Compound C Protects Against Cisplatin-Induced Nephrotoxicity Through Pleiotropic Effects

Li, Fanghua; Sun, Anbang; Cheng, Genyang; Liu, Dong; Xiao, Jing; Zhao, Zhanzheng; Dong, Zheng

doi:10.3389/fphys.2020.614244

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…The application of JAK2 activator (RO8191) and AMPK inhibitor (Compound C) was conducted as previously reported [ 21 , 22 ]. In brief, the mice were treated with RO8191 2 mg/kg/day for intraperitoneal injection.…”

Section: Methodsmentioning

confidence: 99%

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice

Lin

Wang

et al. 2022

Disease Markers

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Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through activating the AMPK/SIRT1 signalling pathway and inhibiting the JAK2/STAT3 signalling pathway in T2DM mice. However, after the application of RO8191 (JAK2 activator) or Compound C (AMPK inhibitor), the positive improvement of the exercise was evidently suppressed. Taken together, our data indicated that long-term aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice.

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Section: Methodsmentioning

confidence: 99%

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice

Lin

Wang

et al. 2022

Disease Markers

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“…Renal tubular injury was scored by the percentage of injured tubules with loss of brush border, cell lysis, and cast formation: 0, no damage; 1, <25%; 2, 25 to 50%; 3, 50 to 75%; 4, >75% ( 60 ). Cleaved Caspase 3 positive tubular epithelial cells were counted in 10 high power fields (40×) and averaged.…”

Section: Methodsmentioning

confidence: 99%

Selective depletion of a CD64-expressing phagocyte subset mediates protection against toxic kidney injury and failure

Salei

Pakalniškytė

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense. However, there is a paucity of models allowing to selectively manipulate subsets of these cells in specific tissues. The steady-state adult kidney contains four MP subsets with Clec9a-expression history that include the main conventional DC1 (cDC1) and cDC2 subtypes as well as two subsets marked by CD64 but varying levels of F4/80. How each of these MP subsets contributes to the different phases of acute kidney injury and repair is unknown. We created a mouse model with a Cre-inducible lox-STOP-lox-diphtheria toxin receptor cassette under control of the endogenous CD64 locus that allows for diphtheria toxin–mediated depletion of CD64-expressing MPs without affecting cDC1, cDC2, or other leukocytes in the kidney. Combined with specific depletion of cDC1 and cDC2, we revisited the role of MPs in cisplatin-induced kidney injury. We found that the intrinsic potency reported for CD11c+ cells to limit cisplatin toxicity is specifically attributed to CD64+ MPs, while cDC1 and cDC2 were dispensable. Thus, we report a mouse model allowing for selective depletion of a specific subset of renal MPs. Our findings in cisplatin-induced injury underscore the value of dissecting the functions of individual MP subsets in kidney disease, which may enable therapeutic targeting of specific immune components in the absence of general immunosuppression.

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“…The cisplatin-induced acute kidney injury model was generated as described previously (Faubel et al, 2004;Li et al, 2020;Sears and Siskind, 2021). Mice (25 ± 5 g) were randomly divided into three groups: wild type + vehicle (WT-saline), wild type + Cisplatin (WT-Cis), and Faah KO + cisplatin (Faah -/-Cis).…”

Section: Mouse Model Of Cisplatin-induced Akimentioning

confidence: 99%

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

Chen¹,

Wang²,

Raymond³

et al. 2023

Mol Pharmacol

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Cisplatin is a potent first-line therapy for many solid malignancies such as breast, ovarian, lung, testicular and head and neck cancer. However, acute kidney injury (AKI) is a major dose-limiting toxicity in cisplatin therapy, which often hampers the continuation of cisplatin treatment. The endocannabinoid system, consisting of anandamide (AEA) and 2-arachidonoylglycerol and cannabinoid receptors, participates in different kidney diseases. Inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme for the degradation of AEA and AEA-related N-acylethanolamines, elicits antiinflammatory effects; however, little is known about its role in cisplatin nephrotoxicity.The current study tested the hypothesis that genetic deletion of Faah mitigates cisplatininduced AKI. Male wild-type C57BL6 (WT) and Faah −/− mice were administered a single dose of intraperitoneal injection of cisplatin (30 mg/kg) and euthanatized 72 hours later.Faah −/− mice showed a reduction of cisplatin-induced blood urea nitrogen, plasma creatinine levels, kidney injury markers and tubular damage in comparison with WT mice. The renal protection from Faah deletion was associated with enhanced tone of AEA-related N-acylethanolamines (PEA and OEA), attenuated NF-κB/p65 activity, DNA damage markers p53, p21 and decreased expression of the inflammatory cytokine IL-1β as well as infiltration of macrophages and leukocytes in the kidneys. Notably, a selective FAAH inhibitor (PF-04457845) did not interfere with or perturb the antitumor effects of cisplatin in two head and neck squamous cell carcinoma cell lines, HN30 and HN12. Our work highlights that FAAH inactivation prevents cisplatin-induced nephrotoxicity in mice and that targeting FAAH could provide a novel strategy to mitigate cisplatin-induced nephrotoxicity.

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Compound C Protects Against Cisplatin-Induced Nephrotoxicity Through Pleiotropic Effects

Cited by 7 publications

References 40 publications

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice

Selective depletion of a CD64-expressing phagocyte subset mediates protection against toxic kidney injury and failure

Genetic Knockout of Fatty Acid Amide Hydrolase Ameliorates Cisplatin-Induced Nephropathy in Mice

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