

  15. Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis

    PubMed Central

    Premkumar, M. H.; Sule, G.; Nagamani, S. C.; Chakkalakal, S.; Nordin, A.; Jain, M.; Ruan, M. Z.; Bertin, T.; Dawson, B.; Zhang, J.; Schady, D.; Bryan, N. S.; Campeau, P. M.; Erez, A.

    2014-01-01

    Necrotizing enterocolitis (NEC), the most common neonatal gastrointestinal emergency, results in significant mortality and morbidity, yet its pathogenesis remains unclear. Argininosuccinate lyase (ASL) is the only enzyme in mammals that is capable of synthesizing arginine. Arginine has several homeostatic roles in the gut and its deficiency has been associated with NEC. Because enterocytes are the primary sites of arginine synthesis in neonatal mammals, we evaluated the consequences of disruption of arginine synthesis in the enterocytes on the pathogenesis of NEC. We devised a novel approach to study the role of enterocyte-derived ASL in NEC by generating and characterizing a mouse model with enterocyte-specific deletion of Asl (Aslflox/flox; VillinCretg/+, or CKO). We hypothesized that the presence of ASL in a cell-specific manner in the enterocytes is protective in the pathogenesis of NEC. Loss of ASL in enterocytes resulted in an increased incidence of NEC that was associated with a proinflammatory state and increased enterocyte apoptosis. Knockdown of ASL in intestinal epithelial cell lines resulted in decreased migration in response to lipopolysaccharide. Our results show that enterocyte-derived ASL has a protective role in NEC. PMID:24904080

  16. A Novel Autoantibody Recognizing 200 and 100 kDa Proteins is Associated with an Immune-Mediated Necrotizing Myopathy

    PubMed Central

    Christopher-Stine, Lisa; Casciola-Rosen, Livia A.; Hong, Grace; Chung, Tae; Corse, Andrea M.; Mammen, Andrew L.

    2010-01-01

    Objective Myofiber necrosis without prominent inflammation is a non-specific finding seen in patients with dystrophies and toxic or immune-mediated myopathies. However, the etiology of a necrotizing myopathy is often obscure and which patients would benefit from immunosuppression remains uncertain. We sought to identify novel autoantibodies in necrotizing myopathy patients. Methods Muscle biopsy and serum were available for 225 myopathy patients. Antibody specificities were determined by performing immunoprecipitations from 35S-methionine-labeled HeLa cell lysates. Selected biopsies were stained for membrane attack complex (MAC), major histocompatability complex I (MHC I), and endothelial cell marker CD31. Results 38 of 225 patients had predominant myofiber necrosis on muscle biopsy. 12 of these had a known autoantibody association or other etiology for their myopathy. 16 of the remaining 26 sera immunoprecipitated 200 and 100 kDa proteins; this specificity was found in only 1/187 patients without necrotizing myopathy. Patients with anti-200/100 specificity had proximal weakness (100%), high creatine kinase (CK) levels (mean 10,333 IU/L), and an irritable myopathy on electromyography (EMG) (88%). 63% had exposure to statins prior to the onset of weakness. All patients responded to immunosuppressive therapy and many relapsed with medication tapering. Immunohistochemical studies showed MAC on small blood vessels in 6/8 and on the surface of non-necrotic myofibers in 4/8. 5/8 had abnormal capillary morphology and 4/8 expressed MHC I on the surface of non-necrotic myofibers. Conclusion An anti-200/100 kDa specificity defines a subgroup of necrotizing myopathy patients previously considered to be "autoantibody negative." We propose that these patients have an immune-mediated myopathy which is frequently associated with prior statin use and should be treated with immunosuppressive therapy. PMID:20496415

  17. Unusual Necrotizing Encephalitis in Raccoons and Skunks Concurrently Infected With Canine Distemper Virus and Sarcocystis sp.

    PubMed

    Kubiski, S V; Sisó, S; Church, M E; Cartoceti, A N; Barr, B; Pesavento, P A

    2016-05-01

    Canine distemper virus commonly infects free-ranging, terrestrial mesopredators throughout the United States. Due to the immunosuppressive effects of the virus, concurrent opportunistic infections are also common. Among these, secondary systemic protozoal infections have been described in a number of species. We report an unusual presentation of necrotizing encephalitis associated withSarcocystissp in four raccoons and one skunk concurrently infected with canine distemper virus. Lesions were characterized by variably sized necrotizing cavitations composed of abundant mineral admixed with inflammatory cells and protozoa.Sarcocystissp was confirmed via immunohistochemistry using a monoclonal antibody toSarcocystis neurona The pathologic changes are similar to lesions in human AIDS patients infected withToxoplasma gondii.

  18. Unusual Necrotizing Encephalitis in Raccoons and Skunks Concurrently Infected With Canine Distemper Virus and Sarcocystis sp.

    PubMed

    Kubiski, S V; Sisó, S; Church, M E; Cartoceti, A N; Barr, B; Pesavento, P A

    2016-05-01

    Canine distemper virus commonly infects free-ranging, terrestrial mesopredators throughout the United States. Due to the immunosuppressive effects of the virus, concurrent opportunistic infections are also common. Among these, secondary systemic protozoal infections have been described in a number of species. We report an unusual presentation of necrotizing encephalitis associated withSarcocystissp in four raccoons and one skunk concurrently infected with canine distemper virus. Lesions were characterized by variably sized necrotizing cavitations composed of abundant mineral admixed with inflammatory cells and protozoa.Sarcocystissp was confirmed via immunohistochemistry using a monoclonal antibody toSarcocystis neurona The pathologic changes are similar to lesions in human AIDS patients infected withToxoplasma gondii. PMID:26374278

  19. Necrotizing sialometaplasia in a patient who is HIV positive: a case report.

    PubMed

    Silva, Alessandra Dutra; Silva, Carolina Amália Barcellos; Furuse, Cristiane; Nunes e Souza, Rodrigo Calado; da Costa, Mauro Henrique Melo; de Araújo, Vera Cavalcanti

    2010-01-01

    Necrotizing sialometaplasia (NS) is a self-limiting, benign, inflammatory disease of the minor salivary glands of the hard palate. The main significance of the NS lesion lies in the fact that it may be mistaken for mucoepidermoid or squamous cell carcinoma. A case report is presented of a patient with NS who was HIV positive; the lesion was located in the minor salivary glands of the hard palate. Clinically, the lesion presented as a deep ulcer with slightly elevated irregular borders and a necrotic base in the hard palate. Histologically, the tissue was characterized by squamous metaplasia of ducts and acini, lobular coagulation necrosis, and pseudoepitheliomatous hyperplasia of the overlying epithelium. The lesion disappeared completely after 2 weeks.

  20. Metabolomic determinants of necrotizing enterocolitis in preterm piglets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Studies in premature infants and animals show that carbohydrate malabsorption and gut microbiota colonisation are key elements for triggering necrotizing enterocolitis (NEC). Our aim was to determine how dietary carbohydrate composition affects the metabolomic profile and whether unique metabolite s...

  1. Descending necrotizing mediastinitis associated with Lactobacillus plantarum

    PubMed Central

    2013-01-01

    Background Descending necrotizing mediastinitis (DNM), a severe infection with a high fatality rate, develops in mediastinal spaces due mainly to deep cervical abscesses. The majority of causative microbes of DNM are Streptococci and oral anaerobes. DNM associated with Lactobacillus-infection is rather rare. Case presentation A 69-year-old male with an unremarkable past medical history was referred to our hospital for surgical resection of advanced laryngeal cancer. Full examination revealed a neck abscess and DNM with a background of untreated diabetes mellitus. Initially, he was treated with meropenem. However, Lactobacillus plantarum was isolated from surgical drainage of a mediastinal abscess. Despite using antibiotics capable of eradicating all isolates with susceptibilities not differing significantly from those of the neck and mediastinal abscesses, we attributed DNM to the L. plantarum detected only in the mediastinal abscess. After DNM treatment, he underwent total pharyngolaryngectomy with bilateral neck dissection followed by reconstruction using free jejunum. He was discharged fully recovered. Conclusion We concluded that L. plantarum as the sole cause of the mediastinal abscess in the present case cannot be ruled out. As the number of immunocompromised patients increases, we should be cautious regarding this “familiar” microbe. PMID:23987907

  2. Necrotizing Urethritis due to Aerococcus urinae.

    PubMed

    Babaeer, Abdulrahman A; Nader, Claudia; Iacoviello, Vito; Tomera, Kevin

    2015-01-01

    A 49-year-old male presented to the emergency with hematuria and pain in the shaft of the penis for one day. The patient was found to be in a state of shock. The shaft of the penis and the scrotum were swollen and tender. No skin necrosis was observed and no crepitus was palpable. Serum white count (WBC) was 29.5 × 10(3)/μL. A CT scan showed gas in the corpus spongiosum. Antibiotics were started with IV metronidazole, vancomycin, and piperacillin/tazobactam. Metronidazole was then replaced by clindamycin. Exploration was performed but no necrotic tissue was identified. Cystourethroscopy revealed dusky looking urethra. A suprapubic tube and a urethral catheter were placed in the bladder. WBC trended down to 13.9 × 10(3)/μL on the fourth postoperative day. Urine culture grew Aerococcus urinae and blood cultures grew Alpha Hemolytic Streptococcus. On the sixth day, the patient was feeling worse and WBC increased. MRI revealed absent blood flow to the corpus spongiosum. Urethroscopy revealed necrosis of the urethra. Urethrectomy was performed via perineal approach. The patient immediately improved. The patient was discharged on the sixth postoperative day to continue ampicillin/sulbactam IV every 6 hours for a total of 4 weeks from the day of urethrectomy. PMID:26171271

  3. [Digestive stenoses following ulcero-necrotizing enterocolitis].

    PubMed

    Dahreddine, M; Fremond, B; Babut, J M

    1995-01-01

    Over a 10-year period, the authors followed the course of 112 neonates treated for primary acute necrotizing enterocolitis. Ten cases of gastrointestinal stricture were diagnosed, regardless of initial treatment, after an interval of 20 days to 6 months. The site of the stricture was colonic in 6 patients, ileal in three other patients and ileal and colonic in the remaining patient. The stricture was treated surgically in 9 patients (resection-anastomosis in 6 cases, resection with gastrointestinal diversion in 2 cases and isolated gastrointestinal diversion in 1 case). A follow-up barium enema in 1 patient showed spontaneous resolution of the stricture. With a mean follow-up of 5 years, the over all result was considered to be good in 7 cases and poor in one case. Two deaths were observed, one on the 10th day and the other at the 3rd postoperative day. These complications appeared to be related to the delayed diagnosis and treatment of the stricture. PMID:8787322

  4. Necrotizing Urethritis due to Aerococcus urinae

    PubMed Central

    Babaeer, Abdulrahman A.; Nader, Claudia; Iacoviello, Vito; Tomera, Kevin

    2015-01-01

    A 49-year-old male presented to the emergency with hematuria and pain in the shaft of the penis for one day. The patient was found to be in a state of shock. The shaft of the penis and the scrotum were swollen and tender. No skin necrosis was observed and no crepitus was palpable. Serum white count (WBC) was 29.5 × 103/μL. A CT scan showed gas in the corpus spongiosum. Antibiotics were started with IV metronidazole, vancomycin, and piperacillin/tazobactam. Metronidazole was then replaced by clindamycin. Exploration was performed but no necrotic tissue was identified. Cystourethroscopy revealed dusky looking urethra. A suprapubic tube and a urethral catheter were placed in the bladder. WBC trended down to 13.9 × 103/μL on the fourth postoperative day. Urine culture grew Aerococcus urinae and blood cultures grew Alpha Hemolytic Streptococcus. On the sixth day, the patient was feeling worse and WBC increased. MRI revealed absent blood flow to the corpus spongiosum. Urethroscopy revealed necrosis of the urethra. Urethrectomy was performed via perineal approach. The patient immediately improved. The patient was discharged on the sixth postoperative day to continue ampicillin/sulbactam IV every 6 hours for a total of 4 weeks from the day of urethrectomy. PMID:26171271

  5. Necrotic enteritis in broilers: an updated review on the pathogenesis.

    PubMed

    Timbermont, L; Haesebrouck, F; Ducatelle, R; Van Immerseel, F

    2011-08-01

    Clostridium perfringens-induced necrotic enteritis and related subclinical disease have become economically significant problems for the broiler industry. Fortunately, scientific interest in this topic has grown: new C. perfringens virulence factors have been discovered and new insight gained about the pathogenesis of necrotic enteritis. It has been shown that alpha toxin, for a long time thought to be the key virulence factor, is not essential for the development of the disease. Moreover, it is now clearly established that only certain C. perfringens strains are capable of inducing necrotic enteritis under specific conditions that predispose to the disease and they constitute only a minority in the intestinal tract of healthy chickens. A novel pore-forming toxin, NetB, has been identified in these virulent avian C. perfringens strains. Using a gene knockout mutant, it has been shown that NetB is a critical virulence factor in the pathogenesis of necrotic enteritis in broilers. In addition to toxin production, other factors have been described that contribute to the ability of certain C. perfringens strains to cause necrotic enteritis in broilers. It has been suggested that proteolytic enzymes play an important role in the initial stages of necrotic enteritis since the villi are first affected at the level of the basement membrane and the lateral domain of the enterocytes. In field outbreaks of necrotic enteritis, a single clone of C. perfringens is dominant in intestines of all affected birds, as opposed to the mixture of different C. perfringens strains that can be isolated from healthy bird intestines. It has been proposed that bacteriocin production is responsible for the dominance of a single strain in necrotic enteritis cases. Furthermore, it has been shown that virulent strains are more able to adhere to extracellular matrix molecules than non-virulent strains. The current knowledge on the pathogenesis of the disease has been summarized in this short review.

  6. Endoplasmic reticulum stress and calcium imbalance are involved in cadmium-induced lipid aberrancy in Saccharomyces cerevisiae.

    PubMed

    Rajakumar, Selvaraj; Bhanupriya, Nagaraj; Ravi, Chidambaram; Nachiappan, Vasanthi

    2016-09-01

    The endoplasmic reticulum is the key organelle which controls protein folding, lipid biogenesis, and calcium (Ca(2+)) homeostasis. Cd exposure in Saccharomyces cerevisiae activated the unfolded protein response and was confirmed by the increased Kar2p expression. Cd exposure in wild-type (WT) cells increased PC levels and the PC biosynthetic genes. Deletion of the two phospholipid methyltransferases CHO2 and OPI3 modulated PC, TAG levels and the lipid droplets with cadmium exposure. Interestingly, we noticed an increase in the calcium levels upon Cd exposure in the mutant cells. This study concluded that Cd interrupted calcium homeostasis-induced lipid dysregulation leading to ER stress. PMID:27344570

  7. Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis.

    PubMed

    Dalton, Timothy P; He, Lei; Wang, Bin; Miller, Marian L; Jin, Li; Stringer, Keith F; Chang, Xiaoqing; Baxter, C Stuart; Nebert, Daniel W

    2005-03-01

    Testicular necrosis is a sensitive endpoint for cadmium (Cd(2+), Cd) toxicity across all species tested. Resistance to Cd-induced testicular damage is a recessive trait assigned to the Cdm locus on mouse chromosome 3. We first narrowed the Cdm-gene-containing region to 880 kb. SNP analysis of this region from two sensitive and two resistant inbred strains demonstrated a 400-kb haplotype block consistent with the Cd-induced toxicity phenotype; in this region is the Slc39a8 gene encoding a member of the solute-carrier superfamily. Slc39a8 encodes SLC39A8 (ZIP8), whose homologs in plant and yeast are putative zinc transporters. We show here that ZRT-, IRT-like protein (ZIP)8 expression in cultured mouse fetal fibroblasts leads to a >10-fold increase in the rate of intracellular Cd influx and accumulation and 30-fold increase in sensitivity to Cd-induced cell death. The complete ZIP8 mRNA and intron-exon splice junctions have no nucleotide differences between two sensitive and two resistant strains of mice; by using situ hybridization, we found that ZIP8 mRNA is prominent in the vascular endothelial cells of the testis of the sensitive strains of mice but absent in these cells of resistant strains. Slc39a8 is therefore the Cdm gene, defining sensitivity to Cd toxicity specifically in vascular endothelial cells of the testis. PMID:15722412

  8. 5-Aminolevulinic acid ameliorates cadmium-induced morphological, biochemical, and ultrastructural changes in seedlings of oilseed rape.

    PubMed

    Ali, Basharat; Huang, C R; Qi, Z Y; Ali, Shafaqat; Daud, M K; Geng, X X; Liu, H B; Zhou, W J

    2013-10-01

    Due to its prolific growth, oilseed rape (Brassica napus L.) can be grown successfully for phytoremediation of cadmium (Cd)-contaminated soils. Nowadays, use of plant growth regulators against heavy metals stress is one of the major objectives of researchers. The present study evaluates the ameliorate effects of 5-aminolevulinic acid (ALA, 0, 0.4, 2, and 10 mg/l) on the growth of oilseed rape (B. napus L. cv. ZS 758) seedlings under Cd stress (0, 100, and 500 μM). Results have shown that Cd stress hampered the seedling growth by decreasing the radical and hypocotyls length, shoot and root biomass, chlorophyll content, and antioxidants enzymes. On the other hand, Cd stress increased the level of malondialdehyde (MDA) and production of H2O2 and accumulation of Cd in the shoots. The microscopic study of leaf mesophyll cells showed that toxicity of Cd totally destroyed the whole cell structure, and accumulation of Cd also appeared in micrographs. Application of ALA at lower dosage (2 mg/l) enhanced the seedling growth and biomass. The results showed that 2 mg/l ALA significantly improved chlorophyll content under Cd stress and decreased the level of Cd contents in shoots. Application of ALA reduced the MDA and H2O2 levels in the cotyledons. The antioxidants enzymes (ascorbate peroxidase, peroxidase, catalase, glutathione reductase, and superoxide dismutase) enhanced their activities significantly with the application of 2 mg/l ALA under Cd stress. This study also indicated that higher dosage of ALA (10 mg/l) imposed the negative effect on the growth of oilseed rape. Microscopic study showed that application of ALA alleviated the toxic effects of Cd in the mesophyll cell and improved the cell structure. Use of 2 mg/l ALA under 500 μM Cd was found to be more effective, and under this dosage, cell structure was clear, with obvious cell wall and cell membrane as well as a big nucleus, which was found with well-developed two or more nucleoli. Chloroplast was almost round

  9. Necrotic platelets provide a procoagulant surface during thrombosis

    PubMed Central

    Hua, Vu Minh; Abeynaike, Latasha; Glaros, Elias; Campbell, Heather; Pasalic, Leonardo; Chen, Vivien M. Y.

    2015-01-01

    A subpopulation of platelets fulfills a procoagulant role in hemostasis and thrombosis by enabling the thrombin burst required for fibrin formation and clot stability at the site of vascular injury. Excess procoagulant activity is linked with pathological thrombosis. The identity of the procoagulant platelet has been elusive. The cell death marker 4-[N-(S-glutathionylacetyl)amino]phenylarsonous acid (GSAO) rapidly enters a subpopulation of agonist-stimulated platelets via an organic anion-transporting polypeptide and is retained in the cytosol through covalent reaction with protein dithiols. Labeling with GSAO, together with exposure of P-selectin, distinguishes necrotic from apoptotic platelets and correlates with procoagulant potential. GSAO+ platelets form in occluding murine thrombi after ferric chloride injury and are attenuated with megakaryocyte-directed deletion of the cyclophilin D gene. These platelets form a procoagulant surface, supporting fibrin formation, and reduction in GSAO+ platelets is associated with reduction in platelet thrombus size and fibrin formation. Analysis of platelets from human subjects receiving aspirin therapy indicates that these procoagulant platelets form despite aspirin therapy, but are attenuated by inhibition of the necrosis pathway. These findings indicate that the major subpopulation of platelets involved in fibrin formation are formed via regulated necrosis involving cyclophilin D, and that they may be targeted independent of platelet activation. PMID:26474813

  10. An update on necrotizing enterocolitis: pathogenesis and preventive strategies

    PubMed Central

    2011-01-01

    Necrotizing enterocolitis (NEC) is one of the most critical morbidities in preterm infants. The incidence of NEC is 7% in very-low-birth-weight infants, and its mortality is 15 to 30%. Infants who survive NEC have various complications, such as nosocomial infection, malnutrition, growth failure, bronchopulmonary dysplasia, retinopathy of prematurity, and neurodevelopmental delays. The most important etiology in the pathogenesis of NEC is structural and immunological intestinal immaturity. In preterm infants with immature gastrointestinal tracts, development of NEC may be associated with a variety of factors, such as colonization with pathogenic bacteria, secondary ischemia, genetic polymorphisms conferring NEC susceptibility, anemia with red blood cell transfusion, and sensitization to cow milk proteins. To date, a variety of preventive strategies has been accepted or attempted in clinical practice with regard to the pathogenesis of NEC. These strategies include the use of breast feeding, various feeding strategies, probiotics, prebiotics, glutamine and arginine, and lactoferrin. There is substantial evidence for the efficacy of breast feeding and the use of probiotics in infants with birth weights above 1,000 g, and these strategies are commonly used in clinical practice. Other preventive strategies, however, require further research to establish their effect on NEC. PMID:22232629

  11. The use of drotrecogin alpha for necrotizing soft tissue infections.

    PubMed

    Rosing, David K; Malepati, Sarath; Yaghoubian, Arezou; Putnam, Brant A; Neville, Angela; Kaji, Amy H; De Virgilio, Christian

    2010-10-01

    The use of Drotrecogin alfa (DAA) (Xigris) in select patients with sepsis has had demonstrable improvement in survival, though its benefit in necrotizing soft tissue infections (NSTI) is unclear. A retrospective review of NSTI patients receiving DAA at our institution from 2006 to 2009 was performed. Our previously derived mortality prediction model, based on classification and regression tree analysis, was applied to patients and the predicted mortality was compared with the actual mortality rate. Ten patients with severe NSTI received DAA. The median admission values were: white blood cell count of 27,000/mm3, serum lactate of 4.0 mmol/L, and serum sodium of 128 mEq/L. Four (40%) patients had systemic complications, five (50%) patients required amputation, and one died (10%). Median time to DAA administration was 12 hours after debridement. There were no bleeding complications attributed to DAA use. Mortality in this series of severe NSTI was only 10 per cent, which compares favorably with the predicted mortality of 18 per cent based on classification and regression tree analysis (P = 0.2). A prospective, randomized study is warranted to determine if the use of DAA should be part of the standard therapy for NSTI patients with a predicted high mortality. PMID:21105620

  12. Intestinal alkaline phosphatase to treat necrotizing enterocolitis

    PubMed Central

    Biesterveld, Ben E.; Koehler, Shannon M.; Heinzerling, Nathan P.; Rentea, Rebecca M.; Fredrich, Katherine; Welak, Scott R.; Gourlay, David M.

    2015-01-01

    Background Intestinal alkaline phosphatase (IAP) activity is decreased in necrotizing enterocolitis (NEC), and IAP supplementation prevents NEC development. It is not known if IAP given after NEC onset can reverse the course of the disease. We hypothesized that enteral IAP given after NEC induction would not reverse intestinal injury. Materials and methods NEC was induced in Sprague–Dawley pups by delivery preterm followed by formula feedings with lipopolysaccharide (LPS) and hypoxia exposure and continued up to 4 d. IAP was added to feeds on day 2 until being sacrificed on day 4. NEC severity was scored based on hematoxylin and eosin-stained terminal ileum sections, and AP activity was measured using a colorimetric assay. IAP and interleukin-6 expression were measured using real time polymerase chain reaction. Results NEC pups' alkaline phosphatase (AP) activity was decreased to 0.18 U/mg compared with controls of 0.57 U/mg (P < 0.01). Discontinuation of LPS and hypoxia after 2 d increased AP activity to 0.36 U/mg (P < 0.01). IAP supplementation in matched groups did not impact total AP activity or expression. Discontinuing LPS and hypoxia after NEC onset improved intestinal injury scores to 1.14 compared with continued stressors, score 2.25 (P < 0.01). IAP supplementation decreased interleukin-6 expression two-fold (P < 0.05), though did not reverse NEC intestinal damage (P = 0.5). Conclusions This is the first work to demonstrate that removing the source of NEC improves intestinal damage and increases AP activity. When used as a rescue treatment, IAP decreased intestinal inflammation though did not impact injury making it likely that IAP is best used preventatively to those neonates at risk. PMID:25840489

  13. 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.

