General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; College of Pharmacy, Hangzhou Medical College, Hangzhou 310059, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
Shanghai Engineering Research Center of Human Intestinal Microflora Function Development, Shanghai Tenth People's Hospital, Shanghai 200072, China.
Biomater Adv. 2023 Nov;154:213592. doi: 10.1016/j.bioadv.2023.213592. Epub 2023 Aug 22.
Acute liver failure (ALF) is a life-threatening clinical syndrome mostly induced by viral infections or drug abuse. As a novel therapeutic adjuvant or delivery vehicle, plant-derived exosome-like nanovesicles (PELNVs) have been extensively studied in recent years. This study aimed to develop garlic-derived exosome-like nanovesicles (GaELNVs) in order to ameliorate liver injury induced by LPS/D-GalN in mice, inhibit inflammatory eruption and reduce inflammatory cells infiltration. The results showed that treatment with GaELNVs improved liver pathology and reduced the levels of soluble inflammatory mediators IL-6, IL-1β and TNF-α in the serum of ALF mice. GaELNVs reversed the upregulation of Cleaved Caspase-9, Cleaved Caspase-3, p53 and Bax expression and decreased Bcl2 activation caused by D-GalN/LPS, and inhibited NF-κB p65 expression and translocation to the nucleus. Meanwhile, treatment with GaELNVs resulted significant reduction in NLRP3 activation and Caspase-1 maturation, as well as decrease in the release of the inflammatory mediator IL-18. Additionally, an upregulation of the expression of proteins related to energy metabolism and autophagy occurrence including Foxo3a, Sirt1, and LC3-II was detected in the liver. Oral administration of GaELNVs also led to significant alteration in the expression of F4/80 and CD11b in the liver. Furthermore, the detection of chemokines in mouse liver tissue revealed that GaELNVs exhibited minimal reduction in the expression of CCL2, CCL3, CCL5 and CCL8. The decreased expression of CCR2 and CCR5 in the liver suggests that GaELNVs have the ability to decrease the recruitment of monocytes from the circulation to the liver. A reduction in the infiltration of F4/80CD11b monocyte-derived macrophages into the liver was also observed. This study provides novel evidence that GaELNVs can ameliorate inflammatory eruptions and hinder the migration of circulating monocytes to the liver, as well as decrease macrophage infiltration by inhibiting CCR2/CCR5 signaling. Consequently, GaELNVs hold promise as a novel therapeutic agent for clinical management of liver disease.
急性肝衰竭（ALF）是一种危及生命的临床综合征，主要由病毒感染或药物滥用引起。作为一种新型治疗佐剂或递药载体，植物来源的外泌体样纳米囊泡（PELNVs）近年来得到了广泛研究。本研究旨在开发大蒜来源的外泌体样纳米囊泡（GaELNVs），以改善 LPS/D-GalN 诱导的小鼠肝损伤，抑制炎症爆发和减少炎症细胞浸润。结果表明，GaELNVs 治疗可改善肝组织病理学，降低 ALF 小鼠血清中可溶性炎症介质 IL-6、IL-1β和 TNF-α的水平。GaELNVs 逆转了 D-GalN/LPS 引起的 Cleaved Caspase-9、Cleaved Caspase-3、p53 和 Bax 表达的上调，并降低了 Bcl2 的激活，抑制了 NF-κB p65 的表达和向核内的易位。同时，GaELNVs 治疗显著抑制了 NLRP3 的激活和 Caspase-1 的成熟，以及炎症介质 IL-18 的释放。此外，还检测到肝组织中与能量代谢和自噬发生相关的蛋白表达上调，包括 Foxo3a、Sirt1 和 LC3-II。口服 GaELNVs 还导致肝组织中 F4/80 和 CD11b 的表达显著改变。此外，检测小鼠肝组织中的趋化因子发现，GaELNVs 使 CCL2、CCL3、CCL5 和 CCL8 的表达最小化。肝组织中 CCR2 和 CCR5 的表达降低表明，GaELNVs 具有减少单核细胞从循环募集到肝脏的能力。F4/80CD11b 单核细胞衍生巨噬细胞向肝脏的浸润也减少。本研究提供了新的证据表明，GaELNVs 可以改善炎症爆发并抑制循环单核细胞向肝脏的迁移，通过抑制 CCR2/CCR5 信号减少巨噬细胞浸润。因此，GaELNVs 有望成为治疗肝脏疾病的新型治疗剂。
