The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis.
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ABSTRACT:
SUBMITTER: Miyano K
PROVIDER: S-EPMC6969174 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To reveal the molecular mechanisms underlying oral ulcerative mucositis-induced pain, we investigated putative pain-associated mediators, pain-related behaviors and gene modulation in a rat oral mucositis model. On day 1 after acetic acid treatment, the mucosal area showed slight redness and swelling but no evidence of ulceration or pain induction. On day 2, oral ulcers were obvious, as was the induction of spontaneous and mechanical pain. In the treated mucosal area, bacterial loading and prostaglandin E2 increased beginning on day 2; no significant changes were observed on day 1. DNA microarray analysis of trigeminal ganglion tissue collected on day 2 identified 32 significantly regulated genes (>1.5-fold change in expression). The up-regulation of the top 3 genes, Hamp (hepcidin antimicrobial peptide), Reg3b (regenerating islet-derived 3β) and Serpina3n (serine peptidase inhibitor A3N), was validated through quantitative RT-PCR. Systemic antibiotic pre-treatment did not increase the mRNA levels. Therefore, we conclude that the oral ulcerative mucositis-induced pain is caused by infectious inflammation of the ulcerative area and stimulates anti-bacterial and anti-peptidase gene expressions in sensory neurons. Oral ulcerative mucositis-induced gene expression in trigeminal ganglion tissue was measured. Ten Wistar rats were divided into the following two groups, control, oral ulcerative mucositis (stomatitis). Five rats were anesthetized with sodium pentobarbital. A piece of filter paper was soaked in 50% acetic acid diluted with water and placed in the labial fornix region of the inferior incisors of rats for 30 sec. Other five rats received only anesthesia without any treatment were used as a control. On day 2 after acetic acid treatment, oral ulcerative mucositis was obvious and trigeminal ganglion tissues in two groups were collected for DNA microarray analysis.
2016-06-15 | E-GEOD-83349 | biostudies-arrayexpress
Project description:To reveal the molecular mechanisms underlying oral ulcerative mucositis-induced pain, we investigated putative pain-associated mediators, pain-related behaviors and gene modulation in a rat oral mucositis model. On day 1 after acetic acid treatment, the mucosal area showed slight redness and swelling but no evidence of ulceration or pain induction. On day 2, oral ulcers were obvious, as was the induction of spontaneous and mechanical pain. In the treated mucosal area, bacterial loading and prostaglandin E2 increased beginning on day 2; no significant changes were observed on day 1. DNA microarray analysis of trigeminal ganglion tissue collected on day 2 identified 32 significantly regulated genes (>1.5-fold change in expression). The up-regulation of the top 3 genes, Hamp (hepcidin antimicrobial peptide), Reg3b (regenerating islet-derived 3β) and Serpina3n (serine peptidase inhibitor A3N), was validated through quantitative RT-PCR. Systemic antibiotic pre-treatment did not increase the mRNA levels. Therefore, we conclude that the oral ulcerative mucositis-induced pain is caused by infectious inflammation of the ulcerative area and stimulates anti-bacterial and anti-peptidase gene expressions in sensory neurons.
2016-06-15 | GSE83349 | GEO
Project description:BackgroundSubjects with head and neck cancer (HNC) often experience post-treatment side effects, particularly radiation-induced oral mucositis (RIOM). This study aimed to explore the association of Chinese herbal medicine use with the sequent risk of RIOM among them.MethodsThis cohort study used a nationwide health insurance database to identify subjects newly diagnosed with HNC, aged 20 to 60 years, who received treatment between 2000 and 2007. Among them, a total of 561 cases received CHM after HNC onset (CHM users); the remaining 2395 cases were non-CHM users. All patients were followed to the end of 2012 to identify any treatment for RIOM as the end point. Cox proportional hazards regression was used to compute the adjusted hazard ratio (aHR) of RIOM by CHM use.ResultsDuring the follow-up period, 183 CHM users and 989 non-CHM users developed RIOM at incidence rates of 40.98 and 57.91 per 1000 person-years, respectively. CHM users had a lower RIOM risk than the non-CHM users (aHR: 0.68; 95% Confidence Interval: 0.58-0.80). The most potent effect was observed in those taking CHM for more than 1 year. Use of Baizhi, Danshen, Shao-Yao-Gan-Cao-Tang, Gan-Lu-Yin, Huangqin, Shu-Jing-Huo-Xue-Tang, and Xin-Yi-Qing-Fei-Tang, was significantly related to a lower risk of RIOM.ConclusionFindings of this study indicated that adding CHM to conventional clinical care could be helpful in protecting those with HNC against the onset of RIOM. Further clinical and mechanistic studies are warranted.
