Exploring the role and mechanism of armillariella tabescens polysaccharides interference in 5-FU-induced intestinal mucosal injury based on ARRB1 / 安徽医科大学学报

Objective @#To investigate the effect and mechanism of ARRB1 on Armillariella tabescens polysaccharides reversal of 5-fluorouracil ( 5-FU ) -induced chemotherapeutic intestinal mucosal injury．@*Methods @# Twelve ARRB1 knockout ( ARRB1 －/ － ) and wild-type ( WT) C57BL /6 mice were randomly divided into Control，Model and ATPS groups (200 mg / kg) ，respectively．5-FU (50 mg / kg) was injected intraperitoneally for 7 days to establish a model of chemotherapeutic intestinal mucosal injury．The histopathological damage of jejunum was evaluated by HE staining ; the activity of serum superoxide dismutase (SOD) and diamine oxidase (DAO) was measured by kits ; the expression of tight junction protein (TJ) markers ZO-1，Occludin，Claudin-1 and proliferation-associated protein Ki-67 was detected by immunohistochemistry．Crypt isolation and organoid culture were used to detect the growth status of small intestinal organoids. @*Results @#5-FU chemotherapy reduced body weight，aggravated histopathological damage in small intestine，decreased SOD level，TJ protein and Ki-67 protein expression，increased serum DAO level，decreased spherical structure formation rate and organoid formation rate ; compared with the model group，after ATPS treatment，WT mice recovered body weight，decreased pathological damage，increased serum SOD level，TJ protein and Ki-67 protein expression，DAO levels decreased，and the rates of spherical structure for- mation and organoid formation were significantly higher．However，ARRB1 －/ － mice failed to reverse the effect of 5- FU after ATPS treatment．@*Conclusion @#ATPS reverses 5-FU-induced intestinal mucositis through the protective effects of ARRB1 on intestinal barrier and organoid growth.

Effects of mild moxibustion on intestinal microbiome and NLRP3 inflammasome in rats with 5-fluorouracil-induced intestinal mucositis / 中西医结合学报

OBJECTIVE@#The present study investigated how mild moxibustion treatment affects the intestinal microbiome and expression of NLRP3-related immune factors in a rat model of intestinal mucositis (IM) induced with 5-fluorouracil (5-Fu).@*METHODS@#Forty male Sprague-Dawley rats were randomly divided into control, chemotherapy, moxibustion and probiotics groups. The IM rat model was established by intraperitoneal injection of 5-Fu. Mild moxibustion treatment and intragastric probiotic administration were provided once daily for 15 days. Tissue morphology, serum levels of inflammatory factors and the expression levels of tight junction proteins, caspase-1, gasdermin D and NLRP3 were evaluated in colon tissue, through hematoxylin and eosin staining, electron microscopy, enzyme-linked immunosorbent assay, Western blotting, quantitative real-time reverse transcription polymerase chain reaction and immunofluorescence. Gut microbiome profiling was conducted through 16S rRNA amplicon sequencing.@*RESULTS@#Moxibustion and probiotic treatments significantly increased the expression levels of tight junction proteins, reduced cell apoptosis and the expression levels of caspase-1, gasdermin D and NLRP3; they also decreased the serum levels of tumor necrosis factor-α, interleukin (IL)-6, IL-1β and IL-18, while increasing serum levels of IL-10. Moxibustion and probiotic treatments also corrected the reduction in α-diversity and β-diversity in IM rats, greatly increased the proportion of the dominant bacterial genus Lactobacillus and reduced the abundance of the genera Roseburia and Escherichia in chemotherapy-treated rats to levels observed in healthy animals. We also found that these dominant genera were firmly correlated with the regulation of pyroptosis-associated proteins and inflammatory factors. Finally, moxibustion and probiotic treatments elicited similar effects in regulating intestinal host-microbial homeostasis and the expression of NLRP3 inflammasome-related factors.@*CONCLUSION@#Moxibustion exerts its therapeutic effect on IM by ameliorating mucosal damage and reducing inflammation. Moreover, moxibustion modulates the gut microbiota, likely via decreasing the expression levels of the NLRP3 inflammasome.

