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Qiu YT, Luo XY, Deng YF, Zheng X, Qiu JG, Zhang LS, Huang XQ, Zheng XB, Huang HY. Modified Pulsatilla decoction alleviates 5-fluorouracil-induced intestinal mucositis by modulating the TLR4/MyD88/NF-κB pathway and gut microbiota. World J Gastroenterol 2025; 31:98806. [PMID: 39991674 PMCID: PMC11755253 DOI: 10.3748/wjg.v31.i7.98806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 11/19/2024] [Accepted: 12/25/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Modified Pulsatilla decoction (PD), a PD with licorice and ejiao, is a classic Traditional Chinese Medicine formula with significant efficacy in treating intestinal mucositis (IM) induced by tumor therapy. However, its specific molecular and biological mechanisms remain unclear. AIM To investigate the therapeutic effect and mechanism of modified PD in IM. METHODS This study used an IM mouse model established using 5-fluorouracil injections to investigate the effects of the modified PD (3, 6, and 12 g/kg) in IM. The primary chemical components of the modified PD were identified using liquid chromatography-mass spectrometry. Body weight loss, diarrhea scores, intestinal length, histopathological scores, and inflammatory cytokine levels were measured to evaluate the effects of the modified PD in IM. Effects on the TLR4/MyD88/NF-κB pathway were evaluated using western blot analysis. The intestinal microbiota was characterized using Illumina NovaSeq sequencing. RESULTS The results showed that modified PD significantly improved weight loss and diarrhea and shortened the intestines in IM mice. Mechanistically, modified PD suppressed the TLR4/MyD88/NF-κB pathway and downregulated the expression of reactive oxygen species, lipopolysaccharides, and pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ, IL-6, IL-8, and IL-17), while increasing the expression of the anti-inflammatory cytokine IL-10. Furthermore, modified PD protected the intestinal mucosal barrier by increasing the expression of tight junction proteins (occludin-1, claudin-1, and ZO-1) and mucin-2. Finally, 16S rDNA sequencing revealed that modified PD improved intestinal dysbiosis. CONCLUSION Our research offers new insights into the potential mechanism of modified PD in alleviating IM and provides experimental evidence supporting its pharmaceutical application in clinical IM treatment.
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Affiliation(s)
- Yi-Tong Qiu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
| | - Xin-Yi Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
- Druggability Research Team, Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan 523808, Guangdong Province, China
| | - Ya-Feng Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
| | - Xue Zheng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
- Druggability Research Team, Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan 523808, Guangdong Province, China
| | - Jian-Guo Qiu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
- Institute of Traditional Chinese Medicine, Dongguan Hospital of Traditional Chinese Medicine, Dongguan 523000, Guangdong Province, China
| | - Lin-Sheng Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
| | - Xiao-Qi Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
- Druggability Research Team, Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan 523808, Guangdong Province, China
| | - Xue-Bao Zheng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 525000, Guangdong Province, China
- Druggability Research Team, Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan 523808, Guangdong Province, China
| | - Hai-Yang Huang
- Institute of Traditional Chinese Medicine, Dongguan Hospital of Traditional Chinese Medicine, Dongguan 523000, Guangdong Province, China
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Zhu J, Li X, Huang M, Zhu H, Tan Y, He X, Sun Z, Cheng H, Li F, Jiang P, Lou H, Ke G, Cao X, Zhu L, Xie P, Yan J, Zhang F. Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial. Int J Radiat Oncol Biol Phys 2024; 120:720-729. [PMID: 38705489 DOI: 10.1016/j.ijrobp.2024.04.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/25/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE The purpose of this study was to evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS AND MATERIALS In this phase 3, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiation therapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiation therapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiation therapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea, ≥G1 and ≥G2 diarrhea lasting at least 3 days, and damage to the rectal mucosa due to radiation therapy measured by endoscopy. RESULTS Two hundred and eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 142). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs 14.8 and 4.5 days, respectively; P < .001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs 55.7%, P < .001). Three patients felt intolerable or abdominal pain after rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P = .061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P < .001). CONCLUSIONS The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.
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Affiliation(s)
- Jiawei Zhu
- Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xiaofan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Manni Huang
- Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Tan
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xia He
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhihua Sun
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Huijun Cheng
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Fenghu Li
- Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ping Jiang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| | - Hanmei Lou
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Guihao Ke
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xinping Cao
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lihong Zhu
- Radiotherapy Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Peng Xie
- Department of Gynecologic Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Junfang Yan
- Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
| | - Fuquan Zhang
- Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
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Teng Y, Li J, Guo J, Yan C, Wang A, Xia X. Alginate oligosaccharide improves 5-fluorouracil-induced intestinal mucositis by enhancing intestinal barrier and modulating intestinal levels of butyrate and isovalerate. Int J Biol Macromol 2024; 276:133699. [PMID: 38972652 DOI: 10.1016/j.ijbiomac.2024.133699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 07/03/2024] [Accepted: 07/04/2024] [Indexed: 07/09/2024]
Abstract
Chemotherapy-induced mucositis (CIM) is the typical side effect of chemotherapy. This study investigates the potential of alginate oligosaccharide (AOS) in ameliorating CIM induced by 5-fluorouracil (5-FU) in a murine model and its underlying mechanisms. AOS effectively mitigated body weight loss and histopathological damage, modulated inflammatory cytokines and attenuated the oxidative stress. AOS restored intestinal barrier integrity through enhancing expression of tight junction proteins via MLCK signaling pathway. AOS alleviated intestinal mucosal damage by inhibiting TLR4/MyD88/NF-κB signaling pathway, downregulating the pro-apoptotic protein Bax and upregulating the anti-apoptotic protein Bcl-2. Moreover, AOS significantly enriched intestinal Akkermansiaceae and increased the production of short-chain fatty acids (SCFAs), most notably butyrate and isovalerate. Pre-treatment with butyrate and isovalerate also alleviated 5-FU-induced CIM. In conclusion, AOS effectively mitigated CIM through strenghthening intestinal barrier, attenuating inflammation, and modulating gut microbiota and intestianl levels of butyrate and isovalerate. These finding indicate that AOS could be potentially utilized as a supplemental strategy for prevention or mitigation of CIM.
