Intestinal Mucositis In Mice Research Articles

Valproic acid alleviates total-body irradiation-induced small intestinal mucositis in mice

Purpose Gastrointestinal (GI) injury is one of the serious problems of total-body irradiation (TBI). However, no fundamental treatment for TBI and other radiation-induced GI injury has yet been established. Valproic acid (VPA) administration reduces mortality in mice subjected to total-body irradiation (TBI) with X-rays. This study aimed to evaluate the effects of VPA on GI injury induced by TBI in mice. Materials and methods Mice were subjected to TBI with X-rays to induce GI injury. Changes in survival and weight were observed after VPA administration. The small intestine was then sampled at 0, 1, 3, 7, and 10 d after irradiation for histological and immunohistological evaluation and measurement of myeloperoxidase (MPO) activity and inflammatory cytokine levels (IL-1β). Results VPA (200 and 600 mg/kg) increased survival rate and reduced weight loss in model mice. IL-1β expression 1 d after irradiation was significantly lower in the VPA group than that in the vehicle group. Furthermore, the increase in MPO activity at 3 and 7 d after irradiation was significantly suppressed by VPA administration. Histological examination (hematoxylin and eosin staining) revealed that 600 mg/kg VPA inhibited inflammatory cell infiltration. Immunostaining for the proliferating cell nuclear antigen involved in cell proliferation showed that VPA suppressed the irradiation-induced decrease in cell proliferative capacity. Conclusions Treatment with VPA in mice with GI injury caused by TBI suppressed inflammatory responses in small intestinal mucosal cells. These results suggest that VPA may be a useful therapeutic agent against TBI-induced small intestinal mucositis.

A polyphenol-rich açaí seed extract protects against 5-fluorouracil-induced intestinal mucositis in mice through the TLR-4/MyD88/PI3K/mTOR/NF-κBp65 signaling pathway

Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1β; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.

Alpinia katsumadai Hayata Volatile Oil Is Effective in Treating 5-Fluorouracil-Induced Mucositis by Regulating Gut Microbiota and Modulating the GC/GR Pathway and the mPGES-1/PGE2/EP4 Pathways.

This study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.

Synergistic synbiotic containing fructooligosaccharides and Lactobacillus delbrueckii CIDCA 133 alleviates chemotherapy-induced intestinal mucositis in mice.

Intestinal mucositis is a commonly reported side effect in oncology patients undergoing chemotherapy and radiotherapy. Probiotics, prebiotics, and synbiotics have been investigated as alternative therapeutic approaches against intestinal mucositis due to their well-known anti-inflammatory properties and health benefits to the host. Previous studies showed that the potential probiotic Lactobacillus delbrueckii CIDCA 133 and the prebiotic Fructooligosaccharides (FOS) alleviated the 5-Fluorouracil (5-FU) chemotherapy-induced intestinal mucosa damage. Based on these previous beneficial effects, this work evaluated the anti-inflammatory property of the synbiotic formulation containing L. delbrueckii CIDCA 133 and FOS in mice intestinal mucosa inflammation induced by 5-FU. This work showed that the synbiotic formulation was able to modulate inflammatory parameters, including reduction of cellular inflammatory infiltration, gene expression downregulation of Tlr2, Nfkb1, and Tnf, and upregulation of the immunoregulatory Il10 cytokine, thus protecting the intestinal mucosa from epithelial damage caused by the 5-FU. The synbiotic also improved the epithelial barrier function by upregulating mRNA transcript levels of the short chain fatty acid (SCFA)-associated GPR43 receptor and the occludin tight junction protein, with the subsequent reduction of paracellular intestinal permeability. The data obtained showed that this synbiotic formulation could be a promising adjuvant treatment to be explored against inflammatory damage caused by 5-FU chemotherapy.

Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis.

5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 μmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.