The effect and mechanism of baicalein on regulating gut microbiota and improving chemotherapy-induced intestinal mucositis in mice / 药学学报

We evaluate the therapeutic effects of baicalein on chemotherapy-induced intestinal mucositis (CIM) in mice. The role of gut microflora regulation in the therapeutic effects of baicalein was investigated meanwhile. Male Balb/c mice were randomly divided into three groups including normal control group, model group and experimental group. Except for normal control group, mice were injected with 5-fluorouracil and irinotecan to induce CIM. Animal welfare and experimental procedures comply follow the rules of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. Baicalein significantly reduced disease activity index (DAI) of CIM mice and decreased the content of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in serum. There were significant differences in the composition of the gut microbiota among groups according to the analysis of α diversity, β diversity, and the species differences. Compared with the normal control group, the Ruminococcaceae_UCG_014 and unclassified_f_Lachnospiraceae in mice of model group were significantly decreased while Bacteroides, Escherichia_Shigella, Enterococcus, Parabacteroides, Clostridium_ sensu_stricto_1, and Lactococcus were significantly increased. Baicalein significantly decreased the abundance of Bacteroides, Escherichia_Shigella, Parabacteroides, Enterococcus, Clostridium_sensu_stricto_1, and Lactococcus. Meantime, norank_f_Muribaculaceae was notably increased by baicalein. The content of IL-6 and TNF-α in the serum of the three groups were positively correlated with the abundance of Clostridium_sensu_ stricto_1, Lactococcus, Bacteroides, and Enterococcus according to correlation analysis. This study suggested the potential therapeutic effect of baicalein on CIM in mice. Regulation of gut microbiota probably plays a critical role in the therapeutic effects of baicalein.

Study on the therapeutic effects and mechanism of cryptotanshinone on mice with chemotherapy-induced mucositis / 药学学报

This study systematically investigated the therapeutic effects of chemotherapy-induced mucositis (CIM) by cryptotanshinone (CTS) in mice. CIM mice were prepared by intraperitoneal injection of 5-fluorouracil (5-FU) and irinotecan for 4 days. A pseudo-sterile mouse model was established by intragastric administration of mixed antibiotics (metronidazole, vancomycin, and penicillin). The body weight, disease activity index (DAI), and defecation of mice were daily monitored. The animal welfare and experimental procedures followed the rules of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. We determined the contents of inflammatory factors, total cholesterol (TC), triglyceride (TG), and lipase activity in serum or colonic mucosa of CIM mice. We also studied the composition and relative abundance of fecal flora. The correlation of the relative abundance of fecal microbiota and environmental factors was further analyzed. CTS significantly decreased DAI and reduced the content of interleukin 6 (IL-6), interleukin 11 (IL-11), myeloperoxidase (MPO), and diamine oxidase (DAO) in the serum of CIM mice. CTS effectively increased the content of TG while reduced TC and lipase activity in serum. Results showed the incidence of CIM in pseudoaseptic model group was significantly reduced. Meanwhile, there was no significant difference in the contents of inflammatory factors and TG/TC ratio between pseudoaseptic model group and normal control group. There was a significant difference in the diversity and composition of fecal microbiota among groups. In addition, CTS restored the composition of fecal microbiota close to normal and significantly increased the abundance of g_norank_f_Muribaculaceae. Especially, g_Ruminiclostridium and g_norank_f_Muribaculaceae exhibited a significant positive correlation to TG but a negative correlation to DAO, MPO, IL-6, lipase, and TC. Cryptotanshinone significantly increased the abundance of g_norank_f_Muribaculaceae and g_ruminococcaceae_UCG-014 in fecal microbiota of CIM mice. In conclusion, we reported CTS effectively alleviated intestinal mucositis in mice induced by 5-fluorouracil and irinotecan by regulating fecal microbiota, inflammatory factors, and serum lipid.