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Affiliation(s)
- Yue Teng
- Dalian Jinshiwan Laboratory, Dalian, Liaoning 116034, China; State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Jiahui Li
- Dalian Jinshiwan Laboratory, Dalian, Liaoning 116034, China; State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Jian Guo
- Dalian Jinshiwan Laboratory, Dalian, Liaoning 116034, China; State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Chunhong Yan
- Dalian Jinshiwan Laboratory, Dalian, Liaoning 116034, China; State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Ailing Wang
- Dalian Jinshiwan Laboratory, Dalian, Liaoning 116034, China; State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China
| | - Xiaodong Xia
- Dalian Jinshiwan Laboratory, Dalian, Liaoning 116034, China; State Key Laboratory of Marine Food Processing and Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, China.
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Kang EJ, Kim JH, Kim YE, Lee H, Jung KB, Chang DH, Lee Y, Park S, Lee EY, Lee EJ, Kang HB, Rhyoo MY, Seo S, Park S, Huh Y, Go J, Choi JH, Choi YK, Lee IB, Choi DH, Seo YJ, Noh JR, Kim KS, Hwang JH, Jeong JS, Kwon HJ, Yoo HM, Son MY, Kim YG, Lee DH, Kim TY, Kwon HJ, Kim MH, Kim BC, Kim YH, Kang D, Lee CH. The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation. Nat Commun 2024; 15:2983. [PMID: 38582860 PMCID: PMC10998920 DOI: 10.1038/s41467-024-47275-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 03/26/2024] [Indexed: 04/08/2024] Open
Abstract
Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/β-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/β-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.
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Affiliation(s)
- Eun-Jung Kang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Jae-Hoon Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Livestock Products Analysis Division, Division of Animal health, Daejeon Metropolitan City Institute of Health and Environment, Daejeon, 34146, Republic of Korea
| | - Young Eun Kim
- Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), Daejeon, 34113, Republic of Korea
- School of Earth Sciences & Environmental Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Hana Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Kwang Bo Jung
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Dong-Ho Chang
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Youngjin Lee
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Shinhye Park
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Eun-Young Lee
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Eun-Ji Lee
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Ho Bum Kang
- Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Moon-Young Rhyoo
- Laboratory Animal Resource Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Seungwoo Seo
- School of Earth Sciences & Environmental Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Sohee Park
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Bio-Molecular Science, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Yubin Huh
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Bio-Molecular Science, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Jun Go
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Jung Hyeon Choi
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Young-Keun Choi
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - In-Bok Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Dong-Hee Choi
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Yun Jeong Seo
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Jung-Ran Noh
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Kyoung-Shim Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Jung Hwan Hwang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Ji-Seon Jeong
- Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), Daejeon, 34113, Republic of Korea
- Department of Measurement Science, Korea Research Institute of Standards and Science (KRISS) School of Precision Measurement, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Ha-Jeong Kwon
- Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), Daejeon, 34113, Republic of Korea
| | - Hee Min Yoo
- Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), Daejeon, 34113, Republic of Korea
- Department of Measurement Science, Korea Research Institute of Standards and Science (KRISS) School of Precision Measurement, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Mi-Young Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Bio-Molecular Science, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Yeon-Gu Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Applied Biological Engineering, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Biotechnology, University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Dae-Hee Lee
- Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Biosystems and Bioengineering, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Biotechnology, University of Science and Technology (UST), Daejeon, 34141, Republic of Korea
| | - Tae-Young Kim
- School of Earth Sciences & Environmental Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Hyo-Jung Kwon
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Myung Hee Kim
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
| | - Byoung-Chan Kim
- Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- HealthBiome Inc., Daejeon, 34141, Republic of Korea
| | - Yong-Hoon Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea.
| | - Dukjin Kang
- Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), Daejeon, 34113, Republic of Korea.
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB) School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Republic of Korea.
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Zhou S, Sun Y, Wang K, Gao X, Dong K, Wang J, Wu X, Guo C. Polyvinylpyrrolidone-Polydatin nanoparticles protect against oxaliplatin induced intestinal toxicity in vitro and in vivo. Food Chem Toxicol 2024; 184:114427. [PMID: 38160781 DOI: 10.1016/j.fct.2023.114427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/18/2023] [Accepted: 12/25/2023] [Indexed: 01/03/2024]
Abstract
Oxaliplatin (OXL) is a first-line drug for the treatment of colon cancer, with excellent efficacy. Intestinal toxicity is a common side effect of OXL, with unclear pathogenesis and a lack of effective treatment strategies. Polydatin (PD) has anti-inflammatory and antioxidant activities and is a potential drug for treating intestinal diseases, but its poor water solubility limits its application. In this study, polyvinylpyrrolidone (PVP) was used as a carrier to prepare nanoparticles loaded with PD (PVP-PD), with a particle size of 92.42 nm and exhibiting sustained release properties. In vitro results showed that PVP-PD protected NCM460 cells from OXL induced injury, mitochondrial membrane potential (MMP) disruption, and accumulation of reactive oxygen species (ROS). The in vivo results demonstrated the protective effect of PVP-PD on intestinal toxicity induced by OXL, such as alleviating weight loss and colon length reduction induced by OXL. Both in vivo and in vitro mechanisms indicated that OXL induced DNA damage and activated the cGAS-STING pathway, further inducing the expression of inflammatory factors such as IL-1β and TNF-α. PVP-PD alleviated the aforementioned changes induced by OXL by inhibiting the DNA damage-cGAS-STING pathway. In summary, our study demonstrated that the DNA damage-cGAS-STING pathway was involved in OXL induced intestinal toxicity, and PVP-PD provided a potential strategy for treating OXL induced intestinal toxicity.