Elucidation of improving effects of a traditional Japanese herbal formula, hochuekkito, comprising Atractylodis rhizoma, on T‐cell‐mediated intestinal mucositis in mice

AbstractAimHochuekkito has been used for gastrointestinal immune depression. Among its 10 herbal components, Atractylodis rhizoma (AtR) and Atractylodis lanceae rhizoma (ALR), and also Hedysari radix (HR) and Astragali radix (AR), can be interchanged based on the patient's symptoms. However, the difference between these formulas for improving gastrointestinal immune depression is not clear. The aim of this study was to compare the effect of AtR‐ and ALR‐hochuekkkito on a T‐cell‐mediated systemic and small intestinal mucosal inflammation model. We also analyzed the active ingredients and mechanism of action of AtR‐hochuekkito on the antiapoptotic effect in the Fas/FasL‐mediated signaling cascade on intestinal epithelial cells.MethodsThe effects of hochuekkito, lipophilic ingredients, and oligosaccharides on the systemic and small intestinal mucosal inflammation induced by anti‐CD3 antibody were analyzed. The effect of the AtR formula on mRNA expression of molecules related to the apoptotic signaling cascade was analyzed.ResultsAtR‐hochuekkito improved intestinal mucosal inflammation even if HR and AR were interchanged. Meanwhile, only the ALR formula suppressed systemic inflammation, whereas the AtR formula failed to improve it even if HR was replaced with AR. AtR formula administration increased gene mRNA expression of antiapoptotic regulatory adapter molecules in the small intestine of anti‐CD3 administered mice. The lipophilic ingredients in the AtR formula improved the effect on the small intestinal mucosal inflammation; liquiritin was an active ingredient. The intermediate‐size inulo‐oligosaccharides suppressed the recruitment of cytotoxic CD8 lymphocytes in the small intestine.ConclusionAtR‐hochuekkito is suitable for the treatment of small intestinal mucosal inflammation induced by spontaneous activation of T lymphocytes.

Therapeutic effects of a lipid transfer protein isolated from Morinda citrifolia L. (noni) seeds on irinotecan-induced intestinal mucositis in mice.

This work aimed to evaluate the activity of a lipid transfer protein isolated from Morinda citrifolia L. seeds, McLTP1, on the development of intestinal mucositis following irinotecan administration. McLTP1 (0.5, 2, and 8 mg/kg, i.v.) was injected into mice 1h before irinotecan administration (75 mg/kg, i.p.; 4 days), and then for additional 6 days. Seven days after the first dose of irinotecan, diarrhea was assessed, and the intestine was removed for histological evaluation, assessment of intestinal over-contractility, measurement of myeloperoxidase (MPO), proinflammatory cytokines and chemokine (IL-1, IL-6, and KC levels - a murine homolog of human IL-8 chemokine), analysis of cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), and nitric oxide synthase (iNOS) expression. At the two highest doses, McLTP1 administration decreased mortality and diarrhea. McLTP1 (8 mg/kg, i.v.) significantly prevented irinotecan-induced intestinal damage and led to a reduction in over-contractility of the intestinal muscle (p < 0.05). Moreover, McLTP1 decreased the MPO, IL-1β, IL-6, and KC levels by 74.7%, 42%, 92.9%, and 95.9%, respectively. Also, the expression of COX-2, NF-κB, and iNOS was reduced. Our study provides a potential new therapeutic for preventing irinotecan-induced mucositis, improved clinical parameters, and reduced inflammation.

Lactobacillus salivarius CPU-01 Ameliorates Temozolomide-Induced Intestinal Mucositis by Modulating Gut Microbiota, Maintaining Intestinal Barrier, and Blocking Pro-inflammatory Cytokines.

