Oral Mucositis In Rats Research Articles

Effects of a semi-interpenetrating network hydrogel loaded with oridonin and DNase-I on the healing of chemoradiotherapy-induced oral mucositis.

The aim of this study was to develop a semi-interpenetrating network (IPN) hydrogel system suitable for the oral environment, capable of controlled release of DNase-I and oridonin (ORI), to exert antimicrobial, anti-inflammatory, and reparative effects on chemoradiotherapy-induced oral mucositis (OM). This IPN was based on the combination of ε-polylysine (PLL) and hetastarch (HES), loaded with DNase-I and ORI (ORI/DNase-I/IPN) for OM treatment. In vitro studies were conducted to evaluate degradation, adhesion, release analysis, and bioactivity including cell proliferation and wound healing assays using epidermal keratinocyte and fibroblast cell lines. Furthermore, the therapeutic effects of ORI/DNase-I/IPN were investigated in vivo using Sprague-Dawley (SD) rats with chemoradiotherapy-induced OM. The results demonstrated that the IPN exhibited excellent adhesion to wet mucous membranes, and the two drugs co-encapsulated in the hydrogel were released in a controlled manner, exerting inhibitory effects on bacteria and degrading NETs in wound tissues. The in vivo wound repair effect, microbiological assays, H&E and Masson staining supported the non-toxicity of ORI/DNase-I/IPN, as well as its ability to accelerate the healing of oral ulcers and reduce inflammation. Overall, ORI/DNase-I/IPN demonstrated a therapeutic effect on OM in rats by significantly accelerating the healing process. These findings provide new insights into possible therapies for OM.

Development and Application of Prototype System Based on Light-Emitting Diode Arrays (660 nm) with a Top Hat Beam Profile in Order to Optimize Photobiomodulation Protocols for Treatment of Radiation-Induced Oral Mucositis in Rats.

Background: Oral mucositis (OM) is a common adverse effect of radiation to the head and neck. Recent research has shown that extra oral photobiomodulation (EO-PBM) reduces the severity of OM. However, appropriate EO-PBM therapy parameters for OM severity reduction have not been documented. Objective: This work aims to optimize EO-PBM radiation parameters for lowering the severity of radiation-induced OM in rats by establishing a photobiomodulation (PBM) treatment system based on light-emitting diode arrays with top-hat beam profile. Methods: The 36 rats are separated into 2 control groups and 4 groups receiving PBM treatment. The PBM groups are exposed to irradiance between 4 and 24 J/cm2 at 660 nm. The cheek pouch mucosa is removed after scarification for biochemical and histological examination. Student's t-test, and one-way analysis of variance (ANOVA) followed by Tukey's Multiple were applied to compare the statistical significance of differences between control groups and PBM treatment groups. Results: Statistical analysis reveals that PBM irradiation at 12 J/cm2 (200 sec) with a flatness of 0.8 and a diameter of 3 cm substantially decreased the level of inflammatory cytokines compared with the positive control group. Conclusions: Our results indicate that the designed treatment PBM system is capable of delivering the optical parameters necessary for therapeutic treatment.

Vitamin E ameliorates oral mucositis in gamma-irradiated rats (an in vivo study)

BackgroundRadiation therapy is the primary treatment for neck and head cancer patients; however, it causes the development of oral mucositis accompanied by tissue structure destruction and functional alteration. This study was conducted to evaluate the effect of different doses of vitamin E as a treatment for radiationinduced oral mucositis in rat model.Methods35 male albino rats were randomly divided into five groups: control, untreated radiation mucositis (single dose of 20 Gy), treated radiation mucositis; radiation (single dose of 20 Gy) then vitamin E at doses of 300, 360 and 500 mg/Kg for seven days started 24 h after irradiation. Body weight and food intake were evaluated for each rat. The mucositis score was assessed every day. Rats were sacrificed once at the end of the experiment, and tongue specimens were stained with hematoxylin and eosin, anti P53 and anti Ki67 antibodies.ResultsResults indicated more food intake and less weight reduction in vitamin E treated groups and the contrary for gamma-irradiated group. Additionally, vitamin E delayed the onset and decreased the severity and duration of mucositis. It also restored the histological structure of lingual tongue papillae. Vitamin E treated groups showed a significant higher Ki67 and lower P53 expression as compared to untreated radiation group. The overall improvement increased as vitamin E dose increased. Finally, the amelioration can be attributed to the decreased apoptosis and increased proliferation of cells.ConclusionsVitamin E especially at dose of 500 mg/Kg could be an effective treatment for radiation-induced oral mucositis.

