scholarly journals Human Lactoferrin Induces Apoptosis-Like Cell Death in Candida albicans: Critical Role of K+-Channel-Mediated K+ Efflux

2008 ◽  
Vol 52 (11) ◽  
pp. 4081-4088 ◽  
Author(s):  
María T. Andrés ◽  
Monica Viejo-Díaz ◽  
José F. Fierro
Keyword(s):  
Candida Albicans ◽  
Chromatin Condensation ◽  
Critical Role ◽  
Blocking Agent ◽  
Human Lactoferrin ◽  
K Channel ◽  
Mitochondrial Activity ◽  
Channel Blockers ◽  
Ros Accumulation ◽  
Intracellular Ros

ABSTRACT Human lactoferrin (hLf) induced an apoptosis-like phenotype in Candida albicans cells, which includes phosphatidylserine externalization, nuclear chromatin condensation, DNA degradation, and increased reactive oxygen species (ROS) production. Intracellular ROS accumulation was seen to correlate with candidacidal activity in hLf-treated cells. Mitochondrial activity was involved as indicated by mitochondrial depolarization and increased hLf resistance of cells preincubated with sordarin or erythromycin, the latter of which inhibits protein synthesis in mitoribosomes. Interestingly, Cl−- and K+-channel blockers prevented the hLf antimicrobial activity, but only when cells were pretreated with the blocking agent (tetraethylammonium) prior to the hLf-induced K+-release period. These results indicate for the first time that K+-channel-mediated K+ efflux is required for the progression of apoptosis-like process in yeast, suggesting that this essential apoptotic event of higher eukaryotes has been evolutionary conserved among species ranging from yeasts to humans.

(+)-Medioresinol leads to intracellular ROS accumulation and mitochondria-mediated apoptotic cell death in Candida albicans

Biochimie ◽  
2012 ◽  
Vol 94 (8) ◽  
pp. 1784-1793 ◽  
Author(s):  
Ji Hong Hwang ◽  
In-sok Hwang ◽  
Qing-He Liu ◽  
Eun-Rhan Woo ◽  
Dong Gun Lee
Keyword(s):  
Cell Death ◽  
Candida Albicans ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Ros Accumulation ◽  
Intracellular Ros

Hodgkin-Huxley and partially coupled inactivation models yield different voltage dependence of block

1997 ◽  
Vol 272 (4) ◽  
pp. H2013-H2022 ◽  
Author(s):  
S. Liu ◽  
R. L. Rasmusson
Keyword(s):  
Voltage Dependence ◽  
Channel Model ◽  
Outward Current ◽  
Blocking Agent ◽  
K Channel ◽  
Transient Outward Current ◽  
Channel Blockers ◽  
Channel Block ◽  
Current Channel ◽  
Voltage Dependent

K+ channel blockers have been shown to exhibit complex time- and voltage-dependent effects on cardiac K+ currents. Whereas much attention has been focused on the state dependence of K+ channel block, how a particular channel model can alter the predicted time and voltage dependence of channel block remains unexplored. In this study, using two different model formalisms for the same cardiac transient outward current channel, we compare the effects of a theoretical open-state specific channel blocker on macroscopic currents. Model 1 is a Hodgkin-Huxley-like model, in which inactivation is an intrinsically voltage-dependent process and occurs independently of activation. Model 2 is a "partially coupled" model, in which inactivation is intrinsically voltage insensitive but requires channel activation before it can proceed. In the absence of drug (blocking agent), the two models reproduce the macroscopic current data. In the presence of blocking agent, the two models can differ substantially, with model 1 displaying much less block than model 2. We also examine simple mathematically convenient modifications to the Hodgkin-Huxley formalism, which reproduce some, but not all, of the use-dependent properties of block. Thus model formalism is important for analysis and simulation of state-specific drug-channel interactions.

scholarly journals Cytosolic Acidification Is the First Transduction Signal of Lactoferrin-induced Regulated Cell Death Pathway