Chemotherapy-induced intestinal mucositis is one of the major toxic side effects in the treatment of cancer patients. The purpose of this study is to screen lactic acid bacteria which could alleviate intestinal inflammation and damage induced by chemotherapeutic agents and explore the possible underlying mechanisms. Lactobacillus salivarius CPU-01 was selected from traditional Chinese fermented foods due to its protective effects on the toxicity of temozolomide in Caenorhabditis elegans. Eighteen ICR mice were randomly divided into 3 groups including control group, temozolomide-induced intestinal mucositis group, and temozolomide + L. salivarius CPU-01 group, and were used to investigate the effect of L. salivarius CPU-01 on chemotherapy-induced intestinal mucositis. It has been demonstrated that the administration of L. salivarius CPU-01 can prevent colon shortening and alleviate colon tissue damage caused by temozolomide-induced intestinal mucositis in mice. L. salivarius CPU-01 relieved the intestinal microbiota disorders caused by temozolomide and contributed to the growth of beneficial bacteria, such as Lactobacillus, Clostridia UCG - 014_norank, and Akkermansia. In vivo experiments also indicated that L. salivarius CPU-01 can suppress the level of temozolomide-induced pro-inflammatory cytokines in serum and mRNA expression in the small intestine tissues. It was also found that L. salivarius CPU-01 significantly increased the expressions of intestinal tight junction (TJ) proteins, ZO-1, and Occludin proteins in mice treated with temozolomide. These findings suggest that L. salivarius CPU-01 can ameliorate temozolomide-induced intestinal mucositis by modulating gut microbiota, blocking pro-inflammatory cytokines, and repairing the intestinal barrier. These findings suggest probiotics may serve as a potential alternative therapeutic strategy for the prevention of chemotherapy-induced intestinal mucositis in the future.

Taxifolin Alleviates DSS-Induced Ulcerative Colitis by Acting on Gut Microbiome to Produce Butyric Acid.

Taxifolin is a bioflavonoid which has been used to treat Inflammatory Bowel Disease. However, taxifolin on DSS-induced colitis and gut health is still unclear. Here, we studied the effect of taxifolin on DSS-induced intestinal mucositis in mice. We measured the degree of intestinal mucosal injury and inflammatory response in DSS treated mice with or without taxifolin administration and studied the changes of fecal metabolites and intestinal microflora using 16S rRNA. The mechanism was further explored by fecal microbiota transplantation. The results showed that the weight loss and diarrhea score of the mice treated with taxifolin decreased in DSS-induced mice and longer colon length was displayed after taxifolin supplementation. Meanwhile, the expression of GPR41 and GPR43 in the colon was significantly increased by taxifolin treatment. Moreover, the expression of TNF-α, IL-1β, and IL-6 in colon tissue was inhibited by taxifolin treatment. The fecal metabolism pattern changed significantly after DSS treatment, which was reversed by taxifolin treatment. Importantly, taxifolin significantly increased the levels of butyric acid and isobutyric acid in the feces of DSS-treated mice. In terms of gut flora, taxifolin reversed the changes of Akkermansia, and further decreased uncultured_bacterium_f_Muribaculaceae. Fecal transplantation from taxifolin-treated mice showed a lower diarrhea score, reduced inflammatory response in the colon, and reduced intestinal mucosal damage, which may be related to the increased level of butyric acid in fecal metabolites. In conclusion, this study provides evidence that taxifolin can ameliorate DSS-induced colitis by altering gut microbiota to increase the production of SCFAs.

Paraprobiotic Enterococcus faecalis EC-12 prevents the development of irinotecan-induced intestinal mucositis in mice

AimsThis study tested the protective effect of purified paraprobiotic Enterococcus faecalis (EC-12) and an E. faecalis-based formulation (Med LanS) on irinotecan-induced intestinal mucositis murine model. Main methodsC57BL/6 male mice received saline, irinotecan (75 mg/Kg, i.p.), EC-12 (0.3, 1, or 3 × 107 CFU/Kg, p.o.) + irinotecan or Med Lan-S (3 × 107 CFU/Kg, p.o.) + irinotecan. Body mass variation was assessed daily, and blood samples were collected for evaluating bacteremia and leukocyte count. The ileum was harvested for myeloperoxidase assay, histopathology, quantitative PCR, and immunofluorescence for macrophages (F4/80), TLR4, and IL-18 binding protein (IL-18BP). Key findingsThe best therapeutic strategy was EC-12 administration at 3 × 107 CFU/Kg, starting 1 week before irinotecan. EC-12 and Med Lan-S did not prevent the irinotecan-induced body mass loss or leukopenia but attenuated the neutrophil infiltration in the intestine and increased the villus/crypt ratio (P < 0.05). Additionally, EC-12 and Med Lan-S reduced the mRNA expression of Cldn-2, Ocln, and Tlr4 versus the irinotecan group (P < 0.05). Irinotecan also augmented the expression of Il-18, IL-18BP, the immunofluorescence of F4/80, and TLR4, while only EC-12 prevented the expression of all these markers. Remarkably, EC-12 and Med Lan inhibited the irinotecan-induced bacterial translocation to the blood. SignificanceParaprobiotic E. faecalis EC-12 prevents the development of intestinal mucositis by downregulating the inflammatory response. Med Lan-S also protects from mucositis. Possibly, the complexity of the formulation accounts for an innate immune-driven protective mechanism.