Ellagic acid for oral mucositis: investigation of the therapeutic effect in rats

The aim of this study was to evaluate the effect of ellagic acid on 5-fluorouracil-induced oral mucositis in rats. Twenty-four 6-month-old male Wistar albino rats were used. The rats were divided into three groups: Experimental Group I, Experimental Group II and Control Group. A superficial scratch was made on the mucosa of the right cheek pouch on the 3rd day and the 5th day. Oral mucositis protocol was applied to the Control Group. Ellagic acid was administered by gavage to the Experimental Group I from the 1st day to the 5th day along with the 5-FU procedure, and to the Experimental Group II from the 5th day to the 10th day. On the 11th day, all rats were sacrificed. The effect of ellagic acid on the healing of oral mucositis was evaluated histopathologically and immunohistochemically. TNF-α expression was observed at various intensities in the infected incision sites of the Experimental Group I sample, especially in the interstitial area in the lamina propria and mostly in the cytoplasm of the inflammatory cells within the vessel. Similar to the Experimental Group I, TNF-α expression of varying intensity occurred in the inflammatory cells in the Experimental Group II, partly in the epithelium and mostly in the inflammatory cells in the lamina propria. Additional research is needed to elucidate the pathogenic inflammatory mechanisms involved in the mucositis site and the prophylactic and therapeutic roles of antioxidants in the healing of oral mucositis by ellagic acid.

The protective effect of bosentan on methotrexate-induced oral mucositis in rats

The protective effect of bosentan on methotrexate-induced oral mucositis in rats

Effect of multidrug solution for the treatment of chemotherapy-induced oral mucositis in vivo

ObjectiveEvaluate the effect of a multidrug solution, adopted by a referral hospital for cancer to control and treat chemotherapy-induced oral mucositis in rats. MethodsOral mucositis (OM) was induced by 5-Fluorouracil (5-FU), and the animals were treated with saline (n = 8, G1), 0.12% chlorhexidine (n = 8, G2); and multidrug solution (n = 8, G3). The animals were submitted to clinical and histological analysis of the lesion using mucosal fragments. The animals' food consumption during treatment was also evaluated. ResultsClinical improvement (p < 0.05) was observed in the groups treated with the multidrug solution and 0.12% chlorhexidine digluconate. In G2 and G3, there was a prevalence of reepithelialization covering <50% of the lesion. Evaluation of the inflammatory infiltrate indicated that the G1 treatment permitted an intense inflammatory response in all animals, yet this evaluation parameter was moderate in groups G2 and G3. The G3 group (p < 0.05) presented higher food consumption than the other groups. ConclusionsThe multidrug solution improved the clinical and histological parameters of the chemotherapy-induced oral mucositis, as well as promoted an increase in food intake.

Sprayable NAHAO® hydrogel alleviates pain and accelerates rat oral mucositis wound healing

ObjectiveTo investigate the promote healing and analgesic effects of NAHAO® Brand Nazhen oral antibacterial care solution (NAHAO® spray) on the 5-fluorouracil-induced oral mucositis in rats. Material and methodSixty male SD rats were randomly divided into normal group, model group, recombinant human epidermal growth factor (rhEGF) group, NAHAO® spray group, and 1/3 concentration of NAHAO® spray group. 5-FU was injected intraperitoneally on the first and third days of the experimental model, and OM was induced using mechanical trauma on the third and fifth days. Wound healing quality was assessed by the appearance of mucosa and histological images on day6 and day10. Pain is measured by facial grooming behavior stimulated by capsaicin, the alternation of body weight and food intake was also recorded to reflect the OM pain. To examine the involvement of the cyclooxygenase pathway in the mechanism underlying oral mucositis, we detected the expression of cyclooxygenase2(COX-2) and matrix metalloproteinase 9(MMP9) via immunohistochemical staining and determined the PGE2 concentrations in rats’ serum during healing of oral mucositis. ResultsNAHAO® spray attenuated pathological damage and reduced pain sensitivity effectively. COX-2 expression levels were inhibited in the NAHAO® spray-treated group. The concentration of PGE2 and the expression of MMP9 were inhibited in NAHAO®-treated rats. Compared with normal rats, the elevated rubbing time following capsaicin stimulation in the model was completely inhibited after being treated with NAHAO® spray. ConclusionNAHAO® spray alleviated OM-induced pain and promoted wound healing partly by inhibiting the cyclooxygenase-related pathway.