2019 ◽  
Vol 20 (23) ◽  
pp. 5838 ◽  
Author(s):  
Andrés ◽  
Acosta-Zaldívar ◽  
González-Seisdedos ◽  
Fierro
Keyword(s):  
Cell Death ◽  
Critical Role ◽  
K Channel ◽  
Antimicrobial Protein ◽  
Channel Blockers ◽  
Cytosolic Ph ◽  
Cell Death Pathway ◽  
Regulated Cell Death ◽  
Transduction Signal ◽  
Cytosolic Acidification

In yeast, we reported the critical role of K+-efflux for the progress of the regulated cell death (RCD) induced by human lactoferrin (hLf), an antimicrobial protein of the innate immune system that blocks Pma1p H+-ATPase. In the present study, the K+ channel Tok1p was identified as the K+ channel-mediating K+-efflux, as indicated by the protective effect of extracellular K+ (30 mM), K+-channel blockers, and the greater hLf-resistance of TOK1-disrupted strains. K+-depletion was necessary but not sufficient to induce RCD as inferred from the effects of valinomycin, NH4Cl or nigericin which released a percentage of K+ similar to that released by lactoferrin without affecting cell viability. Cytosolic pH of hLf-treated cells decreased transiently (0.3 pH units) and its inhibition prevented the RCD process, indicating that cytosolic acidification was a necessary and sufficient triggering signal. The blocking effect of lactoferrin on Pma1p H+-ATPase caused a transitory decrease of cytosolic pH, and the subsequent membrane depolarization activated the voltage-gated K+ channel, Tok1p, allowing an electrogenic K+-efflux. These ionic events, cytosolic accumulation of H+ followed by K+-efflux, constituted the initiating signals of this mitochondria-mediated cell death. These findings suggest, for the first time, the existence of an ionic signaling pathway in RCD.

scholarly journals Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 328
Author(s):  
Tuy An Trinh ◽  
Young Hye Seo ◽  
Sungyoul Choi ◽  
Jun Lee ◽  
Ki Sung Kang
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Defense Mechanism ◽  
Neuroprotective Effect ◽  
Glutamate Release ◽  
Chromatin Condensation ◽  
Critical Role ◽  
Glutamate Toxicity ◽  
Heme Oxygenase 1 ◽  
Brain Functions

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

scholarly journals Signal-mediated localization of Candida albicans pheromone response pathway components

2020 ◽  
Author(s):  
Anna Carolina Borges Pereira Costa ◽  
Raha Parvizi Omran ◽  
Chris Law ◽  
Vanessa Dumeaux ◽  
Malcolm Whiteway
Keyword(s):  
Candida Albicans ◽  
Map Kinase ◽  
Nuclear Localization ◽  
Map Kinases ◽  
Critical Role ◽  
Cell Periphery ◽  
Pheromone Response ◽  
Pheromone Response Pathway ◽  
Localization Signal ◽  
In Cells

Abstract Candida albicans opaque cells release pheromones to stimulate cells of opposite mating type to activate their pheromone response pathway. Although this fungal pathogen shares orthologous proteins involved in the process with Saccharomyces cerevisiae, the pathway in each organism has unique characteristics. We have used GFP-tagged fusion proteins to investigate the localization of the scaffold protein Cst5, as well as the MAP kinases Cek1 and Cek2, during pheromone response in C. albicans. In wild-type cells, pheromone treatment directed Cst5-GFP to surface puncta concentrated at the tips of mating projections. These puncta failed to form in cells defective in either the Gα or β subunits. However, they still formed in response to pheromone in cells missing Ste11, but with the puncta distributed around the cell periphery in the absence of mating projections. These puncta were absent from hst7Δ/Δ cells, but could be detected in the ste11Δ/Δ hst7Δ/Δ double mutant. Cek2-GFP showed a strong nuclear localization late in the response, consistent with a role in adaptation, while Cek1-GFP showed a weaker, but early increase in nuclear localization after pheromone treatment. Activation loop phosphorylation of both Cek1 and Cek2 required the presence of Ste11. In contrast to Cek2-GFP, which showed no localization signal in ste11Δ/Δ cells, Cek1-GFP showed enhanced nuclear localization that was pheromone independent in the ste11Δ/Δ mutant. The results are consistent with CaSte11 facilitating Hst7-mediated MAP kinase phosphorylation and also playing a potentially critical role in both MAP kinase and Cst5 scaffold localization.

