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.

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Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms

Molecules ◽

10.3390/molecules26061676 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1676

Author(s):

Giulia Rossi ◽

Martina Placidi ◽

Chiara Castellini ◽

Francesco Rea ◽

Settimio D'Andrea ◽

...

Keyword(s):

In Vitro Model ◽

Molecular Mechanisms ◽

Biological Effects ◽

Cellular Damage ◽

X Rays ◽

Adolescent Cancer ◽

Radiation Induced ◽

Vitro Model ◽

Underlying Mechanisms

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 μM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period.

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Rab27B enhances drug resistance in hepatocellular carcinoma by promoting exosome-mediated drug efflux

Carcinogenesis ◽

10.1093/carcin/bgaa029 ◽

2020 ◽

Vol 41 (11) ◽

pp. 1583-1591 ◽

Cited By ~ 1

Author(s):

Rui Li ◽

Chengyong Dong ◽

Keqiu Jiang ◽

Rui Sun ◽

Yang Zhou ◽

...

Keyword(s):

Drug Resistance ◽

Liver Cancer ◽

Therapeutic Effect ◽

Efflux Pump ◽

Human Life ◽

Therapeutic Effects ◽

Drug Efflux ◽

Glycoprotein P ◽

Chemotherapy Drugs ◽

Underlying Mechanisms

Abstract Liver cancer is a major threat to human life and health, and chemotherapy has been the standard non-surgical treatment for liver cancer. However, the emergence of drug resistance of liver cancer cells has hindered the therapeutic effect of chemical drugs. The discovery of exosomes has provided new insights into the mechanisms underlying tumour cell resistance. In this study, we aimed to determine the proteins associated with drug resistance in tumour cells and to elucidate the underlying mechanisms. We found that Rab27B expression in drug (5-fluorouracil, 5Fu)-resistant Bel7402 (Bel/5Fu) cells increased significantly compared with that in drug-sensitive Bel7402 cells. In addition, Bel/5Fu cells secreted more exosomes under 5Fu stimulation. The number of exosomes secreted by Bel/5Fu cells significantly reduced after knocking down Rab27B, and the cellular concentration of 5Fu increased, enhancing its therapeutic effect. We also found that the administration of classical drug efflux pump (P-glycoprotein, P-gp) inhibitors together with knockdown of Rab27B further improved the therapeutic effects of chemotherapy drugs. In conclusion, our findings suggest that Rab27B could be a new therapeutic target in liver cancer.

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Effect of a mouth rinse formulation with human trefoil factor 1-secreting Lactococcus lactis in experimental oral mucositis in hamsters

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e14570 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e14570-e14570 ◽

Cited By ~ 2

Author(s):

P. Rottiers ◽

S. Caluwaerts ◽

L. Steidler ◽

K. Vandenbroucke ◽

B. Watkins ◽

...

Keyword(s):

Lactococcus Lactis ◽

Oral Mucosa ◽

Oral Mucositis ◽

Systemic Exposure ◽

Pharmacokinetic Studies ◽

Clinical Approach ◽

Mouth Rinse ◽

Weight Changes ◽

Hamster Model ◽

Radiation Induced

e14570 Background: Oral mucositis (OM) is a painful and dose-limiting toxicity of cancer chemotherapy and irradiation, characterized by breakdown of the oral mucosa. Trefoil factors (TFFs) are involved in protecting and healing mucosal tissue, and might thus represent a pharmacological tool for treatment of OM. Local delivery of recombinant TFFs at the oral mucosa by living, genetically modified Lactococcus (L.) lactis bacteria (ActoBiotics) seems a promising, safe and cost-effective clinical approach for the prevention and attenuation of oral mucositis. Methods: An environmentally contained Lactococcus lactis strain (AG013), engineered to express human (h)TFF1, was formulated for topical administration in the form of a mouth rinse. Efficacy of AG013 was assessed in a clinically relevant hamster model of acute, radiation-induced OM. The dosing regimen was 1.3 x 109 CFU/dose, once (qd) or three rinses (tid) daily, from day 0 (=day of radiation) to day 18. OM was scored from day 6 to day 28 using the WHO grading scale, and compared to the score of placebo-treated hamsters. The viability and survival of live L. lactis and the pharmacokinetics of the hTFF1 secreted were studied in healthy and OM hamsters. Results: Topical application of AG013 to the oral mucosa significantly reduced the severity and course of radiation-induced OM. In the AG013-treated groups, the number of animals days with ulcerative mucositis (grade 3 or higher) was significantly reduced to 27.5% and 30.8% (qd and tid respectively; P < 0.001), compared to 45.8 % in the placebo-treated group. Based on the observed survival and weight changes, AG013 appeared to be well-tolerated. Pharmacokinetic studies demonstrated that both living L. lactis and the hTFF1 secreted could be recovered from the administration site, for maximum 24 hours post-dosing, without systemic exposure. Conclusions: Oral administration of AG013 is safe and effective in reducing the severity and the course of OM in the hamster model, and therefore supports proof-of-concept for a mouth rinse formulation of AG013 to treat OM patients. [Table: see text]

