scholarly journals Alterations in protein kinase C activity and processing during zinc-deficiency-induced cell death

2004 ◽  
Vol 383 (1) ◽  
pp. 63-71 ◽  
Author(s):  
Susan S. CHOU ◽  
Michael S. CLEGG ◽  
Tony Y. MOMMA ◽  
Brad J. NILES ◽  
Jodie Y. DUFFY ◽  
...  
Keyword(s):  
Cell Death ◽  
Zinc Deficiency ◽  
Caspase 3 ◽  
Zinc Content ◽  
Cell Number ◽  
Intracellular Zinc ◽  
Deficient Medium ◽  
Zinc Concentrations ◽  
Cells Cultured ◽  
Deficient Group

Protein kinases C (PKCs) are a family of serine/threonine kinases that are critical for signal transduction pathways involved in growth, differentiation and cell death. All PKC isoforms have four conserved domains, C1–C4. The C1 domain contains cysteine-rich finger-like motifs, which bind two zinc atoms. The zinc-finger motifs modulate diacylglycerol binding; thus, intracellular zinc concentrations could influence the activity and localization of PKC family members. 3T3 cells were cultured in zinc-deficient or zinc-supplemented medium for up to 32 h. Cells cultured in zinc-deficient medium had decreased zinc content, lowered cytosolic classical PKC activity, increased caspase-3 processing and activity, and reduced cell number. Zinc-deficient cytosols had decreased activity and expression levels of PKC-α, whereas PKC-α phosphorylation was not altered. Inhibition of PKC-α with Gö6976 had no effect on cell number in the zinc-deficient group. Proteolysis of the novel PKC family member, PKC-δ, to its 40-kDa catalytic fragment occurred in cells cultured in the zinc-deficient medium. Occurrence of the PKC-δ fragment in mitochondria was co-incident with caspase-3 activation. Addition of the PKC-δ inhibitor, rottlerin, or zinc to deficient medium reduced or eliminated proteolysis of PKC-δ, activated caspase-3 and restored cell number. Inhibition of caspase-3 processing by Z-DQMD-FMK (Z-Asp-Gln-Met-Asp-fluoromethylketone) did not restore cell number in the zinc-deficient group, but resulted in processing of full-length PKC-δ to a 56-kDa fragment. These results support the concept that intracellular zinc concentrations influence PKC activity and processing, and that zinc-deficiency-induced apoptosis occurs in part through PKC-dependent pathways.

scholarly journals Lack of ZnT8 protects pancreatic islets from hypoxia- and cytokine induced cell death

2022 ◽  
Author(s):  
Maria Karsai ◽  
Richard A Zuellig ◽  
Roger Lehmann ◽  
Federica Cuozzo ◽  
Daniela Nasteska ◽  
...  
Keyword(s):  
Cell Death ◽  
Islet Cell ◽  
Islet Cells ◽  
Zinc Content ◽  
Zinc Homeostasis ◽  
Wild Type ◽  
Zinc Chelator ◽  
Zinc Concentrations ◽  
Processing And Storage

Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8, is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of wild-type and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, wild-type islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNFα, IFNγ, IL1β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in wild-type islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to wild-type islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.

scholarly journals The Hexane Fraction of Bursera microphylla A Gray Induces p21-Mediated Antiproliferative and Proapoptotic Effects in Human Cancer–Derived Cell Lines

2017 ◽  
Vol 16 (3) ◽  
pp. 426-435 ◽  
Author(s):  
Sabrina Adorisio ◽  
Alessandra Fierabracci ◽  
Giulia Gigliarelli ◽  
Isabella Muscari ◽  
Lorenza Cannarile ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Lines ◽  
Sonoran Desert ◽  
Caspase 3 ◽  
Human Cancer ◽  
Cell Number ◽  
Hexane Fraction ◽  
Caspase 8 ◽  
P21 Protein