| S-EPMC8422821 | biostudies-literature
Project description:Oral mucositis (OM) is a serious side effect of cancer chemotherapy. The pathobiology of oral mucositis remains incompletely understood due to lack of appropriate models which recapitulate the human condition. Existing rodent models are intraperitoneal and require radiation, chemical or mechanical injury to the chemotherapy protocol to induce oral lesions. We aimed to develop an OM mouse model that is induced solely by chemotherapy and reproduces macroscopic, histopathologic and inflammatory characteristics of the human condition. Female C57BL/6 mice were given intravenous 5-Fluorouracil (5-FU) injections every 48 hours, for 2 weeks. A high daily dose of intraperitoneal administration was tested for comparison. Mice were monitored daily for weight loss. Epithelial histomorphometric analyses in tongue, esophageal and intestinal tissues were conducted coupled with assessment of apoptosis, cell proliferation, neutrophilic infiltration and the integrity of adherens junctions by immunohistochemistry. Neutropenia was assessed in peripheral blood and bone marrow. Tissues were analyzed for pro-inflammatory cytokines at the protein and mRNA levels. Daily intraperitoneal administration of 5-FU led to rapid weight loss and intestinal mucositis, but no oral inflammatory changes. Intravenous administration triggered atrophy of the oral and esophageal epithelium accompanied by reduction in cell proliferation and increased apoptosis. Coincidental with these changes were up-regulation of NF-κB, TNFα, IL-1β, GM-CSF, IL-6 and KC. Despite neutropenia, increased oral neutrophilic infiltration and reduced E-cadherin was observed in oroesophageal mucosae. We developed a novel experimental tool for future mechanistic studies on the pathogenesis of chemotherapy-induced OM.
| S-EPMC5491455 | biostudies-other
Project description:BackgroundGastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues.ResultsOral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity.ConclusionsAltogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis.
| S-EPMC6482518 | biostudies-literature
Project description:Chemotherapy may cause DNA damage within the oral mucosa of cancer patients leading to mucositis, a dose-limiting side effect for effective cancer treatment. We used whole genome gene expression analysis to identify cellular damage to the mucosal tissue occuring two days post induction chemotherapy and identified gene expression patterns that may or may not be predictive of oral mucositis. Keywords: Treatment effect
2009-01-01 | GSE10746 | GEO
Project description:Severe intraoral pain induces difficulty in eating and speaking, leading to a decline in the quality of life. However, the molecular mechanisms underlying intraoral pain remain unclear. Here, we investigated gene modulation in the trigeminal ganglion and intraoral pain-related behavior in a rat model of acetic acid-induced oral ulcerative mucositis. Oral ulceration was observed on day 2 after acetic acid treatment to the oral mucosa of male Wistar rats, causing spontaneous pain and mechanical allodynia. Deoxyribonucleic acid microarray analysis of trigeminal ganglion tissue indicated that Hamp (a hepcidin gene that regulates cellular iron transport) was the most upregulated gene. In the oral ulcerative mucositis model, the upregulation of Hamp was also induced in the ulcer region but not in the liver, with no increase in hepcidin levels in the plasma and saliva, indicating that hepcidin was produced locally in the ulcer region in the model. Systemic antibiotic pretreatment did not increase the mRNA levels of Hamp in the trigeminal ganglion and ulcer regions. Hepcidin injection into the oral mucosa enhanced neuronal excitability in response to noxious mechanical stimulation of the oral mucosa in trigeminal spinal subnucleus interpolaris/caudalis neurons. These results imply that oral ulcerative mucositis induces oral mucosal pain because of infectious inflammation of the ulcerative area and potentiates Hamp, which represents anti-bacterial and anti-peptidase gene expression in the ulcer region and trigeminal ganglion. The regulation of cellular iron transport by hepcidin is likely involved in oral ulcerative mucositis-induced pain.
