scholarly journals AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiao Lin ◽  
Haotuo Ye ◽  
Felix Siaw-Debrah ◽  
Sishi Pan ◽  
Zibin He ◽  
...  
Keyword(s):  
Cell Death ◽  
Intracerebral Hemorrhage ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Neurological Function ◽  
Inflammatory Factors ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
Cell Death Pathways ◽  
Cell Death Pathway

Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

scholarly journals Characterization of Puma-Dependent and Puma-Independent Neuronal Cell Death Pathways following Prolonged Proteasomal Inhibition

2010 ◽  
Vol 30 (23) ◽  
pp. 5484-5501 ◽  
Author(s):  
Liam P. Tuffy ◽  
Caoimhín G. Concannon ◽  
Beatrice D'Orsi ◽  
Matthew A. King ◽  
Ina Woods ◽  
...  
Keyword(s):  
Cell Death ◽  
Proteasome Inhibitor ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nuclear Condensation ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
Induced Apoptosis

ABSTRACT Proteasomal stress and the accumulation of polyubiquitinated proteins are key features of numerous neurodegenerative disorders. Previously we demonstrated that stabilization of p53 and activation of its target gene, puma (p53-upregulated mediator of apoptosis), mediated proteasome inhibitor-induced apoptosis in cancer cells. Here we demonstrated that Puma also contributed to proteasome inhibitor-induced apoptosis in mouse neocortical neurons. Although protection afforded by puma gene deletion was incomplete, we found little evidence indicating contributions from other proapoptotic BH3-only proteins. Attenuation of bax expression did not further reduce Puma-independent apoptosis, suggesting that pathways other than the mitochondrial apoptosis pathway were activated. Real-time imaging experiments in wild-type and puma-deficient neurons using a fluorescence resonance energy transfer (FRET)-based caspase sensor confirmed the involvement of a second cell death pathway characterized by caspase activation prior to mitochondrial permeabilization and, more prominently, a third, caspase-independent and Puma-independent pathway characterized by rapid cell shrinkage and nuclear condensation. This pathway involved lysosomal permeabilization in the absence of autophagy activation and was sensitive to cathepsin but not autophagy inhibition. Our data demonstrate that proteasomal stress activates distinct cell death pathways in neurons, leading to both caspase-dependent and caspase-independent apoptosis, and demonstrate independent roles for Puma and lysosomal permeabilization in this model.

scholarly journals VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-21 ◽  
Author(s):  
Zhezhe Sun ◽  
Mark Nyanzu ◽  
Su Yang ◽  
Xiaohong Zhu ◽  
Kankai Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Blood Brain Barrier ◽  
High Mobility ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Nf Kappa B ◽  
Neuroprotective Effects ◽  
Caspase 1 ◽  
Area Of Interest ◽  
Blood Brain

Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

scholarly journals miR-380-5p facilitates NRF2 and attenuates cerebral ischemia/reperfusion injury-induced neuronal cell death by directly targeting BACH1

2021 ◽  
Vol 12 (1) ◽  
pp. 210-217
Author(s):  
Yibiao Wang ◽  
Min Xu
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Luciferase Assay ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion

Abstract Background This study aimed to explore the role of miR-380-5p in cerebral ischemia/reperfusion (CIR) injury-induced neuronal cell death and the potential signaling pathway involved. Methodology Human neuroblastoma cell line SH-SY5Y cells were used in this study. Oxygen and glucose deprivation/reperfusion (OGD/R) model was used to mimic ischemia/reperfusion injury. CCK-8 assay and flow cytometry were used to examine cell survival. Quantitative real time PCR (RT-qPCR) assay and Western blotting were used to measure the change of RNA and protein expression, respectively. TargetScan and Luciferase assay was used to confirm the target of miR-380-5p. Malondialdehyde (MDA) superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) were measured using commercial kits. Results miR-380-5p was downregulated in SH-SY5Y cells after OGD/R. Cell viability was increased by miR-380-5p, while cell apoptosis was reduced by miR-380-5p mimics. MDA was reduced by miR-380-5p mimics, while SOD and GSHPx were increased by miR-380-5p. Results of TargetScan and luciferase assay have showed that BACH1 is the direct target of miR-380-5p. Expression of NRF2 was upregulated after OGD/R, but was not affected by miR-380-5p. mRNA expression of HO-1 and NQO1 and ARE activity were increased by miR-380-5p. Overexpression of BACH1 reversed the antioxidant and neuroprotective effects of miR-380-5p. Conclusion miR-380-5p inhibited cell death induced by CIR injury through target BACH1 which also facilitated the activation of NRF2, indicating the antioxidant and neuroprotective effects of miR-380-5p.

