Tian Minmin, Liu Fangfang, Liu Han, Zhang Qiong, Li Lei, Hou Xiangbo, Zhao Jianxin, Li Sheng, Chang Xuhong, Sun Yingbiao
a Department of Toxicology, School of Public Health , Lanzhou University , Lanzhou , China.
b Lanzhou Municipal Center for Disease Control , Lanzhou , China.
Syst Biol Reprod Med. 2018 Aug;64(4):246-259. doi: 10.1080/19396368.2018.1450460. Epub 2018 Apr 3.
Cisplatin (CIS) is widely applied for its antihematological malignancies properties and as antisolid tumors drugs. However, it could cause testicular damage related with oxidative stress and testosterone synthesis disorder. Studies reported that grape seed procyanidins extract (GSPE) could improve CIS induced-testes lesion via scavenging free radicals in animals, although its mechanisms were unclear. Therefore, the purpose of the present study was to explore the antagonistic mechanisms of GSPE on CIS-induced testes lesion. Rats were treated with 10 mg/kg by weight CIS by intraperitoneal injection singly on the 11th day, and different doses of GSPE were administrated via intragastric gavage for 15 days consecutively. The results showed that GSPE improved the pathological changes of testicular tissue, and the decreased concentrations of testosterone in serum induced by CIS. GSPE inhibited CIS-induced oxidative/nitrative stress, as well as increased the mRNA and protein levels of testosterone synthetase in rat testes. In conclusion, the main protection exerted by GSPE on CIS-induced testicular toxicity is related to its effects including suppressing oxidative/nitrative stress and up-regulating expression of testosterone synthetase.
CIS: Cisplatin; GSPE: grape seed procyanidins extract; LH: luteinizing hormone; FSH: follicle-stimulating hormone; STAR: steroidogenic acute regulatory protein; CYP11A1: P450 side chain cleavage enzyme; HSD3B1: 3β-hydroxysteroid dehydrogenase; CYP17A1: 17α-hydroxylase; HSD17B: 17β-hydroxysteroid dehydrogenase; ROS: reactive oxygen species; O2: superoxide anion; HO: hydrogen peroxide; •OH: hydroxyl radicals; SOD: superoxide dismutase; CAT: catalase; GSH-Px: glutathione peroxidase; LPO: lipid peroxidation; 8-OHdG: 8-hydroxy-2-deoxyguanosine; HO-1: heme oxygenase-1; MT-1: metallothionein-1; NO: nitric oxide; ONOO-: peroxynitrite; NOS: nitric oxide synthases; nNOS: neuronal NOS; iNOS: inducible NOS; eNOS: endothelial NOS; MDA: malondialdehyde; GSH: glutathione; T-AOC: total antioxidant capacity; TNOS: total nitric oxide synthases; Lhcgr: luteinizing hormone receptor; Scarb1: lipoprotein-receptor; Cyp19a1: 19α-hydroxylase; ELISA: enzyme linked immunosorbent assay; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; PAS: periodic acid-Schiff; MTs: Metallothioneins; cAMP: cyclic adenosine monophosphate; cDNA: complementary DNA; RIPA: radioimmunoprecipitation buffer; PMSF: phenylmethanesulfonyl fluoride; PVDF: polyvinylidenedifluoride; β-actin: beta-actin.
顺铂（CIS）因其抗血液系统恶性肿瘤特性以及作为抗实体瘤药物而被广泛应用。然而，它可能会导致与氧化应激和睾酮合成紊乱相关的睾丸损伤。研究报道，葡萄籽原花青素提取物（GSPE）可通过清除动物体内自由基来改善顺铂诱导的睾丸损伤，尽管其机制尚不清楚。因此，本研究的目的是探讨GSPE对顺铂诱导的睾丸损伤的拮抗机制。在第11天，大鼠单独腹腔注射10mg/kg体重的顺铂，并连续15天通过灌胃给予不同剂量的GSPE。结果表明，GSPE改善了睾丸组织的病理变化以及顺铂诱导的血清睾酮浓度降低。GSPE抑制了顺铂诱导的氧化/硝化应激，并提高了大鼠睾丸中睾酮合成酶的mRNA和蛋白质水平。总之，GSPE对顺铂诱导的睾丸毒性的主要保护作用与其抑制氧化/硝化应激和上调睾酮合成酶表达的作用有关。
CIS：顺铂；GSPE：葡萄籽原花青素提取物；LH：黄体生成素；FSH：卵泡刺激素；STAR：类固醇生成急性调节蛋白；CYP11A1：P450侧链裂解酶；HSD3B1：3β-羟基类固醇脱氢酶；CYP17A1：17α-羟化酶；HSD17B：17β-羟基类固醇脱氢酶；ROS：活性氧；O2：超氧阴离子；HO：过氧化氢；•OH：羟基自由基；SOD：超氧化物歧化酶；CAT：过氧化氢酶；GSH-Px：谷胱甘肽过氧化物酶；LPO：脂质过氧化；8-OHdG：8-羟基-2-脱氧鸟苷；HO-1：血红素加氧酶-1；MT-1：金属硫蛋白-1；NO：一氧化氮；ONOO-：过氧亚硝酸盐；NOS：一氧化氮合酶；nNOS：神经元型一氧化氮合酶；iNOS：诱导型一氧化氮合酶；eNOS：内皮型一氧化氮合酶；MDA：丙二醛；GSH：谷胱甘肽；T-AOC：总抗氧化能力；TNOS：总一氧化氮合酶；Lhcgr：黄体生成素受体；Scarb1：脂蛋白受体；Cyp19a1：19α-羟化酶；ELISA：酶联免疫吸附测定；RT-qPCR：逆转录定量聚合酶链反应；PAS：过碘酸希夫反应；MTs：金属硫蛋白；cAMP：环磷酸腺苷；cDNA：互补DNA；RIPA：放射免疫沉淀缓冲液；PMSF：苯甲基磺酰氟；PVDF：聚偏二氟乙烯；β-肌动蛋白
