PDF(Pubmed)
Abstract：
UNASSIGNED: Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH).
UNASSIGNED: Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson\'s trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression.
UNASSIGNED: Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease.
UNASSIGNED: Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.
UNASSIGNED: Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson\'s trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression.
UNASSIGNED: Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease.
UNASSIGNED: Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.
摘要：
■半乳糖凝集素-3是在纤维化肝脏中高度表达的促纤维化β-半乳糖苷结合凝集素,并且与肝纤维化有关。Selvigaltin（以前称为GB1211）是一种新型的口服活性半乳糖凝集素-3小分子抑制剂，对半乳糖凝集素-3（人KD=25nM；兔KD=12nM）具有高亲和力，在兔和人中具有高口服生物利用度。在这项研究中，在代谢相关脂肪性肝炎（MASH）的高脂饮食（HFD）兔模型中研究了selvigaltin的功效。
■将雄性新西兰白兔在标准条件下在温度和湿度受控的房间中以12小时的光照/黑暗周期单独笼养。1周后的常规饮食（RD），兔子被随机分配到不同的组8或12周：RD/载体，RD/selvigaltin,HFD（8周），HFD/媒介物和HFD/selvigaltin(0.3、1.0、5.0或30mg/kgselvigaltin与媒介物/selvigaltinp.o.从第9周或第12周每周5天进行治疗性q.d.肝脏炎症,脂肪变性,气球，纤维化是通过血液代谢标志物来测量的，组织形态学评价[油红O，Giemsa,马森的毛状体,picrosiriusred（PSR）和二次谐波产生（SHG）]，mRNA和蛋白质表达。
■脂肪变性，炎症,气球，和纤维化从RD到HFD/媒介物组均增加。Selvigaltin通过通过免疫组织化学和mRNA分析测得的显着降低肝脏中的半乳糖凝集素-3水平来证明目标参与。Selvigaltin剂量依赖性地减少肝功能的生物标志物（AST，ALT,胆红素），炎症（细胞病灶），和纤维化(PSR，SHG),以及降低几种关键炎症和纤维化生物标志物的mRNA和蛋白质表达(例如，IL6，TGFβ3，SNAI2，胶原蛋白）。1.0或5.0mg/kg的剂量在大多数生物学终点上表现出一致的功效，支持在肝病中研究的当前临床剂量的selvigaltin。
■Selvigaltin在治疗性给药4周后以剂量依赖性方式显著降低MASH的HFD兔模型中的肝脏炎症和纤维化。这些数据支持100mgb.i.d.的人selvigaltin剂量，已显示在肝硬化的临床研究期间减少关键的肝脏生物标志物。
■将雄性新西兰白兔在标准条件下在温度和湿度受控的房间中以12小时的光照/黑暗周期单独笼养。1周后的常规饮食（RD），兔子被随机分配到不同的组8或12周：RD/载体，RD/selvigaltin,HFD（8周），HFD/媒介物和HFD/selvigaltin(0.3、1.0、5.0或30mg/kgselvigaltin与媒介物/selvigaltinp.o.从第9周或第12周每周5天进行治疗性q.d.肝脏炎症,脂肪变性,气球，纤维化是通过血液代谢标志物来测量的，组织形态学评价[油红O，Giemsa,马森的毛状体,picrosiriusred（PSR）和二次谐波产生（SHG）]，mRNA和蛋白质表达。
■脂肪变性，炎症,气球，和纤维化从RD到HFD/媒介物组均增加。Selvigaltin通过通过免疫组织化学和mRNA分析测得的显着降低肝脏中的半乳糖凝集素-3水平来证明目标参与。Selvigaltin剂量依赖性地减少肝功能的生物标志物（AST，ALT,胆红素），炎症（细胞病灶），和纤维化(PSR，SHG),以及降低几种关键炎症和纤维化生物标志物的mRNA和蛋白质表达(例如，IL6，TGFβ3，SNAI2，胶原蛋白）。1.0或5.0mg/kg的剂量在大多数生物学终点上表现出一致的功效，支持在肝病中研究的当前临床剂量的selvigaltin。
■Selvigaltin在治疗性给药4周后以剂量依赖性方式显著降低MASH的HFD兔模型中的肝脏炎症和纤维化。这些数据支持100mgb.i.d.的人selvigaltin剂量，已显示在肝硬化的临床研究期间减少关键的肝脏生物标志物。