Establishment of a mouse model of 5-fluorouracil-induced intestinal mucositis / 中国实验动物学报

Objective To establish a mouse model of 5-fluorouracil ( 5-FU )-induced intestinal mucositis. Methods Different doses of 5-FU were intraperitonealy injected into mice for once or 5 consecutive days. The body weight and diarrhea score of the mice were recorded every day, and peripheral blood and the morphological changes of small intestine were examined at 24 h or 72 h after the last 5-FU administration. Results Compared with the control group, after administered 5-FU, the dosage groups showed various degrees of body weight loss and diarrhea, and the white blood cell and platelet counts in peripheral blood decreased significantly (P＜0. 05 or P＜0. 01). The small intestine showed evident pathological changes after the single dose 400 mg/kg and the continuous injection of 50 mg/kg, 100 mg/kg. The mortality rate was 100% in the 100 mg/kg group. Conclusions A mouse model of intestinal mucositis can be successfully established by a single injection of 5-FU or for consecutive 5 days, in a dose-dependent manner. The optimal dose for single injection is 400 mg/kg, and that of the continual injection for 5 consecutive days is 50 mg/kg.

Efficacy of probiotics on chemotherapy-induced intestinal mucositis in rats: a meta-analysis / 重庆医学

Objective To evaluate the efficacy of probiotics on chemotherapy-induced intestinal mucositis in rats.Methods The databases including PubMed,EMbase,Cochrane,CBM,CNKI,WanFang and VIP were retrieved from their establishment to April 2016.The related randomized controlled trials(RCT) on the effects of probiotics for treating chemotherapy-induced intestinal mocositis in rats were included.The relevant literatures were screened according to the inclusion and exclusion criteria,then the data were extracted and analyzed.Results Total 6 RCT were included.Compared with the control group,the intestinal secretion and absorption function in the probiotics group was strengtnened[SMD=1.73,95 ％CI(0.79,2.68),P＜0.01],jejunal anti-oxidant capacity was increased [SMD=-2.12,95％CI(-3.56,-0.67),P＜0.01],however low dose probiotics (＜1 × 109 cfu/d)had no protective effect on small intestine[SMDjejunum =-0.06,95％CI(-0.51,0.40),SMDileum =0.02,95％ CI(-0.71,0.75);P ＞0.05],while high dose probiotics(≥ 1 × 109 cfu/d) could reduce the intestinal pathological damage[SMDjejunum =-0.64,95 ％ CI (-1.20,-0.09),SMDileum=-0.85,95％ CI(-1.59,-0.12);P＜0.05].Conclusion High dose probiotics can reduce chemotherapy-induced intestinal mucositis in rats.Because of less included literatures and the influence of publication bias,the effect of probiotics on chemotherapy induced mucositis could be overestimated.

Papel da via S100B/RAGE/NFkB na patogênese da mucosite intestinal experimental por 5-fluorouracil desregulação de células gliais e de neurônios entéricos

5-Fluorouracil (5-FU) promotesintestinal mucositis and motility alterations. Themucositis affect about40% of patients receiving 5-FU and there arereports of patients presentingmucositis afterthe first dose. Under other inflammatory conditions, the S100βprotein is involved in the RAGE activation with subsequent NFκBtranslocation to the nucleus and transcription of TNF-αand iNOS. The enteric glial cells through several mediators, such asS100β, interact with the intestinal epithelial cells and enteric neurons. Therefore, the aim of this study was investigatethe effect of 5-FU in the enteric glial cells and neurons, as well as studythe role of the via S100β/RAGE/NFκB in the pathogenesis of the experimental intestinal mucositis. Swiss male mice received saline (control, 0.9%, i.p.) or5-FU (450 mg/Kg, i.p., single dose). After24h, mice weretreated with pentamidine, aS100 βinhibitor (P0.8 mg/Kg +5FU; P4 mg/Kg +5FU; or onlyP4mg/Kg, i.p.) during two days and euthanized on the fouth day of the experimental protocol...