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Affiliation(s)
- Shilin Zhou
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China
| | - Yuxuan Sun
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China
| | - Kaidi Wang
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China
| | - Xintao Gao
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China
| | - Kehong Dong
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China
| | - Jing Wang
- Department of Biology Science and Technology, Baotou Teacher's College, Baotou, 014030, China
| | - Xiaochen Wu
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
| | - Chuanlong Guo
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China; Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China.
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Tang D, Qiu R, Qiu X, Sun M, Su M, Tao Z, Zhang L, Tao S. Dietary restriction rescues 5-fluorouracil-induced lethal intestinal toxicity in old mice by blocking translocation of opportunistic pathogens. Gut Microbes 2024; 16:2355693. [PMID: 38780487 PMCID: PMC11123560 DOI: 10.1080/19490976.2024.2355693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Chemotherapy remains a major treatment for malignant tumors, yet the application of standard dose intensity chemotherapy is limited due to the side effects of cytotoxic drugs, especially in old populations. The underlying mechanisms of cytotoxicity and strategies to increase the safety and tolerance of chemotherapy remain to be explored. Using 5-fluorouracil (5-FU), a cornerstone chemotherapeutic drug, we demonstrate that the main cause of death in ad libitum (AL) fed mice after 5-FU chemotherapy was infection caused by translocation of intestinal opportunistic pathogens. We show that these opportunistic pathogens greatly increase in the intestine after chemotherapy, which was closely related to loss of intestinal lysozyme. Of note, two weeks of dietary restriction (DR) prior to chemotherapy significantly protected the loss of lysozyme and increased the content of the beneficial Lactobacillus genera, resulting in a substantial inhibition of intestinal opportunistic pathogens and their translocation. The rescue effect of DR could be mimicked by Lysozyme or Lactobacillus gavage. Our study provides the first evidence that DR achieved a comprehensive protection of the intestinal physical, biological and chemical barriers, which significantly improved the overall survival of 5-FU-treated mice. Importantly, the above findings were more prominent in old mice. Furthermore, we show that patients over 65 years old have enriched opportunistic pathogens in their gut microbiota, especially after 5-FU based chemotherapy. Our study reveals important mechanisms for the poor chemotherapy tolerance of the elderly population, which can be significantly improved by short-term DR. This study generates new insights into methods for improving the chemotherapeutic prognosis by increasing the chemotherapy tolerance and safety of patients with malignant tumors.
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Affiliation(s)
- Duozhuang Tang
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Rongrong Qiu
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xingxing Qiu
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Man Sun
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Mingyue Su
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhendong Tao
- Department of Medical Laboratory Medicine, Jiangxi Province Hospital of Integrated Chinese & Western Medicine, Nanchang, Jiangxi, China
| | - Liu Zhang
- Intensive Care Unit, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
| | - Si Tao
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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7
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Luisa Valerio de Mello Braga L, Simão G, Silva Schiebel C, Caroline Dos Santos Maia A, Mulinari Turin de Oliveira N, Barbosa da Luz B, Rita Corso C, Soares Fernandes E, Maria Ferreira D. Rodent models for anticancer toxicity studies: contributions to drug development and future perspectives. Drug Discov Today 2023:103626. [PMID: 37224998 DOI: 10.1016/j.drudis.2023.103626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 05/08/2023] [Accepted: 05/17/2023] [Indexed: 05/26/2023]
Abstract
Antineoplastic treatment induces a type of gastrointestinal toxicity known as mucositis. Findings in animal models are usually easily reproducible, and standardized treatment regimens are often used, thus supporting translational science. Essential characteristics of mucositis, including intestinal permeability, inflammation, immune and oxidative responses, and tissue repair mechanisms, can be easily investigated in these models. Given the effects of mucositis on the quality of life of patients with cancer, and the importance of experimental models in the development of more effective new therapeutic alternatives, this review discusses progress and current challenges in using experimental models of mucositis in translational pharmacology research. Teaser Experimental models for studying gastrointestinal mucositis have provided a wealth of information improving the understanding of antineoplastic toxicity.
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Affiliation(s)
- Lara Luisa Valerio de Mello Braga
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Gisele Simão
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Carolina Silva Schiebel
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Andressa Caroline Dos Santos Maia
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Natalia Mulinari Turin de Oliveira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Bruna Barbosa da Luz
- Departamento de Farmacologia, Universidade Federal do Paraná, Curitiba, PR, Brazil
| | - Claudia Rita Corso
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Elizabeth Soares Fernandes
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Daniele Maria Ferreira
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil; Programa de Pós-graduação em Biotecnologia Aplicada à Saúde da Criança e do Adolescente, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil.