  14. SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin

    PubMed Central

    Pi, Huifeng; Xu, Shangcheng; Reiter, Russel J; Guo, Pan; Zhang, Lei; Li, Yuming; Li, Min; Cao, Zhenwang; Tian, Li; Xie, Jia; Zhang, Ruiqi; He, Mindi; Lu, Yonghui; Liu, Chuan; Duan, Weixia; Yu, Zhengping; Zhou, Zhou

    2015-01-01

    Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 μM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3H248Y) lacking deacetylase activity lost the capacity to suppress Cd-induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial-derived O2•− production and suppressed the autophagy induced by 10 μM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatonin-mediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2•−-stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway. PMID:26120888

  15. SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin.

    PubMed

    Pi, Huifeng; Xu, Shangcheng; Reiter, Russel J; Guo, Pan; Zhang, Lei; Li, Yuming; Li, Min; Cao, Zhenwang; Tian, Li; Xie, Jia; Zhang, Ruiqi; He, Mindi; Lu, Yonghui; Liu, Chuan; Duan, Weixia; Yu, Zhengping; Zhou, Zhou

    2015-01-01

    Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 μM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3(H248Y)) lacking deacetylase activity lost the capacity to suppress Cd-induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial-derived O2(•-) production and suppressed the autophagy induced by 10 μM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatonin-mediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2(•-)-stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway.

  16. Cadmium-induced apoptosis is mediated by the translocation of AIF to the nucleus in rat testes.

    PubMed

    Kim, Jisun; Soh, Jaemog

    2009-07-10

    Cadmium (Cd) is a highly toxic metal that affects a variety of cellular events, such as cell proliferation, differentiation and survival. Cd generates reactive oxygen species (ROS) that induce apoptosis. We previously demonstrated that Cd induces apoptosis in testicular germ cells and that apoptosis was prevented by the administration of ascorbic acid (AA), an ROS scavenger. However, little is known about the signaling pathways underlying Cd-induced apoptosis in rat testes. Here, we report that Cd-induced apoptosis in rat testes was associated with the translocation of apoptosis inducing factor (AIF) from mitochondria to the nucleus, and that this was prevented by treatment with AA. Cd-induced cleavage of poly ADP-ribose polymerase-1 (PARP-1), and this was also inhibited by treatment with AA. Taken together, these results suggest that Cd-induced ROS was responsible for the upregulation of PARP-1, the translocation of AIF to the nucleus, and apoptosis of testicular cells in rat testes. PMID:19433269

  17. Apoptotic and necrotic influence of dental resin polymerization initiators in human gingival fibroblast cultures.

    PubMed

    Masuki, Kouhei; Nomura, Yuji; Bhawal, Ujjal Kumar; Sawajiri, Masahiko; Hirata, Isao; Nahara, Yukinori; Okazaki, Masayuki

    2007-11-01

    The aim of this study was to examine the apoptotic and necrotic influence of four dental resin polymerization initiators--namely benzoyl peroxide (BPO), camphorquinone (CQ), dimethylaminoethyl methacrylate (DMAEMA), and dimethyl-para-toluidine (DMPT)--on human gingival fibroblast (HGF) cells. To this end, the growth inhibition of HGF cells with 1 mM BPO, CQ, and DMAEMA, and 500 microM DMPT was evaluated using Cell Counting Kit-8. Then, cell cycle analysis by flow cytometry was used to assess propidium iodide-stained cells (distribution of cells in G0/G1, S, G2/M phases). All four dental resin polymerization initiators induced G0/G1 cell cycle arrest. As for the patterns of cell death (necrosis and/or apoptosis), they were analyzed using Annexin V-FITC/PI staining with flow cytometry. All four dental resin polymerization initiators most likely induced necrosis.

  18. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium

    SciTech Connect

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N.; Cormet-Boyaka, Estelle

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cadmium induces secretion of IL-6 and IL-8 by two distinct pathways. Black-Right-Pointing-Pointer Cadmium increases NAPDH oxidase activity leading to Erk activation and IL-8 secretion. Black-Right-Pointing-Pointer Curcumin prevents cadmium-induced secretion of both IL-6 and IL-8 by airway cells. Black-Right-Pointing-Pointer Curcumin could be use to suppress lung inflammation due to cadmium inhalation. -- Abstract: Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-{kappa}B dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  19. Necrotizing sialometaplasia: a source of confusion with carcinoma of the palate.

    PubMed

    Fechner, R E

    1977-04-01

    Necrotizing sialometaplasia is a self-healing nonneoplastic disease of the hard and soft palate characterized by one or two deeply excavating ulcers. Histologically, there is necrosis of the mucous cells of the minor salivary gland tissue with partial replacement by squamous epithelium. The deeply situated squamous epithelium intermixed with mucous cells may lead to the erroneous diagnosis of squamous carcinoma or mucoepidermoid carcinoma. The confinement of cytologically benign squamous epithelium to the pre-existing lobular pattern of the salivary gland should permit an accurate histologic diagnosis by biopsy and avert further surgical intervention.

  20. G9a-mediated histone methylation regulates cadmium-induced male fertility damage in pubertal mice.

    PubMed

    Li, Min; Liu, Chuan; Yang, Lingling; Zhang, Lei; Chen, Chunhai; He, Mindi; Lu, Yonghui; Feng, Wei; Pi, Huifeng; Zhang, Yanwen; Zhong, Min; Yu, Zhengping; Zhou, Zhou

    2016-06-11

    Increasing evidence suggests that cadmium (Cd) is associated with male fertility damage. However, the effects of histone modification on Cd-induced male fertility damage remain obscure. This study aims to evaluate the roles of histone methylation mediated by euchromatin histone methyltransferase (EHMT2/G9a) in regulating Cd-induced male fertility damage. We exposed 4-week-old male C57BL/6J mice to Cd by intraperitoneal injection at 2mg/kg for 1, 3 and 5days. Our data showed that Cd exposure decreased the numbers of impregnated females and litter sizes, which was concomitant with sperm count reduction, histological changes in the cauda epididymal ducts and seminiferous epithelium, and testicular cell apoptosis as evaluated by terminal dUTP nick-end labeling (TUNEL) assay and immunoblotting with increased levels of cleaved caspase 3, PARP and Bax and a decreased level of Bcl-2. Cd-induced male fertility damage was accompanied by enhanced G9a activity followed by increased histone H3 lysine 9 monomethylation (H3K9me1) and dimethylation (H3K9me2) in testes. Furthermore, inhibition of G9a by BIX-01294 normalized H3K9me1 and H3K9me2 to basal levels and prevented Cd-induced male fertility damage and testicular cell apoptosis. Our present study revealed that G9a-mediated histone methylation plays a critical role in Cd-induced male fertility damage and testicular cell apoptosis. PMID:27060504

  1. Effect of Ocimum basilicum extract on cadmium-induced testicular histomorphometric and immunohistochemical alterations in albino rats.

    PubMed

    Sakr, Saber A; Nooh, Hanna Z

    2013-06-01

    The present study examined the efficacy of Ocimum basilicum (basil) extract, a natural herb, with antioxidant properties, against testicular toxicity induced by cadmium (Cd), which is one of the most important toxic heavy metals. The intoxicated rats showed significant alterations in the testicular tissue including decreased seminiferous epithelium height and changes in the arrangement of spermatogenic layers. Hypospermatogensis with cytoplasmic vacuolization and pyknotic nuclei were observed. Intertubular hemorrahage and absence of spermatozoa were noted. Decreased cell proliferation was reflected by a decrease in Ki-67 expression, whereas the increase in apoptotic rate was associated with a decrease in the Bcl/Bax ratio. Concomitant treatment with aqueous basil extract led to an improvement in histological, morphometrical and immunohistochemical changes induced by Cd. The beneficial effects of basil extract could be attributed to its antioxidant properties.

  2. Effect of Ocimum basilicum extract on cadmium-induced testicular histomorphometric and immunohistochemical alterations in albino rats.

    PubMed

    Sakr, Saber A; Nooh, Hanna Z

    2013-06-01

    The present study examined the efficacy of Ocimum basilicum (basil) extract, a natural herb, with antioxidant properties, against testicular toxicity induced by cadmium (Cd), which is one of the most important toxic heavy metals. The intoxicated rats showed significant alterations in the testicular tissue including decreased seminiferous epithelium height and changes in the arrangement of spermatogenic layers. Hypospermatogensis with cytoplasmic vacuolization and pyknotic nuclei were observed. Intertubular hemorrahage and absence of spermatozoa were noted. Decreased cell proliferation was reflected by a decrease in Ki-67 expression, whereas the increase in apoptotic rate was associated with a decrease in the Bcl/Bax ratio. Concomitant treatment with aqueous basil extract led to an improvement in histological, morphometrical and immunohistochemical changes induced by Cd. The beneficial effects of basil extract could be attributed to its antioxidant properties. PMID:23869259

  3. Effects of Arctium lappa on Cadmium-Induced Damage to the Testis and Epididymis of Adult Wistar Rats.

    PubMed

    Predes, Fabricia de Souza; Diamante, M A S; Foglio, M A; Dolder, H

    2016-10-01

    The protective role of Arctium lappa (AL) on the testes of rats acutely exposed to cadmium (Cd) was tested. The rats were randomly divided into a control group (C-group) and three major experimental groups, which were further subdivided into minor groups (n = 6) according to the experimental period (7 or 56 days). The C-group was subdivided into C-7 and C-56 [receiving a single saline solution, intraperitoneal (i.p.), on the first day]; the AL-group, AL-7, and AL-56, received AL extract (300 mg/kg/daily); the Cd group, Cd-7 and Cd-56, received a single i.p. dose of CdCl2 (1.2 mg/kg body weight (BW)) on the first day; the CdAL group, CdAL-7 and CdAL-56, received the same Cd dose, followed by AL extract. Water or AL extract was administered daily by gavage. After either 7 or 56 days, the testis and accessory glands were removed after whole-body perfusion. Exposure to Cd and CdAL decreased the weight of the testis and epididymis, the gonadosomatic index, seminiferous tubular (ST) diameter, and ST volumetric proportion, and increased the volumetric proportion of interstitium after 56 days. In the epididymis caput, the tubular volumetric proportion decreased along with an increase of interstitial volumetric proportion and epithelium height after 56 days. The alterations observed were less severe only after 7 days. A progressive testicular damage resulted mainly in tubules lined only by Sertoli cells. The sperm number and cell debris decreased in the epididymis. We demonstrated that the testicular damage induced by single acute i.p. exposure to Cd occurred despite the daily oral intake of AL extract.

  4. Effects of Arctium lappa on Cadmium-Induced Damage to the Testis and Epididymis of Adult Wistar Rats.

    PubMed

    Predes, Fabricia de Souza; Diamante, M A S; Foglio, M A; Dolder, H

    2016-10-01

    The protective role of Arctium lappa (AL) on the testes of rats acutely exposed to cadmium (Cd) was tested. The rats were randomly divided into a control group (C-group) and three major experimental groups, which were further subdivided into minor groups (n = 6) according to the experimental period (7 or 56 days). The C-group was subdivided into C-7 and C-56 [receiving a single saline solution, intraperitoneal (i.p.), on the first day]; the AL-group, AL-7, and AL-56, received AL extract (300 mg/kg/daily); the Cd group, Cd-7 and Cd-56, received a single i.p. dose of CdCl2 (1.2 mg/kg body weight (BW)) on the first day; the CdAL group, CdAL-7 and CdAL-56, received the same Cd dose, followed by AL extract. Water or AL extract was administered daily by gavage. After either 7 or 56 days, the testis and accessory glands were removed after whole-body perfusion. Exposure to Cd and CdAL decreased the weight of the testis and epididymis, the gonadosomatic index, seminiferous tubular (ST) diameter, and ST volumetric proportion, and increased the volumetric proportion of interstitium after 56 days. In the epididymis caput, the tubular volumetric proportion decreased along with an increase of interstitial volumetric proportion and epithelium height after 56 days. The alterations observed were less severe only after 7 days. A progressive testicular damage resulted mainly in tubules lined only by Sertoli cells. The sperm number and cell debris decreased in the epididymis. We demonstrated that the testicular damage induced by single acute i.p. exposure to Cd occurred despite the daily oral intake of AL extract. PMID:26926909

  5. Necrotizing Fasciitis of the Abdominal Wall Caused by Serratia Marcescens.

    PubMed

    Lakhani, Naheed A; Narsinghani, Umesh; Kumar, Ritu

    2015-04-15

    In this article, we present the first case of necrotizing fasciitis affecting the abdominal wall caused by Serratia marcescens and share results of a focused review of S. marcescens induced necrotizing fasciitis. Our patient underwent aorto-femoral bypass grafting for advanced peripheral vascular disease and presented 3 weeks postoperatively with pain, erythema and discharge from the incision site in the left lower abdominal wall and underwent multiple debridement of the affected area. Pathology of debrided tissue indicated extensive necrosis involving the adipose tissue, fascia and skeletal muscle. Wound cultures were positive for Serratia marcescens. She was successfully treated with antibiotics and multiple surgical debridements. Since necrotizing fasciitis is a medical and surgical emergency, it is critical to examine infectivity trends, clinical characteristics in its causative spectrum. Using PubMed we found 17 published cases of necrotizing fasciitis caused by Serratia marcescens, and then analyzed patterns among those cases. Serratia marcescens is prominent in the community and hospital settings, and information on infection presentations, risk factors, characteristics, treatment, course, and complications as provided through this study can help identify cases earlier and mitigate poor outcomes. Patients with positive blood cultures and those patients where surgical intervention was not provided or delayed had a higher mortality. Surgical intervention is a definite way to establish the diagnosis of necrotizing infection and differentiate it from other entities.

  6. Effect of angiotensin II type 1 receptor blocker on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats

    PubMed Central

    Ahmed, Marwa A

    2013-01-01

    Objective: To study the possible effect of angiotensin II type 1 Receptor blocker (AT1 blocker) on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. Forty five rats were divided randomly into a control (group I), group II, received cadmium chloride at a dose of 5 mg/kg/day, orally, for nine weeks, group III received telmisartan (TEL) treatment (1 mg/kg/day, orally) one week before cadmium administration and continued for ten weeks. Results: Telmisartan significantly reduced blood urea nitrogen (BUN) and serum creatinine levels which were increased significantly by cadmium. Telmisartan significantly suppressed lipid peroxidation, compensated deficits in the antioxidant defenses (super oxide dismutase (SOD) level and catalase activity), decreased the elevations of nitric oxide (NO) and cadmium ion concentrations in renal tissue observed in Cd-treated rats. Group III had a significant decrease of urinary levels of total protein, N-acetyl-β-d-glucosaminidase (NAG), alkaline phosphatase (ALP) and γ-glutamyl-transpeptidase (GGT) and urinary 8-isoprostanes than those of group II. Telmisartan decreased the systolic blood pressure significantly than those of group II. Histopathological examination revealed that cadmium-induced renal tissue damage was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the cadmium-induced overexpression of parathyroid hormone receptor 1 (PTHR1) in renal tissue. RT-PCR analysis showed that Cd increased renal expression of PTHrP; however telmisartan could decrease the expression of PTHrP in group III. Conclusion: Blocking AT1 receptors significantly decreases PTHrP over expression and ameliorates renal dysfunction in Cd induced nephrotoxicity. These data suggest that Ang II might contribute to pathophysiology and deleterious effects in cadmium nephrotoxicity. PMID:23750309

  7. Role of Nrf2 antioxidant defense in mitigating cadmium-induced oxidative stress in the olfactory system of zebrafish

    SciTech Connect

    Wang, Lu; Gallagher, Evan P.

    2013-01-15

    Exposure to trace metals can disrupt olfactory function in fish leading to a loss of behaviors critical to survival. Cadmium (Cd) is an olfactory toxicant that elicits cellular oxidative stress as a mechanism of toxicity while also inducing protective cellular antioxidant genes via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, the molecular mechanisms of Cd-induced olfactory injury have not been characterized. In the present study, we investigated the role of the Nrf2-mediated antioxidant defense pathway in protecting against Cd-induced olfactory injury in zebrafish. A dose-dependent induction of Nrf2-regulated antioxidant genes associated with cellular responses to oxidative stress was observed in the olfactory system of adult zebrafish following 24 h Cd exposure. Zebrafish larvae exposed to Cd for 3 h showed increased glutathione S-transferase pi (gst pi), glutamate–cysteine ligase catalytic subunit (gclc), heme oxygenase 1 (hmox1) and peroxiredoxin 1 (prdx1) mRNA levels indicative of Nrf2 activation, and which were blocked by morpholino-mediated Nrf2 knockdown. The inhibition of antioxidant gene induction in Cd-exposed Nrf2 morphants was associated with disruption of olfactory driven behaviors, increased cell death and loss of olfactory sensory neurons (OSNs). Nrf2 morphants also exhibited a downregulation of OSN-specific genes after Cd exposure. Pre-incubation of embryos with sulforaphane (SFN) partially protected against Cd-induced olfactory tissue damage. Collectively, our results indicate that oxidative stress is an important mechanism of Cd-mediated injury in the zebrafish olfactory system. Moreover, the Nrf2 pathway plays a protective role against cellular oxidative damage and is important in maintaining zebrafish olfactory function. -- Highlights: ► Oxidative stress is an important mechanism of Cd-mediated olfactory injury. ► Cd induces antioxidant gene expression in the zebrafish olfactory system. ► The

  8. A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10 -1082 promoter genotype as predictor of disease progression

    PubMed Central

    von Euw, Erika M; Barrio, María M; Furman, David; Levy, Estrella M; Bianchini, Michele; Peguillet, Isabelle; Lantz, Olivier; Vellice, Alejandra; Kohan, Abraham; Chacón, Matías; Yee, Cassian; Wainstok, Rosa; Mordoh, José

    2008-01-01

    Background Sixteen melanoma patients (1 stage IIC, 8 stage III, and 7 stage IV) were treated in a Phase I study with a vaccine (DC/Apo-Nec) composed of autologous dendritic cells (DCs) loaded with a mixture of apoptotic/necrotic allogeneic melanoma cell lines (Apo-Nec), to evaluate toxicity and immune responses. Also, IL-10 1082 genotype was analyzed in an effort to predict disease progression. Methods PBMC were obtained after leukapheresis and DCs were generated from monocytes cultured in the presence of GM-CSF and IL-4 in serum-free medium. Immature DCs were loaded with gamma-irradiated Apo-Nec cells and injected id without adjuvant. Cohorts of four patients were given four vaccines each with 5, 10, 15, or 20 × 106 DC/Apo-Nec cell per vaccine, two weeks apart. Immune responses were measured by ELISpot and tetramer analysis. Il-10 genotype was measured by PCR and corroborated by IL-10 production by stimulated PBMC. Results Immature DCs efficiently phagocytosed melanoma Apo-Nec cells and matured after phagocytosis as evidenced by increased expression of CD83, CD80, CD86, HLA class I and II, and 75.2 ± 16% reduction in Dextran-FITC endocytosis. CCR7 was also up-regulated upon Apo-Nec uptake in DCs from all patients, and accordingly DC/Apo-Nec cells were able to migrate in vitro toward MIP-3 beta. The vaccine was well tolerated in all patients. The DTH score increased significantly in all patients after the first vaccination (Mann-Whitney Test, p < 0.05). The presence of CD8+T lymphocytes specific to gp100 and Melan A/MART-1 Ags was determined by ELISpot and tetramer analysis in five HLA-A*0201 patients before and after vaccination; one patient had stable elevated levels before and after vaccination; two increased their CD8 + levels, one had stable moderate and one had negligible levels. The analysis of IL-10 promoter -1082 polymorphism in the sixteen patients showed a positive correlation between AA genotype, accompanied by lower in vitro IL-10 production by

  9. Cadmium-induced inhibition of photosynthesis and long-term acclimation to cadmium stress in the hyperaccumulator Thlaspi caerulescens.

    PubMed

    Küpper, Hendrik; Parameswaran, Aravind; Leitenmaier, Barbara; Trtílek, Martin; Setlík, Ivan

    2007-01-01

    Acclimation of hyperaccumulators to heavy metal-induced stress is crucial for phytoremediation and was investigated using the hyperaccumulator Thlaspi caerulescens and the nonaccumulators T. fendleri and T. ochroleucum. Spatially and spectrally resolved kinetics of in vivo absorbance and fluorescence were measured with a novel fluorescence kinetic microscope. At the beginning of growth on cadmium (Cd), all species suffered from toxicity, but T. caerulescens subsequently recovered completely. During stress, a few mesophyll cells in T. caerulescens became more inhibited and accumulated more Cd than the majority; this heterogeneity disappeared during acclimation. Chlorophyll fluorescence parameters related to photochemistry were more strongly affected by Cd stress than nonphotochemical parameters, and only photochemistry showed acclimation. Cd acclimation in T. caerulescens shows that part of its Cd tolerance is inducible and involves transient physiological heterogeneity as an emergency defence mechanism. Differential effects of Cd stress on photochemical vs nonphotochemical parameters indicate that Cd inhibits the photosynthetic light reactions more than the Calvin-Benson cycle. Differential spectral distribution of Cd effects on photochemical vs nonphotochemical quenching shows that Cd inhibits at least two different targets in/around photosystem II (PSII). Spectrally homogeneous maximal PSII efficiency (F(v)/F(m)) suggests that in healthy T. caerulescens all chlorophylls fluorescing at room temperature are PSII-associated. PMID:17688582

  10. Ameliorative Effect of Grape Seed Proanthocyanidin Extract on Cadmium-Induced Meiosis Inhibition During Oogenesis in Chicken Embryos.

    PubMed

    Hou, Fuyin; Xiao, Min; Li, Jian; Cook, Devin W; Zeng, Weidong; Zhang, Caiqiao; Mi, Yuling

    2016-04-01

    Cadmium (Cd) is an environmental endocrine disruptor that has toxic effects on the female reproductive system. Here the ameliorative effect of grape seed proanthocyanidin extract (GSPE) on Cd-induced meiosis inhibition during oogenesis was explored. As compared with controls, chicken embryos exposed to Cd (3 µg/egg) displayed a changed oocyte morphology, decreased number of meiotic germ cells, and decreased expression of the meiotic marker protein γH2AX. Real time RT-PCR also revealed a significant down-regulation in the mRNA expressions of various meiosis-specific markers (Stra8, Spo11, Scp3, and Dmc1) together with those of Raldh2, a retinoic acid (RA) synthetase, and of the receptors (RARα and RARβ). In addition, exposure to Cd increased the production of H2 O2 and malondialdehyde in the ovaries and caused a corresponding reduction in glutathione and superoxide dismutase. Simultaneous supplementation of GSPE (150 µg/egg) markedly alleviated the aforementioned Cd-induced embryotoxic effects by upregulating meiosis-related proteins and gene expressions and restoring the antioxidative level. Collectively, the findings provided novel insights into the underlying mechanism of Cd-induced meiosis inhibition and indicated that GSPE might potentially ameliorate related reproductive disorders.

  11. Comparative Physiological and Proteomic Analysis Reveals the Leaf Response to Cadmium-Induced Stress in Poplar (Populus yunnanensis)

    PubMed Central

    Yang, Shihai; Zhou, Yanli; Dong, Chao; Ren, Jian; Sun, Xudong; Yang, Yongping

    2015-01-01

    Excess amounts of heavy metals are important environmental pollutants with significant ecological and nutritional effects. Cdmium (Cd) is of particular concern because of its widespread occurrence and high toxicity. We conducted physiological and proteomic analyses to improve our understanding of the responses of Populus yunnanensis to Cd stress. The plantlets experienced two apparent stages in their response to Cd stress. During the first stage, transiently induced defense-response molecules, photosynthesis- and energy-associated proteins, antioxidant enzymes and heat shock proteins (HSPs) accumulated to enhance protein stability and establish a new cellular homeostasis. This activity explains why plant photosynthetic capability during this period barely changed. During the second stage, a decline of ribulose-1, 5-bisphosphate carboxylase (RuBisCO) and HSP levels led to imbalance of the plant photosynthetic system. Additionally, the expression of Mitogen-activated protein kinase 3 (MPK3), Mitogen-activated protein kinase 6 (MPK6) and a homeobox-leucine zipper protein was higher in the second stage. Higher expression of caffeoyl-CoA O-methyltransferase (CCoAOMT) may regulate plant cell wall synthesis for greater Cd storage. These genes may be candidates for further research and use in genetic manipulation of poplar tolerance to Cd stress. PMID:26349064

  12. In Vitro Cadmium-Induced Alterations in Growth and Oxidative Metabolism of Upland Cotton (Gossypium hirsutum L.)

    PubMed Central

    Daud, M. K.; Mei, Lei; Najeeb, Ullah; Khan, Muhammad Azim; Deeba, Farah; Raza, Irum; Batool, Aliya; Zhu, S. J.

