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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. Cadmium induces acidosis in maize root cells.

    PubMed

    Nocito, Fabio Francesco; Espen, Luca; Crema, Barbara; Cocucci, Maurizio; Sacchi, Gian Attilio

    2008-01-01

    * Cadmium (Cd) stress increases cell metabolic demand for sulfur, reducing equivalents, and carbon skeletons, to sustain phytochelatin biosynthesis for Cd detoxification. In this condition the induction of potentially acidifying anaplerotic metabolism in root tissues may be expected. For these reasons the effects of Cd accumulation on anaplerotic metabolism, glycolysis, and cell pH control mechanisms were investigated in maize (Zea mays) roots. * The study compared root apical segments, excised from plants grown for 24 h in a nutrient solution supplemented, or not, with 10 microM CdCl(2), using physiological, biochemical and (31)P-nuclear magnetic resonance (NMR) approaches. * Cadmium exposure resulted in a significant decrease in both cytosolic and vacuolar pH of root cells and in a concomitant increase in the carbon fluxes through anaplerotic metabolism leading to malate biosynthesis, as suggested by changes in dark CO2 fixation, metabolite levels and enzyme activities along glycolysis, and mitochondrial alternative respiration capacity. This scenario was accompanied by a decrease in the net H(+) efflux from the roots, probably related to changes in plasma membrane permeability. * It is concluded that anaplerotic metabolism triggered by Cd detoxification processes might lead to an imbalance in H(+) production and consumption, and then to cell acidosis. PMID:18537888

  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-induced cell killing in Sacharomyces cerevisiae involves increases in intracellular NO levels.

    PubMed

    Wu, Lihua; Chen, Yanfei; Gao, Huixian; Yin, Jingjing; Huang, Liqun

    2016-03-01

    Cadmium is a widespread environmental pollutant and poses some potential risks to human health. However, the signaling events controlling cadmium toxicity are not fully understood. In this study, we examined the effect of cadmium chloride on cell viability and the intracellular nitric oxide (NO) level in yeast cells. The results showed that exposure of yeast cells to cadmium (0-100 μM) could induce cell killing with significantly increased intracellular NO levels. Morphological analysis of the nuclei with 4('),6-diamidino-2-phenylindole staining and DNA strand breaks analysis showed that cadmium at 50 μM can induce cell apoptosis in yeast cells. Treatment of yeast cells with cadmium (50 μM) and the nitric oxide scavenger c-PTIO [2-(4-carboxyphenyl)-4,4,5,5-teramethylimidazoline-1-oxyl-3-oxide; 0.2 mM] showed that c-PTIO attenuated the cadmium-induced cell killing. Our findings indicated that cadmium-induced yeast cell killing is mediated by a directly increased intracellular NO level. PMID:26872495

  5. Cadmium Induces p53-Dependent Apoptosis in Human Prostate Epithelial Cells

    PubMed Central

    Aimola, Pierpaolo; Carmignani, Marco; Volpe, Anna Rita; Di Benedetto, Altomare; Claudio, Luigi; Waalkes, Michael P.; van Bokhoven, Adrie; Tokar, Erik J.; Claudio, Pier Paolo

    2012-01-01

    Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl2 and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl2 concentrations induced dose- and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis. PMID:22448262

  6. 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.

  7. Higher sensitivity to cadmium induced cell death of basal forebrain cholinergic neurons: a cholinesterase dependent mechanism.

    PubMed

    Del Pino, Javier; Zeballos, Garbriela; Anadon, María José; Capo, Miguel Andrés; Díaz, María Jesús; García, Jimena; Frejo, María Teresa

    2014-11-01

    Cadmium is an environmental pollutant, which is a cause of concern because it can be greatly concentrated in the organism causing severe damage to a variety of organs including the nervous system which is one of the most affected. Cadmium has been reported to produce learning and memory dysfunctions and Alzheimer like symptoms, though the mechanism is unknown. On the other hand, cholinergic system in central nervous system (CNS) is implicated on learning and memory regulation, and it has been reported that cadmium can affect cholinergic transmission and it can also induce selective toxicity on cholinergic system at peripheral level, producing cholinergic neurons loss, which may explain cadmium effects on learning and memory processes if produced on central level. The present study is aimed at researching the selective neurotoxicity induced by cadmium on cholinergic system in CNS. For this purpose we evaluated, in basal forebrain region, the cadmium toxic effects on neuronal viability and the cholinergic mechanisms related to it on NS56 cholinergic mourine septal cell line. This study proves that cadmium induces a more pronounced, but not selective, cell death on acetylcholinesterase (AChE) on cholinergic neurons. Moreover, MTT and LDH assays showed a dose dependent decrease of cell viability in NS56 cells. The ACh treatment of SN56 cells did not revert cell viability reduction induced by cadmium, but siRNA transfection against AChE partially reduced it. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on the function and viability of neurons, and the possible relevance of cadmium in the pathogenesis of neurodegenerative diseases. PMID:25201352

  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. Protective Effect of L-Theanine on Cadmium-Induced Apoptosis in PC12 Cells by Inhibiting the Mitochondria-Mediated Pathway.

    PubMed

    Ben, Peiling; Zhang, Zhengping; Xuan, Chunxia; Sun, Shasha; Shen, Lei; Gao, Yanhong; Cao, Xiang; Zhou, Yi; Lan, Lei; Yin, Zhimin; Luo, Lan

    2015-08-01

    L-Theanine is an amino acid derivative from green tea. The present work was aimed at the effect of L-theanine on neuron-like rat pheochromocytoma (PC12) cells stimulated with cadmium chloride. Treatment with L-theanine before cadmium exposure increased cell viability; the experiments of Annexin V/PI staining indicated that L-theanine inhibited cadmium-induced cell apoptosis. Meanwhile, L-theanine decreased ROS production and protected from cadmium-induced disruption of mitochondrial transmembrane potential. Compared with cadmium-treated cells, L-theanine could also decrease the ratio of Bax/Bcl-2, as well as the level of cleaved caspase-9, caspase-3 and poly(ADP-ribose) polymerase. Furthermore, L-theanine depresses cadmium-induced up regulation of phosphorylations of PI3K/Akt, MAPK ERK1/2, and JNK signaling. These data suggest that L-theanine pretreatment reduces severity of cadmium toxicity probably via antioxidant action. Therefore, it may be concluded that L-theanine could be exploited for prevention of cadmium-induced diseases. PMID:26164708

  11. 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

  12. 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

  13. 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

  14. How are necrotic cells recognized by their predators?

    PubMed Central

    Li, Zao; Zhou, Zheng

    2016-01-01

    Abstract 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 Ca2+, 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. 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.

  16. Cadmium Induces the Expression of Grp78, an Endoplasmic Reticulum Molecular Chaperone, in LLC-PK1 Renal Epithelial Cells

    PubMed Central

    Liu, Fang; Inageda, Kiyoshi; Nishitai, Gen; Matsuoka, Masato

    2006-01-01

    To reveal the effects of cadmium exposure on the endoplasmic reticulum (ER) stress response, we examined the expression and function of 78-kDa glucose-regulated protein (Grp78), an ER-resident molecular chaperone, in LLC-PK1 cells. In cells treated with 10 μM cadmium chloride, Grp78 protein levels increased after 6 hr and remained elevated at 24 hr. When cells were incubated with 1–20 μM CdCl2 for 6 hr, Grp78 increased in a dose-dependent manner. In addition, Grp78 mRNA levels were elevated in response to CdCl2 exposure. After exposure to 10 μM CdCl2, the levels of activating transcription factor 4 (ATF4) were increased at 2 hr, with a further enhancement after that; this accumulation followed the transient but marked phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) on serine 51. Although ATF4 mRNA levels increased mildly by CdCl2 exposure, treatment with actinomycin D did not suppress CdCl2-induced accumulation of ATF4 protein, suggesting the involvement of posttranscriptional and, in part, transcriptional mechanisms. Compared with other heavy-metal compounds such as manganese chloride, zinc chloride, mercuric chloride, and lead chloride, CdCl2 could increase the levels of Grp78, ATF4, and the phosphorylated form of eIF2α more markedly without definite cellular damage. The silencing of Grp78 expression using short-interference RNA enhanced CdCl2-induced cellular damage. These results show that cadmium induces the expression of Grp78 probably via phosphorylation of eIF2α and resultant translation of ATF4, and this ER stress response plays a role in protection against cadmium cytotoxicity in this renal epithelial cell. PMID:16759985

  17. Cadmium induces the expression of Grp78, an endoplasmic reticulum molecular chaperone, in LLC-PK1 renal epithelial cells.

    PubMed

    Liu, Fang; Inageda, Kiyoshi; Nishitai, Gen; Matsuoka, Masato

    2006-06-01

    To reveal the effects of cadmium exposure on the endoplasmic reticulum (ER) stress response, we examined the expression and function of 78-kDa glucose-regulated protein (Grp78) , an ER-resident molecular chaperone, in LLC-PK1 cells. In cells treated with 10 microM cadmium chloride, Grp78 protein levels increased after 6 hr and remained elevated at 24 hr. When cells were incubated with 1-20 microM CdCl2 for 6 hr, Grp78 increased in a dose-dependent manner. In addition, Grp78 mRNA levels were elevated in response to CdCl2 exposure. After exposure to 10 microM CdCl2, the levels of activating transcription factor 4 (ATF4) were increased at 2 hr, with a further enhancement after that ; this accumulation followed the transient but marked phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2(alpha)) on serine 51. Although ATF4 mRNA levels increased mildly by CdCl2 exposure, treatment with actinomycin D did not suppress CdCl2-induced accumulation of ATF4 protein, suggesting the involvement of posttranscriptional and, in part, transcriptional mechanisms. Compared with other heavy-metal compounds such as manganese chloride, zinc chloride, mercuric chloride, and lead chloride, CdCl2 could increase the levels of Grp78, ATF4, and the phosphorylated form of eIF2(alpha) more markedly without definite cellular damage. The silencing of Grp78 expression using short-interference RNA enhanced CdCl2-induced cellular damage. These results show that cadmium induces the expression of Grp78 probably via phosphorylation of eIF2(alpha) and resultant translation of ATF4, and this ER stress response plays a role in protection against cadmium cytotoxicity in this renal epithelial cell. PMID:16759985

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells).

    PubMed Central

    Yang, C F; Shen, H M; Shen, Y; Zhuang, Z X; Ong, C N

    1997-01-01

    Epidemiological evidence suggests that cadmium (Cd) exposure causes pulmonary damage such as emphysema and lung cancer. However, relatively little is known about the mechanisms involved in Cd pulmonary toxicity. In the present study, the effects of Cd exposure on human fetal lung fibroblasts (MRC-5 cells) were evaluated by determination of lipid peroxidation, intra-cellular production of reactive oxygen species (ROS), and changes of mitochondrial membrane potential. A time- and dose-dependent increase of both lactate dehydrogenase leakage and malondialdehyde formation was observed in Cd-treated cells. A close correlation between these two events suggests that lipid peroxidation may be one of the main pathways causing its cytotoxicity. It was also noted that Cd-induced cell injury and lipid peroxidation were inhibited by catalase and superoxide dismutase, two antioxidant enzymes. By using the fluorescent probe 2',7'-dichlorofluorescin diacetate, a significant increase of ROS production in Cd-treated MRC-5 cells was detected. The inhibition of dichlorofluorescein fluorescence by catalase, not superoxide dismutase, suggests that hydrogen peroxide is the main ROS involved. Moreover, the significant dose-dependent changes of mitochondrial membrane potential in Cd-treated MRC-5 cells, demonstrated by increased fluorescence of rhodamine 123 examined using a laser-scanning confocal microscope, also indicate the involvement of mitochondrial damage in Cd cytotoxicity. These findings provide in vitro evidence that Cd causes oxidative cellular damage in human fetal lung fibroblasts, which may be closely associated with the pulmonary toxicity of Cd. Images Figure 1. A Figure 1. B Figure 2. A Figure 2. B Figure 3. A Figure 3. B Figure 4. A Figure 4. B Figure 5. Figure 6. Figure 7. A Figure 7. B PMID:9294717

  4. 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

  5. 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. PMID:24710572

  6. 2D-DIGE and MALDI TOF/TOF MS analysis reveal that small GTPase signaling pathways may play an important role in cadmium-induced colon cell malignant transformation.

    PubMed

    Lu, Jian; Zhou, Zhongping; Zheng, Jianzhou; Zhang, Zhuyi; Lu, Rongzhu; Liu, Hanqing; Shi, Haifeng; Tu, Zhigang

    2015-10-01

    Cadmium is a toxic heavy metal present in the environment and in industrial materials. Cadmium has demonstrated carcinogenic activity that induces cell transformation, but how this occurs is unclear. We used 2D-DIGE and MALDI TOF/TOF MS combined with bioinformatics and immunoblotting to investigate the molecular mechanism of cadmium transformation. We found that small GTPases were critical for transformation. Additionally, proteins involved in mitochondrial transcription, DNA repair, and translation also had altered expression patterns in cadmium treated cells. Collectively, our results suggest that activation of small GTPases contributes to cadmium-induced transformation of colon cells. PMID:26220685

  7. Nitric Oxide Is Involved in Cadmium-Induced Programmed Cell Death in Arabidopsis Suspension Cultures1[C][W

    PubMed Central

    De Michele, Roberto; Vurro, Emanuela; Rigo, Chiara; Costa, Alex; Elviri, Lisa; Di Valentin, Marilena; Careri, Maria; Zottini, Michela; Sanità di Toppi, Luigi; Lo Schiavo, Fiorella

    2009-01-01

    Exposure to cadmium (Cd2+) can result in cell death, but the molecular mechanisms of Cd2+ cytotoxicity in plants are not fully understood. Here, we show that Arabidopsis (Arabidopsis thaliana) cell suspension cultures underwent a process of programmed cell death when exposed to 100 and 150 μm CdCl2 and that this process resembled an accelerated senescence, as suggested by the expression of the marker senescence-associated gene12 (SAG12). CdCl2 treatment was accompanied by a rapid increase in nitric oxide (NO) and phytochelatin synthesis, which continued to be high as long as cells remained viable. Hydrogen peroxide production was a later event and preceded the rise of cell death by about 24 h. Inhibition of NO synthesis by NG-monomethyl-arginine monoacetate resulted in partial prevention of hydrogen peroxide increase, SAG12 expression, and mortality, indicating that NO is actually required for Cd2+-induced cell death. NO also modulated the extent of phytochelatin content, and possibly their function, by S-nitrosylation. These results shed light on the signaling events controlling Cd2+ cytotoxicity in plants. PMID:19261736

  8. 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.

  9. Gap junction blockage promotes cadmium-induced apoptosis in BRL 3A derived from Buffalo rat liver cells

    PubMed Central

    Hu, Di; Zou, Hui; Han, Tao; Xie, Junze; Dai, Nannan; Zhuo, Liling; Gu, Jianhong; Bian, Jianchun; Yuan, Yan; Liu, Xuezhong

    2016-01-01

    Gap junctions mediate direct communication between cells; however, toxicological cascade triggered by nonessential metals can abrogate cellular signaling mediated by gap junctions. Although cadmium (Cd) is known to induce apoptosis in organs and tissues, the mechanisms that underlie gap junction activity in Cd-induced apoptosis in BRL 3A rat liver cells has yet to be established. In this study, we showed that Cd treatment decreased the cell index (a measure of cellular electrical impedance) in BRL 3A cells. Mechanistically, we found that Cd exposure decreased expression of connexin 43 (Cx43), increased expression of p-Cx43 and elevated intracellular free Ca2+ concentration, corresponding to a decrease in gap junctional intercellular communication. Gap junction blockage pretreatment with 18β-glycyrrhizic acid (GA) promoted Cd-induced apoptosis, involving changes in expression of Bax, Bcl-2, caspase-3 and the mitochondrial transmembrane electrical potential (Δψm). Additionally, GA was found to enhance ERK and p38 activation during Cd-induced activation of mitogen-activated protein kinases, but had no significant effect on JNK activation. Our results indicated the apoptosis-related proteins and the ERK and p38 signaling pathways may participate in gap junction blockage promoting Cd-induced apoptosis in BRL 3A cells. PMID:27051341

  10. 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

  11. 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

  12. 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

  13. 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.

  14. 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

  15. Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

    PubMed

    El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

    2016-03-01

    The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats. PMID:26796199

  16. Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms

    PubMed Central

    Li, Zao; Venegas, Victor; Nagaoka, Yuji; Morino, Eri; Raghavan, Prashant; Audhya, Anjon; Nakanishi, Yoshinobu; Zhou, Zheng

    2015-01-01

    Necrosis, a kind of cell death closely associated with pathogenesis and genetic programs, is distinct from apoptosis in both morphology and mechanism. Like apoptotic cells, necrotic cells are swiftly removed from animal bodies to prevent harmful inflammatory and autoimmune responses. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in the excitotoxic necrosis of six touch neurons and their subsequent engulfment and degradation inside engulfing cells. How necrotic cells are recognized by engulfing cells is unclear. Phosphatidylserine (PS) is an important apoptotic-cell surface signal that attracts engulfing cells. Here we observed PS exposure on the surface of necrotic touch neurons. In addition, the phagocytic receptor CED-1 clusters around necrotic cells and promotes their engulfment. The extracellular domain of CED-1 associates with PS in vitro. We further identified a necrotic cell-specific function of CED-7, a member of the ATP-binding cassette (ABC) transporter family, in promoting PS exposure. In addition to CED-7, anoctamin homolog-1 (ANOH-1), the C. elegans homolog of the mammalian Ca2+-dependent phospholipid scramblase TMEM16F, plays an independent role in promoting PS exposure on necrotic cells. The combined activities from CED-7 and ANOH-1 ensure efficient exposure of PS on necrotic cells to attract their phagocytes. In addition, CED-8, the C. elegans homolog of mammalian Xk-related protein 8 also makes a contribution to necrotic cell-removal at the first larval stage. Our work indicates that cells killed by different mechanisms (necrosis or apoptosis) expose a common “eat me” signal to attract their phagocytic receptor(s); furthermore, unlike what was previously believed, necrotic cells actively present PS on their outer surfaces through at least two distinct molecular mechanisms rather than leaking out PS passively. PMID:26061275

  17. Interaction of Late Apoptotic and Necrotic Cells with Vitronectin

    PubMed Central

    Stepanek, Ondrej; Brdicka, Tomas; Angelisova, Pavla; Horvath, Ondrej; Spicka, Jiri; Stockbauer, Petr; Man, Petr; Horejsi, Vaclav

    2011-01-01

    Background Vitronectin is an abundant plasma glycoprotein identified also as a part of extracellular matrix. Vitronectin is substantially enriched at sites of injured, fibrosing, inflamed, and tumor tissues where it is believed to be involved in wound healing and tissue remodeling. Little is known about the mechanism of vitronectin localization into the damaged tissues. Methodology/Principal Findings 2E12 antibody has been described to bind a subset of late apoptotic cells. Using immunoisolation followed by mass spectrometry, we identified the antigen recognized by 2E12 antibody as vitronectin. Based on flow cytometry, we described that vitronectin binds to the late apoptotic and necrotic cells in cell cultures in vitro as well as in murine thymus and spleen in vivo. Confocal microscopy revealed that vitronectin binds to an intracellular cytoplasmic structure after the membrane rupture. Conclusions/Significance We propose that vitronectin could serve as a marker of membrane disruption in necrosis and apoptosis for flow cytometry analysis. Moreover, we suggest that vitronectin binding to dead cells may represent one of the mechanisms of vitronectin incorporation into the injured tissues. PMID:21573223

  18. 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

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

    PubMed

    Yang, Hong; Shu, Yan

    2015-01-01

    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. PMID:25584611

  20. 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

  1. 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

  2. Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels.

    PubMed

    Del Pino, Javier; Zeballos, Gabriela; Anadón, María José; Moyano, Paula; Díaz, María Jesús; García, José Manuel; Frejo, María Teresa

    2016-05-01

    Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer's disease (AD). However, the mechanism through which cadmium induces this effect remains unknown. In this regard, we described in a previous work that cadmium blocks cholinergic transmission and induces a more pronounced cell death on cholinergic neurons from basal forebrain which is partially mediated by AChE overexpression. Degeneration of basal forebrain cholinergic neurons, as happens in AD, results in memory deficits attributable to the loss of cholinergic modulation of hippocampal synaptic circuits. Moreover, cadmium has been described to activate GSK-3β, induce Aβ protein production and tau filament formation, which have been related to a selective loss of basal forebrain cholinergic neurons and development of AD. The present study is aimed at researching the mechanisms of cell death induced by cadmium on basal forebrain cholinergic neurons. For this purpose, we evaluated, in SN56 cholinergic mourine septal cell line from basal forebrain region, the cadmium toxic effects on neuronal viability through muscarinic M1 receptor, AChE splice variants, GSK-3β enzyme, Aβ and tau proteins. This study proves that cadmium induces cell death on cholinergic neurons through blockade of M1 receptor, overexpression of AChE-S and GSK-3β, down-regulation of AChE-R and increase in Aβ and total and phosphorylated tau protein levels. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on cholinergic neurons and suggest that cadmium could mediate these mechanisms by M1R blockade through AChE splices altered expression. PMID:26026611

  3. The Necrotic Signal Induced by Mycophenolic Acid Overcomes Apoptosis-Resistance in Tumor Cells

    PubMed Central

    Dilhuydy, Marie-Sarah; Pinson, Benoît; Mahfouf, Walid; Pasquet, Jean-Max; Mahon, François-Xavier; Pourquier, Philippe; Moreau, Jean-François; Legembre, Patrick

    2009-01-01

    Background The amount of inosine monophosphate dehydrogenase (IMPDH), a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP), is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA) are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. Methodology/Principal Findings Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA–mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL–overexpressing cells). All tested cells remained sensitive to MPA–mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. Conclusions/Significance These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells. PMID:19430526

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

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

    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.

  5. 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

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

    PubMed

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

    2013-06-01

    Screening of a small in-house library of 1863 compounds identified 29 compounds that protected Jurkat cells from hydrogen peroxide-induced cytotoxicity. From the cytoprotective compounds eleven proved to possess antioxidant activity (ABTS radical scavenger effect) and two were found to inhibit poly(ADP-ribosyl)ation (PARylation), a cytotoxic pathway operating in severely injured cells. Four cytoprotective dibenzoylmethane (DBM) derivatives were investigated in more detail as they did not scavenge hydrogen peroxide nor did they inhibit PARylation. These compounds protected cells from necrotic cell death while caspase activation, a parameter of apoptotic cell death was not affected. Hydrogen peroxide activated extracellular signal regulated kinase (ERK1/2) and p38 MAP kinases but not c-Jun N-terminal kinase (JNK). The cytoprotective DBMs suppressed the activation of Erk1/2 but not that of p38. Cytoprotection was confirmed in another cell type (A549 lung epithelial cells), indicating that the cytoprotective effect is not cell type specific. In conclusion we identified DBM analogs as a novel class of cytoprotective compounds inhibiting ERK1/2 kinase and protecting from necrotic cell death by a mechanism independent of poly(ADP-ribose) polymerase inhibition. PMID:23523665

  7. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin

    PubMed Central

    El Mezayen, Rabab; El Gazzar, Mohamed; Seeds, Michael C.; McCall, Charles E.; Dreskin, Stephen C.; Nicolls, Mark R.

    2011-01-01

    Stressed cells undergoing necrosis release molecules that acts as endogenous danger signals to alert and activate innate immune cells. Both HMGB1 and HSP70 are induced in activated monocytes/macrophages and also are released from stressed or injured cells. We investigated whether HMGB1 and HSP70 released from necrotic monocytes/macrophages, can act as danger signals to mediate proinflammatory cytokine responses to bacterial endotoxin or lipopolysaccharide (LPS). We show that cell lysate, obtained from necrotic cells directly stimulates the proinflammatory cytokine and chemokine responses in human monocyte/macrophage cell line, THP-1, as revealed by the induction of TNF-α, IL-6 and IL-8 mRNA expression and protein production. In the presence of LPS, necrotic cell lysate induced a more robust increase in all three proteins. We found that HMGB1 and HSP70 were indeed present in the necrotic cell lysate and were responsible for the significant induction of the proinflammatory cytokine expression, as neutralization with antibodies against both proteins blocked the increase in the cytokine production seen after incubating LPS-stimulated cells with the necrotic cell lysate. We also found that the newly identified triggering receptor expressed on myeloid cells-1 (TREM-1) was involved in mediating the HMGB1- and HSP70-induced cytokine production. Blocking TREM-1 on THP-1 cells with a recombinant chimera prevented the increase in cytokine production, while simultaneous blocking of TLR4 and TREM-1 completely abolished the proinflammatory response, suggesting that TREM-1 synergizes with TLR4 to mediate the effects of such signals from necrotic cells. In addition, blocking HMGB1 or HSP70 simultaneously with TREM-1 did not decrease the cytokine level further, confirming the involvement of TREM-1 in mediating the effect of HMGB1 and HSP70. Although the interaction of HMGB1 and HSP70 with TREM-1 induced IκBα and p38 expression, both of which are required for the inflammatory

  8. 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

  9. Cancer resistance in the blind mole rat is mediated by concerted necrotic cell death mechanism.

    PubMed

    Gorbunova, Vera; Hine, Christopher; Tian, Xiao; Ablaeva, Julia; Gudkov, Andrei V; Nevo, Eviatar; Seluanov, Andrei

    2012-11-20

    Blind mole rats Spalax (BMR) are small subterranean rodents common in the Middle East. BMR is distinguished by its adaptations to life underground, remarkable longevity (with a maximum documented lifespan of 21 y), and resistance to cancer. Spontaneous tumors have never been observed in spalacids. To understand the mechanisms responsible for this resistance, we examined the growth of BMR fibroblasts in vitro of the species Spalax judaei and Spalax golani. BMR cells proliferated actively for 7-20 population doublings, after which the cells began secreting IFN-β, and the cultures underwent massive necrotic cell death within 3 d. The necrotic cell death phenomenon was independent of culture conditions or telomere shortening. Interestingly, this cell behavior was distinct from that observed in another long-lived and cancer-resistant African mole rat, Heterocephalus glaber, the naked mole rat in which cells display hypersensitivity to contact inhibition. Sequestration of p53 and Rb proteins using SV40 large T antigen completely rescued necrotic cell death. Our results suggest that cancer resistance of BMR is conferred by massive necrotic response to overproliferation mediated by p53 and Rb pathways, and triggered by the release of IFN-β. Thus, we have identified a unique mechanism that contributes to cancer resistance of this subterranean mammal extremely adapted to life underground. PMID:23129611

  10. Vibrio cholerae GbpA elicits necrotic cell death in intestinal cells.

    PubMed

    Mandal, Sudipto; Chatterjee, Nabendu Sekhar

    2016-08-01

    Vibrio choleraeN-acetylglucosamine-binding protein GbpA is a secretory protein that facilitates the initial adherence of bacteria in the human intestine. Until now, considerable progress in the characterization of GbpA has been done, yet little is known about its role in host response. Our present studies demonstrated that GbpA at the amount secreted in the intestine resulted in decreased cell viability, altered cell morphology, disruption of cell membrane integrity and damage of cellular DNA indicating necrotic cell death. We observed that GbpA exposure leads to mitochondrial dysfunction, characterized by accumulation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential and depletion of ATP pool in host cells. Additionally, the intra-cellular ROS, accumulated in response to GbpA, were found to induce the migration of NF-κB from cytoplasm into nucleus in host cells. Taken together, these results prompted us to conclude that GbpA orchestrates a necrotic response in host cells which may have implications in immune response. PMID:27324251

  11. 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

  12. 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

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

    PubMed

    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

  14. Biomarkers distinguish apoptotic and necrotic cell death during hepatic ischemia/reperfusion injury in mice.

    PubMed

    Yang, Min; Antoine, Daniel J; Weemhoff, James L; Jenkins, Rosalind E; Farhood, Anwar; Park, B Kevin; Jaeschke, Hartmut

    2014-11-01

    Hepatic ischemia/reperfusion (IRP) injury is a significant clinical problem during tumor-resection surgery (Pringle maneuver) and liver transplantation. However, the relative contribution of necrotic and apoptotic cell death to the overall liver injury is still controversial. To address this important issue with a standard murine model of hepatic IRP injury, plasma biomarkers of necrotic cell death such as micro-RNA 122, full-length cytokeratin 18 (FK18), and high-mobility group box 1 (HMGB1) protein and plasma biomarkers of apoptosis such as plasma caspase-3 activity and caspase-cleaved fragment of cytokeratin 18 (CK18) coupled with markers of inflammation (hyperacetylated HMGB1) were compared by histological features in hematoxylin and eosin-stained and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-stained liver sections. After 45 minutes of hepatic ischemia and 1 to 24 hours of reperfusion, all necrosis markers increased dramatically in plasma by 40- to >10,000-fold over the baseline with a time course similar to that of alanine aminotransferase. These data correlated well with histological characteristics of necrosis. Within the area of necrosis, most cells were TUNEL positive; initially (≤3 hours of reperfusion), the staining was restricted to nuclei, but it later spread to the cytosol, and this is characteristic of karyorrhexis during necrotic cell death. In contrast, the lack of morphological evidence of apoptotic cell death and relevant caspase-3 activity in the postischemic liver correlated well with the absence of caspase-3 activity and CK18 (except for a minor increase at 3 hours of reperfusion) in plasma. A quantitative comparison of FK18 (necrosis) and CK18 (apoptosis) release indicated dominant cell death by necrosis during IRP and only a temporary and very minor degree of apoptosis. These data suggest that the focus of future research should be the elucidation of necrotic signaling mechanisms to

  15. BIOMARKERS DISTINGUISH APOPTOTIC AND NECROTIC CELL DEATH DURING HEPATIC ISCHEMIA-REPERFUSION INJURY IN MICE

    PubMed Central

    Yang, Min; Antoine, Daniel J.; Weemhoff, James L.; Jenkins, Rosalind E.; Farhood, Anwar; Park, B. Kevin; Jaeschke, Hartmut

    2014-01-01

    Hepatic ischemia-reperfusion (IRP) injury is a significant clinical problem during tumor resection surgery (Pringle maneuver), and liver transplantation. However, the relative contribution of necrotic and apoptotic cell death to the overall liver injury is still controversial. In order to address this important issue in a standard murine model of hepatic IRP injury, plasma biomarkers of necrotic cell death such as micro-RNA-122, full-length cytokeratin-18 (FK18) and high mobility group box-1 (HMGB1) protein, and apoptosis including plasma caspase-3 activity and caspase-cleaved cytokeratin-18 (CK18), coupled with markers of inflammation (hyper-acetylated HMGB1) were compared with histological features in H&E- and TUNEL-stained liver sections. After 45 min of hepatic ischemia and 1–24h of reperfusion, all necrosis markers increased dramatically in plasma by 40-to->10,000-fold over baseline with a time course similar to ALT. These data correlated well with histological characteristics of necrosis. Within the area of necrosis, most cells were TUNEL-positive; initially (≤ 3h of RP) the staining was restricted to nuclei but later spread to the cytosol characteristic for karyorrhexis during necrotic cell death. In contrast, the lack of morphological evidence of apoptotic cell death and relevant caspase-3 activity in the postischemic liver correlated well with the absence of caspase-3 activity and CK18 (except a minor increase at 3h RP) in plasma. The quantitative comparison of FK18 (necrosis) and CK18 (apoptosis) release indicated the dominant cell death by necrosis during IRP and only a temporary and very minor degree of apoptosis. These data suggest that the focus of future research should be on the elucidation of necrotic signaling mechanisms to identify relevant targets, which may be used to attenuate hepatic IRP injury. PMID:25046819

  16. Necrotic Effect versus Apoptotic Nature of Camptothecin in Human Cervical Cancer Cells

    PubMed Central

    Zare-Mirakabadi, Abbas; Sarzaeem, Ali; Moradhaseli, Saeed; Sayad, Aida; Negahdary, Masoud

    2012-01-01

    Background Functional defects in mitochondria are involved in the induction of cell death in cancer cells. The process of programmed cell death may occur through the mechanisms of apoptosis. Several potential lead molecules such as Camptothecin (CPT) and its analogues have been isolated from plants with anticancer effect. The aim of the present study was to understand the necrotic effect versus apoptotic nature of CPT in HeLa cancer cells. Methods The anti-proliferative activity of CPT was estimated through 3-(4, 5- Dimethyl Thiazol-2-yl)-2, 5-diphenyl Tetrazolium bromide (MTT) assay and DNA fragmentation analysis using gel electrophoresis. Lactate Dehydrogenase (LDH) activity and cell morphology were assessed under control and CPT exposed conditions to evaluate the necrotic effect of CPT. Results The results showed that CPT inhibited the proliferation of HeLa cells in a dose-dependent manner with an Inhibitory Concentration 50% (IC50) of 0.08±0.012 µg/ml. However the significant (p<0.05) increase happens in LDH activity at concentrations 1×10-1µg/ml and above. Morphological changes showed that CPT in low concentrations induced an apoptotic mechanism of cell death, such as cell shrinkage and characteristic rounding of dying cells, while at high concentrations showed necrosis changes. The characteristic DNA ladder formation of CPT-treated cells in agarose gel electrophoresis confirmed the results obtained by light microscopy and LDH assay. Conclusion Camptothecin as an anticancer drug may have anti-proliferative effect on HeLa cancer cells in low concentrations, through its nature of induction of apoptosis. The border line between necrotic effect and apoptotic nature of CPT in HeLa cancer cells has been found to be at concentration of 1×10-1 µg/ml. PMID:25628829

  17. Mitigative action of mono isoamyl 2, 3-dimercaptosuccinate (MiADMS) against cadmium-induced damage in cultured rat normal liver cells

    PubMed Central

    Odewumi, Caroline O.; Buggs, Rebecca; Badisa, Veera L.D.; Latinwo, Lekan M.; Badisa, Ramesh B.; Ikediobi, Christopher O.; Darling-Reed, Selina F.; Owens, Marcia A.

    2012-01-01

    Cadmium is non-essential, carcinogenic and multitarget pollutant in the environment. Monoisoamyl 2, 3-dimercaptosuccinate (MiADMS) is an ester of dimercaptosuccinicacid that acts as an antioxidant and chelator. Therefore, the mitigative action of MiADMS on viability, morphology, antioxidative enzymes and cell cycle were studied on rat liver cells treated with cadmium chloride (CdCl2). The cells were treated with 150 μM CdCl2 alone or cotreated with 300 μM MiADMS (concurrently, 2 h or 4 h post CdCl2 treatment) for 24 h. The viability of cells treated with CdCl2 alone was decreased in comparison to the control cells. Cotreatment with MiADMS resulted in an increase in cell viability in comparison to the CdCl2 alone treated cells. The CdCl2 treatment altered the morphological shape of the cells, while cotreatment with MiADMS restored the shape. Antioxidative enzymes activities were decreased in the cells treated with CdCl2 alone, while MiADMS cotreatment resulted in an increase in enzyme activities. The CdCl2 arrested the cells in S phase of the cell cycle. Cotreatment with MiADMS alleviated cell cycle arrest by shifting to G1 phase. These results clearly show the mitigative action of MiADMS on CdCl2 toxicity and may suggest that MiADMS can be used as an antidote against cadmium. PMID:21911053

  18. 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

  19. The Role of Necrotic cell death in the pathogenesis of immune mediated nephropathies

    PubMed Central

    Jog, Neelakshi R.; Caricchio, Roberto

    2014-01-01

    Necrosis, an inflammatory form of cell death, has been considered to be an accidental death and/or cell death due to injury. However, the literature in the last decade has established that necrosis is a regulated form of cell death, and that inhibition of specific molecular pathways leading to necrosis can block it and reduce inflammation. Since necrotic lesions are observed in several immune mediated human pathologies, in this review we will discuss the impact that this form of programmed cellular demise has in the pathology of immune mediated nephropathies. PMID:24845790

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Iron-induced Necrotic Brain Cell Death in Rats with Different Aerobic Capacity

    PubMed Central

    Zheng, Mingzhe; Du, Hanjian; Ni, Wei; Koch, Lauren G.; Britton, Steven L.; Keep, Richard F.; Xi, Guohua; Hua, Ya

    2015-01-01

    Brain iron overload has a key role in brain injury after intracerebral hemorrhage (ICH). Our recent study demonstrated that ICH-induced brain injury was greater in low capacity runner (LCR) than in high capacity runner (HCR) rats. The present study examines whether iron-induced brain injury differs between LCRs and HCRs. Adult male LCR and HCR rats had an intracaudate injection of iron or saline. Rats were euthanized at 2 and at 24 hours after T2 magnetic resonance imaging and the brains were used for immunostaining and Western blotting. LCRs had more hemispheric swelling, T2 lesion volumes, blood-brain barrier disruption and neuronal death at 24 hours after iron injection (p < 0.05). Many propidium iodide (PI) positive cells, indicative of necrotic cell death, were observed in the ipsilateral basal ganglia of both HCRs and LCRs at 2 hours after iron injection. PI fluorescence intensity was higher in LCRs than in HCRs. In addition, membrane attack complex (MAC) expression was increased at 2 hours after iron injection and was higher in LCRs than in HCRs. The PI positive cells colocalized with MAC positive cells in the ipsilateral basal ganglia. Iron induces more severe necrotic brain cell death, brain swelling, and blood-brain barrier disruption in LCR rats, which may be related with complement activation and MAC formation. PMID:25649272

  7. 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

  8. Antiphospholipid antibodies prolong the activation of endothelial cells induced by necrotic trophoblastic debris: implications for the pathogenesis of preeclampsia.

    PubMed

    Chen, Q; Guo, F; Hensby-Bennett, S; Stone, P; Chamley, L

    2012-10-01

    The symptoms of preeclampsia are preceded by endothelial cell activation/dysfunction which is induced by a placental trigger(s) but maternal risk factor(s) also contribute to the pathogenesis of preeclampsia. In this work we have investigated the interactions of a maternal risk factor, antiphospholipid antibodies, and a placental trigger, necrotic trophoblastic debris, on the activation of endothelial cells. Trophoblastic debris, from placental explants, was induced to become necrotic by freeze-thawing then exposed to endothelial cells for 24 h. After washing away residual trophoblastic debris antiphospholipid antibodies or a control antibody were added to the cultures then replaced with fresh medium in the presence or absence of antibodies. Endothelial cell activation was quantified by examining cell-surface ICAM-1 expression and monocyte adhesion. Endothelial cells exposed to necrotic trophoblastic debris for 24 h became activated but the activation was lost 24 h after removal of the debris. Antiphospholipid antibodies alone did not active untreated endothelial cells, but did prolong the activation of endothelial cells which had been activated by pre-treatment with necrotic trophoblastic debris. When exposed to antiphospholipid antibodies the endothelial cells remained activated despite removal of the trophoblastic debris. In contrast, a control antibody did not prolong endothelial cell activation. Our data suggest that in women with antiphospholipid antibodies, activation of endothelial cells induced by necrotic trophoblastic debris could be maintained even if the endothelial cells were only intermittently exposed to necrotic debris. This might in part explain why antiphospholipid antibodies are such a strong maternal risk factor for preeclampsia. PMID:22902008

  9. Cadmium-induced synthesis of HSP70 and a role of glutathione in Euglena gracilis.

    PubMed

    Watanabe, Masumi; Suzuki, Tetsuya

    2004-01-01

    The effect of cadmium-induced oxidative stress, with or without glutathione supplementation, was investigated in the single cell eukaryotic phytoflagellate, Euglena gracilis strains Z and its achlorophyllous mutant SMZ as experimental models. Both these strains actively synthesize thiols to prevent or resist cadmium toxicity. The content of glutathione, as a representative antioxidant, was also examined in both strains. Exposure to cadmium induced heat-shock protein 70 (HSP70) synthesis in both strains of E. gracilis. Glutathione supplementation also induced HSP70. Overall, these results indicate that glutathione was closely linked to the induction of stress-related proteins. The sensitivity to cadmium-stress was higher in strain Z than SMZ. The results suggest that chloroplasts may have a role in the regulation of HSP70 expression. The relationship between HSP70 and GSH levels is still far from understood, and further research may shed light upon their up-regulation in the presence of Cd. PMID:15720831

  10. The severity, extent and recurrence of necrotizing periodontal disease in relation to HIV status and CD4+ T cell count.