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8
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Huang B, Gui M, Ni Z, He Y, Zhao J, Peng J, Lin J. Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury. Microbiol Spectr 2022; 10:e0167722. [PMID: 36222691 PMCID: PMC9769542 DOI: 10.1128/spectrum.01677-22] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/20/2022] [Indexed: 02/07/2023] Open
Abstract
5-Fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (L-OHP), and calcium folinate (CF) are widely used chemotherapeutic drugs to treat colorectal cancer. However, chemotherapeutic use is often accompanied by intestinal inflammation and gut microbiota disorder. Changes in gut microbiota may destroy the intestinal barrier, which contributes to the severity of intestinal injury. However, intestinal injury and gut microbiota disorder have yet to be compared among 5-FU, CPT-11, L-OHP, and CF in detail, thereby limiting the development of targeted detoxification therapy after chemotherapy. In this study, a model of chemotherapy-induced intestinal injury in tumor-bearing mice was established by intraperitoneally injecting chemotherapeutic drugs at a clinically equivalent dose. 16S rRNA gene sequencing was used to detect gut microbiota. We found that 5-FU, CPT-11, and l-OHP caused intestinal injury, inflammatory cytokine (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β], and IL-6) secretion, and gut microbiota disorder. We established a complex but clear network between the pattern of changes in gut microbiota and degree of intestinal damage induced by different chemotherapeutic drugs. L-OHP caused the most severe damage in the intestine and disorder of the gut microbiota and showed a considerable overlap of the pattern of changes in microbiota with 5-FU and CPT-11. Analysis by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt v.1.0) showed that the microbiota disorder pattern induced by 5-FU, CPT-11, and L-OHP was related to the NOD-like signaling pathway. Therefore, we detected the protein expression of the NOD/RIP2/NF-κB signaling pathway and found that L-OHP most activated this pathway. Redundancy analysis/canonical correlation analysis (RDA/CCA) revealed that Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, Streptococcus, and "Candidatus Saccharimonas" were highly correlated with the NOD/RIP2/NF-κB signaling pathway and influenced by chemotherapeutic drugs. IMPORTANCE Chemotherapy-induced intestinal injury limits the clinical use of drugs. Intestinal injury involves multiple signaling pathways and gut microbiota disruption. Our results suggested that the degree of intestinal injury caused by different drugs of the first-line colorectal chemotherapy regimen is related to the pattern of changes in microbiota. The activation of the NOD/RIP2/NF-κB signaling pathway was also related to the pattern of changes in microbiota. l-OHP caused the most severe damage to the intestine and showed a considerable overlap of the pattern of changes in microbiota with 5-FU and CPT-11. Thirteen bacterial genera were related to different levels of intestinal injury and correlated with the NOD/RIP2/NF-κB pathway. Here, we established a network of different chemotherapeutic drugs, gut microbiota, and the NOD/RIP2/NF-κB signaling pathway. This study likely provided a new basis for further elucidating the mechanism and clinical treatment of intestinal injury caused by chemotherapy.
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Affiliation(s)
- Bin Huang
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Key Laboratory of Integrative Medicine of Fujian Province University, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Mengxuan Gui
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Zhuona Ni
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Yanbin He
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Jinyan Zhao
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Key Laboratory of Integrative Medicine of Fujian Province University, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Jun Peng
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Key Laboratory of Integrative Medicine of Fujian Province University, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
| | - Jiumao Lin
- Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
- Key Laboratory of Integrative Medicine of Fujian Province University, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China
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9
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Liu Y, Li H, Liu W, Guo J, Yang H, Tang H, Tian M, Nie H, Zhang X, Long W. Design of Monovalent Cerium-Based Metal Organic Frameworks as Bioinspired Superoxide Dismutase Mimics for Ionizing Radiation Protection. ACS APPLIED MATERIALS & INTERFACES 2022; 14:54587-54597. [PMID: 36468174 DOI: 10.1021/acsami.2c17358] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Superoxide dismutase (SOD) is one of the major antioxidants in vivo and is expected to play critical roles on the defense against reactive oxygen species (ROS)-mediated damages, such as ionizing radiation damages. Herein, inspired by the function and structure of natural SODs and cerium oxide nanozymes, two monovalent cerium-based metal organic frameworks (Ce-MOFs), CeIIIBTC and CeIVBTC, were designed for superoxide radical (O2•-) elimination and ionizing radiation protection. These two Ce-MOFs selectively scavenge O2•- and are excellent SOD mimics. Like natural SODs and cerium oxide nanozymes, the SOD-like catalytic mechanism of Ce-MOFs involves a cycle between Ce(IV) and Ce(III). Furthermore, by constructing monovalent Ce-MOFs, we found that high-valent CeIVBTC are more effective SOD-like nanozymes compared to CeIIIBTC. With smaller size, better monodispersity, and more effective SOD-like activity, CeIVBTC nanozymes were further applied for ionizing radiation protection. Both in vitro and in vivo results demonstrated that CeIVBTC nanozymes could efficiently scavenge ROS, prevent cells from γ-ray radiation-induced cell viability decrease and DNA damages, and improve the survival rate of irradiated mice by recovering the bone marrow DNA damage and alleviating oxidative stress of tissues. The protective effect and good biocompatibility of CeIVBTC nanozymes will enable the development of Ce-MOFs-based radioprotectants and facilitate treatment of other ROS-related diseases.