    2014-01-01

    Cadmium (Cd) is a toxic pollutant, which cause both dose- and time-dependent physiological and biochemical alterations in plants. The present in vitro study was undertaken to explore Cd-induced physiological and biochemical changes in cotton callus culture at 0, 550, 700, 850, and 1000 μM Cd for four different stress periods (7, 14, 21, and 28 days). At 1000 μM Cd, mean growth values were lower than their respective control. The cell protein contents decreased only after 7-day and 14-day stress treatment. At 550 μM Cd, malondialdehyde (MDA) contents decreased after various stress periods except 21-day period. Superoxide dismutase (SOD) activity at 1000 μM Cd improved relative to its respective controls in the first three stress regimes. Almost a decreasing trend in the hydrogen peroxide (H2O2) and peroxidase (POD) activities at all Cd levels after different stress periods was noticed. Ascorbate peroxidase (APX) activity descended over its relevant controls in the first three stress regimes except at 700 μM Cd after 14- and 21-day stress duration. Moreover, catalase (CAT) mean values significantly increased as a whole. From this experiment, it can be concluded that lipid peroxidation as well as reactive oxygen species (ROS) production was relatively higher as has been revealed by higher MDA contents and greater SOD, CAT activities. PMID:25013851

  13. Ameliorative Effect of Grape Seed Proanthocyanidin Extract on Cadmium-Induced Meiosis Inhibition During Oogenesis in Chicken Embryos.

    PubMed

    Hou, Fuyin; Xiao, Min; Li, Jian; Cook, Devin W; Zeng, Weidong; Zhang, Caiqiao; Mi, Yuling

    2016-04-01

    Cadmium (Cd) is an environmental endocrine disruptor that has toxic effects on the female reproductive system. Here the ameliorative effect of grape seed proanthocyanidin extract (GSPE) on Cd-induced meiosis inhibition during oogenesis was explored. As compared with controls, chicken embryos exposed to Cd (3 µg/egg) displayed a changed oocyte morphology, decreased number of meiotic germ cells, and decreased expression of the meiotic marker protein γH2AX. Real time RT-PCR also revealed a significant down-regulation in the mRNA expressions of various meiosis-specific markers (Stra8, Spo11, Scp3, and Dmc1) together with those of Raldh2, a retinoic acid (RA) synthetase, and of the receptors (RARα and RARβ). In addition, exposure to Cd increased the production of H2 O2 and malondialdehyde in the ovaries and caused a corresponding reduction in glutathione and superoxide dismutase. Simultaneous supplementation of GSPE (150 µg/egg) markedly alleviated the aforementioned Cd-induced embryotoxic effects by upregulating meiosis-related proteins and gene expressions and restoring the antioxidative level. Collectively, the findings provided novel insights into the underlying mechanism of Cd-induced meiosis inhibition and indicated that GSPE might potentially ameliorate related reproductive disorders. PMID:26799944

  14. Vitamin C modulates cadmium-induced hepatic antioxidants' gene transcripts and toxicopathic changes in Nile tilapia, Oreochromis niloticus.

    PubMed

    El-Sayed, Yasser S; El-Gazzar, Ahmed M; El-Nahas, Abeer F; Ashry, Khaled M

    2016-01-01

    Cadmium (Cd) is one of the naturally occurring heavy metals having adverse effects, while vitamin C (L-ascorbic acid) is an essential micronutrient for fish, which can attenuate tissue damage owing to its chain-breaking antioxidant and free radical scavenger properties. The adult Nile tilapia fish were exposed to Cd at 5 mg/l with and without vitamin C (500 mg/kg diet) for 45 days in addition to negative and positive controls fed with the basal diet and basal diet supplemented with vitamin C, respectively. Hepatic relative mRNA expression of genes involved in antioxidant function, metallothionein (MT), glutathione S-transferase (GST-α1), and glutathione peroxidase (GPx1), was assessed using real-time reverse transcription polymerase chain reaction (RT-PCR). Hepatic architecture was also histopathologically examined. Tilapia exposed to Cd exhibited upregulated antioxidants' gene transcript levels, GST-⍺1, GPx1, and MT by 6.10-, 4.60-, and 4.29-fold, respectively. Histopathologically, Cd caused severe hepatic changes of multifocal hepatocellular and pancreatic acinar necrosis, and lytic hepatocytes infiltrated with eosinophilic granular cells. Co-treatment of Cd-exposed fish with vitamin C overexpressed antioxidant enzyme-related genes, GST-⍺1 (16.26-fold) and GPx1 (18.68-fold), and maintained the expression of MT gene close to control (1.07-fold), averting the toxicopathic lesions induced by Cd. These results suggested that vitamin C has the potential to protect Nile tilapia from Cd hepatotoxicity via sustaining hepatic antioxidants' genes transcripts and normal histoarchitecture.

  15. Cadmium accumulation and buffering of cadmium-induced stress by arbuscular mycorrhiza in three Pisum sativum L. genotypes.

    PubMed

    Rivera-Becerril, Facundo; Calantzis, Catherine; Turnau, Katarzyna; Caussanel, Jean-Pierre; Belimov, Andrei A; Gianinazzi, Silvio; Strasser, Reto J; Gianinazzi-Pearson, Vivienne

    2002-05-01

    The role of arbuscular mycorrhiza in reducing Cd stress was investigated in three genotypes of Pisum sativum L. (cv. Frisson, VIR4788, VIR7128), grown in soil/sand pot cultures in the presence and absence of 2-3 mg kg(-1) bioavailable Cd, and inoculated or not with the arbuscular mycorrhizal fungus Glomus intraradices. Shoot, root and pod biomass were decreased by Cd in non-mycorrhizal plants. The presence of mycorrhiza attenuated the negative effect of Cd so that shoot biomass and activity of photosystem II, based on chlorophyll a fluorescence, were not significantly different between mycorrhizal plants growing in the presence or absence of the heavy metal (HM). Total P concentrations were not significantly different between mycorrhizal and non-mycorrhizal plants treated with Cd. From 20-50-fold more Cd accumulated in roots than in shoots of Cd-treated plants, and overall levels were comparable to other metal-accumulating plants. Genetic variability in Cd accumulation existed between the pea genotypes. Concentration of the HM was lowest in roots of VIR4788 and in pods of VIR4788 and VIR7128. G. intraradices inoculation decreased Cd accumulation in roots and pods of cv. Frisson, whilst high concentrations were maintained in roots and pods of mycorrhizal VIR7128. Shoot concentrations of Cd increased in mycorrhizal cv. Frisson and VIR4788. Sequestration of Cd in root cell walls and/or cytoplasm, measured by EDS/SEM, was comparable between non-mycorrhizal pea genotypes but considerably decreased in mycorrhizal cv. Frisson and VIR7128. Possible mechanisms for mycorrhiza buffering of Cd-induced stress in the pea genotypes are discussed.

  16. Necrotizing fasciitis and death following an insect bite.

    PubMed

    Fernando, Dinesh Malcolm G; Kaluarachchi, Chandishni I; Ratnatunga, Champa N

    2013-09-01

    A healthy man who presented to hospital with painful swelling of the left arm following a history of insect (tick) bite developed shock and died within 48 hours. The postmortem examination revealed swelling and desquamation of skin and erythema on the left arm extending below the elbow. The subcutaneous tissue was necrotic with healthy underlying muscles. Group A β-hemolytic streptococcus was isolated from postmortem swabs of the infected tissue. Histopathologic changes were consistent with necrotizing fasciitis.Secondary bacterial infection is an important possible complication following insect bite, and a high degree of suspicion with aggressive early treatment is required in cases of necrotizing fasciitis to prevent fatalities. Both clinicians and pathologists need to be aware of this rare, rapidly fatal condition that may follow an insect bite.

  17. Craniocervical necrotizing fasciitis of odontogenic origin with mediastinal extension.

    PubMed

    Edwards, John D; Sadeghi, Nader; Najam, Farzad; Margolis, Mark

    2004-08-01

    We review an interesting case of craniocervical necrotizing fasciitis with thoracic extension in an immunocompetent 44-year-old man. The patient underwent aggressive medical and surgical management during a long hospitalization. Multiple surgical debridements, including transcervical mediastinal debridement, and eventually a thoracotomy for mediastinal abscess were required. The patient eventually recovered, and 3 months later he showed no sign of complications or recurrence. Craniocervical necrotizing fasciitis is a fulminant soft-tissue infection, usually of odontogenic origin, that requires prompt identification and treatment to ensure survival. Broad-spectrum intravenous antibiotics, aggressive surgical debridement and wound care, hyperbaric oxygen, and good intensive care are the mainstays of treatment.

  18. Necrotizing sialometaplasia: a sheep in wolf's clothing. Healing as a diagnostic test.

    PubMed

    Kinney, R B; Burton, C S; Vollmer, R T

    1986-02-01

    Necrotizing sialometaplasia is a benign self-limited intraoral lesion that is easily confused both clinically and histologically with squamous cell carcinoma. It presents as a painless ulceration, frequently on the hard palate, that histologically shows necrosis, inflammation, squamous metaplasia, and granulation tissue. It is thought to be due to infarction of minor salivary glands and heals spontaneously in six to 12 weeks. A brief period of observation for evidence of healing can be an important diagnostic clue in distinguishing this entity from cancer, thus saving the patient unnecessary surgery or radiation therapy.

  19. Cadmium-induced testicular injury

    SciTech Connect

    Siu, Erica R.; Mruk, Dolores D.; Porto, Catarina S.; Cheng, C. Yan

    2009-08-01

    Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn{sup 2+} and/or Ca{sup 2+} mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men.

  20. Cadmium-induced testicular injury.

    PubMed

    Siu, Erica R; Mruk, Dolores D; Porto, Catarina S; Cheng, C Yan

    2009-08-01

    Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn(2+) and/or Ca(2+) mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men. PMID:19236889

  1. Cadmium-induced Testicular Injury*

    PubMed Central

    Siu, Erica R.; Mruk, Dolores D.; Porto, Catarina S.; Cheng, C. Yan

    2009-01-01

    Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer the testis sensitivity to Cd, such as Cd transporters and metallothioneins, and the impact of Cd on the testis as an endocrine disruptor, oxidative stress inducer and how it may disrupt the Zn+2 and/or Ca+2 mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity is emerged, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men. PMID:19236889

  2. Paraneoplastic necrotizing myopathy associated with adenocarcinoma of the lung – a rare entity with atypical onset: a case report

    PubMed Central

    2013-01-01

    Introduction Inflammatory myopathies (such as dermatomyositis and polymyositis) are well-recognized paraneoplastic syndromes. However, paraneoplastic necrotizing myopathy is a more recently defined clinical entity, characterized by rapidly progressive, symmetrical, predominantly proximal muscle weakness with severe disability, and associated with a marked increase in serum muscle enzyme levels. Paraneoplastic necrotizing myopathy requires muscle biopsy for diagnosis, which typically shows massive necrosis of muscle fibers with limited or absent inflammatory infiltrates. Case presentation We report the case of an 82-year-old Italian-born Caucasian man who was admitted to hospital because of heart failure and two drop attacks. Over the following days, he developed progressive severe weakness, dysphagia, and dysphonia. Testing showed increasing serum muscle enzyme levels. Electromyography showed irritative myopathy of the proximal muscles and sensorimotor polyneuropathy. Muscle biopsy (left vastus lateralis) showed massive necrosis of muscle fibers with negligible inflammatory infiltrates, complement membrane attack complex deposition on endomysial capillaries, and moderate upregulation of major histocompatibility complex-I. Computed tomography of the thorax showed a nodular mass in the apex of the right lung. The patient was diagnosed with paraneoplastic necrotizing myopathy. In spite of high-dose corticoid therapy, he died 1 month later because of his aggressive cancer. Subsequent electron microscopic examination of a muscle biopsy specimen showed thickened walls and typical pipestem changes of the endomysial capillaries, with swollen endothelial cells. Poorly differentiated adenocarcinoma of the lung was confirmed on post-mortem histological examination. Conclusions Paraneoplastic necrotizing myopathy is a rare syndrome with outcomes ranging from fast progression to complete recovery. Treatment with corticosteroids is often ineffective, and prognosis depends mainly

  3. [Method and procedures in bacteriological study of necrotic teeth].

    PubMed

    Rodríguez-Ponce, A; López Campos, A; López Paz, J; Pazos Sierra, R

    1991-01-01

    Research was conducted of 160 radicular canals with necrotic pulp. Results of different bacteriological analyses are presented. Culture analyses in aerobic and anaerobic media, resulted in the isolation of Staphylococcus Epidermidis, Streptococcus Viridans and Corynebacterium sp in the group studied, as the most frequent bacteria. There was no evidence of a specific germ linked with the pulp necrosis.

  4. Tomato necrotic streak virus, a novel subgroup 2 ilarvirus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel plant virus has been identified infecting fresh market tomato plants in south and southeast Florida. The virus causes necrosis of tomato leaves, petioles and stems, and necrotic rings or spots on tomato fruits. Symptomatic tomato plant tissue was used to mechanically inoculate tomato plant...

  5. IVIG-mediated protection against necrotizing pneumonia caused by MRSA.

    PubMed

    Diep, Binh An; Le, Vien T M; Badiou, Cedric; Le, Hoan N; Pinheiro, Marcos Gabriel; Duong, Au H; Wang, Xing; Dip, Etyene Castro; Aguiar-Alves, Fábio; Basuino, Li; Marbach, Helene; Mai, Thuy T; Sarda, Marie N; Kajikawa, Osamu; Matute-Bello, Gustavo; Tkaczyk, Christine; Rasigade, Jean-Philippe; Sellman, Bret R; Chambers, Henry F; Lina, Gerard

    2016-09-21

    New therapeutic approaches are urgently needed to improve survival outcomes for patients with necrotizing pneumonia caused by Staphylococcus aureus One such approach is adjunctive treatment with intravenous immunoglobulin (IVIG), but clinical practice guidelines offer conflicting recommendations. In a preclinical rabbit model, prophylaxis with IVIG conferred protection against necrotizing pneumonia caused by five different epidemic strains of community-associated methicillin-resistant S. aureus (MRSA) as well as a widespread strain of hospital-associated MRSA. Treatment with IVIG, either alone or in combination with vancomycin or linezolid, improved survival outcomes in this rabbit model. Two specific IVIG antibodies that neutralized the toxic effects of α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL) conferred protection against necrotizing pneumonia in the rabbit model. This mechanism of action of IVIG was uncovered by analyzing loss-of-function mutant bacterial strains containing deletions in 17 genes encoding staphylococcal exotoxins, which revealed only Hla and PVL as having an impact on necrotizing pneumonia. These results demonstrate the potential clinical utility of IVIG in the treatment of severe pneumonia induced by S. aureus. PMID:27655850

  6. An update on sequence diversity of Impatiens necrotic spot virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Impatiens necrotic spot virus (INSV; genus Tospovirus, family Bunyaviridae) is an economically important viral pathogen for a wide range of plants, including greenhouse ornamental and vegetable crops. In many cases, symptoms induced by INSV are similar, though not identical, to those induced by Toma...

  7. Identification of cultivable microorganisms from primary teeth with necrotic pulps.

    PubMed

    Ledezma-Rasillo, Gildardo; Flores-Reyes, Hector; Gonzalez-Amaro, Ana M; Garrocho-Rangel, Arturo; Ruiz-Rodriguez, M del Socorro; Pozos-Guillen, Amaury J

    2010-01-01

    The objective of this study was to identify cultivable microorganisms from primary teeth with necrotic pulps. This experimental study included 21 patients of both sexes between 4 and 7 years of age with necrotic pulps in primary teeth. Twenty-one maxillary and mandibular molars containing at least 1 necrotic canal, an abscess or sinus tract, one or more radiolucent areas in the furcation or periapical region, teeth having at least two thirds of root length, and carious lesions directly exposed to the oral environment were included. After antisepsis of the oral cavity, anesthesia of the affected tooth, and isolation and disinfection of the operative field, 3 sterile absorbent paper points were sequentially placed for 30 seconds for the collection of samples. The samples were immediately processed in an anaerobic chamber, and all isolated microorganisms were identified. Anaerobic species (anaerobic facultative and moderate anaerobes) were isolated in all root canals; 68.4% of root canal samples studied showed a polymicrobial nature. Most of the isolate consisted of Bifidobacterium Spp2 and Streptococcus intermedius. Other less frequently encountered species were Actinomyces israelii, Bifidobacterium spp 1, Clostridium spp, and Candida albicans. Results indicate the existence of combinations of bacterial species in root canal infections of the primary dentition with necrotic pulps, anaerobic bacteria predominating.

  8. Focal transmural necrotic tracheitis in commercial meat turkeys.

    PubMed

    Sentíes-Cué, Gabriel; Crespo, Rocio; Chin, R P

    2003-01-01

    This report describes an unusual presentation of severe focal necrotic tracheitis in a flock of 8-wk-old commercial turkeys. The flock was kept on a range that is located near a cotton field. The cotton field had been chemically defoliated 2 wk before the birds were submitted for necropsy. At necropsy, most of the birds had a 1-cm, yellow-white constricture in the upper third of the trachea at which the lumen was partially occluded by necrotic tissue. Microscopically, there was severe, transmural necrosis with an accumulation of inflammatory exudate in the tracheal lumen and numerous bacteria within the necrotic debris, mucosa, and lamina propria. Mixed bacteria were isolated from the trachea. No viruses were detected. Neither abnormal heavy metal concentrations in the liver nor paraquat in the respiratory tract were detected. The exact cause of this severe, necrotic tracheitis was not determined. Based on the clinical history and laboratory findings, it was concluded that a combination of a toxic irritant, possibly an aerosolized cotton defoliant, and bacterial infections were likely the cause of this lesion. PMID:12713185

  9. Necrotizing fasciitis – a diagnostic dilemma: two case reports

    PubMed Central

    2014-01-01

    Introduction Necrotizing soft tissue infections can affect various tissue planes. Although predisposing etiologies are many, they mostly center on impaired immunity occurring directly or indirectly and loss of integrity of protective barriers which predispose to infection. The nonspecific presentation may delay diagnosis and favor high mortality. Case presentation Two case vignettes are presented. The first patient, a 44-year-old healthy South Asian man with a history of repeated minor traumatic injury presented to a primary health care center with a swollen left lower limb. He was treated with antibiotics with an initial diagnosis of cellulitis. Because he deteriorated rapidly and additionally developed intestinal obstruction, he was transferred to our hospital which is a tertiary health care center for further evaluation and management. Prompt clinical diagnosis of necrotizing soft tissue infection was made and confirmed on magnetic resonance imaging as necrotizing fasciitis. Urgent debridement was done, but the already spread infection resulted in rapid clinical deterioration with resultant mortality. The second patient was a 35-year-old South Asian woman with systemic lupus erythematous receiving immunosuppressive therapy who developed left lower limb pain and fever. Medical attention was sought late as she came to the hospital after 4 days. Her condition deteriorated rapidly as she developed septic shock and died within 2 days. Conclusions Necrotizing fasciitis can be fatal when not recognized and without early intervention. Clinicians and surgeons alike should have a greater level of suspicion and appreciation for this uncommon yet lethal infection. PMID:24965382

  10. Focal transmural necrotic tracheitis in commercial meat turkeys.

    PubMed

    Sentíes-Cué, Gabriel; Crespo, Rocio; Chin, R P

    2003-01-01

    This report describes an unusual presentation of severe focal necrotic tracheitis in a flock of 8-wk-old commercial turkeys. The flock was kept on a range that is located near a cotton field. The cotton field had been chemically defoliated 2 wk before the birds were submitted for necropsy. At necropsy, most of the birds had a 1-cm, yellow-white constricture in the upper third of the trachea at which the lumen was partially occluded by necrotic tissue. Microscopically, there was severe, transmural necrosis with an accumulation of inflammatory exudate in the tracheal lumen and numerous bacteria within the necrotic debris, mucosa, and lamina propria. Mixed bacteria were isolated from the trachea. No viruses were detected. Neither abnormal heavy metal concentrations in the liver nor paraquat in the respiratory tract were detected. The exact cause of this severe, necrotic tracheitis was not determined. Based on the clinical history and laboratory findings, it was concluded that a combination of a toxic irritant, possibly an aerosolized cotton defoliant, and bacterial infections were likely the cause of this lesion.

  11. [Method and procedures in bacteriological study of necrotic teeth].

    PubMed

    Rodríguez-Ponce, A; López Campos, A; López Paz, J; Pazos Sierra, R

    1991-01-01

    Research was conducted of 160 radicular canals with necrotic pulp. Results of different bacteriological analyses are presented. Culture analyses in aerobic and anaerobic media, resulted in the isolation of Staphylococcus Epidermidis, Streptococcus Viridans and Corynebacterium sp in the group studied, as the most frequent bacteria. There was no evidence of a specific germ linked with the pulp necrosis. PMID:1659855

  12. Carbohydrate maldigestion induces necrotizing enterocolitis in preterm pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Necrotizing enterocolitis (NEC) remains the most severe gastrointestinal disorder in preterm infants. It is associated with the initiation of enteral nutrition and may be related to immature carbohydrate digestive capacity. We tested the hypothesis that a formula containing maltodextrin vs. lactose ...

  13. Temporary feed restriction partially protects broilers from necrotic enteritis.

    PubMed

    Tsiouris, V; Georgopoulou, I; Batzios, Chr; Pappaioannou, N; Ducatelle, R; Fortomaris, P

    2014-01-01

    The objective of this study was to investigate the effect of feed restriction on the intestinal ecosystem and on the pathogenesis of experimental necrotic enteritis in broiler chicks. To induce subclinical necrotic enteritis, an experimental challenge model using a specific diet formulation, Gumboro vaccination, oral inoculation of broilers with a 10-fold dose of attenuated anticoccidial vaccine and multiple oral inoculations with a specific strain of Clostridium perfringens was adopted. Two hundred and forty 1-day-old Cobb 500 broilers were randomly allocated to four groups: feed restricted, challenged, both feed restricted and challenged, and negative control. At 21, 22, 23 and 24 days of age, the intestines, gizzard and liver were collected from 15 birds in each group and scored for gross lesions. The intestinal digesta was collected for pH and viscosity determination. One caecum from each bird was taken for microbiological analysis. The application of feed restriction in birds challenged with C. perfringens reduced the necrotic enteritis lesion score significantly (P ≤ 0.05) and feed restriction significantly reduced (P ≤ 0.05) pH in the small intestine, the viscosity of the jejunum digesta as well as the C. perfringens counts in the caeca compared with the controls. In conclusion, feed restriction of broilers has a positive effect on the intestinal ecosystem and a significant protective effect against necrotic enteritis in the subclinical experimental model.

  14. Two cases of an atypical presentation of necrotizing stomatitis

    PubMed Central

    2015-01-01

    Purpose The purpose of this report was to describe the clinical and microbiological characteristics of two rare cases of necrotizing stomatitis, and the outcomes of a non-invasive treatment protocol applied in both cases. Methods We report two cases of necrotizing stomatitis in a rare location in the hard palate of a 40-year-old woman and a 28-year-old man. Neither had a relevant medical history and both presented with highly painful ulceration in the palate and gingival margin that was accompanied by suppuration and necrosis. 3% hydrogen peroxide was applied to the lesions using sterile swabs, and antibiotic and anti-inflammatory treatment was prescribed to both patients in addition to two daily oral rinses of 0.2% chlorhexidine. Results In both cases, radiological examination ruled out bone involvement, and exfoliative cytology revealed a large inflammatory component and the presence of forms compatible with fusobacteria and spirochetes. There was a rapid response to treatment and a major improvement was observed after 48 hours, with almost complete resolution of the ulcerated lesions and detachment of necrotic areas with partial decapitation of gingival papillae. Conclusions Necrotizing periodontal lesions can hinder periodontal probing and the mechanical removal of plaque in some cases due to the extreme pain suffered by the patients. We present a non-invasive treatment approach that can manage these situations effectively. PMID:26734496

  15. [Acute necrotizing esophagitis (black esophagus) with secondary severe stenosis].

    PubMed

    Gómez, Álvaro A; Guerrero, Diego; Hani, Albis C; Cañadas, Raúl

    2015-01-01

    We report the case of a 67 years old patient with a history of diabetes mellitus, atrial fibrillation and chronic renal failure, who developed diabetic ketoacidosis and severe sepsis, later presenting an acute necrotizing esophagitis, and then a esophageal stenosis requiring treatment with self-expanding esophageal prosthesis with good clinical results. PMID:26802889

  16. [Necrotizing sialometaplasia--diagnostic difficulties--literature review].