Main components of ethyl acetate extract of Chimonanthus salicifolius and its effects on intestinal mucositis in mice induced by 5-fluorouracil

This study aimed to analyze the main components of ethyl acetate extract of Chimonanthus salicifolius (EAECS) and investigate its effect on intestinal mucositis in mice induced by 5-fluorouracil. EAECS was prepared, and its main components were analyzed. Fifty mice were randomly divided into control, model and 3, 6 and 9 g/kg EAECS groups. The latter three groups were intragastrically administrated with 3, 6 and 9 g/kg EAECS for 7 days, respectively. The intestinal mucositis model was established in latter four groups from the 1st to 7th day of administration. Results showed that, the main components in EAECS were rutin, scopolamine, isofraxidin, scoparone, quercetin and kaempferol. After administration, compared with model group, in 9 g/kg EAECS group the body weight was increased; the serum tumor necrosis factor α (TNF-α) and interleukin 6 levels were decreased, and the interleukin 10 level was increased; the intestinal tissue superoxide dismutase level was increased, and the malondialdehyde and myeloperoxidase levels wer decreased; the liver tissue TNF-α level was significantly decreased (all P < 0.05). In conclusion, EAECS has rich flavonoids and coumarins. It can alleviate the intestinal mucositis in mice induced by 5-FU. The mechanism may be related to the anti-inflammatory and antioxidant effects.

Alleviative effect of glutamate on 5-fluorouracil-induced intestinal mucositis in mice

Alleviative effect of glutamate on 5-fluorouracil-induced intestinal mucositis in mice

Protective effect of polysaccharides isolated from the seeds of Cuscuta chinensis Lam. on 5-fluorouracil-induced intestinal mucositis in mice.

ABSTRACTPurpose:To evaluate the protective effect of Cuscuta chinensis Lam. polysaccharides (PCCL) on 5-fluorouracil-(5-FU)-induced intestinal mucositis (IM) in mice.Methods:PCCL was orally administered at a dose of 20 mg·kg–1 for 7 days and its protective effect on 5-FU-induced IM (5-FU, 50 mg·kg–1 for 5 days) was evaluated by monitoring changes in body weight, degree of diarrhea, levels of tissue inflammatory factors (tumor necrosis factor α, interleukin 6, and interleukin 1β levels), apoptosis rates, and the expression levels of caspase-3, Bax and Bcl-2.Results:The severity of mucosal injury (as reflected by body weight changes, degree of diarrhea, height of villi, and damage to crypts) was significantly attenuated by PCCL administration. PCCL also reduced the levels of tissue inflammatory factors, the apoptosis rate, and the expression of caspase-3 and Bax, and increased Bcl-2 expression.Conclusions:PCCL administration may be significantly protective against 5-FU-induced IM by inhibiting apoptosis and regulating the abnormal inflammation associated with it.

Evaluating the mucoprotective effects of glycyrrhizic acid-loaded polymeric nanoparticles in a murine model of 5-fluorouracil-induced intestinal mucositis via suppression of inflammatory mediators and oxidative stress.