    PubMed

    Phiri, Reality; Feller, Liviu; Blignaut, Elaine

    2010-10-01

    South Africa ranks among the three countries with the highest prevalence of HIV infection in sub-Saharan Africa, with an estimated 29.5% of women attending antenatal clinics being infected. Necrotizing periodontal disease is a well recognized HIV-associated oral condition. The objective of this investigation was to determine a possible correlation between the extent, severity and treatment outcome of necrotizing periodontal disease in relation to a person's HIV status and CD4+ T cell count. Data from 105 consecutive patients presenting with necrotizing periodontal disease at an academic oral health centre in South Africa were analysed. All patients were provided with an opportunity to undergo voluntary counseling and testing for HIV infection, were treated for necrotizing periodontal disease and followed over a period of nine months. The mean age of the cohort was 28 years old (range 12 - 52). Of 98 (93.3%) patients unaware of their HIV serostatus at the initial visit, 59 (56.2%) consented to testing. In total 45 (42.9%) were HIV-seropositive with a mean CD4+ T cell count of 222.7 cells/microl and 14 (13.3%) were HIV-seronegative, with a significantly higher mean CD4+ T cell count of 830 cells/microl (Fisher's exact test, p < 0.001), while the status of 46 (43.8%) remained unknown. In 101 (96.2%) patients, > or = 5 tooth sites were affected, and in 27 (26%) > or = 4 mm of gingival tissue were affected. This study, which included HIV-seropositive, HIV-seronegative and persons of unknown HIV status, revealed no statistical evidence that HIV infection was associated with the extent, severity or relapse of necrotizing periodontal disease. No statistically significant association could be demonstrated between the extent, severity and recurrence of necrotizing periodontal disease and a CD4+ T cell count < or = 200 cells/microl among HIV-seropositive patients. PMID:21128527

  11. 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

  12. 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.

  13. Cell-to-Cell Trafficking of Macromolecules through Plasmodesmata Potentiated by the Red Clover Necrotic Mosaic Virus Movement Protein.

    PubMed

    Fujiwara, T.; Giesman-Cookmeyer, D.; Ding, B.; Lommel, S. A.; Lucas, W. J.

    1993-12-01

    Direct evidence is presented for cell-to-cell trafficking of macromolecules via plasmodesmata in higher plants. The fluorescently labeled 35-kD movement protein of red clover necrotic mosaic virus (RCNMV) trafficked rapidly from cell to cell when microinjected into cowpea leaf mesophyll cells. Furthermore, this protein potentiated rapid cell-to-cell trafficking of RCNMV RNA, but not DNA. Electron microscopic studies demonstrated that the 35-kD movement protein does not unfold the RCNMV RNA molecules. Thus, if unfolding of RNA is necessary for cell-to-cell trafficking, it may well involve participation of endogenous cellular factors. These findings support the hypothesis that trafficking of macromolecules is a normal plasmodesmal function, which has been usurped by plant viruses for their cell-to-cell spread. PMID:12271056

  14. 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

  15. Cellular mechanisms of cadmium-induced toxicity: a review.

    PubMed

    Rani, Anju; Kumar, Anuj; Lal, Ankita; Pant, Manu

    2014-08-01

    Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life (approximately 20-30 years in humans), low rate of excretion from the body and storage predominantly in soft tissues (primarily, liver and kidneys). It is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. Cadmium is absorbed in significant quantities from cigarette smoke, food, water and air contamination and is known to have numerous undesirable effects in both humans and animals. Cadmium has a diversity of toxic effects including nephrotoxicity, carcinogenicity, teratogenicity and endocrine and reproductive toxicities. At the cellular level, cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Most important seems to be cadmium interaction with DNA repair mechanism, generation of reactive oxygen species and induction of apoptosis. In this article, we have reviewed recent developments and findings on cadmium toxicology. PMID:24117228

  16. Necrotizing Fasciitis

    PubMed Central

    Sadasivan, Jagdish; Maroju, Nanda Kishore; Balasubramaniam, Anandh

    2013-01-01

    Necrotizing fasciitis (NF) is among the most challenging surgical infections faced by a surgeon. The difficulty in managing this entity is due to a combination of difficulty in diagnosis, and also of early as well as late management. For the patient, such a diagnosis means prolonged hospital stay, painful dressings, an extended recovery, and in some unfortunate cases even loss of limb or life. Necrotizing fasciitis is a fairly common condition in surgical practice in the Indian context resulting in a fairly large body of clinical experience. This article reviews literature on MEDLINE with the key words “necrotizing,” “fasciitis,” and “necrotizing infections” from 1970, as well as from articles cross referenced therein. The authors attempt to draw comparisons to their own experience in managing this condition to give an Indian perspective to the condition. PMID:24459334

  17. Commensal Microbiota are Required for Systemic Inflammation Triggered by Necrotic Dendritic Cells

    PubMed Central

    Young, Jennifer A.; He, Tina H.; Reizis, Boris; Winoto, Astar

    2013-01-01

    Summary The relationship between dendritic cells (DCs) and commensal microflora in shaping systemic immune responses is not well understood. Here we report that mice deficient for Fas-associated death domain in DCs developed systemic inflammation associated with elevated pro-inflammatory cytokines and increased myeloid and B cells. These mice exhibited reduced DCs in gut-associated lymphoid tissues due to RIP3-dependent necroptosis, while DC functions remained intact. Induction of systemic inflammation required DC necroptosis and commensal microbiota signals that activated MyD88-dependent pathways in other cell types. Systemic inflammation was abrogated with administration of broad-spectrum antibiotics or complete, but not DC-specific, deletion of MyD88. Thus, we have identified a previously unappreciated role for commensal microbiota in priming immune cells for inflammatory responses against necrotic cells. These studies demonstrate the impact intestinal microflora have on the immune system and their role in eliciting proper immune responses to harmful stimuli. PMID:23727238

  18. 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

  19. 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

  20. 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

  1. Calcium homeostasis disruption - a bridge connecting cadmium-induced apoptosis, autophagy and tumorigenesis.

    PubMed

    Zhou, Xuehai; Hao, Weiming; Shi, Haifeng; Hou, Yongzhong; Xu, Qinggang

    2015-01-01

    Calcium and cadmium are divalent metals and have similar chemical properties. Both can enter cells through, albeit different, channels, or through protein-dependent permeation. However, cadmium disturbs the calcium homeostasis by inhibiting calcium channels and/or related proteins. Cadmium can also alter membrane phospholipid concentrations, and so induce a calcium homeostasis disorder. The altered calcium homeostasis induced by cadmium results in cell apoptosis, autophagy or tumorigenesis. In this review, calcium homeostasis disruption is summarized as a bridge connecting cadmium-induced apoptosis, autophagy, and tumorigenesis. PMID:26045029

  2. Regulation of necrotic cell death: p53, PARP1 and cyclophilin D-overlapping pathways of regulated necrosis?

    PubMed

    Ying, Yuan; Padanilam, Babu J

    2016-06-01

    In contrast to apoptosis and autophagy, necrotic cell death was considered to be a random, passive cell death without definable mediators. However, this dogma has been challenged by recent developments suggesting that necrotic cell death can also be a regulated process. Regulated necrosis includes multiple cell death modalities such as necroptosis, parthanatos, ferroptosis, pyroptosis, and mitochondrial permeability transition pore (MPTP)-mediated necrosis. Several distinctive executive molecules, particularly residing on the mitochondrial inner and outer membrane, amalgamating to form the MPTP have been defined. The c-subunit of the F1F0ATP synthase on the inner membrane and Bax/Bak on the outer membrane are considered to be the long sought components that form the MPTP. Opening of the MPTP results in loss of mitochondrial inner membrane potential, disruption of ATP production, increased ROS production, organelle swelling, mitochondrial dysfunction and consequent necrosis. Cyclophilin D, along with adenine nucleotide translocator and the phosphate carrier are considered to be important regulators involved in the opening of MPTP. Increased production of ROS can further trigger other necrotic pathways mediated through molecules such as PARP1, leading to irreversible cell damage. This review examines the roles of PARP1 and cyclophilin D in necrotic cell death. The hierarchical role of p53 in regulation and integration of key components of signaling pathway to elicit MPTP-mediated necrosis and ferroptosis is explored. In the context of recent insights, the indistinct role of necroptosis signaling in tubular necrosis after ischemic kidney injury is scrutinized. We conclude by discussing the participation of p53, PARP1 and cyclophilin D and their overlapping pathways to elicit MPTP-mediated necrosis and ferroptosis in acute kidney injury. PMID:27048819

  3. NECROTIZING ENTEROCOLITIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Necrotizing enterocolitis (NEC) is the most common astrointestinal emergency in the infant. This disorder encompasses several distinct disease entities that differ from idiopathic NEC, the most common form of the disease. Although the etiology of idiopathic NEC is unknown, specific precipitating fac...

  4. Endoplasmic Reticulum Stress, Unfolded Protein Response and Altered T Cell Differentiation in Necrotizing Enterocolitis

    PubMed Central

    Lu, Peng; Struijs, Marie-Chantal; Mei, Jiaping; Witte-Bouma, Janneke; Korteland-van Male, Anita M.; de Bruijn, Adrianus C. J. M.; van Goudoever, Johannes B.; Renes, Ingrid B.

    2013-01-01

    Background Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) play important roles in chronic intestinal inflammation. Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants and is characterized by acute intestinal inflammation and necrosis. The objective of the study is to investigate the role of ER stress and the UPR in NEC patients. Methods Ileal tissues from NEC and control patients were obtained during surgical resection and/or at stoma closure. Splicing of XBP1 was detected using PCR, and gene expression was quantified using qPCR and Western blot. Results Splicing of XBP1 was only detected in a subset of acute NEC (A-NEC) patients, and not in NEC patients who had undergone reanastomosis (R-NEC). The other ER stress and the UPR pathways, PERK and ATF6, were not activated in NEC patients. A-NEC patients showing XBP1 splicing (A-NEC-XBP1s) had increased mucosal expression of GRP78, CHOP, IL6 and IL8. Similar results were obtained by inducing ER stress and the UPR in vitro. A-NEC-XBP1s patients showed altered T cell differentiation indicated by decreased mucosal expression of RORC, IL17A and FOXP3. A-NEC-XBP1s patients additionally showed more severe morphological damage and a worse surgical outcome. Compared with A-NEC patients, R-NEC patients showed lower mucosal IL6 and IL8 expression and higher mucosal FOXP3 expression. Conclusions XBP1 splicing, ER stress and the UPR in NEC are associated with increased IL6 and IL8 expression levels, altered T cell differentiation and severe epithelial injury. PMID:24194940

  5. Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells

    PubMed Central

    Hirst, A M; Simms, M S; Mann, V M; Maitland, N J; O'Connell, D; Frame, F M

    2015-01-01

    Background: In recent years, the rapidly advancing field of low-temperature atmospheric pressure plasmas has shown considerable promise for future translational biomedical applications, including cancer therapy, through the generation of reactive oxygen and nitrogen species. Method: The cytopathic effect of low-temperature plasma was first verified in two commonly used prostate cell lines: BPH-1 and PC-3 cells. The study was then extended to analyse the effects in paired normal and tumour (Gleason grade 7) prostate epithelial cells cultured directly from patient tissue. Hydrogen peroxide (H2O2) and staurosporine were used as controls throughout. Results: Low-temperature plasma (LTP) exposure resulted in high levels of DNA damage, a reduction in cell viability, and colony-forming ability. H2O2 formed in the culture medium was a likely facilitator of these effects. Necrosis and autophagy were recorded in primary cells, whereas cell lines exhibited apoptosis and necrosis. Conclusions: This study demonstrates that LTP treatment causes cytotoxic insult in primary prostate cells, leading to rapid necrotic cell death. It also highlights the need to study primary cultures in order to gain more realistic insight into patient response. PMID:25839988

  6. Cadmium induces retinoic acid signaling by regulating retinoic acid metabolic gene expression.

    PubMed

    Cui, Yuxia; Freedman, Jonathan H

    2009-09-11

    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, beta,beta-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 microm 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

  7. 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

  8. 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. PMID:21697648

  9. 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.

  10. 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

  11. 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.

  12. Cadmium Induces Histone H3 Lysine Methylation by Inhibiting Histone Demethylase Activity

    PubMed Central

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

    2015-01-01

    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

  13. Mitochondrial Uncoupling Protein 2 Induces Cell Cycle Arrest and Necrotic Cell Death

    PubMed Central

    Palanisamy, Arun P.; Cheng, Gang; Sutter, Alton G.; Evans, Zachary P.; Polito, Carmen C.; Jin, Lan; Liu, John; Schmidt, Michael G.

    2014-01-01

    Abstract Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that regulates energy metabolism and reactive oxygen species (ROS) production. We generated mouse carboxy- and amino-terminal green fluorescent protein (GFP)-tagged UCP2 constructs to investigate the effect of UCP2 expression on cell proliferation and viability. UCP2-transfected Hepa 1–6 cells did not show reduced cellular adenosine triphosphate (ATP) but showed increased levels of glutathione. Flow cytometry analysis indicated that transfected cells were less proliferative than nontransfected controls, with most cells blocked at the G1 phase. The effect of UCP2 on cell cycle arrest could not be reversed by providing exogenous ATP or oxidant supply, and was not affected by the chemical uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP). However, this effect of UCP2 was augmented by treatment with genistein, a tyrosine kinase inhibitor, which by itself did not affect cell proliferation on control hepatocytes. Western blotting analysis revealed decreased expression levels of CDK6 but not CDK2 and D-type cyclins. Examination of cell viability in UCP2-transfected cells with Trypan Blue and Annexin-V staining revealed that UCP2 transfection led to significantly increased cell death. However, characteristics of apoptosis were absent in UCP2-transfected Hepa 1–6 cells, including lack of oligonucleosomal fragmentation (laddering) of chromosomal DNA, release of cytochrome c from mitochondria, and cleavage of caspase-3. In conclusion, our results indicate that UCP2 induces cell cycle arrest at G1 phase and causes nonapoptotic cell death, suggesting that UCP2 may act as a powerful influence on hepatic regeneration and cell death in the steatotic liver. PMID:24320727

  14. 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 ...

  15. Necrotizing soft tissue infection

    MedlinePlus

    Necrotizing fasciitis; Fasciitis - necrotizing; Flesh-eating bacteria; Soft tissue gangrene; Gangrene - soft tissue ... the bacteria Streptococcus pyogenes , which is sometimes called "flesh-eating bacteria." Necrotizing soft tissue infection develops when ...

  16. Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains.

    PubMed

    Ma, Liang; Chan, Kwok-Wah; Trendell-Smith, Nigel J; Wu, Adrian; Tian, Lina; Lam, Audrey C; Chan, Albert K; Lo, Chi-Kin; Chik, Stanley; Ko, King-Hung; To, Christina K W; Kam, Siu-Kee; Li, Xiao-Song; Yang, Cui-Hong; Leung, Suet Yi; Ng, Mun-Hon; Stott, David I; MacPherson, G Gordon; Huang, Fang-Ping

    2005-11-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-gamma and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis. PMID:16224814

  17. 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.

  18. Investigation of cadmium-induced alterations in renal glomerular function

    SciTech Connect

    Long, T.J.

    1982-01-01

    This research was designed to test the hypothesis that certain aspects of cadmium-induced renal dysfunction are the result of glomerular, rather than classic tubular, injury. To determine whether cadmium-induced proteinuria was due to altered glomerular function, cadmium was administered chronically at a concentration of 185 ppm in the drinking water. This protocol resulted in the production of proteinuria which when analyzed by high pressure liquid chromatography and radioimmunoassay was indistinguishable from that occurring in control rats. Glomerular filtration rate, renal blood flow, and filtration fraction were all significantly depressed after 20-30 weeks of exposure. In order to further investigate these alterations in glomerular function, an acute exposure model was developed. It was found that a single i.p. injection of cadmium in mercaptoethanol resulted in the onset of acute renal failure. The clinical picture was characterized by a reduction in glomerular filtrate rate of 50-90% within 24 hours, with partial to total recovery occurring by day 7 post-exposure. Histological evidence indicated that to a large extent the reduction in GFR was due to tubular blockade and/or backleak of filtrate across damaged tubules.

  19. 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

    2016-01-01

    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

  20. 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

  1. Current research in necrotizing enterocolitis.

    PubMed

    Eaton, Simon; Rees, Clare M; Hall, Nigel J

    2016-06-01

    Despite decades of research on necrotizing enterocolitis, we still do not fully understand the pathogenesis of the disease, how to prevent or how to treat the disease. However, as a result of recent significant advances in the microbiology, molecular biology, and cell biology of the intestine of premature infants and infants with necrotizing enterocolitis, there is some hope that research into this devastating disease will yield some important translation into improved outcomes. PMID:26923373

  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. 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

  4. Reversibility of cadmium-induced health effects in rabbits

    SciTech Connect

    Nomiyama, K.; Nomiyama, H.

    1984-03-01

    Twenty-one male rabbits were divided into three groups: rabbits of two groups were given pelleted food containing cadmium chloride at a dose level of 300 ..mu..g Cd/g over periods of 44 or 19 weeks. Rabbits of the last group were given ordinary commercial pelleted food and served as controls. Cadmium increased urinary protein and amino acid by week 19 and increased it to a remarkably high level by week 44. After cessation of cadmium exposure, rabbits of the first group (44 weeks exposure group) showed only little recovery from cadmium health effects: proteinuria and aminoaciduria were slightly improved. Depressed hepatic functions were also slightly improved, but did not return to the control level in 24 weeks. Fat and bone metabolism also remained depressed below the control level. Anemia did not also readily recover. On the other hand, rabbits of the second group (19 weeks exposure) recovered from the effects of cadmium: proteinuria and aminoaciduria in most animals disappeared soon after the end of cadmium exposure, plasma GPT fell after 1 week, and hemoglobin and hematocrit returned to normal in 6-11 weeks. The above results show that after cessation of cadmium exposure, mild cadmium-induced health effects were reversible in a short period, while more severe effects were not readily reversible. High performance liquid chromatographic (HPLC) profiles of renal and hepatic cadmium-thionein (Cd-MT) during and after exposure to cadmium showed no correlation to the degree of cadmium health effects, and therefore, did not help to elucidate mechanisms of the recovery from cadmium-induced health effects, probably because cadmium not bound with metallothionein (non-MT-Cd) is responsible for inducing renal effects. 31 references, 4 figures.

  5. A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses.

    PubMed

    Maueröder, C; Chaurio, R A; Dumych, T; Podolska, M; Lootsik, M D; Culemann, S; Friedrich, R P; Bilyy, R; Alexiou, C; Schett, G; Berens, C; Herrmann, M; Munoz, L E

    2016-06-01

    In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis-necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response. PMID:26943324

  6. 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

  7. Necrotic cell death induced by the protein-mediated intercellular uptake of CdTe quantum dots.

    PubMed

    Lai, Lu; Jin, Jian-Cheng; Xu, Zi-Qiang; Mei, Ping; Jiang, Feng-Lei; Liu, Yi

    2015-09-01

    The toxicity of CdTe QDs with nearly identical maximum emission wavelength but modified with four different ligands (MPA, NAC, GSH and dBSA) to HEK293 and HeLa cells were investigated using flow cytometry, spectroscopic and microscopic methods. The results showed that the cytotoxicity of QDs increased in a dose- and time-dependent manner. No appreciable fraction of cells with sub-G1 DNA content, the loss of membrane integrity, and the swelling of nuclei clearly indicated that CdTe QDs could lead to necrotic cell death in HEK293 cells. JC-1 staining and TEM images confirmed that QDs induced MPT, which resulted in mitochondrial swelling, collapse of the membrane potential. MPT is an important step in QDs-induced necrosis. Moreover, QDs induced MPT through the elevation of ROS. The fluorimetric assay and theoretical analysis demonstrated ROS production has been associated with the internalization of QDs with cells. Due to large surface/volume ratios of QDs, when QDs added in the culture medium, serum proteins in the culture medium will be adsorbed on the surface of QDs. This adsorption of serum protein will change the surface properties and size, and then mediate the cellular uptake of QDs via the clathrin-mediated endocytic pathway. After entering into cells, the translocation of QDs in cells is usually via endosomal or lysosomal vesicles. The rapid degradation of QDs in lysosome and the lysosomal destabilization induce cell necrosis. This study provides a basis for understanding the cytotoxicity mechanism of CdTe QDs, and valuable information for safe use of QDs in the future. PMID:25965003

  8. 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

  9. The marine toxin palytoxin induces necrotic death in HaCaT cells through a rapid mitochondrial damage.

    PubMed

    Pelin, Marco; Sosa, Silvio; Pacor, Sabrina; Tubaro, Aurelia; Florio, Chiara

    2014-09-17

    Palytoxin (PLTX) is one of the most toxic algal biotoxin known so far. It transforms the Na(+)/K(+)-ATPase into a cationic channel inducing a massive intracellular Na(+) influx. However, from a mechanistic point of view, the features and the intracellular pathways leading to PLTX-induced cell death are still not completely characterized. This study on skin HaCaT keratinocytes demonstrates that PLTX induces necrosis since propidium iodide uptake was observed already after 1 h toxin exposure, an effect that was not lowered by toxin removal. Furthermore, necrotic-like morphological alterations were evidenced by confocal microscopy. Apoptosis occurrence was excluded since no caspases 3/7, caspase 8, and caspase 9 activation as well as no apoptotic bodies formation were recorded. Necrosis was preceded by a very early mitochondrial damage as indicated by JC-1 fluorescence shift, recorded already after 5 min toxin exposure. This shift was totally abolished when Na(+) and Ca(2+) ions were withdrawn from culture medium, whereas cyclosporine-A was ineffective, excluding the occurrence of a controlled biochemical response. These results clearly establish necrosis as the primary mechanism for PLTX-induced cell death in HaCaT cells. The rapidity of mitochondrial damage and the consequent irreversible necrosis rise serious concerns about the very fast onset of PLTX toxic effects. PMID:25066017

  10. 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

  11. 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

  12. 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

  13. Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis.

    PubMed

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

    2014-10-10

    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

  14. 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.

  15. Primary spindle cell sarcoma of the breast masquerading as necrotizing fasciitis

    PubMed Central

    Gesakis, Kanellos; Tanos, Grigorios; Onyekwelu, Obi; Gaitis, Anastasios; Gudur, Laxminarayan; Agarwal, Anil

    2014-01-01

    Breast sarcomas are rare neoplasms arising from the few epithelial elements of the gland. It represents much <1% of all breast cancer. Of the heterogeneous group of sarcomas, the more common subtypes include spindle cell sarcoma. The main risk factor for the development of breast sarcomas is previous radiation therapy following breast-conservation surgery for breast cancer or non-Hodgkin's lymphoma. We report on an idiopathic presentation of spindle cell sarcoma in an otherwise healthy middle-aged woman. An emphasis is made on the rare occurrence of lymphatic metastasis. We discuss our recommended management strategy with particular reference to the benefit of multidisciplinary team decision-making. PMID:24876317

  16. 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

  17. 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.

  18. 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.

  19. Identification of autophagy genes participating in zinc-induced necrotic cell death in Saccharomyces cerevisiae

    PubMed Central

    Dziedzic, Slawomir A

    2011-01-01

    Eukaryotes use a common set of genes to perform two mechanistically similar autophagic processes. Bulk autophagy harvests proteins nonselectively and reuses their constitutents when nutrients are scarce. In contrast, different forms of selective autophagy target protein aggregates or damaged organelles that threaten to interfere with growth. Yeast uses one form of selective autophagy, called cytoplasm-to-vacuole targeting (Cvt), to engulf two vacuolar enzymes in Cvt vesicles (“CVT-somes”) within which they are transported to vacuoles for maturation. While both are dispensable normally, bulk and selective autophagy help sustain life under stressful conditions. Consistent with this view, knocking out several genes participating in Cvt and specialized autophagic pathways heightened the sensitivity of Saccharomyces cerevisiae to inhibitory levels of Zn2+. The loss of other autophagic genes, and genes responsible for apoptotic cell death, had no such effect. Unexpectedly, the loss of members of a third set of autophagy genes heightened cellular resistance to zinc as if they encoded proteins that actively contributed to zinc-induced cell death. Further studies showed that both sensitive and resistant strains accumulated similar amounts of H2O2 during zinc treatments, but that more sensitive strains showed signs of necrosis sooner. Although zinc lethality depended on autophagic proteins, studies with several reporter genes failed to reveal increased autophagic activity. In fact, microscopy analysis indicated that Zn2+ partially inhibited fusion of Cvt vesicles with vacuoles. Further studies into how the loss of autophagic processes suppressed necrosis in yeast might reveal whether a similar process could occur in plants and animals. PMID:21317551

  20. 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

  1. Enzymatic Debridement in Necrotizing Pancreatitis

    PubMed Central

    Cakir, Murat; Tekin, Ahmet; Kucukkartallar, Tevfik; Vatansev, Husamettin; Kartal, Adil

    2015-01-01

    Multiple organ failure and pancreatic necrosis are the factors that determine prognosis in acute pancreatitis attacks. We investigated the effects of collagenase on the debridement of experimental pancreatic necrosis. The study covered 4 groups; each group had 10 rats. Group I was the necrotizing pancreatitis group. Group II was the collagenase group with pancreatic loge by isotonic irrigation following necrotizing pancreatitis. Group III was the collagenase group with pancreatic loge following necrotizing pancreatitis. Group IV was the intraperitoneal collagenase group following necrotizing pancreatitis. The progress of the groups was compared hematologically and histopathologically. There was no difference among the groups regarding the levels of leukocyte, hemogram, and urea. The differences in AST levels between Group I and II; and differences in glucose, calcium, LDH, AST, and amylase between Group II and III; between Group II and IV; between Group I and III; and between Group I and IV were statistically significant (P < 0.05). There were statistically significant differences between Group II and III, and Group II and IV regarding edema, acinar necrosis, inflammatory cell infiltration, hemorrhage, and fat necrosis (P < 0.05). In conclusion, the collagenase preparation used in this experimental pancreatitis model was found to be effective in the debridement of pancreatic necrosis. PMID:26011212

  2. 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

  3. PrtT-Regulated Proteins Secreted by Aspergillus fumigatus Activate MAPK Signaling in Exposed A549 Lung Cells Leading to Necrotic Cell Death

    PubMed Central

    Sharon, Haim; Amar, David; Levdansky, Emma; Mircus, Gabriel; Shadkchan, Yana; Shamir, Ron; Osherov, Nir

    2011-01-01

    Aspergillus fumigatus is the most commonly encountered mold pathogen of humans, predominantly infecting the respiratory system. Colonization and penetration of the lung alveolar epithelium is a key but poorly understood step in the infection process. This study focused on identifying the transcriptional and cell-signaling responses activated in A549 alveolar carcinoma cells incubated in the presence of A. fumigatus wild-type and ΔPrtT protease-deficient germinating conidia and culture filtrates (CF). Microarray analysis of exposed A549 cells identified distinct classes of genes whose expression is altered in the presence of germinating conidia and CF and suggested the involvement of both NFkB and MAPK signaling pathways in mediating the cellular response. Phosphoprotein analysis of A549 cells confirmed that JNK and ERK1/2 are phosphorylated in response to CF from wild-type A. fumigatus and not phosphorylated in response to CF from the ΔPrtT protease-deficient strain. Inhibition of JNK or ERK1/2 kinase activity substantially decreased CF-induced cell damage, including cell peeling, actin-cytoskeleton damage, and reduction in metabolic activity and necrotic death. These results suggest that inhibition of MAPK-mediated host responses to treatment with A. fumigatus CF decreases cellular damage, a finding with possible clinical implications. PMID:21412410

  4. 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...

  5. Subacute necrotizing encephalomyelopathy

    PubMed Central

    Faris, Amin A.; Fleckenstein, Loran D.

    1970-01-01

    Clinical and neuropathological features of a case of subacute necrotizing encephalomyelopathy are discussed and compared with the features of central pontine myelinolysis. A hypothesis is offered relating the two diseases to a common aetiological factor. PMID:5478948

  6. Apoptotic and necrotic cells as sentinels of local tissue stress and inflammation: response pathways initiated in nearby viable cells.

    PubMed

    Patel, Vimal A; Lee, Daniel J; Longacre-Antoni, Angelika; Feng, Lanfei; Lieberthal, Wilfred; Rauch, Joyce; Ucker, David S; Levine, Jerrold S

    2009-05-01

    Virtually all cells in the body have the capacity to recognize and respond to dead cells. Viable cells discriminate apo from nec targets via distinct cell surface receptors. Engagement of these receptors induces "recognition-dependent" signaling events in viable responding cells that differ for apo vs. nec targets. Although "engulfment-dependent" signaling events also contribute to the response by viable cells, these events do not differ for apo vs. nec targets. While many signaling events are conserved across diverse cell lineages, other signaling events, especially those involving Akt, demonstrate lineage-specific variation. Whereas apo targets activate Akt in MPhi, they inhibit Akt in kidney epithelial cells. Differences in the responses to dead targets by viable migratory cells, such as MPhi, and viable fixed cells, such as kidney epithelial cells, permit cell-specific adaptations to local environmental change or stress. We propose that dead cells (apo and nec) act as sentinels to alert nearby viable cells to local environmental change or stress. PMID:19811288

  7. Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice

    PubMed Central

    Sangartit, Weerapon; Kukongviriyapan, Upa; Donpunha, Wanida; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Surawattanawan, Praphassorn; Greenwald, Stephen E.

    2014-01-01

    Background Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. Methods Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Results Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. Conclusions Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID:25502771

  8. A Cell-Permeant Amiloride Derivative Induces Caspase-Independent, AIF-Mediated Programmed Necrotic Death of Breast Cancer Cells

    PubMed Central

    Leon, Leonardo J.; Pasupuleti, Nagarekha; Gorin, Fredric; Carraway, Kermit L.

    2013-01-01

    Amiloride is a potassium-sparing diuretic that has been used as an anti-kaliuretic for the chronic management of hypertension and heart failure. Several studies have identified a potential anti-cancer role for amiloride, however the mechanisms underlying its anti-tumor effects remain to be fully delineated. Our group previously demonstrated that amiloride triggers caspase-independent cytotoxic cell death in human glioblastoma cell lines but not in primary astrocytes. To delineate the cellular mechanisms underlying amiloride’s anti-cancer cytotoxicity, cell permeant and cell impermeant derivatives of amiloride were synthesized that exhibit markedly different potencies in cancer cell death assays. Here we compare the cytotoxicities of 5-benzylglycinyl amiloride (UCD38B) and its free acid 5-glycinyl amiloride (UCD74A) toward human breast cancer cells. UCD74A exhibits poor cell permeability and has very little cytotoxic activity, while UCD38B is cell permeant and induces the caspase-independent death of proliferating and non-proliferating breast cancer cells. UCD38B treatment of human breast cancer cells promotes autophagy reflected in LC3 conversion, and induces the dramatic swelling of the endoplasmic reticulum, however these events do not appear to be the cause of cell death. Surprisingly, UCD38B but not UCD74A induces efficient AIF translocation from the mitochondria to the nucleus, and AIF function is necessary for the efficient induction of cancer cell death. Our observations indicate that UCD38B induces programmed necrosis through AIF translocation, and suggest that its cytosolic accessibility may facilitate drug action. PMID:23646172

  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. The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells

    PubMed Central

    Palermo, Christine M.; Bennett, Cecily A.; Winters, Amanda C.; Hemenway, Charles S.

    2008-01-01

    Despite ongoing success in the treatment of childhood acute lymphoblastic leukemia, patients harboring translocations involving the MLL gene at chromosome 11q23 remain resistant to treatment. To improve outcomes, novel therapeutics designed to target the unusual biology of these leukemias need to be developed. Previously, we identified an interaction between the two most common MLL fusion proteins, AF4 and AF9, and designed a synthetic peptide (PFWT) capable of disrupting this interaction. PFWT induced cell death in leukemia cells expressing MLL-AF4 with little effect on the colony forming potential of hematopoietic progenitor cells, suggesting the AF4–AF9 complex is an important pharmacological target for leukemia therapy and PFWT is a promising chemotherapeutic prototype. In these studies, we demonstrate that PFWT induces death by necrosis in MV4-11 cells. Cell death is characterized by rapid loss of plasma membrane integrity with maintenance of nuclear membrane integrity, and is independent of caspase activation, DNA fragmentation, and mitochondrial membrane depolarization. PFWT-mediated necrosis is inhibited by the serine protease inhibitor TLCK, suggesting this death pathway is regulated. Given the resistance of t(4;11) leukemias to conventional chemotherapeutic agents that induce apoptosis, further identification of the molecular events mediating this death process should uncover new avenues for therapeutic intervention. PMID:17875318

  11. Systemic necrotizing vasculitis.

    PubMed

    Gross, W L

    1997-05-01

    The revival of interest in systemic necrotizing vasculitis was initiated by the discovery of its association with anti-neutrophil cytoplasmic antibodies (ANCA). The close association of certain ANCA subspecificities, for example, proteinase 3 (Pr3) and myeloperxoidase ANCA, with Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome has led to their designation as 'ANCA-associated vasculitides'. This article describes the common and divergent clinical and immunological features of the members of this 'new' family of systemic necrotizing vasculitis, which continues to grow with the widespread use of ANCA testing. In addition, the 'standard' treatment for systemic necrotizing vasculitis (daily 'low dose' cyclophosphamide plus glucocorticosteroids or 'Fauci's scheme') is compared with new stage and activity adapted therapeutic regimens. PMID:9220078

  12. Retroperitoneal necrotizing fasciitis.

    PubMed

    Woodburn, K R; Ramsay, G; Gillespie, G; Miller, D F

    1992-04-01

    Necrotizing fasciitis is a mixed infection of the skin and subcutaneous tissues with a characteristic clinical and pathological appearance. Early radical surgical excision of all affected tissue is the treatment of choice. In a series of 19 patients with necrotizing fasciitis, bacteriological assessment in 15 confirmed the mixed nature of the infection, with Bacteroides sp. isolated from ten patients. All 12 patients who underwent radical surgical excision survived. A subgroup of patients was identified in whom the appearance of necrotizing fasciitis in the abdomen or perineum was indicative of more extensive disease in the retroperitoneal tissues. Surgical resection of all affected tissue was not feasible in these cases and the outcome was uniformly fatal, giving an overall mortality rate for the series of 37 per cent. PMID:1576505

  13. 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

  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. Protective role of carnosine in mice with cadmium-induced acute hepatotoxicity.

    PubMed

    Fouad, Amr A; Qureshi, Habib A; Yacoubi, Mohamed T; Al-Melhim, Walid N

    2009-11-01

    The hepatoprotective effect of carnosine was investigated against cadmium-induced acute liver injury in mice. Hepatotoxicity was induced by a single i.p. injection of cadmium chloride (6.5mg/kg). Carnosine treatment (10mg/kg/day, i.p.) was applied for three consecutive days, starting one day before cadmium administration. Carnosine significantly decreased the cadmium-induced elevations in serum aminotransferases. Carnosine suppressed lipid peroxidation and restored the deficits in the antioxidant defense mechanisms (reduced glutathione level, and catalase and superoxide dismutase activities) in liver tissue resulted from cadmium administration. Also, the reductions in hepatic nitric oxide and zinc ion levels, and the increases in hepatic cadmium ion concentration, and myeloperoxidase and caspase-3 activities following cadmium exposure were significantly attenuated by carnosine treatment. In addition, carnosine markedly ameliorated cadmium-induced liver tissue damage as evidenced by light and electron microscopic examinations. It was concluded that carnosine can be considered a potential candidate to protect the liver against the deleterious effect of acute cadmium intoxication. PMID:19748544

  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. PMID:20495888

  17. Retroperitoneal necrotizing fasciitis.

    PubMed

    Rush, B M; Hood, J S; McDonald, J C; Grafton, W D; Burton, G V

    1991-06-01

    We present a case of retroperitoneal necrotizing fasciitis treated by urgent abdomino-perineal resection of the rectum with permanent colostomy. We can find no prior case in the English literature treated in this manner. Retroperitoneal occurrence of this disease is unusual. The process originated from perianal sepsis following chemotherapy for head and neck cancer. PMID:2071998

  18. 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

  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. Lactobacillus bulgaricus Prevents Intestinal Epithelial Cell Injury Caused by Enterobacter sakazakii-Induced Nitric Oxide both In Vitro and in the Newborn Rat Model of Necrotizing Enterocolitis▿

    PubMed Central

    Hunter, Catherine J.; Williams, Monica; Petrosyan, Mikael; Guner, Yigit; Mittal, Rahul; Mock, Dennis; Upperman, Jeffrey S.; Ford, Henri R.; Prasadarao, Nemani V.

    2009-01-01

    Enterobacter sakazakii is an emerging pathogen that has been associated with outbreaks of necrotizing enterocolitis (NEC) as well as infant sepsis and meningitis. Our previous studies demonstrated that E. sakazakii induces NEC in a newborn rat model by inducing enterocyte apoptosis. However, the mechanisms responsible for enterocyte apoptosis are not known. Here we demonstrate that E. sakazakii induces significant production of nitric oxide (NO) in rat intestinal epithelial cells (IEC-6) upon infection. The elevated production of NO, which is due to increased expression of inducible NO synthase, is responsible for apoptosis of IEC-6 cells. Notably, pretreatment of IEC-6 cells with Lactobacillus bulgaricus (ATCC 12278) attenuated the upregulation of NO production and thereby protected the cells from E. sakazakii-induced apoptosis. Furthermore, pretreatment with L. bulgaricus promoted the integrity of enterocytes both in vitro and in the infant rat model of NEC, even after challenge with E. sakazakii. Infection of IEC-6 cells with E. sakazakii upregulated several genes related to apoptosis, cytokine production, and various signaling pathways, as demonstrated by rat gene array analysis, and this upregulation was subdued by pretreatment with L. bulgaricus. In agreement with these data, L. bulgaricus pretreatment protected newborn rats infected with E. sakazakii from developing NEC, resulting in improved survival. PMID:19075027

  1. A Review of Molecular Events of Cadmium-Induced Carcinogenesis

    PubMed Central

    Luevano, Joe; Damodaran, Chendil

    2014-01-01

    Cadmium (Cd) is a toxic, heavy industrial metal that poses serious environmental health hazards to both humans and wildlife. Lately, Cd and Cd containing compounds have been classified as known human carcinogens and epidemiological data show causal associations with prostate, breast and lung cancer. The molecular mechanisms involved in Cd-induced carcinogenesis are poorly understood and are only now beginning to be elucidated. The effects of chronic exposure to Cd have recently become of great interest due to the development of malignancies in Cd-induced tumorigenesis in animal. Briefly, various in vitro studies demonstrate that Cd can act as a mitogen, stimulate cell proliferation, inhibit apoptosis and DNA repair, and induce carcinogenesis in several mammalian tissues and organs. Thus, the various mechanisms involved in chronic Cd exposure and malignant transformations warrant further investigation. In this review, we will focus on recent evidence of various leading general and tissue specific molecular mechanisms that follow chronic exposure to Cd in prostate, breast and lung transformed malignancies. In addition, this review considers less defined mechanisms such as epigenetic modification and autophagy, which are thought to play a role in the development of Cd-induced malignant transformation. PMID:25272057

  2. 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

  3. In vitro reversibility of cadmium-induced inhibition of phagocytosis.

    PubMed

    Levy, L; Vredevoe, D L; Cook, G

    1986-12-01

    Cadmium chloride, administered chronically in the drinking water of CBA/H mice, produced a delayed clearance of particles and soluble material bearing Fc fragments (D. W. Knutson, D. L. Vredevoe, K. R. Aoki, and L. Levy, 1980, Immunology, 40, 17-26; D. L. Vredevoe, L. Levy, D. Knutson, G. Cook, and P. Cohen, 1985, Environ. Res. 37, 373-382). The inhibition was reversed upon removal of the cadmium from the water, even though a tissue load of cadmium persisted. An in vitro system was developed to analyze the mechanism of the inhibition. Binding and ingestion of sheep red blood cells (E) treated with IgG (for measurement of Fc receptor activity) or IgM and complement (C) (for measurement of complement receptor activity) were studied in resident and elicited murine peritoneal macrophages in vitro. Elicited macrophages provided the most definitive test system. With this system, there was significant inhibition of ingestion of E-IgG and E-IgMC. Binding of both types of erythrocytes was not inhibited, except at the highest concentration (10(-4) M) of CdCl2 at which binding of only E-IgMC was affected. These effects were reversible upon removal of cadmium. Migration of Fc and C receptors on the macrophage surface was not significantly affected by cadmium. In general, cadmium did not alter the expression or the binding of Fc or C receptors on macrophages. The mechanism for delayed clearance appears to be due to inhibited internalization of the particles. This is consistent with the interpretation that cadmium is a membrane active agent. PMID:3780638

  4. 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

  5. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway by a genome wide siRNA screen

    PubMed Central

    Hitomi, Junichi; Christofferson, Dana E.; Ng, Aylwin; Yao, Jianhua; Degterev, Alexei; Xavier, Ramnik J.; Yuan, Junying

    2009-01-01

    Stimulation of death receptors by agonists such as FasL and TNFα activates apoptotic cell death in apoptotic competent conditions or a type of necrotic cell death dependent on RIP1 kinase, termed necroptosis, in apoptotic deficient conditions. In a genome-wide siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death receptor mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. We show that the expression of subsets of the 432 genes are enriched in the immune and nervous systems, and cellular sensitivity to necroptosis is regulated by an extensive signaling network mediating innate immunity. Interestingly, Bmf, a BH3-only Bcl-2 family member, is required for death receptor-induced necroptosis. Our study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis. PMID:19109899

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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

  11. Dysregulated expression of arginine metabolic enzymes in human intestinal tissues of necrotizing enterocolitis and response of CaCO2 cells to bacterial components.

