Epigallocatechin-3-gallate improves chronic alcohol-induced cognitive dysfunction in rats by interfering with neuro-inflammatory, cell death and oxido-nitrosative cascade

Abstract Alcohol consumption for a longer period of time is linked with neuronal damage and an increase in inflammatory signaling resulting in cell death and dementia. Natural compounds are the focus of research due to their high efficacy and good safety profile. Here we have investigated the effect of chronic epigallocatechin-3-gallate (EGCG) administration against the alcohol-induced cognitive deficit rats. Male Wistar rats were exposed to the ethanol (10 g/kg; oral gavage) for ten weeks and treated with EGCG (25, 50, and 100 mg/kg) for the same duration. Ethanol exposure led to the impaired spatial memory and learning in rats assessed using the Morris water maze and elevated plus-maze test. Further, we assessed the role of EGCG in mitigating the oxidative stress, neuroinflammatory and cell death signaling associated markers. Co-administration with EGCG significantly prevented all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol-treated rats in a dose-dependent manner. EGCG suppressed the acetylcholinesterase activity, increased oxidative–nitrosative stress, cytokines (TNF-alpha and IL-1beta), NF-kappa β and caspase-3 levels in both the cortex and hippocampus of ethanol-treated rats. Our preliminary study demonstrated that EGCG improves the oxido-nitrosative stress, inflammation, and cell death signaling associated with ethanol-induced cognitive dysfunction. This suggests the potential role of EGCG in mitigating the cognitive deficits associated with chronic alcohol consumption.

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Faculty Opinions recommendation of A cellular genome-wide association study reveals human variation in microtubule stability and a role in inflammatory cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718159039.793490324 ◽

2014 ◽

Author(s):

Kenneth Campellone

Keyword(s):

Cell Death ◽

Association Study ◽

Inflammatory Cell ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Human Variation ◽

Microtubule Stability ◽

Genome Wide ◽

Cellular Genome

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Neurotrophic factor-α1, a novel tropin is critical for the prevention of stress-induced hippocampal CA3 cell death and cognitive dysfunction in mice: comparison to BDNF

Translational Psychiatry ◽

10.1038/s41398-020-01112-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lan Xiao ◽

Vinay Kumar Sharma ◽

Leila Toulabi ◽

Xuyu Yang ◽

Cheol Lee ◽

...

Keyword(s):

Cell Death ◽

Learning And Memory ◽

Cognitive Dysfunction ◽

Neurotrophic Factor ◽

Maternal Separation ◽

Pyramidal Neurons ◽

Neuroprotective Activity ◽

Weaning Stress ◽

Hippocampal Ca3 ◽

Ca3 Neurons

AbstractStress leads to brain pathology including hippocampal degeneration, cognitive dysfunction, and potential mood disorders. Hippocampal CA3, a most stress-vulnerable region, consists of pyramidal neurons that regulate cognitive functions e.g. learning and memory. These CA3 neurons express high levels of the neuroprotective protein, neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), and receive contacts from granule cell projections that release BDNF which has neuroprotective activity. Whether NF-α1-CPE and/or BDNF are critical in protecting these CA3 neurons against severe stress-induced cell death is unknown. Here we show that social combined with the physical stress of maternal separation, ear tagging, and tail snipping at weaning in 3-week-old mice lacking NF-α1-CPE, led to complete hippocampal CA3 degeneration, despite having BDNF and active phosphorylated TrkB receptor levels similar to WT animals. Mice administered TrkB inhibitor, ANA12 which blocked TrkB phosphorylation showed no degeneration of the CA3 neurons after the weaning stress paradigm. Furthermore, transgenic knock-in mice expressing CPE-E342Q, an enzymatically inactive form, replacing NF-α1-CPE, showed no CA3 degeneration and exhibited normal learning and memory after the weaning stress, unlike NF-α1-CPE-KO mice. Mechanistically, we showed that radio-labeled NF-α1-CPE bound HT22 hippocampal cells in a saturable manner and with high affinity (Kd = 4.37 nM). Subsequently, treatment of the HT22cpe−/− cells with NF-α1-CPE or CPE-E342Q equivalently activated ERK signaling and increased BCL2 expression to protect these neurons against H2O2-or glutamate-induced cytotoxicity. Our findings show that NF-α1-CPE is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity.