5-Fluorouracil (5-FU), a chemotherapeutic drug, has severe deteriorating effects on the intestine, leading to mucositis. Glycyrrhizic acid is a compound derived from a common herbal plant Glycyrrhiza glabra, with mucoprotective, antioxidant and anti-inflammatory actions, however, associated with poor pharmacokinetics. Owing to the remarkable therapeutic action of glycyrrhizic acid-loaded polymeric nanocarriers in inflammatory bowel disease, we explored their activity against 5-FU-induced intestinal mucositis in mice. Polymeric nanocarriers have proven to be efficient drug delivery vehicles for the long-term treatment of inflammatory diseases, but have not yet been explored for 5-FU-induced mucositis. Therefore, this study aimed to produce glycyrrhizic acid-loaded polylactic-co-glycolic acid (GA-PLGA) nanoparticles to evaluate their protective and therapeutic effects in a 5-FU-induced mucositis model. GA-PLGA nanoparticles were prepared using a modified double emulsion method, physicochemically characterized, and tested for in vitro drug release. Thereafter, mucositis was induced by 5-FU (50mg/kg; IP) administration to the mice for the first 3 days (day 0, 1, 2), and mice were treated orally with GA-PLGA nanoparticles for 7 days (day 0-6). GA-PLGA nanoparticles significantly reduced mucositis severity measured by body weight, diarrhea score, distress, and anorexia. Further, 5-FU induced intestinal histopathological damage, altered villi-crypt length, reduced goblet cell count, elevated pro-inflammatory mediators, and suppressed antioxidant enzymes, all of which were reversed by GA-PLGA nanoparticles. Morphological, behavioral, histological, and biochemical results suggested that GA-PLGA nanoparticles were efficient, biocompatible, targeted, and sustained release drug delivery nano-vehicle for enhanced mucoprotective, anti-inflammatory, and antioxidant effects in 5-FU-induced intestinal mucositis.

Puerarin Ameliorates 5-Fluorouracil-Induced Intestinal Mucositis in Mice by Inhibiting JAKs.

Intestinal mucositis resulting from 5-fluorouracil (5-FU)-based chemotherapy subjects patients to great pain and hampers cancer treatment progress. Puerarin, the major active ingredient in Pueraria lobata, exerts anti-inflammatory and antioxidative effects. However, whether puerarin has an effect on 5-FU-induced intestinal mucositis remains unknown. We established a mice model of intestinal mucositis through the intraperitoneal injection of 5-FU and then injected puerarin (50 and 100 mg/kg) intraperitoneally for 7 consecutive days. Routine parameters, such as body weight, food intake, and diarrheal incidence, were examined to evaluate the effects of puerarin on intestinal mucositis in mice. The intestinal barrier's functions were also evaluated by measuring the serum recovery of fluorescein isothiocyanate-4kD dextran in this study. The expression levels of inflammatory cytokines, inflammatory mediators, oxidative reactions, as well as apoptotic marker proteins were determined to elucidate the underlying mechanisms of puerarin on intestinal mucositis. The model mice presented symptoms and histopathological changes typical of 5-FU-induced intestinal mucositis. In addition to vigorous inflammatory reactions, oxidative reactions, and cell apoptosis, Janus kinase (JAK) was markedly activated. Puerarin decreased the expression levels of those of inflammatory mediators, oxidative reactions, and apoptosis-related proteins in 5-FU-induced mucositis by blocking the activation of JAK. Puerarin decreased inflammation, oxidative reactions, and apoptosis and protected intestinal barrier functions to ameliorate 5-FU-induced intestinal mucositis by inhibiting the activation of JAK. This study provides novel insights into the pathologic mechanisms of (and treatment alternatives for) 5-FU-induced intestinal mucositis. SIGNIFICANCE STATEMENT: This study reveals the mechanism responsible for the protective effects of puerarin in 5-fluorouracil-induced intestinal mucositis. Puerarin inhibits the activation of JAK, thereby suppressing inflammation, oxidative reactions, cell apoptosis, and protected intestinal barrier functions to ameliorate 5-FU-induced intestinal mucositis. Overall, our results suggest that puerarin can serve as a potential natural JAK inhibitor in the treatment of 5-FU-induced intestinal mucositis.

Attenuation of Doxorubicin-Induced Small Intestinal Mucositis by Pectins is Dependent on Pectin's Methyl-Ester Number and Distribution.

