Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China.
The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Drug Dev Res. 2021 Dec;82(8):1111-1123. doi: 10.1002/ddr.21813. Epub 2021 Mar 17.
CQMUH-011 is a modified adamantane sulfonamide compound, that inhibits macrophage proliferation and possesses anti-inflammatory properties. Here, fresh mouse splenocytes were obtained and stimulated with concanavalin A (ConA, 5 μg/ml) in vitro; and experimental autoimmune hepatitis (AIH) was induced by ConA (20 mg/kg, iv) in vivo, to clarify the protective effects of CQMUH-011 against AIH and its possible mechanisms. Our results demonstrated that CQMUH-011 pretreatment can dose-dependently inhibit the proliferation of splenocytes in vitro. In vivo, CQMUH-011 administration reduced the hepatic histopathological score and the infiltration of lymphocytes in the liver parenchyma; additionally, it downregulated the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and pro-inflammatory cytokines interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 in serum, as well as those of methane dicarboxylic aldehyde and myeloperoxidase in the liver tissues. It also down-regulated the expression of p-NF-κB and related proteins in the liver tissues. Furthermore, CQMUH-011 could maintain the balance of CD3 CD4 /CD3 CD8 and decrease the percentages of CD8 CD69 and CD4 CD25 CD69 T-cells in the splenocytes of ConA-challenged mice. Moreover, we found thatCD4 CD25 CD69 T-cells were significantly correlated with ALT levels, especially CD4 CD25 CD69 T-cells. In conclusion, CQMUH-011 exerts potential protective effects against ConA-induced hepatitis, which may be partially attributed to its inhibition of T cells, especially the suppression of the proliferation of CD4 CD25 CD69 and CD8 CD69 subsets in the spleen. CQMUH-011 also reduced the early apoptosis of lymphocytes in the thymus.
CQMUH-011 是一种改良的金刚烷磺胺化合物，可抑制巨噬细胞增殖并具有抗炎特性。在此，我们从新鲜的小鼠脾细胞中获取并在体外使用伴刀豆球蛋白 A（ConA，5μg/ml）进行刺激；并在体内使用 ConA（20mg/kg，iv）诱导实验性自身免疫性肝炎（AIH），以阐明 CQMUH-011 对 AIH 的保护作用及其可能的机制。我们的结果表明，CQMUH-011 预处理可以剂量依赖性地抑制体外脾细胞的增殖。在体内，CQMUH-011 给药可降低肝组织病理学评分和肝实质中淋巴细胞浸润；此外，它还下调了血清中天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和促炎细胞因子干扰素（IFN）-γ、肿瘤坏死因子（TNF）-α 和白细胞介素（IL）-6 的水平，以及肝组织中的甲烷二羧酸醛和髓过氧化物酶的水平。它还下调了肝组织中 p-NF-κB 和相关蛋白的表达。此外，CQMUH-011 可以维持 CD3 CD4 /CD3 CD8 的平衡，并降低 ConA 攻击小鼠脾细胞中 CD8 CD69 和 CD4 CD25 CD69 T 细胞的百分比。此外，我们发现 CD4 CD25 CD69 T 细胞与 ALT 水平显著相关，尤其是 CD4 CD25 CD69 T 细胞。总之，CQMUH-011 对 ConA 诱导的肝炎具有潜在的保护作用，这可能部分归因于其对 T 细胞的抑制作用，尤其是对脾中 CD4 CD25 CD69 和 CD8 CD69 亚群增殖的抑制作用。CQMUH-011 还减少了胸腺中淋巴细胞的早期凋亡。