scholarly journals Diorcinol D Exerts Fungicidal Action against Candida albicans through Cytoplasm Membrane Destruction and ROS Accumulation

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0128693 ◽  
Author(s):  
Ying Li ◽  
Wenqiang Chang ◽  
Ming Zhang ◽  
Xiaobin Li ◽  
Yang Jiao ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fungicidal Action ◽  
Ros Accumulation

scholarly journals The Class II Phosphatidylinositol 3 kinase C2β Is Required for the Activation of the K+ Channel KCa3.1 and CD4 T-Cells

2009 ◽  
Vol 20 (17) ◽  
pp. 3783-3791 ◽  
Author(s):  
Shekhar Srivastava ◽  
Lie Di ◽  
Olga Zhdanova ◽  
Zhai Li ◽  
Santosha Vardhana ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Class Ii ◽  
K Channel ◽  
Channel Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

The Ca2+-activated K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of T-cells. We previously showed that nucleoside diphosphate kinase beta (NDPK-B), a mammalian histidine kinase, directly phosphorylates and activates KCa3.1 and is required for the activation of human CD4 T lymphocytes. We now show that the class II phosphatidylinositol 3 kinase C2β (PI3K-C2β) is activated by the T-cell receptor (TCR) and functions upstream of NDPK-B to activate KCa3.1 channel activity. Decreased expression of PI3K-C2β by siRNA in human CD4 T-cells resulted in inhibition of KCa3.1 channel activity. The inhibition was due to decreased phosphatidylinositol 3-phosphate [PI(3)P] because dialyzing PI3K-C2β siRNA-treated T-cells with PI(3)P rescued KCa3.1 channel activity. Moreover, overexpression of PI3K-C2β in KCa3.1-transfected Jurkat T-cells led to increased TCR-stimulated activation of KCa3.1 and Ca2+ influx, whereas silencing of PI3K-C2β inhibited both responses. Using total internal reflection fluorescence microscopy and planar lipid bilayers, we found that PI3K-C2β colocalized with Zap70 and the TCR in peripheral microclusters in the immunological synapse. This is the first demonstration that a class II PI3K plays a critical role in T-cell activation.

scholarly journals Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
David Frank ◽  
Shamoon Naseem ◽  
Gian Luigi Russo ◽  
Cindy Li ◽  
Kaustubh Parashar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Candida Albicans ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Wild Type ◽  
Content Type ◽  
Enhanced Production ◽  
Immunological Mechanisms

ABSTRACT Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts−/− mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. To better understand the immunological mechanisms underlying the enhanced resistance of Sts−/− mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts−/− mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts−/− marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo. This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts−/− BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts−/− cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis. IMPORTANCE Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recently, the Sts phosphatases were established as key regulators of the host antifungal immune response. In particular, genetic inactivation of Sts significantly enhanced survival of mice infected intravenously with Candida albicans. The Sts−/− in vivo resistance phenotype is associated with reduced fungal burden and an absence of inflammatory lesions. To understand the underlying mechanisms, we studied phagocyte responses. Here, we demonstrate that Sts−/− phagocytes have heightened responsiveness to C. albicans challenge relative to wild-type cells. Our data indicate the Sts proteins negatively regulate phagocyte activation via regulating selective elements of the Dectin-1–Syk tyrosine kinase signaling axis. These results suggest that phagocytes lacking Sts respond to fungal challenge more effectively and that this enhanced responsiveness partially underlies the profound resistance of Sts−/− mice to systemic fungal challenge.

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