Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach

Eadon, Michael T.; Hause, Ronald J.; Stark, Amy L.; Cheng, Ying; Wheeler, Heather E.; Burgess, Kimberly S.; Benson, Eric A.; Cunningham, Patrick N.; Bacallao, Robert L.; Dagher, Pierre C.; Skaar, Todd C.; Dolan, M. Eileen

doi:10.3390/ijms18030661

Cited by 3 publications

(2 citation statements)

References 63 publications

(84 reference statements)

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“…A goat polyclonal antibody to megalin (1 : 500, SC-16478, Santa Cruz Biotechnology, Inc., Dallas, TX, USA) was incubated for 2 hours at room temperature and a secondary donkey anti-goat antibody (1 : 5000, SC-2020, Santa Cruz Biotechnology, Inc.) for 45 minutes. As previously described [ 29 ], relative megalin expression was calculated as compared to β -actin control (1 : 250, SC-47778, Santa Cruz Biotechnology, Inc.) with ImageJ software (v1.44p, NIH) [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

In Vivo siRNA Delivery and Rebound of Renal LRP2 in Mice

Eadon

Cheng

Hato

et al. 2017

Journal of Drug Delivery

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siRNA stabilized for in vivo applications is filtered and reabsorbed in the renal proximal tubule (PT), reducing mRNA expression transiently. Prior siRNA efforts have successfully prevented upregulation of mRNA in response to injury. We proposed reducing constitutive gene and protein expression of LRP2 (megalin) in order to understand its molecular regulation in mice. Using siRNA targeting mouse LRP2 (siLRP2), reduction of LRP2 mRNA expression was compared to scrambled siRNA (siSCR) in mouse PT cells. Mice received siLRP2 administration optimized for dose, administration site, carrier solution, administration frequency, and administration duration. Kidney cortex was collected upon sacrifice. Renal gene and protein expression were compared by qRT-PCR, immunoblot, and immunohistochemistry (IHC). Compared to siSCR, siLRP2 reduced mRNA expression in PT cells to 16.6% ± 0.6%. In mouse kidney cortex, siLRP2 reduced mRNA expression to 74.8 ± 6.3% 3 h and 70.1 ± 6.3% 6 h after administration. mRNA expression rebounded at 12 h (160.6 ± 11.2%). No megalin renal protein expression reduction was observed by immunoblot or IHC, even after serial twice daily dosing for 3.5 days. Megalin is a constitutively expressed protein. Although LRP2 renal mRNA expression reduction was achieved, siRNA remains a costly and inefficient intervention to reduce in vivo megalin protein expression.

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Section: Methodsmentioning

confidence: 99%

In Vivo siRNA Delivery and Rebound of Renal LRP2 in Mice

Eadon

Cheng

Hato

et al. 2017

Journal of Drug Delivery

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“…A dose dependence was also observed for neurotoxicity [ 75 ]. The aim is to identify not only clinical but also genetic predictors of nephrotoxicity [ 93 ]. However, none of these are currently screened for in clinical practice.…”

Section: Colistin Tdm Benefits and Limits Of Routine Use In Clinical ...mentioning

confidence: 99%

Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review

et al. 2023

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The emerging resistance of Gram-negative bacteria is a growing problem worldwide. Together with the financial cost, limited efficacy, and local unavailability of newer antibiotics or their combinations, it has led to the reintroduction of colistin as a therapeutic alternative. Despite its protracted development and availability on the market, there is now a complex maze of questions surrounding colistin with a more or less straightforward relationship to its safety and efficacy. This review aims to offer a way to navigate this maze. We focus on summarizing the available literature regarding the use of colistin in critically ill patients, particularly on stability, pharmacokinetics, methods for determining plasma concentrations, and therapeutic drug monitoring benefits and limitations. Based on these data, we then highlight the main gaps in the available information and help define directions for future research on this drug. The first gap is the lack of data on the stability of intravenous and nebulization solutions at clinically relevant concentrations and under external conditions corresponding to clinical practice. Furthermore, pharmacokinetic-pharmacodynamic parameters should be validated using standardized dosing, including a loading dose. Based on the pharmacokinetic data obtained, a population model for critically ill patients should be developed. Finally, the interference of colistin with extracorporeal methods should be quantified.

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Unlocking the Potential: PEGylation and Molecular Weight Reduction of Ionenes for Enhanced Antifungal Activity and Biocompatibility

Kurzyna,

Kopiasz,

Paul

et al. 2024

Macromolecular Bioscience

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Numerous synthetic polymers, imitating natural antimicrobial peptides, have demonstrated potent antimicrobial activity, positioning them as potential candidates for new antimicrobial drugs. However, the high activity of these molecules often comes at the cost of elevated toxicity against eukaryotic organisms. In this study, a series of cationic ionenes with varying molecular weights to assess the influence of polymer chain length on ionene activity is investigated. To enhance polymer antimicrobial activity and limit toxicity a PEG side chain is introduced into the repeating unit. The resulting molecules consistently exhibited high activity against three model organisms: E. coli, S. aureus and C. albicans. The incorporation of side PEG chain improves antifungal properties and biocompatibility, regardless of molecular weight. The most important finding of this work is that the reduction of polymer molecular mass led to increased antifungal activity and reduced cytotoxicity against HMF and MRC‐5 cell lines simultaneously. As a result, the best‐performing molecules reported herein displayed minimal inhibitory concentrations (MIC) as low as 2 and 0.0625 µg mL1 for C. albicans and C. tropicalis respectively, demonstrating exceptional selectivity. It is plausible that some of described herein molecules can serve as potential lead candidates for new antifungal drugs.

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Genetic Variants Contributing to Colistin Cytotoxicity: Identification of TGIF1 and HOXD10 Using a Population Genomics Approach

Cited by 3 publications

References 63 publications

In Vivo siRNA Delivery and Rebound of Renal LRP2 in Mice

In Vivo siRNA Delivery and Rebound of Renal LRP2 in Mice

Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review

Unlocking the Potential: PEGylation and Molecular Weight Reduction of Ionenes for Enhanced Antifungal Activity and Biocompatibility

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