Delineation of the molecular mechanisms underlying Colistin-mediated toxicity using metabolomic and transcriptomic analyses

Long, Nguyen Phuoc; Oh, Jung‐Hwa; Park, Se-Myo; Yen, Nguyen Thi Hai; Phat, Nguyen Ky; Cho, Yong‐Soon; Kim, Hyung Min; Yoon, Seokjoo; Shin, Jae‐Gook; Kim, Dong Hyun

doi:10.1016/j.taap.2022.115928

Cited by 8 publications

(6 citation statements)

References 51 publications

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“…So far, most of the in vivo studies have used significantly high CMS doses to invoke the drug’s toxicity. For instance, the most recent experiment by Nguyen et al induced in vivo CMS toxicity by administering 25 mg/kg and 50 mg/kg ( Long et al, 2022 ) at low and high doses, respectively, which are 10-fold higher than the recommended human dose (2.5–5 mg/kg/day). The high-dosing approaches provide ample information on biochemical alterations occurring in extremely toxic conditions, offering clear evidence of the triggered pathways leading to the observed clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo studies of CMS nephrotoxicity have shown histological abnormalities, tubular dilation and cell necrosis, and epithelial cell vacuolation as well ( Gai et al, 2019 ). Although CMS is primarily associated with kidney toxicity, there is some evidence to suggest that it may also have an effect on the liver ( Long et al, 2022 ). It is important to note that the risk of toxicities may vary depending on the dose, duration of treatment, and individual patient factors.…”

Section: Introductionmentioning

confidence: 99%

“…Until now, one metabolomics study has been conducted for the characterization of urinary metabolites as biomarkers of colistin-induced nephrotoxicity in rats ( Jeong et al, 2016 ). Furthermore, Long et al (2022) have studied the alteration of kidney and liver metabolome after the administration of a high CMS dose.…”

Section: Introductionmentioning

confidence: 99%

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Metabolomics highlights biochemical perturbations occurring in the kidney and liver of mice administered a human dose of colistin

Barla,

Dagla,

Daskalopoulou

et al. 2024

Front. Mol. Biosci.

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Introduction: Colistin (CMS) is used for the curation of infections caused by multidrug-resistant bacteria. CMS is constrained by toxicity, particularly in kidney and neuronal cells. The recommended human doses are 2.5–5 mg/kg/day, and the toxicity is linked to higher doses. So far, the in vivo toxicity studies have used doses even 10-fold higher than human doses. It is essential to investigate the impact of metabolic response of doses, that are comparable to human doses, to identify biomarkers of latent toxicity. The innovation of the current study is the in vivo stimulation of CMS's impact using a range of CMS doses that have never been investigated before, i.e., 1 and 1.5 mg/kg. The 1 and 1.5 mg/kg, administered in mice, correspond to the therapeutic and toxic human doses, based on previous expertise of our team, regarding the human exposure. The study mainly focused on the biochemical impact of CMS on the metabolome, and on the alterations provoked by 50%-fold of dose increase. The main objectives were i) the comprehension of the biochemical changes resulting after CMS administration and ii) from its dose increase; and iii) the determination of dose-related metabolites that could be considered as toxicity monitoring biomarkers.Methods: The in vivo experiment employed two doses of CMS versus a control group treated with normal saline, and samples of plasma, kidney, and liver were analysed with a UPLC-MS-based metabolomics protocol. Both univariate and multivariate statistical approaches (PCA, OPLS-DA, PLS regression, ROC) and pathway analysis were combined for the data interpretation.Results: The results pointed out six dose-responding metabolites (PAA, DA4S, 2,8-DHA, etc.), dysregulation of renal dopamine, and extended perturbations in renal purine metabolism. Also, the study determined altered levels of liver suberylglycine, a metabolite linked to hepatic steatosis. One of the most intriguing findings was the detection of elevated levels of renal xanthine and uric acid, that act as AChE activators, leading to the rapid degradation of acetylcholine. This evidence provides a naïve hypothesis, for the potential association between the CMS induced nephrotoxicity and CMS induced 39 neurotoxicity, that should be further investigated.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolomics highlights biochemical perturbations occurring in the kidney and liver of mice administered a human dose of colistin

Barla,

Dagla,

Daskalopoulou

et al. 2024

Front. Mol. Biosci.