    PubMed

    Leung, Kam Tong; Chan, Kathy Yuen Yee; Ma, Terence Ping Yuen; Yu, Jasmine Wai Sum; Tong, Joanna Hung Man; Tam, Yuk Him; Cheung, Hon Ming; To, Ka Fai; Lam, Hugh Simon; Lee, Kim Hung; Li, Karen; Ng, Pak Cheung

    2016-03-01

    The small intestine is the exclusive site of arginine synthesis in neonates. Low levels of circulating arginine have been associated with the occurrence of necrotizing enterocolitis (NEC) but the mechanism of arginine dysregulation has not been fully elucidated. We aimed to investigate (i) expressional changes of arginine synthesizing and catabolic enzymes in human intestinal tissues of NEC, spontaneous intestinal perforation (SIP) and noninflammatory surgical conditions (Surg-CTL) and to investigate the (ii) mechanisms of arginine dysregulation and enterocyte proliferation upon stimulation by bacterial components, arginine depletion, ARG1 overexpression and nitric oxide (NO) supplementation. Our results showed that expressions of arginine synthesizing enzymes ALDH18A1, ASL, ASS1, CPS1, GLS, OAT and PRODH were significantly decreased in NEC compared with Surg-CTL or SIP tissues. Catabolic enzyme ARG1 was increased (>100-fold) in NEC tissues and histologically demonstrated to be expressed by infiltrating neutrophils. No change in arginine metabolic enzymes was observed between SIP and Surg-CTL tissues. In CaCO2 cells, arginine metabolic enzymes were differentially dysregulated by lipopolysaccharide or lipoteichoic acid. Depletion of arginine reduced cell proliferation and this phenomenon could be partially rescued by NO. Overexpression of ARG1 also reduced enterocyte proliferation. We provided the first expressional profile of arginine metabolic enzymes at the tissue level of NEC. Our findings suggested that arginine homeostasis was severely disturbed and could be triggered by inflammatory responses of enterocytes and infiltrating neutrophils as well as bacterial components. Such reactions could reduce arginine and NO, resulting in mucosal damage. The benefit of arginine supplementation for NEC prophylaxis merits further clinical evaluation. PMID:26895666

  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. 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

  14. The protective effect of Physalis peruviana L. against cadmium-induced neurotoxicity in rats.

    PubMed

    Abdel Moneim, Ahmed E; Bauomy, Amira A; Diab, Marwa M S; Shata, Mohamed Tarek M; Al-Olayan, Ebtesam M; El-Khadragy, Manal F

    2014-09-01

    The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p < 0.05) reduction in dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in cerebellum, hippocampus, and cerebral cortex and enhanced significantly (p < 0.05) the levels of lipid peroxidation and nitric oxide in the brain. Cadmium treatment also decreased the amount of nonenzymatic and enzymatic antioxidants significantly (p < 0.05). Pretreatment with MEPh resulted in significant (p < 0.05) decreases in lipid peroxidation and nitric oxide levels and restored the amount of glutathione successfully. Although, preadministration of MEPh also brought the activities of cellular antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase significantly (p < 0.05) to the control levels, as well as the levels of Ca(2+), Cl(-), DA, 5-HT, and serotonin metabolite, 5-HIAA. These data indicated that Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats. PMID:25022246

  15. [Retroperitoneal postoperative necrotizing fasciitis].

    PubMed

    Fichev, G; Poromanski, I; Marina, M

    2000-01-01

    This is a report on clinical experience had with 17 patients presenting necrotizing fasciitis--a complication ever more frequently encountered. The case material is distributed in two group differing by origin and clinical course of the complication. In group one (n = 11) it is a matter of postoperative development of postoperative complication, consistent with the classical "per continuitatem" and "per contiguitatem" mechanisms, while in group two (n = 6) the process originates, evolves and speads within the retroperitoneal space proper. Comprehensive microbiological examinations performed in 13 cases show that in either group different microorganisms are identified. In group one aerobic-anaerobic mixed infection is documented in all patients, with predominance of Enterobacteroidaceae among aerobic ones. In group two, anaerobic bacterial species, mainly Clostridium sp, prevail in all the isolates. The clinical study points to a substantial difference in the time of septic complication occurrence, as well as between the clinical picture of the two species. Accordingly, the final results are radically different--in group one survivorship amounts to 62.6%, whereas in group two--to 16.6% only. PMID:11692928

  16. Rhizomania as seen from inside the beet cell: Identifying proteome differences between sugarbeet infected with Beet necrotic yellow vein virus and healthy sugarbeet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rhizomania, caused by Beet necrotic yellow vein virus (BNYVV) is one of the most economically important diseases affecting sugarbeet. The disease is characterized by excessive growth of lateral roots and constriction of the taproot, the main sucrose storage site in sugarbeet, resulting in decreased ...

  17. Antibiosis of Necrotizing Pancreatitis

    PubMed Central

    Arlt, Alexander; Erhart, Wiebke; Schafmayer, Clemens; Held, Hanns-Christoph; Hampe, Jochen

    2014-01-01

    Summary Background Necrotizing pancreatitis is a life-threatening presentation of acute pancreatitis. The mortality of 20-80% initially depends on the persistence of organ failure and systemic inflammatory response syndrome (SIRS) and, in the later course of the disease, on secondary infection of the necrosis. The questions whether prophylactic antibiotics aiming to prevent this infection should be administered and which antibiotic is the best to use, as well as the problem of fungal infection under antibiotic treatment are still intriguing and insufficiently solved. Methods A search of the literature using PubMed was carried out, supplemented by a review of the programmes of the Digestive Disease Week (DDW) and the United European Gastroenterology Week (UEGW). Results Despite the widely practised prophylactic antibiotic administration in severe pancreatitis, no evidence for the benefit of this strategy exists. One of the drawbacks might be a tendency for disastrous fungal infection under prophylactic antibiotics. Bacterial translocation from the gut in the second week after the onset of symptoms is the major source for infection of pancreatic necrosis and provides a clear indication for antibiotic treatment. However, routine fine-needle aspiration for a calculated antibiotic therapy cannot be recommended, and all other tests offer only indirect signs. Important factors such as enteral versus parenteral feeding and the method of necrosectomy are mostly neglected in the trials but seem to be essential for the outcome of the patient. Conclusions Even though most meta-analyses including the newer double-blind, placebo-controlled trials on prophylactic antibiotics showed no beneficial effects in the prevention of infection of necrosis and/or outcome of the patients, this strategy is still widely used in clinical routine. Since nearly all trials published so far show systematic problems (i.e. inaccurate definition of the severity of the disease, poor statistical testing

  18. Preferential Elimination of Older Erythrocytes in Circulation and Depressed Bone Marrow Erythropoietic Activity Contribute to Cadmium Induced Anemia in Mice

    PubMed Central

    Chatterjee, Sreoshi; Saxena, Rajiv K.

    2015-01-01

    Feeding cadmium chloride (50 or 1000 ppm CdCl2 in drinking water, ad libitum) to C57BL/6 mice resulted in a significant and sustained fall in blood erythrocyte count and hemoglobin levels that started 4 and 3 weeks after the start of 50 and 1000 ppm cadmium doses respectively. A transient yet significant reticulocytosis occurred during the first 4 weeks of cadmium treatment. Using the recently developed double in vivo biotinylation (DIB) technique, turnover of erythrocyte cohorts of different age groups was simultaneously monitored in control and cadmium treated mice. A significant accumulation of younger erythrocytes and a concomitant decline in the relative proportions of older erythrocytes in circulation was observed in both 50 and 1000 ppm cadmium groups indicating that older erythrocytes were preferentially eliminated in cadmium induced anemia. A significant increase in the erythropoietin levels in plasma was seen in mice exposed to 1000 ppm cadmium. Levels of inflammatory cytokines (IL1A, IL6, TNFα, IFNγ) were however not significantly altered in cadmium treated mice. A significant increase in cellular levels of reactive oxygen species (ROS) was observed in older erythrocytes in circulation but not in younger erythrocytes. Erythropoietic activity in the bone marrows and spleens of cadmium treated mice was examined by monitoring the relative proportion of cells belonging to the erythroid line of differentiation in these organs. Erythroid cells in bone marrow declined markedly (about 30%) in mice in the 1000 ppm cadmium group but the decline was not significant in the 50 ppm cadmium group. Cells representing various stages of erythroid differentiation in bone marrow and spleen were enumerated flow cytometrically by double staining with anti-Ter119 and anti-transferrin receptor (CD71) monoclonal antibodies. Decline of erythroid cells was essentially confined to pro-erythroblast and erythroblast-A, along with a concurrent increase in the splenic erythroid

  19. Reversal of Cadmium-induced Oxidative Stress in Chicken by Herbal Adaptogens Withania Somnifera and Ocimum Sanctum.

    PubMed

    Bharavi, K; Reddy, A Gopala; Rao, G S; Reddy, A Rajasekhara; Rao, S V Rama

    2010-07-01

    The present study was carried out to evaluate the herbal adaptogens Withania somnifera and Ocimum sanctum on cadmium-induced oxidative toxicity in broiler chicken. Cadmium administration at the rate of 100 ppm orally along with feed up to 28 days produced peroxidative damage, as indicated by increase in TBARS, reduction in glutathione (GSH) concentration in liver and kidney, and increase in catalase (CAT) and superoxide dismutase (SOD) of erythrocytes. Herbal adaptogens Withania somnifera roots and Ocimum sanctum leaf powder administration at the rate of 0.1% through feed reversed the antioxidant enzyme of RBC, i.e., CAT and SOD, nonenzymatic antioxidants GSH and lipid peroxidation marker TBARS of liver and kidney. Liver and kidney tissue repair and normal function was assessed by alanine aminotransaminase for liver and creatinine and blood urea nitrogen for kidney. In conclusion, oral administration of Withania somnifera root and Ocimum sanctum leaf powder prevented cadmium-induced peroxidation of tissues. PMID:21170246

  20. Reversal of Cadmium-induced Oxidative Stress in Chicken by Herbal Adaptogens Withania Somnifera and Ocimum Sanctum

    PubMed Central

    Bharavi, K.; Reddy, A. Gopala; Rao, G. S.; Reddy, A. Rajasekhara; Rao, S. V. Rama

    2010-01-01

    The present study was carried out to evaluate the herbal adaptogens Withania somnifera and Ocimum sanctum on cadmium-induced oxidative toxicity in broiler chicken. Cadmium administration at the rate of 100 ppm orally along with feed up to 28 days produced peroxidative damage, as indicated by increase in TBARS, reduction in glutathione (GSH) concentration in liver and kidney, and increase in catalase (CAT) and superoxide dismutase (SOD) of erythrocytes. Herbal adaptogens Withania somnifera roots and Ocimum sanctum leaf powder administration at the rate of 0.1% through feed reversed the antioxidant enzyme of RBC, i.e., CAT and SOD, nonenzymatic antioxidants GSH and lipid peroxidation marker TBARS of liver and kidney. Liver and kidney tissue repair and normal function was assessed by alanine aminotransaminase for liver and creatinine and blood urea nitrogen for kidney. In conclusion, oral administration of Withania somnifera root and Ocimum sanctum leaf powder prevented cadmium-induced peroxidation of tissues. PMID:21170246

  1. Cervical necrotizing fasciitis associated with descending necrotizing mediastinitis

    PubMed Central

    2011-01-01

    We report a case of potentially fatal cervical necrotizing fasciitis and descending necrotizing mediastinitis due to deep neck infection in a 66-year-old male patient with no history or evidence of immunocompromising disorders. On admission, he had painful neck movements and the skin over his neck was red, hot and tender. A computerized tomography (CT) scan of his neck and chest showed evidence of air collection in soft tissues. He was treated with broad-spectrum intravenous antibiotics and early massive cervical drainage. Prompt diagnosis by CT of the neck and chest enabled an early surgical treatment of cervical necrotizing fasciitis. Although acute mediastinitis is a fatal infection involving the connective tissues that fill the interpleural spaces and surround the median thoracic organs, an extensive cervicotomy combined with appropriate antibiotics can prevent the need for mediastinal drainage. PMID:22958302

  2. [Necrotizing fasciitis of the neck].

    PubMed

    Kovacić, Marijan; Kovacić, Ivan; Delalija, Boris

    2013-03-01

    Necrotizing fasciitis is a rare and rapidly progressive infection characterized by necrosis of the superficial fascia and spread on the surrounding skin or muscles, which can be fatal. It usually occurs in the limbs, abdominal wall and perineum. In this retrospective review, the authors present 15 patients with cervical necrotizing fasciitis. The patient mean age was 54.7 years and they had one or more comorbid health problems. Five of them had descending necrotizing mediastinitis and three had progressive sepsis with toxic shock syndrome. Broad-spectrum intravenous antibiotic therapy was administered to all patients immediately, and in three of them we used five-day intravenous immunoglobulin therapy for the signs of toxic shock syndrome. After positive computed tomography imaging for necrotizing fasciitis, we used surgical exploration and debridement of necrotic tissue. In five patients, the initial surgery also included mediastinal transcervical drainage. Preoperative tracheotomy was performed in six patients and delayed tracheotomy in one patient. Histopathologically, all cases showed extensive necrosis of debrided fascia and vascular thrombosis of the neck soft tissue. The mortality rate was 6.7% (1/15). The authors point to the importance of early diagnosis and timely surgical management, broad-spectrum antibiotics and intravenous immunoglobulin therapy when patients are too unstable to undergo surgery. PMID:24279256

  3. 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

    2015-01-01

    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

  4. 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

  5. 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

  6. 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

  7. 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

  8. The potential protective role of Physalis peruviana L. fruit in cadmium-induced hepatotoxicity and nephrotoxicity.

    PubMed

    Dkhil, Mohamed A; Al-Quraishy, Saleh; Diab, Marwa M S; Othman, Mohamed S; Aref, Ahmed M; Abdel Moneim, Ahmed E

    2014-12-01

    This study aimed to investigate the potential protective role of Physalis peruviana L. (family Solanaceae) against cadmium-induced hepatorenal toxicity in Wistar rats. Herein, cadmium chloride (CdCl2) (6.5 mg/kg bwt/day) was intraperitoneally injected for 5 days, and methanolic extract of physalis (MEPh) was pre-administered to a group of Cd-treated rats by an oral administration at a daily dose of 200 mg/kg bwt for 5 days. The findings revealed that CdCl2 injection induced significant decreases in kidney weight and kidney index. Cadmium intoxication increased the activities of liver enzymes and the bilirubin level, in addition to the levels of uric acid, urea and creatinine were increased in the serum. The pre-administration of MEPh alleviated hepatorenal toxicity in Cd-treated rats. Physalis was noted to play a good hepatorenal protective role, reducing lipid peroxidation, nitric oxide, and enhancing enzymatic activities and non-enzymatic antioxidant molecule, glutathione, in hepatic and renal tissues of Cd-treated rats. Moreover, physalis treatment was able to reverse the histopathological changes in liver and kidney tissues and also increased the expression of Bcl-2 protein in liver and kidney of rats. Overall, the results showed that MEPh can induce antioxidant and anti-apoptotic effects and also exerts beneficial effects for the treatment of Cd-induced hepatorenal toxicity. PMID:25265456

  9. Infectious causes of necrotizing enterocolitis

    PubMed Central

    Coggins, Sarah A.; Wynn, James L.; Weitkamp, Jörn-Hendrik

    2014-01-01

    Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency among premature infants. Although a large body of research has focused on understanding its pathogenesis, the exact mechanism has not been elucidated. Of particular interest is the potential causative role of infectious culprits in the development of NEC. A variety of reports describe bacterial, viral, and fungal infections occurring in association with NEC; however, no organism has emerged as being definitively involved in NEC pathogenesis. In this review, we summarize the body of research on infectious causes of necrotizing enterocolitis. PMID:25678001

  10. 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

  11. Fatal Necrotizing Fasciitis following Episiotomy

    PubMed Central

    Almarzouqi, Faris; Grieb, Gerrit; Klink, Christian; Bauerschlag, Dirk; Fuchs, Paul C.; Alharbi, Ziyad; Vasku, Marketa; Pallua, Norbert

    2015-01-01

    Introduction. Necrotizing fasciitis is an uncommon condition in general practice but one that provokes serious morbidity. It is characterized by widespread fascial necrosis with relative sparing of skin and underlying muscle. Herein, we report a fatal case of necrotizing fasciitis in a young healthy woman after episiotomy. Case Report. A 17-year-old primigravida underwent a vaginal delivery with mediolateral episiotomy. Necrotizing fasciitis was diagnosed on the 5th postpartum day, when the patient was referred to our tertiary care medical center. Surgical debridement was initiated together with antibiotics and followed by hyperbaric oxygen therapy. The patient died due to septic shock after 16 hours from the referral. Conclusion. Delay of diagnosis and consequently the surgical debridement were most likely the reasons for maternal death. In puerperal period, a physician must consider necrotizing fasciitis as a possible diagnosis in any local sings of infection especially when accompanied by fever and/or tenderness. Early diagnosis is the key for low mortality and morbidity. PMID:26064762

  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. Cadmium-Induced Toxicity and the Hepatoprotective Potentials of Aqueous Extract of Jessiaea Nervosa Leaf

    PubMed Central

    Ibiam, Ama Udu; Ugwuja, Emmanuel Ike; Ejeogo, Christ; Ugwu, Okechukwu

    2013-01-01

    Purpose: Hepatoprotective potentials of Jussiaea nervosa leaf extract against Cadmium-induced hepatotoxicity were investigated. Methods: Forty albino rats were randomly assigned into groups A-G with 4 rats in each of the groups A-F. Group A served as control and were given feed only while rats in groups B-F were orally exposed to varying concentrations of cadmium for six weeks. Effects of cadmium were most significant at 12 mg/Kg body weight (BW), and this dose was used for subsequent test involving oral administration of Jussiaea nervosa leaf extracts. In this segment, group G (n= 16) was sub-divided into four: G1-G4, with each sub-group containing four rats. Rats in sub-group G1 were given cadmium and feed only and served as positive control. Rats in sub-groups G2, G3, and G4 were given cadmium and 20, 50 and 100g/kg BW of Jussiaea nervosa extract, respectively, for six weeks. Blood and liver were analysed using standard laboratory techniques and methods. Results: Liver function parameters (ALT, AST, ALP, bilirubin) were significantly (p<0.05) elevated in exposed rats in comparison to the controls, except for total protein and albumin, which were significantly decreased. Histopathological assessment reveals renal pathology in exposed rats in sharp contrast with the controls. Jussiaea nervosa extract however lowered the values of liver function parameters with 100mg/Kg BW dose producing the highest ameliorative effects. Similarly, the serum albumin and total protein significantly (p<0.05) improved with normal liver architecture. Conclusion: The results show the hepatoprotective potentials of Jussiaea nervosa extract against Cd toxicity. PMID:24312853

  14. 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

  15. Emphysematous cystitis and necrotizing fasciitis

    PubMed Central

    Wang, Peter Zhan Tao; Martin, Paul R.; Luke, Patrick P.W.

    2014-01-01

    Emphysematous cystitis is an uncommon and often severe infectious condition of the bladder that usually affects women and diabetics. We report a case of a 62-year-old male patient who presented with concomitant emphysematous cystitis and necrotizing fasciitis of the right leg. The patient was initially managed with emergent disarticulation of the right leg. Tissue cultures were positive for Ciprofloxacin-resistant Klebsiella pneumoniae. He was treated with Piperacillin-Tazobactam; however, due to the failure of conservative management of the condition, the patient underwent a cystoprostatectomy with ileal conduit. To our knowledge, this is the first report of concomitant emphysematous cystitis and necrotizing fasciitis requiring aggressive surgical intervention for both diseases. PMID:25132897

  16. 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

  17. 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

  18. 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

  19. Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats.

    PubMed

    Zhang, Wenhui; Zhi, Jianming; Cui, Yongyao; Zhang, Fan; Habyarimana, Adélite; Cambier, Carole; Gustin, Pascal

    2014-01-01

    The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases. PMID:25313925

  20. Potentiated Interaction between Ineffective Doses of Budesonide and Formoterol to Control the Inhaled Cadmium-Induced Up-Regulation of Metalloproteinases and Acute Pulmonary Inflammation in Rats

    PubMed Central

    Zhang, Wenhui; Zhi, Jianming; Cui, Yongyao; Zhang, Fan; Habyarimana, Adélite; Cambier, Carole; Gustin, Pascal

    2014-01-01

    The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases. PMID:25313925

  1. Infectious causes of necrotizing enterocolitis.

    PubMed

    Coggins, Sarah A; Wynn, James L; Weitkamp, Jörn-Hendrik

    2015-03-01

    Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency among premature infants. Although a large body of research has focused on understanding its pathogenesis, the exact mechanism has not been elucidated. Of particular interest is the potential causative role of infectious culprits in the development of NEC. A variety of reports describe bacterial, viral, and fungal infections occurring in association with NEC; however, no single organism has emerged as being definitively involved in NEC pathogenesis. In this review, the authors summarize the literature on infectious causes of NEC. PMID:25678001

  2. 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

  3. 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

  4. Staphylococcus pseudintermedius necrotizing fasciitis in a dog

    PubMed Central

    Weese, J. Scott; Poma, Roberta; James, Fiona; Buenviaje, Gilbert; Foster, Robert; Slavic, Durda

    2009-01-01

    Staphylococcus pseudintermedius was implicated as the cause of rapidly progressive and fatal necrotizing fasciitis in a dog. The isolate was methicillin-susceptible and did not contain genes encoding the Panton-Valentine leukocidin. While Streptococcus canis is typically considered to be the main cause of necrotizing fasciitis in dogs, staphylococci should also be considered. PMID:19721787

  5. 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.

  6. 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

  7. 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

  8. Necrotizing pancreatitis: operating for life.

    PubMed

    Miller, B J; Henderson, A; Strong, R W; Fielding, G A; DiMarco, A M; O'Loughlin, B S

    1994-01-01

    Infected necrotizing pancreatitis is the most fulminant variety of this disease. Colonic involvement and retroperitoneal fasciitis are particularly lethal. The reported mortality is up to 50%. The purpose of this study is to review our combined experience at the Princess Alexandra Hospital and the Royal Brisbane Hospital, Brisbane, to determine whether patient survival was related to a particular etiology, treatment, or complication. All patients treated since 1986 with infected pancreatitis who required surgical necrosectomy and then ventilation in the intensive care unit (ICU) were studied. There were 48 patients so managed. The median age of survivors was 52 years, and for those who died it was 64 years (p = 0.001). The etiology was gallstones in 22 and alcoholism in 12. Of the alcoholics, 11 survived and 1 died. Of the patients with gallstones, 13 survived and 9 died. There was an overall mortality of 31%. Survivors were in hospital for a median of 73 days, whereas deaths occurred after a median of 35 days (p = 0.04). Seven patients underwent hemofiltration; five survived, and two died. N-Acetylcysteine has been used in four patients, of whom three survived and one died. The abdomen was left open in 38 patients and kept closed in 10. Although Ranson's criteria at admission to the ICU did not predict survival, it was found that the median APACHE II score in survivors was significantly lower than in those who died (p = 0.025).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7846917

  9. 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. PMID:26944316

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. Strain differences of cadmium-induced toxicity in rats: Insight from spleen and lung immune responses.

    PubMed

    Demenesku, Jelena; Popov Aleksandrov, Aleksandra; Mirkov, Ivana; Ninkov, Marina; Zolotarevski, Lidija; Kataranovski, Dragan; Brceski, Ilija; Kataranovski, Milena

    2016-08-10

    The impact of genetic background on effects of acute i.p. cadmium administration (0.5mg/kg and 1mg/kg) on basic immune activity of spleen and lungs was examined in two rat strains, Albino Oxford (AO) and Dark Agouti (DA), known to react differently to chemicals. More pronounced inhibition of Concanavalin A (ConA)-induced and Interleukin (IL)-2 stimulated spleen cell proliferation as well as higher levels of nitric oxide (known to decrease cell's proliferative ability) in DA rats at 1mg/kg, along with greater inhibition of ConA-induced Interferon (IFN-γ)-production by total and mononuclear (MNC) spleen cells and IL-17 production by spleen MNC in DA vs. AO rats at this dose show greater susceptibility of this strain to Cd effects on spleen cells response. More pronounced infiltration of neutrophils/CD11b(+) cells to lungs of DA rats treated with 1mg/kg of Cd and decreased IL-17 lung cell responses noted solely in DA rats speaks in favor of their higher susceptibility to this metal. However, lack of strain disparity in lung cells IFN-γ responses show that there are regional differences as well. Novel data from this study depict complexity of the influence of genetic background on the effects of cadmium on host immune reactivity. PMID:27234498

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: a review.

    PubMed Central

    Hartwig, A

    1994-01-01

    Compounds of lead and cadmium have been shown to be carcinogenic to humans and experimental animals. However, the underlying mechanisms are still not understood. In mammalian cells in culture, lead(II) is weakly mutagenic after long incubation times and generates DNA strand breaks only after treatment with high, toxic doses. Cadmium(II) induces DNA strand breaks and chromosomal aberrations, but its mutagenic potential is rather weak. However, both metals exert pronounced indirect genotoxic effects. Lead(II) is comutagenic towards UV and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and enhances the number of UV-induced sister chromatid exchanges in V79 Chinese hamster cells. With regard to DNA repair, lead(II) causes an accumulation of DNA strand breaks after UV-irradiation in HeLa cells, indicating an interference with the polymerization or ligation step in excision repair. Cadmium(II) enhances the mutagenicity of UV light in V79 Chinese hamster cells and an increased sensitivity toward UV light is observed in various rodent and human cell lines. Furthermore, an inhibition of unscheduled DNA synthesis after UV-irradiation and a partial inhibition of the removal of UV-induced DNA lesions has been shown. For both metals, the indirect genotoxic effects are observed at low, nontoxic concentrations, suggesting that an interference with DNA repair processes may be predominant at biologically relevant concentrations. This might also explain the conflicting results of epidemiological studies obtained for both metals. Possible mechanisms of repair inhibition are discussed. PMID:7843136

  3. Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways

    PubMed Central

    Han, Tao; Hu, Di; Wang, Yi; Yuan, Yan; Gu, Jianhong; Bian, Jianchun; Zhu, Jiaqiao; Liu, Zong-ping

    2015-01-01

    It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways. PMID:26070151

  4. Necrotizing soft-tissue infection: laboratory risk indicator for necrotizing soft tissue infections score.

    PubMed

    Kulkarni, Madhuri; Vijay Kumar, Gs; Sowmya, Gs; Madhu, Cp; Ramya, Sr

    2014-01-01

    Necrotizing soft tissue infections (NSTI) can be rapidly progressive and polymicrobial in etiology. Establishing the element of necrotizing infection poses a clinical challenge. A 64-year-old diabetic patient presented to our hospital with a gangrenous patch on anterior abdominal wall, which progressed to an extensive necrotizing lesion within 1 week. Successive laboratory risk indicator for necrotizing softtissue infections (LRINEC) scores confirmed the necrotizing element. Cultures yielded Enterococci, Acinetobacter species and Apophysomyces elegans and the latter being considered as an emerging agent of Zygomycosis in immunocompromised hosts. Patient was managed with antibiotics, antifungal treatment and surgical debridement despite which he succumbed to the infection. NSTI's require an early and aggressive management and LRINEC score can be applied to establish the element of necrotizing pathology. Isolation of multiple organisms becomes confusing to establish the etiological role. Apophysomyces elegans, which was isolated in our patient is being increasingly reported in cases of necrotizing infections and may be responsible for high morbidity and mortality. This scoring has been proposed as an adjunct tool to Microbiological diagnosis when NSTI's need to be diagnosed early and managed promptly to decrease mortality and morbidity, which however may not come in handy in an immunocompromised host with polymicrobial aggressive infection. PMID:24696561

  5. 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

  6. Microbial shifts associated with necrotic enteritis.

    PubMed

    Antonissen, Gunther; Eeckhaut, Venessa; Van Driessche, Karolien; Onrust, Lonneke; Haesebrouck, Freddy; Ducatelle, Richard; Moore, Robert J; Van Immerseel, Filip

    2016-06-01

    An outbreak of necrotic enteritis (NE) is a complex process requiring one or a number of predisposing factors rather than just the presence of pathogenic Clostridium perfringens. Examples are dietary influences, such as high levels of non-starch polysaccharides and fishmeal, and factors that evoke epithelial cell damage, such as Fusarium mycotoxins in feed and Eimeria infections. Recent studies have shown that different predisposing factors induce similar shifts in the intestinal microbiota composition. Butyrate-producing-strains of the Ruminococcaceae family are decreased in abundance by both fishmeal and Eimeria. Similarly, a decreased abundance of butyrate-producing-strains belonging to the Lachnospiraceae family has been induced by fishmeal. Also shifts are observed in the lactic acid-producing bacteria, such as decreased abundance of Lactobacillus johnsonii or Weissella confusa, when broilers were fed a fishmeal-based diet or a Fusarium mycotoxin contaminated diet. Finally, the abundance of Candidatus Savagella was decreased in broilers following Eimeria challenge or feeding a fumonisins contaminated diet. The nature of the microbiota shifts indicate that immune modulatory actions of the intestinal microbiota may play a critical role in the effect on the necrosis inducing activity of C. perfringens. Indeed, colonization with butyrate-producing bacteria plays a key role in counteracting inflammation in the gut and preserving intestinal integrity, while Candidatus Savagella is involved in stimulating Th17 and immunoglobulin A responses. Lactic acid bacteria stimulate colonization of lactate-utilizing and butyrate-producing Lachnospiraceae. Future research needs to clarify the role of the microbiota changes in the pathogenesis of NE. PMID:26950294

  7. 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

  8. 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

  9. 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

  10. 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

  11. Cadmium induces apoptosis in primary rat osteoblasts through caspase and mitogen-activated protein kinase pathways

    PubMed Central

    Zhao, Hongyan; Liu, Wei; Wang, Yi; Dai, Nannan; Gu, Jianhong; Yuan, Yan; Liu, Xuezhong; Bian, Jianchun

    2015-01-01

    Exposure to cadmium (Cd) induces apoptosis in osteoblasts (OBs); however, little information is available regarding the specific mechanisms of Cd-induced primary rat OB apoptosis. In this study, Cd reduced cell viability, damaged cell membranes and induced apoptosis in OBs. We observed decreased mitochondrial transmembrane potentials, ultrastructure collapse, enhanced caspase-3 activity, and increased concentrations of cleaved PARP, cleaved caspase-9 and cleaved caspase-3 following Cd treatment. Cd also increased the phosphorylation of p38-mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK)1/2 and c-jun N-terminal kinase (JNK) in OBs. Pretreatment with the caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, ERK1/2 inhibitor (U0126), p38 inhibitor (SB203580) and JNK inhibitor (SP600125) abrogated Cd-induced cell apoptosis. Furthermore, Cd-treated OBs exhibited signs of oxidative stress protection, including increased antioxidant enzymes superoxide dismutase and glutathione reductase levels and decreased formation of reactive oxygen species. Taken together, the results of our study clarified that Cd has direct cytotoxic effects on OBs, which are mediated by caspase- and MAPK pathways in Cd-induced apoptosis of OBs. PMID:26425111

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. Metallothionein from Pseudosciaena crocea: expression and response to cadmium-induced injury in the testes.

    PubMed

    Sheng, Zhang; Yang, Wan-Xi; Zhu, Jun-Quan

    2015-05-01

    Metallothioneins (MTs) are a family of stress proteins that are involved in the process of detoxification and anti-oxidation. Previous studies have focused mostly on the expression and functions of MTs in the non-reproductive tissues of aquatic vertebrates. However, there have been only a few reports regarding the functions of MTs in the reproductive tissues of such vertebrates. In order to investigate the function of MTs during spermatogenesis in Pseudosciaena crocea, reverse-transcription polymerase chain reaction (PCR) and rapid amplification of cDNA ends were performed to obtain the P. crocea MT complete cDNA sequence from the total RNA of the testes for the first time. MT was detected in the liver, kidneys, testes, spleen, gill and muscle of P. crocea by tissue-specific expression analysis. Meanwhile, immunohistochemistry staining indicated that the MT protein was localized in germ cells, Sertoli cells and the peripheral connective tissues in P. crocea testes. Furthermore, acute toxicity tests were conducted with cadmium (Cd) to determine the 96 h-medial lethal concentration value. The toxic effects of Cd on the microstructure and ultrastructure of the testes were observed. In addition, the changes in MT mRNA expression levels in the testes after Cd exposure were measured using real-time quantitative PCR. Consequently, we suggest that MTs play an important role in spermatogenesis and testes protection against Cd toxicity in P. crocea. PMID:25680968

  20. 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

  1. Necrotizing fasciitis: a rare complication of appendicitis.

    PubMed

    Mazza, J F; Augenstein, J S; Kreis, D J

    1987-09-01

    The mortality of acute appendicitis increases sixfold if perforation occurs. We have reported a case of perforated appendix complicated by necrotizing fasciitis of the abdominal wall and retroperitoneum. We believe this complication has not been previously described in the English literature. PMID:2957793

  2. Calciphylaxis causing necrotizing mastitis: a case report.

    PubMed

    Kay, P A; Sanchez, W; Rose, J F; Farley, D R; Reynolds, C

    2001-12-01

    Calciphylaxis is a rare condition most commonly related to ESRD and hyperparathyroidism. We report a case of necrotizing mastitis caused by calciphylaxis following routine breast biopsy for microcalcifications. Early recognition of the potential for this condition should help in clinical management of patients with calciphylaxis. PMID:14965637

  3. 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

  4. 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

  5. [Cadmium-induced cytotoxicity and intracellular Ca2+ alteration in hepatocytes and protection by selenium].

    PubMed

    Wang, Sha Sha; Chen, Long; Xia, Shu Kai; Jiang, Shan Xiang

    2006-08-01

    than in control cells and showed a dose-dependent manner,however, [Ca2+]i level of administered Se in hepatocytes was not enhanced and near to that of control cells. [Ca2+]i level of administered Se in Cd-exposed hepatocytes greatly decreased compared with Cd-exposed cells and significantly lower values of administered Se in 25 micromol/L CdCl2-exposed hepatocytes were observed and near to that of control cells. These results suggest that Cd induce cytotoxicity and damage as well as [Ca2+]i elevation in hepatocytes. Se can relieve the process of cytotoxicity and damage by intervening lipid peroxidation,improving and protecting [Ca2+]i homeostasis in Cd-induced hepatocytes. PMID:16955793

  6. 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

  7. Cadmium-induced fetal growth retardation: protective effect of excess dietary zinc

    SciTech Connect

    Ahokas, R.A.; Dilts, P.V. Jr.; LaHaye, E.B.

    1980-01-15

    Reproductive performance and fetal cellular growth and development were investigated in laboratory rats chronically fed low drinking water levels (0, 1.0, 10.0, and 100 ..mu..g/ml) of cadmium (Cd), a known embryotoxic trace element, through gestation. Maternal daily food and water consumption, total weight gain, maternal weight gain, and feed efficiency all decreased with increasing Cd consumption. Term fetal weight was significantly less than that of control subjects only in the group fed 100 ..mu..g Cd/ml drinking water. Total litter weight, however, gradually decreased with increasing Cd concentration due to reduced litter size. Fetal growth retardation was a result of decreased cell division (DNA) and cell growth (protein/DNA ratio). When dams were pair-fed the average daily amount of food consumed by those fed 100 ..mu..g Cd/ml drinking water, maternal weight gain and fetal weight, DNA, and protein/DNA ratio were increased, but not to control levels. Dietary zinc (Zn) supplementation (5.0 ..mu..g/ml drinking water) of Cd-fed dams increased maternal food consumption and fetal weight, DNA, and protein/DNA ratio to control levels. Fetal levels of Cd were extremely low (0.038 to 0.095 ..mu..g/gm fetus) and did not increase with increasing Cd consumption, while placental Cd increased more than 10-fold. Fetal Zn was decreased in Cd-fed dams, and Zn supplementation increased fetal Zn levels, but not to control levels.These results suggest that Cd-induced fetal growth retardation is an indirect rather than a direct effect, resulting from reduced maternal food consumption and metabolism. Since dietary Zn blocks these effects, Cd may be a result of induced Zn deficiency.

  8. [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

  9. 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.

  10. Cadmium-induced formation of sulphide and cadmium sulphide particles in the aquatic hyphomycete Heliscus lugdunensis.

    PubMed

    Dobritzsch, Dirk; Ganz, Petra; Rother, Michael; Ehrman, James; Baumbach, Renate; Miersch, Jürgen

    2015-01-01

    Freshwater fungi which can survive under metal exposure receive increasing scientific attention. Enhanced synthesis of sulphide and glutathione but no phytochelatin synthesis in response to cadmium (up to 80 μM Cd(2+) in the medium) was measured in the aquatic hyphomycete Heliscus lugdunensis. Up to 25 μmol g(-1) dry mass the fungus formed sulphide in an exponentially Cd(2+)-concentration-dependent manner. Using light microscopy, precipitates were observed outside of the hyphae which could be determined as amorphous particles by X-ray diffraction (XRD). Energy dispersive X-ray spectroscopy (EDS) analysis indicated that these particles were mainly composed of Cd and S with an atomic ratio of 1:1, but some elements of the culture medium such as P and Cl were also present. Fungal cells exposed to Cd(2+) accumulated 12-28 μmol metal g(-1) dry mass over a period of 7-28 days. The results may indicate that sulphide could sequester excess Cd(2+) under oxygen deprived conditions and thereby reduce its toxicity via an additional avoidance mechanism of this fungus. PMID:26004898

  11. 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.

  12. 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

  13. Pathogenesis and modification of cadmium-induced lung injury in mice

    SciTech Connect

    Martin, F.M.

    1984-01-01

    The effects of hyperoxia on Cd-damaged mouse lungs were studied to determine if there was potentiation of the injury by O/sub 2/. Female Balb/c mice were exposed to aerosols of 0.65% CdCl/sub 2/ for one hour by the nose-only method while control animals were exposed to water aerosols. Immediately after, some animals were placed in 70 to 80% O/sub 2/ for days, while others were left in room air. Cd exposed animals had significantly increased levels of hydroxyproline/lung, indicative of increased collagen secretion and hence fibrosis. The Cd + O/sub 2/ exposed animals had even higher levels showing the synergistic effects of O/sub 2/. Experiments on the effects of prednisolone and X radiation in modifying the Cd-induced injury were also done but neither showed any alteration of the Cd-induced lesion. Pretreatment with 1 mg/kg of Cd i.p. for 4 days before Cd inhalation was also shown not to alter fibrosis. Investigations were made of the long term effects of Cd + O/sub 2/ on the fibrotic lesion. Mechanisms of the action of Cd, and a literature survey are included. The study provides an experimental model for the interactions of two inhalants, Cd and O/sub 2/, and elucidates the behavior of different cell populations following injury.

