Human Salivary Histatin 5 Fungicidal Action Does Not Induce Programmed Cell Death Pathways in
            <i>Candida albicans</i>

Wunder, David; Dong, Jin; Baev, Didi; Edgerton, Mira

doi:10.1128/aac.48.1.110-115.2004

Cited by 38 publications

(28 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data provide the demonstration in situ that ROS are generated by mitochondria, and their generation coincides with a process of mitochondrial swelling. Preservation of the transmembrane potential, at least in the initial stage of ROS generation, and the CsA-insensitive character of mitochondrial swelling exclude an involvement of the permeability transition pore, in agreement with the fact that cytochrome c is not released by mitochondria (Petruzzelli et al, 2003;Wunder et al, 2004). Rather, the high energy swelling is explained by a potentialdriven accumulation of cations (mostly Kþ) in the matrix, accompanied by water influx to counterbalance the osmotic gradient (Azzone and Azzi, 1965;Bernardi et al, 1999).…”

Section: Discussionsupporting

confidence: 58%

“…In addition, cell survival was not reduced in C. albicans SOD1 mutants, as compared to wild-type strains, following Hst 5 treatment (Wunder et al, 2004). Likewise, the ROS scavenger TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) was unable to protect C. albicans against the fungicidal effects of Hst 5 or dhvar4, a synthetic peptide with uncoupling properties correlated to low ROS generation (Veerman et al, 2004).…”

Section: Discussionmentioning

confidence: 94%

“…A further effect is the generation of reactive oxygen species (ROS), considered to be a major cause of cell death (Helmerhorts et al, 2001a). On the other hand, the role of ROS appears to be contradicted by the non-protective effect of antioxidants and the low level of protein carbonylation (Veerman et al, 2004;Wunder et al, 2004). Hst 3 and 5 have also been found to induce a non-lytic release of ATP, which activate purinergic receptors with fatal consequences for the cell.…”

Section: Introductionmentioning

confidence: 93%

See 2 more Smart Citations

Mitochondrial alterations and autofluorescent conversion of Candida albicans induced by histatins

Diaz

Polonelli

Conti

et al. 2005

Microscopy Res & Technique

View full text Add to dashboard Cite

The mechanism of the candidacidal activity of histatins 3 and 5 (Hst) is still a matter of debate. Previous studies have indicated that Hst induce cell permeabilization, generation of reactive oxygen species (ROS) by mitochondria, inhibition of the respiratory chain, and energy-dependent cytotoxic release of ATP. On the other hand, the multiplicity of effects and the apparent contrast between experimental data continue to render the mechanism of Hst-induced killing of C. albicans unclear. In this investigation, using fluorescent probes (the potential-sensitive mitochondrial probe tetramethylrhodamine methyl ester perchlorate, TMRM; the ROS-sensitive probe dihydrofluorescein diacetate, DHF; the membrane-impermeant probe, calcein) and autofluorescence data we observed that Hst induce ROS generation by mitochondria undergoing a high energy swelling condition, accompanied by oxidation of cytosolic NAD(P)H and mitochondrial flavoproteins. ROS generation and swelling, attributable to an inhibition of the respiratory chain and to impairment of the K/H-exchanger, were followed by mitochondrial depolarization. Mitochondrial changes were accompanied by massive calcein influx, indicative of cell permeabilization, and prominent alterations of the cell size, shape, and optical density. The loss of proliferative activity was correlated, on a single cell basis, to the acquisition of a lipofuscin-like autofluorescence.

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

Mitochondrial alterations and autofluorescent conversion of Candida albicans induced by histatins

Diaz

Polonelli

Conti

et al. 2005

Microscopy Res & Technique

View full text Add to dashboard Cite

show abstract

“…First, none of the classical markers of ROS-mediated oxidative damage, including protein carbonylation and chromosome laddering, were observed as a result of Hst 5 treatment of C. albicans (51). Second, Veerman et al showed that TEMPO (2,2,66,6-tetramethylpiperidine-N-oxyl), a cell-permeant ROS scavenger, did not inhibit cell killing nor reduce the fluorescence of HEt (52).…”

Section: Atp and Mitochondrion-mediated Mechanismmentioning

confidence: 99%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

Self Cite

View full text Add to dashboard Cite

Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.

show abstract

“…In this alternative model, Hst 5 interferes with the mitochondrial respiratory chain and causes formation of oxygen radicals (reactive oxygen species [ROS]) as the main cause of cell death (15,16). It has been demonstrated that ROS do not initiate apoptosis or programmed cell death pathways in Hst 5-treated cells (41); rather, direct mitochondrial and cytoplasmic membrane damage by ROS is hypothesized to be the essential step for cell killing (15). In this model, activation of oxidative stress response pathways would be the major adaptive response for protection of C. albicans from Hst 5 killing.…”

mentioning

confidence: 99%

Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

Vylkova¹,

Jang²,

et al. 2007

Eukaryot Cell

Self Cite

View full text Add to dashboard Cite

Human Salivary Histatin 5 Fungicidal Action Does Not Induce Programmed Cell Death Pathways in Candida albicans

Cited by 38 publications

References 48 publications

Mitochondrial alterations and autofluorescent conversion of Candida albicans induced by histatins

Mitochondrial alterations and autofluorescent conversion of Candida albicans induced by histatins

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

Contact Info

Product

Resources

About