Research Article | | Peer-Reviewed

Effect of 3–3'diindolylmethane (DIM) on Acute Radiation Lung Injury in Mice Via the TGF-β1 Pathway

Received: 2 September 2023    Accepted: 18 September 2023    Published: 28 October 2023
Views:       Downloads:
Abstract

Objective: We studied the effect of 3–3'diindole methane (DIM) on acute radiation-induced lung injury (RILI) in mice and the possible underlying mechanism. Methods: A total of 45 mice were divided into five groups using the random number table method, namely, blank group, drug group alone (75 mg/kg DIM by peritoneal perfusion), simple irradiation group (one-time irradiation of 16 Gy), irradiation + drug group (one-time irradiation of 16 Gy + intraperitoneal perfusion of 75 mg/kg DIM 30 min before irradiation), and irradiation + prednisone group (one-time irradiation of 16 Gy + intraperitoneal perfusion of 5 mg/kg prednisone 30 min before irradiationas a positive control group). The whole lung was irradiated with a single dose of 16 Gy X-ray. Mice were killed by cervical dislocation at 24 h, 1 week, 2 weeks, and 4 weeks after irradiation, following which the lung tissue samples were subjected to hematoxylin and eosin (HE) staining. In addition, the expression of transforming growth factor (TGF)-β1/vascular endothelial growth factor (VEGF) pathway-related proteins was studied. Results: Under the same irradiation dose, the degree of lung injury in model mice after the intervention of DIM drugs was significantly lower than that in mice in the simple irradiation group. DIM significantly reduced the expression of TGF-β/VEGF-1 (P< 0.05). Conclusion: 3-3'diindolyl methane (DIM) can be downregulated by TGF-β1 signaling pathway, thereby reducing the expression of VEGF in lung tissue, inhibiting radiation-induced oxidative stress and inflammatory factor release in mouse lung tissue, and reducing the degree of RILI. These prospective experimental research results provide necessary experimental and theoretical basis for the application of 3-3'diindolemethane and its derivatives as new radiation protective drugs in clinical tumor radiotherapy.

Published in American Journal of Clinical and Experimental Medicine (Volume 11, Issue 4)
DOI 10.11648/j.ajcem.20231104.11
Page(s) 66-72
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

3–3'diindolylmethane (DIM), TGF-β1/VEGF Pathway, Mice, Radiotherapy, Radiation-Induced Lung Injury