    PubMed

    Jamróz-Wilkońskaa, Lidia; Chomyszyn-Gajewska, Maria; Wilkoński, Wojciech

    2014-01-01

    Necrotizing sialometaplasia is a benign, self-limiting inflammatory process, which concerns small salivary glands. This kind of lesion is very rare, with difficulties in clinical and histopathological diagnosis. Ulceration is the dominating symptom, which may suggest that it is a malignancy. Lesions usually heal spontaneously.

  17. Treatment of Necrotic Calcified Tooth Using Intentional Replantation Procedure

    PubMed Central

    Arvin, Armita; Darvish, Alireza; Aflaki, Sareh

    2014-01-01

    Introduction. If the teeth are impacted by a chronic irritant, the pulp space possibly will undergo calcific changes that may impede access opening during root canal treatment. In such cases that conventional endodontic treatment is impossible or impractical, intentional replantation may be considered as a last solution to preserve the tooth. Methods. After failing to perform conventional root canal therapy for a necrotic calcified right mandibular second premolar, the tooth was gently extracted. The root apex was resected and the root end cavity was prepared and filled with calcium enriched mixture (CEM) cement. Then, the extracted tooth was replanted in its original position. Results. After a year the tooth was asymptomatic, and the size of periapical radiolucency was remarkably reduced and no clinical sign of ankylosis was observed. Conclusion. Intentional replantation of the necrotic calcified teeth could be considered as an alternative to teeth extraction, especially for the single-rooted teeth and when nonsurgical and surgical endodontic procedures seem impossible. PMID:24716000

  18. Treatment of necrotic calcified tooth using intentional replantation procedure.

    PubMed

    Moradi Majd, Nima; Arvin, Armita; Darvish, Alireza; Aflaki, Sareh; Homayouni, Hamed

    2014-01-01

    Introduction. If the teeth are impacted by a chronic irritant, the pulp space possibly will undergo calcific changes that may impede access opening during root canal treatment. In such cases that conventional endodontic treatment is impossible or impractical, intentional replantation may be considered as a last solution to preserve the tooth. Methods. After failing to perform conventional root canal therapy for a necrotic calcified right mandibular second premolar, the tooth was gently extracted. The root apex was resected and the root end cavity was prepared and filled with calcium enriched mixture (CEM) cement. Then, the extracted tooth was replanted in its original position. Results. After a year the tooth was asymptomatic, and the size of periapical radiolucency was remarkably reduced and no clinical sign of ankylosis was observed. Conclusion. Intentional replantation of the necrotic calcified teeth could be considered as an alternative to teeth extraction, especially for the single-rooted teeth and when nonsurgical and surgical endodontic procedures seem impossible.

  19. Transfusion-associated Necrotizing Enterocolitis (TANEC): Evidence and Uncertainty

    PubMed Central

    Gephart, Sheila M.

    2012-01-01

    Transfusion-associated Necrotizing Enterocolitis (TANEC) has been described as necrotizing enterocolitis (NEC) that arises within 48 hours of a blood transfusion. [1, 2] TANEC is concerning to clinicians and has been shown to be associated with 25–35% of NEC in recent studies. Evidence related to TANEC is limited to observational, retrospective studies. Infants who develop TANEC tend to be smaller, born at earlier gestation, more severely ill and develop NEC after 30 days of age. Evidence in two studies support holding feedings during transfusion to protect the preterm gut from the cascade of events that lead to NEC but higher quality research, including prospective randomized controlled trials, is needed to evaluate the effect of feeding on TANEC. PMID:22864004

  20. A case of Apophysomyces trapeziformis necrotizing soft tissue infection.

    PubMed

    Echaiz, Jose F; Burnham, Carey-Ann D; Bailey, Thomas C

    2013-12-01

    Mucormycosis is a rare and devastating disease. Apophysomyces trapeziformis is an environmental mold that was recently implicated in several cases of cutaneous and soft tissue mucormycosis in victims of a tornado in Joplin, Missouri. Here, we report a case of Apophysomyces trapeziformis necrotizing soft tissue infection in a resident of Joplin 10 months after the disaster and without preceding trauma. Aspects of histological and microbiological diagnosis are also reviewed. PMID:23891642

  1. Ahmed glaucoma valve surgery for necrotizing scleritis with secondary glaucoma.

    PubMed

    Ranjan, Abhishek; Rao, Aparna

    2014-04-01

    To report the challenges in management in a case of scleritis with extensive staphylomas with secondary glaucoma. A 35-year-old one eyed female, a known case of scleromalacia perforans, presented with raised intraocular pressure on maximum medical treatment. She underwent successful Ahmed glaucoma valve surgery with exposure of the implant following a repeat episode of necrotizing scleritis after 3 months. Management of eyes with scleritis and secondary glaucoma can be challenging with unexpected complications and postoperative course.

  2. Current trends in the management of infected necrotizing pancreatitis.

    PubMed

    Sakorafas, George H; Lappas, Christos; Mastoraki, Aikaterini; Delis, Spiros G; Safioleas, Michael

    2010-02-01

    Severe acute pancreatitis is a potentially life-threatening disease. Pancreatic necrosis is associated with an aggravated prognosis, while superimposed infection is almost always lethal without surgery. Bacterial translocation mainly from the gut is the most widely accepted mechanism in the pathogenesis of infected pancreatic necrosis. Infected pancreatic necrosis should be suspected in the presence of the usual markers of systemic inflammation (i.e., fever and leukocytosis), organ failure, or a protracted severe clinical course. The diagnostic method of choice to confirm the diagnosis of pancreatic necrosis is contrast-enhanced computed tomography, where necrotic areas are evidenced as regions without enhancement. The presence of pancreatic necrotic infection should be based on a combination of clinical manifestations, results of laboratory investigation (mainly increased levels of CRP and / or procalcitonin), and can be confirmed by image-guided fine-needle aspiration and gram stain /culture of the aspirates. Surgery remains the treatment of choice for the management of infected pancreatic necrosis and involves open necrosectomy (debridement) and wide drainage of the peripancreatic areas, often in association with continuous irrigation. Planned reoperations may be required to achieve complete removal of the necrotic / infected material. The timing of surgery is of paramount importance; ideally, surgery should be performed after 2 or 3 weeks from the onset of pancreatitis. Recently, various minimally invasive approaches have been described, but they have not been compared in prospective trials with the classical open surgery. Antibiotic therapy is routinely used in patients with infected necrotizing pancreatitis, in conjunction with surgical debridement; its role, however, in the management of patients with sterile necrosis is recently questioned. Nutritional support should be taken into consideration in these patients; enteral nutrition should be preferred over

  3. Membranous glomerulopathy with superimposed pauci-immune necrotizing crescentic glomerulonephritis

    PubMed Central

    Fatima, Huma; Siew, Edward D.; Dwyer, Jamie P.; Paueksakon, Paisit

    2012-01-01

    We describe a 61-year-old woman with acute kidney injury, nephrotic range proteinuria and hematuria. Kidney biopsy showed membranous glomerulopathy (MG) with superimposed pauci-immune necrotizing crescentic glomerulonephritis (PNCGN). Coexistent MG and PNCGN is a rare occurrence. The diagnosis of such an exceptionally rare combination relies on the combination of renal biopsy findings and serologic testing. We also review previous reported cases and discuss possible pathogenesis of this rare dual glomerulopathy. PMID:26069808

  4. Necrotizing hepatitis in a domestic pigeon (Columba livia).

    PubMed

    Himmel, L; O'Connor, M; Premanandan, C

    2014-11-01

    An adult male domestic pigeon (Columba livia) was presented for necropsy following natural death after a period of chronic weight loss and severe intestinal ascariasis. Histopathologic examination of the liver found moderate to marked, multifocal necrotizing hepatitis with large, basophilic intranuclear inclusion bodies. Transmission electron microscopy of affected hepatocytes demonstrated numerous intra- and perinuclear icosahedral virions arranged in a lattice structure, consistent with adenoviral infection.

  5. NetB and necrotic enteritis: the hole movable story.

    PubMed

    Rood, Julian I; Keyburn, Anthony L; Moore, Robert J

    2016-06-01

    Clostridium perfringens is the primary causative agent of avian necrotic enteritis. Our understanding of the pathogenesis of this economically important disease has been enhanced by the discovery of C. perfringens NetB toxin, which belongs to the α-haemolysin family of β-pore-forming toxins. In a chicken disease model, the analysis of an isogenic set of strains comprising the wild type, a netB mutant, and its complemented derivative, fulfilled molecular Koch's postulates and revealed that NetB was essential for disease. These results were consistent with epidemiological surveys, which generally found that there was a higher prevalence of netB carriage in C. perfringens isolates from diseased poultry compared to healthy birds. The netB gene has been shown to be located on large conjugative plasmids that are closely related to other toxin plasmids from C. perfringens, which has potential implications for the epidemiology of necrotic enteritis infections. The crystal structures of both monomeric NetB and the heptameric NetB pore have been determined, the latter revealed a central pore diameter of approximately 26 Å. Finally, it has been shown that vaccine preparations that include NetB can protect chickens against disease and a series of single amino acid substitution derivatives of NetB that have potential value for vaccine formulations have been isolated and analysed. It is likely that NetB will be an important antigen to include in an effective, commercially viable, necrotic enteritis vaccine. PMID:27009522

  6. Disseminated necrotic mediastinitis spread from odontogenic abscess: our experience

    PubMed Central

    Filiaci, Fabio; Riccardi, Emiliano; Mitro, Valeria; Piombino, Pasquale; Rinna, Claudio; Agrillo, Alessandro; Ungari, Claudio

    2015-01-01

    Summary Aims Deep neck infections are rare but potentially fatal complication of pulpal abscess of the teeth. If an infection can progress rapidly from a toothache to a life threatening infection, then it is critical that dentists be able to recognize the danger signs and identify the patients who are at risk. Mediastinitis is a severe inflammatory process involving the connective tissues that fills the intracellular spaces and surrounds the organs in the middle of the chest. This pathology has both an acute and a chronic form and, in most cases, it has an infectious etiology. This study want to expose the experience acquired in the Oral and Maxillo-facial Sciences Department, Policlinico Umberto I, “Sapienza” University of Rome, regarding two clinical cases of disseminated necrotizing mediastinitis starting from an odontogenic abscess. Methods We report two clinical cases of disseminated necrotic mediastinitis with two different medical and surgical approaches. The radiographic and photographic documentation of the patients was collected in the pre-and post-operatively. All patients underwent a CT scan and MRI. Results Mediastinitis can result from a serious odontogenic abscess, and the extent of its inflammation process must be never underestimated. Dental surgeons play a key role as a correct diagnosis can prevent further increasing of the inflammation process. Conclusions A late diagnosis and an inadequate draining represent the major causes of the elevated mortality rate of disseminated necrotizing mediastinitis. PMID:26330907

  7. Necrotic Enteritis in Chickens Associated with Clostridium sordellii.

    PubMed

    Rimoldi, Guillermo; Uzal, Francisco; Chin, R P; Palombo, Enzo A; Awad, Milena; Lyras, Dena; Shivaprasad, H L

    2015-09-01

    Three outbreaks of necrotic enteritis-like disease associated with Clostridium sordelii were diagnosed in commercial broiler chicken flocks with 18,000 to 31,000 birds between 18 and 26 days old. Clinical signs in the affected flocks included high mortality up to 2% a day, depression, and diarrhea. The main gross changes included segmental dilation of the small intestine with watery contents, gas, mucoid exudate, and roughened and uneven mucosa, occasionally covered with a pseudomembrane. Microscopic lesions in the small intestine were characterized by extensive areas of coagulative necrosis of the villi, fibrinous exudate in the lumen, and high numbers of large, Gram-positive rods, occasionally containing subterminal spores, seen in the necrotic tissue and lumen. These rods were identified as C. sordellii by immunohistochemistry. Clostridium sordellii was isolated in an almost pure culture from the intestine of affected birds. A retrospective study of commercial broiler chicken and turkey submissions to the California Animal Health and Food Safety Laboratory System revealed that C. sordellii had been isolated from intestinal lesions in outbreaks of necrotic enteritis-like disease in 8 of 39 cases, 5 times together with Clostridium perfringens and 3 times alone. The latter three cases are reported here.

  8. Bacteriological analysis of necrotic pulp and fistulae in primary teeth

    PubMed Central

    FABRIS, Antônio Scalco; NAKANO, Viviane; AVILA-CAMPOS, Mario Júlio

    2014-01-01

    Objectives Primary teeth work as guides for the eruption of permanent dentition, contribute for the development of the jaws, chewing process, preparing food for digestion, and nutrient assimilation. Treatment of pulp necrosis in primary teeth is complex due to anatomical and physiological characteristics and high number of bacterial species present in endodontic infections. The bacterial presence alone or in association in necrotic pulp and fistula samples from primary teeth of boys and girls was evaluated. Material and Methods Necrotic pulp (103) and fistula (7) samples from deciduous teeth with deep caries of 110 children were evaluated. Bacterial morphotypes and species from all clinical samples were determined. Results A predominance of gram-positive cocci (81.8%) and gram-negative coccobacilli (49.1%) was observed. In 88 out of 103 pulp samples, a high prevalence of Enterococcus spp. (50%), Porphyromonas gingivalis (49%), Fusobacterium nucleatum (25%) and Prevotella nigrescens (11.4%) was observed. Porphyromonas gingivalis was detected in three out of seven fistula samples, Enterococcus spp. in two out of seven samples, and F. nucleatum, P. nigrescens and D. pneumosintes in one out of seven samples. Conclusions Our results show that Enterococcus spp. and P. gingivalis were prevalent in necrotic pulp from deciduous teeth in boys from 2 to 5 years old, and that care of the oral cavity of children up to five years of age is important. PMID:24676582

  9. Spider Bite: A Rare Case of Acute Necrotic Arachnidism with Rapid and Fatal Evolution.

    PubMed

    Pezzi, Mario; Giglio, Anna Maria; Scozzafava, Annamaria; Filippelli, Orazio; Serafino, Giuseppe; Verre, Mario

    2016-01-01

    The spider bites are quite frequent and often resolve quickly without leaving outcomes; only some species are capable of causing necrotic and systematic lesions in humans. Among them, we should mention the genus Loxosceles. The venom released from the spider bite of Loxosceles species is composed of proteins, enzymes, and nonenzymatic polypeptides. The phospholipase D family was identified as the active component of the venom. This family of enzymes is responsible for the local and systemic effects observed in loxoscelism. Phospholipases D interact with cell membranes triggering alterations which involve the complement system and activation of neutrophils and they cause the dermonecrotic skin lesions and systemic effects. We describe a fatal case of acute intoxication caused by a spider bite probably belonging to the species Loxosceles. The initial lesion was localized to a finger of a hand. Clinical course was worsening with deep necrotic lesions on limb, shock, hemolysis, acute kidney failure, and disseminated intravascular coagulation. All therapies were ineffective. This is the first fatal case described in Europe. PMID:27651958

  10. Spider Bite: A Rare Case of Acute Necrotic Arachnidism with Rapid and Fatal Evolution

    PubMed Central

    Giglio, Anna Maria; Scozzafava, Annamaria; Filippelli, Orazio; Serafino, Giuseppe; Verre, Mario

    2016-01-01

    The spider bites are quite frequent and often resolve quickly without leaving outcomes; only some species are capable of causing necrotic and systematic lesions in humans. Among them, we should mention the genus Loxosceles. The venom released from the spider bite of Loxosceles species is composed of proteins, enzymes, and nonenzymatic polypeptides. The phospholipase D family was identified as the active component of the venom. This family of enzymes is responsible for the local and systemic effects observed in loxoscelism. Phospholipases D interact with cell membranes triggering alterations which involve the complement system and activation of neutrophils and they cause the dermonecrotic skin lesions and systemic effects. We describe a fatal case of acute intoxication caused by a spider bite probably belonging to the species Loxosceles. The initial lesion was localized to a finger of a hand. Clinical course was worsening with deep necrotic lesions on limb, shock, hemolysis, acute kidney failure, and disseminated intravascular coagulation. All therapies were ineffective. This is the first fatal case described in Europe. PMID:27651958

  11. Spider Bite: A Rare Case of Acute Necrotic Arachnidism with Rapid and Fatal Evolution.

    PubMed

    Pezzi, Mario; Giglio, Anna Maria; Scozzafava, Annamaria; Filippelli, Orazio; Serafino, Giuseppe; Verre, Mario

    2016-01-01

    The spider bites are quite frequent and often resolve quickly without leaving outcomes; only some species are capable of causing necrotic and systematic lesions in humans. Among them, we should mention the genus Loxosceles. The venom released from the spider bite of Loxosceles species is composed of proteins, enzymes, and nonenzymatic polypeptides. The phospholipase D family was identified as the active component of the venom. This family of enzymes is responsible for the local and systemic effects observed in loxoscelism. Phospholipases D interact with cell membranes triggering alterations which involve the complement system and activation of neutrophils and they cause the dermonecrotic skin lesions and systemic effects. We describe a fatal case of acute intoxication caused by a spider bite probably belonging to the species Loxosceles. The initial lesion was localized to a finger of a hand. Clinical course was worsening with deep necrotic lesions on limb, shock, hemolysis, acute kidney failure, and disseminated intravascular coagulation. All therapies were ineffective. This is the first fatal case described in Europe.

  12. Spider Bite: A Rare Case of Acute Necrotic Arachnidism with Rapid and Fatal Evolution

    PubMed Central

    Giglio, Anna Maria; Scozzafava, Annamaria; Filippelli, Orazio; Serafino, Giuseppe; Verre, Mario

    2016-01-01

    The spider bites are quite frequent and often resolve quickly without leaving outcomes; only some species are capable of causing necrotic and systematic lesions in humans. Among them, we should mention the genus Loxosceles. The venom released from the spider bite of Loxosceles species is composed of proteins, enzymes, and nonenzymatic polypeptides. The phospholipase D family was identified as the active component of the venom. This family of enzymes is responsible for the local and systemic effects observed in loxoscelism. Phospholipases D interact with cell membranes triggering alterations which involve the complement system and activation of neutrophils and they cause the dermonecrotic skin lesions and systemic effects. We describe a fatal case of acute intoxication caused by a spider bite probably belonging to the species Loxosceles. The initial lesion was localized to a finger of a hand. Clinical course was worsening with deep necrotic lesions on limb, shock, hemolysis, acute kidney failure, and disseminated intravascular coagulation. All therapies were ineffective. This is the first fatal case described in Europe.

  13. Feedback inhibition by thiols outranks glutathione depletion: a luciferase-based screen reveals glutathione-deficient γ-ECS and glutathione synthetase mutants impaired in cadmium-induced sulfate assimilation.

    PubMed

    Jobe, Timothy O; Sung, Dong-Yul; Akmakjian, Garo; Pham, Allis; Komives, Elizabeth A; Mendoza-Cózatl, David G; Schroeder, Julian I

    2012-06-01

    Plants exposed to heavy metals rapidly induce changes in gene expression that activate and enhance detoxification mechanisms, including toxic-metal chelation and the scavenging of reactive oxygen species. However, the mechanisms mediating toxic heavy metal-induced gene expression remain largely unknown. To genetically elucidate cadmium-specific transcriptional responses in Arabidopsis, we designed a genetic screen based on the activation of a cadmium-inducible reporter gene. Microarray studies identified a high-affinity sulfate transporter (SULTR1;2) among the most robust and rapid cadmium-inducible transcripts. The SULTR1;2 promoter (2.2 kb) was fused with the firefly luciferase reporter gene to quantitatively report the transcriptional response of plants exposed to cadmium. Stably transformed luciferase reporter lines were ethyl methanesulfonate (EMS) mutagenized, and stable M(2) seedlings were screened for an abnormal luciferase response during exposure to cadmium. The screen identified non-allelic mutant lines that fell into one of three categories: (i) super response to cadmium (SRC) mutants; (ii) constitutive response to cadmium (CRC) mutants; or (iii) non-response and reduced response to cadmium (NRC) mutants. Two nrc mutants, nrc1 and nrc2, were mapped, cloned and further characterized. The nrc1 mutation was mapped to the γ-glutamylcysteine synthetase gene and the nrc2 mutation was identified as the first viable recessive mutant allele in the glutathione synthetase gene. Moreover, genetic, HPLC mass spectrometry, and gene expression analysis of the nrc1 and nrc2 mutants, revealed that intracellular glutathione depletion alone would be insufficient to induce gene expression of sulfate uptake and assimilation mechanisms. Our results modify the glutathione-depletion driven model for sulfate assimilation gene induction during cadmium stress, and suggest that an enhanced oxidative state and depletion of upstream thiols, in addition to glutathione depletion

  14. Feedback inhibition by thiols outranks glutathione depletion: a luciferase-based screen reveals glutathione-deficient γ -ECS and glutathione synthetase mutants impaired in cadmium-induced sulfate assimilation

    PubMed Central

    Jobe, Timothy O.; Sung, Dong-Yul; Akmakjian, Garo; Pham, Allis; Komives, Elizabeth A.; Mendoza-Cózatl, David G.; Schroeder, Julian I.

    2015-01-01

    Summary Plants exposed to heavy metals rapidly induce changes in gene expression that activate and enhance detoxification mechanisms, including toxic-metal chelation and the scavenging of reactive oxygen species. However, the mechanisms mediating toxic heavy metal-induced gene expression remain largely unknown. To genetically elucidate cadmium-specific transcriptional responses in Arabidopsis, we designed a genetic screen based on the activation of a cadmium-inducible reporter gene. Microarray studies identified a high-affinity sulfate transporter (SULTR1;2) among the most robust and rapid cadmium-inducible transcripts. The SULTR1;2 promoter (2.2 kb) was fused with the firefly luciferase reporter gene to quantitatively report the transcriptional response of plants exposed to cadmium. Stably transformed luciferase reporter lines were ethyl methanesulfonate (EMS) mutagenized, and stable M2 seedlings were screened for an abnormal luciferase response during exposure to cadmium. The screen identified non-allelic mutant lines that fell into one of three categories: (i) super response to cadmium (SRC) mutants; (ii) constitutive response to cadmium (CRC) mutants; or (iii) non-response and reduced response to cadmium (NRC) mutants. Two nrc mutants, nrc1 and nrc2, were mapped, cloned and further characterized. The nrc1 mutation was mapped to the γ-glutamylcysteine synthetase gene and the nrc2 mutation was identified as the first viable recessive mutant allele in the glutathione synthetase gene. Moreover, genetic, HPLC mass spectrometry, and gene expression analysis of the nrc1 and nrc2 mutants, revealed that intracellular glutathione depletion alone would be insufficient to induce gene expression of sulfate uptake and assimilation mechanisms. Our results modify the glutathione-depletion driven model for sulfate assimilation gene induction during cadmium stress, and suggest that an enhanced oxidative state and depletion of upstream thiols, in addition to glutathione

  15. Feedback inhibition by thiols outranks glutathione depletion: a luciferase-based screen reveals glutathione-deficient γ-ECS and glutathione synthetase mutants impaired in cadmium-induced sulfate assimilation.

