scholarly journals 14-helical β-peptides Elicit Toxicity againstC. albicansby Forming Pores in the Cell Membrane and Subsequently Disrupting Intracellular Organelles

2018 ◽  
Author(s):  
Myung-Ryul Lee ◽  
Namrata Raman ◽  
Patricia Ortiz-Bermudez ◽  
David M. Lynn ◽  
Sean P. Palecek
Keyword(s):  
Cell Death ◽  
Partition Coefficient ◽  
Peptide Binding ◽  
Membrane Disruption ◽  
Bacterial Membranes ◽  
Drug Candidates ◽  
Small Unilamellar Vesicle ◽  
Proteolytic Stability ◽  
Intracellular Organelles ◽  
Insight Into

SummarySynthetic peptidomimetics of antimicrobial peptides are promising as antimicrobial drug candidates because they promote membrane disruption and exhibit greater structural and proteolytic stability. We previously reported selective antifungal 14-helical β-peptides, but the mechanism of antifungal toxicity of β-peptides remains unknown. To provide insight into the mechanism, we studied antifungal β-peptide binding to artificial membranes and livingCandida albicanscells. We investigated the ability of β-peptides to interact with and permeate small unilamellar vesicle models of fungal and bacterial membranes. The partition coefficient supported a pore-mediated mechanism characterized by the existence of a critical β-peptide concentration separating low and high partition coefficient regimes. Live cell intracellular tracking of β-peptides showed that β-peptides translocated into the cytoplasm, and then disrupted the nucleus and vacuole sequentially, leading to cell death. This understanding of the mechanisms of antifungal activity will facilitate design and development of peptidomimetic AMPs, including 14-helical β-peptides, for antifungal applications.Graphical Abstract

New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death

2016 ◽  
Vol 23 (15) ◽  
pp. 1513-1527 ◽  
Author(s):  
Magdalena Gorska ◽  
Alicja Kuban-Jankowska ◽  
Jaroslaw Slawek ◽  
Michal Wozniak
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Cancer Cell Death ◽  
Insight Into

scholarly journals Salicylic Acid Accumulation Controlled by LSD1 Is Essential in Triggering Cell Death in Response to Abiotic Stress

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 962
Author(s):  
Maciej Jerzy Bernacki ◽  
Anna Rusaczonek ◽  
Weronika Czarnocka ◽  
Stanisław Karpiński
Keyword(s):  
Cell Death ◽  
Salicylic Acid ◽  
Abiotic Stress ◽  
Wild Type ◽  
Pr Genes ◽  
Genes Expression ◽  
Salicylic Acid Accumulation ◽  
Cell Death Phenotype ◽  
Insight Into

Salicylic acid (SA) is well known hormonal molecule involved in cell death regulation. In response to a broad range of environmental factors (e.g., high light, UV, pathogens attack), plants accumulate SA, which participates in cell death induction and spread in some foliar cells. LESION SIMULATING DISEASE 1 (LSD1) is one of the best-known cell death regulators in Arabidopsis thaliana. The lsd1 mutant, lacking functional LSD1 protein, accumulates SA and is conditionally susceptible to many biotic and abiotic stresses. In order to get more insight into the role of LSD1-dependent regulation of SA accumulation during cell death, we crossed the lsd1 with the sid2 mutant, caring mutation in ISOCHORISMATE SYNTHASE 1(ICS1) gene and having deregulated SA synthesis, and with plants expressing the bacterial nahG gene and thus decomposing SA to catechol. In response to UV A+B irradiation, the lsd1 mutant exhibited clear cell death phenotype, which was reversed in lsd1/sid2 and lsd1/NahG plants. The expression of PR-genes and the H2O2 content in UV-treated lsd1 were significantly higher when compared with the wild type. In contrast, lsd1/sid2 and lsd1/NahG plants demonstrated comparability with the wild-type level of PR-genes expression and H2O2. Our results demonstrate that SA accumulation is crucial for triggering cell death in lsd1, while the reduction of excessive SA accumulation may lead to a greater tolerance toward abiotic stress.

scholarly journals Apoptosis-like cell death upon kinetoplastid induction by compounds isolated from the brown algae Dictyota spiralis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Olfa Chiboub ◽  
Ines Sifaoui ◽  
Manef Abderrabba ◽  
Mondher Mejri ◽  
José J. Fernández ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Mitochondrial Membrane ◽  
Brown Seaweed ◽  
Cell Permeability ◽  
Oxygen Species ◽  
Potential Drug ◽  
Concentration Cell ◽  
Drug Candidates