ScopeIntestinal mucositis is a common side effect of the chemotherapeutic agent doxorubicin, which is characterized by severe Toll‐like receptor (TLR) 2‐mediated inflammation. The dietary fiber pectin is shown to prevent this intestinal inflammation through direct inhibition of TLR2 in a microbiota‐independent manner. Recent in vitro studies show that inhibition of TLR2 is determined by the number and distribution of methyl‐esters of pectins. Therefore, it is hypothesized that the degree of methyl‐esterification (DM) and the degree of blockiness (DB) of pectins determine attenuating efficacy on doxorubicin‐induced intestinal mucositis.Methods and ResultsFour structurally different pectins that differed in DM and DB are tested on inhibitory effects on murine TLR2 in vitro, and on doxorubicin‐induced intestinal mucositis in mice. These data demonstrate that low DM pectins or intermediate DM pectins with high DB have the strongest inhibitory impact on murine TLR2‐1 and the strongest attenuating effect on TLR2‐induced apoptosis and peritonitis. Intermediate DM pectin with a low DB is, however, also effective in preventing the induction of doxorubicin‐induced intestinal damage.ConclusionThese pectin structures with stronger TLR2‐inhibiting properties may prevent the development of doxorubicin‐induced intestinal damage in patients undergoing chemotherapeutic treatment with doxorubicin.

Oral Administration of Melatonin or Succinyl Melatonin Niosome Gel Benefits 5-FU-Induced Small Intestinal Mucositis Treatment in Mice.

Mucositis is one of the most adverse effects of 5-fluorouracil (5-FU) and had no standard drug for treatment. Melatonin is a neurohormone, and can ameliorate radiotherapy-induced small intestinal mucositis. Melatonin encapsulated in niosomes improved its poor bioavailability. Succinyl melatonin, a melatonin derivative, showed prolonged release compared with melatonin. This study investigated the efficacy of melatonin niosome gel (MNG) and succinyl melatonin niosome gel (SNG) in 5-FU-induced small intestinal mucositis treatment in mice. MNG and SNG with particle sizes of 293 and 270 nm were shown to have mucoadhesive potentials. The effect of a daily oral application of MNG, SNG, or fluocinolone acetonide gel (FAG, positive control) was compared to that of the normal group. The body weight, food consumption, histology, Fourier transform infrared (FTIR) spectroscopy, inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β), and malondialdehyde (MDA) in the small intestine were monitored. The results showed decreased %body weight and food consumption in all 5-FU-injected groups compared with the normal group. The MNG and SNG treatments maintained the food consumption and the normal integrity of the small intestines, as evidenced by villus length and crypt depth, similar to the observations in the normal groups. The FTIR spectra showed no change in lipids of the MNG and SNG groups compared with the normal group. Moreover, SNG could reduce IL-1β content to a level that was not different from the level in the normal groups. Therefore, the oral application of MNG and SNG could protect against 5-FU-induced small intestinal mucositis in mice.

Anti-inflammatory effects of Radix Aucklandiae herbal preparation ameliorate intestinal mucositis induced by 5-fluorouracil in mice

Ethnopharmacological relevance5-Fluorouracil (5-FU) is a chemotherapy agent that is widely used in clinical oncologic practice. However, intestinal mucositis is the most frequently occurring side effect of cancer therapy with 5-FU. Based on a literature survey, Radix Aucklandiae herbal preparation potentially ameliorates intestinal mucositis in 5-FU-treated mice. Aim of the studyThe aim of this study was to investigate the inflammation and gastrointestinal regulation of intestinal mucositis induced by 5-FU, including the intestinal morphology, as well as the reduction in food intake, body weight loss, and diarrhea. Materials and methodsIntestinal mucositis was induced in mice by 5-FU (30 mg/kg, i.p., for 5 consecutive days). The dose-dependent Radix Aucklandiae herbal preparation (0.3, 1, and 3 g/kg/day, p.o.), loperamide (3 mg/kg/day, p.o.) or celecoxib (40 mg/kg/day, p.o.) was concurrently administered until the 7th day. Physical status observation, diarrhea assessment, serum proinflammatory cytokine levels, intestinal villus height and crypt depth, and total goblet cells from tissues were assessed. ResultsThe dosage regimen of 5-FU administration caused severe intestinal mucositis in mice, including damage to the intestinal morphology, accompanied by a reduction in food intake, body weight loss, and diarrhea. The high-dose Radix Aucklandiae herbal preparation significantly relieves 5-FU-induced intestinal mucositis by enhancing proliferative activity in epithelial crypts; improving anepithymia, body weight loss, and diarrhea; and displaying protective effects on goblet cells in intestinal mucosal epithelia. Activation of NF-κB in the intestinal mucositis model was also suppressed by the Radix Aucklandiae herbal preparation, suggesting that it is a potent inhibitor of NF-κB and proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, and COX-2. ConclusionsOur data support the conclusion that the Radix Aucklandiae herbal preparation could effectively ameliorate 5-FU-induced gastrointestinal toxicity and be applied clinically for the prevention of intestinal mucositis during chemotherapy.

