Vitexin along with verapamil downregulates efflux pump P-glycoprotein in macrophages and potentiate M1 to M2 switching via TLR4-NF-κB-TNFR2 pathway in lipopolysaccharide treated mice

IF 2.5 4区 医学 Q3 IMMUNOLOGY
Ayantika Kundu, Pratiti Ghosh , Biswadev Bishayi
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引用次数: 0

Abstract

The lipopolysaccharide, a microbial toxin, is one of the major causative agents of sepsis. P-gp expression and its functions are altered during inflammation. LPS has been known to impair the functions of P-gp, an efflux transporter. But the effect of LPS on P-gp expression in murine peritoneal macrophages is poorly understood. Molecular docking studies reveal that vitexin is a potent substrate and verapamil a potent inhibitor of P-gp. In the present experimental study, the curative potential of vitexin as a fruit component and verapamil treated as a control inhibitor of P-gp was examined in a murine LPS sepsis model. The effects of vitexin and verapamil on P-gp expression in macrophages correlating with changes in macrophage polarization and associated functional responses during LPS induced sepsis were studied. Peritoneal macrophages of LPS (10 mg/kg body weight) challenged mice exhibited elevated levels of H2O2, superoxide, and NO in parallel with lower antioxidant activity. LPS treatment increased P-gp expression through increased TLR4/expression. However, LPS challenged mice treated with vitexin (5 mg/kg body weight) + verapamil (5 mg/kg body weight) showed higher anti-oxidant enzyme activity (SOD, CAT and GRx) resulting in reduced oxidative stress. This combination treatment also elevated TNFR2, concomitant with down-regulation of TLR4, NF-κB and P-gp expression in murine peritoneal macrophages, resulting in a switch from M1 to M2 polarisation of macrophages and reduced inflammatory responses. In conclusion, combined vitexin and verapamil treatment could be used as a promising therapy to regulate P-gp expression and protection against LPS mediated sepsis and inflammatory damages.

Abstract Image

Abstract Image

杨荆素联合维拉帕米下调脂多糖处理小鼠巨噬细胞外排泵p糖蛋白,并通过TLR4-NF-κB-TNFR2通路增强M1到M2的转换
脂多糖是一种微生物毒素,是脓毒症的主要病原体之一。P-gp的表达及其功能在炎症过程中发生改变。已知LPS会损害P-gp(一种外排转运体)的功能。但LPS对小鼠腹腔巨噬细胞P-gp表达的影响尚不清楚。分子对接研究表明牡荆素是一种有效的底物,维拉帕米是一种有效的P-gp抑制剂。在本实验研究中,在小鼠LPS脓毒症模型中,研究了作为水果成分的牡荆素和作为P-gp对照抑制剂的维拉帕米的治疗潜力。研究牡荆素和维拉帕米对LPS诱导的脓毒症中巨噬细胞P-gp表达与巨噬细胞极化变化及相关功能反应的影响。LPS (10 mg/kg体重)刺激小鼠腹腔巨噬细胞中H2O2、超氧化物和NO水平升高,同时抗氧化活性降低。LPS处理通过增加TLR4/表达增加P-gp的表达。然而,用牡荆素(5 mg/kg体重)+维拉帕米(5 mg/kg体重)处理的LPS刺激小鼠显示出更高的抗氧化酶活性(SOD, CAT和GRx),导致氧化应激降低。这种联合治疗还升高了TNFR2,同时下调了小鼠腹膜巨噬细胞中TLR4、NF-κB和P-gp的表达,导致巨噬细胞从M1极化转向M2极化,并减少了炎症反应。综上所述,牡荆素联合维拉帕米可以作为一种有前景的治疗方法来调节P-gp的表达,并对LPS介导的脓毒症和炎症损伤起到保护作用。
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来源期刊
Immunobiology
Immunobiology 医学-免疫学
CiteScore
5.00
自引率
3.60%
发文量
108
审稿时长
55 days
期刊介绍: Immunobiology is a peer-reviewed journal that publishes highly innovative research approaches for a wide range of immunological subjects, including • Innate Immunity, • Adaptive Immunity, • Complement Biology, • Macrophage and Dendritic Cell Biology, • Parasite Immunology, • Tumour Immunology, • Clinical Immunology, • Immunogenetics, • Immunotherapy and • Immunopathology of infectious, allergic and autoimmune disease.
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