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Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability

Cellular Physiology and Biochemistry ◽

10.1159/000485490 ◽

2017 ◽

Vol 44 (4) ◽

pp. 1295-1310 ◽

Cited By ~ 13

Author(s):

Bailong Li ◽

Cheng Li ◽

Mo Zhu ◽

Youjun Zhang ◽

Jicong Du ◽

...

Keyword(s):

Side Effects ◽

Lung Injury ◽

Therapeutic Effect ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Therapeutic Effects ◽

Antioxidant Ability ◽

Radiation Induced ◽

Hypoxia Treatment ◽

Proliferation Potential

Background/Aims: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI. Methods: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O2) or hypoxic conditions (2.5% O2). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included H&E staining, Masson staining and α-SMA staining; meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting. Results: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance. Conclusion: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

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Treatment of Yunnan Baiyao plus Kangfuxin Solution Reduces Inflammatory Response and Prevents Patients with Nasopharyngeal Carcinoma against Radiation-Induced Oral Mucositis

Journal of Nanomaterials ◽

10.1155/2021/9973539 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Xiuyu Tang ◽

Jiahui Sun ◽

Jie Deng ◽

Bin Shi

Keyword(s):

Nasopharyngeal Carcinoma ◽

Inflammatory Response ◽

Oral Mucositis ◽

Additional Treatment ◽

Inflammatory Factors ◽

Control Group ◽

Therapeutic Effects ◽

Study Group ◽

Radiation Induced ◽

Yunnan Baiyao

Oral mucositis refers to secondary mucosal damage, which usually occurs during cancer treatment. Generally, patients with head and neck cancers receiving radiotherapy will develop mucositis. Oral mucositis usually begins with mucosal inflammation and is characterized by erythema and confluent ulcers. The purpose of the study is to explore the therapeutic effects of Yunnan Baiyao combined with Kangfuxin solution on radiation-induced oral mucositis and the influence on production of inflammatory factors in patients with nasopharyngeal carcinoma (NPC) after radiotherapy. Clinical variables of 90 NPC patients were retrospectively analyzed. All patients underwent combined treatment (normal saline and inhalation of dexamethasone, gentamicin, and vitamin B12) 1st after radiotherapy, among which 45 patients received additional treatment of Yunnan Baiyao plus Kangfuxin solution and assigned as the study group. We found that additional treatment of Yunnan Baiyao plus Kangfuxin solution remarkably attenuated pain and dry mouth and reduced the degree of mucosal hyperaemia, edema, and ulceration in NPC patients undergoing radiotherapy ( P < 0.05 ). It was also found that additional treatment of Yunnan Baiyao plus Kangfuxin solution notably inhibited the release of inflammatory factors and cancer-related markers, as evidenced by lower serum levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), matrix metalloproteinase-9 (MMP-9), serum hypoxia-inducible factor-1 α (HIF-1α), and vascular endothelial growth factor (VEGF) detected in the study group than the control group ( P < 0.05 ). Additionally, the numbers of CD+3 and CD+4 subpopulations of T lymphocytes and the ratio of CD+4/CD+8 in the study group were significantly higher than those in the control group ( P < 0.05 ), and the number of CD+8 subpopulations in the study group was significantly lower than those in the control group ( P < 0.05 ). In conclusion, these results indicated that additional treatment of Yunnan Baiyao plus Kangfuxin solution reduces inflammatory response and prevents patients with NPC against radiation-induced oral mucositis.

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DDRE-18. THERAPEUTIC EFFECTS OF TASQUINIMOD ON GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.302 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi78-vi78

Author(s):

Junfeng Liu ◽

Raziye Piranlioglu ◽

Naoyuki Shono ◽

Alexander Lee Ling ◽

Himanshu Soni ◽

...