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Affiliation(s)
- Ya Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - He Li
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Wei Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Jiao Guo
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Haiyu Yang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Haikang Tang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Maoye Tian
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Hongmei Nie
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
| | - Xiaodong Zhang
- Tianjin Key Laboratory of Brain Science and Neural Engineering, Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin300072, China
| | - Wei Long
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin300192, China
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Huang J, Hwang AYM, Jia Y, Kim B, Iskandar M, Mohammed AI, Cirillo N. Experimental Chemotherapy-Induced Mucositis: A Scoping Review Guiding the Design of Suitable Preclinical Models. Int J Mol Sci 2022; 23:15434. [PMID: 36499758 PMCID: PMC9737148 DOI: 10.3390/ijms232315434] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/01/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022] Open
Abstract
Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen's Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans.
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Affiliation(s)
| | | | | | | | | | | | - Nicola Cirillo
- Melbourne Dental School, The University of Melbourne, Carlton, VIC 3053, Australia
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11
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Liao YF, Luo FL, Tang SS, Huang JW, Yang Y, Wang S, Jiang TY, Man Q, Liu S, Wu YY. Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis. Front Pharmacol 2022; 13:1014160. [PMID: 36278232 PMCID: PMC9582754 DOI: 10.3389/fphar.2022.1014160] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/20/2022] [Indexed: 11/21/2022] Open
Abstract
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.
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Affiliation(s)
- Yi-fan Liao
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Feng-lin Luo
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shan-shan Tang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Jing-wei Huang
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Sichuan Engineering & Technology Research Center of Coarse Cereal Industralization, Chengdu University, Chengdu, Sichuan, China
| | - Ying Yang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shuang Wang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Tang-yu Jiang
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Qiong Man
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
- *Correspondence: Yi-ying Wu, ; Qiong Man, ; Sha Liu,
| | - Sha Liu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
- *Correspondence: Yi-ying Wu, ; Qiong Man, ; Sha Liu,
| | - Yi-ying Wu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
- *Correspondence: Yi-ying Wu, ; Qiong Man, ; Sha Liu,
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12
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Ceylanlı D, Şehirli AÖ, Gençosman S, Teralı K, Şah H, Gülmez N, Sayıner S. Protective Effects of Alpha-Lipoic Acid against 5-Fluorouracil-Induced Gastrointestinal Mucositis in Rats. Antioxidants (Basel) 2022; 11:1930. [PMID: 36290656 PMCID: PMC9598092 DOI: 10.3390/antiox11101930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 03/23/2024] Open
Abstract
Alpha-lipoic acid (ALA) is extensively utilized in multivitamin formulas and anti-aging products. The purpose of this study was to investigate the potential protective benefits of ALA on 5-fluorouracil (5-FU)-induced gastrointestinal mucositis in Wistar albino rats. Tissues from the stomach, small intestine, and large intestine were excised, and blood sera were obtained to identify biochemical indices such as TNF-α, IL-1β, MDA, GPx, SOD, MMP-1, -2, -8, and TIMP-1. A histopathological study was also performed. The results revealed mucositis-elevated TNF-, IL-1, MDA, MMP-1, -2, -8, and TIMP-1 levels in both tissues and sera, and these values dropped dramatically following ALA treatment. Reduced SOD and GPx activities in mucositis groups were reversed in ALA-treated groups. The damage produced by mucositis in the stomach and small intestine regressed in the ALA-treated group, according to histopathological evaluation. Consequently, the implementation of ALA supplementation in 5-FU therapy may act as a protective intervention for cancer patients with gastrointestinal mucositis. In light of the findings, ALA, a food-derived antioxidant with pleiotropic properties, may be an effective treatment for 5-FU-induced gastrointestinal mucositus, and prevent oxidative stress, inflammation, and tissue damage in cancer patients receiving 5-FU therapy.
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Affiliation(s)
- Deniz Ceylanlı
- Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, 99138 Nicosia, North Cyprus, Turkey
| | - Ahmet Özer Şehirli
- Department of Pharmacology, Faculty of Dentistry, Near East University, 99138 Nicosia, North Cyprus, Turkey
| | - Sevgi Gençosman
- Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, 99138 Nicosia, North Cyprus, Turkey
| | - Kerem Teralı
- Department of Medical Biochemistry, Faculty of Medicine, Cyprus International University, 99258 Nicosia, Northern Cyprus, Turkey
| | - Hüseyin Şah
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Near East University, 99138 Nicosia, North Cyprus, Turkey
| | - Nurhayat Gülmez
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Siirt University, 56100 Siirt, Turkey
| | - Serkan Sayıner
- Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, 99138 Nicosia, North Cyprus, Turkey
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13
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Protective Effects of Oxyberberine in 5-Fluorouracil-Induced Intestinal Mucositis in the Mice Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1238358. [PMID: 35677366 PMCID: PMC9170416 DOI: 10.1155/2022/1238358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 04/10/2022] [Accepted: 05/03/2022] [Indexed: 11/27/2022]
Abstract
Berberine (BBR), a major active constituent of Rhizoma coptidis, was reported to exert beneficial effects on intestinal mucositis (IM) induced by 5-fluorouracil (5-FU). However, the bioavailability of BBR is extremely low, and its metabolites were perceived to contribute to its prominent pharmacological activities. Oxyberberine (OBB) is a gut metabolite of BBR, which has been reported to have a superior anti-inflammatory effect in experimental colitis. However, its anti-inflammatory effects against 5-FU-induced IM mice have not yet been investigated. Hence, the purpose of this study was to reveal the protective effects of OBB on IM induced by 5-FU and investigate its potential underlying mechanism. The IM mice model was induced by receiving 5-FU (60 mg/kg, i.p.) for five days. Meanwhile, BBR (50 mg/kg) and OBB (12.5, 25, and 50 mg/kg) were given prior to 30 min intraperitoneal injection of 5-FU for seven days. Results indicated that OBB ameliorated body weight loss, anorexia, diarrhea, and histopathological damage in 5-FU-induced IM mice. After OBB administration, the amounts of MDA, SOD, and GSH altered by IM were remarkably restored. OBB was also observed to dramatically decrease the levels of TNF-α, IL-8, IL-6, COX-2, and iNOS and promote the release of IL-10. Besides, OBB distinctly upregulated the mRNA expressions of PCNA, ZO-1, occludin, and mucin-1, which could improve intestinal homeostasis in IM mice. OBB also blocked the activation of the upstream TLR4/MyD88 signaling pathway, and then it inhibited the phosphorylation of the NF-κB and MAPK pathways. Importantly, compared with BBR, OBB displayed a superior therapeutic effect to BBR in alleviating 5-FU-induced IM mice. These results indicated that OBB has considerable potential to become a novel candidate drug against IM.