  14. 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

  15. Arsenic- and Cadmium-Induced Toxicogenomic Response in Mouse Embryos Undergoing Neurulation

    PubMed Central

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

    2010-01-01

    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 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. PMID:20883709

  16. Mechanism of cadmium-induced contraction in ileal longitudinal muscle of guinea-pig.

    PubMed Central

    Asai, F.; Nishimura, M.; Satoh, E.; Urakawa, N.

    1982-01-01

    1 The mechanism of cadmium (Cd2+)-induced contraction was studied in isolated ileal longitudinal muscle of guinea-pig. 2 CdCl2 (1x10(-8) to 1x10-4M)) caused a transient contraction which subsided within approximately 6 min of application. The contraction was reproducible and dependent on the concentration. The dose-response curve was bell-shaped. A maximal response was observed at concentrations of 5x10(-6) to 1x10(-5) M. 3 The contractile effect was inhibited to some degree at 20 degree C or by tetrodotoxin (0.1 microgram/ml), hyoscine (o.1 microgram/ml), but completely inhibited by Ca2+ -removal from the medium. 4 Cd2+ increased the output of [14C]-acetylcholine biosynthesized from [14C] by the preparation depending on the concentration. The increase terminated within the first 6 min and was reduced by tetrodotoxin (0.1 microgram/ml) or by removal of Ca2+ from the medium. 5 Both the contractile and transmitter releasing effects of Cd2+ were dependent on the concentration of external Ca2+. Strontium ions were able to replace Ca2+ -induced transmitter release. 6 It is suggested that Cd2+ contracts ileal longitudinal muscle through a release of cholinergic transmitter from the parasympathetic nerve terminals, which is dependent on external Ca2+. It also has a smaller hyoscine-resistant contractile effect, presumably due to a direct action on smooth muscle cells. PMID:7066605

  17. Cadmium-induced genomic instability in Arabidopsis: Molecular toxicological biomarkers for early diagnosis of cadmium stress.

    PubMed

    Wang, Hetong; He, Lei; Song, Jie; Cui, Weina; Zhang, Yanzhao; Jia, Chunyun; Francis, Dennis; Rogers, Hilary J; Sun, Lizong; Tai, Peidong; Hui, Xiujuan; Yang, Yuesuo; Liu, Wan

    2016-05-01

    Microsatellite instability (MSI) analysis, random-amplified polymorphic DNA (RAPD), and methylation-sensitive arbitrarily primed PCR (MSAP-PCR) are methods to evaluate the toxicity of environmental pollutants in stress-treated plants and human cancer cells. Here, we evaluate these techniques to screen for genetic and epigenetic alterations of Arabidopsis plantlets exposed to 0-5.0 mg L(-1) cadmium (Cd) for 15 d. There was a substantial increase in RAPD polymorphism of 24.5, and in genomic methylation polymorphism of 30.5-34.5 at CpG and of 14.5-20 at CHG sites under Cd stress of 5.0 mg L(-1) by RAPD and of 0.25-5.0 mg L(-1) by MSAP-PCR, respectively. However, only a tiny increase of 1.5 loci by RAPD occurred under Cd stress of 4.0 mg L(-1), and an additional high dose (8.0 mg L(-1)) resulted in one repeat by MSI analysis. MSAP-PCR detected the most significant epigenetic modifications in plantlets exposed to Cd stress, and the patterns of hypermethylation and polymorphisms were consistent with inverted U-shaped dose responses. The presence of genomic methylation polymorphism in Cd-treated seedlings, prior to the onset of RAPD polymorphism, MSI and obvious growth effects, suggests that these altered DNA methylation loci are the most sensitive biomarkers for early diagnosis and risk assessment of genotoxic effects of Cd pollution in ecotoxicology. PMID:26907594

  18. 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

  19. 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

  20. Necrotic ulcer: a manifestation of leukemia cutis.

    PubMed

    Aksu, Ayse Esra Koku; Saracoglu, Zeynep Nurhan; Sabuncu, Ilham; Ciftci, Evrim; Gulbas, Zafer; Isiksoy, Serap

    2012-01-01

    A 71-year-old man presented to our dermatological clinic with a 3-month history of a wound on his leg. He complained of weakness for the past few months. On his dermatological examination he had a 3x3-cm necrotic ulcer on his left tibia (Figure 1). On physical examination, there was 1 x 1-cm axillary lymphadenopathy. There was no other lymph node enlargement, hepatosplenomegaly, or gingival hypertrophy. Peripheral blood results showed 2.4x103/mm3 leukocytes (normal range 4-11 x 103/mm3) with 66% neutrophils. The hemoglobin value was 10.1 g/dL (13-18 g/dL), and the platelet count was 63x103/mm3 (150-440 x 103/mm3). No blasts were detected in a peripheral blood smear. His lactate dehydrogenase level was 567 U/L (240-480 U/L). All other results of blood chemistry were within normal limits. Punch biopsy of the skin lesion showed ulceration and dense dermal acute and chronic inflammation. There was a superficial and deep perivascular and periadnexal infiltrate of neoplastic cells composed of relatively abundant eosinophilic cytoplasm and large nuclei with blastic chromatin and occasional small nucleoli (Figure 2). Mitotic figures were prominent. Immunohistochemical stains were performed, and the neoplastic cells were CD3, CD20, CD138, and S100 protein negative. Myeloperoxidase and CD68 were positive. The histopathological findings were consistent with leukemic infiltration. Examination of bone marrow biopsy revealed that the blastic cells constituted more than 20% of the bone marrow cellularity. Cytogenetic analysis of bone marrow aspiration with fluorescence in situ hybridization was negative for inversion 16, t(8;21) and t(15;7). Histochemical stains for myeloperoxidase, sudan black, periodic acid-Schiff, and alpha naphthyl acetate were also negative. Blastic cells were DR, CD13, CD117, and CD34 positive and CD5, CD7, CD10, CD14, CD19, CD20, CD33, CD41, CD56, CD64, and CD79 negative according to flow cytometry immunophenotyping. Blastic cells were 35% in the bone

  1. Macrophage Supply and Demand at the Core of the Necrotic Granuloma.

    PubMed

    Randolph, Gwendalyn J

    2015-07-01

    Central necrosis of granulomas is linked to progression of major diseases, including tuberculosis and atherosclerosis. In this issue of Cell Host & Microbe, Pagán et al. (2015) reveal that necrotic granulomas develop when macrophage supply is insufficient. These findings suggest augmenting macrophage availability as a therapeutic strategy in tuberculosis. PMID:26159712

  2. Necrotizing pancreatitis: a review of multidisciplinary management.

    PubMed

    Sabo, Anthony; Goussous, Naeem; Sardana, Neeraj; Patel, Shirali; Cunningham, Steven C

    2015-03-01

    The objective of this review is to summarize the current state of the art of the management of necrotizing pancreatitis, and to clarify some confusing points regarding the terminology and diagnosis of necrotizing pancreatitis, as these points are essential for management decisions and communication between providers and within the literature. Acute pancreatitis varies widely in its clinical presentation. Despite the publication of the Atlanta guidelines, misuse of pancreatitis terminology continues in the literature and in clinical practice, especially regarding the local complications associated with severe acute pancreatitis. Necrotizing pancreatitis is a manifestation of severe acute pancreatitis associated with significant morbidity and mortality. Diagnosis is aided by pancreas-protocol computed tomography or magnetic resonance imaging, ideally 72 h after onset of symptoms to achieve the most accurate characterization of pancreatic necrosis. The extent of necrosis correlates well with the incidence of infected necrosis, organ failure, need for debridement, and morbidity and mortality. Having established the diagnosis of pancreatic necrosis, goals of appropriately aggressive resuscitation should be established and adhered to in a multidisciplinary approach, ideally at a high-volume pancreatic center. The role of antibiotics is determined by the presence of infected necrosis. Early enteral feeds improve outcomes compared with parenteral nutrition. Pancreatic necrosis is associated with a multitude of complications which can lead to long-term morbidity or mortality. Interventional therapy should be guided by available resources and the principle of a minimally invasive approach. When open debridement is necessary, it should be delayed at least 3-6 weeks to allow demarcation of necrotic from viable tissue. PMID:25791545

  3. 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

  4. 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

  5. [Cutaneous necrotic loxoscelism. A case report].

    PubMed

    Sánchez-Olivas, Manuel Anastacio; Valencia-Zavala, Martha Patricia; Sánchez-Olivas, Jesús Alberto; Sepulveda-Velázquez, Guadalupe; Vega-Robledo, Gloria

    2011-01-01

    Brown recluse (Loxosceles spp.) spiders are arachnid species known to cause necrotic arachnidism. The envenomation, described as loxoscelism, is associated with localized pain, erythema, and edema followed by the development of necrosis. However, the specific pathophysiological mechanisms by which Loxosceles venom exerts these noxious symptoms are multifactorial and not fully understood. The causative factor for production of necrotic lesions is generally considered to be the enzyme sphingomyelinase D (SMD), which cleaves sphingomyelin to form choline and ceramide 1-phosphate. Four active forms of SMD with molecular weight of 32 000 are found in L recluse. Sphingomyelinases of comparable size are also described in the venoms of Loxosceles intermedia, gaucho and laeta. Here we describe the case of a young male adult who suffered a spider bite on his left forearm which evolved into a necrotic lesion, and after a few days the injury healed completely. One week later the patient developed two similar lesions on his left leg. The diagnosis was established by clinical data and by biopsy findings. The patient did not developed systemic complications. PMID:22027681

  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. Necrotic enteritis in young calves.

    PubMed

    Morris, Winston E; Venzano, Agustín J; Elizondo, Ana; Vilte, Daniel A; Mercado, Elsa C; Fernandez-Miyakawa, Mariano E

    2011-03-01

    Non-enterotoxin (CPE)-producing Clostridium perfringens type A has been associated with enteritis in calves. Recent evidence has suggested that a novel toxin, named beta2 (CPB2), is implicated in the pathogenesis of this disease, although there is little evidence supporting this. In the current study, the role of C. perfringens type A in an outbreak of enteritis in calves was studied. Two 20-day-old dairy calves exhibiting apathy and reluctance to eat, with paresis of the anterior limbs, were euthanized for postmortem examination. Gross and histological changes compatible with acute enteritis, rumenitis, meningitis, and pneumonia were seen in both calves. Clostridium perfringens type A non-CPE, non-CPB2 was isolated from the abomasum and the small intestine. Escherichia coli ONTH8 (with cdtBIII and f17 virulence genes detected by polymerase chain reaction) was also isolated from the brain, abomasum, and intestine from both calves. All the samples were negative for Salmonella spp. When the C. perfringens strain was inoculated into bovine ligated small and large intestinal loops, cell detachment, erosion, and hemorrhage of the lamina propria were observed, predominantly in the small intestine. The results suggest that non-CPE, non-CPB2 C. perfringens type A is able to induce pathologic changes in the intestine of calves, probably enhanced by other pathogens, such as some pathogenic E. coli strains. PMID:21398444

  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. The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD.

    PubMed

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

    2015-09-01

    Mycobacterium tuberculosis (Mtb) induces necrosis of infected cells to evade immune responses. Recently, we found that Mtb uses the protein CpnT to kill human macrophages by secreting its C-terminal domain, named tuberculosis necrotizing toxin (TNT), which 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 coenzyme NAD(+). Expression or injection of a noncatalytic TNT mutant showed no cytotoxicity in macrophages or in zebrafish zygotes, respectively, thus 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 new NAD(+) glycohydrolase fold of TNT, the founding member of a toxin family widespread in pathogenic microorganisms. PMID:26237511

  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. 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

  12. [Necrotizing cutaneous infections and Fournier's gangrene].

    PubMed

    Lasocki, S; Geffroy, A; Montravers, P

    2006-09-01

    Fournier's gangrene is a necrotizing infection of skin and soft tissue of the perineum. Several sources of contamination have been described: cutaneous, urological or anorectal. Anatomy of the perineum helps in the prediction of the extension of the infection. The bacterial flora (usually mixed aero-anaerobic flora) depends on the source of infection: gram-positive cocci (skin source) combined with gram-negative bacilli and anaerobes (urological or anorectal source). CT scan and echography are useful tools for the diagnosis without delaying surgery. In the diagnostic procedure and the management, proctological examination, retrograde uretrography, bowel and urine derivation should be discussed. PMID:16675183

  13. Multidisciplinary intensive care in extensive necrotizing fasciitis.

    PubMed

    Tu, Guo-Wei; Hwabejire, J O; Ju, Min-Jie; Yang, Yuan-Feng; Zhang, Guang-Jian; Xu, Jian-Wei; Xue, Zhang-Gang; Jiang, Chun; Jiang, C; Luo, Zhe; Luo, Z

    2013-04-01

    This is a case report of extensive necrotizing fasciitis (NF). A 65-year-old man presented with high fever, pain, swelling, and redness of the perineum, scrotum, and right lower limb. Based on the clinical symptoms and an imaging examination, a diagnosis of NF was made. The patient underwent an extensive exploration followed by daily bedside debridement. A diversion colostomy and six additional debridement procedures on the right thigh and perineum were subsequently performed. Although the patient had an eventful course, he recovered well under a multidisciplinary treatment regimen. The treatment and hospital course of the patient are described. PMID:23104255

  14. Necrotizing fasciitis caused by Aeromonas caviae

    PubMed Central

    Kumar, Simit; Mukhopadhyay, Prabir; Chatterjee, Mitali; Bandyopadhyay, Manas K; Bandyopadhyay, Maitreyi; Ghosh, Tapashi; Samaddar, Debopriyo

    2012-01-01

    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. PMID:23826556

  15. 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

  16. Timing of predisposing factors is important in necrotic enteritis models.

    PubMed

    Van Waeyenberghe, Lieven; De Gussem, Maarten; Verbeke, Joren; Dewaele, Isabelle; De Gussem, Jeroen

    2016-06-01

    Since the ban of antimicrobial growth promotors, the importance of necrotic enteritis in broilers increases. Reliable and reproducible infection models are required for pathogenesis studies and product screening. Two major predisposing factors in necrotic enteritis models are fishmeal supplementation to feed and Eimeria infection. However, many unsolved issues regarding these predisposing factors still exist. Therefore, the influence of timepoint of fishmeal administration (onset on day 8 or day 18), timing of coccidiosis challenge (day 15 or day 19) and strain of coccidiosis challenge (field strain vs. commercial vaccine) on the induction of necrotic enteritis lesions was investigated. The birds were inoculated with Clostridium perfringens three times per day for four consecutive days (day 17 until day 20) and were scored for the presence of necrotic enteritis on days 22, 23, 24, 25 and 26. Supplementation of the diet with fishmeal from day 8 onwards increased the likelihood of necrotic enteritis compared to supplementation from day 18 onwards. Birds challenged on day 19 with coccidiosis were more likely to have necrotic enteritis on scoring days 23 and 24 compared to birds challenged on day 15. Differences on other scoring days were less pronounced. Finally, the strain of coccidiosis challenge had little influence on the induction of necrotic enteritis. Findings of this study can help researchers to set up successful necrotic enteritis infection models. PMID:26927291

  17. 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

  18. Necrotizing fasciitis as the clinical presentation of a retroperitoneal abscess.

    PubMed

    Amitai, Allon; Sinert, Richard

    2008-01-01

    Infections of the retroperitoneal space may present with insidiously vague symptoms and non-specific clinical signs. We report a case of a retroperitoneal abscess presenting as necrotizing fasciitis of the thigh from direct spread over the iliac crest. In cases of necrotizing fasciitis of the thigh with no obvious source, an intra-abdominal nidus of infection may be considered. PMID:17976803

  19. Acute necrotizing encephalopathy of childhood: report of a Spanish case.

    PubMed

    San Millan, Beatriz; Teijeira, Susana; Penin, Carmen; Garcia, Jose L; Navarro, Carmen

    2007-12-01

    Acute necrotizing encephalopathy of childhood is a rare disease with a broad clinical, radiologic, and biochemical spectrum. In the few postmortem studies published to date, the neuropathologic findings involved symmetric, necrotic brain lesions as the hallmark. Here we report on the clinical and neuropathologic findings of a Spanish child with the most severe form of the disease. PMID:18021928

  20. 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

  1. 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.

  2. [NECROTIZING FASCIITIS OF THE CHEST WALL].

    PubMed

    Farah, Raymond; Asla, Husam

    2016-04-01

    Necrotizing fasciitis (NF) is a bacterial dermo-hypodermitis affecting the soft tissue and muscular fascia. It is an uncommon and severe infection caused by microorganisms called 'flesh eating bacteria', mainly represented by group A beta-haemolytic streptococcus. NF remains a life-threatening condition associated with a high mortality rate. Its location on the chest wall is extremely rare. The few reported cases are subsequent to thoracic drainage, lung surgery or esophageal resection. This is a case report of an 80-year old female with comorbidity of heart disease, a past history of coronary artery by-pass and diabetes. She was admitted to the emergency room with acute NF of the chest and shortly after diagnosis, the patient died. Due to the fast decline observed in this disease, we would like to emphasize the importance of early recognition and diagnosis. PMID:27323534

  3. Epidemic occurrence of neonatal necrotizing enterocolitis.

    PubMed

    Guinan, M; Schaberg, D; Bruhn, F W; Richardson, C J; Fox, W W

    1979-06-01

    In case-control studies of three epidemics of neonatal necrotizing enterocolitis (NEC) in three different high-risk nurseries in three states, no particular risk factor was associated with affected infants or their mothers. Epidemic cases had higher birth weights and Apgar scores and fewer perinatal difficulties than those previously reported for sporadic cases. Seven infants fed primarily breast milk were not protected against disease. Early antibiotic therapy was associated with a significantly decreased risk of disease in one outbreak. In two hospitals, affected infants who received antibiotic therapy during the first three days of life had a significantly later disease onset. The occurrence of the disease in epidemics and the decreased risk or modification of disease with antibiotic therapy support an infectious etiology for NEC. PMID:108997

  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. 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

  6. Necrotizing arteritis causing fatal massive intraperitoneal hemorrhage from a pancreatic pseudocyst.

    PubMed

    Ito, Y; Tanegashima, A; Nishi, K; Sukegawa, Y; Kimura, H

    1994-01-01

    We report the histopathological findings from a medicolegal autopsy case caused by sudden massive hemorrhage from a necrotic pancreatic cyst into the abdominal cavity. The histological examination revealed that the wall of the cyst was filled with hematoma and consisted of granuloma at a relative early stage, involving marginating lymphocytes, foamy lipophages, cholesterin crystals, foreign body giant cells with neutrophiles, mast cells and fibrous tissues. Since there was no epithelial lining, the lesion was diagnosed as a pseudocyst. In the wall of this pseudocyst, small arteries showed acute intense necrotizing inflammatory reactions in association with fresh thrombi. Trace of elastic fibers remained in the wall of the arteries. Since the small veins in the wall showed varix-like changes without necrosis or inflammation, it is proposed that the lethal bleeding was caused by rupture of the small arteries that exhibited severe arteritis. PMID:7947341

  7. Novel method for the detection of necrotic lesions in human cancers

    SciTech Connect

    Epstein, A.L.; Chen, F.M.; Taylor, C.R.

    1988-10-15

    Data are presented in support of the hypothesis that malignant tumors, containing abnormally permeable, degenerating cells, can be selectively detected using monoclonal antibodies to intracellular antigens. Biodistribution, imaging, and autoradiographic studies were performed in nude mice transplanted with four different human tumor cell lines to demonstrate the binding of radiolabeled antinuclear monoclonal antibodies within bulky tumors containing necrotic lesions. For these studies, two monoclonal antibodies, designated TNT-1 (IgG2a) and TNT-2 (IgM) were chosen since they were found to bind to abundant nuclear antigens which are retained in permeable, dying cells. F(ab')2 fragments prepared by pepsin digestion were radiolabeled with iodine-125 or iodine-131 by the iodogen method for i.v. administration. Biodistribution studies in nontumor-bearing BALB/c mice at various time intervals revealed normal patterns of antibody excretion with no accumulation of antibody in healthy organs. In contrast, biodistribution studies performed on Day 3 in tumor-bearing nude mice showed high tumor to organ ratios in those animals bearing necrotic tumors. Necrotic regions dissected at necropsy gave tumor to blood ratios as high as 131:1. Transplants having little demonstrable necrosis were found to have low tumor to blood ratios (0.4:1). Sequential imaging studies confirmed the high tumor-to-organ ratios and showed positive tumor imaging as early as 4 h. Autoradiographic studies of excised tumors showed the presence of label selectively in necrotic areas with preferential labeling over the nuclei of degenerating cells. Because of the universal presence of these nuclear antigens and the known prevalence of necrosis in tumors, this approach may be of value for the imaging and treatment of a wide variety of cancers in humans.

  8. SIGIRR Genetic Variants in Premature Infants With Necrotizing Enterocolitis

    PubMed Central

    Menden, Heather; Helbling, Daniel; Li, Keguo; Gastonguay, Adam; Ramchandran, Ramani; Dimmock, David P.

    2015-01-01

    Necrotizing enterocolitis (NEC) is a severe form of bowel disease that develops in premature infants. Although animal data and human studies suggest that aberrant activation of the intestinal immune system contributes to NEC, the pathogenesis remains unclear. We hypothesized that inherited defects in the regulation of Toll-like receptor signaling can contribute to NEC susceptibility in premature infants. A forward genetic screen done in an infant with lethal NEC using exome sequencing identified a novel stop mutation (p.Y168X) and a rare missense variant (p.S80Y) in SIGIRR, a gene that inhibits intestinal Toll-like receptor signaling. Functional studies carried out in human embryonic kidney cells and intestinal epithelial cells demonstrated that SIGIRR inhibited inflammation induced by lipopolysaccharide, a cell wall component of Gram-negative bacteria implicated in NEC. The genetic variants identified in the infant with NEC resulted in loss of SIGIRR function and exaggerated inflammation in response to lipopolysaccharide. Additionally, Sanger sequencing identified missense, stop, or splice region SIGIRR variants in 10 of 17 premature infants with stage II+ NEC. To the best of our knowledge, this is one of the first reports of a phenotype associated with SIGIRR in humans. Our data provide novel mechanistic insight into the probable causation of NEC and support additional investigation of the hypothesis that inherited defects in the regulation of innate immune signaling can contribute to NEC susceptibility in premature infants. PMID:25963006

  9. [Cosmetic blepharoplasty complicated by necrotizing periorbital fasciitis: a case report].

    PubMed

    Laouar, K; Ruban, J-M; Baggio, E; Dupeyron, G

    2012-06-01

    Necrotizing periorbital or palpebro-orbital fasciitis represents a unique anatomical site for necrotizing fasciitis, which is an extremely rare and very severe, potentially devastating bacterial infection, rapidly leading to facial necrosis with loss of vision and even death of the patient from toxic shock. In this paper, we report a case of necrotizing periorbital fasciitis as a complication of cosmetic lower eyelid blepharoplasty. Necrotizing fasciitis most often affects the upper and lower limbs, the trunk and the perineal area. It is rarely observed in the facial region due to the rich blood supply in this area. The most commonly implicated pathogen is group A, β-hemolytic "pyogenic"Streptococcus, either alone or in combination with other bacteria, such as staphylococcus or pseudomonas. Mortality varies according to the series and anatomical site. The mortality rate for necrotizing fasciitis is approximately 28 %. It is slightly lower in the periorbital area (15 %). Risk factors for death include alcoholism, diabetes mellitus, immunocompromise, hematologic or pulmonary diseases, and the identity of the causative agent (group A Streptococcus), although approximately 50 % of patients have no predisposing conditions. Management of periorbital necrotizing fasciitis is based on early detection of initial symptoms and on aggressive multidisciplinary treatment including surgical debridement of necrotic areas and antibiotic coverage. The timeliness of treatment and the multidisciplinary approach are considered to be the two essential factors in influencing the mortality and morbidity of this condition. PMID:22633216

  10. Polymicrobial abdominal wall necrotizing fasciitis after cesarean section.

    PubMed

    DeMuro, Jp; Hanna, Af; Chalas, E; Cunha, Ba

    2012-01-01

    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. PMID:24960796

  11. 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

  12. Argininosuccinate lyase in enterocytes protects from development of necrotizing enterocolitis.

    PubMed

    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; Lee, B

    2014-08-01

    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 (Asl(flox/flox); VillinCre(tg/+), 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

  13. 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

  14. 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

  15. Necrotizing pancreatitis: A review of the interventions.

    PubMed

    Bugiantella, Walter; Rondelli, Fabio; Boni, Marcello; Stella, Paolo; Polistena, Andrea; Sanguinetti, Alessandro; Avenia, Nicola

    2016-04-01

    Acute pancreatitis may have a wide range of severity, from a clinically self-limiting to a quickly fatal course. Necrotizing pancreatitis (NP) is the most dreadful evolution associated to a poor prognosis: mortality is approximately 15% and up to 30-39% in case of infected necrosis, which is the major cause of death. Intervention is generally required for infected pancreatic necrosis and less commonly in patients with sterile necrosis who are symptomatic (gastric or duodenal outlet or biliary obstruction). Traditionally the most widely used approach to infected necrosis has been open surgical necrosectomy, but it is burdened by high morbidity (34-95%) and mortality (11-39%) rates. In the last two decades the treatment of NP has significantly evolved from open surgery towards minimally invasive techniques (percutaneous catheter drainage, per-oral endoscopic, laparoscopy and rigid retroperitoneal videoscopy). The objective of this review is to summarize the current state of the art of the management of NP and to clarify some aspects about its diagnosis and treatment. PMID:26708848

  16. Fecal calprotectin concentration in neonatal necrotizing enterocolitis

    PubMed Central

    Park, Ju Yi; Ko, Kyung Ok; Lim, Jae Woo; Cheon, Eun Jeong; Kim, Hyo Jeong

    2014-01-01

    Purpose Among the many factors associated with acute intestinal mucosal infection, numerous studies have proposed the usefulness of fecal calprotectin. The aim of this study was to evaluate the usefulness of fecal calprotectin in the diagnosis of necrotizing enterocolitis (NEC). Methods We collected 154 stool samples from 16 very low birth weight and premature newborns at the Konyang University Hospital neonatal intensive care unit or neonatal nursery. The stool samples were collected using the Calprest device, and the fecal calprotectin level was measured with the BÜHLMANN Calprotectin enzyme-linked immunosorbent assay kit. Results Fecal calprotectin levels were significantly higher in the NEC group than in the non-NEC group (P=0.02). There was a significant positive linear relationship between the fecal calprotectin level and number of days after birth (P=0.00) in the gestational age <26 weeks group. There was a significant negative linear relationship between the calprotectin level and number of days after birth (P=0.03) in the gestational age ≥26 weeks and <30 weeks group. There was no difference in the calprotectin levels according to the type and method of feeding between the NEC and non-NEC groups. Conclusion Fecal calprotectin levels were significantly increased in premature infants with NEC. The fecal calprotectin test is a noninvasive, easy, and useful tool for the diagnosis of NEC. PMID:25210522

  17. Treatment and prevention of necrotizing enterocolitis.

    PubMed

    Lee, Jane S; Polin, Richard A

    2003-12-01

    Necrotizing enterocolitis (NEC) is the most common serious, acquired gastrointestinal disorder in the newborn infant. Although many variables are associated with development of NEC, only prematurity has been consistently identified in case-controlled studies. Traditionally, the diving seal reflex has been invoked as the mechanism responsible for ischaemic injury and necrosis. Intestinal ischaemia is likely to be the final common pathway in NEC; however, it is due to the release of vasoconstricting substances, such as platelet activating factor, rather than perinatal asphyxia. Bacteria and/or bacterial toxins are likely to have a key role in the pathogenesis of NEC by fostering production of inflammatory mediators. The role of feeding practices in the pathogenesis of NEC remains controversial. Treatment of infants with NEC generally includes a regimen of bowel rest, gastric decompression, systemic antibiotics and parenteral nutrition. Infants with perforation are generally operated upon; however, there has been recent interest in primary peritoneal drainage as an alternative. Prevention of NEC still remains elusive. Avoidance of preterm birth, use of antenatal steroids and breast-milk feeding are practices that offer the greatest potential benefits. Use of any other strategy should await further trials. PMID:15001117

  18. [NUG--necrotizing ulcerative gingivitis: a review].

    PubMed

    Mizrahi, Y

    2014-07-01

    Necrotizing Ulcerative Gingivitis (NUG) is an acute and rare (0.5-11% of the population) infectious disease of the gum tissue, which is characterized by ulceration and inflammation of the inter-dental gum tissue. NUG was documented by historians since the fourth century BC, most of the reports from the ancient world were in the context of illness among fighting troops, present studies of NUG in the modern world are still common among soldiers. NUG is associated with poor oral hygiene and weakening of the host, especially in immunocompromised patients, malnutrition and poor living conditions, as well as in the context of mental stress. NUG is more common in young adults, but reports of morbidity in young children with malnutrition in the background are not uncommon. NUG diagnosis is based on three essential symptoms: sore gums, bleeding gums and the most diagnostic characteristic, ulceration and necrosis of the interdental papillae. The disease is considered to have a clear initial infectious etiology, when the main bacteria, associated with the disease, include: Bacteroides intermedius and Fusobacterium sp. The infection involves anaerobic \\ aerobic bacteria with a majority of Gram-negative bacteria. The treatment of NUG is based on combining mechanical removal of tartar with local and systemic delivery of antimicrobial agents. Adequate treatment usually prevent the progression of the disease and ulcer healing is expected in a few days. Nevertheless, lack of treatment can lead to deterioration in the form NUP to Noma. PMID:25219100

  19. Descending necrotizing mediastinitis complicating hyperimmunoglobulin E syndrome

    PubMed Central

    Hayakawa, Takamitsu; Neyatani, Hiroshi; Funai, Kazuhito

    2016-01-01

    Abstract Descending necrotizing mediastinitis (DNM) is a potentially lethal disease that originates from a deep neck infection (DNI); it is often associated with an immunocompromised state. Hyperimmunoglobulin E syndrome (HIES) is an extremely rare complex immune deficiency characterized by recurrent abscesses of staphylococcal etiology. A rare case of a 34‐year‐old woman wherein HIES putatively promoted the development of DNI into DNM is described. She presented with cervical purulent lymphadenitis and retropharyngeal abscess. Despite immediate cervical drainage and use of broad‐spectrum antibiotics, she developed DNI and subsequently DNM. Mediastinal drainage with thoracotomy and subsequent deep neck drainage were performed. Bacterial culture of the abscess isolated methicillin‐resistant Staphylococcus aureus (MRSA). Although a postoperative recurrent deep neck abscess required a second surgery, we succeeded in conservative remission of recurrent mediastinal abscess with long‐term use of anti‐MRSA drugs. Sufficient drainage under thoracotomy and robust administration of postoperative antibiotics resulted in successful management of HIES‐associated DNM. PMID:27512566

  20. 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

  1. 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

  2. Case Report of Necrotizing Fasciitis Associated with Streptococcus pneumoniae.

    PubMed

    Jiao, Lei; Chagla, Zain; Kaki, Reham Mohammedsaeed; Gohla, Gabriela; Smieja, Marek

    2016-01-01

    Necrotizing fasciitis, caused by Streptococcus pneumoniae, is an extremely rare and life-threatening bacterial soft tissue infection. We report a case of early necrotizing fasciitis associated with Streptococcus pneumoniae infection in a 26-year-old man who was immunocompromised with mixed connective tissue disease. The patient presented with acute, painful, erythematous, and edematous skin lesions of his right lower back, which rapidly progressed to the right knee. The patient underwent surgical exploration, and a diagnosis of necrotizing fasciitis was confirmed by pathological evidence of necrosis of the fascia and neutrophil infiltration in tissue biopsies. Cultures of fascial tissue biopsies and blood samples were positive for Streptococcus pneumoniae. To our knowledge, this is the first report of necrotizing fasciitis resulting from Streptococcus pneumoniae diagnosed at early phase; the patient recovered well without surgical debridement. PMID:27366176

  3. Avian necrotic enteritis: Experimental models, climate change, and vaccine development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review summarizes recent developments in disease models, pathogenesis, host immunity, risk factors, and vaccine development for Clostridium perfringens infection of poultry and necrotic enteritis (NE). The increasing trends of legislative restrictions and voluntary removal of antibiotic growth...

  4. 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...

  5. Necrotizing stomatitis: report of 3 Pseudomonas aeruginosa-positive patients.

    PubMed

    Barasch, Andrei; Gordon, Sara; Geist, Rose Y; Geist, James R

    2003-08-01

    Necrotizing oral lesions have been described in immunosuppressed patients, usually in association with gingival and periodontal pathoses. The etiology of these lesions has not been completely elucidated. We present 3 patients with a type of necrotizing stomatitis in which clinical patterns appear distinct from the periodontal forms of the disease. The lesions yielded bacterial cultures positive for Pseudomonas aeruginosa and reverted to no growth in 2 patients after proper antibiotic therapy. We propose that P aeruginosa may be responsible for selected necrotizing oral lesions with a clinical presentation lacking typical necrotizing periodontal disease and that this condition may represent the intraoral counterpart of ecthyma gangrenosum. In such cases, bacterial culture of the lesion becomes imperative because the disease does not respond to typical periodontal and antimicrobial therapy. PMID:12931084

  6. Descending necrotizing Mediastinitis caused by Kocuria rosea: a case report

    PubMed Central

    2013-01-01

    Background Kocuria species are gram-positive, non-pathogenic commensals. However, in immunocompromised patients such as transplant recipients, cancer patients, or patients with chronic medical conditions, they can cause opportunistic infections. Case presentation We report the first case of descending necrotizing mediastinitis in a 58-year-old, relatively healthy woman caused by Kocuria rosea. Conclusion Descending necrotizing mediastinitis due to Kocuria rosea can be successfully treated with prompt surgical drainage combined with antimicrobial therapy. PMID:24112281

  7. Retroperitoneal necrotizing fasciitis in a 4-year-old girl.

    PubMed

    Paya, K; Hayek, B F; Rebhandl, W; Pollak, A; Horcher, E

    1998-05-01

    Necrotizing fasciitis is a rare but serious condition with a poor prognosis both in adults and in children. Retroperitoneal localization is mostly associated with fatal outcome. Early diagnosis, extensive and repeated surgical debridement, and use of antibiotics are necessary. Herein the authors report on a 4-year-old girl in whom retroperitoneal necrotizing fasciitis developed after she suffered from pyelonephritis. In this case, the outcome was favorable because of early surgical intervention, confirming the diagnosis. PMID:9607500

  8. Necrotizing Soft Tissue Infection Caused by Spilled Gallstones

    PubMed Central

    Pandit, Narendra; Kumar, Hemanth; Verma, GR

    2016-01-01

    We report a case of a 57-year-old woman who presented with a necrotizing soft tissue infection of the right anterior abdominal wall, 1 year after open cholecystectomy for gallbladder perforation. Surgical exploration revealed pigmented gallstones along with pus in the abdominal wall and gallbladder fossa. Intraoperative spillage of gallstones is common during both open and laparoscopic cholecystectomy, but, in rare cases, can lead to serious complications including necrotizing infection of the abdominal wall. PMID:27144208

  9. Necrotic platelets provide a procoagulant surface during thrombosis.

    PubMed

    Hua, Vu Minh; Abeynaike, Latasha; Glaros, Elias; Campbell, Heather; Pasalic, Leonardo; Hogg, Philip J; Chen, Vivien M Y

    2015-12-24

    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. 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

  11. 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

  12. Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans

    PubMed Central

    Coburn, Cassandra; Allman, Erik; Mahanti, Parag; Benedetto, Alexandre; Cabreiro, Filipe; Pincus, Zachary; Matthijssens, Filip; Araiz, Caroline; Mandel, Abraham; Vlachos, Manolis; Edwards, Sally-Anne; Fischer, Grahame; Davidson, Alexander; Pryor, Rosina E.; Stevens, Ailsa; Slack, Frank J.; Tavernarakis, Nektarios; Braeckman, Bart P.; Schroeder, Frank C.; Nehrke, Keith; Gems, David

    2013-01-01

    For cells the passage from life to death can involve a regulated, programmed transition. In contrast to cell death, the mechanisms of systemic collapse underlying organismal death remain poorly understood. Here we present evidence of a cascade of cell death involving the calpain-cathepsin necrosis pathway that can drive organismal death in Caenorhabditis elegans. We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway. Such death fluorescence marks an anterior to posterior wave of intestinal cell death that is accompanied by cytosolic acidosis. This wave is propagated via the innexin INX-16, likely by calcium influx. Notably, inhibition of systemic necrosis can delay stress-induced death. We also identify the source of the blue fluorescence, initially present in intestinal lysosome-related organelles (gut granules), as anthranilic acid glucosyl esters—not, as previously surmised, the damage product lipofuscin. Anthranilic acid is derived from tryptophan by action of the kynurenine pathway. These findings reveal a central mechanism of organismal death in C. elegans that is related to necrotic propagation in mammals—e.g., in excitotoxicity and ischemia-induced neurodegeneration. Endogenous anthranilate fluorescence renders visible the spatio-temporal dynamics of C. elegans organismal death. PMID:23935448

  13. Cadmium-Induced Apoptosis in Primary Rat Cerebral Cortical Neurons Culture Is Mediated by a Calcium Signaling Pathway

    PubMed Central

    Xu, Hui; Sun, Ya; Hu, Fei-fei; Bian, Jian-chun; Liu, Xue-zhong; Gu, Jian-hong; Liu, Zong-ping

    2013-01-01

    Cadmium (Cd) is an extremely toxic metal, capable of severely damaging several organs, including the brain. Studies have shown that Cd disrupts intracellular free calcium ([Ca2+]i) homeostasis, leading to apoptosis in a variety of cells including primary murine neurons. Calcium is a ubiquitous intracellular ion which acts as a signaling mediator in numerous cellular processes including cell proliferation, differentiation, and survival/death. However, little is known about the role of calcium signaling in Cd-induced apoptosis in neuronal cells. Thus we investigated the role of calcium signaling in Cd-induced apoptosis in primary rat cerebral cortical neurons. Consistent with known toxic properties of Cd, exposure of cerebral cortical neurons to Cd caused morphological changes indicative of apoptosis and cell death. It also induced elevation of [Ca2+]i and inhibition of Na+/K+-ATPase and Ca2+/Mg2+-ATPase activities. This Cd-induced elevation of [Ca2+]i was suppressed by an IP3R inhibitor, 2-APB, suggesting that ER-regulated Ca2+ is involved. In addition, we observed elevation of reactive oxygen species (ROS) levels, dysfunction of cytochrome oxidase subunits (COX-I/II/III), depletion of mitochondrial membrane potential (ΔΨm), and cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) during Cd exposure. Z-VAD-fmk, a pan caspase inhibitor, partially prevented Cd-induced apoptosis and cell death. Interestingly, apoptosis, cell death and these cellular events induced by Cd were blocked by BAPTA-AM, a specific intracellular Ca2+ chelator. Furthermore, western blot analysis revealed an up-regulated expression of Bcl-2 and down-regulated expression of Bax. However, these were not blocked by BAPTA-AM. Thus Cd toxicity is in part due to its disruption of intracellular Ca2+ homeostasis, by compromising ATPases activities and ER-regulated Ca2+, and this elevation in Ca2+ triggers the activation of the Ca2+-mitochondria apoptotic signaling pathway. This

  14. 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.