Keyword(s):

Therapeutic Effect ◽

Bone Marrow Cells ◽

Ex Vivo ◽

Xenograft Model ◽

Mouse Bone Marrow ◽

Therapeutic Effects ◽

M1 Phenotype ◽

Suppressive Phenotype ◽

Human Gbm ◽

Underlying Mechanisms

Abstract Glioblastoma is the most aggressive and most common primary malignant brain tumor in adults. This disease is still incurable despite multimodal therapies. We evaluated Tasquinimod, an oral HDAC4 inhibitor, in use with oncolytic HSV therapy. Tasquinimod is known to bind to HDAC4 and S100A9 to modulate myeloid population and angiogenesis in the tumors. This drug is being clinically evaluated in prostate and other solid tumors and multiple myeloma. However, the therapeutic effect of Tasquinimod in glioblastoma is not known. We found that Tasquinimod could change the immune-suppressive phenotype of MDSCs and polarize M2 macrophages towards M1 phenotype in ex vivo assay using mouse bone marrow cells treated with glioma conditioned media. We also tested Tasquinimod and oncolytic HSV in murine CT2A in C57/B6 mice and primary human GBM xenograft model in athymic mice. While the therapeutic effect of Tasquinimod or oHSV alone was not significant or marginal, the combo group show significantly longer survival. The study of underlying mechanisms is still ongoing. In conclusion, Tasquinimod combined with oncolytic HSV could have a better therapeutic effect on glioblastoma.

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A longitudinal evaluation of oral mucositis in patients receiving radiation therapy (IMRT) with/without chemotherapy (CTX)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e20572 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e20572-e20572

Author(s):

M. J. Dodd ◽

M. Cho ◽

C. Miaskowski ◽

J. Quivey

Keyword(s):

Weight Loss ◽

Functional Status ◽

Head And Neck ◽

Oral Mucositis ◽

Karnofsky Performance Status ◽

Performance Status ◽

Self Report ◽

Weight Changes ◽

Subjective Pain ◽

Underlying Mechanisms

e20572 Background: Oral mucositis is a major side effect of RT ± CTX to the head and neck. A variety of instruments and techniques have been used to quantify oral cavity changes during treatment. Few studies have reported on the evaluation of oral mucositis using both subjective and objective methods. A secondary aim in our study testing an innovative mouthwash is to increase our understanding of using subjective and objective methods for measuring oral mucositis, functional status, and weight changes over time. Methods: Patients reported functional status, pain and investigators measured oral mucositis and weight at four times (beginning of RT [T1], onset of mucositis [T2], end of RT [T3], and healing of mucositis [T4]) over a 10 - 15 week period, using the Karnofsky Performance Status [KPS]) and the Oral Mucositis Assessment Scale (OMAS). The OMAS measures researcher-evaluated ulceration/pseudomembrane formation and erythema in specific sites in the mouth, and self-report by patients, rating severity of mouth pain, ability to swallow and chew. Results: Of 51 head and neck cancer patients enrolled, 3 never developed mucositis. Mean days to onset of mucositis was 15.58 (SD 6.85), and mean days to healing of mucositis was 77.86 (SD 40.1). Mucositis pain scores (possible range 0–45) were moderate at T2 (x=6.25, SD 3.5) and T3 (x=12, SD 5.0). Subjective pain, chewing, and swallowing scores were positively correlated with each other (r= .31 - .73, p<.05) and objective oral mucositis scores were positively correlated with each other (r= .49 - .77, p<.01), however, no significant correlations were obtained between the subjective and objective scores. In both the RT-only group as well as the RT+CTX group, weight significantly decreased from T1 to T4, and KPS significantly decreased from T1 to T3. RT+CTX patients showed lower KPS and greater weight loss from T1 to T4 (X=10lbs) compared to the RT-only group (X=3 lbs), but neither was significantly different. Conclusions: During RT+CTX, patients need more supportive care to maintain functional status and avoid weight loss. Lack of correlations between the subjective and objective scores is interesting in that they are measuring something quite different, which may provide some insight into underlying mechanisms. No significant financial relationships to disclose.

