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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.

SUBMITTER: Yan XX

PROVIDER: S-EPMC7468365 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Yan Xiao-Xia XX Li Hai-Long HL Zhang Yi-Ting YT Wu Shou-Yan SY Lu Heng-Lei HL Yu Xiao-Lu XL Meng Fan-Guo FG Sun Jian-Hua JH Gong Li-Kun LK

Acta pharmacologica Sinica 20190910 3

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<sup>®</sup> (MS-AOE<sup>®</sup>) is a new recombinant SOD with better resistance to pepsin and trypsin. We referred it ...[more]

PMID: 31506573

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Project description:BackgroundIntestinal mucositis is a common side effect of chemotherapy and radiotherapy. Very few drugs can efficiently ameliorate it. Tertiary butylhydroquinone (TBHQ) is a widely used food preservative with known immunomodulatory activity. Whether it has an effect on intestinal mucositis remains unknown. In this study, we investigated the role and mechanism of action of TBHQ on 5-fluorouracil-induced (5-FU-induced) human intestinal epithelial cell (HIEC) injury and intestinal mucositis in mice.MethodsWe established a cell model of HIEC injury and a mouse model of intestinal mucositis via treatment with 5-FU. Cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release were assessed for the HIECs. Diarrhea, body weight, intestinal length, mucosal damage, and the levels of IL-6, TNF-α, IL-1β, glutathione, reactive oxygen species, and malondialdehyde were determined for the mice. Additionally, we performed immunohistochemical analysis, immunofluorescence, western blotting, quantitative real-time PCR, and ELISA to examine the effects of TBHQ. Finally, HIECs were transfected with an Nrf2 gene silencer to verify its role in ferroptosis. All data were analyzed using one-way analysis of variance or paired t-tests.ResultsTBHQ markedly decreased LDH release and cell death and improved the proliferative ability of 5-FU-treated HIECs. The TBHQ-treated mice showed reduced weight loss, a lower diarrhea score, and longer colons than the 5-FU-treated mice. The in vivo expressions of IL-1β, IL-6, and TNF-α were suppressed by TBHQ treatment. Ferroptosis was shown to be involved in 5-FU-induced intestinal mucositis, and TBHQ markedly hampered its activation. Mechanistically, TBHQ activated Nrf2 effectively and selective Nrf2 knockdown significantly reduced the anti-ferroptotic functions of TBHQ in 5-FU-treated HIECs.ConclusionsTBHQ attenuates ferroptosis in 5-FU-induced intestinal mucositis, making it a potential novel protective agent against intestinal mucositis.

Project description:Intestinal mucositis is a commonly encountered toxic side effect in patients undergoing 5-fluorouracil (5-FU)-based chemotherapy. Numerous studies have shown that probiotics enable improving chemotherapy-induced intestinal mucositis, but the beneficial effects of probiotics differ depending on the strain. Therefore, in the present studies we suggest that S. thermophilus ST4 separated from raw milk may assess mucoprotective activity in 5-FU-induced intestinal mucositis. In our causal-comparative study design, fifteen mice were randomized assigned into three groups (n = 5/each group): control group, 5-FU group and 5-FU+S. thermophilus ST4 group. The control group was orally administrated saline only, and the 5-FU group was followed by intraperitoneal injection of 5-FU for 3 days after 10-day saline administration, and the 5-FU+S. thermophilus ST4 group was intragastrically subjected for S. thermophilus ST4 once per day during the whole experiment, starting from the first day of the experiment, followed by 5-FU intraperitoneal injection for 3 days after 10-day S. thermophilus ST4 pretreatment. Diarrhea score, pro-inflammatory cytokines serum levels, intestinal histopathology and short chain fatty acid were assessed. Here, we demonstrated the beneficial effects of S. thermophilus ST4 derived from raw milk against 5-FU-induced intestinal mucositis, including body weight reduction, appetite loss and diarrhea. Intrinsically, S. thermophilus ST4 effectively maintained epithelium structure in small intestines and colons as well as reduced the intestinal inflammation. Besides, S. thermophilus ST4 significantly increased the expression of acetic acid, reinforcing the muco-protective effects. In conclusion, our results demonstrate that S. thermophilus ST4 supplementation ameliorates 5-FU-induced intestinal mucositis. This suggests probiotic may serve as an alternative therapeutic strategy for the prevention or management of 5-FU-induced mucositis in the future.

Project description:Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.

Dataset Information

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

Publications

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

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