The therapeutic effect of bovine colostrum on 5-Fluorouracil-Induced oral mucositis in rats

ObjectiveThe purpose of this study is to determine the effect of bovine colostrum on 5-fluorouracil-induced oral mucositis in rats. Material and MethodTwenty-four male Wistar albino rats were randomly divided into three groups as the Preoperative, Postoperative and Control groups. All rats were administered 100 mg/kg 5-fluorouracil on the first day and 65 mg/kg 5-FU on the third day intraperitoneally. On the third and fifth days, a superficial incision was created on the mucosa of the right cheek pouch. The oral mucositis protocol was applied in the control group. The preoperative group was given bovine colostrum by gavage from the 1st day of the 5-FU procedure to the 5th day, while the postoperative group was given bovine colostrum by gavage from the 5th day to the 10th day. ResultsAccording to the scoring made in terms of secondary infections, two cases in the control group had moderate infections, and two cases in each of the preoperative and postoperative groups had severe infections. The difference between the control group and the preoperative and postoperative groups was significant (p=0.020). There was no significant difference between the preoperative and postoperative groups. While the degree of wound healing in the postoperative group was higher than the other groups, the difference was not statistically significant. ConclusionNo significant effect of bovine colostrum on the healing of oral mucositis was observed. Additional studies are needed to shed light on the pathogenic inflammatory mechanisms in mucositis and the prophylactic and therapeutic roles of antioxidants.

Effect of intraperitoneal injection of Nigella sativa oil on 5-fluorouracil-induced oral mucositis in rats

Although many studies have shown that administration of Nigella sativa oil can decrease inflammation and facilitate tissue regeneration, the efficacy of its systemic administration for treatment of chemotherapy-induced oral mucositis has not been investigated. This study aimed to assess the effect of intraperitoneal injection of N. sativa oil on 5-fluorouracil (5-FU)-induced oral mucositis in rats. This study evaluated 72 healthy Wistar rats, weighing 250-300 g. The rats were randomly divided into three groups of control, placebo, and treatment (n=24). The rats received intraperitoneal injection of 5-FU on days 1 and 3. The rats’ cheek mucosa was then wounded with a linear scratch by an 18-gauge needle on day 3. The placebo and N. sativa oil were administered in groups B and C, respectively during the study period. Histological changes in oral mucosa were assessed on days 4, 6, and 8. Data were statistically analyzed using SPSS via the ANOVA, and the Kruskal-Wallis test, followed by the Mann Whitney multiple comparisons test. The mucositis score and inflammation score significantly decreased in the treatment group compared with the control and placebo groups (P&lt;0.05). But there was no significant different between the groups regarding the connective tissue changes (P&gt;0.05). Our findings suggest that N. sativa oil can have a notable efficacy for improvement of oral mucositis and can decrease the inflammation score in rats undergoing chemotherapy. Our results suggest that Nigella sativa can be used as a valuable remedial agent and can be a possible candidate for treatment of chemotherapy-induced oral mucositis.

Antibiotic-Induced Gut Microbiota Depletion Accelerates the Recovery of Radiation-Induced Oral Mucositis in Rats