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Therapeutic Assessment of Fractions of Hawthorn on Gastrointestinal Motility Disorder by UPLC-MS/MS-based Metabolomics

10.21203/rs.3.rs-47503/v1 ◽

2020 ◽

Author(s):

Kaiyang Wang ◽

Lan Luo ◽

Xiaoli Xu ◽

Xingyu Chen ◽

Qiong He ◽

...

Keyword(s):

Small Intestine ◽

Therapeutic Effect ◽

Gastrointestinal Motility ◽

High Performance ◽

Motility Disorder ◽

Therapeutic Effects ◽

Gastric Emptying Rate ◽

Gastrointestinal Motility Disorder ◽

Underlying Mechanisms ◽

Polar Parts

Abstract Background: Hawthorn, a commonly-used traditional Chinese medicine (TCM) for treating dyspepsia，dysmenorrhea and hyperlipidemia, etc., has been proven to improve gastrointestinal motility, avoid food retention. Due to its complex ingredients, the active fractions responsible for the treatment of improving digestion remain largely unknown. To explore the underlying material and interpret its potential mechanism, the therapeutic effect of extract from different polar parts of hawthorn on gastrointestinal motility disorder was studied based on the ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) metabolomics . Materials and Methods: The rat model of gastrointestinal motility disorder was established by subcutaneous injecting with atropine. The modeled rats were then treated with 4 polar parts (T1-4 in descending polarity, corresponding to water, n-butanol, ethyl acetate and petroleum ether extracts, respectively) of hawthorn for 5 consecutive days. The stomach, small intestine, plasma samples were collected and then subjected to related measurement (gastric emptying rate and small intestine propulsion rate), UPLC-MS/MS metabolic profiling and multivariate/univariate statistical analysis. Results: The results showed that T3 had the best therapeutic effect, and T1, T2 and T4 with no obvious therapeutic effect, demonstrating that the effective components of hawthorn should be compounds of medium polarity. T3 achieved good therapeutic effects due to the gastrointestinal motility promotion activity, and by rectifying the disturbed amino acid metabolism in gastrointestinal motility disorder model. Conclusion: This integrated metabolomics approach proved the validity of the therapeutic effect of extract from different polar parts of hawthorn on gastrointestinal motility disorder, providing new insights into the underlying mechanisms, and demonstrating the feasibility of metabolomics to evaluate efficacy of herbal drug, which is often difficult by traditional means.

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Probiotic Streptococcus salivarius K12 Alleviates Radiation-Induced Oral Mucositis in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.684824 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yan Wang ◽

Jiatong Li ◽

Haonan Zhang ◽

Xin Zheng ◽

Jiantao Wang ◽

...

Keyword(s):

Quality Of Life ◽

Treatment Outcome ◽

Oral Cavity ◽

Cancer Patients ◽

Oral Mucositis ◽

Oral Microbiota ◽

Microbial Culture ◽

Streptococcus Salivarius ◽

Radiation Induced

BackgroundOral mucositis is the most common oral complication of cancer patients receiving radiotherapy and/or chemotherapy, leading to poor quality of life. Limitations of the current interventions on radiation-induced oral mucositis (RIOM) urge the development of novel therapeutics. Here, we evaluated the treatment outcome of probiotic Streptococcus salivarius K12 on RIOM mice, and oral microbiota that is associated with the progress of RIOM was further investigated.MethodsAn experimental RIOM mouse model was established, and S. salivarius K12 was applied to the mouse oral cavity daily. Histological analyses were performed to evaluate the severity of oral mucositis and the treatment outcome of S. salivarius K12. The oral microbiota of mice was further analyzed by 16S rRNA sequencing, microbial culture and qPCR.Results Irradiation induced conspicuous mucositis in the oral cavity of mice. S. salivarius K12 treatment was beneficial for the healing of RIOM, as reflected by reduced ulcer size, increased basal layer epithelial cellularity and mucosal thickness, and elevated epithelial proliferation and attenuated apoptosis. RIOM mice presented significant oral microbial dysbiosis, with an overgrowth of oral anaerobes. S. salivarius K12 treatment reconstituted the oral microbiota and decreased the abundance of oral anaerobes of RIOM mice. In addition, S. salivarius K12 treatment inhibited NI1060 in Pasteurella genus and downregulated the expression of nitrate reductase.ConclusionsS. salivarius K12 treatment can alleviate RIOM and reconstituted the dysbiotic oral microbiota in mice. S. salivarius K12 may represent a promising adjuvant treatment to improve the quality of life of cancer patients receiving radiotherapy.

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