O 5-Fluorouracil (5-FU) promove mucosite intestinal e alterações da motilidade.A mucositeatinge cerca de 40% dos pacientes em tratamento com5-FUe há relatos de pacientes que a apresentam na primeira dose administrada.Em outras condições inflamatórias, a proteína S100β está envolvida na ativação de RAGE com consequente translocação de NFκB para o núcleo e transcrição de TNF-αe de iNOS.As células gliais entéricas por meio deS100β,interagem com as células epiteliais intestinais e com os neurônios entéricos.Nesse contexto, oobjetivodeste estudo éinvestigar o efeito do5-FU nas células gliais e nos neurôniosentéricos, bem como estudar o papel da via S100β/RAGE/NFκB na patogênese da mucosite intestinal induzida por esse quimioterápico. Os camundongos Swiss machos receberam salina (0,9%, i.p.) ou 5-FU (450 mg/Kg, i.p. dose única). Após 24h da administração do quimioterápico, administrou-se pentamidina, inibidor de S100β (P0,8 mg/Kg +5FU; P4 mg/Kg +5FU; ou somente P4mg/Kg, i.p.) durante dois dias e os animais foram eutanasiadosno quarto dia do protocolo experimental...

Lactobacillus spp. e bifidobacterium sp. atenuam a mucosite intestinal experimental induzidapor 5-fluorouracil em camundongos

A mucosite intestinal é um dos efeitos adversos mais incidentes do tratamento com 5-Fluorouracil. Nesse contexto, microrganismos probióticos são cada vez mais utilizados como alternativas para proteção da mucosa gastrintestinal deste efeito colateral e distúrbios associados. Este estudo teve como objetivo avaliar o efeito de Probiotil®composto pelosprobióticos Lactobacillus acidophilus e Bifidobacterium lactis, e Probiatop® composto porLactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus rhamnosus eBifidobacterium lactis na mucosite intestinal experimental induzida por 5-FU. Para aexecução do protocolo utilizou-se camundongos machos Swiss (25-30g) que foram tratadoscom dose única intraperitoneal de 5-FU (450mg/Kg i.p.), com exceção dos controles (Salina eDMSO). Os grupos probióticos foram tratados com o Probiotil®ou Probiatop®1h, 24h e 48h(v.o.) após a indução por 5-FU, sendo eutanasiados após 72h da indução de mucosite.Segmentos do duodeno, jejuno e íleo foram obtidos para as seguintes avaliações: mensuração da relação vilo/cripta; escores histológicos; dosagem de glutationa (GSH), malondialdeído(MDA), citocinas pró-inflamatórias (TNF-α e IL-6) e atividade da enzima mieloperoxidase(MPO). Além disso, avaliou-se a análise ponderal, leucograma, esvaziamento gástrico etrânsito intestinal dos animais. Observou-se que Probiatop®diminuiu a perda de peso induzida por 5-FU, mas este efeito não foi demonstrado pelo Probiotil®...

Intestinal Mucositis is a higher adverse effects of treatment with 5-fluorouracil. In thiscontext, probiotics are widely used to protect gastrointestinal disorders. Here we report theeffect Probiotil®composed by probiotics Lactobacillus acidophilus and Bifidobacteriumlactis, and Probiatop®composed by Lactobacillus acidophilus, Lactobacillus paracasei,Lactobacillus rhamnosus and Bifidobacterium lactis in intestinal mucositis induced by 5-FU.Such methodology was used male Swiss mice (25-30g), treated with a single intraperitonealdose by 5-FU (450 mg / kg ip), and controls with(saline and DMSO). In the Probiotics groupswas administrated Probiotil®or Probiatop®1h, 24h and 48h (V.O.) after induction by 5-FU .72h after 5-FU administration, mice was euthanized. Segments from Duodenum, jejunum andileum were removed for evaluations: measurement of villous / crypt ratio; Histological scores;concentration of glutathione (GSH), malondialdehyde (MDA), proinflammatory cytokines(TNF-α and IL-6) activity and myeloperoxidase (MPO). In addition, we investigated theweight analysis, leukogram, gastric emptying and intestinal transit of animals. Our resultsshowed that Probiatop®decreased the weight loss induced by 5-FU, but Probiotil®did notchange weight loss...