Bursera microphylla (BM), one of the common elephant trees, is widely distributed in the Sonoran desert in Mexico. The Seri ethnic group in the Sonoran desert uses BM as an anti-inflammatory and painkiller drug for the treatment of sore throat, herpes labialis, abscessed tooth, and wound healing. Dried stems and leaves of BM are used in a tea to relieve painful urination and to stimulate bronchial secretion. Furthermore, BM is used for fighting venereal diseases. To investigate the effects of the hexane fraction of resin methanol extract (BM-H) on cell growth, the acute myeloid cell line (OCI-AML3) was treated with 250, 25, or 2.5 µg/mL of BM-H. The first 2 concentrations were able to significantly decrease OCI-AML3 cell number. This reduced cell number was associated with decreased S-phase, blockade of G2/M phase of the cell cycle, and increased cell death. Similar results were obtained on all tested tumor cell lines of different origins. We found that blockade of the cell cycle was a result of upregulation of p21 protein in a p53-independent way. Increase of p21 was possibly a result of upstream upregulation of p-ERK (which stabilizes p21 protein) and downregulation of p-38 (which promotes its degradation). Regarding cell death, activation of caspase-3, but not of caspase-8 or -9, was detectable after BM-H treatment. In conclusion, these data suggest that BM-H inhibited proliferation of cell lines mainly by a p21-dependent, p53-independent mechanism and promoted apoptosis through activation of caspase-3 but not caspase-8 or -9.

scholarly journals Human TSC-associated renal angiomyolipoma cells are hypersensitive to ER stress

2012 ◽  
Vol 303 (6) ◽  
pp. F831-F844 ◽  
Author(s):  
Brian J. Siroky ◽  
Hong Yin ◽  
Justin T. Babcock ◽  
Lu Lu ◽  
Anna R. Hellmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Caspase 3 ◽  
Renal Involvement ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Cell Number ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Renal Angiomyolipoma

Tuberous sclerosis complex (TSC), an inherited tumor predisposition syndrome associated with mutations in TSC1 or TSC2, affects ∼1 in 6,000 individuals. Eighty percent of TSC patients develop renal angiomyolipomas, and renal involvement is a major contributor to patient morbidity and mortality. Recent work has shown that mammalian target of rapamycin complex 1 (mTORC1) inhibition caused angiomyolipoma shrinkage but that this treatment may cause cytostatic not a cytotoxic effect. Endoplasmic reticulum (ER) stress can develop in TSC-associated cells due to mTORC1-driven protein translation. We hypothesized that renal angiomyolipoma cells experience ER stress that can be leveraged to result in targeted cytotoxicity. We used immortalized human angiomyolipoma cells stably transfected with empty vector or TSC2 (encoding tuberin). Using cell number quantification and cell death assays, we found that mTORC1 inhibition with RAD001 suppressed angiomyolipoma cell proliferation in a cytostatic manner. Angiomyolipoma cells exhibited enhanced sensitivity to proteasome inhibitor-induced ER stress compared with TSC2-rescued cells. After proteasome inhibition with MG-132, Western blot analyses showed greater induction of C/EBP-homologous protein (CHOP) and more poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage, supporting ER stress-induced apoptosis. Live cell numbers also were decreased and cell death increased by MG-132 in angiomyolipoma cells compared with TSC2 rescued. Intriguingly, while pretreatment of angiomyolipoma cells with RAD001 attenuated CHOP and BiP induction, apoptotic markers cleaved PARP and caspase-3 and eukaryotic translation initiation factor 2α phosphorylation were increased, along with evidence of increased autophagy. These results suggest that human angiomyolipoma cells are uniquely susceptible to agents that exacerbate ER stress and that additional synergy may be achievable with targeted combination therapy.