    PubMed

    Jobe, Timothy O; Sung, Dong-Yul; Akmakjian, Garo; Pham, Allis; Komives, Elizabeth A; Mendoza-Cózatl, David G; Schroeder, Julian I

    2012-06-01

    Plants exposed to heavy metals rapidly induce changes in gene expression that activate and enhance detoxification mechanisms, including toxic-metal chelation and the scavenging of reactive oxygen species. However, the mechanisms mediating toxic heavy metal-induced gene expression remain largely unknown. To genetically elucidate cadmium-specific transcriptional responses in Arabidopsis, we designed a genetic screen based on the activation of a cadmium-inducible reporter gene. Microarray studies identified a high-affinity sulfate transporter (SULTR1;2) among the most robust and rapid cadmium-inducible transcripts. The SULTR1;2 promoter (2.2 kb) was fused with the firefly luciferase reporter gene to quantitatively report the transcriptional response of plants exposed to cadmium. Stably transformed luciferase reporter lines were ethyl methanesulfonate (EMS) mutagenized, and stable M(2) seedlings were screened for an abnormal luciferase response during exposure to cadmium. The screen identified non-allelic mutant lines that fell into one of three categories: (i) super response to cadmium (SRC) mutants; (ii) constitutive response to cadmium (CRC) mutants; or (iii) non-response and reduced response to cadmium (NRC) mutants. Two nrc mutants, nrc1 and nrc2, were mapped, cloned and further characterized. The nrc1 mutation was mapped to the γ-glutamylcysteine synthetase gene and the nrc2 mutation was identified as the first viable recessive mutant allele in the glutathione synthetase gene. Moreover, genetic, HPLC mass spectrometry, and gene expression analysis of the nrc1 and nrc2 mutants, revealed that intracellular glutathione depletion alone would be insufficient to induce gene expression of sulfate uptake and assimilation mechanisms. Our results modify the glutathione-depletion driven model for sulfate assimilation gene induction during cadmium stress, and suggest that an enhanced oxidative state and depletion of upstream thiols, in addition to glutathione depletion

  16. Necrotizing fasciitis: epidemiology and clinical predictors for amputation

    PubMed Central

    Khamnuan, Patcharin; Chongruksut, Wilaiwan; Jearwattanakanok, Kijja; Patumanond, Jayanton; Tantraworasin, Apichat

    2015-01-01

    Background Necrotizing fasciitis, a relatively uncommon infection involving the skin, subcutaneous tissue, and fascia, is a rapidly progressive soft tissue infection and a medical and surgical urgency. Delayed debridement, with subsequent huge soft tissue loss is associated with loss of limb and infection and is the most common cause of mortality. The purpose of this work is to describe the epidemiology of necrotizing fasciitis and to identify the clinical characteristics that may be used to predict amputation in routine clinical practice. Methods Retrospective cohort study data were collected from three general hospitals located in the Chiang Rai, Kamphaeng Phet, and Phayao provinces in northern Thailand. Epidemiologic data for all patients with a surgically confirmed diagnosis of necrotizing fasciitis between 2009 and 2012 were collected. Medical records and reviews were retrieved from inpatient records, laboratory reports, and registers. Clinical predictors for amputation were analyzed by multivariable risk regression. Results A total of 1,507 patients with a diagnosis of necrotizing fasciitis were classified as being with amputation (n=127, 8.4%) and without amputation (n=1,380, 91.6%). The most common causative Gram-positive and Gram-negative pathogens were Streptococcus pyogenes (33.3% in the amputation group and 40.8% in the non-amputation group) and Escherichia coli (25% in the amputation group and 17.1% in the non-amputation group). Predictive factors for amputation included gangrene (risk ratio [RR] 4.77, 95% confidence interval [CI] 2.70–8.44), diabetes mellitus (RR 3.08, 95% CI 1.98–4.78), skin necrosis (RR 2.83, 95% CI 2.52–3.18), soft tissue swelling (RR 1.76, 95% CI 1.24–2.49), and serum creatinine values ≥1.6 mg/dL on admission (RR 1.71, 95% CI 1.38–2.12). All data were analyzed using the multivariable risk regression generalized linear model. Conclusion The most causative pathogens were S. pyogenes and E. coli. Clinical predictors for

  17. Severity of necrotizing enterocolitis: influence on outcome at 2 years of age.

    PubMed

    Walsh, M C; Kliegman, R M; Hack, M

    1989-11-01

    The long-term outcome of very low birth weight (VLBW) infants with necrotizing enterocolitis has been reported to be similar to that of other VLBW infants. To examine the influence of disease severity on outcome, the growth and neurodevelopment of survivors of necrotizing enterocolitis were evaluated when the babies were 20 months' corrected age. Between 1975 and 1983, 1506 VLBW infants were admitted to the hospital, and necrotizing enterocolitis developed in 84 (5.6%). Forty infants (48%) survived to be 20 months' corrected age, and complete follow-up data were available for 36. Survivors were classified by modified Bell's criteria into four groups by increasing severity of disease; 13 had mild necrotizing enterocolitis (stage IIA, IIB), and 23 had severe necrotizing enterocolitis (stage IIIA, IIIB). The 36 survivors were compared with 766 surviving VLBW infants without necrotizing enterocolitis. There were no perinatal or socioeconomic differences between groups. Compared with infants with stage II necrotizing enterocolitis at 20 months, infants with stage III necrotizing enterocolitis had a higher rate of subnormal body weight (39% vs 15%) and subnormal head circumference (30% vs 0%). Thirty-three percent of necrotizing enterocolitis survivors had significant neurodevelopmental impairment; the majority of impaired infants (10 of 12) were survivors of stage III necrotizing enterocolitis. These findings highlight the importance of continued evaluations for medical and neurodevelopmental sequelae.

  18. Red clover necrotic mosaic virus: Biophysics and Biotechnology

    NASA Astrophysics Data System (ADS)

    Lockney, Dustin M.

    Red clover necrotic mosaic virus (RCNMV) is a highly robust (Tm=60 °C), 36 nm icosahedral plant virus. The capsid of RCNMV is assembled from 180 chemically equivalent coat proteins (CPs). The CPs arrange in a T=3 symmetry, in 1 of 3 conformations forming the asymmetric subunit (ASU). There are two Ca(II) binding sites per CP; the removal of divalent cations causes the CP subunits of the ASU to rotate away from each other forming a ˜13 A channel. These channels lead to the highly organized bipartite genome of RCNMV and can be closed by adding back Ca(II). Titrimetric analysis and tryptophan fluorescence was used to determine the affinity of RCNMV for Ca(II) to be ˜Kd < 300 nM. It has been shown that doxorubicin (Dox) can be infused into the capsid at a mole ratio of ˜1000:1, Dox-to-virus, and unlike other nanoparticles, there is no detectable leakage. The high loading of Dox is most likely due to intercalation into the genome and significant intercalation or exposure to denaturants was observed to cause loss of capsid stability. To better understand the limitations of cargo loading, Dox and other intercalating molecules (rhodamine 800, ethidium bromide, and propidium iodide) were assayed to determine optimum infusion conditions. Dox was observed to have a propensity to aggregate. In order to manage the Dox aggregation, the infusion buffer was changed from 50 mM Tris-HCl/50 mM NaOAc/50 mM EDTA or 200 mM EDTA at pH 8.0 to 5 mM HEPES/5 mM Na4EDTA/10 mM NaCl pH 7.8. The Dox:RCNMV infusion mole ratio was also lowered from 5000:1 to 500:1 and the incubation temperature was changed from 4 °C to 22 °C for <12 hours, opposed to 24 hours. To impart targeting functionality to RCNMV, biomimetic peptides were conjugated to either the surface capsid lysines or cysteines using standard bioconjugation methods. For all of the biomimetic peptides screened, sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) was used to orthogonally attach the

  19. Adenosquamous carcinoma of the larynx associated with necrotizing sialometaplasia--a diagnostic challenge.

    PubMed

    Ravn, Tomaas; Trolle, Waldemar; Kiss, Katalin; Balle, Viggo Hulthin

    2009-12-01

    Necrotizing sialometaplasia is a benign, self-limiting, inflammatory process involving salivary glands, commonly associated with tissue ischemia. Clinically, necrotizing sialometaplasia is most often found in the hard palate as a deep ulcer with raised, indurated edges that can be indolent. This, as well as the histopathologic findings of necrotizing sialometaplasia, can be confused with those of a malignant neoplasm. We report a rare case of necrotizing sialometaplasia in the larynx, probably initiated by an underlying malignant process. We suggest an aggressive diagnostic approach, when necrotizing sialometaplasia involves the larynx and no recent exposure to radiation, surgery or trauma has been recorded. Necrotizing sialometaplasia of the larynx should be regarded as secondary to malignancy until proven otherwise.

  20. Necrotizing Sialometaplasia of the Hard Palate: A Rare Entity of Dilemma on Cytology, Confirmatory on Histopathology.

    PubMed

    Shetty, Archana; Chowdappa, Vijaya; Devasamudra, Chidananda R; Janardhan, Jayalakshmi Valligari

    2015-12-01

    Necrotizing sialometaplasia is a rare, benign reactive necrotizing lesion, involving sites where salivary gland tissue is usually present. The importance of this lesion is that it mimics malignancy clinically leading to treatments ranging from conservative excision to total maxillectomy. Cytologically and histologically also the lesion is often confused with neoplasms. We present a case of a lady with a hard palatal swelling, which was non - ulcerative unlike typical cases of necrotizing sialometaplsia. FNAC features made us strongly suspect a low grade mucoepidermiod carcinoma, following which the swelling was excised. Histopathology came to the rescue, on which the final diagnosis of necrotizing sialometaplasia of the hard palate was made. Necrotizing siaometaplasia is often misdiagnosed by the inexperienced cytologist, with histopathological examination being confirmatory. We also emphasize the fact that lesions like necrotizing sialometaplasia need a high degree of suspicion along with clinical co relation before subjecting the patient to unnecessary surgical procedures.

  1. Inflammatory pseudotumor containing necrotizing granulomatous lesions of kidney: a hitherto undescribed entity.

    PubMed

    Terada, Tadashi

    2014-01-01

    Herein reported is a case of inflammatory pseudotumor (IPT) of kidney. It is not described in WHO, AFIP, and other books. A review of the literature revealed about 35 cases. A 76-year-old man underwent nephrectomy under clinical diagnosis of renal pelvic carcinoma. Grossly, a solid tumor was seen in renal parenchyma. Microscopically, it was composed of spindle cell tissue with inflammation and many necrotizing granulomas. Epithelioid histiocytes were abundant but giant cells were few. Lymphocytes and plasma cells were also seen. The features suggested tuberculosis (TB), but Ziehl-Neelsen stains and PCR revealed no TB bacillus. Immunohistochemistry showed that the tumor spindle cells were positive for vimentin, CD68, CD45, and Ki-67 (labeling = 18%), α-smooth muscle antigen, and NSE. Focal staining of KIT (mast cells), S100 protein (Langerhans cells), and CD10 (spindle cells) was present. IgG4 was negative. The tumor spindle cells were negative for other antigens examined. PMID:25379319

  2. A Large Bladder Tumor Covered With a Thick “Shell” of Necrotic Material

    PubMed Central

    Wang, Lei; Zhou, Zhe; Gong, Miao-zi; Pan, Dong-liang; Zhang, Xiang-hua; Li, Ning-chen; Na, Yan-qun

    2016-01-01

    Abstract Bladder tumor arising in a spina bifida patient is rare and may be clinically latent. We report the case of a 61-year-old female patient with spina bifida, neurogenic bladder, and a history of recurrent urinary tract infections. A B-ultrasound and non-contrast computed tomography scan did not reveal any bladder mass, but an unexplained “well-filled” bladder was observed, which was confusing as the catheter was present and open. However, a subsequent cystoscopic evaluation revealed a large bladder mass measuring 9.5 × 9.0 × 6.5 cm3, which almost filled the entire bladder. The mass had coarse and flocculent surface and seemed to be free from each observed wall of the urinary bladder. It was diagnosed as an infectious necrotic mass based on its appearance. During transurethral resection of the mass, a bladder tumor was suspected as small blood vessels and bleeding appeared within the inner layer of the mass. Pathological examination revealed necrotic material, inflammatory cells, and urothelial carcinoma cells. Then, a radical cystectomy was performed, and the pathological results indicated stage pT3bN0M0 transitional cell carcinoma. In the gross specimen, the base of the tumor measured 3 × 3 cm2 on the top of the back wall of the bladder. Bladder tumors may have atypical presentations in patients with spina bifida. Regular screening is helpful for earlier detection and improving outcomes of bladder tumors in such patients. PMID:27100442

  3. Fatal Systemic Necrotizing Infections Associated with a Novel Paramyxovirus, Anaconda Paramyxovirus, in Green Anaconda Juveniles

    PubMed Central

    Lau, Susanna K. P.; Martelli, Paolo; Hui, Suk-Wai; Lau, Candy C. Y.; Fan, Rachel Y. Y.; Groff, Joseph M.; Tam, Emily W. T.; Chan, Kwok-Hung

    2014-01-01

    Beginning in July 2011, 31 green anaconda (Eunectes murinus) juveniles from an oceanarium in Hong Kong died over a 12-month period. Necropsy revealed at least two of the following features in 23 necropsies: dermatitis, severe pan-nephritis, and/or severe systemic multiorgan necrotizing inflammation. Histopathological examination revealed severe necrotizing inflammation in various organs, most prominently the kidneys. Electron microscopic examination of primary tissues revealed intralesional accumulations of viral nucleocapsids with diameters of 10 to 14 nm, typical of paramyxoviruses. Reverse transcription (RT)-PCR results were positive for paramyxovirus (viral loads of 2.33 × 104 to 1.05 × 108 copies/mg tissue) in specimens from anaconda juveniles that died but negative in specimens from the two anaconda juveniles and anaconda mother that survived. None of the other snakes in the park was moribund, and RT-PCR results for surveillance samples collected from other snakes were negative. The virus was isolated from BHK21 cells, causing cytopathic effects with syncytial formation. The virus could also replicate in 25 of 27 cell lines of various origins, in line with its capability for infecting various organs. Electron microscopy with cell culture material revealed enveloped virus with the typical “herringbone” appearance of helical nucleocapsids in paramyxoviruses. Complete genome sequencing of five isolates confirmed that the infections originated from the same clone. Comparative genomic and phylogenetic analyses and mRNA editing experiments revealed a novel paramyxovirus in the genus Ferlavirus, named anaconda paramyxovirus, with a typical Ferlavirus genomic organization of 3′-N-U-P/V/I-M-F-HN-L-5′. Epidemiological and genomic analyses suggested that the anaconda juveniles acquired the virus perinatally from the anaconda mother rather than from other reptiles in the park, with subsequent interanaconda juvenile transmission. PMID:25078906

  4. Fatal systemic necrotizing infections associated with a novel paramyxovirus, anaconda paramyxovirus, in green anaconda juveniles.

    PubMed

    Woo, Patrick C Y; Lau, Susanna K P; Martelli, Paolo; Hui, Suk-Wai; Lau, Candy C Y; Fan, Rachel Y Y; Groff, Joseph M; Tam, Emily W T; Chan, Kwok-Hung; Yuen, Kwok-Yung

    2014-10-01

    Beginning in July 2011, 31 green anaconda (Eunectes murinus) juveniles from an oceanarium in Hong Kong died over a 12-month period. Necropsy revealed at least two of the following features in 23 necropsies: dermatitis, severe pan-nephritis, and/or severe systemic multiorgan necrotizing inflammation. Histopathological examination revealed severe necrotizing inflammation in various organs, most prominently the kidneys. Electron microscopic examination of primary tissues revealed intralesional accumulations of viral nucleocapsids with diameters of 10 to 14 nm, typical of paramyxoviruses. Reverse transcription (RT)-PCR results were positive for paramyxovirus (viral loads of 2.33 × 10(4) to 1.05 × 10(8) copies/mg tissue) in specimens from anaconda juveniles that died but negative in specimens from the two anaconda juveniles and anaconda mother that survived. None of the other snakes in the park was moribund, and RT-PCR results for surveillance samples collected from other snakes were negative. The virus was isolated from BHK21 cells, causing cytopathic effects with syncytial formation. The virus could also replicate in 25 of 27 cell lines of various origins, in line with its capability for infecting various organs. Electron microscopy with cell culture material revealed enveloped virus with the typical "herringbone" appearance of helical nucleocapsids in paramyxoviruses. Complete genome sequencing of five isolates confirmed that the infections originated from the same clone. Comparative genomic and phylogenetic analyses and mRNA editing experiments revealed a novel paramyxovirus in the genus Ferlavirus, named anaconda paramyxovirus, with a typical Ferlavirus genomic organization of 3'-N-U-P/V/I-M-F-HN-L-5'. Epidemiological and genomic analyses suggested that the anaconda juveniles acquired the virus perinatally from the anaconda mother rather than from other reptiles in the park, with subsequent interanaconda juvenile transmission. PMID:25078906

  5. Fatal systemic necrotizing infections associated with a novel paramyxovirus, anaconda paramyxovirus, in green anaconda juveniles.

    PubMed

    Woo, Patrick C Y; Lau, Susanna K P; Martelli, Paolo; Hui, Suk-Wai; Lau, Candy C Y; Fan, Rachel Y Y; Groff, Joseph M; Tam, Emily W T; Chan, Kwok-Hung; Yuen, Kwok-Yung

    2014-10-01

    Beginning in July 2011, 31 green anaconda (Eunectes murinus) juveniles from an oceanarium in Hong Kong died over a 12-month period. Necropsy revealed at least two of the following features in 23 necropsies: dermatitis, severe pan-nephritis, and/or severe systemic multiorgan necrotizing inflammation. Histopathological examination revealed severe necrotizing inflammation in various organs, most prominently the kidneys. Electron microscopic examination of primary tissues revealed intralesional accumulations of viral nucleocapsids with diameters of 10 to 14 nm, typical of paramyxoviruses. Reverse transcription (RT)-PCR results were positive for paramyxovirus (viral loads of 2.33 × 10(4) to 1.05 × 10(8) copies/mg tissue) in specimens from anaconda juveniles that died but negative in specimens from the two anaconda juveniles and anaconda mother that survived. None of the other snakes in the park was moribund, and RT-PCR results for surveillance samples collected from other snakes were negative. The virus was isolated from BHK21 cells, causing cytopathic effects with syncytial formation. The virus could also replicate in 25 of 27 cell lines of various origins, in line with its capability for infecting various organs. Electron microscopy with cell culture material revealed enveloped virus with the typical "herringbone" appearance of helical nucleocapsids in paramyxoviruses. Complete genome sequencing of five isolates confirmed that the infections originated from the same clone. Comparative genomic and phylogenetic analyses and mRNA editing experiments revealed a novel paramyxovirus in the genus Ferlavirus, named anaconda paramyxovirus, with a typical Ferlavirus genomic organization of 3'-N-U-P/V/I-M-F-HN-L-5'. Epidemiological and genomic analyses suggested that the anaconda juveniles acquired the virus perinatally from the anaconda mother rather than from other reptiles in the park, with subsequent interanaconda juvenile transmission.

  6. A Fatal Case of Necrotizing Fasciitis Caused by a Highly Virulent Escherichia coli Strain

    PubMed Central

    Vincent, André; Lin, Alex; Harel, Josée; Côté, Jean-Charles; Tremblay, Cécile

    2016-01-01

    Necrotizing fasciitis is a serious disease characterized by the necrosis of the subcutaneous tissues and fascia. E. coli as the etiologic agent of necrotizing fasciitis is a rare occurrence. A 66-year-old woman underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy. She rapidly developed necrotizing fasciitis which led to her death 68 hours following surgery. An E. coli strain was isolated from blood and fascia cultures. DNA microarray revealed the presence of 20 virulence genes. PMID:27366162

  7. [Necrotizing periodontal disease: a manifestation of systemic disorders].

    PubMed

    Bascones-Martínez, Antonio; Escribano-Bermejo, Marta

    2005-11-19

    Necrotizing periodontal disease (NPD) is an infection characterized by gingival necrosis presenting as "punched-out" papillae, with gingival bleeding, and pain. Prevotella intermedia and spirochetes have been associated with the gingival lesions. Predisposing factors may include emotional stress, immunosuppression, especially secondary to human immunodeficiency virus (HIV) infection, cigarette smoking, poor diet and pre-existing gingivitis. During the last few years, diagnosis of NPD has became more important not only because of its contribution to the appearance of clinical attachment loss and gingival sequelae, but also because it has been revealed as a marker for immune deterioration in HIV-seropositive patients.

  8. Necrotizing lung infection caused by the protozoan Balantidium coli

    PubMed Central

    Sharma, Sat; Harding, Godfrey

    2003-01-01

    Balantidium coli, a ciliated protozoan, is well known to cause intestinal infection in humans. Extraintestinal spread to the peritoneal cavity and genitourinary tract has rarely been reported. There have also been a few cases of lung involvement from this parasite. A case of B coli causing a thick-walled right upper lobe cavity in an organic farmer who had contact with aerosolized pig manure is reported. Bronchoalveolar lavage fluid examined for ova and parasite revealed trophozoites of B coli in large numbers. Treatment with doxycycline hyclate led to marked improvement. Necrotizing lung infection caused by the protozoan B coli should be considered in individuals who report contact with pigs. PMID:18159451

  9. Update in Pathogenesis and Prospective in Treatment of Necrotizing Enterocolitis

    PubMed Central

    Terrin, Gianluca; Scipione, Antonella; De Curtis, Mario

    2014-01-01

    Necrotizing enterocolitis (NEC) is among the most common and devastating diseases in neonates and, despite the significant advances in neonatal clinical and basic science investigations, its etiology is largely understood, specific treatment strategies are lacking, and morbidity and mortality remain high. Improvements in the understanding of pathogenesis of NEC may have therapeutic consequences. Pharmacologic inhibition of toll-like receptor signaling, the use of novel nutritional strategies, and microflora modulation may represent novel promising approaches to the prevention and treatment of NEC. This review, starting from the recent acquisitions in the pathogenic mechanisms of NEC, focuses on current and possible therapeutic perspectives. PMID:25147804

  10. Olanzapine-Induced Hypertriglyceridemia Resulting in Necrotizing Pancreatitis

    PubMed Central

    Roy-Chaudhury, Prabir; Yadlapalli, Ganesh

    2016-01-01

    Olanzapine is an atypical antipsychotic agent that was approved by the Food and Drug Administration in 1996 for treatment of psychotic disorders, bipolar disorder, and schizophrenia. Since that time, numerous case reports have been published that describe the association of olanzapine and the development of pancreatitis. Furthermore, 3 reports suggest the mechanism of olanzapine-induced hypertriglyceridemia as the etiology of this progression. We report a case of a 36-year-old man who developed necrotizing pancreatitis secondary to olanzapine-induced hypertriglyceridemia. This case, to our knowledge, is the most severe case of this progression and the first case requiring plasmapheresis for acute management. PMID:27807566

  11. Necrotizing lung infection caused by the protozoan Balantidium coli.

    PubMed

    Sharma, Sat; Harding, Godfrey

    2003-05-01

    Balantidium coli, a ciliated protozoan, is well known to cause intestinal infection in humans. Extraintestinal spread to the peritoneal cavity and genitourinary tract has rarely been reported. There have also been a few cases of lung involvement from this parasite. A case of B coli causing a thick-walled right upper lobe cavity in an organic farmer who had contact with aerosolized pig manure is reported. Bronchoalveolar lavage fluid examined for ova and parasite revealed trophozoites of B coli in large numbers. Treatment with doxycycline hyclate led to marked improvement. Necrotizing lung infection caused by the protozoan B coli should be considered in individuals who report contact with pigs. PMID:18159451

  12. Nuclear scanning in necrotizing progressive ''malignant'' external otitis

    SciTech Connect

    Parisier, S.C.; Lucente, F.E.; Som, P.M.; Hirschman, S.Z.; Arnold, L.M.; Roffman, J.D.

    1982-09-01

    The usefulness of radionuclear scanning in the treatment of 18 patients with necrotizing progressive ''malignant'' external otitis is discussed. A Tc 99-m bone scan, a valuable test since results are positive in early cases of osteomyelitis of the temporal bone and base of skull, showed increased uptake in all 18 patients. In 6 patients, Ga-67 citrate scans were obtained at the start of therapy and at 5-6 week intervals thereafter. The serial gallium scans were useful in evaluating the effectiveness of therapy since the uptake decrease with control of infection.

  13. Necrotizing sialometaplasia. A self-limited pseudotumoral palatal ulcer.

    PubMed

    Spark, R P; Duncan, D G

    1978-01-01

    Necrotizing sialometaplasia of the palate, an enigmatic pseudomalignant penetrating ulcer, is a benign lesion which heals spontaneously in three to ten weeks. Relative painlessness contributes to patient delay in seeking medical attention, and suggest that many cases are subclinical. Clinically, the patient age group and morbid gross appearance mimic malignant palatal tumors. Lack of awareness of this entity has led to the misdiagnosis of carcinoma in several previous cases. However, the histopathologic features of sialadenitis, focal lobular necrosis with mucosal ulceration and glandular squamous metaplasia, are distinctly benign. A typical case and literature review are presented.

  14. Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium.

    PubMed

    Rennolds, Jessica; Malireddy, Smitha; Hassan, Fatemat; Tridandapani, Susheela; Parinandi, Narasimham; Boyaka, Prosper N; Cormet-Boyaka, Estelle

    2012-01-01

    Cadmium is a toxic metal present in the environment and its inhalation can lead to pulmonary disease such as lung cancer and chronic obstructive pulmonary disease. These lung diseases are characterized by chronic inflammation. Here we show that exposure of human airway epithelial cells to cadmium promotes a polarized apical secretion of IL-6 and IL-8, two pivotal pro-inflammatory cytokines known to play an important role in pulmonary inflammation. We also determined that two distinct pathways controlled secretion of these proinflammatory cytokines by human airway epithelial cells as cadmium-induced IL-6 secretion occurs via an NF-κB dependent pathway, whereas IL-8 secretion involves the Erk1/2 signaling pathway. Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation.

