Assessing modulators of cytochrome c oxidase activity in Galleria mellonella larvae

Frawley, Kristin L.; Praekunatham, Hirunwut; Cronican, Andrea A.; Peterson, Jim; Pearce, Linda L.

doi:10.1016/j.cbpc.2019.02.009

Cited by 4 publications

(11 citation statements)

References 47 publications

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“…This behavior is analogous to that obtained employing the bona fide cytochrome c oxidase inhibitors azide, cyanide, and sulfide. 24 Consequently, while we have not set out to examine this particular question rigorously, our observations concerning the caterpillars do appear to be at least consistent with a mechanism of acute phosphine toxicity primarily involving inhibition of cytochrome c oxidase. If this is so, then it follows that the different response to the antidotes of phosphine-challenged mice (Figure 5) compared to the caterpillars (Figure 3) is plausibly due to another toxic mechanism operating in the mice, which might not involve reversible inhibition of cytochrome c oxidase.…”

Section: ■ Discussionmentioning

confidence: 68%

“…We have previously shown that G. mellonella caterpillars provide a reasonable model for screening antidotes to cytochrome c oxidase toxicants, such as cyanide. 24 Oxygen consumption was initiated by adding cytochrome c (to replace any lost when the mitochondria were lysed) along with the electron donor succinate, and rotenone (complex I inhibitor) to prevent backflow. The respirometric inhibition (decreased oxygen flux, JO 2 ) of G. mellonella mitochondrial particles 24 observed was quite linear (R 2 = 0.95) with respect to micromolar phosphine additions as shown in Figure 1.…”

Section: ■ Resultsmentioning

confidence: 99%

“…After exposure, the wax worms were removed from the chamber and monitored for recovery from paralysis ("knockdown"). Recovery was determined by the repeated performance of righting behavior as described by Frawley et al 24 Gold compounds and control solutions were administered at determined time points either before or after phosphine exposure. All injections were a maximum volume of 10 μL and into the most distal left abdominal proleg.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Following phosphine exposure, the duration of time required for the recovery of pole climbing in mice was measured following a procedure originated by Frawley et al 24 This test evaluates the ability of the mouse to climb a lightly roughened, 24 inch pole (3/8″ diameter) before and after exposure to a toxicant as well as the recovery, post exposure when receiving a treatment. This test is based on the observed natural curiosity of the mouse to climb to the top of the pole; it is relatively simple and requires minimal equipment.…”

Section: Animal Studiesmouse Model the University Of Pittsburghmentioning

confidence: 99%

“…In addition, we have previously shown that Galleria mellonella larvae (caterpillars) can usefully be applied to the screening of antidotes for mitochondrial toxicants, namely, azide, cyanide, and sulfide. 24 Accordingly, we have employed G. mellonella larvae to find an exposure level to phosphine gas useful for testing both the prophylactic and therapeutic effects toward phosphine of three antiarthytic Au(I) compounds, namely, auro-bisthiosulfate (AuTS), sodium aurothiomalate (AuTM), and aurothioglucose (AuTG). All of these compounds contain sulfide donors, keeping the gold in its reduced univalent state, lowering toxicity, and promoting affinity for phosphine.…”

Section: ■ Introductionmentioning

confidence: 99%

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Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity

Garrett

Frawley

Totoni

et al. 2019

Chem. Res. Toxicol.

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Phosphine (PH3) poisoning continues to be a serious problem worldwide, for which there is no antidote currently available. An invertebrate model for examining potential toxicants and their putative antidotes has been used to determine if a strategy of using Au(I) complexes as phosphine-scavenging compounds may be antidotally beneficial. When Galleria mellonella larvae (or wax worms) were subjected to phosphine exposures of 4300 (±700) ppm·min over a 20 min time span, they became immobile (paralyzed) for ∼35 min. The administration of Au(I) complexes auro-sodium bisthiosulfate (AuTS), aurothioglucose (AuTG), and sodium aurothiomalate (AuTM) 5 min prior to phosphine exposure resulted in a drastic reduction in the recovery time (0–4 min). When the putative antidotes were given 10 min after the phosphine exposure, all the antidotes were therapeutic, resulting in mean recovery times of 14, 17, and 19 min for AuTS, AuTG, and AuTM, respectively. Since AuTS proved to be the best therapeutic agent in the G. mellonella model, it was subsequently tested in mice using a behavioral assessment (pole-climbing test). Mice given AuTS (50 mg/kg) 5 min prior to a 3200 (±500) ppm·min phosphine exposure exhibited behavior comparable to mice not exposed to phosphine. However, when mice were given a therapeutic dose of AuTS (50 mg/kg) 1 min after a similar phosphine exposure, only a very modest improvement in performance was observed.

