Black mulberry fruit extract alleviates streptozotocin-induced diabetic nephropathy in rats: targeting TNF-α inflammatory pathway Tarek Kamal Abouzed a , Kadry M. Sadek b , Emad Waded Ghazy c , Walied Abdo d , Mohmed Atef Kassab e , Salma Hago f , Samia Abdel-Wahab g , Engy A. Mahrous g , Essam Abdel-Sattar g and Doaa H. Assar c a Department of Biochemistry, Faculty of Veterinary Medicine, Kafr-Elsheikh University, Kafr-Elsheikh, b Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, c Department of Clinical Pathology, Faculty of Veterinary Medicine, d Department of Pathology, Faculty of Veterinary Medicine, e Department of Cytology and Histology, Faculty of Veterinary Medicine, Kafr-Elsheikh University, Kafr-Elsheikh, Egypt, f Department of Pharmacognosy, Faculty of Pharmacy, Gezira University, Wad Medani City, Sudan and g Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt Keywords cyanidin glycosides; diabetic nephropathy; Morus nigra fruit extract; oxidative stress; phenolic compounds; proinflammatory cytokines Correspondence Essam Abdel-Sattar, Department of Pharmacognosy, Faculty of Pharmacy, Cairo University , El-Kasr El-Aini St, Cairo 11562, Egypt. E-mail: essam.abdelsattar@pharma.cu.edu.eg Received February 7, 2020 Accepted June 28, 2020 doi: 10.1111/jphp.13338 Abstract Objectives This study was designed to investigate the effect of Morus nigra fruit extract in retarding the progression of diabetic nephropathy in streptozotocin (STZ)-induced diabetic rats. Methods Diabetic male Wistar rats were injected with black mulberry fruit extract (BMFE) at doses of 150 and 300 mg/kg body weight. After 4 weeks, microalbuminuria was estimated in addition to serum concentrations of glucose, insulin, creatinine and albumin. Key findings The study revealed a significant amelioration of all the measured parameters in diabetic animals. In addition, MDA, lipid peroxide levels and cata- lase activity were also improved. The histopathological examination of kidney tis- sues revealed significant improvement of the pathological changes and glomerular sclerosis in diabetic rats treated with BMFE. Treated rats showed downregulation of TNF-α, vascular cell adhesion molecule-1 (VCAM-1) and fibronectin mRNA expression. Conclusion The ameliorative effect of BMFE on diabetic nephropathy is not only through its potent antioxidant and hypoglycaemic effects but also through its downregulation of TNF-α, VCAM-1 and fibronectin mRNA expression in renal tissues of diabetic-treated rats. Therefore, BMFE as dietary supplement could be a promising agent in improving diabetic nephropathy. Introduction Diabetes mellitus (DM) is a metabolic disorder character- ized by decreased antioxidant enzyme activity causing oxidative stress-induced damage to pancreatic beta cells. [1] As a result, insulin secretion is decreased and the subse- quent hyperglycaemia further exacerbates the oxidative stress conditions through the generation of reactive oxygen (ROS) and nitrogen species (RNS). [2] Diabetic nephropathy is considered the most common cause of renal failure among diabetic patients. [3] Growing evidence indicates that pathogenesis of DM is widely related to the activation of the innate immune system and the presence of a low-grade chronic inflammation. [4] It is currently believed that macrophages infiltrate the diabetic kidney in the setting of subclinical chronic inflammation with subsequent produc- tion of proinflammatory cytokines that ultimately results in diabetic kidney injury. [5] The most important inflamma- tory cytokines induced in this setting are TNF-α,, in addi- tion to increased activation of transcription factor NF-κB, which contributes also to the progression of DM. [6] TNF-α may cause direct cytotoxicity to renal cells, inducing direct renal injury, [7] apoptosis and necrotic cell death. [8] It can also produce alterations of intraglomerular blood flow and reduction of glomerular filtration as consequence of the disequilibrium between factors promoting vasoconstriction © 2020 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 72 (2020), pp. 1615–1628 1615 Research Paper Downloaded from https://academic.oup.com/jpp/article/72/11/1615/6132642 by guest on 16 June 2022