  15. Two successive necrotic lesions secondary to presumed loxosceles envenomation.

    PubMed

    Tarullo, David B; Jacobsen, Ryan C; Algren, D Adam

    2013-06-01

    Brown recluse spider (Loxosceles reclusa) envenomations with subsequent necrotic skin lesions occur infrequently, and systemic loxoscelism is rarer still. We report a case of 2 successive developing necrotic lesions, each on adjacent medial aspects of the legs, secondary to presumed Loxosceles envenomation. A 31-year-old man with no significant past medical history presented to the emergency department with 2, large, necrotic lesions, 1 on each medial thigh. They had progressed over the course of 1 month from small blisters to large necrotic lesions with eschar. He underwent surgical debridement without skin grafting with no further complications. Bites from recluse spiders that progress to necrosis usually present as single lesions. The differential diagnoses for a necrotic skin lesion is large. The presence of more than 1 lesion argues against Loxosceles envenomation; however, in the absence of underlying infection, systemic diseases, immunodeficiency, or malignancy, the diagnosis must be considered if the case presents in an endemic area. Brown recluse spiders rarely bite multiple times, thus confounding the diagnosis of an already nonspecific clinical finding. PMID:23352313

  16. 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. PMID:26294949

  17. 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

  18. 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

  19. 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

  20. 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. PMID:23921771

  1. Necrotizing scleritis as a complication of cosmetic eye whitening procedure

    PubMed Central

    2013-01-01

    Background We report necrotizing scleritis as a serious complication of a cosmetic eye whitening procedure that involves the use of intraoperative and postoperative topical mitomycin C. Findings This is a single case report. A 59-year-old Caucasian male with a history of blepharitis status post uncomplicated LASIK refractive surgery reported chronic conjunctival hyperemia for 15 years prior to undergoing a cosmetic eye whitening procedure. He presented to our clinic 12 months after the cosmetic eye whitening procedure with progressive bilateral necrotizing scleritis and scleral calcification. Conclusions Chronic conjunctival hyperemia may prompt patients to seek surgical correction with cosmetic eye whitening procedures. However, conjunctival hyperemia secondary to tear deficiency and evaporative dry eye may predispose to poor wound healing. Serious complications including necrotizing scleritis may result from cosmetic eye whitening procedures and the use of topical mitomycin C. PMID:23514228

  2. Massive soft tissue infections: necrotizing fasciitis and purpura fulminans.

    PubMed

    Edlich, Richard F; Winters, Kathryne L; Woodard, Charles R; Britt, L D; Long, William B

    2005-01-01

    Necrotizing fasciitis and purpura fulminans are two destructive infections that involve both skin and soft tissue. Necrotizing fasciitis is characterized by widespread necrosis of subcutaneous tissue and the fascia. Historically, group A beta-hemolytic streptococcus has been identified as a major cause of this infection. However, this monomicrobial infection is usually associated with some underlying cause, such as diabetes mellitus. During the last two decades, scientists have found that the pathogenesis of necrotizing fasciitis is polymicrobial. The diagnosis of necrotizing fasciitis must be made as soon as possible by examining the skin inflammatory changes. Magnetic resonance imaging is strongly recommended to detect the presence of air within the tissues. Percutaneous aspiration of the soft tissue infection followed by prompt Gram staining should be conducted with the "finger-test" and rapid-frozen section biopsy examination. Intravenous antibiotic therapy is one of the cornerstones of managing this life-threatening skin infection. Surgery is the primary treatment for necrotizing fasciitis, with early surgical fasciotomy and debridement. Following debridement, skin coverage by either Integra Dermal Regeneration Template or AlloDerm should be undertaken. Hyperbaric oxygen therapy complemented by intravenous polyspecific immunoglobulin are useful adjunctive therapies. Purpura fulminans is a rare syndrome of intravascular thrombosis and hemorrhagic infarction of the skin; it is rapidly progressive and accompanied by vascular collapse. There are three types of purpura fulminans: neonatal purpura fulminans, idiopathic or chronic purpura fulminans, and acute infectious purpura fulminans. Clinical presentation of purpura fulminans involves a premonitory illness followed by the rapid development of a septic syndrome with fever, shock, and disseminated intravascular coagulation. The diagnosis and treatment of these conditions is best accomplished in a regional burn

  3. 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

  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. Bacillus cereus necrotizing pneumonia in a patient with nephrotic syndrome.

    PubMed

    Miyata, Jun; Tasaka, Sadatomo; Miyazaki, Masaki; Yoshida, Syuichi; Naoki, Katsuhiko; Sayama, Koichi; Asano, Koichiro; Fujiwara, Hiroshi; Ohkusu, Kiyofumi; Hasegawa, Naoki; Betsuyaku, Tomoko

    2013-01-01

    Bacillus cereus (B. cereus) is a Gram-positive rod that is widely distributed in the environment and can be a cause of food poisoning. We herein present a case of B. cereus necrotizing pneumonia in a patient with nephrotic syndrome under corticosteroid treatment after developing transient gastroenteritis symptoms. B. cereus was isolated from bronchial lavage fluid and transbronchial biopsy specimens. A multiplex polymerase chain reaction analysis of the toxin genes revealed a strain possessing enterotoxicity. The patient recovered after one week of intravenous meropenem followed by a combination of oral moxifloxacin and clindamycin. B. cereus is a pathogen that causes necrotizing pneumonia in immunocompromised hosts. PMID:23291682

  6. 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

  7. Acinar inflammatory response to lipid derivatives generated in necrotic fat during acute pancreatitis.

    PubMed

    Mateu, A; Ramudo, L; Manso, M A; Closa, D; De Dios, I

    2014-09-01

    Lipids play a role in acute pancreatitis (AP) progression. We investigate the ability of pancreatic acinar cells to trigger inflammatory response in the presence of lipid compounds generated in necrotic areas of peripancreatic adipose tissue (AT) during AP induced in rats by 5% sodium taurocholate. Lipid composition of AT was analyzed by HPLC-mass spectrometry. Acinar inflammatory response to total lipids as well as to either the free fatty acid (FFA) fraction or their chlorinated products (Cl-FFAs) was evaluated. For this, mRNA expression of chemokine (C-C motif) ligand 2 (CCL2) and P-selectin as well as the activation of MAPKs, NF-κB and STAT-3 were analyzed in pancreatic acini. Myeloperoxidase (MPO) activity, as an inducer of Cl-FFA generation, was also analyzed in AT. MPO activity significantly increased in necrotic (AT-N) induced changes in lipid composition of necrotic fat, such as increase in FFA and phospholipid (PL) content, generation of Cl-FFAs and increases in saturated FFAs and in the poly-:mono-unsaturated FFA ratio. Total lipids from AT-N induced overexpression of CCL2 and P-selectin in pancreatic acini as well as MAPKs phosphorylation and activation of NF-κB and STAT3. FFAs, but not Cl-FFAs, up-regulated CCL2 and P-selectin in acinar cells. We conclude that FFAs are capable of up-regulating inflammatory mediators in pancreatic acini and given that they are highly produced during AP, mainly may contribute to the inflammatory response triggered in acinar cells by fat necrosis. No role is played by Cl-FFAs generated as a result of neutrophil infiltration. PMID:24959971

  8. 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

  9. 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

  10. 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

  11. 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

  12. Carcinogenic sulfide salts of nickel and cadmium induce H2O2 formation by human polymorphonuclear leukocytes.

    PubMed

    Zhong, Z J; Troll, W; Koenig, K L; Frenkel, K

    1990-12-01

    Some derivatives of nickel, cadmium, and cobalt are carcinogenic in humans and/or animals but their mechanisms of action are not known. We show that they are capable of stimulating human polymorphonuclear leukocytes (PMNs), as measured by H2O2 formation, a known tumor promoter. Most effective were the carcinogens nickel subsulfide, which caused a 550% net increase in H2O2 over that formed by resting PMNs, followed by cadmium sulfide, 400%, and nickel disulfide, 200%. Nickel sulfide and cobalt sulfide caused statistically nonsignificant increases of 45 and 20%, respectively. Noncarcinogenic barium and manganese sulfides, and sulfates of nickel, cadmium, and cobalt were inactive. The enhancement of H2O2 formation by CdS and Ni3S2 (1 mumol/2.5 x 10(5) PMNs) was comparable to that mediated by the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate, used at 0.5 and 1 nM, respectively. Concurrent treatment of 12-O-tetradecanoylphorbol-13-acetate-stimulated PMNs with Ni3S2 or NiS caused a decrease in H2O2 accumulation from that expected if the effects were additive. Including catalase in the reaction mixture proved that the oxidant formed by stimulated PMNs was H2O2, whereas adding superoxide dismutase showed that superoxide was also present in PMN samples treated with NiS but not with Ni3S2. Since nickel- and cadmium-containing particulates are deposited in the lungs and cause infiltration of PMNs, the ability to activate those cells and induce H2O2 formation may contribute to their carcinogenicity. PMID:2253206

  13. Crystallization and preliminary X-ray diffraction analysis of red clover necrotic mosaic virus

    SciTech Connect

    Martin, Stanton L.; Guenther, Richard H.; Sit, Tim L.; Swartz, Paul D.; Meilleur, Flora; Lommel, Steven A.; Rose, Robert B.

    2010-11-12

    Red clover necrotic mosaic virus (RCNMV) is a species that belongs to the Tombusviridae family of plant viruses with a T = 3 icosahedral capsid. RCNMV virions were purified and were crystallized for X-ray analysis using the hanging-drop vapor-diffusion method. Self-rotation functions and systematic absences identified the space group as I23, with two virions in the unit cell. The crystals diffracted to better than 4 {angstrom} resolution but were very radiation-sensitive, causing rapid decay of the high-resolution reflections. The data were processed to 6 {angstrom} in the analysis presented here.

  14. The necrotic venom of the brown recluse spider induces dysregulated endothelial cell-dependent neutrophil activation. Differential induction of GM-CSF, IL-8, and E-selectin expression.

    PubMed Central

    Patel, K D; Modur, V; Zimmerman, G A; Prescott, S M; McIntyre, T M

    1994-01-01

    Brown recluse spider (Loxosceles reclusa) venom induces severe dermonecrotic lesions. The mechanism for this is unknown but presents an interesting paradox: necrosis is completely dependent on the victim's neutrophils, yet neutrophils are not activated by the venom. We show Loxosceles venom is a potent, but disjointed, endothelial cell agonist. It weakly induced E-selectin expression, but not intercellular adhesion molecule-1 or IL-6 expression, yet significantly stimulated release of IL-8 and large amounts of GM-CSF by 4 h. In contrast, TNF strongly induced all of these, except for GM-CSF. PMN bound to E-selectin on venom-activated endothelial cells, apparently via counterreceptors different from those that bind E-selectin on TNF alpha-activated monolayers. Notably, PMN bound venom-activated monolayers only at intercellular junctions, did not polarize, and completely failed to migrate beneath the monolayer. Despite this, bound PMN demonstrated increased intracellular Ca2+ levels and secreted primary and secondary granule markers. The latter event was suppressed by sulfones used to treat envenomation. We have defined a new endothelial cell agonist, Loxosceles venom, that differentially stimulates the inflammatory response of endothelial cells. This, in turn, leads to a dysregulated PMN response where adhesion and degranulation are completely dissociated from shape change and transmigration. Images PMID:7518841

  15. 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. PMID:20831135

  16. 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 ...

  17. [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

  18. 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

  19. 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...

  20. Dietary lactose and its effects on the disease necrotic enteritis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clostridium perfringens (CP) is the etiologic agent of Necrotic enteritis (NE) and is ubiquitous in nature. The incidence of NE has increased in poultry flocks that have stopped using antibiotic growth promoters. The mechanisms of colonization of CP and the factors involved in onset of NE are not ...

  1. 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

  2. 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

  3. Characterization of the cadmium complex of peptide 49-61: a putative nucleation center for cadmium-induced folding in rabbit liver metallothionein IIA.

    PubMed

    Muñoz, A; Laib, F; Petering, D H; Shaw, C F

    1999-08-01

    The synthetic peptide fragment containing residues 49-61 of rabbit liver metallothionein II (MT-II) (Ac-Ile-Cys-Lys-Gly-Ala-Ser-Asp-Lys-Cys-Ser-Cys-Cys-Ala-COOH), which includes the only sequential four cysteines bound to the same metal ion in Cd7MT, forms a stable, monomeric Cd-peptide complex with 1:1 stoichiometry (Cd:peptide) via Cd-thiolate interactions. This represents the first synthesis of a single metal-binding site of MT independent of the domains. The 111Cd NMR chemical shift at 716 ppm indicates that the 111Cd2+ in the metal site is terminally coordinated to four side-chain thiolates of the cysteine residues. The pH of half dissociation for this Cd-peptide derivative, approximately 3.3, demonstrates an affinity similar to that for Cd7MT. Molecular mechanics calculations show that the thermodynamically most stable folding for this isolated Cd2+ center has the same counterclockwise chirality (lambda or S) observed in the native holo-protein. These properties are consistent with its proposed role as a nucleation center for cadmium-induced protein folding. However, the kinetic reactivity of the CdS4 structure toward 5,5'-dithiobis(5-nitrobenzoate) (DTNB) and EDTA is greatly increased compared to the complete cluster (a-domain or holo-protein). The rate law for the reaction with DTNB is rate = (k(uf) + k(1,f) + k(2,f) [DTNB])[peptide], where k(uf) = 0.15 s(-1), k(1,f)= 2.59x10(-3) s(-1), and k(2,f) = 0.88 M(-1) s(-1). The ultrafast step (uf), observable only by stopped-flow measurement, is unprecedented for mammalian (M7MT) and crustacean (M6MT) holo-proteins or the isolated domains. The accommodation of other metal ions by the peptide indicates a rich coordination chemistry, including stoichiometries of M-peptide for Hg2+, Cd2+, and Zn2+, M2-peptide for Hg2+ and Au+, and (Et3PAu)2-peptide. PMID:10555583

  4. 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

  5. Cobra venom cytotoxins; apoptotic or necrotic agents?

    PubMed

    Ebrahim, Karim; Shirazi, Farshad H; Mirakabadi, Abbas Zare; Vatanpour, Hossein

    2015-12-15

    Organs homeostasis is controlled by a dynamic balance between cell proliferation and apoptosis. Failure to induction of apoptosis has been implicated in tumor development. Cytotoxin-I (CTX-I) and cytotoxin-II (CTX-II) are two physiologically active polypeptides found in Caspian cobra venom. Anticancer activity and mechanism of cell death induced by these toxins have been studied. The toxins were purified by different chromatographic steps and their cytotoxicity and pattern of cell death were determined by MTT, LDH release, acridine orange/ethidium bromide (AO/EtBr) double staining, flow cytometric analysis, caspase-3 activity and neutral red assays. The IC50 of CTX-II in MCF-7, HepG2, DU-145 and HL-60 was 4.1 ± 1.3, 21.2 ± 4.4, 9.4 ± 1.8 μg/mL and 16.3 ± 1.9 respectively while the IC50 of this toxin in normal MDCK cell line was 54.5 ± 3.9 μg/mL. LDH release suddenly increase after a specific toxins concentrations in all cell lines. AO/EtBr double staining, flow cytometric analysis and caspase-3 activity assay confirm dose and time-dependent induction of apoptosis by both toxins. CTX-I and CTX-II treated cells lost their lysosomal membrane integrity and couldn't uptake neutral red day. CTX-I and CTX-II showed significant anticancer activity with minimum effects on normal cells and better IC50 compared to current anticancer drug; cisplatin. They induce their apoptotic effect via lysosomal pathways and release of cathepsins to cytosol. These effects were seen in limited rage of toxins concentrations and pattern of cell death rapidly changes to necrosis by increase in toxin's concentration. In conclusion, significant apoptogenic effects of these toxins candidate them as a possible anticancer agent. PMID:26482932

  6. Pyelonephritis can be a source of a life-threatening necrotizing myofasciitis

    PubMed Central

    Kamel, Haytham; Awed, Mohamed Soliman Edris; Kotb, Ahmed Fouad

    2014-01-01

    Necrotizing fasciitis is a progressive, rapidly spreading, inflammatory infection located in deep fascia. It may cause necrosis of skin and subcutaneous tissue and can even results in involvement of adjacent soft tissues such as muscles resulting in necrotizing myositis. We report the case of an adult male presenting with necrotizing myofasciitis secondary to left pyelonephritis. We also review the relevant literature. PMID:25024809

  7. Cervical necrotizing fasciitis caused by Serratia marcescens in a 2 year old.

    PubMed

    Newton, Christopher L; deLEMOS, David; Abramo, Thomas J; Murrey, Allen; Noell, Courtney

    2002-12-01

    We report an unusual, life-threatening complication of producing fulminant cervical necrotizing fasciitis in a previously healthy 2-year-old girl. We reviewed the literature for necrotizing fasciitis in children and its morbidity, mortality, and treatment. This case illustrates the necessity of prompt recognition and aggressive management in patients presenting with cervical necrotizing fasciitis. PMID:12488837

  8. 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.

  9. 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

  10. 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

  11. Vanadate induces necrotic death in neonatal rat cardiomyocytes through mitochondrial membrane depolarization.

    PubMed

    Soares, Sandra Sofia; Henao, Fernando; Aureliano, Manuel; Gutiérrez-Merino, Carlos

    2008-03-01

    Besides the well-known inotropic effects of vanadium in cardiac muscle, previous studies have shown that vanadate can stimulate cell growth or induce cell death. In this work, we studied the toxicity to neonatal rat ventricular myocytes (cardiomyocytes) of two vanadate solutions containing different oligovanadates distribution, decavanadate (containing decameric vanadate, V 10) and metavanadate (containing monomeric vanadate and also di-, tetra-, and pentavanadate). Incubation for 24 h with decavanadate or metavanadate induced necrotic cell death of cardiomyocytes, without significant caspase-3 activation. Only 10 microM total vanadium of either decavanadate (1 microM V 10) or metavanadate (10 microM total vanadium) was needed to produce 50% loss of cell viability after 24 h (assessed with MTT and propidium iodide assays). Atomic absorption spectroscopy showed that vanadium accumulation in cardiomyocytes after 24 h was the same when incubation was done with decavanadate or metavanadate. A decrease of 75% of the rate of mitochondrial superoxide anion generation, monitored with dihydroethidium, and a sustained rise of cytosolic calcium (monitored with Fura-2-loaded cardiomyocytes) was observed after 24 h of incubation of cardiomyocytes with decavanadate or metavanadate concentrations close to those inducing 50% loss of cell viability produced. In addition, mitochondrial membrane depolarization within cardiomyocytes, monitored with tetramethylrhodamine ethyl esther or with 3,3',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide, were observed after only 6 h of incubation with decavanadate or metavanadate. The concentration needed for 50% mitochondrial depolarization was 6.5 +/- 1 microM total vanadium for both decavanadate (0.65 microM V 10) and metavanadate. In conclusion, mitochondrial membrane depolarization was an early event in decavanadate- and monovanadate-induced necrotic cell death of cardiomyocytes. PMID:18251508

  12. Timing of catheter drainage in infected necrotizing pancreatitis.

    PubMed

    van Grinsven, Janneke; van Santvoort, Hjalmar C; Boermeester, Marja A; Dejong, Cornelis H; van Eijck, Casper H; Fockens, Paul; Besselink, Marc G

    2016-05-01

    Acute pancreatitis is the most common gastrointestinal indication for hospital admission, and infected pancreatic and/or extrapancreatic necrosis is a potentially lethal complication. Current standard treatment of infected necrosis is a step-up approach, consisting of catheter drainage followed, if necessary, by minimally invasive necrosectomy. International guidelines recommend postponing catheter drainage until the stage of 'walled-off necrosis' has been reached, a process that typically takes 4 weeks after onset of acute pancreatitis. This recommendation stems from the era of primary surgical necrosectomy. However, postponement of catheter drainage might not be necessary, and earlier detection and subsequent earlier drainage of infected necrosis could improve outcome. Strong data and consensus among international expert pancreatologists are lacking. Future clinical, preferably randomized, studies should focus on timing of catheter drainage in patients with infected necrotizing pancreatitis. In this Perspectives, we discuss challenges in the invasive treatment of patients with infected necrotizing pancreatitis, focusing on timing of catheter drainage. PMID:26956064

  13. 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

  14. [Pyoderma gangraenosum. Case report and comparison with necrotizing fasciitis].

    PubMed

    Heermann, R; Kiehl, P; Issing, P R; Lenarz, T

    2002-03-01

    The differential diagnosis of patients with ulcerative trachelophyma repeatedly causes difficulties. Particularly in view of the possibly fatal outcome, early differentiation between two clinical pictures is very important. Necrotizing fasciitis is often misdiagnosed or the diagnosis is delayed with a mortality rate of approximately 25-40%. It is characterized by local disintegration of the subcutaneous fascia and extensive gangrene of the skin. Sometimes it is not even possible to control the disease using combined antibiotics. Early surgical exploration is mandatory to stop progression of the disease. Pyoderma gangrenosum develops following an initial lesion with pustules and bullae in an ulceration with slight bleeding. Therapy consists of i.v. glucocorticoids (60-200 mg prednisolone/day) administered as early as possible. In complete contrast to the therapy for necrotizing fasciitis, surgical intervention should be strictly avoided in cases of pyoderma gangrenosum. PMID:11975081

  15. 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

  16. Retroperitoneal necrotizing fasciitis - when a simple procedure turns ugly.

    PubMed

    Alvi, Abdul; Shamsi, Ghina

    2009-01-01

    We present a case series of patients who underwent simple perianal procedures outside this hospital but developed postoperative and life-threatening retroperitoneal necrotizing fasciitis. With a high index of clinical suspicion and radiological imaging, we were able to establish earlier diagnosis. Resuscitation, the use of intravenous broad-spectrum antibiotics, aggressive surgical debridement and continuous organ support were essential in achieving a positive outcome in both of these patients. PMID:19211434

  17. Intestinal failure following necrotizing enterocolitis: A clinical approach.

    PubMed

    Jones, Kelsey D J; Howarth, Lucy J

    2016-06-01

    Intestinal failure is a recognized complication of surgically-managed necrotizing enterocolitis (NEC). Functional adaptation of remaining bowel means that many children are eventually able to achieve enteral autonomy. Integrated multidisciplinary care in the early post-operative phase is key to long-term success. The objective of this review is to outline a clinical approach to management of intestinal and nutritional complications experienced by children following intestinal resection for NEC. PMID:27080372

  18. 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

  19. Necrotizing postsurgical infection complicating midurethral sling procedure with unrecognized cystotomy.

    PubMed

    Mahal, Amandeep Singh; Bradley, Catherine S

    2012-01-01

    A 39-year-old woman with stress urinary incontinence underwent a retropubic midurethral sling procedure. On postoperative day 1, she presented with persistent abdominal pain and fever. A computed tomographic scan showed subcutaneous lower abdominal wall edema and gas above the fascia suggesting a necrotizing soft tissue infection. She was surgically debrided twice, which included removal of the mesh sling on postoperative day 4. Cystoscopy suggested unrecognized bladder perforation had occurred during the initial procedure, and record rerevealed untreated bacteriuria before sling placement. The patient required wound vacuum therapy and a later secondary wound closure procedure. Six months after the initial surgery, she was reevaluated for stress urinary incontinence and underwent a transobturator midurethral sling procedure with resolution of these symptoms. Necrotizing postsurgical infection is a rarely described complication of midurethral slings. Treatment for this potentially life-threatening complication includes aggressive surgical debridement, administration of broad-spectrum antibiotic, removal of infected implants, and supportive therapy. Unrecognized bladder injury and preoperative bacteriuria are discussed as potential risk factors for postsling necrotizing infection. PMID:22543774

  20. 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

  1. Necrotizing fasciitis caused by perforated appendicitis: a case report

    PubMed Central

    Hua, Jie; Yao, Le; He, Zhi-Gang; Xu, Bin; Song, Zhen-Shun

    2015-01-01

    Acute appendicitis is one of the most common causes of acute abdominal pain. Accurate diagnosis is often hindered due to various presentations that differ from the typical signs of appendicitis, especially the position of the appendix. A delay in diagnosis or treatment may result in increased risks of complications, such as perforation, which is associated with increased morbidity and mortality rates. Necrotizing fasciitis caused by perforated appendicitis is extremely rare. We herein report a case of 50-year-old man presenting with an appendiceal abscess in local hospital. After ten days of conservative treatment with intravenous antibiotics, the patient complained about pain and swelling of the right lower limb and computed tomography (CT) demonstrated a perforated appendix and gas and fluid collection extending from his retroperitoneal cavity to the subcutaneous layer of his right loin and right lower limb. He was transferred to our hospital and was diagnosed with necrotizing fasciitis caused by perforated appendicitis. Emergency surgery including surgical debridement and appendectomy was performed. However, the patient died of severe sepsis and multiple organ failure two days after the operation. This case represents an unusual complication of a common disease and we should bear in mind that retroperitoneal inflammation and/or abscesses may cause necrotizing fasciitis through lumbar triangles. PMID:26045863

  2. Necrotizing fasciitis caused by perforated appendicitis: a case report.

    PubMed

    Hua, Jie; Yao, Le; He, Zhi-Gang; Xu, Bin; Song, Zhen-Shun

    2015-01-01

    Acute appendicitis is one of the most common causes of acute abdominal pain. Accurate diagnosis is often hindered due to various presentations that differ from the typical signs of appendicitis, especially the position of the appendix. A delay in diagnosis or treatment may result in increased risks of complications, such as perforation, which is associated with increased morbidity and mortality rates. Necrotizing fasciitis caused by perforated appendicitis is extremely rare. We herein report a case of 50-year-old man presenting with an appendiceal abscess in local hospital. After ten days of conservative treatment with intravenous antibiotics, the patient complained about pain and swelling of the right lower limb and computed tomography (CT) demonstrated a perforated appendix and gas and fluid collection extending from his retroperitoneal cavity to the subcutaneous layer of his right loin and right lower limb. He was transferred to our hospital and was diagnosed with necrotizing fasciitis caused by perforated appendicitis. Emergency surgery including surgical debridement and appendectomy was performed. However, the patient died of severe sepsis and multiple organ failure two days after the operation. This case represents an unusual complication of a common disease and we should bear in mind that retroperitoneal inflammation and/or abscesses may cause necrotizing fasciitis through lumbar triangles. PMID:26045863

  3. 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

  4. Necrotic pyknosis is a morphologically and biochemically distinct event from apoptotic pyknosis.

    PubMed

    Hou, Lin; Liu, Kai; Li, Yuhong; Ma, Shuang; Ji, Xunming; Liu, Lei

    2016-08-15

    Classification of apoptosis and necrosis by morphological differences has been widely used for decades. However, this usefulness of this method has been seriously questioned in recent years, mainly due to a lack of functional and biochemical evidence to interpret the morphology changes. To address this matter, we devised genetic manipulations in Drosophila to study pyknosis, a process of nuclear shrinkage and chromatin condensation that occurs in apoptosis and necrosis. By following the progression of necrotic pyknosis, we surprisingly observed a transient state of chromatin detachment from the nuclear envelope, followed by the nuclear envelope completely collapsing onto chromatin. This phenomenon led us to discover that phosphorylation of barrier-to-autointegration factor (BAF) mediates this initial separation of nuclear envelope from chromatin. Functionally, inhibition of BAF phosphorylation suppressed necrosis in both Drosophila and human cells, suggesting that necrotic pyknosis is conserved in the propagation of necrosis. In contrast, during apoptotic pyknosis the chromatin did not detach from the nuclear envelope and inhibition of BAF phosphorylation had no effect on apoptotic pyknosis and apoptosis. Our research provides the first genetic evidence supporting a morphological classification of apoptosis and necrosis through different forms of pyknosis. PMID:27358477

  5. 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

  6. 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

  7. 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

  8. Necrotizing Sialometaplasia of the Hard Palate: A Rare Entity of Dilemma on Cytology, Confirmatory on Histopathology

    PubMed Central

    Chowdappa, Vijaya; Devasamudra, Chidananda R.; Janardhan, Jayalakshmi Valligari

    2015-01-01

    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. PMID:26816899

  9. Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de Novo DNA methyltransferase

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aberrant DNA methylation is common in carcinogenesis. The typical pattern appears to involve reduced expression of maintenance DNA methyltransferase, DNMT1, inducing genomic hypomethylation, whereas increased expression of de novo DNMT3a or 3b causes gene-specific hypermethylation. During cadmium-in...

  10. Ipilimumab-induced necrotic myelopathy in a patient with metastatic melanoma: A case report and review of literature.

    PubMed

    Abdallah, Al-Ola; Herlopian, Aline; Ravilla, Rahul; Bansal, Meghana; Chandra-Reddy, Sowmya; Mahmoud, Fade; Ong, Shirley; Gokden, Murat; Hutchins, Laura

    2016-06-01

    Ipilimumab is a novel humanized monoclonal antibody directed against cytotoxic T lymphocyte antigen 4, a T-cell surface molecule involved in down-regulation and suppression of the T cell response to stimuli. Patients treated with ipilimumab are at risk for immune-related adverse events involving the skin, digestive tract, liver and endocrine organs. Few case reports of immune-related adverse effects involving central or peripheral nervous system due to ipilimumab are published. These include inflammatory myopathy, aseptic meningitis, severe meningo-radiculo-neuritis, temporal arteritis, Guillain-Barre syndrome, and posterior reversible encephalopathy syndrome. We report the first case of ipilimumab-induced progressive necrotic myelopathy. PMID:25712627

  11. 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

  12. 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

  13. 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

  14. [Necrotizing gastritis in a patient in severe neutropenia].

    PubMed

    Pielaciński, Konrad; Lech-Marańda, Ewa; Warzocha, Krzysztof; Dedecjus, Marek; Prochorec-Sobieszek, Monika; Szczepanik, Andrzej B

    2014-12-01

    One extremely rare complication of chemotherapy for hematologic malignancies that is burdened with a high mortality rate (50%-80%) is necrotizing gastritis and gastric gangrene as result of poor clinical outcome of neutropenic gastritis (NG). We present a unique case of a neutropenic patient with necrotizing full thickness gastritis due to bacterial and fungal infection. Up to date only few such cases have been reported in world literature. A 28-year-old patient was subjected to dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), (chemotherapy regimen) for Hodgkin lymphoma. In neutropenic patient abdominal pain, bleeding from the alimentary tract was observed. Hemorrhagic gastritis was recognized at endoscopy and CT demonstrated marked gastric wall thickness. Following NG diagnosis intensive treatment was initiated. On day 2 the patient's condition deteriorated (septic shock, multiple organ failure). Repeat endoscopy revealed gastric necrosis and laparotomy was performed. As consequence of cardiac arrest and cardiopulmonary resuscitation the surgical procedure was limited to total gastrectomy, feeding jejustomy and esophageal drainage through nasoesophageal catherization. Roux-loop esophagojejunostomy was performed on day 22 and supplemented 4 days later by endoscopic placement of covered self-expandable stent due to anastomosis leak. The procedure proved successful and oral feeding was well-tolerated. The patient was discharged in 32 days following recognition of gastric necrosis. Chemotherapy complications in neutropenic patients are life-threatening conditions. Immediate pharmacological treatment usually leads to improvement. Surgical management usually the resection of necrotic zones is restricted to cases of poor prognosis or deterioration of patient's condition and complications. PMID:25715575

  15. Necrotizing Fasciitis: A Life-threatening Complication of Intraoperative Electromyography

    PubMed Central

    Shoakazemi, Alireza; Tubbs, R. Shane; Wingerson, Mary; Ajayi, Olaide; Zwillman, Michael E; Gottlieb, Jourdan; Hanscom, David

    2016-01-01

    Intraoperative neurophysiological monitoring is a commonly used practice during spine surgery. Complications of electromyography (EMG) needle electrode placement are very uncommon. We present a patient who was infected with necrotizing fasciitis in her left thigh due to an EMG needle electrode during a two-stage complex spine procedure. This case demonstrates that providers should continue to meticulously adhere to protocol when inserting and removing EMG needles, but also be cognizant during postoperative observation of the possibility of infection caused by EMG needles. PMID:26973803

  16. Descending necrotizing mediastinitis: trends in a developing country.

    PubMed

    Chaudhary, Neena; Agrawal, Sanjay; Rai, Anil K

    2005-04-01

    Descending necrotizing mediastinitis is believed to be a rare and serious complication of odontogenic and oropharyngeal infections. It is associated with a high (up to 40%) mortality rate, which can be attributed to delays in diagnosis and inadequate surgical drainage. Between May 1999 and September 2002, we treated 7 cases at our institution in New Delhi, indicating that such fulminating infections are not so rare in developing countries. In our 7 cases, a high index of suspicion and early computed tomography helped us make a rapid diagnosis and initiate prompt treatment, which resulted in a favorable outcome in 6 cases (mortality rate: 14.3%). PMID:15929325

  17. Necrotizing Craniocervical Soft Tissue Infections: Clinical Experience and Personal Considerations

    PubMed Central

    Lenzi, Riccardo; Castelnuovo, Paolo; Dallan, Iacopo

    2012-01-01

    Necrotizing cervical soft tissue infections (NCSTIs) are devastating uncommon clinical entities that are often life threatening. We report two patients suffering from NCSTI and treated at our institution. Diagnosis of NCSTI has been confirmed histologically and surgically. Both patients were managed with very aggressive treatment (medical and surgical) and survived with minimal morbidity. Early diagnosis and aggressive, multimodality treatment can reduce mortality and morbidity rates. Thoracic and mediastinal involvement requires appropriate management. A strong clinical suspicion remains one of the most important aspects of the management of such shattering conditions. PMID:23304596

  18. Pathogenesis of necrotizing enterocolitis: modeling the innate immune response.

    PubMed

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

    2015-01-01

    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

  19. 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.

  20. Cutaneous necrotizing vasculitis as a manifestation of familial Mediterranean fever.

    PubMed

    Komatsu, Shigetsuna; Honma, Masaru; Igawa, Satomi; Tsuji, Hitomi; Ishida-Yamamoto, Akemi; Migita, Kiyoshi; Ida, Hiroaki; Iizuka, Hajime

    2014-09-01

    Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, which is characterized by recurrent and paroxysmal fever, peritonitis, arthritis, myalgia, and skin rashes. Although various skin lesions such as "erysipelas-like erythema", urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. We report a Japanese case of sporadic FMF accompanied by cutaneous arteritis at the time of febrile attacks of FMF. Gene analysis revealed M694I mutation in a single allele of the MEFV gene, and oral colchicine successfully controlled both periodic fever and subcutaneous nodules of arteritis. Cutaneous necrotizing vasculitis repeatedly emerging with febrile attacks should be included among the skin manifestations of FMF. PMID:25109905

  1. Surgical Management of Necrotizing Mediastinitis With Large Aortic Pseudoaneurysm.

    PubMed

    Chevalier, Andrew T; Khaja, Minhaj S; Yang, Bo

    2016-05-01

    We report a patient with necrotizing mediastinitis complicated by a giant retrosternal mycotic pseudoaneurysm and prosthetic valve endocarditis successfully managed with a redo sternotomy under hypothermic circulatory arrest. The approach then included extensive débridement of the mediastinum, replacement of the ascending aorta and aortic arch with selective antegrade cerebral perfusion, redo aortic valve replacement, and wound closure with omental flap and myocutaneous flap. After a 2-year survival, the patient suffered reinfection from hemodialysis. Our approach is also applicable to more common presentations of mediastinitis. PMID:27106461

  2. Toll-like Receptor Regulation of Intestinal Development and Inflammation in the Pathogenesis of Necrotizing Enterocolitis

    PubMed Central

    Lu, Peng; Hackam, David J.

    2014-01-01

    Toll-like receptors (TLRs) are a structurally related family of molecules that respond to a wide variety of endogenous and exogenous ligands, and which serve as important components of the innate immune system. While TLRs have established roles in host defense, these molecules have also been shown to play important roles in the development of various disease states. A particularly important example of the role of TLRs in disease induction includes necrotizing enterocolitis (NEC), which is the most common gastrointestinal disease in preterm infants, and which is associated with extremely high morbidity and mortality rates. The development of NEC is thought to reflect an abnormal interaction between microorganisms and the immature intestinal epithelium, and emerging evidence has clearly placed the spotlight on an important and exciting role for TLRs, particularly TLR4, in NEC pathogenesis. In premature infants, TLR4 signaling within the small intestinal epithelium regulates apoptosis, proliferation and migration of enterocytes, affects the differentiation of goblet cells, and reduces microcirculatory perfusion, which in combination result in the development of NEC. This review will explore the signaling properties of TLRs on hematopoietic and non-hematopoietic cells, and will examine the role of TLR4 signaling in the development of NEC. In addition, the effects of dampening TLR4 signaling using synthetic and endogenous TLR4 inhibitors and active components from amniotic fluid and human milk on NEC severity will be reviewed. In so doing, we hope to present a balanced approach to the understanding of the role of TLRs in both immunity and disease pathogenesis, and to dissect the precise roles for TLR4 in both the cause and therapeutic intervention of necrotizing enterocolitis. PMID:24365655

  3. Prosthetic metals have a variable necrotic threshold in human fibroblasts: an in vitro study.

    PubMed

    Mostardi, Richard A; Pentello, Amie; Kovacik, Mark W; Askew, Michael J

    2002-03-15

    The generation of metal particles from prosthetic joints has been an evolving problem in orthopedics. Numerous factors have been involved including cells, metals, and responding cytokines, but determining roles of these factors or cascades of factors has been elusive. This laboratory has published threshold levels for commercially pure titanium (CpTi), which led to cell necrosis, but noted that cell viability differed among donor patients. To compliment the previous work we examined two other metals, Tantalum (Ta) and cobalt-chrome (CoCr), while making comparative measurements in these different donor patients. Retrieved human fibroblasts (superior medial plica) were cultured in a standard manner and exposed to various dosages of the three metals. Cell counts and interleukin (IL) 6 were used as dependent variables within a three-way analysis of variance. The data show that fibroblast necrosis was significantly affected by both type and mass of metal, with each metal having a distinct threshold (CpTi most necrotic, followed by Ta and CoCr). The cell counts and IL-6 at control levels varied significantly among all three donors. However, the response to the metals and dosages did not differ among tissue donors. Thus, although each patient had a different starting value for cell counts and IL-6, they responded to the metal particles in the same proportionate manner. PMID:11774321

  4. 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

  5. Aspergillus fumigatus Endophthalmitis with Necrotizing Scleritis following Pars Plana Vitrectomy

    PubMed Central

    Allen, Felicity; 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

  6. 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

  7. Cervical necrotizing fasciitis: management challenges in poor resource environment.

    PubMed

    Adekanye, Abiola Grace; Umana, A N; Offiong, M E; Mgbe, R B; Owughalu, B C; Inyama, M; Omang, H M

    2016-09-01

    Necrotizing fasciitis of the head and neck is a rare and potentially fatal disease. It is a bacterial infection characterized by spreading along fascia planes and subcutaneous tissue resulting in tissue necrosis and likely death. It is commonly of dental or pharyngeal origin. Factors affecting the success of the treatment are early diagnosis, appropriate antibiotics and surgical debridement. Our study showed eight patients, five males and three females with mean age of 49.25 years (range 20-71 years). Clinical presentations were a rapidly progressing painful neck swelling, fever, dysphagia and trismus. The aetiology varied from idiopathic, pharyngeal/tonsillar infection, trauma and nasal malignancy. There were associated variable comorbidities (diabetes mellitus, HIV infection, hypertension and congestive cardiac failure). All the patients received early and aggressive medical treatment. The earliest time of surgery was 12 h after admission because of the poor financial status of patients. Three cases came in with complications of the disease and were not fit for extensive debridement under general anaesthesia. For them limited and reasonable bed side debridement was done. Mortality was 50 % from multiple organ failure, HIV encephalopathy, aspiration pneumonitis and septicemia. The duration of hospital stay for the patients that died ranged from 1 to 16 days and 4 to 34 days for the survivor. Our study heightens awareness and outlines the management challenges of necrotizing fasciitis of the head and neck in a poor resource setting. PMID:26626324

  8. Necrotizing fasciitis in association with Ludwig’s angina – A case report

    PubMed Central

    Kavarodi, A.M.

    2011-01-01

    A 28 year old male diabetic patient developed Ludwig’s angina which subsequently evolved into cervicofacial necrotizing fasciitis. The differential characteristic of Ludwig’s angina and cervicofacial necrotizing fasciitis, as it relates to this rare presentation is discussed. The clinical and radiological features, pathophysiology, diagnosis and the management that resulted in a successful outcome are presented. PMID:24151421

  9. 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.

