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  • methylguanine dna methyltransferase Overexpression of AR can

    2024-06-06

    Overexpression of AR can lead to sorbitol accumulation, leading to diabetic complications (Ransohoff and Cardona, 2010). Therefore, AR is an important enzyme in the growth and development of organisms. With the aim of inhibiting the activity of AR methylguanine dna methyltransferase in diabetic patients, screening for inhibitors and investigation of the mechanism of inhibition have become a ubiquitous focus of research on AR (Balestri et al., 2017; Kranthi et al., 2016). In vivo, AR is significantly upregulated in diabetic patients, and the clinical manifestations generally include weight gain (Drel et al., 2006; Nigro et al., 2006). In the present study, BmAR was found to be significantly downregulated in q-l compared with 932VR, and the weight of the q-l mutant was also generally lower than that of the wildtype 932VR strain. Downregulation of the expression of BmAR through RNAi also decreased the weight of the silkworms. These results indicated that the expression levels of AR might be positively correlated with the weight of the organism. As an important gene closely related to human diseases, AR has scarcely been studied in Insecta and even Arthropoda in general. Hence, this study might lay the foundation for research on the AR gene in insects. Simultaneously, this study provides new ideas regarding the study of AR inhibitors and may therefore contribute to the treatment of diabetic complications.
    Declaration of interest
    Acknowledgements
    This work was supported by grants from the National Natural Science Foundation of China [grant numbers 31372378, Qiaoling Zhao] and the National Natural Science Foundation of China [grant numbers 31672490, Xingjia Shen]. This work was also supported by the Graduate Student Innovation Program of Jiangsu province [grant numbers KYCX17-1857, Pingyang Wang] and the Graduate Student Innovation Program of Jiangsu University of Science and Technology [grant numbers YCX16B-02, Pingyang Wang]. This work was also supported by the open fund project of Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture [grant numbers KL201704, Zhiyong Qiu].
    Introduction Diabetes mellitus is a chronic metabolic disease characterized by abnormally elevated levels of blood glucose. It is estimated that around 4% of the population worldwide currently suffers from diabetes (Chen, Magliano, & Zimmet, 2012), with soaring rates of type 2 methylguanine dna methyltransferase especially in both developed and developing countries, and the number of diabetes patients being projected to rise to 552million in 2030 (Jain & Saraf, 2010). Long-term secondary complications are the main causes of morbidity and mortality in diabetic patients (Brownlee, 2001). Untreated or ineffectively treated diabetes can lead to microvascular (blindness, nephropathy, and neuropathy) and macrovascular (cardiovascular and stroke) complications (Michael & Fowler, 2008), hyperglycemia being the primary pathogenesis factor (American Diabetes Association, 2010). Although sustained control of hyperglycemia can delay the development of diabetic complications, the increased risk of complications cannot be reduced (Gleissner, Galkina, Nadler, & Ley, 2007; UK Prospective Diabetes Study (UKPDS) Group, 1998). Consequently, the emergence of these debilitating pathologies appears to be unavoidable in the majority of diabetic patients (Brownlee, 2005). This makes the identification of new agents for the treatment of diabetic complications an unmet urgent therapeutic need. Aldose reductase (AR, EC 1.1.1.21) is a member of the aldo-keto reductase superfamily and is present in most human cells. The major physiological function of AR appears to be the degradation of toxic aldehydes originating from lipid peroxidation, such as 4-hydroxy-trans-2-nonenal (HNE) and its glutathione adduct glutathione-HNE (Rittner et al., 1999). However, in diabetes mellitus, this enzyme plays a pivotal role in the polyol pathway, mediating hyperglycemia-induced oxidative stress and consequent tissue and vascular damage through the NADPH-dependent reduction of glucose to sorbitol and consequent modifications of cellular osmolarity and redox status (Brownlee, 2001). A positive correlation between hyperglycemia and AR expression has been observed in many studies (Chang, Snow, LaBarbera, & Petrash, 2015). In recent years, important advances in understanding the physiological and pathological roles of AR demonstrated that this enzyme is involved in cellular inflammatory signaling (Maccari & Ottanà, 2015). Thus, AR has been widely investigated as an enzyme critically involved in the onset and progression of various pathologies associated with diabetes mellitus (Costantino, Rastellia, Vianello, Cignarella, & Barlocco, 1999; Srivastave, Ramana, & Bhatnagar, 2005). In addition, there is a growing interest in the development of novel and effective AR inhibitors (ARIs) for amelioration of the pathologies.