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The Intestinal Redox System and Its Significance in Chemotherapy-Induced Intestinal Mucositis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7255497. [PMID: 35585883 PMCID: PMC9110227 DOI: 10.1155/2022/7255497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/09/2022] [Indexed: 12/12/2022]
Abstract
Chemotherapy-induced intestinal mucositis (CIM) is a significant dose-limiting adverse reaction brought on by the cancer treatment. Multiple studies reported that reactive oxygen species (ROS) is rapidly produced during the initial stages of chemotherapy, when the drugs elicit direct damage to intestinal mucosal cells, which, in turn, results in necrosis, mitochondrial dysfunction, and ROS production. However, the mechanism behind the intestinal redox system-based induction of intestinal mucosal injury and necrosis of CIM is still undetermined. In this article, we summarized relevant information regarding the intestinal redox system, including the composition and regulation of redox enzymes, ROS generation, and its regulation in the intestine. We innovatively proposed the intestinal redox “Tai Chi” theory and revealed its significance in the pathogenesis of CIM. We also conducted an extensive review of the English language-based literatures involving oxidative stress (OS) and its involvement in the pathological mechanisms of CIM. From the date of inception till July 31, 2021, 51 related articles were selected. Based on our analysis of these articles, only five chemotherapeutic drugs, namely, MTX, 5-FU, cisplatin, CPT-11, and oxaliplatin were shown to trigger the ROS-based pathological mechanisms of CIM. We also discussed the redox system-mediated modulation of CIM pathogenesis via elaboration of the relationship between chemotherapeutic drugs and the redox system. It is our belief that this overview of the intestinal redox system and its role in CIM pathogenesis will greatly enhance research direction and improve CIM management in the future.
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Coêlho MC, Viana Filho JMC, Souza BFD, Valença AMG, Persuhn DC, Oliveira NFPD. Genetic polymorphisms of genes involved in oxidative stress and inflammatory management in oncopediatric patients with chemo-induced oral mucositis. J Appl Oral Sci 2022; 30:e20210490. [PMID: 35319668 PMCID: PMC8963388 DOI: 10.1590/1678-7757-2021-0490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 01/20/2022] [Indexed: 11/21/2022] Open
Abstract
Oral mucositis (OM) is a painful inflammatory oral condition that affects children who undergo chemotherapy. Oxidative stress is a known OM mediator and pro-inflammatory cytokines contribute to the amplification of the immune response.
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Affiliation(s)
- Marina Castro Coêlho
- Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, João Pessoa, Paraíba, Brasil
| | - José Maria Chagas Viana Filho
- Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, João Pessoa, Paraíba, Brasil
| | - Beatriz Fernandes de Souza
- Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, João Pessoa, Paraíba, Brasil
| | - Ana Maria Gondim Valença
- Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, João Pessoa, Paraíba, Brasil
| | - Darlene Camati Persuhn
- Universidade Federal da Paraíba - UFPB, Centro de Ciências Exatas e da Natureza, Departamento de Biologia Molecular, João Pessoa, Paraíba, Brasil
| | - Naila Francis Paulo de Oliveira
- Universidade Federal da Paraíba - UFPB, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, João Pessoa, Paraíba, Brasil.,Universidade Federal da Paraíba - UFPB, Centro de Ciências Exatas e da Natureza, Departamento de Biologia Molecular, João Pessoa, Paraíba, Brasil
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16
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Wang XL, Jiang RW. Therapeutic Potential of Superoxide Dismutase Fused with Cell-Penetrating Peptides in Oxidative Stress-Related Diseases. Mini Rev Med Chem 2022; 22:2287-2298. [PMID: 35227183 DOI: 10.2174/1389557522666220228150127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/17/2021] [Accepted: 12/27/2021] [Indexed: 11/22/2022]
Abstract
Superoxide dismutase (SOD) is a well-known cellular antioxidant enzyme. However, exogenous SOD cannot be used to protect tissues from oxidative damage due to the low permeability of the cell membrane. Cell-penetrating peptides (CPPs) are a class of short peptides that can cross the cell membrane. Recombinant fusion protein that fuses SOD protein with CPP (CPP-SOD) can cross various tissues and organs as well as the blood-brain barrier. CPP-SODs can relieve severe oxidative damage in various tissues caused by radiation, ischemia, inflammation, and chemotherapy by clearing the reactive oxygen species, reducing the expression of inflammatory factors, and inhibiting NF-κB/MAPK signaling pathways. Therefore, the clinical application of CPP-SODs provide new therapeutic strategies for a variety of oxidative stress-related disorders, such as Parkinson's disease, diabetes, obesity, cardiac fibrosis, and premature aging.