  10. 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...

  11. 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

  12. Evidence of chitinase activity within necrotic enteritis-associated subtypes of Clostridium perfringens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    C. perfringens (Cp) is associated with the necrotic gastrointestinal condition known as necrotic enteritis (NE) in the chicken. rep-PCR subtyping identified subtypes of Cp from the gastrointestinal tracts of broiler chickens afflicted with NE that were distinguished from strains from environmental,...

  13. 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

  14. 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

  15. 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

  16. 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

  17. [Clinical course of purulent and necrotic complications in diabetes mellitus].

    PubMed

    Genyk, S N; Grushetskiĭ, N N

    1993-05-01

    Experience in the treatment of 214 patients with diabetic angiopathy complicated by pyonecrotic processes is generalized. Adequate correction of diabetes mellitus, improvement of microcirculation, dietotherapy, and sanitation of the pyonecrotic foci are the main trends in the complex of therapeutic measures. Hemosorption was applied successfully for detoxifixation in 24 patients. Prolonged intraarterial therapy was also conducted with a [symbol: see text] B-1 gent dosing apparatus. Necrosis of the soft tissues and gangrene of the toes or foot were managed by thorough excision of the necrotic tissues and exarticulation or amputation of the toes and metatarsals, and, in exceptional cases, amputation of the limb through the thigh was resorted to. With such complex therapy the number of amputations through the middle and upper third of the thigh was reduced to 18.3%. PMID:8089982

  18. Minor trauma triggering cervicofacial necrotizing fasciitis from odontogenic abscess.

    PubMed

    Jain, Shraddha; Nagpure, Prakash S; Singh, Roohie; Garg, Deepika

    2008-07-01

    Necrotizing fasciitis (NF) of the face and neck is a very rare complication of dental infection. Otolaryngologists and dentists should be familiar with this condition because of its similarity to odontogenic deep neck space infection in the initial stages, its rapid spread, and its life-threatening potential. Trauma has been reported to be an important predisposing factor for NF of the face. In this paper, we describe the presentation and treatment of a 62-year-old man who developed NF of the face and neck following bilateral odontogenic deep neck space abscesses. The disease progressed rapidly, with necrosis of the skin, after the patient inflicted minor trauma in the form of application of heated medicinal leaves. The organism isolated in culture from pus was Acinetobacter sp. The comorbid conditions in our patient were anemia and chronic alcoholism. The patient was managed by immediate and repeated extensive debridements and split-skin grafting. PMID:19561990

  19. Immune-Mediated Necrotizing Myopathy: Update on Diagnosis and Management.

    PubMed

    Basharat, Pari; Christopher-Stine, Lisa

    2015-12-01

    The idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune disorders that target skeletal muscle. They are characterized by typical laboratory and clinical features including muscle weakness, elevated muscle enzymes, characteristic histopathology of muscle biopsies, as well as electromyography abnormalities. The IIMs are divided into polymyositis, dermatomyositis, inclusion body myositis, nonspecific myositis, and immune-mediated necrotizing myopathy (IMNM). IMNM is distinguished by the absence of primary inflammation on muscle biopsy. IMNM may be associated with myositis-specific autoantibodies (i.e., anti-SRP and anti-HMGCR) and malignancy, in association with viral infections (HIV or hepatitis C), or in relation to other connective tissue diseases (i.e., scleroderma). Typical clinical findings such as severe muscle weakness, highly elevated creatine kinase (CK) levels, as well as resistance to conventional immunosuppressive therapy are associated with this subtype of IIM. This review provides an overview of this disease entity and focuses on its diagnosis and treatment. PMID:26515574

  20. 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

  1. Clinical complications in the revascularization of immature necrotic permanent teeth.

    PubMed

    Dabbagh, Basma; Alvaro, Emanuel; Vu, Duy-Dat; Rizkallah, Jean; Schwartz, Stephane

    2012-01-01

    The purpose of this case series was to report on the use of a technique of revascularization for necrotic immature permanent teeth, several problems encountered, and solutions to those problems. Eighteen pulp revascularizations were performed in 2009 using the original protocol of revascularization (adapted from the AAE/AAPD joint meeting in 2007 in Chicago). The protocol consisted of opening the canal and disinfecting it with sodium hypochlorite, sealing in a triple antibiotic paste for 2-6 weeks, re-opening, re-irrigating, creating a blood clot in the canal, and sealing with an MTA barrier over the clot. Three problems were encountered during the treatment: (1) bluish discoloration of the crown; (2) failure to produce bleeding; and (3) collapse of the mineral trioxide aggregate (MTA) material into the canal. Modifications to solve these problems included: changing one of the antibiotics, using a local anesthesia without epinephrine, and adding collagen matrix to the blood clot. PMID:23211919

  2. 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

  3. 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

    2013-01-01

    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

  4. 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

  5. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3.

    PubMed

    Wang, Huayi; Sun, Liming; Su, Lijing; Rizo, Josep; Liu, Lei; Wang, Li-Feng; Wang, Fu-Sheng; Wang, Xiaodong

    2014-04-10

    Programmed necrotic cell death induced by the tumor necrosis factor alpha (TNF-α) family of cytokines is dependent on a kinase cascade consisting of receptor-interacting kinases RIP1 and RIP3. How these kinase activities cause cells to die by necrosis is not known. The mixed lineage kinase domain-like protein MLKL is a functional RIP3 substrate that binds to RIP3 through its kinase-like domain but lacks kinase activity of its own. RIP3 phosphorylates MLKL at the T357 and S358 sites. Reported here is the development of a monoclonal antibody that specifically recognizes phosphorylated MLKL in cells dying of this pathway and in human liver biopsy samples from patients suffering from drug-induced liver injury. The phosphorylated MLKL forms an oligomer that binds to phosphatidylinositol lipids and cardiolipin. This property allows MLKL to move from the cytosol to the plasma and intracellular membranes, where it directly disrupts membrane integrity, resulting in necrotic death. PMID:24703947

  6. 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

  7. 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

  8. The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis.

    PubMed

    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

    2014-10-01

    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

  9. 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

  10. 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

  11. [Kikuchi-Fujimoto subacute necrotizing lymphadenitis: two histologic forms observed in the same patient].

    PubMed

    el Mezni, F; Mrad, K; el Mezni-Benzarti, A; Zermani, R; Ben Abdeladhim, A; Ben Jilani, S

    1998-11-01

    Histiocytic necrotizing lymphadenitis, also known as Kikuchi-Fujimoto disease is a rare self-limited condition of young adults usually misdiagnosed as malignant hematologic disease. The diagnosis depends on microscopic findings. Two histologic types are classically described, proliferative and necrotic types. This is a case report of 17 year-old girl who presented cervical lymphadenopathy. The first lymph node biopsy was in favor of malignant lymphoma. The second lymph node biopsy, done one month later, showed typical histiocytic necrotizing lymphadenitis. To our knowledge, this is the first time that the two forms of this disease are described in the same patient. PMID:9864579

  12. 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

  13. Paenibacillus vulneris sp. nov., isolated from a necrotic wound.

    PubMed

    Glaeser, Stefanie P; Falsen, Enevold; Busse, Hans-Jürgen; Kämpfer, Peter

    2013-02-01

    A Gram-positive-staining, aerobic, endospore-forming bacterium, isolated from a necrotic wound of a 35-year-old man was studied in detail to determine its taxonomic position. Based on 16S rRNA gene sequence similarity comparisons, strain CCUG 53270(T) was grouped into the genus Paenibacillus, most closely related to the type strains of Paenibacillus rigui (97.2 %), Paenibacillus xylanisolvens (96.3 %) and Paenibacillus chinjuensis (96.1 %). The 16S rRNA gene sequence similarity to strains of other Paenibacillus species was ≤96 %. Chemotaxonomic characterization supported the allocation of the strain to the genus Paenibacillus. The major menaquinones were MK-7 (85 %) and MK-6 (15 %). The polar lipid profile contained the major compounds diphosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine and phosphatidylglycerol. The polyamine pattern contained predominantly spermidine. The major fatty acids were iso- and anteiso-branched fatty acids. The results of physiological and biochemical tests allowed phenotypic differentiation of strain CCUG 53270(T) from closely related species. Thus, strain CCUG 53270(T) represents a novel species of the genus Paenibacillus, for which the name Paenibacillus vulneris sp. nov. is proposed, with CCUG 53270(T) ( = JCM 18268(T)) as the type strain. PMID:22581904

  14. Genetic Susceptibility to Non-Necrotizing Erysipelas/Cellulitis

    PubMed Central

    Hannula-Jouppi, Katariina; Massinen, Satu; Siljander, Tuula; Mäkelä, Siru; Kivinen, Katja; Leinonen, Rasko; Jiao, Hong; Aitos, Päivi; Karppelin, Matti; Vuopio, Jaana; Syrjänen, Jaana; Kere, Juha

    2013-01-01

    Background Bacterial non-necrotizing erysipelas and cellulitis are often recurring, diffusely spreading infections of the skin and subcutaneous tissues caused most commonly by streptococci. Host genetic factors influence infection susceptibility but no extensive studies on the genetic determinants of human erysipelas exist. Methods We performed genome-wide linkage with the 10,000 variant Human Mapping Array (HMA10K) array on 52 Finnish families with multiple erysipelas cases followed by microsatellite fine mapping of suggestive linkage peaks. A scan with the HMA250K array was subsequently performed with a subset of cases and controls. Results Significant linkage was found at 9q34 (nonparametric multipoint linkage score (NPLall) 3.84, p = 0.026), which is syntenic to a quantitative trait locus for susceptibility to group A streptococci infections on chromosome 2 in mouse. Sequencing of candidate genes in the 9q34 region did not conclusively associate any to erysipelas/cellulitis susceptibility. Suggestive linkage (NPLall>3.0) was found at three loci: 3q22-24, 21q22, and 22q13. A subsequent denser genome scan with the HMA250K array supported the 3q22 locus, in which several SNPs in the promoter of AGTR1 (Angiotensin II receptor type I) suggestively associated with erysipelas/cellulitis susceptibility. Conclusions Specific host genetic factors may cause erysipelas/cellulitis susceptibility in humans. PMID:23437094

  15. Preterm birth and necrotizing enterocolitis alter gut colonization in pigs.

    PubMed

    Cilieborg, Malene S; Boye, Mette; Mølbak, Lars; Thymann, Thomas; Sangild, Per T

    2011-01-01

    Necrotizing enterocolitis (NEC) in preterm neonates is dependent on bacterial colonization, but it remains unclear whether a particular microbiota or specific pathogens are involved. We hypothesized that gut colonization differs between preterm and term neonates and that overgrowth of Clostridium perfringens predisposes to NEC. By using terminal-RFLP and FISH, we characterized the gut microbiota of preterm, caesarean-delivered, formula-fed pigs (n = 44) with or without NEC and of formula- or colostrum-fed term, and vaginally born pigs (n = 13). A different microbiota with high C. perfringens abundance was observed in preterm pigs with NEC compared with healthy individuals. However, immunization against C. perfringens toxins did not prevent NEC, and C. perfringens inoculation (3.6 × 10 cfu/d) failed to induce NEC (n = 16), whereas prophylactic broad-spectrum antibiotics treatment prevented NEC (n = 24). Colonization in both groups of term pigs differed from preterm pigs and was dominated by Lactobacilli spp. In conclusion, gestational age (GA) and NEC influence neonatal gut colonization, whereas diet has minor effects. C. perfringens is more abundant in pigs with NEC but rather as a consequence than a cause of disease. The general bacterial load and underdeveloped gut immune responses in preterm neonates seem more important for NEC development than specific pathogens. PMID:20924317

  16. Necrotizing fasciitis of the neck after total laryngectomy.

    PubMed

    Danic Hadzibegovic, Ana; Sauerborn, Damir; Grabovac, Stjepan; Matic, Ivo; Danic, Davorin

    2013-01-01

    Necrotizing fasciitis (NF) is an unusual, life threatening, rapidly advancing infection characterized by widespread fascial and subcutaneous tissue necrosis and gangrene of the skin. It most commonly affects the extremities, abdominal wall and perineum, whereas cervical NF is rare. NF of the head and neck is often caused by both aerobic and anaerobic microorganisms found in the upper aerodigestive tract. Usually, cervical NF originates from odontogenic, tonsillar and pharyngeal infection, and it is very rarely a complication of surgical procedure. Without immediate surgical treatment, cervical NF leads to mediastinitis and fatal sepsis. There is only one case of cervical NF after total laryngectomy described in the literature. We report two cases of cervical NF after total laryngectomy, selective neck dissection and primary vocal prosthesis insertion. In both cases, the infection spreads to thoracic region and in one of them NF was associated with Lemierre's syndrome, i.e., thrombosis of the internal jugular vein. In both patients, vocal prosthesis was inserted during the infection and did not influence the healing process. PMID:22430034

  17. Feeding during Blood Transfusions and the Association with Necrotizing Enterocolitis.

    PubMed

    Doty, Megan; Wade, Christine; Farr, Julie; Gomezcoello, Vanessa Celleri; Martin, Gregory; Nasr, Tala

    2016-07-01

    Objective The aim of this study was to determine whether very low-birth-weight (VLBW) infants who had feedings withheld during all blood transfusions had a lower incidence of necrotizing enterocolitis (NEC) compared with infants who were fed during transfusions. Study Design A retrospective chart review over a 3-year period in a level-3 neonatal intensive care unit was conducted. A total of 108 inborn VLBW infants (weight range: 500-1,500 g) who had received a transfusion before 36 weeks were reviewed. Diagnosis of NEC (≥ Bell stage II), demographics, feeds, transfusions, outcomes, and variables associated with NEC were collected. Results The percentage of NEC cases was lower in infants who had feeds withheld during transfusions: 5/64 (7.8%) compared with 16/116 (13.8%) infants who were fed during transfusions. While potentially clinically important (6% absolute difference), this difference was not statistically significant (p = 0.33 by two-tailed Fisher exact test). Conclusions No significant decrease in the incidence of NEC was found when feeds were withheld during blood transfusions. Holding feeds during transfusions is not without consequences such as the need for intravenous access, additional fluids, and the disruption of optimum nutrition. Further studies are needed to establish the relationship between blood transfusions, feeds, and NEC. PMID:27031053

  18. Pectoralis myocutaneous flap for salvage of necrotic wounds

    SciTech Connect

    Price, J.C.; Davis, R.K.; Koltai, P.J.

    1985-02-01

    The authors have utilized six pectoralis major myocutaneous flaps in attempts to salvage extensive necrotic wounds of the pharynx and neck. The flap was employed in the following situations: massive necrosis of the entire neck skin with both carotid artery systems exposed, radiation necrosis of the neck skin with exposure of carotid artery, dehiscence of gastric pull-up from pharynx with resultant carotid exposure, failed trapezius flap in a radionecrotic oral cavity, and two cases of pharyngocutaneous fistula with extensive soft tissue necrosis. These flaps achieved healing in all cases. One death occurred 3 weeks following complete cutaneous healing secondary to a ruptured carotid pseudoaneurysm. One flap underwent total skin loss but the entirety of the muscle survived and the fistula was successfully closed with the back of the muscle being subsequently skin grafted. One case of dehiscence of the flap from oral mucosa resulted in a minor exposure of mandible with limited osteoradionecrosis controlled by topical means. This flap has performed extremely well in these precarious and difficult situations that previously may not have been salvageable. It has also been effective in abbreviating the required hospitalization and wound care. The authors conclude that the pectoralis myocutaneous flap should be the primary choice for the management of extensive postsurgical wound necrosis.

  19. Craniocervical necrotizing fasciitis in Ile-Ife, Nigeria.

    PubMed

    Ndukwe, K C; Fatusi, O A; Ugboko, V I

    2002-02-01

    Sixteen cases of necrotizing fasciitis were seen at the Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria from 1990 to 2000. Primary craniocervical involvement was recorded in seven patients (five men and two women). The clinical records of five patients were sufficiently detailed to allow us to report their age, aetiology, predisposing illness, clinical features, complications, management regimen and outcome. The patients were aged 30-75 years and in four of them odontogenic infections were the cause of the condition. Hypertension, diabetes mellitus and obesity were the underlying systemic diseases in three cases and the body/angle region of the mandible was the predominant site of the infection on the face. All five cases had involvement of the neck. Mediastinal extension was recorded in three cases. Two patients had complications: one had septicaemia and renal failure and the other developed bone necrosis. Pre-existing ill health, old age, late surgical intervention, and mediastinal and thoracic extension of infection were responsible for the only death. Treatment involved frequent and multiple surgical debridement, aggressive antimicrobial treatment and control of systemic disease. Early recognition, prompt surgical intervention, and aggressive antimicrobial treatment are essential to minimize morbidity and mortality. Rapid progression of infection, financial constraints, delayed referrals from rural clinics and distance to the tertiary hospital caused problems. PMID:11883974

  20. Placental Vascular Obstructive Lesions: Risk Factor for Developing Necrotizing Enterocolitis

    PubMed Central

    Dix, Laure; Roth-Kleiner, Matthias; Osterheld, Maria-Chiara

    2010-01-01

    Necrotizing enterocolitis (NEC) is a severe neonatal disease affecting particularly preterm infants. Its exact pathogenesis still remains unknown. In this study, we have compared the prevalence of vascular obstructive lesions in placentae of premature newborns which developed NEC and of a control group. We further compared separately the findings of placentae of infants of less than 30 weeks of gestation, the age group in which NEC occurs most frequently. We found signs of fetal vascular obstructive lesions in 65% of the placentae of preterm patients developing NEC, compared to only 17% of the placentae of preterm patients in the control group. In the age groups below 30 weeks of gestation, 58.5% of placentae of later NEC patients presented such lesions compared to 24.5% in the control group. The significant difference between NEC and control group suggests a strong association between fetal vascular obstructive lesions and NEC. Therefore, we propose that fetal vascular obstructive lesions might be considered as a risk factor for the development of NEC in premature infants. PMID:21151528

  1. A cluster of cases of streptococcal necrotizing fasciitis in Gloucestershire.

    PubMed Central

    Cartwright, K.; Logan, M.; McNulty, C.; Harrison, S.; George, R.; Efstratiou, A.; McEvoy, M.; Begg, N.

    1995-01-01

    We describe the first cluster of cases of necrotizing fasciitis (NF) in this century in the United Kingdom (UK). Between 1 January and 30 June 1994 there were six cases (five confirmed, one probable) of Streptococcus pyogenes NF in west Gloucestershire, population 320,000. Two cases died. The first two patients probably acquired their infections during the course of elective surgery performed in the same operating theatre, possibly from a nasopharyngeal carrier amongst the theatre staff. The remaining infections were community-acquired. Of 5 S. pyogenes isolates there were 2 M1 strains, 1 M3, 1 M5 and 1 M non-typeable strain. S. pyogenes NF had not been recorded in west Gloucestershire in the preceding 10 years and the incidence of S. pyogenes bacteraemia in England and Wales had not risen in the past 5 years. The two presumably theatre-acquired infections raised several issues. The need for detailed bacteriological investigation of all cases of post-surgical NF was confirmed. Clusters of S. pyogenes infection following surgery should be managed by closure of the operating theatre until all staff have been screened for carriage. Closure of an operating theatre and screening of staff following a sporadic case is probably not justified because of the infrequency of surgical cross-infection with S. pyogenes. Regular, routine screening of theatre staff is neither practical nor necessary. PMID:8557070

  2. Preformed silastic silos in the management of necrotizing enterocolitis.

    PubMed

    Moore, Amy B; Nakayama, Don K

    2009-02-01

    Necrotizing enterocolitis (NEC) is sometimes complicated by abdominal compartment syndrome, a clinical syndrome characterized by multiple organ dysfunction that arises as a consequence of increased intra-abdominal pressure. The evolving clinical picture of NEC sometimes requires "second-look" operations done after initial abdominal exploration to more accurately gauge the optimal extent of surgery. Placing intestines in a preformed, spring-loaded, transparent Silastic silo, traditionally used in the staged treatment of gastroschisis, addresses both situations: decompression of the abdomen and allowing periodic inspection of the intestines. Standard silos were used in three infants with advanced (Bell Class 3) NEC without perforation before definitive surgery. Clinical indices and laboratory values were recorded during the patients' hospital courses. All three infants had extensive areas of intestinal ischemia and necrosis. FiO2, acidosis, and urinary output remained stable or improved in two patients. Silo placement corrected abdominal compartment syndrome in the third patient. Intestinal resection was required in all infants, each achieving surgical resolution of NEC. Two patients ultimately died from respiratory and neurologic complications. Application of a silo addresses abdominal compartment syndrome as a complication of NEC and allows continual inspection of the intestines. Physiological indices may improve the patient's overall clinical status. PMID:19280813

  3. Necrotizing sialometaplasia of the palatal mucosa in patient with history of anorexia: review and case report.

    PubMed

    Gilowski, Łukasz; Wiench, Rafał; Polakiewicz-Gilowska, Anna; Dwornicka, Katarzyna

    2014-01-01

    Necrotizing sialometaplasia is a self-limiting disorder affecting minor salivary glands resembling a malignant process both clinically and histopathologically. The etiology of this rare inflammatory` disorder is related to an ischemic event. Identified risk factors include alcohol abuse, smoking, drugs, denture wearing, injury and systemic diseases. Also reported are cases of necrotizing sialometaplasia associated with bulimia. This paper identifies the whole body incitement among additional risk factors by presenting a case of necrotizing sialometaplasia in an 18 year old patient with the history of anorexia nervosa. Furthermore it describes the effects of extreme cooling of palatal mucosa with ice chips resulting in constriction of blood vessels as the direct cause, reinforcing ischemic etiology of necrotizing sialometaplasia. PMID:24667056

  4. Necrotizing scleritis after intraocular surgery associated with the use of polyester nonabsorbable sutures.

    PubMed

    Stokes, John; Wright, Mark; Ramaesh, Kanna; Smith, Colin; Dhillon, Baljean

    2003-09-01

    We present 2 elderly patients who developed necrotizing scleritis after cataract extraction in which the wound was sutured with polyester. In the first case, a 73-year-old woman who had right phacoemulsification via a limbal incision developed necrotizing scleritis 8 months after surgery. The eye became progressively painful and phthisical, necessitating enucleation. Microscopic examination of the enucleated globe showed a predominantly lymphocytic infiltration of the ocular tissues with no evidence of an infectious agent. In the second case, a 78-year-old woman had bilateral extracapsular cataract extraction through a limbal incision closed with a polyester suture. The patient presented 3 years later with bilateral necrotizing sclerokeratitis. No underlying systemic vasculitis or autoimmune condition was identified in either patient. To our knowledge, the association of necrotizing scleritis after intraocular surgery and polyester fiber suture material (Mersilene) has not been described. PMID:14522309

  5. Protection against avian necrotic enteritis after immunisation with NetB genetic or formaldehyde toxoids☆

    PubMed Central

    Fernandes da Costa, Sérgio P.; Mot, Dorien; Bokori-Brown, Monika; Savva, Christos G.; Basak, Ajit K.; Van Immerseel, Filip; Titball, Richard W.

    2013-01-01

    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. PMID:23727000

  6. Tigecycline salvage therapy for necrotizing fasciitis caused by Vibrio vulnificus: Case report in a child.

    PubMed

    Lin, Yu-San; Hung, Min-Hsiang; Chen, Chi-Chung; Huang, Kuo-Feng; Ko, Wen-Chien; Tang, Hung-Jen

    2016-02-01

    Necrotizing fasciitis caused by Vibrio vulnificus is rarely reported in children. We describe a 12-year-old immunocompetent boy with necrotizing fasciitis caused by V. vulnificus. He was cured by radical and serial debridement and salvage therapy with intravenous cefpirome plus tigecycline. The in vitro antibacterial activity of combination regimens and a literature review of pediatric V. vulnificus infection are described. PMID:23751766

  7. Abdominal Compartment Syndrome and Necrotizing Pancreatitis Following Extracorporeal Shock Wave Lithotripsy.

    PubMed

    Gupta, S; Scambia, J; Gandillon, C; Aversano, F; Batista, R

    2016-09-01

    Extracorporeal shock wave lithotripsy (ESWL) is a common procedure in the treatment of renal calculi. There have been major complications reported with ESWL such as acute pancreatitis, bower perforation, venous thrombosis, and biliary obstruction. There are few reports in the literature of necrotizing pancreatitis secondary to ESWL. We have a case report of a 29-year-old female that developed an abdominal compartment syndrome with an acute necrotizing pancreatitis hours after extracorporeal shock wave lithotripsy. PMID:27462545

  8. Necrotizing fasciitis: a case of hip disarticulation in a postnatal intravenous drug abuser

    PubMed Central

    Rajeswari, J; Smith, N A; Glass, K; Howarth, F

    2009-01-01

    An interesting case of necrotizing fasciitis of the leg following emergency caesarian section in a known intravenous drug user. Postnatal day two she developed pain and swelling in the left leg. In view of her previous history, deep vein thrombosis (DVT) was the initial diagnosis. But, due to clinically worsening symptoms and no response to anticoagulation, further investigations were done which showed necrotizing fasciitis. Due to disease progression, a hip disarticulation was performed and the patient went on to full recovery.

  9. Necrotizing Periodontal Diseases in Children: A Literature Review and Adjustment of Treatment.

    PubMed

    Marty, Mathieu; Palmieri, James; Noirrit-Esclassan, Emmanuelle; Vaysse, Frédéric; Bailleul-Forestier, Isabelle

    2016-08-01

    Necrotizing ulcerative gingivitis, sometimes observed in young children, may lead to necrotizing stomatitis and noma. Therefore, its interception is a necessity and a challenge for the paediatric practitioners. First, this article aims to propose a systematic review of recent literature on the use of local antiseptic and antibiotic prescription in this particular periodontal condition. Then, a protocol is proposed to have a simple, costless and reproducible treatment on children. PMID:26966241

  10. [Pyoderma gangrenosum after intramedullary nailing of tibial shaft fracture: A differential diagnosis to necrotizing fasciitis].

    PubMed

    Hackl, S; Merkel, P; Hungerer, S; Friederichs, J; Müller, N; Militz, M; Bühren, V

    2015-12-01

    Pyoderma gangrenosum is a rare non-infectious neutrophilic dermatitis, whereas necrotizing fasciitis is a life-threatening bacterial soft tissue infection of the fascia and adjacent skin. As in the case described here after intramedullary nailing, the clinical appearance of both diseases can be similar. Because of the completely different therapeutic approach and a worse outcome in the case of false diagnosis, pyoderma gangrenosum should always be taken into consideration before treating necrotizing fasciitis. PMID:25672810

  11. Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic

    PubMed Central

    Pelte, Nadège; Robertson, Andrew S.; Zou, Zhen; Belorgey, Didier; Dafforn, Timothy R.; Jiang, Haobo; Lomas, David; Reichhart, Jean-Marc; Gubb, David

    2007-01-01

    The Drosophila Necrotic protein is a serine proteinase inhibitor, which regulates the Toll-mediated innate immune response. Necrotic specifically inhibits an extracellular serine proteinase cascade leading to activation of the Toll ligand, Spätzle. Necrotic carries a polyglutamine extension amino-terminal to the core serpin structure. We show here that cleavage of this N-terminal extension occurs following immune challenge. This modification is blocked in PGRP-SAsemmelweiss mutants after Gram-positive bacterial challenge and in persephone mutants after fungal or Gram-positive bacterial challenge, indicating that activation of either of the Toll pathway upstream branches induces N-terminal cleavage of the serpin. The absolute requirement of persephone gene product for this cleavage indicates that Gram-positive bacteria activate a redundant set of proteinases upstream of Toll. Both full-length Necrotic and the core serpin are active inhibitors of a range of serine proteinases: the highest affinity being for cathepsin G and elastases. We found a 13-fold increase in the specificity of the core serpin over that of full-length Necrotic for one of the tested proteinases (porcine pancreatic elastase). This finding indicates that cleavage of the Necrotic amino-terminal extension might modulate Toll activation following the initial immune response. PMID:16360948

  12. A fatal case of multidrug resistant acinetobacter necrotizing fasciitis: the changing scary face of nosocomial infection.

    PubMed

    Sinha, Nupur; Niazi, Masooma; Lvovsky, Dmitry

    2014-01-01

    Necrotizing fasciitis is an uncommon soft-tissue infection, associated with high morbidity and mortality. Early recognition and treatment are crucial for survival. Acinetobacter baumannii is rarely associated with necrotizing fasciitis. Wound infections due to A. baumannii have been described in association with severe trauma in soldiers. There are only sporadic reports of monomicrobial A. baumannii necrotizing fasciitis. We report a unique case of monomicrobial necrotizing fasciitis caused by multidrug resistant (MDR) A. baumannii, in absence of any preceding trauma, surgery, or any obvious breech in the continuity of skin or mucosa. A 48-year-old woman with history of HIV, asthma, hypertension, and tobacco and excocaine use presented with acute respiratory failure requiring mechanical ventilation. She was treated for pneumonia for 7 days and was successfully extubated. All septic work-up was negative. Two days later, she developed rapidly spreading nonblanching edema with bleb formation at the lateral aspect of right thigh. Emergent extensive debridement and fasciotomy were performed. Operative findings and histopathology were consistent with necrotizing fasciitis. Despite extensive debridement, she succumbed to septic shock in the next few hours. Blood, wound, and tissue cultures grew A. baumannii, sensitive only to amikacin and polymyxin. Histopathology was consistent with necrotizing fasciitis. PMID:25349748

  13. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody.

    PubMed

    Allenbach, Yves; Keraen, Jeremy; Bouvier, Anne-Marie; Jooste, Valérie; Champtiaux, Nicolas; Hervier, Baptiste; Schoindre, Yoland; Rigolet, Aude; Gilardin, Laurent; Musset, Lucile; Charuel, Jean-Luc; Boyer, Olivier; Jouen, Fabienne; Drouot, Laurent; Martinet, Jeremie; Stojkovic, Tanya; Eymard, Bruno; Laforêt, Pascal; Behin, Antony; Salort-Campana, Emmanuelle; Fain, Olivier; Meyer, Alain; Schleinitz, Nicolas; Mariampillai, Kuberaka; Grados, Aurelie; Benveniste, Olivier

    2016-08-01

    Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients. PMID:27086869

  14. 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

  15. Rapamycin ameliorates cadmium-induced activation of MAPK pathway and neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A.

    PubMed

    Xu, Chong; Wang, Xiaoxue; Zhu, Yu; Dong, Xiaoqing; Liu, Chunxiao; Zhang, Hai; Liu, Lei; Huang, Shile; Chen, Long

    2016-06-01

    Cadmium (Cd) is a highly toxic metal that affects the central nervous system. Recently we have demonstrated that inhibition of mTOR by rapamycin rescues neuronal cells from Cd-poisoning. Here we show that rapamycin inhibited Cd-induced mitochondrial ROS-dependent neuronal apoptosis. Intriguingly, rapamycin remarkably blocked phosphorylation of JNK, Erk1/2 and p38 in neuronal cells induced by Cd, which was strengthened by co-treatment with Mito-TEMPO. Inhibition of JNK and Erk1/2 by SP600125 and U0126, respectively, potentiated rapamycin's prevention from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or MKK1 also potently improved the inhibitory effect of rapamycin on Cd neurotoxicity. Furthermore, pretreatment with SP600125 or U0126, or expression of dominant negative c-Jun or MKK1 enhanced the inhibitory effects of rapamycin or Mito-TEMPO on Cd-induced ROS. Further investigation found that co-treatment with Mito-TEMPO/rapamycin more effectively rescued cells by preventing Cd inactivation of PP2A than treatment with rapamycin or Mito-TEMPO alone. Over-expression of wild-type PP2A reinforced rapamycin or Mito-TEMPO suppression of activated JNK and Erk1/2 pathways, as well as ROS production and apoptosis in neuronal cells in response to Cd. The findings indicate that rapamycin ameliorates Cd-evoked neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A, thereby suppressing activation of JNK and Erk1/2 pathways. Our results underline that rapamycin may have a potential in preventing Cd-induced oxidative stress and neurodegenerative diseases. PMID:26805420

  16. Modeling the interactions of bacteria and Toll-like receptor-mediated inflammation in necrotizing enterocolitis

    PubMed Central

    Arciero, Julia; Ermentrout, G. Bard; Siggers, Richard; Afrazi, Amin; Hackam, David; Vodovotz, Yoram; Rubin, Jonathan

    2016-01-01

    Necrotizing enterocolitis (NEC) is a severe disease of the gastrointestinal tract in premature infants, characterized by a disrupted intestinal epithelium and an exaggerated pro-inflammatory response. Since the activation of Toll-like receptor-4 (TLR4) blocks cell migration and proliferation and contributes to an uncontrolled inflammatory response within the intestine, this receptor has been identified as a key contributor to the development of NEC. Toll-like receptor-9 (TLR9) has been shown to sense bacterial genome components (CpG DNA) and to play an anti-inflammatory role in NEC. We present in vitro results demonstrating direct inhibition of TLR4 activation by CpG DNA, and we develop a mathematical model of bacteria–immune interactions within the intestine to investigate how such inhibition of TLR4 signaling might alter inflammation, associated bacterial invasion of tissue, and resulting outcomes. The model predicts that TLR9 can inhibit both the beneficial and detrimental effects of TLR4, and thus a proper balance of action by these two receptors is needed to promote intestinal health. The model results are also used to explore three interventions that could potentially prevent the development of NEC: reducing bacteria in the mucus layer, administering probiotic treatment, and blocking TLR4 activation. While the model shows that these interventions would be successful in most cases, the model is also used to identify situations in which the proposed treatments might be harmful. PMID:23238281

  17. Paeoniflorin ameliorates acute necrotizing pancreatitis and pancreatitis‑induced acute renal injury.

    PubMed

    Wang, Peng; Wang, Weixing; Shi, Qiao; Zhao, Liang; Mei, Fangchao; Li, Chen; Zuo, Teng; He, Xiaobo

    2016-08-01

    Acute renal injury caused by acute necrotizing pancreatitis (ANP) is a common complication that is associated with a high rate of mortality. Paeoniflorin is the active ingredient of paeonia radix and exhibits a number of pharmacological effects, such as anti‑inflammatory, anticancer, analgesic and immunomodulatory effects. The present study detected the potential treatment effects of paeoniflorin on acute renal injury induced by ANP in a rat model. The optimal dose of paeoniflorin for preventing acute renal injury induced by ANP was determined. Then, the possible protective mechanism of paeoniflorin was investigated. The serum levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β and IL‑6 were measured with enzyme‑linked immunosorbent assay kits. Renal inflammation and apoptosis were measured by immunohistochemistry and terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling assay. The expression of nitric oxide in kidney tissues was also evaluated. The p38 mitogen‑activated protein kinases (MAPKs) were measured by western blotting. The results shown that paeoniflorin may ameliorate acute renal injury following ANP in rats by inhibiting inflammatory responses and renal cell apoptosis. These effects may be associated with the p38MAPK and nuclear factor‑κB signal pathway. PMID:27279569

  18. Paeoniflorin ameliorates acute necrotizing pancreatitis and pancreatitis-induced acute renal injury

    PubMed Central

    Wang, Peng; Wang, Weixing; Shi, Qiao; Zhao, Liang; Mei, Fangchao; Li, Chen; Zuo, Teng; He, Xiaobo

    2016-01-01

    Acute renal injury caused by acute necrotizing pancreatitis (ANP) is a common complication that is associated with a high rate of mortality. Paeoniflorin is the active ingredient of paeonia radix and exhibits a number of pharmacological effects, such as anti-inflammatory, anticancer, analgesic and immunomodulatory effects. The present study detected the potential treatment effects of paeoniflorin on acute renal injury induced by ANP in a rat model. The optimal dose of paeoniflorin for preventing acute renal injury induced by ANP was determined. Then, the possible protective mechanism of paeoniflorin was investigated. The serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were measured with enzyme-linked immunosorbent assay kits. Renal inflammation and apoptosis were measured by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The expression of nitric oxide in kidney tissues was also evaluated. The p38 mitogen-activated protein kinases (MAPKs) were measured by western blotting. The results shown that paeoniflorin may ameliorate acute renal injury following ANP in rats by inhibiting inflammatory responses and renal cell apoptosis. These effects may be associated with the p38MAPK and nuclear factor-κB signal pathway. PMID:27279569

  19. Association of Cord Blood Digitalis-Like Factor and Necrotizing Enterocolitis

    PubMed Central

    Graves, SW; Esplin, MS; McGee, P; Rouse, DJ; Leveno, KJ; Mercer, BM; Iams, JD; Wapner, RJ; Sorokin, Y; Thorp, JM; Ramin, SM; Malone, FD; O’Sullivan, MJ; Peaceman, AM; Hankins, GD; Dudley, DJ; Caritis, SN

    2014-01-01

    Objective Endogenous digoxin-like factor (EDLF) has been linked to vasoconstriction, altered membrane transport and apoptosis. Our objective was to determine whether increased EDLF in the cord sera of preterm infants was associated with an increased incidence of necrotizing enterocolitis (NEC). Methods Cord sera from pregnant women enrolled in a randomized trial of MgSO4 for fetal neuroprotection were analyzed for EDLF using a red cell Rb+ uptake assay where inhibition of sodium pump-mediated Rb+ transport was used as a functional assay of EDLF. Specimens were assayed blinded to neonatal outcome. Cases (NEC, n=25) and controls (neonates not developing stage 2 or 3 NEC, n=24) were matched by study center and gestational age. None of the women had preeclampsia. Cases and controls were compared using the Wilcoxon test for continuous and the Fisher’s exact test for categorical variables. Conditional logistic regression analysis was used to assess the odds of case versus control by EDLF level. Results Cases and controls were not significantly different for gestational age (GA), race, maternal steroid use, premature rupture of membranes (PPROM) or MgSO4 treatment. In logistic models adjusted for treatment group, race, PPROM and GA, cord sera EDLF was significantly associated with development of NEC (p=0.023). Conclusions These data demonstrated an association between cord sera EDLF and NEC. PMID:24215859

  20. Dysbiosis Anticipating Necrotizing Enterocolitis in Very Premature Infants

    PubMed Central

    Sim, Kathleen; Shaw, Alexander G.; Randell, Paul; Cox, Michael J.; McClure, Zoë E.; Li, Ming-Shi; Haddad, Munther; Langford, Paul R.; Cookson, William O. C. M.; Moffatt, Miriam F.; Kroll, J. Simon

    2015-01-01

    Background. Necrotizing enterocolitis (NEC) is a devastating inflammatory bowel disease of premature infants speculatively associated with infection. Suspected NEC can be indistinguishable from sepsis, and in established cases an infant may die within hours of diagnosis. Present treatment is supportive. A means of presymptomatic diagnosis is urgently needed. We aimed to identify microbial signatures in the gastrointestinal microbiota preceding NEC diagnosis in premature infants. Methods. Fecal samples and clinical data were collected from a 2-year cohort of 369 premature neonates. Next-generation sequencing of 16S ribosomal RNA gene regions was used to characterize the microbiota of prediagnosis fecal samples from 12 neonates with NEC, 8 with suspected NEC, and 44 controls. Logistic regression was used to determine clinical characteristics and operational taxonomic units (OTUs) discriminating cases from controls. Samples were cultured and isolates identified using matrix-assisted laser desorption/ionization–time of flight. Clostridial isolates were typed and toxin genes detected. Results. A clostridial OTU was overabundant in prediagnosis samples from infants with established NEC (P = .006). Culture confirmed the presence of Clostridium perfringens type A. Fluorescent amplified fragment-length polymorphism typing established that no isolates were identical. Prediagnosis samples from NEC infants not carrying profuse C. perfringens revealed an overabundance of a Klebsiella OTU (P = .049). Prolonged continuous positive airway pressure (CPAP) therapy with supplemental oxygen was also associated with increased NEC risk. Conclusions. Two fecal microbiota signatures (Clostridium and Klebsiella OTUs) and need for prolonged CPAP oxygen signal increased risk of NEC in presymptomatic infants. These biomarkers will assist development of a screening tool to allow very early diagnosis of NEC. Clinical Trials Registration. NCT01102738. PMID:25344536

  1. Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants

    PubMed Central

    Autmizguine, Julie; Hornik, Christoph P.; Benjamin, Daniel K.; Laughon, Matthew M.; Clark, Reese H.; Cotten, C. Michael; Cohen-Wolkowiez, Michael; Benjamin, Daniel K.