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Section: ■ Discussionmentioning

confidence: 68%

Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Animal Studiesmouse Model the University Of Pittsburghmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity

Garrett

Frawley

Totoni

et al. 2019

Chem. Res. Toxicol.

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Peptide-Conjugated Probe Inducing Mitochondrial Dysfunction and Self-Reporting Cell Apoptosis by Aggregated Proteins

Chen,

Hu,

Ouyang

et al. 2023

Anal. Chem.

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Inducing and monitoring cell apoptosis in a real-time manner are crucial for evaluating the therapeutic effect of drugs and avoiding excessive treatment. Although promising advancements have been made to monitor cell apoptosis by assessing cell membrane integrity, the chronic compromise of cellular fitness caused by imbalance proteostasis is not visible and hard to be detected. As an indicator for cell apoptosis, imaging of aggregated proteins provides a new direction. Herein, we design a peptide-conjugated probe (QRKN) that can induce mitochondrial dysfunction for self-reporting cell apoptosis by imaging aggregated proteins. Specifically, QRKN can be cleaved into the α-helix-forming part (QRK) and azide-modified small-molecule part (N) by overexpressed cathepsin B (CB) in tumor cells. The QRK part can destroy the mitochondrial membrane and promote cytochrome c (Cyt c) efflux and caspase 3 expression. The other N part can inhibit the activity of mitochondrial complex IV (Mito-IV) and decrease the expression level of adenosine triphosphate (ATP). Two signaling pathways cooperatively induce mitochondrial dysfunction, resulting in protein aggregation and cell apoptosis ultimately. Meanwhile, the cell apoptosis process can be monitored based on QRKN, which is highly sensitive to the aggregated protein-triggered viscosity change. The self-reporting probe can monitor therapeutic responses and provide valuable diagnosis information.

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A Cobalt Schiff-Base Complex as a Putative Therapeutic for Azide Poisoning

Praekunatham

Garrett

Bae

et al. 2019

Chem. Res. Toxicol.

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There is presently no antidote available to treat azide poisoning. Here, the Schiff-base compound Co(II)-2, 12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl dibromide (Co(II)N 4 [11.3.1]) is investigated to determine if it has the capability to antagonize azide toxicity through a decorporation mechanism. The stopped-flow kinetics of azide binding to Co(II)N 4 [11.3.1] in the absence of oxygen exhibited three experimentally observable phases: I (fast); II (intermediate); and III (slow). The intermediate phase II accounted for ∼70% of the overall absorbance changes, representing the major process observed, with second-order rate constants of 29 (±4) M −1 s −1 at 25 °C and 70 (±10) M −1 s −1 at 37 °C. The data demonstrated pH independence of the reaction around neutrality, suggesting the unprotonated azide anion to be the attacking species. The binding of azide to Co(II)N 4 [11.3.1] appears to have a complicated mechanism leading to less than ideal antidotal capability; nonetheless, this cobalt complex does protect against azide intoxication. Administration of Co(II)N 4 [11.3.1] at 5 min post sodium azide injection (ip) to mice resulted in a substantial decrease of righting-recovery times, 12 (±4) min, compared to controls, 40 (±8) min. In addition, only two out of seven mice "knocked down" when the antidote was administered compared to the controls given toxicant only (100% knockdown).

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Assessing modulators of cytochrome c oxidase activity in Galleria mellonella larvae

Cited by 4 publications

References 47 publications

Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity

Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity

Peptide-Conjugated Probe Inducing Mitochondrial Dysfunction and Self-Reporting Cell Apoptosis by Aggregated Proteins

A Cobalt Schiff-Base Complex as a Putative Therapeutic for Azide Poisoning

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