Non-Toxic and Ultra-Small Biosilver Nanoclusters Trigger Apoptotic Cell Death in Fluconazole-Resistant Candida albicans via Ras Signaling

Silver-based nanostructures are suitable for many biomedical applications, but to be useful therapeutic agents, the high toxicity of these nanomaterials must be eliminated. Here, we biosynthesize nontoxic and ultra-small silver nanoclusters (rsAg@NCs) using metabolites of usnioid lichen (a symbiotic association of algae and fungi) that exhibit excellent antimicrobial activity against fluconazole (FCZ)-resistant Candida albicans that is many times higher than chemically synthesized silver nanoparticles (AgNPs) and FCZ. The rsAg@NCs trigger apoptosis via reactive oxygen species accumulation that leads to the loss of mitochondrial membrane potential, DNA fragmentation, chromosomal condensation, and the activation of metacaspases. The proteomic analysis clearly demonstrates that rsAg@NCs exposure significantly alters protein expression. Most remarkable among the down-regulated proteins are those related to glycolysis, metabolism, free radical scavenging, anti-apoptosis, and mitochondrial function. In contrast, proteins involved in plasma membrane function, oxidative stress, cell death, and apoptosis were upregulated. Eventually, we also established that the apoptosis-inducing potential of rsAg@NCs is due to the activation of Ras signaling, which confirms their application in combating FCZ-resistant C. albicans infections.

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Silver nanoparticles induce apoptotic cell death in Candida albicans through the increase of hydroxyl radicals

FEBS Journal ◽

10.1111/j.1742-4658.2012.08527.x ◽

2012 ◽

Vol 279 (7) ◽

pp. 1327-1338 ◽

Cited By ~ 118

Author(s):

In-sok Hwang ◽

Juneyoung Lee ◽

Ji Hong Hwang ◽

Keuk-Jun Kim ◽

Dong Gun Lee

Keyword(s):

Silver Nanoparticles ◽

Cell Death ◽

Candida Albicans ◽

Hydroxyl Radicals ◽

Apoptotic Cell ◽

Apoptotic Cell Death

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Autophagy gene ATG5 knockdown upregulates apoptotic cell death during Candida albicans infection in human vaginal epithelial cells

American Journal of Reproductive Immunology ◽

10.1111/aji.13056 ◽

2018 ◽

Vol 80 (6) ◽

pp. e13056 ◽

Cited By ~ 3

Author(s):

Ankit Shroff ◽

Kudumula Venkata Rami Reddy

Keyword(s):

Cell Death ◽

Candida Albicans ◽

Epithelial Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Autophagy Gene ◽

Vaginal Epithelial Cells ◽

Candida Albicans Infection

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

Biochimie ◽

10.1016/j.biochi.2012.04.010 ◽

2012 ◽

Vol 94 (8) ◽

pp. 1784-1793 ◽

Cited By ~ 44

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

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Dexamethasone blocks antioestrogen- and oxidant-induced death of pituitary tumour cells

Journal of Endocrinology ◽

10.1677/joe.0.1690249 ◽

2001 ◽

Vol 169 (2) ◽

pp. 249-261 ◽

Cited By ~ 3

Author(s):

CJ Newton ◽

D Bilko ◽

S Pappa ◽

SL Atkin

Keyword(s):

Cell Death ◽

Cell Membrane ◽

Tumour Cell ◽

Time Course ◽

Apoptotic Cell ◽

Cell Types ◽

Pituitary Tumour ◽

Tumour Cell Line ◽

Membrane Function ◽

Membrane Blebbing

The oestrogen receptor is fundamental to the growth and survival of the rat pituitary tumour cell line, GH(3). Our previous studies have shown that antioestrogens such as RU 58668 and ZM 182780 will reduce the rate of cell division and also induce cell death. Death of these cells in response to antioestrogen treatment appears to be due to a heightened sensitivity to reactive oxygen species (ROS). As part of a study to determine the cross-talk between steroid receptor systems in these cells, we have observed that the glucocorticoid, dexamethasone (Dex), inhibits antioestrogen-induced cell death. Cell death induced by H(2)O(2) is enhanced by ZM 182780 and this effect is also blocked by Dex. As apoptotic cell death in a number of systems involves an early loss of mitochondrial membrane potential (DeltaPsi(m)), we have performed detailed studies on the time-course of DeltaPsi(m) loss in relation to the loss in cell membrane function. These studies have indicated that a loss of DeltaPsi(m) parallels a loss of cell membrane function - this is more characteristic of necrosis than of apoptosis. From microscopic observations of these cells in response to H(2)O(2), it has been noted that early cell membrane blebbing, induced by H(2)O(2), is blocked in the presence of ZM 182780. Cell membrane blebbing can precede necrosis as well as apoptosis and it is thought to involve cytoskeletal changes, for which localised glycolytic reactions provide ATP. These observations, together with those showing that removal of glucose, but not inhibition of mitochondrial function, enhances ROS-induced cell death, prompted studies on the glycolytic pathway. As a strong candidate mechanism, it would appear that, via an effect on one of the rate-limiting glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase, Dex is able to overcome the antioestrogen-enhanced loss of glycolytic function following exposure of cells to ROS. This report contributes to the growing body of evidence showing that glucocorticoids provide a survival advantage to both normal and tumour cell types.

