香叶基香叶基丙酮(GGA),一种在亚洲广泛用作抗溃疡药的类异戊二烯化合物,赋予对缺血的保护,缺氧,和氧化应激通过快速增强HSP70的表达。然而,GGA对脓毒症相关肠损伤的影响尚待研究.因此,本研究旨在阐明GGA对脓毒症肠损伤的保护作用和潜在机制.我们的发现表明GGA显著延长了脓毒症小鼠的存活时间,并减轻脂多糖(LPS)诱导的肠通透性和组织损伤的改变。此外,GGA有效抑制LPS诱导的细胞因子释放,减弱活性氧(ROS)和丙二醛的水平,并增强了LPS刺激的小鼠肠组织中与抗氧化剂相关的参数。机械上,GGA显著增加HSP70的表达,促进E3泛素连接酶CHIP在核蛋白-α2(KPNA2)的泛素化和降解中发挥作用,抑制NF-κB的核转位,降低NOX1,NOX2和NOX4的表达。在用LPS处理的IEC-6细胞中,CHIP敲除消除了GGA对细胞因子释放和ROS产生的抑制作用。同时,CHIP的下调逆转了GGA在LPS诱导的NF-κB激活和IEC-6细胞中NOX1,NOX2和NOX4表达中的抑制作用。GGA对减轻肠道损伤的作用,在CHIP敲除小鼠中消除了由LPS引起的炎症和氧化应激。我们的结果表明,GGA对LPS引起的小鼠肠损伤的保护作用依赖于CHIP的激活。促进KPNA2降解,抑制NF-κB转位入核,导致抑制LPS诱导的炎症反应和氧化应激。
Geranylgeranylacetone (GGA), an isoprenoid compound widely utilized as an antiulcer agent in Asia, confers protection against ischemia, anoxia, and oxidative stress by rapidly enhancing the expression of HSP70. Nevertheless, the impact of GGA on sepsis-associated intestinal injury remains unexplored. Thus, this study is crafted to elucidate the protective efficacy and underlying mechanisms of GGA against septic intestinal damage. Our findings revealed that GGA significantly extended the survival duration of septic mice, and mitigated lipopolysaccharide (LPS)-induced alterations in intestinal permeability and tissue damage. Furthermore, GGA effectively suppressed LPS-induced cytokine release, attenuated levels of reactive oxygen species (ROS) and malondialdehyde, and bolstered antioxidant-related parameters within the intestinal tissue of LPS-stimulated mice. Mechanistically, GGA significantly increased HSP70 expression and promoted E3 ubiquitin ligase
CHIP to play the role in ubiquitination and degradation of karyopherin-α2 (KPNA2), resulting in inhibition of nuclear translocation of NF-κB and reduced NOX1, NOX2 and NOX4 expression. The inhibitory action of GGA on cytokine release and ROS generation was abolished by
CHIP knockdown in IEC-6 cells treated with LPS. Simultaneously, the downregulation of
CHIP reversed the suppressive role of GGA in the LPS-induced NF-κB activation and the expression of NOX1, NOX2 and NOX4 in IEC-6 cells. The effects of GGA on mitigating intestinal damage, inflammation and oxidative stress caused by LPS were eliminated in
CHIP knockout mice. Our results demonstrate that the protective effect of GGA against LPS-caused intestinal injury of mice is dependent on
CHIP activation, which promotes KPNA2 degradation and restrains translocation of NF-κB into nucleus, leading to suppressing LPS-induced inflammatory response and oxidative stress.