Plagiochin E, an antifungal active macrocyclic bis(bibenzyl), induced apoptosis in Candida albicans through a metacaspase-dependent apoptotic pathway

Wu, Xintong; Chang, Wenqiang; Cheng, Ai‐Xia; Sun, Libo; Lou, Hongxiang

doi:10.1016/j.bbagen.2010.01.001

Cited by 119 publications

(98 citation statements)

References 59 publications

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“…17,[41][42][43][44] Likewise, in the fungus C. albicans, it was suggested that the antifungal compound Plagiochin E activated metacaspases based on the appearance of FITC-VAD-fmk labeled cells. 45 In the phytoplankton Chlamydomonas reinhardtii and other marine species, such as the diatom Thalassiosira pseudonana and the unicellular coccolithore Emiliania huxlei, increased caspase-like activity was correlated with increased accumulation of metacaspase mRNA and protein, thereby providing indirect evidence that metacaspases had caspase-like activity. [46][47][48] Also in plants, silencing of mcII-Pa in the Norway spruce embryos reduced the level of the VEIDase caspase-like activity.…”

Section: Measurement and Inhibition Of Metacaspase Activitiesmentioning

confidence: 97%

Metacaspases

et al. 2011

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Metacaspases are cysteine-dependent proteases found in protozoa, fungi and plants and are distantly related to metazoan caspases. Although metacaspases share structural properties with those of caspases, they lack Asp specificity and cleave their targets after Arg or Lys residues. Studies performed over the past 10 years have demonstrated that metacaspases are multifunctional proteases essential for normal physiology of non-metazoan organisms. This article provides a comprehensive overview of the metacaspase function and molecular regulation during programmed cell death, stress and cell proliferation, as well as an analysis of the first metacaspase-mediated proteolytic pathway. To prevent further misapplication of caspase-specific molecular probes for measuring and inhibiting metacaspase activity, we provide a list of probes suitable for metacaspases.

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Section: Measurement and Inhibition Of Metacaspase Activitiesmentioning

confidence: 97%

Metacaspases

et al. 2011

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“…Translocation of mitochondrial cyt c to the cytosol leads to its binding with apoptotic protease-activating factor to form a complex with caspase-9, resulting in activation of the caspase cascade (26,28). Release of cyt c requires an increase in mitochondrial membrane permeability during apoptosis (28).…”

Section: Discussionmentioning

confidence: 99%

“…These enzymes are closely associated with the generation of ROS and mitochondrial dysfunction (26). Caspase-like activity was measured in R. oryzae, C. bertholletiae, and M. circinelloides germlings pretreated with PCZ (0.125 to 4 g/ml) or ICZ (0.06 to 4 g/ml) in conjunction with TCR (0.015 g/ml) for 3 h at 37°C using the CaspACE FITC-benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (VAD-FMK) in situ marker (Promega, Madison, WI), according to the manufacturer's instructions (28). cyt c release from mitochondria.…”

Section: Methodsmentioning

confidence: 99%

The Calcineurin Pathway Inhibitor Tacrolimus Enhances the In Vitro Activity of Azoles against Mucorales via Apoptosis

Shirazi

Kontoyiannis

2013

Eukaryot Cell

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The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales. We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca 2؉ , phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 g/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 g/ml) for Rhizopus oryzae, Cunninghamella bertholletiae, and Mucor circinelloides. Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca 2؉ and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.

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“…In fact, various antifungal agents, such as plagiochin E and melittin have already been demonstrated to act as yeast-specific apoptotic inducers. 35,36) It is commonly known that AmB can complex with the sterols in the fungal cell membrane and induces structural changes that allow small ions to follow across the cell membrane resulting in cell death. Phillips et al 12) reported that AmB could induce apoptosis of C. albicans, indicating a new antifungal mechanism of AmB.…”

Section: Discussionmentioning

confidence: 99%

Combination of Baicalein and Amphotericin B Accelerates Candida albicans Apoptosis

Zhu

et al. 2011

Biological & Pharmaceutical Bulletin

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Candida albicans is the most important human fungal pathogen, causing various diseases from superficial mucosal infections to life-threatening systemic disorders.1,2) Compared to bacterial infections, few drugs are available to treat fungal infections. The polyene macrolide antibiotic amphotericin B (AmB) is effective in the treatment of many systemic mycoses. But due to its poor permeability across the membrane, an increased amount of AmB must be administered to patients in clinical situations, thus often resulting in severe side effects. [3][4][5] To lessen the severity of the side effects, AmB is often combined with other antifungal drugs such as the azoles, but coincident with the increased use of antifungal azole derivatives, the incidences of drug resistance have been recently increasing.6-8) Thus investigation of reducing the AmB dose by combining it with other compounds is necessary.Programmed cell death responses have been described in a variety of fungi after exposure of the organisms to a range of conditions such as weak acid stress, oxidative stress, or ultraviolet irradiation. [9][10][11] It was demonstrated that C. albicans could be triggered to undergo an apoptotic cell death response when exposed to H 2 O 2 , intracellular acidification, or AmB. A single-cell death assay was used to show that a majority of AmB-treated cells were nonviable and impermeable to propidium iodide. Apoptotic changes were further confirmed by electron microscopy and by the production of intracellular reactive oxygen species (ROS).12,13) However, the mechanism by which C. albicans undergoes apoptosis remains unclear. In mammalian cells, acquisition of an apoptotic morphology depends on the activation of cysteine dependent aspartate specific proteases (caspases). Functional analyses of genes in Saccharomyces cerevisiae have revealed similarities between fungal apoptosis and apoptosis in mammalian cells. A homologue of mammalian caspases, YCA1 (Yeast Caspase 1), has been identified. Overexpression of YCA1 increases hydrogen peroxide-induced caspase-like activity and apoptosis in S. cerevisiae.14-17) Caspase superfamily consists of three families; YCA1 belongs to the metacaspase family of enzymes which are found in plants, fungi and protozoa. We recently found that CaMCA1, a homologue of S. cerevisiae metacaspase YCA1, was involved in oxidative stress-induced apoptosis in C. albicans. 18)Baicalein (BE) is a compound that was originally extracted from the Scutellaria baicalensis root, and it is a promising herbal medicine in Chinese Pharmacopoeia (Fig. 1). BE exhibits antioxidant, antibacterial, antiviral, and antifungal activities. [19][20][21][22][23] In this study, we described a synergic effect of BE with AmB against C. albicans and the potential mechanism. Our results showed that combination of BE and AmB enhanced C. albicans apootosis accompanied with an increase of reactive oxygen species (ROS). We also found that AmB could induce the caspase activity and mRNA expression of the gene encoding C. albicans caspase, CaMCA1...

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Plagiochin E, an antifungal active macrocyclic bis(bibenzyl), induced apoptosis in Candida albicans through a metacaspase-dependent apoptotic pathway

Cited by 119 publications

References 59 publications

Metacaspases

Metacaspases

The Calcineurin Pathway Inhibitor Tacrolimus Enhances the In Vitro Activity of Azoles against Mucorales via Apoptosis

Combination of Baicalein and Amphotericin B Accelerates Candida albicans Apoptosis

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