scholarly journals Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1827 ◽  
Author(s):  
Khurshid Ahmad ◽  
Vishal M. Balaramnavar ◽  
Navaneet Chaturvedi ◽  
Saif Khan ◽  
Shafiul Haque ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Structural Information ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Caspase 8 ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
Zinc Database ◽  
Dynamics Simulations

Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.

scholarly journals The Human Cytomegalovirus UL36 Gene Controls Caspase-Dependent and -Independent Cell Death Programs Activated by Infection of Monocytes Differentiating to Macrophages

2010 ◽  
Vol 84 (10) ◽  
pp. 5108-5123 ◽  
Author(s):  
A. Louise McCormick ◽  
Linda Roback ◽  
Devon Livingston-Rosanoff ◽  
Courtney St. Clair
Keyword(s):  
Cell Death ◽  
Human Cytomegalovirus ◽  
Caspase 8 ◽  
Specific Cell ◽  
Macrophage Differentiation ◽  
Antiviral Responses ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
The Impact ◽  
Late Stages

ABSTRACT The cellular protease caspase-8 activates extrinsic apoptosis and also functions to promote monocyte-to-macrophage differentiation. Differentiation-induced alterations to antiviral caspase-8-dependent cell death pathways are unclear. Here, we show THP-1 monocyte-to-macrophage differentiation alters the specific cell death pathways activated in response to human cytomegalovirus (HCMV) infection. Employing viruses with mutations in UL36, the gene that encodes the viral inhibitor of caspase-8 activation (vICA), our data indicate that both caspase-dependent and -independent death pathways are activated in response to infection. Activation of caspase-dependent and -independent cell death responses restricted growth of vICA-deficient viruses, and vICA/pUL36 inhibited either response. Thus, these studies also reveal that the UL36 gene controls a caspase-independent cell death pathway. The impact of caspases on control of antiviral responses differed at early and late stages of macrophage differentiation. Early in differentiation, vICA-deficient virus-induced cell death was dependent on caspases and inhibited by the pan-caspase inhibitor z-VAD(OMe)-fluoromethyl ketone. In contrast, virus-induced death at late times of differentiation was caspase independent. Additional unlabeled and fluorescent inhibitors indicated that caspase-8 promoted death from within infected cells at early but not late stages of differentiation. These data highlight the multifunctional role of vICA/pUL36 as HCMV encounters various antiviral responses during macrophage differentiation.

Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function

2014 ◽  
Vol 307 (1) ◽  
pp. E14-E23 ◽  
Author(s):  
Yonggang Wang ◽  
Zhiguo Zhang ◽  
Weiying Guo ◽  
Weixia Sun ◽  
Xiao Miao ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Normal Diet ◽  
Caspase 8 ◽  
Testicular Cell ◽  
Cell Death Pathways ◽  
Induce Insulin Resistance ◽  
And Function ◽  
Nrf2 Expression

Diabetes-induced testicular cell death is due predominantly to oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor in controlling the antioxidative system and is inducible by sulforaphane (SFN). To test whether SFN prevents diabetes-induced testicular cell death, an insulin-defective stage of type 2 diabetes (IDS-T2DM) was induced in mice. This was accomplished by feeding them a high-fat diet (HFD) for 3 mo to induce insulin resistance and then giving one intraperitoneal injection of streptozotocin to induce hyperglycemia while age-matched control mice were fed a normal diet (ND). IDS-T2DM and ND-fed control mice were then further subdivided into those with or without 4-mo SFN treatment. IDS-T2DM induced significant increases in testicular cell death presumably through receptor and mitochondrial pathways, shown by increased ratio of Bax/Bcl2 expression and cleavage of caspase-3 and caspase-8 without significant change of endoplasmic reticulum stress. Diabetes also significantly increased testicular oxidative damage and inflammation. All of these diabetic effects were significantly prevented by SFN treatment with upregulated Nrf2 expression. These results suggest that IDS-T2DM induces testicular cell death presumably through caspase-8 activation and mitochondria-mediated cell death pathways and also by significantly downregulating testicular Nrf2 expression and function. SFN upregulates testicular Nrf2 expression and its target antioxidant expression, which was associated with significant protection of the testis from IDS-T2DM-induced germ cell death.

Abstract 143: A Novel TAK1 Signaling Network Regulating Programmed Necrosis and Myocardial Remodeling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Qinghang Liu ◽  
Lei Li ◽  
Yi Chen ◽  
Jessica Doan ◽  
Jeffery Molkentin
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cell Survival ◽  
Cardiac Fibrosis ◽  
Signaling Network ◽  
Specific Gene ◽  
Caspase 8 ◽  
Programmed Necrosis ◽  
Genetic Ablation ◽  
Cell Death Pathway

