KAN0438757, a novel PFKFB3 inhibitor, prevent the progression of severe acute pancreatitis via the Nrf2/HO-1 pathway in infiltrated macrophage

被引：9

作者：

Ergashev, Akmal ^{[1
,2
,3
]}

Shi, Fengyu ^{[1
,2
,3
]}

Liu, Zhu ^{[1
,2
,3
]}

Pan, Zhenyan ^{[1
,2
,3
]}

Xie, Haonan ^{[1
,2
,3
]}

Kong, Lingming ^{[1
,2
,3
]}

Wu, Lijun ^{[1
,2
,3
]}

Sun, Hongwei ^{[1
,2
]}

Jin, Yuepeng ^{[1
,2
]}

Kong, Hongru ^{[1
,2
]}

Geng, Dandan ^{[5
]}

Ibrohimov, Alisherjon ^{[6
]}

Obeng, Enoch ^{[7
]}

Wang, Yi ^{[4
]}

Ma, Feng ^{[2
,8
,9
]}

Chen, Gang ^{[1
,2
,3
]}

Zhang, Tan ^{[1
,2
,3
]}

机构：

[1] Wenzhou Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Wenzhou 325000, Zhejiang, Peoples R China

[2] Wenzhou Med Univ, Key Lab Diag & Treatment Severe Hepato Pancreat Di, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China

[3] Zhejiang Germany Interdisciplinary Joint Lab Hepat, Wenzhou 325035, Zhejiang, Peoples R China

[4] Wenzhou Med Univ, Sch Publ Hlth & Management, Dept Epidemiol & Biostat, Wenzhou 325035, Zhejiang, Peoples R China

[5] Wenzhou Med Univ, Dept Neurol, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China

[6] Wenzhou Med Univ, Dept Urol, Affiliated Hosp 1, Wenzhou 325035, Zhejiang, Peoples R China

[7] Wenzhou Med Univ, Sch Ophthalmol & Optometry, Sch Biomed Engn, Wenzhou 325035, Zhejiang, Peoples R China

[8] Chinese Acad Med Sci & Peking Union Med Coll, Natl Key Lab Immun & Inflammat, Suzhou 215123, Peoples R China

[9] Chinese Acad Med Sci & Peking Union Med Coll, Suzhou Inst Syst Med, CAMS Key Lab Synthet Biol Regulatory Elements, Suzhou 215123, Peoples R China

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2024年 / 210卷

基金：

中国国家自然科学基金;

关键词：

Acute pancreatitis; KAN0438757; Inflammation; Oxidative stress; Macrophage; HEME OXYGENASE-1 EXPRESSION; NF-KAPPA-B; OXIDATIVE STRESS; CARBON-MONOXIDE; ACINAR-CELLS; ACTIVATION; NRF2; MONOCYTES;

D O I：

10.1016/j.freeradbiomed.2023.11.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Acute pancreatitis (AP) is a non-infectious pancreatic enzyme-induced disorder, a life-threatening inflammatory condition that can cause multi-organ dysfunction, characterized by high morbidity and mortality. Several therapies have been employed to target this disorder; however, few happen to be effectively employable even in the early phase. PFKFB3(6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) is a critical regulator of glycolysis and is upregulated under inflammatory, mitogenic, and hypoxia conditions. Essential information on the targeting of the inflammatory pathway will present the termination of the disorder and recovery. Herein we investigated the protective function of KAN0438757, a potent inhibitor of PFKFB3, and its mechanism of impeding AP induced in mice. KAN0438757 was confirmed to activate the Nrf2/HO-1 inflammatory signaling pathways in response to caerulein induced acute pancreatitis (CAE-AP) and fatty acid ethyl ester induced severe acute pancreatitis (FAEE-SAP). Additionally, KAN0438757 alleviated the inflammatory process in infiltrated macrophage via the Nrf2/HO-1 inflammatory signaling pathway and demonstrated a significant effect on the growth of mice with induced AP. And more importantly, KAN0438757 displayed negligible toxicity in vivo. Taken together our data suggest KAN0438757 directly suppresses the inflammatory role of PFKFB3 and induces a protective role via the Nrf2/HO-1 pathway, which could prove as an excellent therapeutic platform for SAP amelioration.

引用

页码：130 / 145

页数：16

共 61 条

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