Abstract Background The in vitro activity of the brown seaweed Dictyota spiralis against both Leishmania amazonensis and Trypanosoma cruzi was evaluated in a previous study. Processing by bio-guided fractionation resulted in the isolation of three active compounds, classified as diterpenes. In the present study, we performed several assays to detect clinical features associated to cell death in L. amazonensis and T. cruzi with the aim to elucidate the mechanism of action of these compounds on parasitic cells. Methods The aims of the experiments were to detect and evaluate specific events involved in apoptosis-like cell death in the kinetoplastid, including DNA condensation, accumulation of reactive oxygen species and changes in ATP concentration, cell permeability and mitochondrial membrane potential, respectively, in treated cells. Results The results demonstrated that the three isolated diterpenes could inhibit the tested parasites by inducing an apoptosis-like cell death. Conclusions These results encourage further investigation on the isolated compounds as potential drug candidates against both L. amazonensis and T. cruzi. Graphic abstract

scholarly journals Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qin Gong ◽  
Kim Robinson ◽  
Chenrui Xu ◽  
Phuong Thao Huynh ◽  
Kelvin Han Chung Chong ◽  
...  
Keyword(s):  
Cell Death ◽  
Inner Core ◽  
Inflammatory Diseases ◽  
Structural Features ◽  
Structural Basis ◽  
Cultured Human Cells ◽  
Structural Insight ◽  
Sensor Proteins ◽  
Insight Into

AbstractNod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells—a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.

scholarly journals prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2

1996 ◽  
Vol 316 (1) ◽  
pp. 25-28 ◽  
Author(s):  
Miriam J. SMYTH ◽  
David K. PERRY ◽  
Jiandi ZHANG ◽  
Guy G. POIRIER ◽  
Yusuf A. HANNUN ◽  
...  
Keyword(s):  
Cell Death ◽  
Inhibitory Action ◽  
Second Messenger ◽  
The Novel ◽  
Over Expression ◽  
Downstream Target ◽  
Induced Apoptosis ◽  
Insight Into

The novel lipid second messenger, ceramide, specifically induced poly(ADP-ribose) polymerase cleavage through activation of the protease prICE. Over-expression of Bcl-2 inhibited ceramide-induced poly(ADP-ribose) polymerase proteolysis and protected cells from ceramide-induced death. These data provide the first insight into the mechanism by which ceramide mediates apoptosis and suggest a mechanism by which Bcl-2 protects from cell death.

scholarly journals IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos

Blood ◽  
2018 ◽  
Vol 132 (20) ◽  
pp. 2166-2178 ◽  
Author(s):  
Pasquale L. Fedele ◽  
Simon N. Willis ◽  
Yang Liao ◽  
Michael S. Low ◽  
Jai Rautela ◽  
...  
Keyword(s):  
Cell Death ◽  
Regulatory Networks ◽  
Nk Cell ◽  
Surface Expression ◽  
Nucleosome Remodeling ◽  
Interferon Stimulated Genes ◽  
Cd38 Expression ◽  
Cycle Arrest ◽  
Transcriptional Changes ◽  
Insight Into

Abstract Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC “axis,” as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.

scholarly journals Role of two metacaspases in development and pathogenicity of the Rice Blast fungus, Magnaporthe oryzae

2020 ◽  
Author(s):  
Jessie Fernandez ◽  
Victor Lopez ◽  
Lisa Kinch ◽  
Mariel A. Pfeifer ◽  
Hillery Gray ◽  
...  
Keyword(s):  
Cell Death ◽  
Food Security ◽  
Life Cycle ◽  
Magnaporthe Oryzae ◽  
Rice Blast ◽  
Rice Blast Disease ◽  
Blast Disease ◽  
Complex Life Cycle ◽  
Insight Into

ABSTRACTRice blast disease caused by Magnaporthe oryzae is a devastating disease of cultivated rice worldwide. Infections by this fungus lead to a significant reduction in rice yields and threats to food security. To gain better insight into growth and cell death in M. oryzae during infection, we characterized two predicted M. oryzae metacaspase proteins, MoMca1 and MoMca2. These proteins appear to be functionally redundant and are able to complement the yeast Yca1 homologue. Biochemical analysis revealed that M. oryzae metacaspases exhibited Ca2+ dependent caspase activity in vitro. Deletion of both MoMca1 and MoMca2 in M. oryzae resulted in reduced sporulation, delay in conidial germination and attenuation of disease severity. In addition, the double ΔMomca1mca2 mutant strain showed increased radial growth in the presence of oxidative stress. Interestingly, the ΔMomca1mca2 strain showed an increase accumulation of insoluble aggregates compared to the wild-type strain during vegetative growth. Our findings suggest that MoMca1 and MoMca2 promote the clearance of insoluble aggregates in M. oryzae, demonstrating the important role these metacaspases have in fungal protein homeostasis. Furthermore, these metacaspase proteins may play additional roles, like in regulating stress responses, that would help maintain the fitness of fungal cells required for host infection.IMPORTANCEMagnaporthe oryzae causes rice blast disease that threatens global food security by resulting in the severe loss of rice production every year. A tightly regulated life cycle allows M. oryzae to disarm the host plant immune system during its biotrophic stage before triggering plant cell death in its necrotrophic stage. The ways M. oryzae navigates its complex life cycle remains unclear. This work characterizes two metacaspase proteins with peptidase activity in M. oryzae that are shown to be involved in the regulation of fungal growth and development prior to infection by potentially helping maintain fungal fitness. This study provides new insight into the role of metacaspase proteins in filamentous fungi by illustrating the delays in M. oryzae morphogenesis in the absence of these proteins. Understanding the mechanisms by which M. oryzae morphology and development promote its devastating pathogenicity may lead to the emergence of proper methods for disease control.

