中国中西医结合急救杂志2025，Vol.32Issue(5)：561-569,9.DOI:10.3969/j.issn.1008-9691.2025.05.009
蒙药巴特日-7调控SLC7A11/GPX4信号通路抑制铁死亡缓解脓毒症模型大鼠肠黏膜损伤的机制研究
Mechanism of Mongolian medicine Bateri-7 inhibiting ferroptosis via solute carrier family 7 member 11/glutathione peroxidase 4 pathway to alleviate intestinal mucosal injury in septic rat models
摘要
Abstract
Objective To investigate the mechanism by which Mongolian medicine Bateri-7 alleviates intestinal mucosal injury in septic rats by regulating the solute carrier family 7 member 11/glutathione peroxidase 4(SLC7A11/GPX4)signaling pathway to inhibit ferroptosis.Methods A total of 56 male SPF-grade Sprague-Dawley(SD)rats were selected and randomly divided into sham surgery group,model group,high-dose Bateri-7 group(administered Bateri-7 at 630 mg/kg),medium-dose Bateri-7 group(administered Bateri-7 at 315 mg/kg),low-dose Bateri-7 group(administered Bateri-7 at 162.5 mg/kg),Meropenem group(intraperitoneally injected with Meropenem at 105 mg/kg),and nuclear factor-E2-related factor 2(Nrf2)inhibitor ML385 group(intraperitoneally injected 30 mg/kg),with 8 rats in each group.The rat model of sepsis was established by performing a cecal ligation and puncture(CLP).Pathological damage to the ileal tissue of rats was observed using light microscopy staining techniques and electron microscopy;the levels of intestinal mucosal injury markers D-lactic acid,diamine oxidase(DAO),and oxidative stress parameters superoxide dismutase(SOD)activity and malondialdehyde(MDA)content,as well as inflammatory factors tumor necrosis factor-α(TNF-α),interleukins(IL-6,IL-1β),were measured using enzyme-linked immunosorbent assay(ELISA);the expression levels of key proteins in the ferroptosis signaling pathway,including Nrf2,heme oxygenase-1(HO-1),SLC7A11,GPX4,and ferritin heavy chain 1(FTH1),were determined by Western blotting;and the localization distribution of SLC7A11 and GPX4 in the tissue microenvironment was observed using immunohistochemistry.Results Hematoxylin-eosin(HE)staining and electron microscopy revealed that Bateri-7 alleviated inflammatory infiltration and edema of enterocyte tissues,and reduced damage to structures such as villi,glands,mitochondria,and endoplasmic reticulum.Compared with the sham surgery group,the model group showed significant increases in intestinal mucosal injury and inflammatory factors D-lactic acid,DAO,MDA,TNF-α,IL-6,and IL-1β[D-lactic acid(ng/L):1 124.01±83.52 vs.523.11±60.55,DAO(ng/L):123.47±12.96 vs.62.24±7.59,MDA(ng/L):5.64±0.39 vs.2.66±0.52,TNF-α(ng/L):83.20±5.39 vs.22.50±3.14,IL-6(ng/L):161.10±8.28 vs.98.81±6.25,IL-1β(ng/L):105.63±8.80 vs.41.39±6.98],the levels of SOD and the oxidative-stress and ferroptosis-related proteins Nrf2,HO-1,SLC7A11,GPX4 and FTH1 were significantly reduced[SOD(ng/L):72.88±7.14 vs.110.52±7.52,Nrf2 protein expression(gray value):0.37±0.07 vs.1.26±0.07,HO-1 protein expression(gray value):0.31±0.12 vs.1.01±0.09,SLC7A11 protein expression(gray value):0.35±0.11 vs.1.18±0.08,GPX4 protein expression(gray value):0.56±0.12 vs.1.63±0.12,FTH1 protein expression(gray value):0.45±0.18 vs.1.19±0.11,all P<0.05].Compared with the model group,the high-dose Bateri-7 group and meropenem group showed significant decreases in D-lactic acid,DAO,MDA,TNF-α,IL-6,and IL-1β,and significant increases in SOD and oxidative stress and ferroptosis-related proteins Nrf2,HO-1,SLC7A11,GPX4,and FTH1 levels(all P<0.01).The changes in the Baterite-7 groups were most pronounced in the high-dose group[D-lactic acid(ng/L):657.41±92.44 vs.1 124.01±83.52,DAO(ng/L):82.94±9.56 vs.123.47±12.96,MDA(ng/L):3.54±0.72 vs.5.64±0.39,TNF-α(ng/L):40.66±5.94 vs.83.20±5.39,IL-6(ng/L):120.56±11.21 vs.161.10±8.28,IL-1β(ng/L):54.51±9.66 vs.105.63±8.80,SOD(ng/L):102.43±9.81 vs.72.88±7.14,oxidative stress indicators:Nrf2 protein expression(gray value):0.86±0.13 vs.0.37±0.07,HO-1 protein expression(gray value):0.82±0.07 vs.0.31±0.12,ferroptosis-related proteins:SLC7A11 protein expression(gray value):0.83±0.12 vs.0.35±0.11,GPX4 protein expression(gray value):1.35±0.17 vs.0.56±0.12,FTH1 protein expression(gray value):0.90±0.17 vs.0.45±0.18,all P<0.05].The Nrf2 inhibitor ML385 significantly reversed the protective effect of Mongolian medicine Bateri-7 on intestinal mucosal injury in sepsis,with increasing dosage correlating with enhanced efficacy,indicating a dose-response relationship.Conclusions Mongolian medicine Bateri-7 may alleviate intestinal mucosal injury in sepsis model rats by regulating upstream and downstream factors of the SLC7A11/GPX4 signaling pathway to inhibit ferroptosis and reduce oxidative stress via the Nrf2/HO-1 signaling pathway.关键词
铁死亡/脓毒症/肠黏膜损伤/蒙药巴特日-7Key words
Ferroptosis/Sepsis/Intestinal mucosal injury/Mongolian medicine Bateri-7引用本文复制引用
青格勒,巴特金,乌云必力格,包巴根那,吴超群,特日格乐,关文祥,郝浩,隆云..蒙药巴特日-7调控SLC7A11/GPX4信号通路抑制铁死亡缓解脓毒症模型大鼠肠黏膜损伤的机制研究[J].中国中西医结合急救杂志,2025,32(5):561-569,9.基金项目
内蒙古自治区公立医院高水平临床专科发展示范项目(2023SGGZ137) （2023SGGZ137）
内蒙古自治区蒙医药学会科研项目(MXK-162) （MXK-162）
内蒙古医学科学院公立医院科研联合基金科技项目(2024GLLH0137) Demonstration Project for the Development of High-Level Clinical Specialties in Public Hospitals of Inner Mongolia Autonomous Region(2023SGGZ137) （2024GLLH0137）
Research Project of the Mongolian Medicine Society of Inner Mongolia Autonomous Region(MXK-162) （MXK-162）
Joint Fund Scientific Research Project of Public Hospitals of Inner Mongolia Medical Academy(2024GLLH0137) （2024GLLH0137）