The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia

2008 ◽  
Vol 294 (6) ◽  
pp. L1127-L1136 ◽  
Author(s):  
Beth Besecker ◽  
Shengying Bao ◽  
Barbara Bohacova ◽  
Audrey Papp ◽  
Wolfgang Sadee ◽  
...  
Keyword(s):  
Cell Survival ◽  
Zinc Content ◽  
Zinc Transporters ◽  
Rt Pcr ◽  
Intracellular Zinc ◽  
Inflammatory Stress ◽  
Tnf Α ◽  
Zinc Concentrations ◽  
Interfering Rna ◽  
Cellular Zinc

Zinc is an essential micronutrient and cytoprotectant involved in the host response to inflammatory stress. We tested whether zinc transporters, the critical regulators that maintain intracellular zinc concentrations, play a role in cell survival, particularly in lung epithelia, during inflammation. Initially, mRNA transcripts were quantitatively measured by RT-PCR for all known human zinc transporters, including 14 importers (SLC39A1–14) and 10 exporters (SLC30A1–10), in primary human lung epithelia obtained from multiple human donors and BEAS-2B cell cultures under baseline and TNF-α-stimulated conditions. While many zinc transporters were constitutively expressed, only SLC39A8 (Zip8) mRNA was strongly induced by TNF-α. Endogenous Zip8 protein was not routinely detected under baseline conditions. In sharp contrast, TNF-α induced the expression of a glycosylated protein that translocated to the plasma membrane and mitochondria. Increased Zip8 expression resulted in an increase in intracellular zinc content and coincided with cell survival in the presence of TNF-α. Inhibition of Zip8 expression using a short interfering RNA probe reduced cellular zinc content and impaired mitochondrial function in response to TNF-α, resulting in loss of cell viability. These data are the first to characterize human Zip8 and remarkably demonstrate that upregulation of Zip8 is sufficient to protect lung epithelia against TNF-α-induced cytotoxicity. We conclude that Zip8 is unique, relative to other Zip proteins, by functioning as an essential zinc importer at the onset of inflammation, thereby facilitating cytoprotection within the lung.

Zinc in subterranean clover (Trifolium subterraneum L. cv. Seaton Park). II. Effects of phosphorus supply on the relationship between zinc concentrations in plant parts and yield

1982 ◽  
Vol 33 (6) ◽  
pp. 1001 ◽  
Author(s):  
DJ Reuter ◽  
JF Loneragan ◽  
AD Robson ◽  
D Plaskett
Keyword(s):  
Zinc Deficiency ◽  
Subterranean Clover ◽  
Zinc Content ◽  
Trifolium Subterraneum ◽  
Plant Analysis ◽  
Plant Parts ◽  
Phosphorus Toxicity ◽  
Zinc Concentrations ◽  
High Concentrations ◽  
The Relationship

The effect of phosphorus on the relationship of zinc concentrations in various plant parts to yield of Seaton Park subterranean clover was examined. Plants were grown in a glasshouse at three levels of phosphorus (39, 65 and 130 mg phosphorus/pot; denoted P1, P2 and P3 respectively) and six levels of zinc added in factorial combination to a sand deficient in both phosphorus and zinc. At the lowest three levels of zinc supply, plants were severely to moderately deficient in zinc: in them, increasing levels of phosphorus depressed growth and induced high concentrations of phosphorus (> 1 % DM) in several plant parts and symptoms of phosphorus toxicity in leaves. At the highest three levels of zinc supply, plants at P1 were phosphorus deficient: application of P2 and P3 increased growth and induced zinc deficiency primarily by diluting the available zinc. In addition, P3 appeared to depress slightly the zinc content of plant tops by another mechanism. In severely zinc-deficient plants, phosphorus supply changed the relationships between zinc concentrations in various plant parts and yield of whole tops, probably as the result of phosphorus toxicity. In the youngest open leaf blades, an asymptotic relationship at P1 changed at P2 and P3 to sigmoidal and to 'Piper-Steenbjerg' relationships respectively. These changes would not have invalidated the use of plant analysis for diagnosing zinc deficiency. In moderately zinc-deficient plants, phosphorus supply had little or no effect on the relationships of zinc concentration in plant parts to yield of shoots. As a result, critical concentrations in plant parts generally remained constant over the whole range of phosphorus supply. The data refute suggestions that high levels of phosphorus in plant parts inactivate the zinc within them, thus removing a potential problem in the use of plant analysis for diagnosing zinc deficiency in subterranean clover. The results confirm the previous suggestion that a concentration range of 12-14 �g zinc/g in the youngest, open leaf blade is critical for diagnosis of zinc deficiency in subterranean clover.