  15. Necrotizing vasculitis in a case of disseminated neonatal herpes simplex infection.

    PubMed

    Phinney, P R; Fligiel, S; Bryson, Y J; Porter, D D

    1982-02-01

    A term newborn suffered disseminated herpes simplex virus (HSV) type II infection five days after cesarean section delivery for fetal distress. The mother had no history or evidence of herpetic lesions; the father had a history of genital herpetic lesions. The infant's terminal course was dominated by disseminated intravascular coagulation (DIC) with hepatic and renal failure. Microscopic examination revealed a necrotizing vasculitis of small and medium-sized lung and peripancreatic arteries. Nuclear inclusions characteristic of HSV were found in these arteries, as well as in the adrenal parenchyma, spleen, and lymph node; electron microscopy confirmed replication of virus within the arterial endothelial cells. The mechanism of arterial damage in severe herpetic infection contrasts with the immune-complex mechanism postulated for other viral vasculitides. Direct, virally induced arterial damage resulting in exposure of collagen may set the stage of DiC, a commonly fatal complication of this disease.

  16. 2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53.

    PubMed

    Mattiolo, Paolo; Barbero-Farran, Ares; Yuste, Víctor J; Boix, Jacint; Ribas, Judit

    2014-10-01

    2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. Here, we demonstrate PES elicits a caspase- and BAX/BAK-independent non-necroptotic necrotic cell death, since it is not inhibited by necrostatin-1. This process is characterized by an early generation of reactive oxygen species (ROS) resulting in p53 up-regulation. Accordingly, thiolic antioxidants protect cells from PES-induced death. Furthermore, inhibiting the natural sources of glutathione with l-buthionine-sulfoximine (BSO) strongly cooperates with PES in triggering cytotoxicity. Genetically modified p53-null or p53 knocked-down cells show resistance to PES-driven necrosis. The predominant localization of p53 in chromatin-enriched fractions added to the up-regulation of the p53-responsive gene p21, strongly suggest the involvement of a transcription-dependent p53 program. On the other hand, we report an augmented production of ROS in p53-positive cells that, added to the increased p53 content in response to PES-elicited ROS, suggests that p53 and ROS are mutually regulated in response to PES. In sum, p53 up-regulation by ROS triggers a positive feedback loop responsible of further increasing ROS production and reinforcing PES-driven non-necroptotic necrosis. PMID:25139326

  17. Predicting development of infected necrosis in acute necrotizing pancreatitis.

    PubMed

    Dambrauskas, Zilvinas; Pundzius, Juozas; Barauskas, Giedrius

    2006-01-01

    The incidence of severe acute pancreatitis is about 30 cases per 100,000 inhabitants, and it carries an overall mortality rate of 10-15%. Infection of pancreatic necrosis occurs in 20-30% of patients with severe acute pancreatitis and triples the mortality rate. Therefore, early prediction and diagnosis of infection in necrotizing pancreatitis are extremely important. The aim of the studies included in this review was to investigate the potential of specific prognostic factors to predict the development of secondary pancreatic infection in severe acute pancreatitis. This is seen as an important tool allowing to perform a computed tomography- or ultrasound-guided fine needle aspiration for bacteriological sampling at the right moment, to confirm the diagnosis, and, finally, to select the subgroup of patients who would benefit from the antibiotic prophylaxis. Precise patients' selection could possibly result in more rational use of antibiotics in patients with acute necrotizing pancreatitis and reduction of multi-resistant bacteria. Recent studies show that C-reactive protein is an important prognostic marker of pancreatic necrosis with the highest sensitivity and negative prognostic value in this respect. Procalcitonin alone or in combination with interleukin-6 best identifies patients not at risk for infection. However, a review of the clinical studies suggests that we still do not have an optimal model, thus there is a need for new more reliable biochemical and/or clinical predictive systems.

  18. Biofilm in group A streptococcal necrotizing soft tissue infections

    PubMed Central

    Siemens, Nikolai; Chakrakodi, Bhavya; Shambat, Srikanth Mairpady; Morgan, Marina; Bergsten, Helena; Skrede, Steinar; Madsen, Martin B.; Johansson, Linda; Juarez, Julius; Bosnjak, Lidija; Mörgelin, Matthias; Svensson, Mattias

    2016-01-01

    Necrotizing fasciitis caused by group A streptococcus (GAS) is a life-threatening, rapidly progressing infection. At present, biofilm is not recognized as a potential problem in GAS necrotizing soft tissue infections (NSTI), as it is typically linked to chronic infections or associated with foreign devices. Here, we present a case of a previously healthy male presenting with NSTI caused by GAS. The infection persisted over 24 days, and the surgeon documented the presence of a “thick layer biofilm” in the fascia. Subsequent analysis of NSTI patient tissue biopsies prospectively included in a multicenter study revealed multiple areas of biofilm in 32% of the patients studied. Biopsies associated with biofilm formation were characterized by massive bacterial load, a pronounced inflammatory response, and clinical signs of more severe tissue involvement. In vitro infections of a human skin tissue model with GAS NSTI isolates also revealed multilayered fibrous biofilm structures, which were found to be under the control of the global Nra gene regulator. The finding of GAS biofilm formation in NSTIs emphasizes the urgent need for biofilm to be considered as a potential complicating microbiological feature of GAS NSTI and, consequently, emphasizes reconsideration of antibiotic treatment protocols.

  19. Aspergillus fumigatus Endophthalmitis with Necrotizing Scleritis following Pars Plana Vitrectomy.

    PubMed

    Gruener, Anna M; Allen, Felicity; Stanford, Miles R; Graham, Elizabeth M

    2016-01-01

    We present a case of Aspergillus fumigatus endophthalmitis complicated by necrotizing scleritis in a 68-year-old man with diet-controlled diabetes, after retinal detachment repair. He was initially treated with systemic steroids for surgically induced necrotizing scleritis following routine pars plana vitrectomy. An additional diagnosis of endophthalmitis was made when the patient developed a hypopyon. Repeat vitreous culture isolated Aspergillus fumigatus. Symptoms improved following antifungal treatment leaving the patient with scleromalacia and an advanced postoperative cataract. Fungal scleritis and endophthalmitis are rare complications of intraocular surgery with sight-threatening consequences, and, as this case demonstrates, may even occur concomitantly. The overlapping features of both conditions can make differentiating one from the other difficult. A fungal aetiology should be considered in cases of postoperative scleritis and endophthalmitis that are protracted and refractory to standard therapy. Even in cases of early diagnosis and treatment, visual outcomes in Aspergillus endophthalmitis and scleritis are variable and often disappointing, not infrequently necessitating enucleation of a painful blind eye.

  20. Biofilm in group A streptococcal necrotizing soft tissue infections

    PubMed Central

    Siemens, Nikolai; Chakrakodi, Bhavya; Shambat, Srikanth Mairpady; Morgan, Marina; Bergsten, Helena; Skrede, Steinar; Madsen, Martin B.; Johansson, Linda; Juarez, Julius; Bosnjak, Lidija; Mörgelin, Matthias; Svensson, Mattias

    2016-01-01

    Necrotizing fasciitis caused by group A streptococcus (GAS) is a life-threatening, rapidly progressing infection. At present, biofilm is not recognized as a potential problem in GAS necrotizing soft tissue infections (NSTI), as it is typically linked to chronic infections or associated with foreign devices. Here, we present a case of a previously healthy male presenting with NSTI caused by GAS. The infection persisted over 24 days, and the surgeon documented the presence of a “thick layer biofilm” in the fascia. Subsequent analysis of NSTI patient tissue biopsies prospectively included in a multicenter study revealed multiple areas of biofilm in 32% of the patients studied. Biopsies associated with biofilm formation were characterized by massive bacterial load, a pronounced inflammatory response, and clinical signs of more severe tissue involvement. In vitro infections of a human skin tissue model with GAS NSTI isolates also revealed multilayered fibrous biofilm structures, which were found to be under the control of the global Nra gene regulator. The finding of GAS biofilm formation in NSTIs emphasizes the urgent need for biofilm to be considered as a potential complicating microbiological feature of GAS NSTI and, consequently, emphasizes reconsideration of antibiotic treatment protocols. PMID:27699220

  1. Regenerative endodontic treatment for necrotic immature permanent teeth.

    PubMed

    Chueh, Ling-Huey; Ho, Yi-Ching; Kuo, Tien-Chun; Lai, Wing-Hong; Chen, Yea-Huey Melody; Chiang, Chun-Pin

    2009-02-01

    This retrospective study included 23 necrotic immature permanent teeth treated for either short-term (treatment period <3 months) or long-term (treatment period >3 months) using conservative endodontic procedures with 2.5% NaOCl irrigations without instrumentation but with Ca(OH)(2) paste medication. For seven teeth treated short-term, the gutta-percha points were filled onto an artificial barrier of mineral trioxide aggregate (MTA). For 16 teeth treated long-term, the gutta-percha points, amalgam, or MTA were filled onto the Ca(OH)(2)-induced hard tissue barrier in the root canal. We found that all apical lesions showed complete regression in 3 to 21 (mean, 8) months after initial treatment. All necrotic immature permanent teeth achieved a nearly normal root development 10 to 29 (mean, 16) months after initial treatment. We conclude that immature permanent teeth with pulp necrosis and apical pathosis can still achieve continued root development after proper short-term or long-term regenerative endodontic treatment procedures. PMID:19166764

  2. Aspergillus fumigatus Endophthalmitis with Necrotizing Scleritis following Pars Plana Vitrectomy.

    PubMed

    Gruener, Anna M; Allen, Felicity; Stanford, Miles R; Graham, Elizabeth M

    2016-01-01

    We present a case of Aspergillus fumigatus endophthalmitis complicated by necrotizing scleritis in a 68-year-old man with diet-controlled diabetes, after retinal detachment repair. He was initially treated with systemic steroids for surgically induced necrotizing scleritis following routine pars plana vitrectomy. An additional diagnosis of endophthalmitis was made when the patient developed a hypopyon. Repeat vitreous culture isolated Aspergillus fumigatus. Symptoms improved following antifungal treatment leaving the patient with scleromalacia and an advanced postoperative cataract. Fungal scleritis and endophthalmitis are rare complications of intraocular surgery with sight-threatening consequences, and, as this case demonstrates, may even occur concomitantly. The overlapping features of both conditions can make differentiating one from the other difficult. A fungal aetiology should be considered in cases of postoperative scleritis and endophthalmitis that are protracted and refractory to standard therapy. Even in cases of early diagnosis and treatment, visual outcomes in Aspergillus endophthalmitis and scleritis are variable and often disappointing, not infrequently necessitating enucleation of a painful blind eye. PMID:27379189

  3. Computed tomography of necrotizing meningoencephalitis in 3 Yorkshire Terriers.

    PubMed

    Ducoté, J M; Johnson, K E; Dewey, C W; Walker, M A; Coates, J R; Berridge, B R

    1999-01-01

    A necrotizing meningoencephalitis of Yorkshire terriers has recently been reported in 6 dogs in Switzerland, 1 dog in Japan and 1 dog in the United States. The purpose of this report is to describe the computed tomographic (CT) findings in 3 dogs with this disease, and to correlate the CT abnormalities with the clinical and pathologic findings in each case. Three Yorkshire Terriers between 2 and 10 years old were evaluated. Physical and neurologic examinations, complete blood count (CBC), serum biochemistry profile, cerebrospinal fluid analysis, and CT scan were performed on all 3 dogs. Brainstem auditory evoked responses (BAER) were evaluated for 2 dogs. Two dogs were euthanized at the owners' request and necropsies were performed. Neurologic examination findings were consistent with a multifocal/diffuse encephalitis involving the cerebrum and brainstem in all 3 dogs. Complete blood count and biochemistry profiles were normal. Elevated protein concentration and a mononuclear pleocytosis were demonstrated in 2 of 3 dogs on cerebrospinal fluid evaluation. Multifocal, extensive areas of decreased opacity throughout the cerebral hemispheres, asymmetric ventriculomegaly, and lack of contrast enhancement were appreciated on CT images of all three dogs. No mass effect was seen. These findings correlated well with pathologic findings at necropsy, which included multiple malacic cavitations within the brain, representing areas of locally extensive necrosis. CT abnormalities in combination with signalment, clinical findings and cerebrospinal fluid analysis should facilitate a presumptive diagnosis of Yorkshire Terrier necrotizing meningoencephalitis.

  4. Trichoderma L-Lysine-α-Oxidase Producer Strain Culture Fluid Inhibits Impatiens Necrotic Spot Virus.

    PubMed

    Smirnova, I P; Shneider, Yu A; Karimova, E V

    2016-01-01

    A method for PCR diagnosis of impatiens necrotic spot virus is developed. Concentrated culture fluid with active L-lysine-α-oxidase (0.54 U/ml) from Trichoderma harzianum Rifai fungus producer strain F-180 inhibits vitally hazardous impatiens necrotic spot phytovirus. PMID:26742733

  5. Paediatric necrotizing fasciitis complicating third molar extraction: report of a case.

    PubMed

    Ricalde, P; Engroff, S L; Jansisyanont, P; Ord, R A

    2004-06-01

    Necrotizing fasciitis is an uncommon but well-described entity. In the paediatric population compromising risk factors are frequently absent. We describe the successful treatment of a case of cervicofacial necrotizing fasciitis in a healthy 14-year-old male following routine extraction of an uninfected wisdom tooth for orthodontic purposes. PMID:15145048

  6. Bilateral Necrotizing Fasciitis around the Hips Differentiated from Fournier Gangrene: A Case Report

    PubMed Central

    Yang, Bo Kyu; Yi, Seung Rim; Lee, Ye Hyun; Kim, Hyun See; Nam, Seok Woo; Ahn, Young Joon; Kim, Seong Wan; Yang, Sung Wook

    2014-01-01

    As an emergency encountered in orthopedic practice requiring prompt diagnosis and aggressive treatment, necrotizing fasciitis around the hip must be discriminated from Fournier gangrene. The current case report describes a patient who suffered from bilateral type I necrotizing fasciitis around the hips, which was alleviated by prompt surgical debridement and intensive postoperative care. PMID:27536594

  7. Effect of bismuth citrate, lactose, and organic acid on necrotic enteritis in broilers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clostridium perfringens – associated necrotic enteritis causes significant losses and increased morbidity in poultry. The objective of this study was to evaluate the effect of bismuth citrate and acidifiers on the development of necrotic enteritis in broilers. The first study was a dose response t...

  8. Trichoderma L-Lysine-α-Oxidase Producer Strain Culture Fluid Inhibits Impatiens Necrotic Spot Virus.

    PubMed

    Smirnova, I P; Shneider, Yu A; Karimova, E V

    2016-01-01

    A method for PCR diagnosis of impatiens necrotic spot virus is developed. Concentrated culture fluid with active L-lysine-α-oxidase (0.54 U/ml) from Trichoderma harzianum Rifai fungus producer strain F-180 inhibits vitally hazardous impatiens necrotic spot phytovirus.

  9. Leigh's Disease: The Acute Clinical Course of a Two-Year-Old Child with Subacute Necrotizing Encephalomyelopathy

    PubMed Central

    Zinka, Bettina; Buettner, Andreas; Graw, Matthias

    2010-01-01

    We report the untypical clinical course of a previously healthy two-year-old girl, who died suddenly and unexpectedly after an episode of vomiting. At forensic autopsy no other pathological findings could be diagnosed than multiple reddish, sunken areas in brain stem, mesencephalon, and pons. Histologically they presented as areas of spongiosis of the neuropil with prominent endothelial hyperplasia and vascular proliferation whereas nerve cells were well preserved. On the basis of the characteristic neuropathological findings in combination with the age of the child, we had to take into consideration that the child might have died from subacute necrotizing encephalomyelopathy (Leigh's Disease) despite the untypical, fulminant clinical course. PMID:20593000

  10. Leigh's Disease: The Acute Clinical Course of a Two-Year-Old Child with Subacute Necrotizing Encephalomyelopathy.

    PubMed

    Zinka, Bettina; Buettner, Andreas; Graw, Matthias

    2010-01-01

    We report the untypical clinical course of a previously healthy two-year-old girl, who died suddenly and unexpectedly after an episode of vomiting. At forensic autopsy no other pathological findings could be diagnosed than multiple reddish, sunken areas in brain stem, mesencephalon, and pons. Histologically they presented as areas of spongiosis of the neuropil with prominent endothelial hyperplasia and vascular proliferation whereas nerve cells were well preserved. On the basis of the characteristic neuropathological findings in combination with the age of the child, we had to take into consideration that the child might have died from subacute necrotizing encephalomyelopathy (Leigh's Disease) despite the untypical, fulminant clinical course. PMID:20593000

  11. Characterization of Melon necrotic spot virus Occurring on Watermelon in Korea

    PubMed Central

    Kwak, Hae-Ryun; Kim, Jeong-Soo; Cho, Jeom-Deog; Lee, Joong-Hwan; Kim, Tae-sung; Kim, Mi-Kyeong; Choi, Hong-Soo

    2015-01-01

    Melon necrotic spot virus (MNSV) was recently identified on watermelon (Citrullus vulgaris) in Korea, displaying as large necrotic spots and vein necrosis on the leaves and stems. The average occurrence of MNSV on watermelon was found to be 30–65% in Hapcheon and Andong City, respectively. Four isolates of the virus (MNSV-HW, MNSV-AW, MNSV-YW, and MNSV-SW) obtained from watermelon plants in different areas were non-pathogenic on ten general indicator plants, including Chenopodium quinoa, while they infected systemically six varieties of Cucurbitaceae. The virus particles purified by 10–40% sucrose density gradient centrifugation had a typical ultraviolet spectrum, with a minimum at 245 nm and a maximum at 260 nm. The morphology of the virus was spherical with a diameter of 28–30 nm. Virus particles were observed scattered throughout the cytoplasm of watermelon cells, but no crystals were detected. An ELISA was conducted using antiserum against MNSV-HW; the optimum concentrations of IgG and conjugated IgG for the assay were 1 μl/ml and a 1:8,000–1:10,000 dilutions, respectively. Antiserum against MNSV-HW could capture specifically both MNSV-MN from melon and MNSV-HW from watermelon by IC/RT-PCR, and they were effectively detected with the same specific primer to produce product of 1,172 bp. The dsRNA of MNSV-HW had the same profile (4.5, 1.8, and 1.6 kb) as that of MNSV-MN from melon. The nucleotide sequence of the coat protein of MNSV-HW gave a different phylogenetic tree, having 17.2% difference in nucleotide sequence compared with MNSV isolates from melon. PMID:26673673

  12. Characterization of Melon necrotic spot virus Occurring on Watermelon in Korea.

    PubMed

    Kwak, Hae-Ryun; Kim, Jeong-Soo; Cho, Jeom-Deog; Lee, Joong-Hwan; Kim, Tae-Sung; Kim, Mi-Kyeong; Choi, Hong-Soo

    2015-12-01

    Melon necrotic spot virus (MNSV) was recently identified on watermelon (Citrullus vulgaris) in Korea, displaying as large necrotic spots and vein necrosis on the leaves and stems. The average occurrence of MNSV on watermelon was found to be 30-65% in Hapcheon and Andong City, respectively. Four isolates of the virus (MNSV-HW, MNSV-AW, MNSV-YW, and MNSV-SW) obtained from watermelon plants in different areas were non-pathogenic on ten general indicator plants, including Chenopodium quinoa, while they infected systemically six varieties of Cucurbitaceae. The virus particles purified by 10-40% sucrose density gradient centrifugation had a typical ultraviolet spectrum, with a minimum at 245 nm and a maximum at 260 nm. The morphology of the virus was spherical with a diameter of 28-30 nm. Virus particles were observed scattered throughout the cytoplasm of watermelon cells, but no crystals were detected. An ELISA was conducted using antiserum against MNSV-HW; the optimum concentrations of IgG and conjugated IgG for the assay were 1 μl/ml and a 1:8,000-1:10,000 dilutions, respectively. Antiserum against MNSV-HW could capture specifically both MNSV-MN from melon and MNSV-HW from watermelon by IC/RT-PCR, and they were effectively detected with the same specific primer to produce product of 1,172 bp. The dsRNA of MNSV-HW had the same profile (4.5, 1.8, and 1.6 kb) as that of MNSV-MN from melon. The nucleotide sequence of the coat protein of MNSV-HW gave a different phylogenetic tree, having 17.2% difference in nucleotide sequence compared with MNSV isolates from melon. PMID:26673673

  13. Characterization of Melon necrotic spot virus Occurring on Watermelon in Korea.

    PubMed

    Kwak, Hae-Ryun; Kim, Jeong-Soo; Cho, Jeom-Deog; Lee, Joong-Hwan; Kim, Tae-Sung; Kim, Mi-Kyeong; Choi, Hong-Soo

    2015-12-01

    Melon necrotic spot virus (MNSV) was recently identified on watermelon (Citrullus vulgaris) in Korea, displaying as large necrotic spots and vein necrosis on the leaves and stems. The average occurrence of MNSV on watermelon was found to be 30-65% in Hapcheon and Andong City, respectively. Four isolates of the virus (MNSV-HW, MNSV-AW, MNSV-YW, and MNSV-SW) obtained from watermelon plants in different areas were non-pathogenic on ten general indicator plants, including Chenopodium quinoa, while they infected systemically six varieties of Cucurbitaceae. The virus particles purified by 10-40% sucrose density gradient centrifugation had a typical ultraviolet spectrum, with a minimum at 245 nm and a maximum at 260 nm. The morphology of the virus was spherical with a diameter of 28-30 nm. Virus particles were observed scattered throughout the cytoplasm of watermelon cells, but no crystals were detected. An ELISA was conducted using antiserum against MNSV-HW; the optimum concentrations of IgG and conjugated IgG for the assay were 1 μl/ml and a 1:8,000-1:10,000 dilutions, respectively. Antiserum against MNSV-HW could capture specifically both MNSV-MN from melon and MNSV-HW from watermelon by IC/RT-PCR, and they were effectively detected with the same specific primer to produce product of 1,172 bp. The dsRNA of MNSV-HW had the same profile (4.5, 1.8, and 1.6 kb) as that of MNSV-MN from melon. The nucleotide sequence of the coat protein of MNSV-HW gave a different phylogenetic tree, having 17.2% difference in nucleotide sequence compared with MNSV isolates from melon.

  14. Effects of infliximab on bacterial translocation in experimental acute necrotizing pancreatitis

    PubMed Central

    Aydin, Sezai; Isik, A. Turan; Unal, Bulent; Comert, Bilgin; Ozyurt, Mustafa; Deveci, Salih; Ozgur, Gokhan; Cengiz, Omer; Tasci, Ilker; Mas, M. Refik

    2012-01-01

    Background & objectives: Translocation of bacteria from the gut is an important factor in the development of septic complications and mortality in acute pancreatitis (AP). The present study was designed to assess the effects of infliximab treatment on bacterial translocation (BT) in experimental acute necrotizing pancreatitis. Methods: Male Sprague-Dawley rats (n=45) were allocated into three groups. AP was induced in group II (positive control, n=15) and group III (Infliximab; n=15) by retrograde injection of taurocholate into the common biliopancreatic duct. Group I rats (Sham; n=15) received normal saline infusion into the common biliopancreatic duct as placebo. Groups I and II were treated by normal saline and group III was treated with infliximab intraperitoneally on 6, 30 and 54 h after induction of pancreatitis. All surviving animals were killed 60 h after the induction of pancreatitis, and specimens were collected for amylase measurement as well as histopathologic and microbiologic examinations. Results: Oedema, acinar cell necrosis, inflammatory infiltration, haemorrhage, fat necrosis and perivascular inflammation in group III rats were decreased with infliximab treatment when compared with group II (P<0.001). BT to mesentery lymph node in groups I, II and III were 20, 100 and 46 per cent, respectively. BT to peritoneum and pancreas in group III was lower than group II (P<0.05). Interpretation & conclusions: Infliximab administration resulted in beneficial effects on BT and histopathologic changes in the experimental necrotizing pancreatitis. Whether anti-TNF therapy has a role in prevention of complications of ANP needs to be established. PMID:22771595

  15. Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis.