    2015-01-01

    OBJECTIVE: To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants. METHODS: We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort. RESULTS: A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95). CONCLUSIONS: Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality. PMID:25511117

  2. Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis?

    PubMed Central

    Franklin, Ashanti L.; Said, Mariam; Cappiello, Clint D.; Gordish-Dressman, Heather; Tatari-Calderone, Zohreh; Vukmanovic, Stanislav; Rais-Bahrami, Khodayar; Luban, Naomi L. C.; Devaney, Joseph M.; Sandler, Anthony D.

    2015-01-01

    Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48–29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56–32.52). Neonates with TGFβ-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08–0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01 – 8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09–19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFβ-1 (rs2241712) were associated with NEC- related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC. PMID:26670709

  3. [Acute necrotizing pancreatitis--diagnostic and treatment strategy].

    PubMed

    Madzhov, R; Georgiev, K; Arnaudov, P; Radev, R; Bankov, P

    2003-01-01

    Despite of the current achievements of medicine, the mortality of necrotizing pancreatitis (NP) is still too high--up to 35-40% and stands as a serious diagnostic and treatment problem. The results of treatment of 148 patients, admitted in the clinic with diagnosis NP, 95 males and 53 females, are discussed. The ratio between patients with acute oedematic and acute NP is 81.1% to 18.9%. According to the hystopatology findings, the results are as follows: pancreatic necrosis--128 patients, peripancreatic necrosis--42 patients, retropancreatic necrosis--29 patients, phlegmonous cholecystitis--31 patients. For the exact diagnostic estimation of the development and prognosis of NP, we are based on: Clinic symptomatology, biochemical constellations (the prognostic scale of Ranson), ultrasonography, CT, ERCP, ES, laparoscopy (48 pts), and laparoscopic drainage (34 pts) of the abdominal cavity with one or two drains, in order to decrease the intoxication and manage intraperitoneal irrigation with antibiotics and enzymes. The operative intervations consists of a thorough exploration, broad necrectomy combined with lavage and large drainage. COLD (controlled open lesser sac drainage) has been performed at 34 cases. In 31 pts cholecystectomy and choledochotomy with T-tube drainage of d. choledochus (Kehr drainage) was performed. Reoperations have been made at 34 pts (22.9%); in 11 of them--2 operative revisions have been carried out, in 3 cases--three, and in 3 cases--4 operative revisions were performed. The total postoperative death rate was 21.6% (32 patients). The most common postoperative complications were as follows: pulmonary complications at 11 cases, pleural effusions--9 pts, intraabdominal abscesses--6 patients, postnecrotic pseudocysts--9 cases, pancreatic fistulas--6 cases, fistulas of the colon--2 pts, bleeding--4 patients. PMID:15584453

  4. Optic neuritis and rapidly progressive necrotizing retinitis as the initial signs of subacute sclerosing panencephalitis: a case report with clinical and histopathologic findings.

    PubMed

    Oray, Merih; Tuncer, Samuray; Kir, Nur; Karacorlu, Murat; Tugal-Tutkun, Ilknur

    2014-08-01

    We report a case of subacute sclerosing panencephalitis (SSPE) presenting first with optic neuritis and rapidly progressive necrotizing retinitis at the posterior pole. We reviewed the clinical, laboratory, photographic, angiographic, and histopathologic records of a patient with SSPE. A 15-year-old girl was referred after rapid loss of vision due to optic neuritis and macular necrosis in the right eye. She had a history of cardiac valve surgery, but had no systemic symptoms and extensive work-up was unrewarding. Contralateral involvement with rapidly progressive optic neuritis and macular necrotizing retinitis prompted retinochoroidal biopsy of the right eye, which revealed necrosis of inner retinal layers and perivascular lymphoplasmocytic infiltration with intact choroid and outer retina without any findings of inclusion bodies, microorganisms, or atypical cells. The diagnosis was based on histopathologic findings consistent with SSPE, and detection of elevated measles antibody titers in cerebrospinal fluid and serum. It was further confirmed by development of typical electroencephalography pattern at 6 months and neurological symptoms at 4-year follow-up. Clinicians need to be aware that optic neuritis and necrotizing retinitis at the posterior pole may be the presenting features of SSPE. PMID:24522882

  5. A novel pore-forming toxin in type A Clostridium perfringens is associated with both fatal canine hemorrhagic gastroenteritis and fatal foal necrotizing enterocolitis.

    PubMed

    Mehdizadeh Gohari, Iman; Parreira, Valeria R; Nowell, Victoria J; Nicholson, Vivian M; Oliphant, Kaitlyn; Prescott, John F

    2015-01-01

    A role for type A Clostridium perfringens in acute hemorrhagic and necrotizing gastroenteritis in dogs and in necrotizing enterocolitis of neonatal foals has long been suspected but incompletely characterized. The supernatants of an isolate made from a dog and from a foal that died from these diseases were both found to be highly cytotoxic for an equine ovarian (EO) cell line. Partial genome sequencing of the canine isolate revealed three novel putative toxin genes encoding proteins related to the pore-forming Leukocidin/Hemolysin Superfamily; these were designated netE, netF, and netG. netE and netF were located on one large conjugative plasmid, and netG was located with a cpe enterotoxin gene on a second large conjugative plasmid. Mutation and complementation showed that only netF was associated with the cytotoxicity. Although netE and netG were not associated with cytotoxicity, immunoblotting with specific antisera showed these proteins to be expressed in vitro. There was a highly significant association between the presence of netF with type A strains isolated from cases of canine acute hemorrhagic gastroenteritis and foal necrotizing enterocolitis. netE and netF were found in all cytotoxic isolates, as was cpe, but netG was less consistently present. Pulsed-field gel electrophoresis showed that netF-positive isolates belonged to a clonal population; some canine and equine netF-positive isolates were genetically indistinguishable. Equine antisera to recombinant Net proteins showed that only antiserum to rNetF had high supernatant cytotoxin neutralizing activity. The identifica-tion of this novel necrotizing toxin is an important advance in understanding the virulence of type A C. perfringens in specific enteric disease of animals. PMID:25853427

  6. A Novel Pore-Forming Toxin in Type A Clostridium perfringens Is Associated with Both Fatal Canine Hemorrhagic Gastroenteritis and Fatal Foal Necrotizing Enterocolitis

    PubMed Central

    Nowell, Victoria J.; Nicholson, Vivian M.; Oliphant, Kaitlyn; Prescott, John F.

    2015-01-01

    A role for type A Clostridium perfringens in acute hemorrhagic and necrotizing gastroenteritis in dogs and in necrotizing enterocolitis of neonatal foals has long been suspected but incompletely characterized. The supernatants of an isolate made from a dog and from a foal that died from these diseases were both found to be highly cytotoxic for an equine ovarian (EO) cell line. Partial genome sequencing of the canine isolate revealed three novel putative toxin genes encoding proteins related to the pore-forming Leukocidin/Hemolysin Superfamily; these were designated netE, netF, and netG. netE and netF were located on one large conjugative plasmid, and netG was located with a cpe enterotoxin gene on a second large conjugative plasmid. Mutation and complementation showed that only netF was associated with the cytotoxicity. Although netE and netG were not associated with cytotoxicity, immunoblotting with specific antisera showed these proteins to be expressed in vitro. There was a highly significant association between the presence of netF with type A strains isolated from cases of canine acute hemorrhagic gastroenteritis and foal necrotizing enterocolitis. netE and netF were found in all cytotoxic isolates, as was cpe, but netG was less consistently present. Pulsed-field gel electrophoresis showed that netF-positive isolates belonged to a clonal population; some canine and equine netF-positive isolates were genetically indistinguishable. Equine antisera to recombinant Net proteins showed that only antiserum to rNetF had high supernatant cytotoxin neutralizing activity. The identifica-tion of this novel necrotizing toxin is an important advance in understanding the virulence of type A C. perfringens in specific enteric disease of animals. PMID:25853427

  7. Cadmium-Induced Upregulation of Lipid Peroxidation and Reactive Oxygen Species Caused Physiological, Biochemical, and Ultrastructural Changes in Upland Cotton Seedlings

    PubMed Central

    Mei, Lei; Chen, Yue; Cheng, Xin; Zhu, S. J.

    2013-01-01

    Cadmium (Cd) toxicity was investigated in cotton cultivar (ZMS-49) using physiological, ultrastructural, and biochemical parameters. Biomass-based tolerance index decreased, and water contents increased at 500 μM Cd. Photosynthetic efficiency determined by chlorophyll fluorescence and photosynthetic pigments declined under Cd stress. Cd contents were more in roots than shoots. A significant decrease in nutrient levels was found in roots and stem. A significant decrease in nutrient levels was found in roots and stems. In response to Cd stress, more MDA and ROS contents were produced in leaves than in other parts of the seedlings. Total soluble proteins were reduced in all parts except in roots at 500 μM Cd. Oxidative metabolism was higher in leaves than aerial parts of the plant. There were insignificant alterations in roots and leaves ultrastructures such as a little increase in nucleoli, vacuoles, starch granules, and plastoglobuli in Cd-imposed stressful conditions. Scanning micrographs at 500 μM Cd showed a reduced number of stomata as well as near absence of closed stomata. Cd depositions were located in cell wall, vacuoles, and intracellular spaces using TEM-EDX technology. Upregulation of oxidative metabolism, less ultrastructural modification, and Cd deposition in dead parts of cells show that ZMS-49 has genetic potential to resist Cd stress, which need to be explored. PMID:24459668

  8. Temporal regulation of cell-wall pectin methylesterase and peroxidase isoforms in cadmium-treated flax hypocotyl

    PubMed Central

    Paynel, Florence; Schaumann, Annick; Arkoun, Mustapha; Douchiche, Olfa; Morvan, Claudine

    2009-01-01

    Background and Aims In hypocotyls of flax (Linum usitatissimum) cadmium-induced reorientation of growth (i.e. an increase in expansion and a decrease in elongation) coincides with marked changes in the methylesterification and cross-linking of homogalacturonans within various cell-wall (CW) domains. The aim of the present study was to examine the involvement of pectin methylesterase (PME) and peroxidase (PER) in this cadmium-induced CW remodelling. Methods CW proteins were extracted from hypocotyls of 10- and 18-d-old flax that had been treated or not treated with 0·5 mm Cd(NO3)2. PME and PER expression within these extracts was detected by LC/MS, by isoelectric focusing and enzyme activity assays. Transcript expression by RT-PCR of known flax PME and PER genes was also measured in corresponding samples. Key Results In cadmium-treated seedlings, PME activity increased as compared with controls, particularly at day 10. The increased activity of PME was accompanied by increased abundance of both a basic protein isoform (B2) and a particular transcript (Lupme5). In contrast, induction of PER activity by cadmium was highest at day 18. Among the four reported PER genes, Flxper1 and 3 increased in abundance in the presence of cadmium at day 18. Conclusions The temporal regulation of Lupme and Flxper genes and of their respective enzyme activities fits the previously reported cadmium-induced structural changes of homogalacturonans within the CWs. After PME-catalysed de-esterification of homogalacturonans, their cross-linking would depend on the activity of PERs interacting with calcium-dimerized blocks and reinforce the cell cohesion during the cadmium-induced swelling. PMID:19815572

  9. Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line.

    PubMed

    Wang, Bin; Schneider, Scott N; Dragin, Nadine; Girijashanker, Kuppuswami; Dalton, Timothy P; He, Lei; Miller, Marian L; Stringer, Keith F; Soleimani, Manoocher; Richardson, Douglas D; Nebert, Daniel W

    2007-04-01

    Resistance to cadmium (Cd)-induced testicular necrosis is an autosomal recessive trait defined as the Cdm locus. Using positional cloning, we previously identified the Slc39a8 (encoding an apical-surface ZIP8 transporter protein) as the gene most likely responsible for the phenotype. In situ hybridization revealed that endothelial cells of the testis vasculature express high ZIP8 levels in two sensitive inbred mouse strains and negligible amounts in two resistant strains. In the present study, we isolated a 168.7-kb bacterial artificial chromosome (BAC), carrying only the Slc39a8 gene, from a Cd-sensitive 129/SvJ BAC library and generated BAC-transgenic mice. The BTZIP8-3 line, having three copies of the 129/SvJ Slc39a8 gene inserted into the Cd-resistant C57BL/6J genome (having its normal two copies of the Slc39a8 gene), showed tissue-specific ZIP8 mRNA expression similar to wild-type mice, mainly in lung, testis, and kidney. The approximately 2.5-fold greater expression paralleled the fact that the BTZIP8-3 line has five copies, whereas wild-type mice have two copies, of the Slc39a8 gene. The ZIP8 mRNA and protein localized especially to endothelial cells of the testis vasculature in BTZIP8-3 mice. Cd treatment reversed Cd resistance (seen in nontransgenic littermates) to Cd sensitivity in BTZIP8-3 mice; reversal of the testicular necrosis phenotype confirms that Slc39a8 is unequivocally the Cdm locus. ZIP8 also localized specifically to the apical surface of proximal tubule cells in the BTZIP8-3 kidney. Cd treatment caused acute renal failure and signs of proximal tubular damage in the BTZIP8-3 but not nontransgenic littermates. BTZIP8-3 mice should be a useful model for studying Cd-induced disease in kidney. PMID:17108009

  10. The Cytotoxic Necrotizing Factor of Yersinia pseudotuberculosis (CNFY) Enhances Inflammation and Yop Delivery during Infection by Activation of Rho GTPases

    PubMed Central

    Schweer, Janina; Kulkarni, Devesha; Kochut, Annika; Pezoldt, Joern; Pisano, Fabio; Pils, Marina C.; Genth, Harald; Huehn, Jochen; Dersch, Petra

    2013-01-01

    Some isolates of Yersinia pseudotuberculosis produce the cytotoxic necrotizing factor (CNFY), but the functional consequences of this toxin for host-pathogen interactions during the infection are unknown. In the present study we show that CNFY has a strong influence on virulence. We demonstrate that the CNFY toxin is thermo-regulated and highly expressed in all colonized lymphatic tissues and organs of orally infected mice. Most strikingly, we found that a cnfY knock-out variant of a naturally toxin-expressing Y. pseudotuberculosis isolate is strongly impaired in its ability to disseminate into the mesenteric lymph nodes, liver and spleen, and has fully lost its lethality. The CNFY toxin contributes significantly to the induction of acute inflammatory responses and to the formation of necrotic areas in infected tissues. The analysis of the host immune response demonstrated that presence of CNFY leads to a strong reduction of professional phagocytes and natural killer cells in particular in the spleen, whereas loss of the toxin allows efficient tissue infiltration of these immune cells and rapid killing of the pathogen. Addition of purified CNFY triggers formation of actin-rich membrane ruffles and filopodia, which correlates with the activation of the Rho GTPases, RhoA, Rac1 and Cdc42. The analysis of type III effector delivery into epithelial and immune cells in vitro and during the course of the infection further demonstrated that CNFY enhances the Yop translocation process and supports a role for the toxin in the suppression of the antibacterial host response. In summary, we highlight the importance of CNFY for pathogenicity by showing that this toxin modulates inflammatory responses, protects the bacteria from attacks of innate immune effectors and enhances the severity of a Yersinia infection. PMID:24244167

  11. A Large Bladder Tumor Covered With a Thick "Shell" of Necrotic Material: Misdiagnosis of a Patient With Spina Bifida.

    PubMed

    Wang, Lei; Zhou, Zhe; Gong, Miao-Zi; Pan, Dong-Liang; Zhang, Xiang-Hua; Li, Ning-Chen; Na, Yan-Qun

    2016-04-01

    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 cm, 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 cm 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

  12. Endoplasmic reticulum stress eIF2α-ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney.

    PubMed

    Luo, B; Lin, Y; Jiang, S; Huang, L; Yao, H; Zhuang, Q; Zhao, R; Liu, H; He, C; Lin, Z

    2016-01-01

    The heavy metal cadmium (Cd) is nephrotoxic. Recent studies show that autophagy plays an essential role in Cd-induced kidney injury. However, the mechanisms of Cd-induced kidney injury accompanied by autophagy are still obscure. In the present study, we first confirmed that Cd induced kidney damage and dysfunction, along with autophagy, both in vivo and in vitro. Then, we observed that cyclooxygenase-2 (COX-2) and the eIF2α-ATF4 pathway of endoplasmic reticulum (ER) stress were induced by Cd in both kidney tissues and cultured cells. Further studies showed that inhibition of COX-2 with celecoxib or RNA interference (RNAi) inhibited the Cd-induced autophagy in kidney cells. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and autophagy induced by Cd, which suggested that ER stress was required for Cd-induced kidney autophagy. Significantly, our results showed that Cd activated ATF4 and induced its translocation to the nucleus. Knockdown of ATF4 inhibited Cd-induced COX-2 overexpression. While COX-2 overexpression is involved in renal dysfunction, there is no prior report on the role of COX-2 in autophagy regulation. The results of the current study suggest a novel molecular mechanism that the ER stress eIF2α-ATF4 pathway-mediated COX-2 overexpression contributes to Cd-induced kidney autophagy and injury. The present study implies that COX-2 may be a potential target for therapy against Cd-induced nephrotoxicity. PMID:27253415

  13. N-benzyl-D-glucamine dithiocarbamate and N-p-isopropylbenzyl-D-glucamine dithiocarbamate improve the protective effect of diethyldithiocarbamate against cadmium-induced testicular toxicity in rats.

    PubMed

    Kojima, S; Sugimura, Y; Ono, H; Shimada, H; Funakoshi, T

    1993-03-01

    The protective effects of combined treatment with diethyldithiocarbamate (DED) plus N-benzyl-D-glucamine dithiocarbamate (BGD) or DED plus N-p-isopropylbenzyl-D-glucamine dithiocarbamate (PBGD) against the testicular toxicity caused by acute exposure to cadmium (Cd) in rats were studied. Rats were injected subcutaneously with 109CdCl2 (3 mg Cd and 74 kBq of 109Cd/kg) and 30 min later, they were injected intraperitoneally with the chelating agents (1 mmol/kg each). Cd injection increased lipid peroxidation and concentrations of hemoglobin, Ca and Fe in the testes, decreased the testicular weight and nonprotein SH (NP-SH), and caused sterility. The coadministration of DED with BGD or PBGD significantly prevented the increase in the lipid peroxidation, hemoglobin, Ca and Fe in the testes, the decrease in the testicular weight and NP-SH, and the sterility caused by Cd injection. DED plus BGD or DED plus PBGD significantly decreased the Cd concentration in the testes without the redistribution of Cd to the brain and kidney, which is observed following treatment with DED alone. The coadministration of DED plus BGD or DED plus PBGD significantly increased the blood Cd concentration and the Cd distribution in the red blood cells compared to Cd alone. These results indicate that the coadministration of BGD or PBGD with DED prevents the accumulation of Cd in the testes on the basis of greater blood distribution of Cd, which results from the uptake of Cd by the red blood cells, without the redistribution of Cd to the brain, resulting in an improvement of the protective effect of DED against the Cd-induced testicular toxicity. PMID:8395932

  14. In vivo studies of cadmium-induced apoptosis in testicular tissue of the rat and its modulation by a chelating agent.

    PubMed

    Xu, C; Johnson, J E; Singh, P K; Jones, M M; Yan, H; Carter, C E

    1996-01-22

    In vivo CdCl2-induced apoptotic DNA fragmentation in the testes of the male Wistar rat has been demonstrated on agarose gel. Characteristic DNA migration patterns (laddering) provide evidence of apoptosis (programmed cell death) in testicular tissue of rats administered CdCl2 at a level of 0.03 mmol/kg 48 h previously. Evidence that administration of an appropriate cadmium chelating agent within the first 24 h can suppress some or all of the apoptotic changes in testicular DNA has also been obtained for the first time. A greater reduction in apoptosis is observed as the interval between the administration of the cadmium and that of the chelating agent is shortened. Administration of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) to male Wistar rats given CdCl2 is effective in the modulation of the typically apoptotic DNA fragmentation and associated histopathologic injury when the antagonist is given within approximately 1 h after the CdCl2 exposure. When the antagonist is given at later times there is a progressively more pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern found with apoptosis. There is also a progressive increase in histopathological tissue changes as the antagonist is administered at progressively greater intervals after the cadmium. PMID:8597027

  15. Detection of Enterococcus faecalis in Necrotic Teeth Root Canals by Culture and Polymerase Chain Reaction Methods

    PubMed Central

    Cogulu, Dilsah; Uzel, Atac; Oncag, Ozant; Aksoy, Semiha C.; Eronat, Cemal

    2007-01-01

    Objectives The aim of this study was to investigate the presence of Enterococcus faecalis in endodontic infections in both deciduous and permanent teeth by culture and polymerase chain reaction (PCR) methods. Methods A total of 145 children aged 5–13 years old were involved in this study. The presence of E. faecalis in necrotic deciduous and permanent teeth root canals was studied using culture and polymerase chain reaction methods. Results Among 145 molar teeth, 57% (n=83) presented necrotic asymptomatic pulp tissues and were included in this study. Culture and PCR methods detected the test species in 18 and 22 of 83 teeth involved, respectively. E. faecalis was cultured from 8 (18%) of 45 necrotic deciduous teeth and from 10 (26%) of 38 necrotic permanent teeth. PCR detection identified the target species in 10 (22%) and 12 (32%) of necrotic deciduous and permanent teeth respectively. Statistically significant difference in the presence of E. faecalis in deciduous and permanent teeth was found by culture and PCR methods (P=0.03 and 0.02, respectively). The difference in the presence of E. faecalis between two different methods was not statistically significant (P>.05). Conclusions The results of the present study confirm that both culture and PCR methods are sensitive to detect E. faecalis in root canals. PMID:19212470

  16. Necrotizing fasciitis – a rare complication following common obstetric operative procedures: report of two cases

    PubMed Central

    Medhi, Robin; Rai, Suditi; Das, Arpana; Ahmed, Mansur; Das, Banani

    2015-01-01

    Necrotizing fasciitis, a near-fatal soft-tissue infection complicating obstetric operative wounds, is a rare entity in obstetrics. Herein, we report two cases of necrotizing fasciitis in severely undernourished and anemic women following obstetric operative procedures. Both undernourishment and anemia compounded the already existing immune-suppressed state in pregnancy and may have lead to life-threatening necrotizing fasciitis. One of the patients developed necrotizing fasciitis following episiotomy and the other following cesarean section. Both the cases were diagnosed clinically. Management was done by total parenteral nutrition, prompt correction of anemia, and surgical debridement under broad-spectrum antibiotic coverage. The raw areas were later reconstructed by split skin grafting in the first case, whereas, in the second case, due to the patient’s refusal of skin grafting, the wound was allowed to heal by secondary intention. Both patients survived, although with morbidity. Our study aims to emphasize prompt correction of comorbidities along with aggressive management of necrotizing fasciitis for better outcomes in the obstetric population. Prompt correction of nutritional status improves the survival rate. PMID:25897266

  17. Contralateral recurrence of necrotizing sialometaplasia of the hard palate after five months: a case report.

    PubMed

    Jeong, Chan-Woo; Youn, Taegyun; Kim, Hyun Sil; Park, Kwang-Ho; Huh, Jong-Ki

    2015-12-01

    Necrotizing sialometaplasia usually heals within 4 to 10 weeks with conservative treatment, and rarely recurs. When necrotizing sialometaplasia is present on the hard palate it may occur unilaterally or bilaterally. In this case, necrotizing ulceration occurred on the left hard palate of a 36-year-old woman after root canal treatment of the upper left first premolar under local anesthesia. After only saline irrigation the defect of the lesion completely healed and filled with soft tissue. After 5 months, however, a similar focal necrosis was found on the contralateral hard palate without any dental treatment having been performed on that side and progressed in similar fashion as the former lesion. We conducted an incisional biopsy and obtained a final pathological diagnosis for the palatal mass of necrotizing sialometaplasia. At the 3-year follow-up, the patient's oral mucosa of the hard palate was normal, without any signs and symptoms of the condition. We report a case of a second occurrence of necrotizing sialometaplasia on the contralateral side from the first, with a time lapse between the first and second occurrence. PMID:26734562

  18. Contralateral recurrence of necrotizing sialometaplasia of the hard palate after five months: a case report

    PubMed Central

    2015-01-01

    Necrotizing sialometaplasia usually heals within 4 to 10 weeks with conservative treatment, and rarely recurs. When necrotizing sialometaplasia is present on the hard palate it may occur unilaterally or bilaterally. In this case, necrotizing ulceration occurred on the left hard palate of a 36-year-old woman after root canal treatment of the upper left first premolar under local anesthesia. After only saline irrigation the defect of the lesion completely healed and filled with soft tissue. After 5 months, however, a similar focal necrosis was found on the contralateral hard palate without any dental treatment having been performed on that side and progressed in similar fashion as the former lesion. We conducted an incisional biopsy and obtained a final pathological diagnosis for the palatal mass of necrotizing sialometaplasia. At the 3-year follow-up, the patient's oral mucosa of the hard palate was normal, without any signs and symptoms of the condition. We report a case of a second occurrence of necrotizing sialometaplasia on the contralateral side from the first, with a time lapse between the first and second occurrence. PMID:26734562

  19. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    SciTech Connect

    Kandasamy, Neelamegam; Ashokkumar, Natarajan

    2014-09-01

    nephrotoxicant whether ingested or inhaled. • Myricetin enhances insulin secretion from the damaged pancreatic β-cells. • Myricetin can eliminate metals and scavenge chemical induced free radicals. • Myricetin enhances the glucose uptake by regulating insulin signaling pathway.

  20. Anti-Apoptotic and Anti-Oxidant Effects of Caffeic Acid Phenethyl Ester on Cadmium-Induced Testicular Toxicity in Rats.

    PubMed

    Erboga, Mustafa; Kanter, Mehmet; Aktas, Cevat; Bozdemir Donmez, Yeliz; Fidanol Erboga, Zeynep; Aktas, Emel; Gurel, Ahmet

    2016-05-01

    Cadmium (Cd) is a serious environmental and occupational contaminant and may represent a serious health hazard to humans and other animals. Cd is reported to induce the generation of reactive oxygen species, and induces testicular damage in many species of animals. The goal of our study was to examine the anti-apoptotic and anti-oxidant effects of caffeic acid phenethyl ester (CAPE) on Cd-induced oxidative stress, apoptosis, and testicular injury in rats. A total of 40 male Wistar albino rats were divided into four groups: control, CAPE alone, Cd-treated, and Cd-treated with CAPE; each group consisted of 10 animals. To induce toxicity, Cd (1 mg/kg body weight) was dissolved in normal saline and subcutaneously injected into rats for 30 days. The rats in CAPE-treated group were given a daily dose of 10 μmol/kg body weight of CAPE by using intraperitoneal injection. This application was continued daily for a total of 30 days. To date, no examinations of the anti-apoptotic and anti-oxidant properties of CAPE on Cd-induced apoptosis, oxidative damage, and testicular injury in rat testes have been reported. CAPE-treated animals showed an improved histological appearance and serum testosterone levels in Cd-treated group. Our data indicate a significant reduction in the number of apoptotic cells in testis tissues of the Cd-treated group with CAPE treatment. Moreover, CAPE significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses in testes tissue resulted from Cd administration. These findings suggest that the protective potential of CAPE in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced testicular injury. PMID:26424218

  1. Thymoquinone Ameliorates Cadmium-Induced Nephrotoxicity, Apoptosis, and Oxidative Stress in Rats is Based on its Anti-Apoptotic and Anti-Oxidant Properties.

    PubMed

    Erboga, Mustafa; Kanter, Mehmet; Aktas, Cevat; Sener, Umit; Fidanol Erboga, Zeynep; Bozdemir Donmez, Yeliz; Gurel, Ahmet

    2016-03-01

    Cadmium (Cd), an environmental and industrial pollutant, generates free radicals responsible for oxidative stress. Cd can also lead to various renal toxic damage such as the proximal tubules and glomerulus dysfunction. Thymoquinone (TQ) is the main constituent of the essential oil obtained from black seeds (Nigella sativa) and has various pharmacological effects. The aim of the present study was to examine the nephroprotective, anti-oxidant, and anti-apoptotic effect of the TQ against Cd-induced nephrotoxicity. A total of 24 male Wistar albino rats were divided into three groups: control, Cd-treated, and Cd-treated with TQ; each group contain eight animals. The Cd-treated group was injected subcutaneously with CdCl2 dissolved in saline in the amount of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in TQ-treated groups were given TQ (50 mg/kg body weight) once a day orally together with first Cd injection during the study period. The histopathological studies in the kidney of rats also showed that TQ markedly reduced the toxicity of Cd and preserved the normal histological architecture of the renal tissue. Immunohistochemical analysis revealed that TQ significantly decreased the Cd-induced over expression of nuclear factor-κB in renal tissue. Furthermore, TQ treatment resulted in decreased the number of apoptotic cells. TQ significantly suppressed lipid peroxidation, compensated deficits in the anti-oxidant defenses (reduced superoxide dismutase, glutathione peroxidase and catalase activities) in renal tissue resulted from Cd administration. These findings suggest that the nephroprotective potential of TQ in Cd toxicity might be due to its anti-oxidant and anti-apoptotic properties, which could be useful for achieving optimum effects in Cd-induced nephrotoxicity. PMID:26226832

  2. Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets.

    PubMed

    Jensen, Michael L; Thymann, Thomas; Cilieborg, Malene S; Lykke, Mikkel; Mølbak, Lars; Jensen, Bent B; Schmidt, Mette; Kelly, Denise; Mulder, Imke; Burrin, Douglas G; Sangild, Per T

    2014-01-01

    Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum antibiotic treatment improves NEC resistance and intestinal structure, function, and immunity in neonates. Caesarean-delivered preterm pigs were fed 3 days of parenteral nutrition followed by 2 days of enteral formula. Immediately after birth, they were assigned to receive either antibiotics (oral and parenteral doses of gentamycin, ampicillin, and metronidazole, ANTI, n = 11) or saline in the control group (CON, n = 13), given twice daily. NEC lesions and intestinal structure, function, microbiology, and immunity markers were recorded. None of the ANTI but 85% of the CON pigs developed NEC lesions by day 5 (0/11 vs. 11/13, P < 0.05). ANTI pigs had higher intestinal villi (+60%), digestive enzyme activities (+53-73%), and goblet cell densities (+110%) and lower myeloperoxidase (-51%) and colonic microbial density (10(5) vs. 10(10) colony-forming units, all P < 0.05). Microarray transcriptomics showed strong downregulation of genes related to inflammation and innate immune response to microbiota and marked upregulation of genes related to amino acid metabolism, in particular threonine, glucose transport systems, and cell cycle in 5-day-old ANTI pigs. In a follow-up experiment, 5 days of antibiotics prevented NEC at least until day 10. Neonatal prophylactic antibiotics effectively reduced gut bacterial load, prevented NEC, intestinal atrophy, dysfunction, and inflammation and enhanced expression of genes related to gut metabolism and immunity in preterm pigs. PMID:24157972

  3. Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates.

    PubMed

    Siggers, Jayda; Ostergaard, Mette V; Siggers, Richard H; Skovgaard, Kerstin; Mølbak, Lars; Thymann, Thomas; Schmidt, Mette; Møller, Hanne K; Purup, Stig; Fink, Lisbeth N; Frøkiær, Hanne; Boye, Mette; Sangild, Per T; Bering, Stine B

    2013-05-15

    Preterm neonates are susceptible to gastrointestinal disorders such as necrotizing enterocolitis (NEC). Maternal milk and colostrum protects against NEC via growth promoting, immunomodulatory, and antimicrobial factors. The fetal enteral diet amniotic fluid (AF), contains similar components, and we hypothesized that postnatal AF administration reduces inflammatory responses and NEC in preterm neonates. Preterm pigs (92% gestation) were delivered by caesarean section and fed parental nutrition (2 days) followed by enteral (2 days) porcine colostrum (COLOS, n = 7), infant formula (FORM, n = 13), or AF supplied before and after introduction of formula (AF, n = 10) in experiment 1, and supplied only during the enteral feeding period in experiment 2 (FORM, n = 16; AF, n = 14). The NEC score was reduced in both AF and COLOS pigs, relative to FORM, when AF was provided prior to full enteral feeding (9.9 and 7.7 compared with 17.3, P < 0.05). There was no effect of AF when provided only during enteral feeding. AF pigs showed decreased bacterial abundance in colon and intestinal inflammation-related genes (e.g., TNF-α, IL-1α, IL-6, NOS) were downregulated, relative to FORM pigs with NEC. Anti-inflammatory properties of AF were supported by delayed maturation and decreased TNF-α production in murine dendritic cells, as well as increased proliferation and migration, and downregulation of IL-6 expression in intestinal cells (IEC-6, IPEC-J2). Like colostrum, AF may reduce NEC development in preterm neonates by suppressing the proinflammatory responses to enteral formula feeding and gut colonization when provided before the onset of NEC. PMID:23518680

  4. Coccidia-induced mucogenesis promotes the onset of necrotic enteritis by supporting Clostridium perfringens growth.

    PubMed

    Collier, C T; Hofacre, C L; Payne, A M; Anderson, D B; Kaiser, P; Mackie, R I; Gaskins, H R

    2008-03-15

    This study tested the hypothesis that a host mucogenic response to an intestinal coccidial infection promotes the onset of necrotic enteritis (NE). A chick NE model was used in which birds were inoculated with Eimeria acervulina and E. maxima and subsequently with Clostridium perfringens (EAM/CP). A second group of EAM/CP-infected birds was treated with the ionophore narasin (NAR/EAM/CP). These groups were compared to birds that were either non-infected (NIF), or infected only with E. acervulina and E. maxima (EAM), or C. perfringens (CP). The impact of intestinal coccidial infection and anti-coccidial treatment on host immune responses and microbial community structure were evaluated with histochemical-, cultivation- and molecular-based techniques. Barrier function was compromised in EAM/CP-infected birds as indicated by elevated CFUs for anaerobic bacteria and C. perfringens in the spleen when compared to NIF controls at day 20, with a subsequent increase in intestinal NE lesions and mortality at day 22. These results correlate positively with a host inflammatory response as evidenced by increased ileal interleukin (IL)-4, IL-10 and IFN-gamma RNA expression. Concurrent increases in chicken intestinal mucin RNA expression, and goblet cell number and theca size indicate that EAM/CP induced an intestinal mucogenic response. Correspondingly, the growth of mucolytic bacteria and C. perfringens as well as alpha toxin production was greatest in EAM/CP-infected birds. The ionophore narasin, which directly eliminates coccidia, reduced goblet cell theca size, IL-10 and IFN-gamma expression, the growth of mucolytic bacteria including C. perfringens, coccidial and NE lesions and mortality in birds that were co-infected with coccidia and C. perfringens. Collectively the data support the hypothesis that coccidial infection induces a host mucogenic response providing a growth advantage to C. perfringens, the causative agent of NE. PMID:18068809

  5. Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets

    PubMed Central

    Jensen, Michael L.; Thymann, Thomas; Cilieborg, Malene S.; Lykke, Mikkel; Mølbak, Lars; Jensen, Bent B.; Schmidt, Mette; Kelly, Denise; Mulder, Imke; Burrin, Douglas G.

    2013-01-01

    Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum antibiotic treatment improves NEC resistance and intestinal structure, function, and immunity in neonates. Caesarean-delivered preterm pigs were fed 3 days of parenteral nutrition followed by 2 days of enteral formula. Immediately after birth, they were assigned to receive either antibiotics (oral and parenteral doses of gentamycin, ampicillin, and metronidazole, ANTI, n = 11) or saline in the control group (CON, n = 13), given twice daily. NEC lesions and intestinal structure, function, microbiology, and immunity markers were recorded. None of the ANTI but 85% of the CON pigs developed NEC lesions by day 5 (0/11 vs. 11/13, P < 0.05). ANTI pigs had higher intestinal villi (+60%), digestive enzyme activities (+53–73%), and goblet cell densities (+110%) and lower myeloperoxidase (−51%) and colonic microbial density (105 vs. 1010 colony-forming units, all P < 0.05). Microarray transcriptomics showed strong downregulation of genes related to inflammation and innate immune response to microbiota and marked upregulation of genes related to amino acid metabolism, in particular threonine, glucose transport systems, and cell cycle in 5-day-old ANTI pigs. In a follow-up experiment, 5 days of antibiotics prevented NEC at least until day 10. Neonatal prophylactic antibiotics effectively reduced gut bacterial load, prevented NEC, intestinal atrophy, dysfunction, and inflammation and enhanced expression of genes related to gut metabolism and immunity in preterm pigs. PMID:24157972

  6. Cadmium-inducible expression of the ABC-type transporter AtABCC3 increases phytochelatin-mediated cadmium tolerance in Arabidopsis.