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Affiliation(s)
- Xiao-Lu Wang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China
| | - Ren-Wang Jiang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China
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17
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Hennigan JN, Lynch MD. The past, present, and future of enzyme-based therapies. Drug Discov Today 2022; 27:117-133. [PMID: 34537332 PMCID: PMC8714691 DOI: 10.1016/j.drudis.2021.09.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/15/2021] [Accepted: 09/10/2021] [Indexed: 01/03/2023]
Abstract
Enzyme-based therapeutics (EBTs) have the potential to tap into an almost unmeasurable amount of enzyme biodiversity and treat myriad conditions. Although EBTs were some of the first biologics used clinically, the rate of development of newer EBTs has lagged behind that of other biologics. Here, we review the history of EBTs, and discuss the state of each class of EBT, their potential clinical advantages, and the unique challenges to their development. Additionally, we discuss key remaining technical barriers that, if addressed, could increase the diversity and rate of the development of EBTs.
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Affiliation(s)
| | - Michael D Lynch
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
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18
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Deng S, Wu D, Li L, Li J, Xu Y. TBHQ attenuates ferroptosis against 5-fluorouracil-induced intestinal epithelial cell injury and intestinal mucositis via activation of Nrf2. Cell Mol Biol Lett 2021; 26:48. [PMID: 34794379 PMCID: PMC8600870 DOI: 10.1186/s11658-021-00294-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 11/05/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Intestinal mucositis is a common side effect of chemotherapy and radiotherapy. Very few drugs can efficiently ameliorate it. Tertiary butylhydroquinone (TBHQ) is a widely used food preservative with known immunomodulatory activity. Whether it has an effect on intestinal mucositis remains unknown. In this study, we investigated the role and mechanism of action of TBHQ on 5-fluorouracil-induced (5-FU-induced) human intestinal epithelial cell (HIEC) injury and intestinal mucositis in mice. METHODS We established a cell model of HIEC injury and a mouse model of intestinal mucositis via treatment with 5-FU. Cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release were assessed for the HIECs. Diarrhea, body weight, intestinal length, mucosal damage, and the levels of IL-6, TNF-α, IL-1β, glutathione, reactive oxygen species, and malondialdehyde were determined for the mice. Additionally, we performed immunohistochemical analysis, immunofluorescence, western blotting, quantitative real-time PCR, and ELISA to examine the effects of TBHQ. Finally, HIECs were transfected with an Nrf2 gene silencer to verify its role in ferroptosis. All data were analyzed using one-way analysis of variance or paired t-tests. RESULTS TBHQ markedly decreased LDH release and cell death and improved the proliferative ability of 5-FU-treated HIECs. The TBHQ-treated mice showed reduced weight loss, a lower diarrhea score, and longer colons than the 5-FU-treated mice. The in vivo expressions of IL-1β, IL-6, and TNF-α were suppressed by TBHQ treatment. Ferroptosis was shown to be involved in 5-FU-induced intestinal mucositis, and TBHQ markedly hampered its activation. Mechanistically, TBHQ activated Nrf2 effectively and selective Nrf2 knockdown significantly reduced the anti-ferroptotic functions of TBHQ in 5-FU-treated HIECs. CONCLUSIONS TBHQ attenuates ferroptosis in 5-FU-induced intestinal mucositis, making it a potential novel protective agent against intestinal mucositis.
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Affiliation(s)
- Shihua Deng
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China.,The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China
| | - Dongming Wu
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China.,The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China
| | - Li Li
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China.,The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China
| | - Jin Li
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China.,The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China
| | - Ying Xu
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China. .,The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China. .,School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan, 610500, People's Republic of China.
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Zeeshan M, Atiq A, Ain QU, Ali J, Khan S, Ali H. 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. Inflammopharmacology 2021; 29:1539-1553. [PMID: 34420176 DOI: 10.1007/s10787-021-00866-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 08/13/2021] [Indexed: 01/04/2023]
Abstract
OBJECTIVES 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. METHODS 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 (50 mg/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). RESULTS 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. CONCLUSION 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.
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Affiliation(s)
- Mahira Zeeshan
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Ayesha Atiq
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Qurat Ul Ain
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Jawad Ali
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Salman Khan
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan
| | - Hussain Ali
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, 45320, Pakistan.
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20
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Rosa AC, Corsi D, Cavi N, Bruni N, Dosio F. Superoxide Dismutase Administration: A Review of Proposed Human Uses. Molecules 2021; 26:1844. [PMID: 33805942 PMCID: PMC8037464 DOI: 10.3390/molecules26071844] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
Superoxide dismutases (SODs) are metalloenzymes that play a major role in antioxidant defense against oxidative stress in the body. SOD supplementation may therefore trigger the endogenous antioxidant machinery for the neutralization of free-radical excess and be used in a variety of pathological settings. This paper aimed to provide an extensive review of the possible uses of SODs in a range of pathological settings, as well as describe the current pitfalls and the delivery strategies that are in development to solve bioavailability issues. We carried out a PubMed query, using the keywords "SOD", "SOD mimetics", "SOD supplementation", which included papers published in the English language, between 2012 and 2020, on the potential therapeutic applications of SODs, including detoxification strategies. As highlighted in this paper, it can be argued that the generic antioxidant effects of SODs are beneficial under all tested conditions, from ocular and cardiovascular diseases to neurodegenerative disorders and metabolic diseases, including diabetes and its complications and obesity. However, it must be underlined that clinical evidence for its efficacy is limited and consequently, this efficacy is currently far from being demonstrated.
