Proper enterocytic proliferation/differentiation, besides providing adequate adherens junctions (AJ) integrity, are responsible for strengthening of the gut barrier that acts as a first line defense against endotoxemia. However, the preferential role of the underlying PI3K/Akt (PKB) axis in triggering enterocytic proliferation/differentiation signaling and AJ assembly is still obscure in sepsis. Additionally, the potential involvement of dipeptidyl peptidase (DPP)-IV in cholestatic sepsis has not yet been reported. Common bile duct ligation (CBDL) insult was performed in adult male Sprague-Dawley rats except for sham operated animals; three doses of vildagliptin (VLD3, 10 and 30 mg/kg/d; p.o) were administered for 10 consecutive days post CBDL. VLD3/10/30 dose-dependently decreased DPP-IV and elevated GLP-1, IGF-1, PI3K, pS473-Akt (PKB), pS9-GSK-3β, pS133-CREB and cyclin-D1. VLD3/10 reduced fever, portal/aortic endotoxin and IgG, body weight loss as well as ileal NF-κB, TNF-α, MPO, TBARS, subepithelial/pericryptal and submucosal collagen deposition, vimentin immunoreactivity, N-cadherin, Zeb1 and pY654-β-catenin but increased E-cadherin, NPSH and colon/spleen indices — effects that were quite the opposite of VLD30. Accordingly, maintaining proper enterocytic proliferation/differentiation and phosphorylation inputs consequent to adequate DPP-IV inhibition is integral to AJ assembly in cholestatic sepsis; however, perturbed signals by excessive suppression of the enzyme activity induce toxic effects manifested as AJ disassembly and EMT, hence gut leakage and overt endotoxemia.

适当的肠细胞增殖/分化，除了提供足够的粘附连接（AJ）完整性外，还可以增强肠屏障，这是抵抗内毒素血症的一线防御。然而，在脓毒症中，潜在的PI3K / Akt（PKB）轴在触发肠细胞增殖/分化信号和AJ组装中的优先作用仍然不清楚。此外，尚未报道二肽基肽酶（DPP）-IV可能与胆汁淤积性脓毒症有关。除假手术动物外，在成年雄性Sprague-Dawley大鼠中进行胆总管结扎术（CBDL）。在CBDL后连续10天服用三剂维达列汀（VLD3、10和30 mg / kg / d；口服）。VLD3 / 10/30剂量依赖性地降低DPP-IV和升高的GLP-1，IGF-1，PI3K，pS473化Akt（PKB），p S9-GSK-3β，p S133-CREB和细胞周期蛋白D1。VLD3 / 10减少发烧，门静脉/主动脉内毒素和IgG，体重减轻以及回肠NF-κB，TNF-α，MPO，TBARS，上皮下/膜周和粘膜下胶原沉积，波形蛋白免疫反应性，N-钙黏着蛋白，Zeb1和p Y654-β-catenin可增加E-cadherin，NPSH和结肠/脾指数-效果与VLD30相反。因此，在胆汁淤积性败血症中，维持适当的肠细胞增殖/分化和磷酸化输入是适当的DPP-IV抑制所必需的。然而，由于过度抑制酶活性而引起的干扰信号会引起毒性作用，表现为AJ分解和EMT，从而导致肠道泄漏和明显的内毒素血症。