Due to its pivotal role in the modulation of immune and inflammatory responses, the gut microbiota has emerged as a key modulator of cancer treatment-induced gastrointestinal mucositis. However, it is not clear yet how it affects radiation therapy-induced oral mucositis (OM). As such, this study aimed to explore the gut microbiota's role in the pathogenesis of radiation-induced OM in rats. Male Sprague Dawley rats were treated with 20 Gy x-ray radiation (Rx) delivered to the snout, with or without antibiotic-induced microbiota depletion (AIMD). OM severity was assessed, and tongue tissues were collected on day 9 and 15 postradiation for tissue injury and inflammatory markers assessment. AIMD+Rx had a significantly shorter duration of severe OM compared with Rx alone group. Macroscopically, the tongue ulcer-like area was smaller in AIMD+Rx compared with the Rx group. Microscopically, a smaller percentage of the mucosal ulcer was observed in the dorsal tongue of AIMD+Rx compared with the Rx group. AIMD+Rx also had significantly lower levels of interleukin 6, interleukin 1 beta, and toll like receptor 4 in the tongue tissues than the Rx group. The gut microbiota plays a role in OM pathogenesis, mainly in the recovery phase, through the modulation of proinflammatory pathways. Future microbiota-targeted interventions may improve OM in clinical settings.

Evaluation of the antiapoptotic and anti-inflammatory properties of chitosan in methotrexate-induced oral mucositis in rats.

Methotrexate (MTX), a chemotherapeutic agent, is known to cause oral mucositis. Chitosan has been shown to have a protective effect in inflammatory animal models. This research aimed to examine the protective effect of chitosan against oral mucositis caused by MTX. Wistar albino rats were randomly divided into three groups. Control (n = 8), (saline via oral gavage for 5days), MTX (n = 8), (60mg/kg single dose MTX intraperitoneally on the 1st day and for the following 4days saline via oral gavage), and MTX + chitosan (n = 8), (1st day single dose 60mg/kg MTX intraperitoneally and followed with 200mg/kg chitosan via oral gavage for 4days). After 24h of the last dose, the animals were euthanised. Blood, tongue, buccal and palatal mucosa tissues were collected. Serum interleukin 1-beta (IL1-β), tumour necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP-1, and MMP-2) activities, tissue bcl-2/bax ratio and the expression of caspase-3 (casp-3), and casp-9 were detected. The tissues were also examined histologically. Serum TNF-α, IL1-β, MMP-1 and MMP-2 activities and tissue casp-3 and casp-9 activities significantly increased but the bcl-2/bax ratio significantly decreased in the MTX group compared those of the control group. Histologically, diffuse inflammatory cells were observed in MTX group. However, In the MTX + chitosan group, all the values were close to those of the control group. It was demonstrated that chitosan has a protective effect against oral mucosal damage caused by MTX. Thus, it may be a candidate agent against MTX induced oral mucositis.

Effect of taxifolin on methotrexate-induced oxidative and inflammatory oral mucositis in rats: biochemical and histopathological evaluation.

The role of oxidative stress, as well as inflammation in the pathogenesis of methotrexate (MTX)-induced oral mucositis, is a known fact. The anti-inflammatory, antitumor, antimicrobial, and antioxidant properties of taxifolin—the effect we tested against MTX-induced oral mucosal damage—are well known. Objective Evaluating biochemically and histopathologically the effects of taxifolin on methotrexate-induced oral mucosal damage in rats.Methodology In the taxifolin+MTX (TMTX) group, 50 mg/kg taxifolin was orally administered to rats by gavage. In the MTX and healthy (HG) groups, normal saline was applied to rats as solvent by the same method. One hour after administration of taxifolin and solvent, 5 mg/kg MTX was orally administered to rats in the MTX and TMTX groups. Taxifolin and methotrexate were administered once a day for 30 days. Macroscopic, biochemical, and histopathological evaluations were performed on the inner cheek and tongue tissues of rats. These parts were removed after rats were killed with a high-dose anesthesia.Results Taxifolin with MTX prevented the increase in oxidant and pro-inflammatory parameters, such as malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), on the inner cheek and tongue tissues of rats. Moreover, taxifolin antagonized the decrease in total glutathione (tGSH). Taxifolin decreased MTX-induced histopathological damage.Conclusion These findings suggest that taxifolin may be useful to treat MTX-associated oral mucositis.

Comparative study of royal jelly, propolis, and photobiomodulation therapies in 5-fluorouracil-related oral mucositis in rats.