scholarly journals Acute Increases in Intracellular Zinc Lead to an Increased Lysosomal and Mitochondrial Autophagy and Subsequent Cell Demise in Malignant Melanoma

2021 ◽  
Vol 22 (2) ◽  
pp. 667
Author(s):  
Emil Rudolf ◽  
Kamil Rudolf
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Zinc Content ◽  
Time Frame ◽  
Biological Behavior ◽  
Clinical Samples ◽  
Mitochondrial Activity ◽  
Intracellular Zinc ◽  
Growth And Survival ◽  
Cancer Breast

Changes in zinc content and dysregulated zinc homeostatic mechanisms have been recognized in several solid malignancies such as prostate cancer, breast cancer, or pancreatic cancer. Moreover, it has been shown that zinc serum and/or tissue levels are altered in melanoma with varying effects on melanoma development and biology. This study was conducted to explore the effects of acute increases of intracellular zinc in a set of melanoma tissue explants obtained from clinical samples. Measurements of their zinc content showed an extant heterogeneity in total and free intracellular zinc pools associated with varying biological behavior of individual cells, e.g., autophagy levels and propensity to cell death. Use of zinc pyrithione elevated intracellular zinc in a short time frame which resulted in marked changes in mitochondrial activity and lysosomes. These alterations were accompanied by significantly enhanced autophagy flux and subsequent cell demise in the absence of typical apoptotic cell death markers. The present results show for the first time that acutely increased intracellular zinc in melanoma cells specifically enhances their autophagic activity via mitochondria and lysosomes which leads to autophagic cell death. While biologically relevant, this discovery may contribute to our understanding and exploration of zinc in relation to autophagy as a means of controlling melanoma growth and survival.

scholarly journals Low zinc levels at clinical admission associates with poor outcomes in COVID-19

2020 ◽  
Author(s):  
Marina Vogel-González ◽  
Marc Talló-Parra ◽  
Víctor Herrera-Fernández ◽  
Gemma Pérez-Vilaró ◽  
Miguel Chillón ◽  
...  
Keyword(s):  
Zinc Deficiency ◽  
Randomized Clinical Trials ◽  
Serum Zinc ◽  
Zinc Content ◽  
Zinc Concentrations ◽  
Infected Cells ◽  
Poor Outcomes ◽  
Zinc Levels ◽  
Serum Zinc Levels

AbstractBackgroundBiomarkers to predict Coronavirus disease-19 (COVID-19) outcome early at infection are urgently needed to improve prognosis and treatment. Zinc balances immune responses and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with more severe COVID-19 outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression and thus might represent a useful biomarker.MethodsWe run a retrospective observational study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel we have studied SARS-CoV2 replication in the Vero E6 cell line modifying zinc concentrations.FindingsOur study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dl at admission correlated with worse clinical presentation, longer time to reach stability and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV2 infected cells.InterpretationSZC is a novel biomarker to predict COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.FundingSpanish Ministry of Science and Innovation, “Maria de Maeztu” Programme for Units of Excellence in R&D and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement of the Generalitat de Catalunya. Instituto Carlos III Fondos de Investigaciones Sanitarias (FIS), CIBER on Frailty and Healthy Ageing and FEDER funds

scholarly journals Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways

2015 ◽  
Vol 308 (9) ◽  
pp. G757-G766 ◽  
Author(s):  
Qian Sun ◽  
Wei Zhong ◽  
Wenliang Zhang ◽  
Qiong Li ◽  
Xiuhua Sun ◽  
...  
Keyword(s):  
Cell Death ◽  
Zinc Deficiency ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Apoptotic Cell Death ◽  
Zinc Homeostasis ◽  
Initiation Factor ◽  
Cell Death Pathways

