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砷诱导的代谢损伤和疾病易感性的代谢组学分析和生化特征分析。

Metabolomics Analysis and Biochemical Profiling of Arsenic-Induced Metabolic Impairment and Disease Susceptibility.

机构信息

Department of Pharmaceutical Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan.

Department of Pharmaceutical Chemistry, Government College University, Faisalabad 38000, Pakistan.

出版信息

Biomolecules. 2023 Sep 20;13(9):1424. doi: 10.3390/biom13091424.

Abstract

Our study aimed to conduct a comprehensive biochemical profiling and metabolomics analysis to investigate the effects of arsenic-induced metabolic disorders, with a specific focus on disruptions in lipid metabolism, amino acid metabolism, and carbohydrate metabolism. Additionally, we sought to assess the therapeutic potential of resveratrol (RSV) as a remedy for arsenic-induced diabetes, using metformin (MF) as a standard drug for comparison. We measured the total arsenic content in mouse serum by employing inductively coupled plasma mass spectrometry (ICP-MS) after administering a 50-ppm solution of sodium arsenate (50 mg/L) in purified water. Our findings revealed a substantial increase in total arsenic content in the exposed group, with a mean value of 166.80 ± 8.52 ppb ( < 0.05). Furthermore, we investigated the impact of arsenic exposure on various biomarkers using enzyme-linked immunosorbent assay (ELISA) methods. Arsenic exposed mice exhibited significant hyperglycemia ( < 0.001) and elevated levels of homeostatic model assessment of insulin resistance (HOMA-IR), hemoglobin A1c (Hb1Ac), Inflammatory biomarkers as well as liver and kidney function biomarkers ( < 0.05). Additionally, the levels of crucial enzymes linked to carbohydrate metabolism, including α-glucosidase, hexokinase, and glucose-6-phosphatase (G6PS), and oxidative stress biomarkers, such as levels of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), were significantly reduced in the arsenic-exposed group compared to the control group ( < 0.05). However, the level of MDA was significantly increased. Molecular analysis of gene expression indicated significant upregulation of key enzymes involved in lipid metabolism, such as carnitine palmitoyl-transferase-I (CPT-I), carnitine palmitoyl-transferase-II (CPT-II), lecithin-cholesterol acyltransferase (LCAT), and others. Additionally, alterations in gene expression related to glucose transporter-2 (GLUT-2), glucose-6-phosphatase (G6PC), and glucokinase (GK), associated with carbohydrate metabolism, were observed. Amino acid analysis revealed significant decreases in nine amino acids in arsenic-exposed mice. Metabolomics analysis identified disruptions in lipid metabolomes, amino acids, and arsenic metabolites, highlighting their involvement in essential metabolic pathways. Histopathological observations revealed significant changes in liver architecture, hepatocyte degeneration, and increased Kupffer cells in the livers of arsenic-exposed mice. In conclusion, these findings enhance our comprehension of the impact of environmental toxins on metabolic health and offer potential avenues for remedies against such disruptions.

摘要

我们的研究旨在进行全面的生化特征分析和代谢组学分析,以研究砷诱导的代谢紊乱的影响,特别是关注脂质代谢、氨基酸代谢和碳水化合物代谢的紊乱。此外,我们还试图评估白藜芦醇(RSV)作为治疗砷诱导糖尿病的潜在疗效,并用二甲双胍(MF)作为对照标准药物。我们通过电感耦合等离子体质谱法(ICP-MS)测量了小鼠血清中的总砷含量,在纯化水中给予 50ppm 的砷酸钠(50mg/L)溶液后进行了测量。我们的研究结果表明,暴露组的总砷含量显著增加,平均值为 166.80±8.52ppb(<0.05)。此外,我们还使用酶联免疫吸附测定(ELISA)方法研究了砷暴露对各种生物标志物的影响。暴露于砷的小鼠表现出显著的高血糖(<0.001)和胰岛素抵抗稳态模型评估(HOMA-IR)、糖化血红蛋白(Hb1Ac)、炎症生物标志物以及肝肾功能生物标志物的升高(<0.05)。此外,与对照组相比,暴露于砷的小鼠的碳水化合物代谢关键酶,包括α-葡萄糖苷酶、己糖激酶和葡萄糖-6-磷酸酶(G6PS)以及氧化应激生物标志物,如谷胱甘肽(GSH)、谷胱甘肽还原酶(GR)、谷胱甘肽过氧化物酶(GPx)、过氧化氢酶和超氧化物歧化酶(SOD)的水平显著降低(<0.05)。然而,丙二醛的水平显著升高。基因表达的分子分析表明,参与脂质代谢的关键酶的表达显著上调,如肉碱棕榈酰转移酶-I(CPT-I)、肉碱棕榈酰转移酶-II(CPT-II)、卵磷脂-胆固醇酰基转移酶(LCAT)等。此外,还观察到与碳水化合物代谢相关的葡萄糖转运蛋白-2(GLUT-2)、葡萄糖-6-磷酸酶(G6PC)和葡萄糖激酶(GK)相关的基因表达的改变。氨基酸分析显示,暴露于砷的小鼠中有 9 种氨基酸含量显著降低。代谢组学分析发现,脂质代谢物、氨基酸和砷代谢物的代谢发生紊乱,这表明它们参与了重要的代谢途径。组织病理学观察显示,暴露于砷的小鼠的肝脏结构发生了显著变化,肝细胞变性,库普弗细胞增多。总之,这些发现增强了我们对环境毒素对代谢健康影响的理解,并为针对这些紊乱的治疗方法提供了潜在的途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f882/10526798/d1b2910e9bf7/biomolecules-13-01424-g001.jpg

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