This study aimed to evaluate the effects and mechanisms of action of royal jelly (RJ) and propolis compared to photobiomodulation therapy (PBMT) in an animal model of 5-fluorouracil-related oral mucositis (OM). Seventy-two male Wistar rats were randomly allocated to four groups (n = 18 each): control (no treatment), PBMT (intraoral laser, 6J/cm2), RJ, and propolis. On days 0 and 2, the animals received an injection of 5-fluorouracil (5-FU). The buccal mucosa was scratched (days 3 and 4) and the treatments were initiated on day 5. Six animals of each group were euthanized on days 8, 10, and 14. Phytochemical analysis (thin-layer chromatography, TLC) and clinical, histopathological, and immunohistochemical analysis of pS6, pAKT, and NF-κB were performed, and oxidative stress markers were also investigated. TLC revealed the presence of large amounts of sucrose (Rf 0.34) in RJ and of flavonoids in propolis. Lower clinical OM scores were observed on day 8, and improved morphological data were observed on day 10 in the PBMT, RJ, and propolis groups (p < 0.05). On day 8, immunoexpression of pS6, pAKT, and NF-κB was increased compared to control. On day 14, reduced glutathione (GSH) antioxidant levels were increased in the propolis group compared to control (p < 0.05). Our results showed that RJ and propolis, as well as PBMT, are effective in the treatment of OM. Considering that some patients who develop OM do not have access to PBMT, the present study demonstrated that topical application of RJ and propolis may be an important alternative for the treatment of OM.

The effect of systemic application of propolis on tongue damage and oral mucositis in rats exposed to radiation.

In this experimental study, the effect of dose-dense systemic application of propolis on oral mucosity, histological changes in papilla, and inflammatory and hypoxic markers in rats exposed to radiation was investigated. Seven rats were in the control and 30 rats in the experimental group. Three experimental groups were formed. In Group 1 RT (15Gy) was delivered only to the head and neck region. In Group 2, RT (15Gy) and systemic administration of 100mg/kg/ml propolis, in Group 3, RT (15Gy) and systemic administration of 200mg/kg/ml propolis were applied. Oral mucositis index (OMI) was scored in control and experimental groups. Proinflammatory markers [interleukin-6 (IL-6), myeloperoxidase (MPO), tumor-necrosis factor-α (TNF-α)] hypoxia markers [glucose transporter-1 (GLUT-1), hypoxia-inducible factor 1α (HIF-1α)] were studied histomorphologically. The significantly highest OMI score was observed in the G1. OMI score was statistically significantly decreased in experimental groups receiving systemic propolis, especially in G3. Proinflammatory markers increased significantly only in the experimental RT group, G1. Serum levels of MPO and TNF-α significantly decreased in the dose-dense systemic propolis arm. The highest levels of hypoxia markers (HIF-1α and GLUT-1) were detected in the RT group, then in G2, G3, and control groups in order of decreasing frequency. However, the difference between the groups did not reach the level of statistical significance. Systemic propolis can be reduced acute mucositis with its anti-inflammatory effect without developing resistance to RT (tumor protection). However, greater number of clinical studies should be designed to arrive at definitive conclusions.

Ecdysterone Attenuates the Development of Radiation-Induced Oral Mucositis in Rats at Early Stage.

Oral mucositis is a common adverse reaction of radiotherapy used for head and neck cancers. Our research investigates the therapeutic effect and potential mechanisms of ecdysterone, a compound which was used as a functional food additive, isolated from the root of medicine-food herbs Achyranthes bidentata (Blume), on radiation-induced oral mucositis in rats during the early development stages of mucositis. In this study, male Sprague-Dawley rats received a single 20 Gy X-ray dose to the head and neck after placement of each animal in a specially-constructed 5-mm lead jig. At 24 h postirradiation, ecdysterone was administrated orally. Therapeutic effects of ecdysterone were investigated by observing weight changes and development of mucositis on days 5 and 10 after treatment. Determination of superoxide dismutase and malondialdehyde concentration was performed 5 days after treatment. H&E and leukocyte common antigen staining and TUNEL assays were performed 10 days after treatment. After 10 days of treatment, total protein from the tongue samples was extracted and Western blot analysis was performed to evaluate changes in protein expression. The results of this study showed that ecdysterone prevented the development of radiation-induced oral mucositis in rats during the early stages. Ecdysterone significantly attenuated radiation-induced decrease in cellular superoxide dismutase concentration and increase in malondialdehyde concentration. Ecdysterone was also linked to up-regulation of anti-apoptotic protein Bcl-2 and down-regulation of pro-apoptotic proteins Bax and cleaved caspase-3. In conclusion, these findings suggest that orally administrated ecdysterone alleviates the development of radiation-induced oral mucositis in rats with remarkable anti-oxidant and anti-apoptotic activities at early stages after irradiation.