    PubMed

    Brunetti, Patrizia; Zanella, Letizia; De Paolis, Angelo; Di Litta, Davide; Cecchetti, Valentina; Falasca, Giuseppina; Barbieri, Maurizio; Altamura, Maria Maddalena; Costantino, Paolo; Cardarelli, Maura

    2015-07-01

    The heavy metal cadmium (Cd) is a widespread environmental contaminant with harmful effects on living cells. In plants, phytochelatin (PC)-dependent Cd detoxification requires that PC-Cd complexes are transported into vacuoles. Here, it is shown that Arabidopsis thaliana seedlings defective in the ABCC transporter AtABCC3 (abcc3) have an increased sensitivity to different Cd concentrations, and that seedlings overexpressing AtABCC3 (AtABCC3ox) have an increased Cd tolerance. The cellular distribution of Cd was analysed in protoplasts from abcc3 mutants and AtABCC3 overexpressors grown in the presence of Cd, by means of the Cd-specific fluorochromes 5-nitrobenzothiazole coumarin (BTC-5N) and Leadmium™ Green AM dye. This analysis revealed that Cd is mostly localized in the cytosol of abcc3 mutant protoplasts whereas there is an increase in vacuolar Cd in protoplasts from AtABCC3ox plants. Overexpression of AtABCC3 in cad1-3 mutant seedlings defective in PC production and in plants treated with l-buthionine sulphoximine (BSO), an inhibitor of PC biosynthesis, had no effect on Cd tolerance, suggesting that AtABCC3 acts via PCs. In addition, overexpression of AtABCC3 in atabcc1 atabcc2 mutant seedlings defective in the Cd transporters AtABCC1 and AtABCC2 complements the Cd sensitivity of double mutants, but not in the presence of BSO. Accordingly, the level of AtABCC3 transcript in wild type seedlings was lower than that of AtABCC1 and AtABCC2 in the absence of Cd but higher after Cd exposure, and even higher in atabcc1 atabcc2 mutants. The results point to AtABCC3 as a transporter of PC-Cd complexes, and suggest that its activity is regulated by Cd and is co-ordinated with the activity of AtABCC1/AtABCC2. PMID:25900618

  7. Cadmium-inducible expression of the ABC-type transporter AtABCC3 increases phytochelatin-mediated cadmium tolerance in Arabidopsis

    PubMed Central

    Brunetti, Patrizia; Zanella, Letizia; De Paolis, Angelo; Di Litta, Davide; Cecchetti, Valentina; Falasca, Giuseppina; Barbieri, Maurizio; Altamura, Maria Maddalena; Costantino, Paolo; Cardarelli, Maura

    2015-01-01

    The heavy metal cadmium (Cd) is a widespread environmental contaminant with harmful effects on living cells. In plants, phytochelatin (PC)-dependent Cd detoxification requires that PC–Cd complexes are transported into vacuoles. Here, it is shown that Arabidopsis thaliana seedlings defective in the ABCC transporter AtABCC3 (abcc3) have an increased sensitivity to different Cd concentrations, and that seedlings overexpressing AtABCC3 (AtABCC3ox) have an increased Cd tolerance. The cellular distribution of Cd was analysed in protoplasts from abcc3 mutants and AtABCC3 overexpressors grown in the presence of Cd, by means of the Cd-specific fluorochromes 5-nitrobenzothiazole coumarin (BTC-5N) and Leadmium™ Green AM dye. This analysis revealed that Cd is mostly localized in the cytosol of abcc3 mutant protoplasts whereas there is an increase in vacuolar Cd in protoplasts from AtABCC3ox plants. Overexpression of AtABCC3 in cad1-3 mutant seedlings defective in PC production and in plants treated with l-buthionine sulphoximine (BSO), an inhibitor of PC biosynthesis, had no effect on Cd tolerance, suggesting that AtABCC3 acts via PCs. In addition, overexpression of AtABCC3 in atabcc1 atabcc2 mutant seedlings defective in the Cd transporters AtABCC1 and AtABCC2 complements the Cd sensitivity of double mutants, but not in the presence of BSO. Accordingly, the level of AtABCC3 transcript in wild type seedlings was lower than that of AtABCC1 and AtABCC2 in the absence of Cd but higher after Cd exposure, and even higher in atabcc1 atabcc2 mutants. The results point to AtABCC3 as a transporter of PC–Cd complexes, and suggest that its activity is regulated by Cd and is co-ordinated with the activity of AtABCC1/AtABCC2. PMID:25900618

  8. NetB, a New Toxin That Is Associated with Avian Necrotic Enteritis Caused by Clostridium perfringens

    PubMed Central

    Keyburn, Anthony L; Boyce, John D; Vaz, Paola; Bannam, Trudi L; Ford, Mark E; Parker, Dane; Di Rubbo, Antonio; Rood, Julian I; Moore, Robert J

    2008-01-01

    For over 30 years a phospholipase C enzyme called alpha-toxin was thought to be the key virulence factor in necrotic enteritis caused by Clostridium perfringens. However, using a gene knockout mutant we have recently shown that alpha-toxin is not essential for pathogenesis. We have now discovered a key virulence determinant. A novel toxin (NetB) was identified in a C. perfringens strain isolated from a chicken suffering from necrotic enteritis (NE). The toxin displayed limited amino acid sequence similarity to several pore forming toxins including beta-toxin from C. perfringens (38% identity) and alpha-toxin from Staphylococcus aureus (31% identity). NetB was only identified in C. perfringens type A strains isolated from chickens suffering NE. Both purified native NetB and recombinant NetB displayed cytotoxic activity against the chicken leghorn male hepatoma cell line LMH; inducing cell rounding and lysis. To determine the role of NetB in NE a netB mutant of a virulent C. perfringens chicken isolate was constructed by homologous recombination, and its virulence assessed in a chicken disease model. The netB mutant was unable to cause disease whereas the wild-type parent strain and the netB mutant complemented with a wild-type netB gene caused significant levels of NE. These data show unequivocally that in this isolate a functional NetB toxin is critical for the ability of C. perfringens to cause NE in chickens. This novel toxin is the first definitive virulence factor to be identified in avian C. perfringens strains capable of causing NE. Furthermore, the netB mutant is the first rationally attenuated strain obtained in an NE-causing isolate of C. perfringens; as such it has considerable vaccine potential. PMID:18266469

  9. Influence of serum and necrotic soft tissue on the antimicrobial effects of intracanal medicaments.

    PubMed

    Oliveira, Julio C Machado de; Alves, Flávio R F; Uzeda, Milton de; Rôças, Isabela N; Siqueira, José F

    2010-01-01

    The purpose of this study was to investigate the influence of serum and necrotic soft tissue on the antimicrobial activity of intracanal medicaments. The medicaments tested were: calcium hydroxyde/glycerin paste, calcium hydroxide/chlorhexidine paste, calcium hydroxide/camphorated paramonochlorophenol/glycerin paste, and chlorhexidine/zinc oxide paste. Survival of Enterococcus faecalis and Candida albicans exposed to the medicaments tested in the presence or absence of serum or necrotic tissue was monitored in three in vitro experiments where samples for culturing were taken at different time periods. The overall results demonstrated that the antimicrobial activity of all intracanal medicaments tested was slowed down in the presence of necrotic tissue. Calcium hydroxide pastes in glycerin or chlorhexidine were significantly affected by serum. Of the medicaments tested in this study, the least affected was the calcium hydroxide/camphorated paramonochlorophenol/glycerin paste. PMID:20976377

  10. [A case of necrotizing tracheitis and tracheobronchomalacia in a patient with severe motor and intellectual disabilities].

    PubMed

    Sakamoto, Kei; Ukaji, Koutarou; Mizuno, Yuji

    2008-07-01

    We report a 23-year-old male patient with severe motor and intellectual disabilities due to sequelae of intracranial hemorrhage, who have had suffered from pneumonia with pleural effusion after influenza infection followed by mechanical ventilation. This patient also had complication of tracheobronchomalacia. Positive pressure ventilation in addition to thoracheocentesis was necessary for the drainage of pleural effusion. Abrupt hypooxygenation during mechanical ventilation revealed the presence of necrotizing tracheitis, which was improved with removal of necrotic tissues by bronchoscopy and inhalation of steroid thereafter. To relieve the compression which worsened the tracheobronchomalacia, partial resection of the sternal bone was performed. This patient died of complications after operation. This case suggests the importance of accurate diagnosis and treatment of the mechanical ventilation complications including necrotizing tracheitis and tracheobronchomalacia which may be life-threating. PMID:18634418

  11. Fulminating nonclostridial gas-forming infection: a case of necrotizing fasciitis.

    PubMed

    Blanchard, R J

    1975-07-01

    Perianal infection in a 40-year-old man resulted in extensive necrotizing fasciitis of the retroperitoneal space and septic shock. Despite the fact that radiography revealed linear streaking in the belly of the psoas muscle due to gas formation, the nature of the infection was necrotizing fasciitis and not myonecrosis. This contradicts Brightmore's contention that such a finding always indicates clostridial myonecrosis. Despite the absence of Clostridium welchii, necrotizing fascitis is none the less extremely serious, usually occurring in the limbs or abdominal wall superficial to muscle layers. The case reported is unusual in that infection affected the fascia deep to abdominal muscles in the retroperitoneal space, where surgical exposure is difficult. An appropriate surgical approach afforded adequate treatment. PMID:1148960

  12. Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy.

    PubMed

    Schneider, Ilka; Stoltenburg, Gisela; Deschauer, Marcus; Winterholler, Martin; Hanisch, Frank

    2014-05-01

    Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper- CKemia. We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANO5 c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy. PMID:24843231

  13. A Report of Peritonitis from Aeromonas sobria in a Peritoneal Dialysis (PD) Patient with Necrotizing Fasciitis.

    PubMed

    Janma, Jirayut; Linasmita, Patcharasarn; Changsirikulchai, Siribha

    2015-11-01

    A 70-years of age, male patient with underlying type 2 diabetes mellitus, hypertension, dyslipidemia and ischemic heart disease had undergone continuous ambulatory peritoneal dialysis (CAPD)for 3 years without any episodes of peritonitis. He was diagnosed with necrotizing fasciitis and later developed peritonitis after receiving a laceration from an aquatic injury suffered during the flood disaster of 2011. The blood culture, necrotic tissue and the clear dialysate collected upon admission had shown Aeromonas sobria. The route of peritonitis may be from the hematogenous spread of A. sobria resulting in necrotizing fasciitis. A. sobria should be considered as the pathogen of peritonitis in PD patients who have history of wounds from contaminated water. We suggest that the PD patients who present with septicemia and did not meet the criteria for peritonitis, the initial dialysate effluent should be sent for culture. The benefit of this is to allow early recognition and treatment of peritonitis. PMID:27276849

  14. Surgical treatment of peripheral ulcerative keratitis and necrotizing scleritis in granulomatosis with polyangiitis

    PubMed Central

    Lu, Cheng-Wei; Zhou, Dan-Dan; Wang, Jiao; Hao, Ji-Long

    2016-01-01

    The efficacy of surgical management of refractory ophthalmic complications of granulomatosis with polyangiitis (GPA), which is a sight threatening was reported. A 70-year-old man presented with a progressively worsening pain and redness in his right eye during the previous 6 months, and decreasing visual acuity that started one month earlier. He was misdiagnosed and treated as keratitis elsewhere, but the pain has not decreased. The diagnosis of necrotizing scleritis with peripheral ulcerative keratitis (PUK) in GPA was made in our department. Surgery was performed with necrotic tissue removal, combined with cryotherapy and a conjunctival flap covering surgery. The symptom was relieved after surgery, and the patient’s ocular condition remained stable thereafter. This case first demonstrates limited ophthalmic GPA (such as, PUK and necrotizing scleritis) that was not sensitive or aggravated for traditional methods can be successfully treated by combined surgical interventions. PMID:26837405

  15. 'Potato peel dressing': a novel adjunctive in the management of necrotizing fasciitis.

    PubMed

    Manjunath, K S; Bhandage, Supriya; Kamat, Shishir

    2015-03-01

    Management of necrotizing fasciitis, a rare and potentially fatal, polymicrobial disease comprises of aggressive debridement, intravenous antibiotics and application of various adjunctives. So far adjunctives like hyperbaric oxygen therapy, intravenous immunoglobulins, vacuum assisted or foam dressing, and guided tissue regeneration with amniotic dressing have been put to use. Each of these adjunctives has faced criticism for their shortcomings. Potato peel has been used as a dressing for chronic wounds but there is no literature available on its application over wounds afflicted with necrotizing fasciitis. Owing to various medicinal properties of potato peel and its use as a dressing in other medical conditions, same was used as an adjunctive in the present case. Here we present a case of cervical necrotizing fasciitis of dentogenous origin, treated by mainstay surgical treatment with debridement, drainage in combination with broad spectrum antibiotics and a novel adjunctive, 'potato peel dressing', which has shown promising results. PMID:25848140

  16. Necrotizing pulmonary aspergillosis and ventricular assist device infection: case report and review of literature.

    PubMed

    Kornberger, A; Walter, V; Jaeger, F; Lehnert, T; Soriano, M; Moritz, A; Stock, U A; Beiras-Fernandez, A

    2015-10-01

    Necrotizing pulmonary aspergillosis and Aspergillus device infection are rare and have potentially fatal complications after left ventricular assist device (LVAD) implantation. To date, few cases of patients surviving Aspergillus device infection have been published, with survival reported only after device removal. We present a patient implanted with an LVAD in whom necrotizing pulmonary aspergillosis with device involvement was successfully treated by segmentectomy and prolonged antifungal treatment without device exchange or removal. Similar cases in the literature were searched for and are discussed in view of the severity of this complication. PMID:26224318

  17. Necrotizing Fasciitis - Report of ten cases and review of recent literature

    PubMed Central

    Al Shukry, S; Ommen, J

    2013-01-01

    Necrotizing fasciitis is an uncommon disease that results in gross morbidity and mortality if not diagnosed and 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. We present ten cases of necrotizing fasciitis managed in a provincial secondary hospital in Oman over 3 years ago. A review of recent literature is also presented. PMID:23904882

  18. Necrotizing Fasciitis of the Chest in a Neonate in Southern Nigeria

    PubMed Central

    Awe, Oluwafemi Olasupo; Kesieme, Emeka B.; Aigbonoga, Quinzy O.

    2014-01-01

    We discuss the successful saving of a male neonate with necrotizing fasciitis of the chest following a hot fomentation of the umbilicus with exposure of the ribs and the pleural space on the right side. He recovered 5 weeks after admission. We stressed the need to recognize necrotizing fasciitis extending from the upper anterior abdominal wall to the chest following hot fomentation of the umbilicus. The need for multidisciplinary cooperation for excellent outcome is very important, that is, neonatologist, medical microbiologist, and plastic and chest surgeons. PMID:25610690

  19. [Necrotizing fasciitis after "banal" back pain. An unusual course of a retrocoecal appendicitis and its sequellae].

    PubMed

    Wilharm, A; Gras, F; Mückley, T; Hofmann, G O

    2010-05-01

    Necrotizing fasciitis is a life-threatening disease which can only be successfully treated by an interdisciplinary team. An immediate and radical debridement with opening of all compartments and debridement of the affected fascia is the basis for a successful therapy. We report about the treatment of a 21-year-old man who was taken to hospital due to "banal" back pain which was caused by a perforated appendicitis. In only 2 days necrotizing fasciitis developed which spread out over the complete right leg. PMID:19812905

  20. Alternatives to Antibiotics to Prevent Necrotic Enteritis in Broiler Chickens: A Microbiologist's Perspective

    PubMed Central

    Caly, Delphine L.; D'Inca, Romain; Auclair, Eric; Drider, Djamel

    2015-01-01

    Since the 2006 European ban on the use of antibiotics as growth promoters in animal feed, numerous studies have been published describing alternative strategies to prevent diseases in animals. A particular focus has been on prevention of necrotic enteritis in poultry caused by Clostridium perfringens by the use of microbes or microbe-derived products. Microbes produce a plethora of molecules with antimicrobial properties and they can also have beneficial effects through interactions with their host. Here we review recent developments in novel preventive treatments against C. perfringens-induced necrotic enteritis in broiler chickens that employ yeasts, bacteria and bacteriophages or secondary metabolites and other microbial products in disease control. PMID:26648920

  1. [Group a streptococcal necrotizing fasciitis of the genital area (Fournier's gangrene): a case report].

    PubMed

    Ochi, Atsuhiko; Naoi, Makito; Enatsu, Noritoshi; Fujisaki, Akira; Funada, Satoshi; Suzuki, Koichiro; Shiga, Naoki; Ota, Tomonori; Kuji, Hiroshi; Hosokawa, Naoto; Iwata, Kentaro

    2011-07-01

    A necrotizing fasciitis especially caused by group A streptococcal infection is a life-threatening disease. This infection cause death due to septic shock and multiple organ failure in a short time without the immediate and adequate treatment. Currently a rapid test kit for streptococcal pharyngitis (strep A) is useful for prediction of group A streptococcal infection. We here demonstrate a 61 years old man's case of life-saved necrotizing fasciitis in genital area (Fournier's gangrene) by group A streptococcus infection, and usefulness of this kit for rapid diagnosis, aggressive debridement, and selection of adequate antibiotics. PMID:21961278

  2. Functional Genomic Characterization of Virulence Factors from Necrotizing Fasciitis-Causing Strains of Aeromonas hydrophila

    PubMed Central

    Grim, Christopher J.; Kozlova, Elena V.; Ponnusamy, Duraisamy; Fitts, Eric C.; Sha, Jian; Kirtley, Michelle L.; van Lier, Christina J.; Tiner, Bethany L.; Erova, Tatiana E.; Joseph, Sandeep J.; Read, Timothy D.; Shak, Joshua R.; Joseph, Sam W.; Singletary, Ed; Felland, Tracy; Baze, Wallace B.; Horneman, Amy J.

    2014-01-01

    The genomes of 10 Aeromonas isolates identified and designated Aeromonas hydrophila WI, Riv3, and NF1 to NF4; A. dhakensis SSU; A. jandaei Riv2; and A. caviae NM22 and NM33 were sequenced and annotated. Isolates NF1 to NF4 were from a patient with necrotizing fasciitis (NF). Two environmental isolates (Riv2 and -3) were from the river water from which the NF patient acquired the infection. While isolates NF2 to NF4 were clonal, NF1 was genetically distinct. Outside the conserved core genomes of these 10 isolates, several unique genomic features were identified. The most virulent strains possessed one of the following four virulence factors or a combination of them: cytotoxic enterotoxin, exotoxin A, and type 3 and 6 secretion system effectors AexU and Hcp. In a septicemic-mouse model, SSU, NF1, and Riv2 were the most virulent, while NF2 was moderately virulent. These data correlated with high motility and biofilm formation by the former three isolates. Conversely, in a mouse model of intramuscular infection, NF2 was much more virulent than NF1. Isolates NF2, SSU, and Riv2 disseminated in high numbers from the muscular tissue to the visceral organs of mice, while NF1 reached the liver and spleen in relatively lower numbers on the basis of colony counting and tracking of bioluminescent strains in real time by in vivo imaging. Histopathologically, degeneration of myofibers with significant infiltration of polymorphonuclear cells due to the highly virulent strains was noted. Functional genomic analysis provided data that allowed us to correlate the highly infectious nature of Aeromonas pathotypes belonging to several different species with virulence signatures and their potential ability to cause NF. PMID:24795370

  3. Necrotizing sialometaplasia-like change of the esophageal submucosal glands is associated with Barrett's esophagus.

    PubMed

    Braxton, David R; Nickleach, Dana C; Liu, Yuan; Farris, Alton B

    2014-08-01

    The esophageal submucosal glands (SMG) protect the squamous epithelium from insults such as gastroesophageal reflux disease by secreting mucins and bicarbonate. We have observed metaplastic changes within the SMG acini that we have termed oncocytic glandular metaplasia (OGM), and necrotizing sialometaplasia-like change (NSMLC). The aim of this study is to evaluate the associated clinicopathological parameters of, and to phenotypically characterize the SMG metaplasias. Esophagectomy specimens were retrospectively assessed on hematoxylin and eosin sections and assigned to either a Barrett's esophagus (BE) or non-BE control group. Clinicopathologic data was collected, and univariate analysis and multivariate logistic regression models were performed to assess the adjusted associations with NSMLC and OGM. Selected cases of SMG metaplasia were characterized. SMG were present in 82 esophagi that met inclusion criteria. On univariate analysis, NSMLC was associated with BE (p = 0.002). There was no relationship between NSMLC and patient age, sex, tumor size, or treatment history. OGM was associated with BE (p = 0.031). No relationship was found between OGM and patient age, sex, or tumor size. On multivariate analysis, BE was independently associated with NSMLC (odds ratio [OR] 4.95, p = 0.003). Treatment history was also independently associated with OGM (p = 0.029), but not NSMLC. Both NSMLC and OGM were non-mucinous ductal type epithelia retaining a p63-smooth muscle actin co-positive myoepithelial cell layer. NSMLC and OGM were present in endoscopic mucosal resection specimens. Our study suggests that SMG metaplasia is primarily a reflux-induced pathology. NSMLC may pose diagnostic dilemmas in resection specimens or when only partially represented in mucosal biopsies or endoscopic resection specimens. PMID:24863247

  4. Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse

    PubMed Central

    Alagarsamy, Jeyashree; Hur, Junguk; Siemens, Nikolai; Svensson, Mattias; Hyldegaard, Ole; Norrby-Teglund, Anna; Kotb, Malak

    2016-01-01

    Host genetic variations play an important role in several pathogenic diseases, and we have previously provided strong evidences that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive Group A Streptococcus (GAS) infections, including sepsis and necrotizing soft tissue infections (NSTIs). Our initial studies with conventional mouse strains revealed that host genetic variations and sex differences play an important role in orchestrating the severity, susceptibility and outcomes of NSTIs. To understand the complex genetic architecture of NSTIs, we utilized an unbiased, forward systems genetics approach in an advanced recombinant inbred (ARI) panel of mouse strains (BXD). Through this approach, we uncovered interactions between host genetics, and other non-genetic cofactors including sex, age and body weight in determining susceptibility to NSTIs. We mapped three NSTIs-associated phenotypic traits (i.e., survival, percent weight change, and lesion size) to underlying host genetic variations by using the WebQTL tool, and identified four NSTIs-associated quantitative genetic loci (QTL) for survival on mouse chromosome (Chr) 2, for weight change on Chr 7, and for lesion size on Chr 6 and 18 respectively. These QTL harbor several polymorphic genes. Identification of multiple QTL highlighted the complexity of the host-pathogen interactions involved in NSTI pathogenesis. We then analyzed and rank-ordered host candidate genes in these QTL by using the QTLminer tool and then developed a list of 375 candidate genes on the basis of annotation data and biological relevance to NSTIs. Further differential expression analyses revealed 125 genes to be significantly differentially regulated in susceptible strains compared to their uninfected controls. Several of these genes are involved in innate immunity, inflammatory response, cell growth, development and proliferation, and apoptosis. Additional network analyses using

  5. Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse.

    PubMed

    Chella Krishnan, Karthickeyan; Mukundan, Santhosh; Alagarsamy, Jeyashree; Hur, Junguk; Nookala, Suba; Siemens, Nikolai; Svensson, Mattias; Hyldegaard, Ole; Norrby-Teglund, Anna; Kotb, Malak

    2016-07-01

    Host genetic variations play an important role in several pathogenic diseases, and we have previously provided strong evidences that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive Group A Streptococcus (GAS) infections, including sepsis and necrotizing soft tissue infections (NSTIs). Our initial studies with conventional mouse strains revealed that host genetic variations and sex differences play an important role in orchestrating the severity, susceptibility and outcomes of NSTIs. To understand the complex genetic architecture of NSTIs, we utilized an unbiased, forward systems genetics approach in an advanced recombinant inbred (ARI) panel of mouse strains (BXD). Through this approach, we uncovered interactions between host genetics, and other non-genetic cofactors including sex, age and body weight in determining susceptibility to NSTIs. We mapped three NSTIs-associated phenotypic traits (i.e., survival, percent weight change, and lesion size) to underlying host genetic variations by using the WebQTL tool, and identified four NSTIs-associated quantitative genetic loci (QTL) for survival on mouse chromosome (Chr) 2, for weight change on Chr 7, and for lesion size on Chr 6 and 18 respectively. These QTL harbor several polymorphic genes. Identification of multiple QTL highlighted the complexity of the host-pathogen interactions involved in NSTI pathogenesis. We then analyzed and rank-ordered host candidate genes in these QTL by using the QTLminer tool and then developed a list of 375 candidate genes on the basis of annotation data and biological relevance to NSTIs. Further differential expression analyses revealed 125 genes to be significantly differentially regulated in susceptible strains compared to their uninfected controls. Several of these genes are involved in innate immunity, inflammatory response, cell growth, development and proliferation, and apoptosis. Additional network analyses using

  6. Does Every Necrotizing Granulomatous Inflammation Identified by NSCLC Resection Material Require Treatment?

    PubMed Central

    Yakar, Fatih; Yakar, Aysun; Büyükpınarbaşılı, Nur; Erelel, Mustafa

    2016-01-01

    Background Lung cancer and tuberculosis (TB) are two major public health problems. They can coexist or appear sequentially. In patients with TB, lung cancer risk is increased. However, vice versa is not crystal clear. In this study, we aimed to determine the development of TB in patients with resectabled non-small cell lung cancer (NSCLC) in a 2-year postoperative follow-up period. Material/Methods We conducted a retrospective cohort study at three university hospitals. Patients who had NSCLC surgery between 2009 and 2013 were included and patient records were reviewed for the presence of necrotizing granulomatous inflammation (NGI) in resected specimens. Demographic properties, tumor type, stage, location, type of surgery, tuberculosis history, and thorax CT findings were recorded. We searched for the development of tuberculosis within a 2-year period after surgery. Results A total of 1027 patient cases were reviewed, of which 48 patients had NGI. The median age was 63 years. The most common type of cancer was squamous carcinoma; and lobectomy was the preferred operation (70.8%). Cancer involvement most commonly included the right lung (61.8%) and upper lobes (47,9%). Only 11 patients had anti-TB treatment postoperatively, which was based on radiological findings. Prior tuberculosis or anti-TB history, type, stage or localization of cancer, and adjuvant/neoadjuvant therapy were not found to be related to TB treatment. None of the study population had TB during the two-year follow-up period. Treatment decisions appeared mostly related to physician experience. There was no difference in the risk of developing TB between patients with or without treatment. This finding may change the management of our patients. Conclusions Every NGI discovered in NSCLC resected material does not always require anti-TB treatment. PMID:27064420

  7. Necrotizing fasciitis caused by methicillin-resistant Staphylococcus pseudintermedius at a previously irradiated site in a dog

    PubMed Central

    Mayer, Monique N.; Rubin, Joseph E.

    2012-01-01

    A great Dane dog was presented with a small, superficial wound on the left tarsus that rapidly progressed to a large necrotic area. The dog had undergone radiation therapy in the left tarsal region 33 months previously. Necrotizing fasciitis was diagnosed on histopathological examination, and bacterial culture revealed methicillin-resistant Staphylococcus pseudintermedius. PMID:23633717

  8. In vitro cow's milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis.

    PubMed

    Abdelhamid, Adel E; Chuang, Shu-Ling; Hayes, Peter; Fell, John M E

    2011-02-01

    Enteral feeding with cow's milk formula is associated with neonatal necrotizing enterocolitis (NEC) and sepsis. Dietary antigen sensitization may play a role in promoting and/or sustaining inflammation in both conditions. Aiming at investigating cow's milk protein (CMP)-specific cytokine responses in preterm infants with NEC and sepsis, 14 babies with NEC, 14 matched healthy controls, and 10 septic controls were recruited. Unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) secreting IFN-γ, IL-4, IL-10, and TGF-β1 were counted by the single-cell enzyme-linked immunospot (ELISPOT) assay. During the acute phase of NEC, patients showed a general pattern of a high level of cytokine secretion both when unstimulated and stimulated by mitogen [phytohaemagglutinin (PHA)] and CMPs: beta-lactoglobulin (β-lg) and casein. These responses were more marked to β-lg for IFN-γ, IL-4, and IL-10 than TGF-β1. Cytokine responses in sepsis were lower than in NEC (lowest in healthy controls, with a minimal TGF-β1 response). At term, lower frequencies of cytokine-secreting cells were elicited than during the acute phase, except for TGF-β1 secreting cells, which increased at term (in response to PHA and CMPs) particularly following not only NEC but also sepsis. PMID:20975616

  9. First report of Impatiens necrotic spot virus infecting greenhouse-grown potatoes in Washington State

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In April and May 2010, potato (Solanum tuberosum L. cv. Atlantic) plants grown from pre-nuclear minitubers in three separate greenhouses located at the USDA-ARS facility in Prosser, WA exhibited necrotic spots on leaves similar to those produced by the early blight pathogen, Alternaria solani (Sor.)...

  10. Oral lactoferrin for the prevention of sepsis and necrotizing enterocolotis in preterm infants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lactoferrin, a normal component of human colostrum, milk, tears and saliva can enhance host defence and may be effective in the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. To assess the safety and effectiveness of oral lactoferrin in the prevention of sepsis and NEC...

  11. DIET- AND COLONIZATION-DEPENDENT INTESTINAL DYSFUNCTION PREDISPOSES TO NECROTIZING ENTEROCOLITIS IN PRETERM PIGS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND & AIMS: Preterm birth and formula feeding are key risk factors associated with necrotizing enterocolitis (NEC) in infants, but little is known about intestinal conditions that predispose to disease. Thus, structural, functional, and microbiologic indices were used to investigate the etiol...

  12. Sugar beet storability and the influence of beet necrotic yellow vein virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rhizomania in sugar beets caused by Beet necrotic yellow vein virus (BNYVV) and storage losses are serious problems in sugar beet production. Storage issues associated with outdoor piles may be exacerbated by disease problems such as rhizomania. To investigate the influence of BNYVV on storability...

  13. The effect of commonly used anticoccidials and antibiotics in a subclinical necrotic enteritis model.

    PubMed

    Lanckriet, A; Timbermont, L; De Gussem, M; Marien, M; Vancraeynest, D; Haesebrouck, F; Ducatelle, R; Van Immerseel, F

    2010-02-01

    Necrotic enteritis poses an important health risk to broilers. The ionophore anticoccidials lasalocid, salinomycin, maduramicin, narasin and a combination of narasin and nicarbazin were tested in feed for their prophylactic effect on the incidence of necrotic enteritis in a subclinical experimental infection model that uses coccidia as a predisposing factor. In addition, drinking water medication with the antibiotics amoxicillin, tylosin and lincomycin was evaluated as curative treatment in the same experimental model. The minimal inhibitory concentrations (MICs) of all antibiotics and anticoccidials were determined in vitro against 51 Clostridium perfringens strains isolated from broilers. The strains examined appeared uniformly susceptible to lasalocid, maduramicin, narasin, salinomycin, amoxicillin and tylosin, whereas an extended frequency distribution range of MICs for lincomycin was seen, indicating acquired resistance in 36 isolates in the higher range of MICs. Nicarbazin did not inhibit the in vitro growth of the C. perfringens strains even at a concentration of 128 microg/ml. Supplementation of the diet from day 1 onwards with lasalocid, salinomycin, narasin or maduramicin led to a reduction in birds with necrotic enteritis lesions as compared with the non-medicated infected control group. A combination product of narasin and nicarbazin had no significant protective effect. Treatment with amoxicillin, lincomycin and tylosin completely stopped the development of necrotic lesions. PMID:20390538

  14. Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis

    PubMed Central

    Wong, Ka-Wing; Jacobs Jr, William R

    2011-01-01

    Summary Induction of necrotic death in macrophages is a primary virulence determinant of Mycobacterium tuberculosis. The ESX-1 secretion system and its substrate ESAT-6 are required for M. tuberculosis to induce necrosis, but host factors that mediate the ESAT-6-promoted necrosis remain unknown. Here we report that ESAT-6-promoted necrotic death in THP-1 human macrophages is dependent on the NLRP3 inflammasome, as shown by RNA interference and pharmacological inhibitions. Phagosomes containing ESAT-6-expressing M. tuberculosis recruit markers previously associated with damaged phagosomal membrane, such as galectin-3 and ubiquitinated protein aggregates. In addition, ESAT-6 promoted lysosomal permeabilization by M. tuberculosis. ESAT-6 mutants defective for ubiquitination were unable to trigger NLRP3 activation and necrotic death. Furthermore, Syk tyrosine kinase, recently implicated in NLRP3 activation during fungal and malarial infections, was necessary for mediating the ESAT-6-promoted necrosis and NLRP3 activation. Our results thus link phagosomal damage and Syk activity to NLRP3-mediated necrotic death triggered by M. tuberculosis ESAT-6 during infection. PMID:21740493

  15. Role of Wheat Based Diet on the Pathology of Necrotic Enteritis in Turkeys.

    PubMed

    Umar, Sajid; Younus, Muhammad; Shahzad, Muhammad; Aqil, Kiran; Qayyum, Rizwan; Mushtaq, Aqsa; Shah, Muhammad Ali Abdullah; Munir, Muhammad Tanveer

    2016-01-01

    The study was conducted to investigate the effects of wheat based diet on the pathology of necrotic enteritis in turkeys. Turkeys were divided into four groups. Groups A and B were kept as noninoculated and fed normal commercial diet while groups C and D were challenged orally with C. perfringens and fed wheat based diet to promote the development of experimental disease. Infected turkeys showed clinical signs of depression, ruffled feathers, and dark yellowish faeces showing the most prominent disease signs in turkeys of group D with 30% mortality. Similarly, turkeys of group D showed more striking gross and histopathologic lesions as compared to turkeys of group C. The most severe gross lesions comprised intestinal distension, small necrotic spots and haemorrhages on intestine, fragile intestinal wall, and gas bubble formation in the small intestine. Histologically, inoculated turkeys showed patchy necrosis, desquamation of intestinal epithelium, and intense leukocyte infiltration in the intestine. Microscopic examination showed significant decrease in the height of intestinal villi of inoculated birds. Haematological studies showed significant influence of necrotic enteritis on the blood profile of turkeys in group D. The findings revealed that simultaneous feeding of wheat enhanced the pathology of necrotic enteritis in turkeys. PMID:27239373

  16. Presence of necrotic strains of Potato virus Y in Mexican potatoes

    PubMed Central

    Ramírez-Rodríguez, Victoriano Roberto; Frías-Treviño, Gustavo; Aviña-Padilla, Katia; Martínez-Soriano, Juan Pablo

    2009-01-01

    Correction to Ramírez-Rodríguez VR, Frías-Treviño G, Aviña-Padilla K, Silva-Rosales L, Martínez-Soria JP: Presence of necrotic strains of Potato virus Y in Mexican potatoes. Virology Journal 2009, 6:48

  17. Avian necrotic enteritis: experimental models, host immunity, pathogenesis, risk factors, and vaccine development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The increasing trends of legislative restrictions and voluntary removal of antibiotic growth promoters worldwide has already impacted, and will continue to affect, poultry production and animal health. Necrotic enteritis (NE) is being considered among the most important infectious diseases in the c...

  18. Genetically disparate Fayoumi chicken lines show different response to avian Necrotic Enteritis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Necrotic enteritis (NE) has reemerged as a significant problem as a result of growing restrictions of antibiotics in agricultural animal production and increasing concerns over antibiotic resistance in human pathogens. To enhance our understanding of host-pathogen immunobiology in NE, transcriptomi...

  19. Characterization of a Flowering Cherry Strain of Cherry Necrotic Rusty Mottle Virus usty

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The host range and complete nucleotide sequences of two Cherry necrotic rusty mottle virus (CNRMV) isolates (FC4 and FC5) infecting flowering cherry accessions imported from Japan are described. Of the plants tested, sweet cherry cvs. ‘Bing’, ‘Canindex’, ‘Mazzard’ and ‘Sam’, flowering cherry cv. ‘Kw...

  20. Effects of dietary selenium on host response to necrotic enteritis in young broilers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of dietary supplementation of young broiler chickens with a new organic selenium (Se) formulation, B-Traxim Se, on the host response to experimental necrotic enteritis (NE) were studied. Broiler chickens treated with three Se doses (0.25, 0.50, 1.00 mg/kg) from hatch were orally challeng...

  1. Genomic regions associated with necrotic enteritis resistance in Fayoumi and White Leghorn chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, we used two breeds of chicken to identify genomic regions corresponding to necrotic enteritis (NE) resistance. We scanned the genomes of a resistant and susceptible line of Fayoumi and White Leghorn chicken using a chicken 60K Illumina SNP panel. A total of 235 loci with divergently ...

  2. Antibiotics modulate intestinal immunity and prevent necrotizing enterocolitis in preterm neonatal piglets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Preterm birth, bacterial colonization, and formula feeding predispose to necrotizing enterocolitis (NEC). Antibiotics are commonly administered to prevent sepsis in preterm infants, but it is not known whether this affects intestinal immunity and NEC resistance. We hypothesized that broad-spectrum a...

  3. Pneumomediastinum and subcutaneous emphysema in a cat associated with necrotizing bronchopneumonia caused by feline herpesvirus-1

    PubMed Central

    Maes, Sofie; Van Goethem, Bart; Saunders, Jimmy; Binst, Dominique; Chiers, Koen; Ducatelle, Richard

    2011-01-01

    This report describes a 1-year-old cat with acute dyspnea. Thoracic radiography revealed a pneumomediastinum and severe subcutaneous emphysema. Lower airway surgical exploration was unable to determine the cause. At postmortem examination, acute necrotizing bronchopneumonia and fibrinonecrotic tracheitis due to feline herpesvirus-1 were diagnosed. PMID:22467969

  4. Prognostic factors and monomicrobial necrotizing fasciitis: gram-positive versus gram-negative pathogens

    PubMed Central

    2011-01-01

    Background Monomicrobial necrotizing fasciitis is rapidly progressive and life-threatening. This study was undertaken to ascertain whether the clinical presentation and outcome for patients with this disease differ for those infected with a gram-positive as compared to gram-negative pathogen. Methods Forty-six patients with monomicrobial necrotizing fasciitis were examined retrospectively from November 2002 to January 2008. All patients received adequate broad-spectrum antibiotic therapy, aggressive resuscitation, prompt radical debridement and adjuvant hyperbaric oxygen therapy. Eleven patients were infected with a gram-positive pathogen (Group 1) and 35 patients with a gram-negative pathogen (Group 2). Results Group 2 was characterized by a higher incidence of hemorrhagic bullae and septic shock, higher APACHE II scores at 24 h post-admission, a higher rate of thrombocytopenia, and a higher prevalence of chronic liver dysfunction. Gouty arthritis was more prevalent in Group 1. For non-survivors, the incidences of chronic liver dysfunction, chronic renal failure and thrombocytopenia were higher in comparison with those for survivors. Lower level of serum albumin was also demonstrated in the non-survivors as compared to those in survivors. Conclusions Pre-existing chronic liver dysfunction, chronic renal failure, thrombocytopenia and hypoalbuminemia, and post-operative dependence on mechanical ventilation represent poor prognostic factors in monomicrobial necrotizing fasciitis. Patients with gram-negative monobacterial necrotizing fasciitis present with more fulminant sepsis. PMID:21208438

  5. The Nucleotide Sequence of Blackberry chlorotic ringspot and Strawberry necrotic shock viruses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Small fruit crops were thought to be infected with distinct stains of Tobacco streak virus (TSV) for more than 50 years. Two novel ilarviruses, Blackberry chlorotic ringspot virus (BCRV) and Strawberry necrotic shock virus (SNSV) were found to infect small fruit crops. Using TSV specific molecular ...

  6. Abdominal near-infrared spectroscopy measurements are lower in preterm infants at risk for necrotizing enterocolitis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Near-infrared spectroscopy is a noninvasive method of measuring local tissue oxygenation (StO[2]). Abdominal StO[2] measurements in preterm piglets are directly correlated with changes in intestinal blood flow and markedly reduced by necrotizing enterocolitis. The objectives of this study were to us...

  7. Biology and Genetics of Lettuce Dieback Disease and Lettuce Necrotic Stunt Virus.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lettuce dieback, a new soil-borne disease of lettuce, emerged in the 1990s to cause severe losses for lettuce production in the western United States. The disease is caused by Tomato bushy stunt virus (TBSV) and the recently described tombusvirus, Lettuce necrotic stunt virus (LNSV). The complete ge...

  8. Microbial and metabolic signatures of necrotizing enterocolitis in formula-fed piglets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Major risk factors for necrotizing enterocolitis (NEC) include premature birth, formula feeding, and microbial colonization of the gastrointestinal tract. We previously showed that feeding formula composed of lactose vs corn syrup solids protects against NEC in preterm pigs, however the microbial an...

  9. Innate immune response to Clostridium perfringens and Eimeria maxima in necrotic enteritis model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have investigated various aspects of host immune responses using a disease model for necrotic enteritis (NE) in which the severity of lesions produced by Clostridium perfringens was increased, and the growth performance of broiler chickens was decreased by prior infection with Eimeria maxima. Qu...

  10. Penile abscess and necrotizing fasciitis secondary to neglected false penile fracture.

    PubMed

    Al-Reshaid, Reshaid Abdullah; Madbouly, Khaled; Al-Jasser, Abdullah

    2010-05-01

    Penile infection and abscess formation have been described in association with priapism, cavernosography, intracavernosal injection therapy, trauma and penile prosthesis. We report a case of penile abscess and necrotizing fasciitis of penile skin in a 37-year-old male, presented 3 weeks after neglected false penile fracture. PMID:20882163

  11. Modulation of microrna in two genetically disparate chicken lines showing different necrotic enteritis disease susceptibility

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Necrotic enteritis (NE) is a re-emerging disease as a result of an increased restriction on the use of antibiotics in poultry. However, the molecular mechanisms underlying the pathology of NE are unclear. Therefore, we carried out small RNA transcriptome analysis in an experimentally induced NE m...

  12. Detection of mixed virus population in freesea plants with necrotic disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Necrotic disorder of freesia (Freesia refracta hyb., Family Iridaceae) was first described in The Netherlands before 1970. In subsequent years, the disorder was widely reported in other European countries and more recently also in the United States and in New Zealand. The presence of the Ophiovirus ...

  13. Epitope mapping for monoclonal antibodies recognizing tuber necrotic isolates of Potato virus Y

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Potato virus Y (PVY) is an important viral pathogen of potato responsible for reducing tuber yield and quality across the globe. The PVYN and PVYNTN strains, the latter of which induces potato tuber necrotic ringspot disease (PTNRD), are regulated for international potato trade, and have been routin...

  14. Dietary supplementation of young broiler chickens with Capsicum and turmeric oleoresins increases resistance to necrotic enteritis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Clostridium-related poultry disease, necrotic enteritis (NE), causes substantial economic losses on a global scale. In this study, a mixture of two plant-derived phytonutrients, Capsicum oleoresin and turmeric oleoresin (XT), was evaluated for its effects on local and systemic immune responses ...

  15. Necrotic pharyngitis associated with Mycoplasma bovis infections in American bison (Bison bison)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mycoplasma bovis (M. bovis) has recently emerged as a significant and costly infectious