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Affiliation(s)
- Arianna Carolina Rosa
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
| | - Daniele Corsi
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
| | - Niccolò Cavi
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
| | - Natascia Bruni
- Istituto Farmaceutico Candioli, Strada Comunale di None, 1, 10092 Beinasco, Italy;
| | - Franco Dosio
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
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21
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Chen KJ, Chen YL, Ueng SH, Hwang TL, Kuo LM, Hsieh PW. Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil-induced intestinal mucositis. Biomed Pharmacother 2021; 134:111152. [PMID: 33373916 DOI: 10.1016/j.biopha.2020.111152] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/03/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND 5-Fluorouracil (5-FU)-based chemotherapy is first-line chemotherapy for colorectal cancer. However, 5-FU-induced intestinal mucositis (FUIIM) is a common adverse effect that severely impairs drug tolerance and results in poor patient health. METHODS Male C57BL/6 mice were given 5-FU (50 mg/kg/day, i.p.) and treated with MPH-966 (5 and 7.5 mg/kg/day, p.o.) for five days. The body weight loss and the amount of food intake, and histopathological findings were recorded and analyzed. In addition, the neutrophil infiltration, levels of neutrophil serine proteases and pro-inflammatory cytokines, and tight junction proteins expression in intestinal tissues were determined. The ecology of gut microbiota was performed through next-generation sequencing technologies. RESULTS Neutrophil elastase (NE) overexpression is a key feature in FUIIM. This study showed that treatment with the specific NE inhibitor MPH-966 (7.5 mg/kg/day, p.o.) significantly reversed 5-FU-induced loss in body weight and food intake; reversed villous atrophy; significantly suppressed myeloperoxidase, NE, and proteinase 3 activity; and reduced pro-inflammatory cytokine expression in an FUIIM mouse model. In addition, MPH-966 prevented 5-FU-induced intestinal barrier dysfunction, as indicated by the modulated expression of the tight junction proteins zonula occludin-1 and occludin. MPH-966 also reversed 5-FU-induced changes in gut microbiota diversity and abundances, specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae, Ruminococcaceae, and Eggerthellaceae abundances at the family level; and Candidatus Arthromitus abundance at the genus level. CONCLUSION These data indicate that NE inhibitor is a key treatment candidate to alleviate FUIIM by regulating abnormal inflammatory responses, intestinal barrier dysfunction, and gut microbiota imbalance.
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Affiliation(s)
- Kung-Ju Chen
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Li Chen
- Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shir-Hwa Ueng
- Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan
| | - Liang-Mou Kuo
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, 613, Taiwan.
| | - Pei-Wen Hsieh
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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22
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The gut microbiota attenuates muscle wasting by regulating energy metabolism in chemotherapy-induced malnutrition rats. Cancer Chemother Pharmacol 2020; 85:1049-1062. [PMID: 32415349 DOI: 10.1007/s00280-020-04060-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/12/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Malnutrition is a common clinical symptom in cancer patients after chemotherapy, which is characterized by muscle wasting and metabolic dysregulation. The regulation of muscle metabolism by gut microbiota has been studied recently. However, there is no direct convincing evidence proving that manipulating gut microbiota homeostasis could regulate muscle metabolic disorder caused by chemotherapy. Here, we investigate the potential role of gut microbiota in the regulation of the muscle metabolism in 5-fluorouracil (5-Fu)-induced malnutrition rat model. METHODS Male Sprague-Dawley rats were randomly divided into two groups (n = 8/group): control group and 5-Fu group. In the 5-Fu group, rats received 5-Fu (40 mg/kg/day) by intraperitoneal injection for 4 days, and all rats were raised for 8 days. Nutritional status, muscle function, muscle metabolites, and gut microbiota were assessed. Fecal microbiota transplantation (FMT) was applied to explore the potential regulation of gut microbiota on muscle metabolism. RESULTS 5-Fu-treated rats exhibited loss of body weight and food intake compared to control group. 5-Fu decreased the levels of total protein and albumin in serum, and significantly increased the levels of IL-6 and TNF-α in muscle tissue. Rats that received 5-Fu displayed concurrent reduction of muscle function and fiber size. Moreover, 5-Fu group showed a distinct profile of gut microbiota compared to control group, including the relative lower abundance of Firmicutes and a higher abundance of Proteobacteria and Verrucomicrobia. Fourteen differential muscle metabolites were identified between two groups, which were mainly related to glycolysis, amino acid metabolism, and TCA cycle pathway. Furthermore, fecal transplantation from healthy rats improved nutritional status and muscle function in 5-Fu-treated rats. Notably, FMT inhibited the inflammatory response in muscle, and reversed the changes of several differential muscle metabolites and energy metabolism in 5-Fu-treated rats. CONCLUSIONS Our study demonstrated that gut microbiota played an important role in the regulation of muscle metabolism and promoting muscle energy production in 5-Fu-induced malnutrition rats, suggesting the potential attenuation of chemotherapy-induced muscle wasting by manipulating gut microbiota homeostasis.
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