scholarly journals Asc Modulates the Function of NLRC4 in Response to Infection of Macrophages by Legionella pneumophila

mBio ◽  
2011 ◽  
Vol 2 (4) ◽  
Author(s):  
Christopher L. Case ◽  
Craig R. Roy
Keyword(s):  
Cell Death ◽  
Legionella Pneumophila ◽  
Fluorescent Protein ◽  
Microbial Infection ◽  
Content Type ◽  
Caspase 1 ◽  
Cell Death Pathway ◽  
Dependent Cell ◽  
Green Fluorescent ◽  
In Cells

ABSTRACTNucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) activate caspase-1 in response to a variety of bacterium-derived signals in macrophages. NLR-mediated activation of caspase-1 byLegionella pneumophilaoccurs through both an NLRC4/NAIP5-dependent pathway and a pathway requiring the adapter protein Asc. Both pathways are needed for maximal activation of caspase-1 and for the release of the cytokines interleukin-1β (IL-1β) and IL-18. Asc is not required for caspase-1-dependent pore formation and cell death induced upon infection of macrophages byL. pneumophila. Here, temporal and spatial localization of caspase-1-dependent processes was examined to better define the roles of Asc and NLRC4 during infection. Imaging studies revealed that caspase-1 localized to a single punctate structure in infected cells containing Asc but not in cells lacking this adapter. Both endogenous Asc and ectopically produced NLRC4 tagged with green fluorescent protein (GFP) were found to localize to caspase-1 puncta followingL. pneumophilainfection, suggesting that NLRC4 and Asc coordinate signaling through this complex during caspase-1 activation. Formation of caspase-1-containing puncta correlated with caspase-1 processing, suggesting a role for the Asc/NLRC4/caspase-1 complex in caspase-1 cleavage. In cells deficient for Asc, NLRC4 did not assemble into discrete puncta, and pyroptosis occurred at an accelerated rate. These data indicate that Asc mediates integration of NLR components into caspase-1 processing platforms and that recruitment of NLR components into an Asc complex can dampen pyroptotic responses. Thus, a negative feedback role of complexes containing Asc may be important for regulating caspase-1-mediated responses during microbial infection.IMPORTANCECaspase-1 is a protease activated during infection that is central to the regulation of several innate immune pathways. Studies examining the macromolecular complexes containing this protein, known as inflammasomes, have provided insight into the regulation of this protease. This work demonstrates that the intracellular bacteriumLegionella pneumophilainduces formation of complexes containing caspase-1 by multiple mechanisms and illustrates that an adapter molecule called Asc integrates signals from multiple independent upstream caspase-1 activators in order to assemble a spatially distinct complex in the macrophage. There were caspase-1-associated activities such as cytokine processing and secretion that were controlled by Asc. Importantly, this work uncovered a new role for Asc in dampening a caspase-1-dependent cell death pathway called pyroptosis. These findings suggest that Asc plays a central role in controlling a distinct subset of caspase-1-dependent activities by both assembling complexes that are important for cytokine processing and suppressing processes that mediate pyroptosis.

scholarly journals Callicarpa Nudiflora Extract Exerts Anti-Inflammatory Effect on H. Pylori-Associated Gastritis Through Repression of ROS/NLRP3/Caspase-1/IL-1β Signaling Axis

2021 ◽  
Author(s):  
Lili Li ◽  
Xiaohui Zhu ◽  
Xingxing Chai ◽  
Xiaoyu Chen ◽  
Xiaohua Su ◽  
...  
Keyword(s):  
Cell Damage ◽  
Underlying Mechanism ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Ros Production ◽  
Gastric Diseases ◽  
Caspase 1 ◽  
Signaling Axis ◽  
H Pylori