Irinotecan-induced intestinal mucositis in mice: a histopathological study.

Intestinal mucositis is an important adverse effect of antineoplastic therapy, which remains without adequate treatment. The present study aimed to carry out a complete evaluation of the histopathological changes during irinotecan-induced intestinal mucositis, using the protocol most found in the pharmacological reports nowadays to better understand irinotecan toxicity and support future studies on drug discovery. Intestinal mucositis was induced by treating swiss mice for 4days with irinotecan (75mg/kg, i.p.). After 72h post irinotecan, the mice were sacrificed and the small intestine and colon were excised to performed histological analysis by stained tissue with hematoxylin/eosin (H&E). Histoarchitecture loss, villus/crypt ratio reduction, atrophy of the muscular layer, hypertrophy in the submucosal and mucous layers, ruptures in the epithelium, as well as extent cellular infiltrate and presence of micro abscesses and the fusion of the crypts were observed in the histological analysis. Moreover, duodenum and colon had increased intraepithelial lymphocytes and mitotic figures. However, submucosal ganglia were decreased in the duodenum and increased in the colon. The data obtained in the present study provides new evidence that irinotecan-induced intestinal mucositis highly affects small intestine and colon, further contributing to establish criteria in light of the histopathological changes induced by irinotecan during intestinal mucositis and facilitating inter-study comparisons.

Rutin flavonoid attenuates oxidative stress and decreases morphological changes in experimental mucositis model

Intestinal mucositis is a frequent complication in the treatment of cancer with 5‐fluorouracil (5‐FU) chemotherapeutic agent. Rutin bioflavonoid extracted from Dimorphandra gardneriana has been reported as a potent anti‐inflammatory and antioxidant agent. Therefore, this study aims to investigate whether rutin reverses morphological elevations and oxidative stress promoted by 5‐fluorouracil in an experimental model of intestinal mucositis in mice. Swiss mice stratified into the following groups were used: Saline group (0.9% NaCl), 5‐FU group, Rutin group (RUT) (200 mg/kg Rutin, vo). For the oxidative damage evaluation, the levels of the reduced antioxidant glutathione and the lipid peroxidation product, malondylaldehyde, of the duodenal segments were determined. To investigate the morphological changes, hematoxylin and eosin staining was performed. The 5‐FU group showed a significant increase in MDA levels (8127 ± 561.5, p &lt;0.05) when compared to the saline group (4587 ± 367.5, p &lt;0.05). For GSH levels, 5‐FU (20.48 ± 4.89, p &lt;0.05) promoted a significant decrease in duodenum antioxidant levels when compared to the saline group (112.8 ± 19.45, p &lt;0.05). Pretreatment with RUT 200 mg/kg decreased MDA levels (3750 ± 405.3, p &lt;0.05) and increased GSH levels (74.67 ± 12.73, p &lt;0.05) when compared to the 5‐FU injury group. The results of the histopathological analysis showed that 5‐FU promoted structural alterations of the intestinal mucosa, reduction of villus height, deepening of the crypts and inflammatory infiltrate, compared to the Saline group, characterized by the integrity of the villi and crypts and absence of inflammatory infiltrate. Rutin‐treated animals showed a significant reversal of antineoplastic‐induced morphological changes. From the results we found that rutin promotes attenuation of oxidative stress by reducing the levels of Malonylaldehyde and increasing the levels of the antioxidant glutathione. In addition, we found that rutin reverses antineoplastic‐induced morphological changes.