We recently identified a novel signaling molecule, TAK1 (TGFβ-activated kinase 1, also known as MAP3K7), as a key regulator of the hypertrophic signaling network. Importantly, TAK1 is activated in mouse models of heart failure as well as in diseased human myocardium. Here, we defined a previously unidentified, novel role for TAK1 in promoting cardiac cell survival and homeostasis using cardiac-specific gene-targeted mice. Indeed, cardiac-specific ablation of TAK1 in mice using a Cre-LoxP system showed enhanced pathological cardiac remodeling and massive cell death, and these mice gradually developed heart failure and spontaneous death. Remarkably, ablation of TNF receptor 1 (TNFR1) largely rescued the pathological phenotype of TAK1-deficient mice, preventing early lethality and cardiac fibrosis, suggesting that TNFR1 signaling is critical in mediating adverse remodeling and heart failure associated with TAK1 deficiency. Genetic or pharmacological inactivation of TAK1 in cardiomyocytes markedly induced programmed necrosis and apoptosis in response to TNFα. Conversely, overexpression of the constitutively active TAK1 mutant, or TAK1 plus its activator TAB1, protected cardiomyocytes from TNFα-induced cell death. Mechanistically, inactivation of TAK1 promoted formation of the necroptotic cell death complex consisting of RIP1, RIP3, caspase 8, and FADD. Genetic ablation of RIP1, RIP3, caspase 8, or FADD largely blocked TNFα-induced cell death in TAK1-deficient cells, whereas deletion of Bax/Bak or cyclophilin D showed no effects. Further, IKK/NFκB-mediated cell survival signaling was greatly impaired in TAK1-deficient cardiomyocytes. Taken together, our data indicate that TAK1 functions as a critical “molecular switch” in TNFα-induced programmed necrosis in cardiomyocytes, by interacting with the RIP1/3-caspase 8-FADD cell death pathway as well as the IKK-NFκB cell survival pathway. These findings thus define an important TAK1-mediated cardio-protective signaling network in the heart, which may suggest new therapeutic strategies in the treatment of heart disease.

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.

NETosis: how vital is it?

Blood ◽  
2013 ◽  
Vol 122 (16) ◽  
pp. 2784-2794 ◽  
Author(s):  
Bryan G. Yipp ◽  
Paul Kubes
Keyword(s):  
Innate Immunity ◽  
Cell Death ◽  
Critical Role ◽  
Neutrophil Extracellular Traps ◽  
Live Cell ◽  
Extracellular Traps ◽  
Cell Death Pathway ◽  
A Cell ◽  
Net Release

Abstract In this review, we examine the evidence that neutrophil extracellular traps (NETs) play a critical role in innate immunity. We summarize how NETs are formed in response to various stimuli and provide evidence that NETosis is not universally a cell death pathway. Here we describe at least 2 different mechanisms by which NETs are formed, including a suicide lytic NETosis and a live cell or vital NETosis. We also evaluate the evidence for NETs in catching and killing pathogens. Finally, we examine how infections are related to the development of autoimmune and vasculitic diseases through unintended but detrimental bystander damage resulting from NET release.

scholarly journals Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
José Belizário ◽  
Luiz Vieira-Cordeiro ◽  
Sylvia Enns
Keyword(s):  
Cell Death ◽  
Knockout Mice ◽  
Critical Role ◽  
Stress Conditions ◽  
Dna Integrity ◽  
Caspase 8 ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Injury Death ◽  
Regulated Necrosis

Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents) or intracellular (DNA damage and Ca2+overload) stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER), cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identifiedcaspase-8,flip, andfaddgenes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1), RIPK3, and the mixed kinase domain-like (MLKL) for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice.

Mitochondrial DNA–Related Mitochondrial Dysfunction in Neurodegenerative Diseases

2002 ◽  
Vol 126 (3) ◽  
pp. 271-280
Author(s):  
Russell H. Swerdlow
Keyword(s):  
Cell Death ◽  
Mitochondrial Dna ◽  
Programmed Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Cell Lines ◽  
Late Onset ◽  
Cell Death Pathways ◽  
Mitochondrial Genotype ◽  
Cybrid Cell

Abstract Mitochondrial dysfunction occurs in several late-onset neurodegenerative diseases. Determining its origin and significance may provide insight into the pathogeneses of these disorders. Regarding origin, one hypothesis proposes mitochondrial dysfunction is driven by mitochondrial DNA (mtDNA) aberration. This hypothesis is primarily supported by data from studies of cytoplasmic hybrid (cybrid) cell lines, which facilitate the study of mitochondrial genotype-phenotype relationships. In cybrid cell lines in which mtDNA from persons with certain neurodegenerative diseases is assessed, mitochondrial physiology is altered in ways that are potentially relevant to programmed cell death pathways. Connecting mtDNA-related mitochondrial dysfunction with programmed cell death underscores the crucial if not central role for these organelles in neurodegenerative pathophysiology. This review discusses the cybrid technique and summarizes cybrid data implicating mtDNA-related mitochondrial dysfunction in certain neurodegenerative diseases.

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.

Genetic Regulation of RIPK1 and Necroptosis

2021 ◽  
Vol 55 (1) ◽  
pp. 235-263
Author(s):  
Daichao Xu ◽  
Chengyu Zou ◽  
Junying Yuan
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Genetic Regulation ◽  
Caspase 8 ◽  
Inflammatory Signaling ◽  
Interacting Protein ◽  
Multiple Factors ◽  
Cell Death Pathways ◽  
Upstream Regulator ◽  
Multiple Cell

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

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