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“…Overall, the recruitment of AMPK in sepsis plays a crucial role in maintaining cellular energy homeostasis and promoting cell survival in the face of metabolic stress. The impact of colistin on sepsis may be linked to a reduction in AMPK activity, which has been found to result in the abnormal buildup of autophagy-related proteins and impaired mitophagy, thus bridging cellular energy sensing with autophagy and mitophagy [ 28 , 31 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin D1 is a key regulator of the G1-S transition in the cell cycle, and a decrease in cyclin D1 levels may contribute to impaired muscle regeneration and repair. On the other hand, both colistin and sepsis itself have been shown to lead to G1 arrest, as cells attempt to minimize energy consumption and protect themselves from dying [ 32 , 34 , 36 ]. The observation that vasoconstriction elevates the effects of colistin on cyclin D1 levels suggests that vasoconstriction may decrease the skeletal muscle bioavailability or potency of colistin.…”

Section: Discussionmentioning

confidence: 99%

Critical-Illness: Combined Effects of Colistin and Vasoactive Drugs: A Pilot Study

Stamatiou,

Vasilaki,

Tzini

et al. 2023

Antibiotics

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Colistin is often used as a last resort for treating multidrug-resistant infections, particularly in critically ill patients in intensive care units. Nonetheless, its side effects, including myopathy, require careful monitoring. Vasoconstrictive drugs are also used in intensive care to increase blood pressure and improve blood flow to vital organs, which can be compromised in critically ill patients. The exact mechanism of colistin-induced muscle toxicity is of significant interest due to its potential intensive-care clinical implications. Colistin alone or in combination with vasoconstrictive agents was administrated in non-septic and LPS-induced septic animals for 10 days. Histopathological evaluation of the gastrocnemius muscle and dot-blot protein tissue analysis were performed. Increased intramuscular area, de-organization of the muscle fibers and signs of myopathy were observed in colistin-treated animals. This effect was ameliorated in the presence of vasoconstrictive drugs. Administration of colistin to septic animals resulted in a decrease of AMPK and cyclin-D1 levels, while it had no effect on caspase 3 levels. Vasoconstrictive drugs’ administration reversed the effects of colistin on AMPK and cyclin D1 levels. Colistin’s effects on muscle depend on septic state and vasoconstriction presence, highlighting the need to consider these factors when administering it in critically ill patients.

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Protective effects of naringin on colistin‐induced damage in rat testicular tissue: Modulating the levels of Nrf‐2/HO‐1, AKT‐2/FOXO1A, Bax/Bcl2/Caspase‐3, and Beclin‐1/LC3A/LC3B signaling pathways

Kankılıç,

Şimşek,

Akaras

et al. 2024

J Biochem & Molecular Tox

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Antimicrobial agent resistance has become a growing health issue across the world. Colistin (COL) is one of the drugs used in the treatment of multidrug‐resistant bacteria resulting in toxic effects. Naringin (NRG), a natural flavonoid, has come to the fore as its antioxidant, anti‐inflammatory, and antiapoptotic activities. The aim of the present study was to determine whether NRG has protective effects on COL‐induced toxicity in testicular tissue. Thirty‐five male Spraque rats were randomly divided into five groups (n = 7 per group): Control, COL, NRG, COL + NRG 50, COL + NRG 100. COL (15 mg/kg b.w., i.p., once per/day), and NRG (50 or 100 mg/kg, oral, b.w./once per/day) were administered for 7 days. The parameters of oxidative stress, inflammation, apoptosis, and autophagic damage were evaluated by using biochemical, molecular, western blot, and histological methods in testicular issues. NRG treatment reversed the increased malondialdehyde level and reduced antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione) levels due to COL administration (p < 0.001), and oxidative stress damage was mitigated. Nuclear factor erythroid 2‐related factor‐2 pathway, one of the antioxidant defence systems, was stimulated by NRG (p < 0.001). NRG treatment reduced the levels of markers for the pathways of apoptotic (p < 0.001) and autophagic (p < 0.001) damages induced by COL. Sperm viability and the live/dead ratio were reduced by COL but enhanced by NRG treatment. Testicular tissue integrity was damaged by COL but showed a tendency to improve by NRG. In conclusion, COL exhibited toxic effect on testicular tissue by elevating the levels of oxidative stress, apoptosis, autophagy, inflammation, and tissue damage. NRG demonstrated a protective effect by alleviating toxic damage.

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Delineation of the molecular mechanisms underlying Colistin-mediated toxicity using metabolomic and transcriptomic analyses

Cited by 8 publications

References 51 publications

Metabolomics highlights biochemical perturbations occurring in the kidney and liver of mice administered a human dose of colistin

Metabolomics highlights biochemical perturbations occurring in the kidney and liver of mice administered a human dose of colistin

Critical-Illness: Combined Effects of Colistin and Vasoactive Drugs: A Pilot Study

Protective effects of naringin on colistin‐induced damage in rat testicular tissue: Modulating the levels of Nrf‐2/HO‐1, AKT‐2/FOXO1A, Bax/Bcl2/Caspase‐3, and Beclin‐1/LC3A/LC3B signaling pathways

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