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Amentoflavone Stimulates Mitochondrial Dysfunction and Induces Apoptotic Cell Death in Candida albicans

Mycopathologia ◽

10.1007/s11046-011-9503-x ◽

2011 ◽

Vol 173 (4) ◽

pp. 207-218 ◽

Cited By ~ 30

Author(s):

In-sok Hwang ◽

Juneyoung Lee ◽

Hong-Guang Jin ◽

Eun-Rhan Woo ◽

Dong Gun Lee

Keyword(s):

Cell Death ◽

Candida Albicans ◽

Mitochondrial Dysfunction ◽

Apoptotic Cell ◽

Apoptotic Cell Death

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Quercetin Sensitizes Fluconazole-Resistant Candida albicans To Induce Apoptotic Cell Death by Modulating Quorum Sensing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03599-14 ◽

2015 ◽

Vol 59 (4) ◽

pp. 2153-2168 ◽

Cited By ~ 36

Author(s):

B. N. Singh ◽

D. K. Upreti ◽

B. R. Singh ◽

G. Pandey ◽

S. Verma ◽

...

Keyword(s):

Cell Death ◽

Candida Albicans ◽

Quorum Sensing ◽

Apoptotic Cell ◽

Hyphal Growth ◽

Binding Pocket ◽

Docking Studies ◽

Apoptotic Cell Death ◽

Content Type ◽

Dose Dependent

ABSTRACTQuorum sensing (QS) regulates group behaviors ofCandida albicanssuch as biofilm, hyphal growth, and virulence factors. The sesquiterpene alcohol farnesol, a QS molecule produced byC. albicans, is known to regulate the expression of virulence weapons of this fungus. Fluconazole (FCZ) is a broad-spectrum antifungal drug that is used for the treatment ofC. albicansinfections. While FCZ can be cytotoxic at high concentrations, our results show that at much lower concentrations, quercetin (QC), a dietary flavonoid isolated from an edible lichen (Usnealongissima), can be implemented as a sensitizing agent for FCZ-resistantC. albicansNBC099, enhancing the efficacy of FCZ. QC enhanced FCZ-mediated cell killing of NBC099 and also induced cell death. These experiments indicated that the combined application of both drugs was FCZ dose dependent rather than QC dose dependent. In addition, we found that QC strongly suppressed the production of virulence weapons—biofilm formation, hyphal development, phospholipase, proteinase, esterase, and hemolytic activity. Treatment with QC also increased FCZ-mediated cell death in NBC099 biofilms. Interestingly, we also found that QC enhances the anticandidal activity of FCZ by inducing apoptotic cell death. We have also established that this sensitization is reliant on the farnesol response generated by QC. Molecular docking studies also support this conclusion and suggest that QC can form hydrogen bonds with Gln969, Thr1105, Ser1108, Arg1109, Asn1110, and Gly1061 in the ATP binding pocket of adenylate cyclase. Thus, this QS-mediated combined sensitizer (QC)-anticandidal agent (FCZ) strategy may be a novel way to enhance the efficacy of FCZ-based therapy ofC. albicansinfections.

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Apoptosis Dependent Decrease of the Intramembrane Ion Traffic in Cultured Mouse Fibroblasts Shown by Conductivity Dispersion

Bioscience Reports ◽

10.1023/a:1027364308147 ◽

1997 ◽

Vol 17 (6) ◽

pp. 547-556 ◽

Cited By ~ 11

Author(s):

Adalberto Bonincontro ◽

Anna Iacoangeli ◽

Gianna Melucci-Vigo ◽

Gianfranco Risuleo

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Cell Suspensions ◽

Membrane Function ◽

Membrane Conductivity ◽

Nucleosomal Dna ◽

Membrane Structure And Function ◽

And Function ◽

Single Cell Electrophoresis ◽

Histological Staining

We have investigated the intramembranal ion traffic in apoptotic 3T6 cells in culture. Apoptosis was induced by various treatments, such as serum deprivation, high density growth and hydrogen peroxide at subnecrotic doses. Cell death was assessed by nucleosomal DNA fragmentation, single cell electrophoresis, immunofluorescence and histological staining. To study the modifications of membrane structure and function, we adopted a well established biophysical strategy based on the measurement of the electrical conductivity of cell suspensions, as a function of the frequency of the electrical field applied to the sample. A comparison between the conductivity of normal and apoptotic cell suspensions shows that programmed cell death causes a decrease of membrane conductivity which indicates a diminished intramembranal ion traffic. Our results strongly suggest that one of the early events in the triggering of apoptosis is represented by an overall reduction of plasma membrane function. Finally, our results are in agreement with the idea that the nucleus is not the sole target of the apoptotic process.

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