    PubMed

    Kojima, Hiroshi; Kosugi, Tomoki; Sato, Waichi; Sato, Yuka; Maeda, Kayaho; Kato, Noritoshi; Kato, Kiyonari; Inaba, Shinichiro; Ishimoto, Takuji; Tsuboi, Naotake; Matsuo, Seiichi; Maruyama, Shoichi; Yuzawa, Yukio; Kadomatsu, Kenji

    2013-02-01

    Inflammatory cell infiltration and fibrin deposition play important roles in the development of crescentic glomerulonephritis (GN). In particular, activation of coagulation is an indispensable factor in crescent formation. However, the mechanisms underlying the pathogenesis of crescent formation have not been completely elucidated. We identified the growth factor midkine (MK) as a novel key molecule in the progression of crescentic GN induced by anti-glomerular basement membrane antibody. Despite the lack of significant differences in autologous and heterologous reactions, MK-deficient (Mdk(-/-)) mice unexpectedly showed a greater number of necrotizing glomerular injuries than wild-type (Mdk(+/+)) mice. Likewise, more tubulointerstitial damage was observed in Mdk(-/-) mice, and this damage positively correlated with glomerular injury. Plasminogen activator inhibitor (PAI)-1 was strongly induced in the injured glomerulus of Mdk(-/-) mice, particularly in crescents and endothelial cells. This enhanced PAI-1 production was associated with an increase in inflammatory cell infiltration and matrix deposition in the glomerulus and the interstitium of Mdk(-/-) mice. In line with these in vivo data, primary cultured endothelial cells derived from Mdk(-/-) mice exhibited higher PAI-1 mRNA expression on fibrin challenge and less fibrinolysis than Mdk(+/+) mice. In contrast, the expression of plasminogen activators was not affected. Our combined data suggest that MK leads to a blockade of PAI-1, which is closely associated with the suppression of crescentic GN.

  16. A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy.

    PubMed

    Bauer, C R; Morrison, J C; Poole, W K; Korones, S B; Boehm, J J; Rigatto, H; Zachman, R D

    1984-05-01

    In a large multicentered, collaborative randomized and blinded trial utilizing antenatal corticosteroids, the goals included determining the effectiveness of these agents in accelerating lung maturation, as well as monitoring any short-term or long-term adverse effects of this treatment on the parturient, fetus, and/or infant. More than 100 specific items, pertaining to diagnoses, complications, and outcomes were recorded for the 696 mothers enrolled in the study and their 745 infants. A significantly decreased incidence of necrotizing enterocolitis (P = .002) was found in the infants treated with steroids. The possibility of accelerated intestinal maturation induced by antenatal maternal steroid therapy exists. This treatment regimen is particularly attractive as adverse aspects of steroid therapy at the dosage utilized have not been demonstrated. PMID:6371696

  17. Necrotizing enterocolitis--150 years of fruitless search for the cause.

    PubMed

    Obladen, Michael

    2009-01-01

    Necrotizing enterocolitis (NEC) is not a new disease but one that has been reported since special care units began to house preterm infants. It was observed in foundling hospitals in Paris [Billard, 1828] and Vienna [Bednar, 1850] and, as it occurred in clusters, was regarded as a nosocomial infection in the infant hospitals of Zurich [Willi, 1944] and Berlin [Ylppo, 1931]. Clinical and patho-anatomic characterization was achieved by Schmidt and Quaiser in 1952. The unproven hypothesis of mesenteric hypoperfusion as a major etiological factor arose from animal models and analogous perforating disorders in term infants. Despite similarities between NEC and clostridial infections, few studies employed anaerobic culture techniques. The pathogenesis remains unclear and its distinction from related disorders uncertain. It is unlikely that strategies to prevent NEC will be successful unless the disease is better understood.

  18. Necrotizing fasciitis of the head and neck: a case report

    PubMed Central

    2015-01-01

    Necrotizing fasciitis (NF) is an infection that spreads along the fascial planes, causing subcutaneous tissue death characterized by rapid progression, systemic toxicity, and even death. NF often appears as a red, hot, painful, and swollen wound with an ill-defined border. As the infective process continues, local pain is replaced by numbness or analgesia. As the disease process continues, the skin initially becomes pale, then mottled and purple, and finally, gangrenous. The ability of NF to move rapidly along fascial planes and cause tissue necrosis is secondary to its polymicrobial composition and the synergistic effect of the enzymes produced by the bacteria. Treatment involves securing the airway, broad-spectrum antimicrobial therapy, intensive care support, and prompt surgical debridement, repeated as needed. Reducing mortality rests on early diagnosis and prompt aggressive treatment. PMID:25922821

  19. Propolis-induced descending necrotizing mediastinitis and aspiration pneumonia.

    PubMed

    Wu, Jeng-Yuan; Hsu, Nan-Yung

    2013-04-01

    Propolis is a resinous substance collected by bees as a sealant for their hives. It is also used in traditional medicine as an antioxidant and antiinflammatory agent to treat ulcers, superficial burns, and microbial diseases. In this report, a 40-year-old woman who took liquid propolis for relief of her common cold experienced severe sore throat, dysphagia, and easy choking followed by fever and chills. Descending necrotizing mediastinitis and concomitant aspiration pneumonia were evident on the image studies. We performed video-assisted thoracoscopic surgery to achieve immediate and adequate drainage, and the patient resumed normal deglutition 2 months later. Early diagnosis and prompt video-assisted thoracoscopic surgery intervention are paramount to manage this life-threatening situation.

  20. Necrotizing fasciitis secondary to enterocutaneous fistula: three case reports.

    PubMed

    Gu, Guo-Li; Wang, Lin; Wei, Xue-Ming; Li, Ming; Zhang, Jie

    2014-06-28

    Necrotizing fasciitis (NF) is an uncommon, rapidly progressive, and potentially fatal infection of the superficial fascia and subcutaneous tissue. NF caused by an enterocutaneous fistula has special clinical characters compared with other types of NF. NF caused by enterocutaneous fistula may have more rapid progress and more severe consequences because of multiple germs infection and corrosion by digestive juices. We treated three cases of NF caused by postoperative enterocutaneous fistula since Jan 2007. We followed empirically the principle of eliminating anaerobic conditions of infection, bypassing or draining digestive juice from the fistula and changing dressings with moist exposed burn therapy impregnated with zinc/silver acetate. These three cases were eventually cured by debridement, antibiotics and wound management. PMID:24976737

  1. Acute necrotizing pancreatitis as first manifestation of primary hyperparathyroidism

    PubMed Central

    Lenz, Jeroen I; Jacobs, Jimmy M; Op de Beeck, Bart; Huyghe, Ivan A; Pelckmans, Paul A; Moreels, Tom G

    2010-01-01

    We report the case of a female patient with severe acute necrotizing pancreatitis associated with hypercalcemia as first manifestation of primary hyperparathyroidism caused by a benign parathyroid adenoma. Initially the acute pancreatitis was treated conservatively. The patient subsequently underwent surgical resection of the parathyroid adenoma and surgical clearance of a large infected pancreatic pseudocyst. Although the association of parathyroid adenoma-induced hypercalcemia and acute pancreatitis is a known medical entity, it is very uncommon. The pathophysiology of hypercalcemia-induced acute pancreatitis is therefore not well known, although some mechanisms have been proposed. It is important to treat the provoking factor. Therefore, the cause of hypercalcemia should be identified early. Surgical resection of the parathyroid adenoma is the ultimate therapy. PMID:20556845

  2. Necrotizing sialometaplasia of the parotid gland in a dog.

    PubMed

    Kim, Ha-Young; Woo, Gye-Hyeong; Bae, You-Chan; Park, Yeon-Hee; Joo, Yi-Seok

    2010-11-01

    Necrotizing sialometaplasia (NS) is a self-limiting, benign, ischemic, inflammatory disease that is most often described in the submandibular glands of dogs, with clinical and histologic features that resemble malignancy. Unilateral swelling of the parotid salivary gland in a 7-year-old Cocker Spaniel dog was diagnosed as NS. The dog also had otitis externa on the same side as the parotid gland lesions. The main histologic features were included lobular necrosis of salivary tissue; fibrinoid necrosis of some arteries; marked squamous metaplasia of duct and/or acinar epithelium, with intercellular bridge formation; preservation of salivary lobular morphology; and variable inflammation and fibrosis. Etiologic factors for NS in both humans and animals remain obscure.

  3. Necrotizing sialometaplasia obscuring an underlying malignancy: report of a case.

    PubMed

    Poulson, T C; Greer, R O; Ryser, R W

    1986-07-01

    Necrotizing sialometaplasia poses many diagnostic problems, both clinically and microscopically. Caution had most frequently been urged for distinguishing between malignancy and NS, so as to avoid mutilating surgical treatment resulting from the misdiagnosis of a lesion that is benign and self-limiting. This case has been presented to alert the practitioner to the possibility that NS may obscure an underlying malignant disease process, possibly resulting in delays in referral or treatment. The exceedingly rapid growth of this mesenchymal neoplasm may have caused obstruction of the blood supply to the overlying mucosa and submucosa, thereby producing the ischemic alterations observed in the first biopsy specimens. Some of the difficulties encountered in the detection and diagnosis of neoplasms arising in the parapharyngeal space were discussed, and some previously published suggestions to aid in these efforts were reiterated.

  4. A peptide antagonist of CD28 signaling attenuates toxic shock and necrotizing soft-tissue infection induced by Streptococcus pyogenes.

    PubMed

    Ramachandran, Girish; Tulapurkar, Mohan E; Harris, Kristina M; Arad, Gila; Shirvan, Anat; Shemesh, Ronen; Detolla, Louis J; Benazzi, Cinzia; Opal, Steven M; Kaempfer, Raymond; Cross, Alan S

    2013-06-15

    Staphylococcus aureus and group A Streptococcus pyogenes (GAS) express superantigen (SAg) exotoxin proteins capable of inducing lethal shock. To induce toxicity, SAgs must bind not only to the major histocompatibility complex II molecule of antigen-presenting cells and the variable β chain of the T-cell receptor but also to the dimer interface of the T-cell costimulatory receptor CD28. Here, we show that the CD28-mimetic peptide AB103 (originally designated "p2TA") protects mice from lethal challenge with streptococcal exotoxin A, as well as from lethal GAS bacterial infection in a murine model of necrotizing soft-tissue infection. Administration of a single dose of AB103 increased survival when given up to 5 hours after infection, reduced inflammatory cytokine expression and bacterial burden at the site of infection, and improved muscle inflammation in a dose-dependent manner, without compromising cellular and humoral immunity. Thus, AB103 merits further investigation as a potential therapeutic in SAg-mediated necrotizing soft-tissue infection.

  5. A novel autoantibody against ephrin type B receptor 2 in acute necrotizing encephalopathy

    PubMed Central

    2013-01-01

    Acute necrotizing encephalopathy (ANE) is characterized by symmetrical brain necrosis, suggested to be due to breakdown of the blood–brain barrier (BBB). We experienced a rare case of ANE complicated with systemic lupus erythematosus (SLE), and found that the patient’s serum (V10-5) had binding activity to human umbilical vein endothelial cells (HUVECs). By SARF (Serological identification system for Autoantigens using a Retroviral vector and Flow cytometry) method using V10-5 IgG, a clone bound to V10-5 IgG was isolated. This cell clone was integrated with cDNA identical to EphB2, which plays critical roles in neuronal cells and endothelial cells. HUVECs and human brain microvascular endothelial cells expressed EphB2 and the V10-5 IgG bound specifically to EphB2-transfected cells. Anti-EphB2 antibody was not detected in other SLE patients without ANE. In this report, we identified EphB2 as a novel autoantigen, and anti-EphB2 antibody may define a novel group of brain disorders. Anti-EphB2 antibody can interfere not only with endothelial cells including those of the BBB (acting as an anti-endothelial cell antibody), but also neuronal cells (acting as an anti-neuronal antibody) if the BBB has been breached. Future studies should determine the clinical prevalence and specificity of anti-EphB2 antibody, and the molecular mechanisms by which anti-EphB2 antibody mediates neuronal and vascular pathological lesions. PMID:24139226

  6. A novel autoantibody against ephrin type B receptor 2 in acute necrotizing encephalopathy.

    PubMed

    Shirai, Tsuyoshi; Fujii, Hiroshi; Ono, Masao; Watanabe, Ryu; Shirota, Yuko; Saito, Shinichiro; Ishii, Tomonori; Nose, Masato; Harigae, Hideo

    2013-10-18

    Acute necrotizing encephalopathy (ANE) is characterized by symmetrical brain necrosis, suggested to be due to breakdown of the blood-brain barrier (BBB). We experienced a rare case of ANE complicated with systemic lupus erythematosus (SLE), and found that the patient's serum (V10-5) had binding activity to human umbilical vein endothelial cells (HUVECs). By SARF (Serological identification system for Autoantigens using a Retroviral vector and Flow cytometry) method using V10-5 IgG, a clone bound to V10-5 IgG was isolated. This cell clone was integrated with cDNA identical to EphB2, which plays critical roles in neuronal cells and endothelial cells. HUVECs and human brain microvascular endothelial cells expressed EphB2 and the V10-5 IgG bound specifically to EphB2-transfected cells. Anti-EphB2 antibody was not detected in other SLE patients without ANE. In this report, we identified EphB2 as a novel autoantigen, and anti-EphB2 antibody may define a novel group of brain disorders. Anti-EphB2 antibody can interfere not only with endothelial cells including those of the BBB (acting as an anti-endothelial cell antibody), but also neuronal cells (acting as an anti-neuronal antibody) if the BBB has been breached. Future studies should determine the clinical prevalence and specificity of anti-EphB2 antibody, and the molecular mechanisms by which anti-EphB2 antibody mediates neuronal and vascular pathological lesions.

  7. Current Concepts in the Management of Necrotizing Fasciitis

    PubMed Central

    Misiakos, Evangelos P.; Bagias, George; Patapis, Paul; Sotiropoulos, Dimitrios; Kanavidis, Prodromos; Machairas, Anastasios

    2014-01-01

    Necrotizing fasciitis (NF) is a severe, rare, potentially lethal soft tissue infection that develops in the scrotum and perineum, the abdominal wall, or the extremities. The infection progresses rapidly, and septic shock may ensue; hence, the mortality rate is high (median mortality 32.2%). Prognosis becomes poorer in the presence of co-morbidities, such as diabetes mellitus, immunosuppression, chronic alcohol disease, chronic renal failure, and liver cirrhosis. NF is classified into four types, depending on microbiological findings. Most cases are polymicrobial, classed as type I. The clinical status of the patient varies from erythema, swelling, and tenderness in the early stage to skin ischemia with blisters and bullae in the advanced stage of infection. In its fulminant form, the patient is critically ill with signs and symptoms of severe septic shock and multiple organ dysfunction. The clinical condition is the most important clue for diagnosis. However, in equivocal cases, the diagnosis and severity of the infection can be secured with laboratory-based scoring systems, such as the laboratory risk indicator for necrotizing fasciitis score or Fournier’s gangrene severity index score, especially in regard to Fournier’s gangrene. Computed tomography or ultrasonography can be helpful, but definitive diagnosis is attained by exploratory surgery at the infected sites. Management of the infection begins with broad-spectrum antibiotics, but early and aggressive drainage and meticulous debridement constitute the mainstay of treatment. Postoperative management of the surgical wound is also important for the patient’s survival, along with proper nutrition. The vacuum-assisted closure system has proved to be helpful in wound management, with its combined benefits of continuous cleansing of the wound and the formation of granulation tissue. PMID:25593960

  8. Apoptotic and necrotic changes in the midgut glands of the wolf spider Xerolycosa nemoralis (Lycosidae) in response to starvation and dimethoate exposure.

    PubMed

    Wilczek, G; Rost-Roszkowska, M; Wilczek, P; Babczyńska, A; Szulińska, E; Sonakowska, L; Marek-Swędzioł, M

    2014-03-01

    In the present study, the intensity of degenerative changes (apoptosis, necrosis) in the cells of the midgut glands of male and female wolf spiders, Xerolycosa nemoralis (Lycosidae), exposed to natural (starvation) and anthropogenic (the organophosphorous pesticide dimethoate) stressors under laboratory conditions were compared. The spiders were collected from two differentially polluted sites, both located in southern Poland: Katowice-Welnowiec, which is heavily polluted with metals, and Pilica, the reference site. Starvation and dimethoate treatment resulted in enhancement of apoptotic and necrotic changes in the midgut glands of the spiders. The frequency of degenerative changes in starving individuals was twice as high as in the specimens intoxicated with dimethoate. The percentage of apoptotic and necrotic cells was higher in starving males than in starving females. A high intensity of necrotic changes, together with increased Cas-3 like activity and a greater percentage of cells with depolarized mitochondria, were typical of starving males from the polluted site. The cell death indices observed in females depended more strongly on the type of stressor than on previous preexposure to pollutants.

  9. The Yersinia pseudotuberculosis cytotoxic necrotizing factor (CNFY) selectively activates RhoA.

    PubMed

    Hoffmann, Claudia; Pop, Marius; Leemhuis, Jost; Schirmer, Jörg; Aktories, Klaus; Schmidt, Gudula

    2004-04-16

    The cytotoxic necrotizing factors (CNF)1 and CNF2 from pathogenic Escherichia coli strains activate RhoA, Rac1, and Cdc42 by deamidation of Gln63 (RhoA) or Gln61 (Rac and Cdc42). Recently, a novel cytotoxic necrotizing factor termed CNFY was identified in Yersinia pseudotuberculosis strains (Lockman, H. A., Gillespie, R. A., Baker, B. D., and Shakhnovich, E. (2002) Infect. Immun. 70, 2708-2714). We amplified the cnfy gene from genomic DNA of Y. pseudotuberculosis, cloned and expressed the recombinant protein, and studied its activity. Recombinant GST-CNFY induced morphological changes in HeLa cells and caused an upward shift of RhoA in SDS-PAGE, as is known for GST-CNF1 and GST-CNF2. Mass spectrometric analysis of GST-CNFY-treated RhoA confirmed deamidation at Glu63. Treatment of RhoA, Rac1, and Cdc42 with GST-CNFY decreased their GTPase activities, indicating that all of these Rho proteins could serve as substrates for GST-CNFY in vitro. In contrast, RhoA, but not Rac or Cdc42, was the substrate of GST-CNFY in culture cells. GST-CNFY caused marked stress fiber formation in HeLa cells after 2 h. In contrast to GST-CNF1, formation of filopodia or lamellipodia was not induced with GST-CNFY. Accordingly, effector pull-down experiments with lysates of toxin-treated cells revealed strong activation of RhoA but no activation of Rac1 or Cdc42 after 6 h of GST-CNFY-treatment. Moreover, in rat hippocampal neurons, GST-CNFY results in the retraction of neurites, indicating RhoA activation. In contrast, no activation of Rac or Cdc42 was found. Altogether, our data suggest that CNFY from Y. pseudotuberculosis is a strong, selective activator of RhoA, which can be used as a powerful tool for constitutive RhoA activation without concomitant activation of Rac1 or Cdc42. PMID:14761941

  10. The ErbB4 Ligand Neuregulin-4 Protects against Experimental Necrotizing Enterocolitis

    PubMed Central

    McElroy, Steven J.; Castle, Shannon L.; Bernard, Jessica K.; Almohazey, Dana; Hunter, Catherine J.; Bell, Brandon A.; Al Alam, Denise; Wang, Larry; Ford, Henri R.; Frey, Mark R.

    2015-01-01

    Necrotizing enterocolitis (NEC) affects up to 10% of premature infants, has a mortality of 30%, and can leave surviving patients with significant morbidity. Neuregulin-4 (NRG4) is an ErbB4-specific ligand that promotes epithelial cell survival. Thus, this pathway could be protective in diseases such as NEC, in which epithelial cell death is a major pathologic feature. We sought to determine whether NRG4-ErbB4 signaling is protective in experimental NEC. NRG4 was used i) in the newborn rat formula feeding/hypoxia model; ii) in a recently developed model in which 14- to 16-day-old mice are injected with dithizone to induce Paneth cell loss, followed by Klebsiella pneumoniae infection to induce intestinal injury; and iii) in bacterially infected IEC-6 cells in vitro. NRG4 reduced NEC incidence and severity in the formula feed/hypoxia rat model. It also reduced Paneth cell ablation–induced NEC and prevented dithizone-induced Paneth cell loss in mice. In vitro, cultured ErbB4−/− ileal epithelial enteroids had reduced Paneth cell markers and were highly sensitive to inflammatory cytokines. Furthermore, NRG4 blocked, through a Src-dependent pathway, Cronobacter muytjensii–induced IEC-6 cell apoptosis. The potential clinical relevance of these findings was demonstrated by the observation that NRG4 and its receptor ErbB4 are present in human breast milk and developing human intestine, respectively. Thus, NRG4-ErbB4 signaling may be a novel pathway for therapeutic intervention or prevention in NEC. PMID:25216938

  11. Heme oxygenase-1-mediated apoptosis under cadmium-induced oxidative stress is regulated by autophagy, which is sensitized by tumor suppressor p53.

    PubMed

    So, Keum-Young; Oh, Seon-Hee

    2016-10-01

    Heme oxygenase-1 (HO-1) is a stress-inducible cytoprotective enzyme. It is often overexpressed in different types of cancers and promotes cell survival. However, the role of HO-1 and the underlying molecular mechanism of cadmium (Cd)-induced oxidative stress in cancer cells remain undefined. Here we show that the role of HO-1 under Cd-induced oxidative stress is dependent upon autophagy, which is sensitized by the tumor suppressor p53. The sensitivity to Cd was 3.5- and 14-fold higher in p53-expressing YD8 and H460 cells than in p53-null YD10B and H1299 cells, respectively. The levels of p53 in YD8 and H460 cells decreased in a Cd concentration-dependent manner, which was inhibited by pretreatment with N-acetylcysteine. In both cell lines, Cd exposure resulted in caspase-3-mediated PARP-1 cleavage and the induction of CHOP, LC3-II, and HO-1, which were limited in YD10B and H1299 cells exposed to high concentrations of Cd. Cd exposure to p53-overexpressing YD10B cells enhanced Cd-induced HO-1 and LC3-II levels, whereas genetic knockdown of p53 in YD8 cells resulted in the suppression of Cd-induced levels of HO-1 and LC3-II, indicating that p53 is required in the sensing of HO-1 and induction of autophagy. The inhibition of autophagy using small interfering RNA (siRNA) for the autophagy-related gene atg5 enhanced HO-1, CHOP, and PARP-1 cleavage induced by Cd. However, transfection with HO-1 siRNA increased Cd-induced LC3-II, and suppressed the expression of CHOP and cleavage of PARP-1. Collectively, the role of HO-1 in apoptosis could be modulated by autophagy, which is sensitized by p53 expression in human cancer cell lines.

  12. Severe necrotizing encephalitis in a Yorkshire terrier: topographic and immunohistochemical study.

    PubMed

    Lezmi, S; Toussaint, Y; Prata, D; Lejeune, T; Ferreira-Neves, P; Rakotovao, F; Fontaine, J J; Marchal, T; Cordonnier, N

    2007-05-01

    Necrotizing encephalitis of the Yorkshire terrier is a chronic non-suppurative encephalitis that was reported in approximately 15 cases worldwide. We report the case of a 10-year-old female Yorkshire terrier with gross evidence of severe cortical degeneration and necrosis. Microscopically, affected areas were mainly located in the cortical white matter and in the mesencephalon without implication of the cerebellum. Cavitation necrosis, demyelination, gemistocytic astrocytosis, marked perivascular lymphocytic cuffing with a diffuse lymphocytic/histiocytic/gitter cell infiltration characterized the lesions. Immunohistochemical analysis identified the major infiltration of T lymphocytes and macrophages with implication of some cytotoxic lymphocytes and IgG-producing plasma cells; depositions of IgG in the affected white matter were also observed. Specific stains did not reveal fungal, protozoal or bacterial organisms and reverse transcriptase-polymerase chain reaction analysis for distemper virus was also negative. The lympho-histiocytic inflammation suggests a T-cell-mediated and a delayed-type immune reaction as a possible pathogenic mechanism for this brain disorder.

  13. Cytotoxic Necrotizing Factor-Y Boosts Yersinia Effector Translocation by Activating Rac Protein*

    PubMed Central

    Wolters, Manuel; Boyle, Erin C.; Lardong, Kerstin; Trülzsch, Konrad; Steffen, Anika; Rottner, Klemens; Ruckdeschel, Klaus; Aepfelbacher, Martin

    2013-01-01

    Pathogenic Yersinia spp. translocate the effectors YopT, YopE, and YopO/YpkA into target cells to inactivate Rho family GTP-binding proteins and block immune responses. Some Yersinia spp. also secrete the Rho protein activator cytotoxic necrotizing factor-Y (CNF-Y), but it has been unclear how the bacteria may benefit from Rho protein activation. We show here that CNF-Y increases Yop translocation in Yersinia enterocolitica-infected cells up to 5-fold. CNF-Y strongly activated RhoA and also delayed in time Rac1 and Cdc42, but when individually expressed, constitutively active mutants of Rac1, but not of RhoA, increased Yop translocation. Consistently, knock-out or knockdown of Rac1 but not of RhoA, -B, or -C inhibited Yersinia effector translocation in CNF-Y-treated and control cells. Activation or knockdown of Cdc42 also affected Yop translocation but much less efficiently than Rac. The increase in Yop translocation induced by CNF-Y was essentially independent of the presence of YopE, YopT, or YopO in the infecting Yersinia strain, indicating that none of the Yops reported to inhibit translocation could reverse the CNF-Y effect. In summary, the CNF-Y activity of Yersinia strongly enhances Yop translocation through activation of Rac. PMID:23803609

  14. Stage-dependency of apoptosis and the blood-testis barrier in the dogfish shark (Squalus acanthias): cadmium-induced changes as assessed by vital fluorescence techniques.