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Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Cells ◽

10.3390/cells9081823 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1823 ◽

Cited By ~ 2

Author(s):

Jenny Sprooten ◽

Pieter De Wijngaert ◽

Isaure Vanmeerbeek ◽

Shaun Martin ◽

Peter Vangheluwe ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Immunotherapy ◽

Inflammatory Cell ◽

Necrotic Cell Death ◽

Immunogenic Cell Death ◽

Necrotic Cell ◽

Cell Death Pathway ◽

Immune Checkpoint Blockers ◽

Anticancer Immunity

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To “break” cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

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A Type III Effector NleF from EHEC Inhibits Epithelial Inflammatory Cell Death by Targeting Caspase-4

BioMed Research International ◽

10.1155/2017/4101745 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Ting Song ◽

Kaiwu Li ◽

Wei Zhou ◽

Jing Zhou ◽

Yuan Jin ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Cell ◽

Gastrointestinal Disease ◽

Highly Pathogenic ◽

E Coli ◽

Caspase 1 ◽

T3ss Effector ◽

Inflammatory Caspases ◽

Epithelial Cell Death ◽

Host Inflammatory Response

EnterohemorrhagicE. coli(EHEC) is a highly pathogenic bacterial strain capable of inducing severe gastrointestinal disease. Here, we show that EHEC uses the T3SS effector NleF to counteract the host inflammatory response by dampening caspase-4-mediated inflammatory epithelial cell death and by preventing the production of IL-1β. The other two inflammatory caspases, caspase-1 and caspase-5, are not involved in EHEC ΔnleF-induced inflammatory cell death. We found that NleF not only interrupted the heterodimerization of caspase-4-p19 and caspase-4-p10, but also inhibited the interaction of caspase-1 and caspase-4. The last four amino acids of the NleF carboxy terminus are essential in inhibiting caspase-4-dependent inflammatory cell death.

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Evasion of Necroptosis and Inflammasome Activation Promotes Myeloid Leukemogenesis

Blood ◽

10.1182/blood.v128.22.2856.2856 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2856-2856

Author(s):

Ulrike Höckendorf ◽

Yabal Monica ◽

Christian Peschel ◽

Philipp J. Jost

Keyword(s):

Stem Cells ◽

Cell Death ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Protein Level ◽

Inflammatory Cell ◽

Leukemic Cells ◽

Inflammasome Activation ◽

Short Term ◽

Hematopoietic Stem

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic neoplasms driven partly by the loss of differentiation and theblockade of cell death. AML is sustained by leukemia-initiating cells (LICs) that arise from pre-leukemic hematopoietic stem and progenitor cells (HSPCs) that carry genetic alterations being selected for during leukemogenesis. The resistance of LICs to standard chemotherapies presents a major clinical challenge as they eventually cause disease relapse and death. Understanding the mechanisms of LIC resistance to undergoing cell death is therefore critical for a curative therapy of AML. While the regulatory factors that maintain HSPC proliferation and differentiation under normal conditions are well understood, significantly less is known about how LIC fate is regulated. As many hematopoietic disorders are characterized by the overproduction of pro-inflammatory cytokines, we hypothesized that necroptosis controlled cytokine secretion and inflammatory cell death might influence AML development. We therefore addressed the role of MLKL and XIAP in AML and tested whether deletion of Mlkl or Xiap would affect disease progression. Here we show that MLKL limits oncogene-mediated leukemogenesis by promoting the inflammatory cell death of common myeloid progenitors (CMPs) and short-term hematopoietic stem cells (HSCs) in experimental mice. Upon oncogenic stress MLKL-dependent necroptosis and subsequent inflammasome activation were triggered, promoting the production of IL-1β, a potent stimulator of HSPC differentiation and maturation, thus, suppressing the emergence of LICs and limiting leukemogenesis. In a murine bone marrow transplantation model of AML the absence of MLKL accelerated AML development significantly. The enhanced disease was due to the expansion of common myeloid progenitors (CMPs) and short-term hematopoietic stem cells (ST-HSCs), being the cellular compartments to contain LICs. The survival advantage of Mlkl-/- HSPCs became apparent in colony-forming assays and liquid cultures specifically within the CMP and ST-HSC compartments. Sorted ST-HSCs from Mlkl-/- produced more GEMM colonies than WT, the colony type harboring the multipotential myeloid progenitor cells, and both ST-HSCs and CMPs retained significantly more lineage-negative cells in liquid culture. In addition, Mlkl-/- colonies showed a reduction in propidium iodide (PI)-positive dead cells compared with WT colonies. Importantly, WT cells showed caspase activation and produced substantial amounts of the inflammatory cytokine IL-1β which was severely blunted by Mlkl deficiency. We also observed reduced expression of MLKL in leukemic cells on both mRNA and protein level, implying that suppression of cell death was beneficial for the survival of LICs. In contrast, deletion of Xiap did not alter survival or differentiation of leukemic cells when compared with WT cells. Furthermore, XIAP was not differentially expressed on mRNA or protein level compared with WT, indicating that XIAP does not play a critical role in leukemogenesis. In agreement with the murine data, gene expression analysis from primary leukemia cells from two large patient cohorts newly diagnosed with AML showed significantly lower expression of MLKL, but not XIAP, in a variety of AML subtypes compared to healthy controls. Overall, our data demonstrate a key role for MLKL-mediated cell death and activation of the inflammasome in AML and represents a novel tumor-suppressive mechanism. Disclosures Peschel: MophoSys: Honoraria.

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