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Miltefosine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Andrew Stewardson, Douglas Johnson
With regard to miltefosine resistance among fungi, in vitro resistance selection studies with Saccharomyces cerevisiae implicated disruption of yeast metacaspase (Mca1) mediated by MCA1 mutation (Biswas et al., 2014). Miltefosine resistance is also induced in S. cerevisiae by deletion of Lem3p, a drug transporter equivalent to LdMT-LdRos3 in leishmania (Zuo et al., 2011).
Investigation of Dependency of Boric Acid and Lithium Metaborate Induced Yeast Toxicity on the Expressions of Antioxidative and Apoptotic Genes
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Berna Kavakcıoğlu Yardımcı, Zehra Mollaoğlu, Fatih Altıntaş, Ayşenur Güler
We conclude that the following results were reached about the toxic effects of BA and LMB on eukaryotic model organism S. cerevisiae: While △CTT1, △GSH2 and △TRR2 mutants do not show sensitivity to BA-induced toxicity, △GSH2 and △TRR2 mutant strains are especially more sensitive to LMB-induced toxicity compared to wild-type yeast strain.Both agents induce toxicity in a metacaspase-independent manner.Inductions of the expression levels of the AIF1 and NDI1 genes were determined compared to control groups, particularly at the highest concentrations of BA and LMB, which suggest the roles of these gene products in the toxic effect mechanisms of the agents.BIR1 may play an important role in the mechanism of BA and LMB-induced stress tolerance in this yeast model.
Antifungal effects and potential mechanisms of lonidamine in combination with fluconazole against Candida albicans
Published in Expert Review of Anti-infective Therapy, 2021
Xueqi Chen, Yinping Shi, Yiman Li, Shan Su, Peng Wang, Shujuan Sun
In addition, the activation of metacaspase is a distinct biochemical marker of apoptosis in C. albicans [27,40,41]. Caspase-dependent apoptosis makes up 40% in yeast cell death scenarios, and caspases can be activated in the early stage of apoptosis [40,46]. In order to detect whether C. albicans undergoes caspase-dependent apoptosis when it exposed to the tested drugs, we tested the metacaspase activity using the Caspase FITC-VAD-FMK. As shown in Figure 2, the metacaspase activity was significantly activated by the LND-FLC combination in resistant C. albicans, illustrating that the antifungal activities induced by the two drugs were mediated by the metacaspase-dependent apoptotic pathway. These results indicated that LND-FLC combination against C. albicans could activate metacaspase, but couldn’t induce apoptosis by increasing ROS production. Moreover, the molecular mechanism of the combination of LND and FLC against C. albicans does require further in-depth research.
Programmed cell death in human pathogenic fungi – a possible therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2018
Éva Leiter, László Csernoch, István Pócsi
Candida albicans is a human opportunistic pathogenic fungus, which normally occurs in the gut microflora [38]. Some elements of the apoptotic machinery of S. cerevisiae have also been found in C. albicans [38] (Figure 1). For example, the YCA1 (MCA1) yeast metacaspase homologue CaMCA1 is also involved in the oxidative stress-induced mitochondrial degradation and finally cell death [39,40]. The deletion of the CaMCA1 gene resulted in less ROS generation, lower mitochondrial membrane potential, and decreased caspase activity, i.e. lower apoptotic rate [41]. Manipulation of the RAS-cAMP-PKA signaling pathway also influenced the apoptotic cell death in this fungus. Blocking the elements of this signaling, e.g. in ras1Δ, cdc35Δ (adenylate cyclase), tpk1Δ and tpk2Δ (encoding catalytic subunits of PKA) resulted in abolishment of cell death, while stimulation of RAS signaling – like in RAS1val13 (hyperactivated dominant mutant) and pde2Δ (phosphodiesterase mutant strain that contains elevated levels of cAMP) mutants – stimulated apoptotic cell death [42]. The deletion of the bZip transcription factor Cap1 increased apoptosis in the presence of apoptosis inducing agents like H2O2 or AMB [43]. MCA1 metacaspase as well as caspase activities increased in the cap1Δ/Δ mutant with concomitant ROS elevation and mitochondrial membrane potential dissipation. In the cap1Δ/Δ mutant, the accumulation of ROS was caused by the depletion of intracellular GSH and glutathione reductase enzyme activities [43].