Abstract Helicobacter pylori ( H. pylori ) is a major pathogenic factor for the development of gastric diseases including chronic gastritis and gastric cancer. Callicarpa nudiflora (CN), an air-dried leaves extract of Callicarpa nudiflora Hook. & Arn., has been found to exhibit a broad-spectrum antibacterial effect. In our study, we extracted the active ingredient from air-dried leaves of Callicarpa nudiflora, detected the effect of CN against H. pylori -infected GES-1 cells in vitro , and elucidated the underlying mechanism. GES-1 cells were cocultured with HPSS1 at MOI = 100:1 and treated with different concentrations of CN. Results indicated that CN not only significantly decreased cellular lactate dehydrogenase leakage, but also markedly attenuated H. pylori -induced cell apoptosis and ROS production in GSE-1 cells, therefore protecting gastric epithelial cells against injuries caused by H. pylori . CN also inhibited the secretions of inflammatory factors, such as tumor necrosis factor-α (TNF-α), IL-1β, IL-6 and IL-8. Furthermore, CN remarkably decreased the expression levels of NLRP3, PYCARD, active Caspase-1. In conclusion, CN exhibited highly efficient protective effect against H. pylori -induced gastritis and cell damage; Mechanismly, CN suppressed H. pylori -triggered inflammatory response and pyroptosis through depressing ROS production and NLRP3 inflammasome activation via ROS/NLRP3/IL-1β signaling axis.

Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives

2021 ◽  
Vol 21 ◽  
Author(s):  
Sinem Yilmaz ◽  
Fatih Tok ◽  
Esra A. Sahar ◽  
Bedia K. Kaymakcioglu ◽  
Petek B. Kirmizibayrak
Keyword(s):  
Flow Cytometry ◽  
Cell Death ◽  
Er Stress ◽  
Cytotoxic Activity ◽  
Cancer Biology ◽  
Chemotherapy Resistance ◽  
Annexin V ◽  
Double Positive ◽  
Cell Death Pathways ◽  
Cell Death Pathway

Background: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR) has been proposed as potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. Objective: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. Methods: Cell proliferation assays were performed on HeLa, Capan1, MCF7, HCC1937, and MRC5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. Results: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of pro-apoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and -7. Flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, which is also demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). Conclusion: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways.

scholarly journals Neuroprotective Effects of Gagam-Sipjeondaebo-Tang, a Novel Herbal Formula, against MPTP-Induced Parkinsonian Mice and MPP+-Induced Cell Death in SH-SY5Y Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jade Heejae Ko ◽  
Ju-Hee Lee ◽  
Bobin Choi ◽  
Ju-Yeon Park ◽  
Young-Won Kwon ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Apoptotic Cell ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Motor Dysfunction ◽  
Herbal Formula ◽  
Neuroprotective Effects

Parkinson’s disease is a neurodegenerative disease characterized by progressive cell death of dopaminergic neuron and following neurological disorders. Gagam-Sipjeondaebo-Tang (GST) is a novel herbal formula made of twelve medicinal herbs derived from Sipjeondaebo-Tang, which has been broadly used in a traditional herbal medicine. In the present study, we investigated the effects of GST against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor abnormalities in mice and 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in SH-SY5Y cell. First, we found that GST alleviated motor dysfunction induced by MPTP, and the result showed dopaminergic neurons recovery in substantia nigra. In the cell experiment, pretreatment with GST increased the cell viability and attenuated apoptotic cell death in MPP+-treated SH-SY5Y cells. GST also inhibited reactive oxygen species production and restored the mitochondrial membrane potential loss, which were induced by MPP+. Furthermore, GST extract significantly activated ERK and Akt, cell survival-related proteins, in SH-SY5Y cells. The effect of GST preventing mitochondrial dysfunction was antagonized by pretreatment of PD98059 and LY294002, selective inhibitors of ERK and Akt, respectively. Taken together, GST alleviated abnormal motor functions and recovered neuronal cell death, mitochondrial dysfunction, possibly via ERK and Akt activation. Therefore, we suggest that GST may be a candidate for the treatment and prevention of Parkinson’s disease.

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