Hepatic zinc deficiency has been well documented in alcoholic patients, but the mechanisms by which zinc deficiency mediates cell death have not been well defined. The objectives of this study were to determine whether alcohol perturbs subcellular zinc homeostasis and how organelle zinc depletion may link with cell death pathways. Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure significantly reduced zinc level in isolated hepatic endoplasmic reticulum (ER) and mitochondria. Among the detected zinc transporters, ER Zrt/Irt-like protein (ZIP)13 and mitochondrial ZIP8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. Mitochondrial zinc transporter (ZnT) 4, which transports zinc from cytosol to mitochondria, was also increased. ER phosphorylated eukaryotic initiation factor 2α, activating transcription factor 4, and C/EBP homologous protein were significantly upregulated, and mitochondrial cytochrome c release and Bax insertion were detected in association with caspase-3 activation and apoptotic cell death. To define the role of zinc deficiency in ER and mitochondrial stress, H4IIEC3 cells were treated with 3 μM N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine for 6 h with or without supplementation with zinc or N-acetylcysteine (NAC). The results demonstrated that zinc deprivation induced caspase-3 activation and apoptosis in association with ER and mitochondria dysfunction, which were inhibited by zinc as low as 10 μM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced in ER and mitochondrial zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment.

scholarly journals Zinc Chelation Mediates the Lysosomal Disruption without Intracellular ROS Generation

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Andreza Cândido Matias ◽  
Tânia Maria Manieri ◽  
Giselle Cerchiaro
Keyword(s):  
Cell Death ◽  
Molecular Mechanism ◽  
Caspase 3 ◽  
Neuroblastoma Cells ◽  
P38 Map Kinase ◽  
Ros Generation ◽  
Intracellular Zinc ◽  
Intracellular Ros ◽  
Zinc Depletion ◽  
Zinc Chelation

We report the molecular mechanism for zinc depletion caused by TPEN (N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine) in neuroblastoma cells. The activation of p38 MAP kinase and subsequently caspase 3 is not due to or followed by redox imbalance or ROS generation, though these are commonly observed in literature. We found that TPEN is not responsible for ROS generation and the mechanism involves essentially lysosomal disruption caused by intracellular zinc depletion. We also observed a modest activation of Bax and no changes in the Bcl-2 proteins. As a result, we suggest that TPEN causes intracellular zinc depletion which can influence the breakdown of lysosomes and cell death without ROS generation.

scholarly journals Low Zinc Levels at Admission Associates with Poor Clinical Outcomes in SARS-CoV-2 Infection

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 562 ◽  
Author(s):  
Marina Vogel-González ◽  
Marc Talló-Parra ◽  
Víctor Herrera-Fernández ◽  
Gemma Pérez-Vilaró ◽  
Miguel Chillón ◽  
...  
Keyword(s):  
Zinc Deficiency ◽  
Randomized Clinical Trials ◽  
Serum Zinc ◽  
Zinc Content ◽  
Increased Risk ◽  
Zinc Concentrations ◽  
Infected Cells ◽  
Zinc Levels ◽  
Serum Zinc Levels

Background: Zinc is an essential micronutrient that impacts host–pathogen interplay at infection. Zinc balances immune responses, and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with an increased risk for severe severe coronavirus disease 2019 (COVID-19) outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression, and thus might represent a useful biomarker. Methods: We ran an observational cohort study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel, we have studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) replication in the Vero E6 cell line modifying zinc concentrations. Findings: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV-2 infected cells. Interpretation: Low SZC is a risk factor that determines COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.

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