References
[1] Lina Lu, Chao Sun, Qiong Su, Yanbin Wang, Jia Li, Zhong Guo,, et al. Radiation-induced lung injury: latest molecular developments, therapeutic approaches, and clinical guidance [J]. Clinical and Experimental Medicine, 2019, 19 (4): 417–426.
[2] Lorena Giuranno, Jonathan Ient, Dirk De Ruysscher. Radiation-Induced Lung Injury (RILI) [J]. Frontiers in Oncology, 2019, 9 (9): 877-877.
[3] DY Zhao, HJ Qu, JM Guo, HN Zhao, YY Yang, P Zhang, et al. Protective Effects of Myrtol Standardized Against Radiation-Induced Lung Injury [J]. Cellular Physiology & Biochemistry International Journal of Experimental Cellular Physiology Biochemistry & Pharmacology, 2016, 38 (2): 619-619.
[4] Fan S, Meng Q, Auborn K. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells [J]. British Journal of Cancer, 2006, 94 (3): 407-426.
[5] Fan S, Meng Q, Xu J. DIM (3,3"-diindolylmethane) confers protection against ionizing radiation by a unique mechanism [J]. Proceedings of the National Academy of Sciences, 2013, 110 (46): 18650-18655.
[6] Hanania A N, Mainwaring W, Ghebre Y T, Hanania N A, Ludwig M. Radiation-Induced Lung Injury: Assessment and Management [J]. Chest, 2019, 156 (1): 150-162.
[7] Hong ZY, Song KH, Yoon JH, Cho J, Story MD. An Experimental Model-Based Exploration of Cytokines in Ablative Radiation-Induced Lung Injury In Vivo and In Vitro [J]. Lung, 2015, 193 (3): 409-419.
[8] Reed GA, Sunega JM, Sullivan DK, Gray JC, Mayo MS, Crowell JA, et al. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'-diindolylmethane in healthy subjects [J]. Cancer Epidemiol Biomarkers Prev, 2008, 17 (10): 2619–2624.
[9] Chen Chen, Chen Shi-Ming, Xu Bin, Chen Zhe, Wang Fei, Ren Jie, et al. In vivo and in vitro study on the role of 3,3'-diindolylmethane in treatment and prevention of nasopharyngeal carcinoma. [J]. Carcinogenesis, 2013, 34 (8): 1815-1821.
[10] Li Yiwei, Kong Dejuan, Ahmad Aamir, Bao Bin, Sarkar Fazlul H., Cicek Muzaffer. Targeting Bone Remodeling by Isoflavone and 3,3'-diindolylmethane in the Context of Prostate Cancer [J]. Plos One, 2011, 7 (3): 1-11.
[11] Yiwei Li, Dejuan Kong, Aamir Ahmad, Bin Bao, Fazlul H Sarkar. Antioxidant function of isoflavone and 3,3'-diindolylmethane: are they important for cancer prevention and therapy? [J]. Antioxidants & Redox Signaling, 2013, 19 (2): 139-150.
[12] Singh NP, Singh UP, Rouse M, Zhang J, Chatterjee S, Nagarkatti PS, et al. Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA [J]. Journal of immunology. 2016; 196 (3): 1108-1122.
[13] X Wang, H He, Y Lu, W Ren, KY Teng, CL Chiang, et al. Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog [J]. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014, 1853 (1): 244-253.
[14] Zhang, Zhengping, Gao, Zhongfei, Hu, Wei, Yin, Shan, Wang, Chunming, Zang, Yuhui, et al. 3,3′-Diindolylmethane ameliorates experimental hepatic fibrosis via inhibiting miR-21 expression [J]. British Journal of Pharmacology, 2013, 170 (3): 649-660.
[15] Wenjing Wang, Maomin Lv, Chaoji Huangfu, Fang Wang, Jingang Zhang. 3,3'-Diindolylmethane: A Promising Sensitizer of γ-Irradiation. [J]. Biomed Research International, 2015, 2015 (5): 1-6.
[16] L Lu, J Dong, D Li, J Zhang, S Fan. 3,3-diindolylmethane mitigates total body irradiation-induced hematopoietic injury in mice [J]. Free Radic Biol Med, 2016, 99 (10): 463-471.
[17] Lina. Lu, Chao. Sun, Qiong. Su, Yanbin. Wang, Jia. Li, Zhong. Guo, et al. Radiation-induced lung injury: latest molecular developments, therapeutic approaches, and clinical guidance. Clin Exp Med. 2019 Nov; 19 (4): 417-426.
[18] Thompson HG, Mih JD, Krasieva TB, Tromberg BJ, George SC. Epithelial-derived TGF-beta2 modulates basal and wound-healing subepithelial ma-trix homeostasis [J]. Am J Physiol Lung Cell Mol Physiol, 2006, 291 (6): 1277-1285.
[19] Khalil N. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation [J]. J Exp Med, 1989, 170 (3): 727-737.
[20] Vujaskovic Z, Groen HJ. TGF-beta, radiation-induced pulmonary injury and lung cancer [J]. Intern J Rad Biol, 2000, 76 (4): 511-516.
[21] ANITA, B., ROBERTS, ANGELO, RUSSO, ANGELINA, FELICI, et al. Smad3: A Key Player in Pathogenetic Mechanisms Dependent on TGF-β [J]. Ann New York Acad Sci, 2003, 995 (1): 1-10.
[22] Mitchell S. Anscher M. D., Jennifer Garst M. D., Lawrence B. Marks M. D., Nicole Larrier M. D., Frank Dunphy M. D., James E. Herndon II Ph. D., et al. Assessing the ability of the antiangiogenic and anticytokine agent thalidomide to modulate radiation-induced lung injury [J]. Int J Rad Oncol Biol Phys, 2006, 66 (2): 477-482.
[23] SM Black, A Grobe, E Mata-Greenwood, Y Noskina. cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-β1 and reactive oxygen species: a requirement for NAD (P) H oxidase [J]. Am J Physiol Lung Cell Mol Physiol, 2005, 289 (2): 288-289.
Cite This Article
  • APA Style

