The regulation of apoptotic cell death

Amarante-Mendes, Gustavo P.; Green, Douglas R.

doi:10.1590/s0100-879x1999000900001

Cited by 52 publications

(34 citation statements)

References 55 publications

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“…4 One of the important responses of UV irradiated mammalian cells is cell killing by the induction of an active process of cell death, also known as apoptosis. 7 DNA damages, mainly CPDs, were shown to be a necessary signal of UV-induced apoptosis in human cells, as their removal by photorepair prevents cell death. 2 Besides being a target for DNA repair, these lesions obstruct DNA replication and RNA synthesis, which can be upstream in signaling the cascade that leads to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Photorepair of RNA polymerase arrest and apoptosis after ultraviolet irradiation in normal and XPB deficient rodent cells

et al. 2002

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Cyclobutane pyrimidine dimers (CPDs) are directly involved in signaling for UV-induced apoptosis in mammalian cells. Failure to remove these lesions, specially those located at actively expressing genes, is critical, as cells defective in transcription coupled repair have increased apoptotic levels. Thus, the blockage of RNA synthesis by lesions is an important candidate event triggering off active cell death. In this work, wild-type and XPB mutated Chinese hamster ovary (CHO) cells expressing a marsupial photolyase, that removes specifically CPDs from the damaged DNA, were generated, in order to investigate the importance of this lesion in both RNA transcription blockage and apoptotic induction. Photorepair strongly recovers RNA synthesis in wild-type CHO cell line, although the resumption of transcription is decreased in XPB deficient cells. This recovery is accompanied by the prevention of cells entering into apoptosis. These results demonstrate that marsupial photolyase has access to CPDs blocking RNA synthesis in vivo, and this may be affected by the presence of a mutated XPB protein.

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Section: Introductionmentioning

confidence: 99%

Photorepair of RNA polymerase arrest and apoptosis after ultraviolet irradiation in normal and XPB deficient rodent cells

et al. 2002

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“…In all three cases, death occurs through a genetically controlled program know as apoptosis. 3 At least in the cases of elimination of autoreactive or chronically stimulated T cells, apoptosis is initiated by the interaction of CD95 (Fas) and CD95L (FasL) in a process known as activation-induced cell death (AICD). In fact, genetic defects in one of these two proteins lead to lymphoproliferative disorders associated with autoimmune syndromes in mice and humans.…”

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confidence: 99%

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

et al. 2008

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Antigen-presenting cells (APCs) control T-cell responses by multiple mechanisms, including the expression of co-stimulatory molecules and the production of cytokines and other mediators that control T-cell proliferation, survival and differentiation. Here, we demonstrate that soluble factor(s) produced by Toll-like receptor (TLR)-activated APCs suppress activation-induced cell death (AICD). This effect was observed in non-stimulated APCs, but it was significantly increased after lipopolysaccharide (LPS) treatment. Using different KO mice, we found that the LPS-induced protective factor is dependent on TLR4/MyD88. We identified the protective factor as prostaglandin E 2 (PGE 2 ) and showed that both APC-derived supernatants and PGE 2 prevented CD95L upregulation in T cells in response to TCR/CD3 stimulation, thereby avoiding both AICD and activated T cell killing of target macrophages. The PGE 2 receptors, EP2 and EP4, appear to be involved since pharmacological stimulation of these receptors mimics the protective effect on T cells and their respective antagonists interfere with the protection induced by either APCs derived or synthetic PGE 2 . Finally, the engagement of EP2 and EP4 synergistically activates protein kinase A (PKA) and exchange protein directly activated by cAMP pathways to prevent AICD. Taken together, these results indicate that APCs can regulate T-cell levels of CD95L by releasing PGE 2 in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival. Cell Death and Differentiation (2008) 15, 1901-1909 doi:10.1038/cdd.2008 ; published online 26 September 2008Proper activation of T cells is imperative to achieve an efficient immunity against pathogens and tumors and, at the same time, to avoid undesirable collateral effects, such as the appearance of autoimmune diseases. Secondary lymphoid organs provide a particular microenvironment specialized in assembling all the cohorts necessary to perform such a remarkable task. 1 In the presence of antigens, antigenpresenting cells (APCs) and their soluble products, including a variety of cytokines, lipid mediators and chemokines, T cells are activated through the engagement of their T-cell receptors (TCR) and co-stimulatory molecules. As a result, T cells can proliferate, differentiate to effector or memory cells, or eventually die.Deletion of autoreactive T cells is one of the key mechanisms involved in the process of peripheral tolerance that helps to prevent the appearance of autoimmune diseases. 2 Similarly, elimination of chronically stimulated T cells that can potentially be harmful to the host by the means of the production of abnormal levels of inflammatory cytokines is another feature of an efficient immune system. Finally, death of effector T cells at the end of an immune response is a very important homeostatic mechanism designed to shrink an enlarged, no longer necessary cell population that can compete for growth and survival factors with newly activated antigen-specific T-cell clones. In a...

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“…The antifungal activity of the compounds 11 and 12 against C. albicans ATCC 10231 can be attributed probably to the reactive oxygen species (ROS) generation, because these compounds do not have the triazole group and because of the presence of naphthoquinone core with recognized pharmacological action via formation of ROS. 1,42 The MICs for the compounds 4, 11 and 12 against yeasts indicate that these compounds are excellent choices for the development of novel drugs to treat fungal infections. However, our data highlighted that the compound 4 showed superior antifungal activity against C. albicans ATCC 10231 when compared to ketoconazole, the basis for most drugs available for treatment of fungal infections currently on the market.…”

Section: Discussionmentioning

confidence: 99%

Synthesis,in vitroAntifungal Activity and Molecular Modeling Studies of New Mannich Bases Derived from Lawsone

Filho¹,

Roldi²,

Delarmelina³

et al. 2016

Journal of the Brazilian Chemical Society

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Hydroxynaphthoquinones such as lawsone (2-hydroxy-1,4-naphthoquinone) have proven to be effective antifungal agents. These compounds were tested for antifungal activity against yeast standard and clinical strains by the broth microdilution method. Among the synthetic lawsone derivatives, 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl)naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione showed high activity against Candida albicans ATCC 10231, with minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs) ranging from 20 to 330 and from 80 to 330 μg mL -1 , respectively. Moreover, they also showed a mechanism of action on exogenous ergosterol. Therapeutic concentrations (CC 50 ) of 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl) naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione were 52.81, 52.58 and 85.94 μg mL -1 , respectively, which can be considered moderate or low. In addition, docking studies showed that these compounds had similar binding energy to standard ketoconazole, which are recognized as the molecular target by van der Waals interactions. Furthermore, they are under Lipinski's rule of 5 with a druglikeness score better than ketoconazole and nystatin. These findings suggest that 2-hydroxy-3-((2-hydroxyphenyl)(pyrrolidin-1-yl)methyl) naphthalene-1,4-dione, 2-hydroxy-3-(((4-nitrophenyl)amino)(phenyl)methyl)naphthalene-1,4-dione and 2-hydroxy-3-((2-hydroxyphenyl)((4-nitrophenyl)amino)methyl)naphthalene-1,4-dione have potential as leading compounds against human fungal infections.

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The regulation of apoptotic cell death

Cited by 52 publications

References 55 publications

Photorepair of RNA polymerase arrest and apoptosis after ultraviolet irradiation in normal and XPB deficient rodent cells

Photorepair of RNA polymerase arrest and apoptosis after ultraviolet irradiation in normal and XPB deficient rodent cells

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

Synthesis,in vitroAntifungal Activity and Molecular Modeling Studies of New Mannich Bases Derived from Lawsone

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