scholarly journals Insight into the Double-Edged Role of Ferroptosis in Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1790
Author(s):  
Lei Zhang ◽  
Ruohan Jia ◽  
Huizhen Li ◽  
Huarun Yu ◽  
Keke Ren ◽  
...  
Keyword(s):  
Cell Death ◽  
Digestive System ◽  
Kidney Injury ◽  
Oxygen Species ◽  
Disease Treatment ◽  
The Relationship ◽  
Insight Into ◽  
New Strategies ◽  
Research Hotspots

Ferroptosis, a newly described type of iron-dependent programmed cell death that is distinct from apoptosis, necroptosis, and other types of cell death, is involved in lipid peroxidation (LP), reactive oxygen species (ROS) production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for ferroptosis in multiple diseases, including acute kidney injury, cancer, hepatic fibrosis, Parkinson’s disease, and Alzheimer’s disease. Therefore, ferroptosis has become one of the research hotspots for disease treatment and attracted extensive attention in recent years. This review mainly summarizes the relationship between ferroptosis and various diseases classified by the system, including the urinary system, digestive system, respiratory system, nervous system. In addition, the role and molecular mechanism of multiple inhibitors and inducers for ferroptosis are further elucidated. A deeper understanding of the relationship between ferroptosis and multiple diseases may provide new strategies for researching diseases and drug development based on ferroptosis.

scholarly journals Therapeutic Efficacy of Antibacterial Ocellatin Peptides- A Comprehensive Review

2021 ◽  
Vol 12 (5) ◽  
pp. 6804-6814
Keyword(s):  
Therapeutic Efficacy ◽  
Innate Immune ◽  
South American ◽  
Hydrophobic Residues ◽  
Microbial Drug Resistance ◽  
Bacterial Membranes ◽  
Drug Candidates ◽  
Small Molecule Drugs ◽  
Living Organisms ◽  
Dynamic Interplay

Antimicrobial peptides (AMPs), ascribed to their decreased microbial drug resistance, can be employed as potent small-molecule drugs to treat various diseases. AMPs have been conserved in a wide variety of living organisms as a result of the evolution of the innate immune system. Notably, Ocellatin AMPs derived from South American Leptodactylus genus frogs have a higher therapeutic efficacy against infections. Inhibitory activity of Ocellatin AMPs against bacterial membranes is determined by the dynamic interplay of peptide cationic, hydrophobicity, helicity, and amphipathicity. Another advantage of using AMPs as drug candidates is their cell selectivity that is non-hemolytic to human cells. Ocellatin AMPs with optimal hydrophobic residues would therefore be a recommended therapeutic candidate. Henceforth, such AMPs could be used as an alternative strategy in curbing antimicrobial resistance. It is noteworthy that the therapeutic efficacy of Ocellatins is to be appreciated for its broad application as it has been proved to be active against several humans, animal, and plant bacterial pathogens.

Depression: An insight into Heterocyclic and Cyclic Hydrocarbon Compounds inspired from Natural Sources

2021 ◽  
Vol 19 ◽  
Author(s):  
Abdul Jalil Shah ◽  
Reyaz Hassan Mir ◽  
Roohi Mohi-ud-din ◽  
Faheem Hyder Pottoo ◽  
Mubashir Hussain Masoodi ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Herbal Medicines ◽  
Aminobutyric Acid ◽  
Cyclic Hydrocarbon ◽  
Natural Sources ◽  
Drug Candidates ◽  
Signalling Molecules ◽  
Symptoms Of Depression ◽  
Insight Into

: Depression, a well know mental disorder has global prevalence, nearly affecting 17% of population. Due to various limitations of the currently available drugs, people have been adopting traditional herbal medicines to alleviate the symptoms of depression. It is notable to mention that natural products, their derivatives, and their analogs are the main source for new drug candidates in depression. The mechanisms include interplay with γ-aminobutyric acid (GABA) receptors, serotonergic, dopaminergic noradrenergic systems, and elevation of BDNF levels. The focus of this review is to revisit the role of signalling molecules in depression and highlight the use of plant-derived natural compounds to counter depression in the CNS.

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