A new recombinant MS-superoxide dismutase alleviates 5-fluorouracil-induced intestinal mucositis in mice

Abstract

Intestinal mucositis is a common side effect of anticancer regimens that exerts a negative impact on chemotherapy. Superoxide dismutase (SOD) is a potential therapy for mucositis but efficient product is not available because the enzyme is degraded following oral administration or induces an immune reaction after intravascular infusion. Multi-modified Stable Anti-Oxidant Enzymes ® (MS-AOE ® ) is a new recombinant SOD with better resistance to pepsin and trypsin. We referred it as MS-SOD to distinguish from other SODs. In this study we investigated its potential to alleviate 5-FU-induced intestinal injury and the mechanisms. An intestinal mucositis model was established in C57/BL6 mice by 5-day administration of 5-FU (50 mg/kg every day, ip). MS-SOD (800 IU/10 g, ig) was given once daily for 9 days. 5-FU caused severe mucositis with intestinal morphological damage, bodyweight loss and diarrhea; MS-SOD significantly decreased the severity. 5-FU markedly increased reactive oxygen species (ROS) and inflammatory cytokines in the intestine which were ameliorated by MS-SOD. Furthermore, MS-SOD modified intestinal microbes, particularly reduced Verrucomicrobia, compared with the 5-FU group. In Caco2 cells, MS-SOD (250–1000 U/mL) dose-dependently decreased tBHP-induced ROS generation. In RAW264.7 cells, MS-SOD (500 U/mL) had no effect on LPS-induced inflammatory cytokines, but inhibited iNOS expression. These results demonstrate that MS-SOD can scavenge ROS at the initial stage of injury, thus play an indirect role in anti-inflammatory and barrier protein protection. In conclusion, MS-SOD attenuates 5-FU-induced intestinal mucositis by suppressing oxidative stress and inflammation, and influencing microbes. MS-SOD may exert beneficial effect in prevention of intestinal mucositis during chemotherapy in clinic.

Superoxide Dismutase Administration: A Review of Proposed Human Uses

“…The administration of SOD was therefore also tested in a model of 5-fluorouracil-induced intestinal mucositis in mice. The study showed that Multi-modified Stable Anti-Oxidant Enzymes ® (MS-AOE ® ), an rMnSOD obtained from a mutant high-temperature-resistant SOD strain, alleviates the mucositis caused by 5-fluorouracil, primarily in the first 3–5 days [ 172 ].…”

Chemotherapy drugs induce different gut microbiota disorder pattern and NODs/RIP2/NF-κB signaling pathway activation that lead to different degrees of intestinal injury

“…Chemotherapy drugs can induce damage to the jejunum and colon, especially in the jejunum (18, 19). Therefore, we used the jejunum as the main tissue for the subsequent experiment.…”

Evaluating the Mucoprotective Effects of Glycyrrhizic Acid Loaded Polymeric Nanoparticles Against 5-Fluorouracil Induced Intestinal Mucositis in Murine Model via Suppression of Inflammatory Mediators and Oxidative Stress

“…To date, pathogenesis of 5-FU mediated intestinal mucositis is not completely elucidated. However, several underlying elements that are responsible for mucositis damages DNA and cellular and subcellular structures because of overproduction of ROS, uncontrolled in ammation that destroy intestinal homeostasis and natural microbial ora alterations (Yan et al 2020). In fact, ROS excessive production trigger the in ammatory pathways and pro-in ammatory cytokines production (Gelen et al 2018;Yan et al 2020).…”

“…However, several underlying elements that are responsible for mucositis damages DNA and cellular and subcellular structures because of overproduction of ROS, uncontrolled in ammation that destroy intestinal homeostasis and natural microbial ora alterations (Yan et al 2020). In fact, ROS excessive production trigger the in ammatory pathways and pro-in ammatory cytokines production (Gelen et al 2018;Yan et al 2020). Among many others, some basic transcription factors activated by ROS are NF-ĸB and MAPK proteins that increase the production of pro-in ammatory cytokines including TNF-α, IL-6 and IL-1β (Chang et al 2012;Song et al 2013;Zhang et al 2017).…”