Sumatriptan alleviates radiation-induced oral mucositis in rats by inhibition of NF-kB and ERK activation, prevention of TNF-α and ROS release

ObjectivesOral mucositis caused by radiation therapy is a common problem in cancer patients, especially those with head and neck cancer. Numerous experimental and clinical studies have attempted to find a drug to alleviate oral mucositis. Sumatriptan, is conventionally used to treat migraine attack and cluster headache. Recently, low doses have been shown to have anti-inflammatory properties. In this study we aimed to measure the effect of sumatriptan on experimental radiotherapy-induced oral mucositis. Material and MethodsThis study evaluates the use of sumatriptan 0.3 and 1 mg/kg in radiation-induced oral mucositis. In order to induce oral mucositis, six rats from each group received 8-Gy of X-ray in a single session. Likewise, three rats from each group received 26-Gy of X-ray. The latter dose of X-ray was used for inducing severe mucositis and apoptosis evaluation by TUNEL assay, while the first dose was used for histopathological and molecular assessments. On 8th day after irradiation, specimens were collected from their tongues for histology, TUNEL and molecular assessments. ResultsRadiation caused mucosal atrophy, derangement of the tissue and vasodilation. Sumatriptan significantly decreased histopathological score and alleviated mucosal atrophy. As well, there was no evidence of vasodilation in the sumatriptan group. Likewise, sumatriptan decreased the increased level of NF-kB and prevented its activation as well as ERK phosphorylation. In addition, Sumatriptan-treated rats had lower tissue level of TNF-α, reactive oxygen species and fewer apoptotic cells in TUNEL assay. ConclusionBased on study results, sumatriptan mitigate radiation-induced oral mucositis by inhibiting NF-kB, ERK and limiting the release of TNF-α, oxidative stress factor and apoptosis.

Preventive Effect of Glycine on 5-FU-Induced Oral Mucositis in Rats (Histological and Immunohistochemical Study)

OM is the most popular side effects of chemotherapy and it’s commonly caused by 5-Fluorouracil (5-FU). This study was aimed to assess the impact of glycine as a new option of treatment on experimentally induced oral mucositis in adult male rats. Thirty two male rats (Rattus novergicus) were divided at random in to control group (8 rats), 5-FU untreated group and 5-FU-glycine treated group (12 animals each). OM model induced by chemotherapy was instituted by intraperitoneal injection of 5-FU (60 mg\kg body weight) on days 0, 5, 10, 15 and the dorsal tongue was scratched (days 3, 4) by needle with gauge 18 to induce mucositis. The rats in treated group were received a 2mg\g intraperitoneal injection of 5% glycine daily (day 0-20). All rats were scarified at day 21, dorsal tongue mucosa sample was removed, prepared and examine by using histological and immunohistochemical (PCNA and BCL-2 immunostining) analysis. Glycine can protect the dorsal tongue mucosa from 5-FU induced cytotoxicity and alleviated the associated damage. In 5-FU/glycine group, both of the PCNA and BCL-2 immune expression was significantly increased (p?0.05) in comparison with 5-FU untreated group. Glycine provides protection toward 5-Fluorouracil induced tongue mucositis. It show fast epithelial propagation and wound healing through its antioxidant, anti-inflammatory and cytoprotective features.