    PubMed

    McClusky, Leon M

    2006-09-01

    Naturally occurring heavy metals and synthetic compounds are potentially harmful for testicular function but evidence linking heavy metal exposure to reduced semen parameters is inconclusive. Elucidation of the exact stage at which the toxicant interferes with spermatogenesis is difficult because the various germ cell stages may have different sensitivities to any given toxicant, germ cell development is influenced by supporting testicular somatic cells and the presence of inter-Sertoli cell tight junctions create a blood-testis barrier, sequestering meiotic and postmeiotic germ cells in a special microenvironment. Sharks such as Squalus acanthias provide a suitable model for studying aspects of vertebrate spermatogenosis because of their unique features: spermatogenesis takes place within spermatocysts and relies mainly on Sertoli cells for somatic cell support; spermatocysts are linearly arranged in a maturational order across the diameter of the elongated testis; spermatocysts containing germ cells at different stages of development are topographically separated, resulting in visible zonation in testicular cross sections. We have used the vital dye acridine orange and a novel fluorescence staining technique to study this model to determine (1) the efficacy of these methods in assays of apoptosis and blood-testis barrier function, (2) the sensitivity of the various spermatogonial generations in Squalus to cadmium (as an illustrative spermatotoxicant) and (3) the way that cadmium might affect more mature spermatogenic stages and other physiological processes in the testis. Our results show that cadmium targets early spermatogenic stages, where it specifically activates a cell death program in susceptible (mature) spermatogonial clones, and negatively affects blood-testis barrier function. Since other parameters are relatively unaffected by cadmium, the effects of this toxicant on apoptosis are presumably process-specific and not attributable to general toxicity

  15. Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants with Spontaneous Intestinal Perforation or Surgical Necrotizing Enterocolitis

    PubMed Central

    Wadhawan, Rajan; Oh, William; Hintz, Susan R; Blakely, Martin L; Das, Abhik; Bell, Edward F.; Saha, Shampa; Laptook, Abbot R.; Shankaran, Seetha; Stoll, Barbara J.; Walsh, Michele C.; Higgins, Rosemary D.

    2013-01-01

    Objective To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18–22 months corrected age compared to infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation. Study Design Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000–2005. The study infants were designated into 3 groups: 1) Spontaneous intestinal perforation without necrotizing enterocolitis; 2) Surgical necrotizing enterocolitis (Bell's stage III); and 3) Neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center. Results Infants with surgical necrotizing enterocolitis had the highest rate of death prior to hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared to infants in the spontaneous intestinal perforation group (39.1% and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1% and 53.3%; p<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted OR 2.21, 95% CI: 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9 respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4 respectively). Conclusions Spontaneous intestinal perforation and surgical necrotizing

  16. Reduction of ventricular M2 muscarinic receptors in cardiomyopathic hamster (CHF 147) at the necrotic stage of the myopathy.

    PubMed

    Wilkinson, M; Horackova, M; Giles, A

    1994-04-01

    We have previously demonstrated that isolated ventricular myocytes from cardiomyopathic hamsters (CHF 147) during the necrotic stage (70-100 days) exhibit an attenuated contractile response to muscarinic stimulation. In the present study we have investigated whether this dysfunction may be related to a change in the density (or affinity) of cardiac muscarinic receptors. Thus, we have characterized and quantified the binding of the muscarinic antagonist [3H]-N-methyl scopolamine (NMS) to M2 muscarinic receptors in cardiac micropunches and in suspensions of isolated intact cardiomyocytes obtained from cardiomyopathic (CHF 147) and Golden Syrian hamsters. The hamsters were either 70-100 days old, when the cardiomyopathy had reached the cytolytic and necrotic stage or 30 days old, i.e. before the onset of the cardiomyopathy. In both preparations (micropunches and dissociated cardiomyocytes) the specific binding of [3H]-NMS was stereospecific, reversible, saturable, of high affinity and linearly dependent upon increasing amounts of tissue and cells. The binding site also possessed the drug specificity typical of an M2 muscarinic receptor. Saturation binding analysis revealed that the hearts of the older CHF 147 hamsters contain significantly fewer M2 muscarinic receptors than the control Golden Syrian hamsters while the affinity (Kd) was not altered. This reduction of M2 receptor number was not observed in CHF 147 hamsters at 30 days. Further, we found no differences in beta-adrenergic or in alpha 1-adrenergic binding in the two strains of hamster at either age. Thus, our results indicate that the parasympathetic regulation of cardiac function in CHF 147 hamsters may be compromised by a decreased number of muscarinic receptors at the necrotic stage of the cardiomyopathy.

  17. Paraneoplastic Necrotizing Myopathy with a Mild Inflammatory Component: A Case Report and Review of the Literature

    PubMed Central

    Wegener, Susanne; Bremer, Juliane; Komminoth, Paul; Jung, Hans H.; Weller, Michael

    2010-01-01

    Inflammatory myopathies such as dermatomyositis and polymyositis are well-recognized paraneoplastic syndromes. Little is known, however, about necrotizing myopathies in association with cancer. We here describe a case of paraneoplastic necrotizing myopathy with a mild inflammatory infiltrate in a patient with adenocarcinoma. After the rapid development of a severe, disabling muscle weakness, the patient experienced near complete recovery within 4 months under oral prednisone treatment. In the context of the presented case, we will review current knowledge about paraneoplastic necrotizing myopathies. PMID:20740165

  18. Limb salvage in a diabetic with necrotizing fasciitis: case report and literature review.

    PubMed

    Carlow, S B; Jacobs, R L; Vedder, D K

    1986-02-01

    Necrotizing fasciitis must be considered in a diabetic with cutaneous ulceration. A case report of limb salvage in a 48-year-old diabetic female with progressive necrotizing fasciitis is presented. Methods of early diagnosis including clinical signs, radiographs, and soft tissue biopsy of the involved extremity are reviewed. The microbiology of the disease is also discussed. A modification of the Orr technique using infrequent dressing changes in the management of necrotizing fasciitis is presented. In our case this resulted in preservation of life and a functional limb.

  19. P-glycoprotein induction by breast milk attenuates intestinal inflammation in experimental necrotizing enterocolitis

    PubMed Central

    Guner, Yigit S.; Franklin, Ashanti L.; Chokshi, Nikunj K.; Castle, Shannon L.; Pontarelli, Elizabeth; Wang, Jin; Wang, Larry; Prasadarao, Nemani V.; Upperman, Jeffrey S.; Grishin, Anatoly V.; Ford, Henri R.

    2014-01-01

    P-glycoprotein (Pgp), a product of the multi-drug resistance gene MDR1a, is a broad specificity efflux ATP cassette transmembrane transporter that is predominantly expressed in epithelial tissues. Because mdr1a−/− mice tend to develop spontaneous colitis in bacteria-dependent manner, Pgp is believed to have a role in protection of the intestinal epithelium from luminal bacteria. Here we demonstrate that levels of Pgp in the small intestine of newborn rodents dramatically increase during breastfeeding, but not during formula feeding (FF). In rats and mice, levels of intestinal Pgp peak on days 3–7 and 1–5 of breastfeeding, respectively. The mdr1a−/− neonatal mice subjected to FF, hypoxia, and hypothermia have significantly higher incidence and pathology, as well as significantly earlier onset of necrotizing enterocolitis (NEC) than congenic wild type mice. Breast-fed mdr1a−/− neonatal mice are also more susceptible to intestinal damage caused by the opportunistic pathogen Cronobacter sakazakii that has been associated with hospital outbreaks of NEC. Breast milk, but not formula, induces Pgp expression in enterocyte cell lines in a dose- and time-dependent manner. High levels of ectopically expressed Pgp protect epithelial cells in vitro from apoptosis induced by C. sakazakii. Taken together, these results show that breast milk-induced expression of Pgp may have a role in the protection of the neonatal intestinal epithelium from injury associated with nascent bacterial colonization. PMID:21788941

  20. Necrotizing meningoencephalitis and pneumonitis in a simian immunodeficiency virus-infected rhesus macaque due to Acanthamoeba.

    PubMed

    Westmoreland, S V; Rosen, J; MacKey, J; Romsey, C; Xia, D-L; Visvesvera, G S; Mansfield, K G

    2004-07-01

    Free-living amoebae of the genus Acanthamoeba can cause a fatal disease of the brain in humans called granulomatous amoebic encephalitis. We present a case of meningoencephalitis and pneumonitis in a simian immunodeficiency virus (SIV)-infected rhesus macaque caused by Acanthamoeba sp. The animal became ill 176 days after intravenous inoculation with SIVmac251 after a short history of weight loss and a sudden onset of hind limb paresis and abnormal head movements. Histopathologic examination of hematoxylin and eosin-stained tissues revealed multifocal to coalescing necrotizing neutrophilic meningoencephalitis and pneumonitis. Immunofluorescence and polymerase chain reaction were used to identify the genus of amoeba as Acanthamoeba. Immunohistochemistry of immune cell markers was used to characterize the animal's immune response to the opportunistic amoebic infection with features of both innate and adaptive cell-mediated immunity. Although not previously reported, the potential transmission to humans, either through environmental contamination or contact with an infected animal, makes this disease a threat to laboratory animal care staff and pathologists. PMID:15232140

  1. Melon necrotic spot virus Replication Occurs in Association with Altered Mitochondria.

    PubMed

    Gómez-Aix, Cristina; García-García, María; Aranda, Miguel A; Sánchez-Pina, María Amelia

    2015-04-01

    Melon necrotic spot virus (MNSV) (genus Carmovirus, family Tombusviridae) is a single-stranded, positive-sense RNA virus that has become an experimental model for the analysis of cell-to-cell virus movement and translation of uncapped viral RNAs, whereas little is known about its replication. Analysis of the cytopathology after MNSV infection showed the specific presence of modified organelles that resemble mitochondria. Immunolocalization of the glycine decarboxylase complex (GDC) P protein in these organelles confirmed their mitochondrial origin. In situ hybridization and immunolocalization experiments showed the specific localization of positive-sense viral RNA, capsid protein (CP), and double-stranded (ds)RNA in these organelles meaning that replication of the virus takes place in association with them. The three-dimensional reconstructions of the altered mitochondria showed the presence of large, interconnected, internal dilations which appeared to be linked to the outside cytoplasmic environment through pores and/or complex structures, and with lipid bodies. Transient expression of MNSV p29 revealed that its specific target is mitochondria. Our data document the extensive reorganization of host mitochondria induced by MNSV, which provides a protected environment to viral replication, and show that the MNSV p29 protein is the primary determinant of this effect in the host.

  2. Short-interfering RNA-mediated silencing of thioredoxin reductase 1 alters the sensitivity of HeLa cells toward cadmium.

    PubMed

    Nishimoto, Michie; Sakaue, Motoharu; Hara, Shuntaro

    2006-03-01

    The mammalian thioredoxin reductase (TrxR) is a selenocysteine-containing flavoprotein that regulates the thioredoxin system, one of the major systems that maintain the intracellular redox balance. We previously reported that cytosolic TrxR (TrxR1), one of three mammalian TrxR isozymes, was induced by treatment with cadmium. In the present study, to study the role of cadmium-induced TrxR1 in cellular defense, we silenced the expression of TrxR1 in HeLa cells by using small interfering RNA and examined the effect of TrxR1 silencing on the sensitivity of the cells toward cadmium. We found that the gene silencing of TrxR1 had a dual effect on cadmium-induced cell death, depending on the concentration of cadmium. The TrxR1 silencing increased the sensitivity toward a low dose (less than 10 microM) of cadmium but decreased the sensitivity toward a high dose of cadmium. These results suggested that TrxR1 might play an important role in the cellular defense system against cadmium in two ways. TrxR1 might rescue the cells from a low dose of cadmium-induced moderate injury, while it might promote the death of cells severely injured by a high dose of cadmium.

  3. Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity.

    PubMed

    Lee, Jin-Yong; Tokumoto, Maki; Fujiwara, Yasuyuki; Hasegawa, Tatsuya; Seko, Yoshiyuki; Shimada, Akinori; Satoh, Masahiko

    2016-01-01

    Chronic cadmium (Cd) exposure can induce renal toxicity. In Cd renal toxicity, p53 is thought to be involved. Our previous studies showed that Cd down-regulated gene expression of the UBE2D (ubiquitin-conjugating enzyme E2D) family members. Here, we aimed to define the association between UBE2D family members and p53-dependent apoptosis in human proximal tubular cells (HK-2 cells) treated with Cd. Cd increased intracellular p53 protein levels and decreased UBE2D2 and UBE2D4 gene expression via inhibition of YY1 and FOXF1 transcription factor activities. Double knockdown of UBE2D2 and UBE2D4 caused an increase in p53 protein levels, and knockdown of p53 attenuated not only Cd-induced apoptosis, but also Cd-induced apoptosis-related gene expression (BAX and PUMA). Additionally, the mice exposed to Cd for 6 months resulted in increased levels of p53 and induction of apoptosis in proximal tubular cells. These findings suggest that down-regulation of UBE2D family genes followed by accumulation of p53 in proximal tubular cells is an important mechanism for Cd-induced renal toxicity.

  4. 5-Aminolevolinic acid mitigates the cadmium-induced changes in Brassica napus as revealed by the biochemical and ultra-structural evaluation of roots.

    PubMed

    Ali, Basharat; Tao, Qiaojing; Zhou, Yuanfei; Gill, Rafaqat A; Ali, Shafaqat; Rafiq, Muhammad T; Xu, Ling; Zhou, Weijun

    2013-06-01

    In the present study, the ameliorating effects of 5-aminolevulinic acid (ALA) under cadmium (Cd) stress conditions were studied with special emphasis on root morphology and ultra-structure in oilseed rape. For this purpose, plants were treated hydroponically at three different Cd levels (0, 100, 500μM) and foliar spray of ALA with three concentrations (0, 12.5, 25mg/l) simultaneously. The results showed that foliar application of ALA improved the plant growth, root morphology and reduced the reactive oxygen species and malondialdehyde contents in roots under Cd stress conditions. The higher concentration of Cd (500μM) decreased the activities of antioxidants enzymes like catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione reductase (GR) and also reduced the oxidized glutathione and total glutathione contents in roots. Application of ALA at 25mg/l dosage significantly enhanced the antioxidant activities e.g. APX, SOD, POD, and GSH contents under Cd stress. The microscopic micrographs showed that application of exogenous ALA improved the cell structure under Cd toxicity. A whole cell with developed nucleus, nuclear membrane, smooth cell wall, continuous endoplasmic reticulum, and well shaped mitochondria was observed under the combine application of ALA and Cd. These results suggest that, application of ALA helped the plants to improve root growth, root antioxidant enzymes, and ultra-structural changes in root tip cells under fifteen days Cd-induced stress. PMID:23490193

  5. Accumulation of p53 via down-regulation of UBE2D family genes is a critical pathway for cadmium-induced renal toxicity

    PubMed Central

    Lee, Jin-Yong; Tokumoto, Maki; Fujiwara, Yasuyuki; Hasegawa, Tatsuya; Seko, Yoshiyuki; Shimada, Akinori; Satoh, Masahiko

    2016-01-01

    Chronic cadmium (Cd) exposure can induce renal toxicity. In Cd renal toxicity, p53 is thought to be involved. Our previous studies showed that Cd down-regulated gene expression of the UBE2D (ubiquitin-conjugating enzyme E2D) family members. Here, we aimed to define the association between UBE2D family members and p53-dependent apoptosis in human proximal tubular cells (HK-2 cells) treated with Cd. Cd increased intracellular p53 protein levels and decreased UBE2D2 and UBE2D4 gene expression via inhibition of YY1 and FOXF1 transcription factor activities. Double knockdown of UBE2D2 and UBE2D4 caused an increase in p53 protein levels, and knockdown of p53 attenuated not only Cd-induced apoptosis, but also Cd-induced apoptosis-related gene expression (BAX and PUMA). Additionally, the mice exposed to Cd for 6 months resulted in increased levels of p53 and induction of apoptosis in proximal tubular cells. These findings suggest that down-regulation of UBE2D family genes followed by accumulation of p53 in proximal tubular cells is an important mechanism for Cd-induced renal toxicity. PMID:26912277

  6. Protection against avian necrotic enteritis after immunisation with NetB genetic or formaldehyde toxoids.

    PubMed

    Fernandes da Costa, Sérgio P; Mot, Dorien; Bokori-Brown, Monika; Savva, Christos G; Basak, Ajit K; Van Immerseel, Filip; Titball, Richard W

    2013-08-20

    NetB (necrotic enteritis toxin B) is a recently identified β-pore-forming toxin produced by Clostridium perfringens. This toxin has been shown to play a major role in avian necrotic enteritis. In recent years, a dramatic increase in necrotic enteritis has been observed, especially in countries where the use of antimicrobial growth promoters in animal feedstuffs has been banned. The aim of this work was to determine whether immunisation with a NetB toxoid would provide protection against necrotic enteritis. The immunisation of poultry with a formaldehyde NetB toxoid or with a NetB genetic toxoid (W262A) resulted in the induction of antibody responses against NetB and provided partial protection against disease.

  7. The phylum Synergistetes in gingivitis and necrotizing ulcerative gingivitis.

    PubMed

    Baumgartner, Angelica; Thurnheer, Thomas; Lüthi-Schaller, Helga; Gmür, Rudolf; Belibasakis, Georgios N

    2012-11-01

    The clinical manifestation of necrotizing ulcerative gingivitis (NUG) is distinct from that of common gingivitis in that it is characterized by local necrosis of the gingival tissues, rapid onset, pain and extensive bleeding. The phylum Synergistetes is a novel bacterial phylum consisting of Gram-negative anaerobes, with evidence of presence in biofilms associated with periodontal and endodontic infections. To date, the involvement of members of this phylum in NUG has not been investigated. This study aimed to evaluate the presence and levels of known human oral Synergistetes bacterial clusters in dental plaque from patients with NUG and compare them with those found in gingivitis. Marginal dental plaque samples from 21 NUG and 21 gingivitis patients were analysed quantitatively by fluorescent in situ hybridization and microscopy for members of two oral Synergistetes clusters (A and B) and for Jonquetella anthropi. Synergistetes cluster A bacteria were detected in all samples but at higher levels (9.4-fold) and proportions (2.5-fold) in NUG patients than in gingivitis patients. However, with regard to Synergistetes cluster B bacteria, there were no differences between NUG and gingivitis patients. J. anthropi was detected in only half of the samples and at lower levels than the other taxa. In conclusion, these data demonstrate that Synergistetes cluster A bacteria, but not cluster B bacteria or J. anthropi, are more strongly associated with NUG than with gingivitis.

  8. Necrotizing retinitis due to syphilis in a patient with AIDS.

    PubMed

    Shinha, Takashi; Weaver, Bree A

    2016-01-01

    The ocular manifestations of syphilis are varied. Ocular syphilis can occur during any stage of infection and involve virtually any part of the eye. In immunocompetent individuals, the most common etiologies include syphilitic uveitis. Although the clinical presentation of ocular syphilis in HIV-infected patients is also widespread, posterior segment involvement has been more commonly described particularly in patients with AIDS. The diagnosis of syphilitic retinitis is challenging since its clinical presentation mimics retinitis caused by other viral etiologies. In addition, HIV-infected individuals with syphilis are more likely to develop aberrant serologic responses. Recognition of syphilitic retinitis and prompt initiation of penicillin therapy is of critical importance since syphilitic retinitis generally responds well to treatment and loss of vision is reversible. In this report, we describe a 39-year-old female with advanced stages of AIDS who developed necrotizing retinitis due to syphilis. Prompt initiation of intravenous penicillin led to excellent visual outcome for this patient despite significantly decreased visual acuity on presentation. PMID:27635383

  9. Novel Phaeoacremonium species associated with necrotic wood of Prunus trees.

    PubMed

    Damm, U; Mostert, L; Crous, P W; Fourie, P H

    2008-06-01

    The genus Phaeoacremonium is associated with opportunistic human infections, as well as stunted growth and die-back of various woody hosts, especially grapevines. In this study, Phaeoacremonium species were isolated from necrotic woody tissue of Prunus spp. (plum, peach, nectarine and apricot) from different stone fruit growing areas in South Africa. Morphological and cultural characteristics as well as DNA sequence data (5.8S rDNA, ITS1, ITS2, beta-tubulin, actin and 18S rDNA) were used to identify known, and describe novel species. From the total number of wood samples collected (257), 42 Phaeoacremonium isolates were obtained, from which 14 species were identified. Phaeoacremonium scolyti was most frequently isolated, and present on all Prunus species sampled, followed by Togninia minima (anamorph: Pm. aleophilum) and Pm. australiense. Almost all taxa isolated represent new records on Prunus. Furthermore, Pm. australiense,Pm. iranianum, T. fraxinopennsylvanica and Pm. griseorubrum represent new records for South Africa, while Pm. griseorubrum, hitherto only known from humans, is newly reported from a plant host. Five species are newly described, two of which produce a Togninia sexual state. Togninia africana, T. griseo-olivacea and Pm. pallidum are newly described from Prunus armeniaca, while Pm. prunicolum and Pm. fuscum are described from Prunus salicina.

  10. Necrotizing Autoimmune Myopathy: A Unique Subset of Idiopathic Inflammatory Myopathy.

    PubMed

    Carroll, Matthew B; Newkirk, Michelle R; Sumner, Nathan S

    2016-10-01

    Necrotizing autoimmune myopathy (NAM) is a recently recognized entity within the spectrum of idiopathic inflammatory myopathies. Diagnosis critically rests on histopathologic demonstration of macrophage predominant myocyte destruction, with few to no lymphocytes. We report our experience with identifying and treating this subset of inflammatory myositis, highlighting the importance of muscle biopsy in diagnosis, association with statin use and malignancy, and challenges of therapy.We present 3 cases that presented to 2 hospitals within our academic system in calendar year 2014 with acute/subacute onset of profound proximal muscle weakness and markedly elevated creatine kinase levels. All patients had been exposed to statins for varying periods. While each electromyogram (EMG) study showed changes with a diffuse inflammatory myopathy, it was not until muscle biopsy was performed when histopathologic features consistent with NAM solidified the diagnosis in all 3 cases. While high-dose glucocorticoids helped provide some degree of improvement in symptoms, none of our cases returned to their preillness baseline independent functioning. Additional immunosuppressive therapy was considered in each case but limited because of comorbidities.These cases demonstrate the importance of pursuing muscle biopsy in all patients with proximal muscle weakness and markedly elevated creatine kinase levels. While symptoms appear consistent with polymyositis, only through muscle biopsy can the diagnosis of NAM be made. Statins have been implicated in NAM, acting through an antibody-dependent mechanism. Combination immunosuppressive therapy has been advocated, but our patient's comorbidities precluded safe use of medications beyond glucocorticoids. PMID:27660937

  11. Probiotics, Prebiotics, and Synbiotics for the Prevention of Necrotizing Enterocolitis.

    PubMed

    Johnson-Henry, Kathene C; Abrahamsson, Thomas R; Wu, Richard You; Sherman, Philip M

    2016-09-01

    Necrotizing enterocolitis (NEC) is a devastating intestinal disease in preterm infants characterized by barrier disruption, intestinal microbial dysbiosis, and persistent inflammation of the colon, which results in high mortality rates. Current strategies used to manage this disease are not sufficient, although the use of human breast milk reduces the risk of NEC. Mother's milk is regarded as a fundamental nutritional source for neonates, but pasteurization of donor breast milk affects the composition of bioactive compounds. Current research is evaluating the benefits and potential pitfalls of adding probiotics and prebiotics to pasteurized milk so as to improve the functionality of the milk and thereby reduce the burden of illness caused by NEC. Probiotics (live micro-organisms that confer health to the host) and prebiotics (nondigestible oligosaccharides that stimulate the growth of healthy bacteria) are functional foods known to mediate immune responses and modulate microbial populations in the gut. Clinical research shows strain- and compound-specific responses when probi