| S-EPMC10118189 | biostudies-literature
Project description:Ulcerative colitis (UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing (MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.
| S-EPMC6305528 | biostudies-other
Project description:BackgroundOral mucositis is the most common complication after radiotherapy of nasopharyngeal carcinoma (NPC). Previous studies had revealed that oral microbiota took great alteration soon after and during radiotherapy. Here, we aimed to investigate if the alteration of oral microbiota was related to delayed healing of oral mucositis after six month of radiotherapy.MethodsWe recruited 64 NPC patients and collected samples after six month of radiotherapy. 32 patients were included into normal healing group (N), 22 patients were mild delayed healing group (M), while 10 patients were severe delayed healing group (S). 16S rRNA gene sequencing was used to assess and identify oral microbiota alteration.ResultsThe diversity of oral microbial communities was not significantly different. Composition of oral microbial was huge different among S group, for the Actinobacteria and Veillonella were significantly increased, which showed significant dysbiosis of the oral microbiome. Functional analysis of metabolic pathways of oral microbiota demonstrated that degradation of organic acids and amino acids were significantly increased in S group. Moreover, phenotype analysis found that relative abundance of aerobic and biofilm formation were higher in S group. We also found the Actinobacteria co-occurred with Veillonellaceae, but anti-occurred with other biofilm oral bacteria. These two biomarkers may be predictable for severe delayed healing of oral mucositis after radiotherapy.ConclusionThis study suggests a potential association between oral microbiome and delayed healing of oral mucositis. The Actinobacteria and Veillonellaceae may be biomarkers in predicting the risks for the severe delayed healing of oral mucositis after radiotherapy of NPC.
| S-EPMC9807904 | biostudies-literature
Project description:Oral mucositis is a common side effect of cancer chemotherapy, with significant adverse impact on the delivery of anti-neoplastic treatment. There is a lack of consensus regarding the role of oral commensal microorganisms in the initiation or progression of mucositis because relevant experimental models are non-existent. The goal of this study was to develop an in vitro mucosal injury model that mimics chemotherapy-induced mucositis, where the effect of oral commensals can be studied. A novel organotypic model of chemotherapy-induced mucositis was developed based on a human oral epithelial cell line and a fibroblast-embedded collagen matrix. Treatment of organotypic constructs with 5-fluorouracil (5-FU) reproduced major histopathologic characteristics of oral mucositis, such as DNA synthesis inhibition, apoptosis and cytoplasmic vacuolation, without compromising the three-dimensional structure of the multilayer organotypic mucosa. Although structural integrity of the model was preserved, 5-FU treatment resulted in a widening of epithelial intercellular spaces, characterized by E-cadherin dissolution from adherens junctions. In a neutrophil transmigration assay we discovered that this treatment facilitated transport of neutrophils through epithelial layers. Moreover, 5-FU treatment stimulated key proinflammatory cytokines that are associated with the pathogenesis of oral mucositis. 5-FU treatment of mucosal constructs did not significantly affect fungal or bacterial biofilm growth under the conditions tested in this study; however, it exacerbated the inflammatory response to certain bacterial and fungal commensals. These findings suggest that commensals may play a role in the pathogenesis of oral mucositis by amplifying the proinflammatory signals to mucosa that is injured by cytotoxic chemotherapy.
| S-EPMC5945319 | biostudies-literature