Gui Zhongxuan, Ye Yingquan, Yuan Mengru, Wang Ting, Wan Xinru, Li Ping, Jiang Haili, Zhang Mei
Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China.
The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, Hefei, People's Republic of China.
Am J Physiol Gastrointest Liver Physiol. 2025 Sep 1;329(3):G443-G456. doi: 10.1152/ajpgi.00348.2024. Epub 2025 Aug 1.
polysaccharides (ATPS) were investigated for their protective effects against 5-fluorouracil (5-FU)-induced intestinal mucositis in intestinal epithelial cell 6 (IEC-6) cells and a murine model, with a focus on the role of β-arrestin1 (ARRB1) in endoplasmic reticulum stress (ERS) suppression. The study evaluated cell viability, apoptosis, inflammatory cytokine secretion (interleukin-1β, interleukin-6, tumor necrosis factor-α), and lactate dehydrogenase (LDH) release in IEC-6 cells, whereas diarrhea severity, body weight loss, intestinal histopathology, and tight junction protein expression were assessed in C57BL/6 mice. Western blot, immunohistochemistry, and transmission electron microscopy were used to investigate the underlying mechanisms of ATPS-mediated ERS inhibition. ATPS significantly improved cell survival and proliferation, reduced inflammatory cytokines and apoptosis, alleviated diarrhea severity, mitigated weight loss, and preserved intestinal barrier integrity by upregulating tight junction protein. Mechanistically, ATPS suppressed ERS activation by reducing glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α subunit (p-eIF2α), and C/EBP homologous protein (CHOP) expression, effects that were significantly attenuated in ARRB1-knockdown IEC-6 cells and mice, indicating that ARRB1 is essential for ATPS-mediated ERS suppression and intestinal protection. These findings suggest that ATPS protects against 5-FU-induced intestinal mucositis by modulating ARRB1 and inhibiting ERS, highlighting its potential as a novel therapeutic strategy for chemotherapy-induced intestinal injury. This study provides new insights into the therapeutic potential of ATPS in alleviating 5-FU-induced intestinal mucositis by modulating ARRB1 and suppressing ERS. The protective effects of ATPS were validated in both IEC-6 cells and a murine model, demonstrating its ability to enhance intestinal barrier integrity, inhibit apoptosis, and reduce inflammation. These findings suggest that ARRB1-mediated ERS suppression is a critical mechanism underlying ATPS-induced intestinal protection, presenting a novel strategy for mitigating chemotherapy-induced gastrointestinal toxicity.
研究了多糖（ATPS）对5-氟尿嘧啶（5-FU）诱导的肠上皮细胞6（IEC-6）细胞和小鼠模型肠道黏膜炎的保护作用，重点关注β-抑制蛋白1（ARRB1）在内质网应激（ERS）抑制中的作用。该研究评估了IEC-6细胞的细胞活力、凋亡、炎性细胞因子分泌（白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α）和乳酸脱氢酶（LDH）释放，而在C57BL/6小鼠中评估了腹泻严重程度、体重减轻、肠道组织病理学和紧密连接蛋白表达。采用蛋白质免疫印迹法、免疫组织化学法和透射电子显微镜法研究ATPS介导的ERS抑制的潜在机制。ATPS通过上调紧密连接蛋白显著提高细胞存活和增殖能力，减少炎性细胞因子和凋亡，减轻腹泻严重程度，缓解体重减轻，并维持肠道屏障完整性。机制上，ATPS通过降低葡萄糖调节蛋白78（GRP78）、磷酸化蛋白激酶R样内质网激酶（p-PERK）、磷酸化真核翻译起始因子2α亚基（p-eIF2α）和C/EBP同源蛋白（CHOP）的表达来抑制ERS激活，在ARRB1基因敲低的IEC-6细胞和小鼠中这些作用显著减弱，表明ARRB1对ATPS介导的ERS抑制和肠道保护至关重要。这些发现表明，ATPS通过调节ARRB1和抑制ERS来预防5-FU诱导的肠道黏膜炎，突出了其作为化疗诱导肠道损伤新治疗策略的潜力。本研究通过调节ARRB1和抑制ERS，为ATPS在减轻5-FU诱导的肠道黏膜炎方面的治疗潜力提供了新见解。ATPS的保护作用在IEC-6细胞和小鼠模型中均得到验证，证明其具有增强肠道屏障完整性、抑制凋亡和减轻炎症的能力。这些发现表明，ARRB介导的ERS抑制是ATPS诱导肠道保护的关键机制，为减轻化疗诱导的胃肠道毒性提供了一种新策略。
