title: Iridoid glycoside from Cornus officinalis ameliorated diabetes mellitus-induced testicular damage in male rats: Involvement of suppression of the AGEs/RAGE/p38 MAPK signaling pathway.
abstract: BACKGROUND
  Cornus officinalis (CO) has been widely used as a traditional Chinese medicine for treating diabetes mellitus (DM) and its complications. Iridoid glycoside from C. officinalis (IGCO) can resist apoptosis, hyperglycemia, oxidation and so on. The aim of this study was to investigate the therapeutic effects of IGCO on DM-induced testicular damage through inhibition of the AGEs/RAGE/p38 MAPK signaling pathway.
  
  
  METHODS
  A DM model of male Wistar rats was induced with streptozotocin injection (30mg/kg, i.p.) and high-fat diet. The DM rats were administrated with IGCO at low and high doses (15 and 30mg/kg, p.o.) for 12 weeks. Testicular damage was evaluated by estimating relative testicular weights, testicular pathohistology, sperm count, live sperm rate, endogenous sex hormone level and activity of testicular marker enzymes. Besides, general diabetic symptoms, renal function, oxidative stress parameters and testicular apoptosis marker were also determined. Finally, the mechanism was explored based on the AGEs/RAGE/p38 MAPK pathway.
  
  
  RESULTS
  IGCO effectively mitigated the general symptoms of DM rats including weight loss, polydipsia, polyphagia, polyuria, elevated blood glucose level and low serum insulin level. Nourishing the kidney evidently, IGCO reduced serum creatinine, urea nitrogen and urine protein excretion, and also markedly protected against DM-induced testicular damage by increasing testis/body weight ratio and live sperm rate, improving the histomorphology of testes, upregulating testosterone, LH, FSH and GnRH levels and preventing the decrease of testicular marker enzymes LDH, ACP and γ-GT. Moreover, IGCO showed considerable anti-oxidative and anti-apoptotic effects, which downregulated the increase of ROS and MDA levels, restored SOD and CAT activities, and decreased spermatogenic cell apoptosis and Bax/Bcl-2 ratio. In the end, the increased AGEs, RAGE and p-p38 MAPK protein levels in DM rats were also reversed by IGCO significantly.
  
  
  CONCLUSIONS
  The kidney tonic IGCO well protected DM rats from testicular damage, which may be related to suppression of the AGEs-RAGE-p38 MAPK pathway.
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Nursing department, Chemistry and Life Science College, Nanjing University Jinling College, Nanjing, Jiangsu 210089, China. Electronic address: 156628573@163.com.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: 15951933091@163.com.
authors.forename: Yunhao
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: ganxiaowd@163.com.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Gan
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: landarykailau@126.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: lvxinggt@163.com.
authors.forename: Xing
authors.initials: X
authors.lastname: Lv
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: 15951933091@163.com.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Shen
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: 562122687@qq.com.
authors.forename: Guoying
authors.initials: G
authors.lastname: Dai
authors.affiliation: Key Laboratory of efficacy and safety evaluation of traditional Chinese medicine in Jiangsu Province, Nanjing 210023, China; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: hqxu309@yeah.net.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D029768:Cornus / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D004365:Drugs, Chinese Herbal; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D057889:Iridoid Glycosides / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D013733:Testicular Diseases / Q000188:drug therapy* / Q000209:etiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593874:Ager protein, rat; D004365:Drugs, Chinese Herbal; D017127:Glycation End Products, Advanced; D057889:Iridoid Glycosides; D010936:Plant Extracts; D000067759:Receptor for Advanced Glycation End Products; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Advanced glycation end-products; Cornus officinalis; Diabetic testicular damage; Iridoid glycoside; P38 MAPK