El-Baz Ahmed M, Shata Ahmed, Nouh Nehal A, Jamil Lubna, Hafez Mohamed M, Negm Sally, El-Kott Attalla F, AlShehri Mohammed A, Khalaf Eman M
Department of Microbiology and Immunology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt.
Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
AMB Express. 2024 Aug 2;14(1):89. doi: 10.1186/s13568-024-01731-2.
Therapeutics that interfere with the damage/pathogen-associated molecular patterns (DAMPs/PAMPs) have evolved as promising candidates for hepatic inflammation like that occurring in non-alcoholic fatty liver disease (NAFLD). In the current study, we examined the therapeutic impact of the phosphodiesterase-1 inhibitor vinpocetine (Vinpo), alone or when combined with Lactobacillus, on hepatic abnormalities caused by a 13-week high-fat diet (HFD) and diabetes in rats. The results show that Vinpo (10 and 20 mg/kg/day) dose-dependently curbed HFD-induced elevation of liver injury parameters in serum (ALT, AST) and tissue histopathology. These effects were concordant with Vinpo's potential to ameliorate HFD-induced fibrosis (Histological fibrosis score, hydroxyproline, TGF-β) and oxidative stress (MDA, NOx) alongside restoring the antioxidant-related parameters (GSH, SOD, Nrf-2, HO-1) in the liver. Mechanistically, Vinpo attenuated the hepatocellular release of DAMPs like high mobility group box (HMGB)1 alongside lowering the overactivation of the pattern recognition receptors including, toll-like receptor (TLR)4 and receptor for advanced glycation end-products (RAGE). Consequently, there was less activation of the transcription factor nuclear factor-kappa B that lowered production of the proinflammatory cytokines TNF-α and IL-6 in Vinpo-treated HFD/diabetes rats. Compared to Vinpo treatment alone, Lactobacillus probiotics as adjunctive therapy with Vinpo significantly improved the disease-associated inflammation and oxidative stress injury, as well as the insulin resistance and lipid profile abnormalities via enhancing the restoration of the symbiotic microbiota. In conclusion, combining Vinpo and Lactobacillus probiotics may be a successful approach for limiting NAFLD in humans.
干扰损伤/病原体相关分子模式（DAMPs/PAMPs）的疗法已成为治疗肝脏炎症（如非酒精性脂肪性肝病（NAFLD）中出现的炎症）的有前景的候选方法。在本研究中，我们研究了磷酸二酯酶-1抑制剂长春西汀（Vinpo）单独使用或与乳酸杆菌联合使用时，对大鼠13周高脂饮食（HFD）和糖尿病引起的肝脏异常的治疗效果。结果表明，Vinpo（10和20mg/kg/天）剂量依赖性地抑制了HFD诱导的血清（ALT、AST）肝损伤参数升高和组织病理学变化。这些作用与Vinpo改善HFD诱导的纤维化（组织学纤维化评分、羟脯氨酸、TGF-β）和氧化应激（MDA、NOx）的潜力一致，同时恢复了肝脏中与抗氧化相关的参数（GSH、SOD、Nrf-2、HO-1）。从机制上讲，Vinpo减少了高迁移率族蛋白盒（HMGB）1等DAMPs的肝细胞释放，同时降低了包括Toll样受体（TLR）4和晚期糖基化终产物受体（RAGE）在内的模式识别受体的过度激活。因此，在Vinpo治疗的HFD/糖尿病大鼠中，转录因子核因子-κB的激活减少，从而降低了促炎细胞因子TNF-α和IL-6的产生。与单独使用Vinpo治疗相比，乳酸杆菌益生菌作为Vinpo的辅助治疗，通过增强共生微生物群的恢复，显著改善了疾病相关的炎症和氧化应激损伤，以及胰岛素抵抗和脂质谱异常。总之，联合使用Vinpo和乳酸杆菌益生菌可能是限制人类NAFLD的成功方法。