Growth hormone modulates the inflammatory and apoptotic pathways incorporated in fluorouracil-induced oral mucositis in rats

Introduction: Oral mucositis (OM) is a well-known complication of radiotherapy (RT) and chemotherapy (CT) in cancer patients. Although, 5-flourouracil (5-FU) is one of the standard cytotoxic therapies, it is one of the most common causes of OM, which results in delay, dose reduction or treatment discontinuation, thus this intensifies the need for an effective chemoprotective agent. We aimed to investigate the potential chemoprotective effect of growth hormone (GH) on 5-FU-induced OM in rats. Material & Methods: Rats were either exposed to a single 5-FU injection (160 mg/kg ip) and/or treated with GH (1 mg/kg s.c). Oxidative stress, inflammatory and apoptotic markers were assessed. Results: An array of mucosal damage was produced as a result of 5-FU injection, which was evident by histopathology. 5-FU induced a remarkable increase in lipid peroxidation accompanied with a significant depletion of glutathione level. Besides, inflammatory cascades, including NF-κB and IL-6, were elevated significantly. Furthermore, 5-FU stimulated cell death through the significant increase of caspase-3. Interestingly, Pre-treatment with GH markedly ameliorated the deleterious effects of 5-FU through counteracting the oxidative stress and inflammation-mediated apoptosis. In addition, GH rescued the oral mucosal histology following chemotherapy. Conclusions: Our study is the first to demonstrate evidences for the effective chemoprotection provided by GH against 5-FU induced OM along with the underlying mechanisms, which may offer a promising adjuvant therapy for cancer patients.

Therapeutic Effect of Ecdysterone Combine Paeonol Oral Cavity Direct Administered on Radiation-Induced Oral Mucositis in Rats.

Radiation-induced oral mucositis represents an influential factor in cancer patients’ accepted radiation therapy, especially in head and neck cancer. This research investigates the treatment effect of Ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) and Paeonol (a compound derived from Cortex Moutan) on radiation-induced oral mucositis and possible underlying mechanisms. Concisely, 20 Gy of X-rays (single-dose) irradiated the cranial localization in rats for the modeling of oral mucositis. The therapeutic effects of Ecdysterone-Paeonol oral cavity directly administered on radiation-induced oral mucositis were investigated by weight changes, direct observations, visual scoring methods, ulcer area/total area, and basic recovery days. Assessments of tumor necrosis factor α and interleukin-6 were performed to evaluate the inflammatory cytokines secretion in the damaged areas of tongues harvested post-treatment, and changes in signaling pathways were investigated by Western blotting. System Drug Target (SysDT) methods revealed the targets of Ecdysterone-Paeonol in order to support compound-target network construction. Four representative targets with different functions were chosen. The binding interactions between the compound and receptor were evaluated by molecular docking to investigate the binding affinity of the ligand to their protein targets. Ecdysterone-Paeonol, administered orally, effectively improved radiation-induced oral mucositis in rats, and the therapeutic effect was better than Ecdysterone administered orally on its own. In this study, calculational chemistry revealed that Ecdysterone-Paeonol affected 19 function targets associated with radiation-induced oral mucositis, including apoptosis, proliferation, inflammation, and wound healing. These findings position Ecdysterone-Paeonol as a potential treatment candidate for oral mucositis acting on multiple targets in the clinic.

Ecdysterone Accelerates Healing of Radiation-Induced Oral Mucositis in Rats by Increasing Matrix Cell Proliferation.

Development of oral mucositis represents a rate-limiting factor in radiation therapy for the treatment of head and neck, as well as other cancers. In this work, we investigated the treatment effect of ecdysterone (a steroid derived from the dry root of Achyranthes bidentate) on radiation-induced oral mucositis, and examined possible underlying mechanisms. Male Sprague-Dawley rats were exposed to 20 Gy X-ray irradiation (single dose, cranial localization) to induce oral mucositis. Possible therapeutic effects of ecdysterone on radiation-induced oral mucositis were investigated by monitoring weights, direct observations, visual scoring method and evaluation of hematoxylin and eosin staining. Assessments of leukocyte common antigen and proliferating cell nuclear antigen staining were also performed in the damaged areas of tongues harvested after irradiation, and changes in signaling pathways were investigated using Western blotting. The development and progression of radiation-induced oral mucositis in this model was similar to that observed in clinic patients. Ecdysterone effectively improved radiation-induced oral mucositis as assessed by direct observation and histopathology, and also increased proliferation of matrix cells, since the Ras-Raf-ERK signal pathway was found to be activated by its use. It was concluded that orally administered ecdysterone accelerated the healing process in a rat model of radiation-induced oral mucositis by upregulating the Ras-Raf-ERK signal pathway.