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MRNA-sequencing uncovered the underlying mechanisms of xylazine related liver injury

ABSTRACT: Objective: The present study is aimed to study the liver injury in xylazine poisoning and uncover the underlying mechanism. Method: Forty male SD rats were randomly dived into four groups, control (saline), low dose (10mg/kg xylazine), median dose (20mg/kg xylazine) and high dose (40mg/kg xylazine). And the rats were injected the drug intraperitoneal continuous 28 days, and then collected serum and liver tissues, Elisa, RNA sequencing, histopathology examination, RT-qPCR were performed. Results: Compared to the control group, the body weight of 40mg/kg group was decreased, the level of ALT and AST in serum of 40mg/kg group was increased. Histopathological examination showed fatty degeneration, necrosis and fibrosis of the liver. 192 up-regulated and 277 down-regulated genes were identified through RNA sequencing in the 40mg/kg group and the PPAR signaling pathway ranked first in the KEGG pathway analysis, The common DEG in the 10mg/kg and 40mg/kg (Lox), four common DEGs in the 20mg/kg and 40mg/kg (Srebf1, Nr1dl, Fasn, SCD1), and four genes PCK1, FABP5, ACOX2, CPT2 in the PPAR signaling pathway in the 40mg/kg group were validated through Real-Time PCR Analysis. Conclusion：Long term xylazine injection can cause liver injury and the PAPR signaling pathway play a core role in the process of xylazine related liver injury.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE271044 | GEO | 2025/01/02

REPOSITORIES: GEO

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Project description:In this study, we aim to identify candidate biomarkers which may be useful as surrogate indicators of toxicity for pre-clinical development of panPPAR-agonist drug candidates. Gene expression microarray, histopathology and clinical chemistry data were generated from liver, heart, kidney and skeletal muscles of three groups of mice administered with three different dosages of an experimental pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, PPM-201, for 14 days. The histopathology and clinical chemistry data were compared with the gene expression analysis and candidate biomarker genes were identified. Nine wild type mice (strain: C57BL/6J) were randomly divided into three groups - Group-I, II and III. PPM-201 in the vehicle base was administered daily for 14 days at 6 mg/kg body weight dose rate to each mouse in Group-II and at 20mg/kg body weight dose rate to each mouse in Group-III while the mice in Group-I received only the vehicle base. On 15th day, the mice were sacrificed to harvest blood, heart, skeletal muscle, liver and kidney tissues for clinical chemistry, microarray and histopathology analysis. In the clinical chemistry analysis, alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), creatinine kinase (CK, U/L), blood urea nitrogen (BUN, mmol/L), creatinine (umol/L) and lactate dehydrogenase (LDH, U/L) were measured from the blood of each mouse. Two sections of liver, two sections of kidney, one or two sections of skeletal muscle, and one section of heart were prepared from each mouse, stained with hematoxylin and eosin (H&E), and examined by a veterinary pathologist. RNA was extracted and processed as per the established protocol from heart, skeletal muscle, liver and kidney tissue samples of all the 9 mice for profiling with Affymetrix Mouse Genome 430 2.0 Array and in total 36 chips were prepared. Using various quality control measures, the data was analysed for its quality. As it was found to be good in quality, the data from all the 36 chips were used for further analysis. The results from histopathology and clinical chemistry analysis were compared with the gene expression to determine if the dosages selected for the study were associated with findings in target organs.

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MRNA-sequencing uncovered the underlying mechanisms of xylazine related liver injury

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