    Qin Ge. (2023). Effect of 3–3'diindolylmethane (DIM) on Acute Radiation Lung Injury in Mice Via the TGF-β1 Pathway. American Journal of Clinical and Experimental Medicine, 11(4), 66-72. https://doi.org/10.11648/j.ajcem.20231104.11

    Copy | Download

    ACS Style

    Qin Ge. Effect of 3–3'diindolylmethane (DIM) on Acute Radiation Lung Injury in Mice Via the TGF-β1 Pathway. Am. J. Clin. Exp. Med. 2023, 11(4), 66-72. doi: 10.11648/j.ajcem.20231104.11

    Copy | Download

    AMA Style

    Qin Ge. Effect of 3–3'diindolylmethane (DIM) on Acute Radiation Lung Injury in Mice Via the TGF-β1 Pathway. Am J Clin Exp Med. 2023;11(4):66-72. doi: 10.11648/j.ajcem.20231104.11

    Copy | Download

  • @article{10.11648/j.ajcem.20231104.11,
      author = {Qin Ge},
      title = {Effect of 3–3'diindolylmethane (DIM) on Acute Radiation Lung Injury in Mice Via the TGF-β1 Pathway},
      journal = {American Journal of Clinical and Experimental Medicine},
      volume = {11},
      number = {4},
      pages = {66-72},
      doi = {10.11648/j.ajcem.20231104.11},
      url = {https://doi.org/10.11648/j.ajcem.20231104.11},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajcem.20231104.11},
      abstract = {Objective: We studied the effect of 3–3'diindole methane (DIM) on acute radiation-induced lung injury (RILI) in mice and the possible underlying mechanism. Methods: A total of 45 mice were divided into five groups using the random number table method, namely, blank group, drug group alone (75 mg/kg DIM by peritoneal perfusion), simple irradiation group (one-time irradiation of 16 Gy), irradiation + drug group (one-time irradiation of 16 Gy + intraperitoneal perfusion of 75 mg/kg DIM 30 min before irradiation), and irradiation + prednisone group (one-time irradiation of 16 Gy + intraperitoneal perfusion of 5 mg/kg prednisone 30 min before irradiationas a positive control group). The whole lung was irradiated with a single dose of 16 Gy X-ray. Mice were killed by cervical dislocation at 24 h, 1 week, 2 weeks, and 4 weeks after irradiation, following which the lung tissue samples were subjected to hematoxylin and eosin (HE) staining. In addition, the expression of transforming growth factor (TGF)-β1/vascular endothelial growth factor (VEGF) pathway-related proteins was studied. Results: Under the same irradiation dose, the degree of lung injury in model mice after the intervention of DIM drugs was significantly lower than that in mice in the simple irradiation group. DIM significantly reduced the expression of TGF-β/VEGF-1 (PConclusion: 3-3'diindolyl methane (DIM) can be downregulated by TGF-β1 signaling pathway, thereby reducing the expression of VEGF in lung tissue, inhibiting radiation-induced oxidative stress and inflammatory factor release in mouse lung tissue, and reducing the degree of RILI. These prospective experimental research results provide necessary experimental and theoretical basis for the application of 3-3'diindolemethane and its derivatives as new radiation protective drugs in clinical tumor radiotherapy.
    },
     year = {2023}
    }
    

    Copy | Download

  • TY  - JOUR
    T1  - Effect of 3–3'diindolylmethane (DIM) on Acute Radiation Lung Injury in Mice Via the TGF-β1 Pathway
    AU  - Qin Ge
    Y1  - 2023/10/28
    PY  - 2023
    N1  - https://doi.org/10.11648/j.ajcem.20231104.11
    DO  - 10.11648/j.ajcem.20231104.11
    T2  - American Journal of Clinical and Experimental Medicine
    JF  - American Journal of Clinical and Experimental Medicine
    JO  - American Journal of Clinical and Experimental Medicine
    SP  - 66
    EP  - 72
    PB  - Science Publishing Group
    SN  - 2330-8133
    UR  - https://doi.org/10.11648/j.ajcem.20231104.11
    AB  - Objective: We studied the effect of 3–3'diindole methane (DIM) on acute radiation-induced lung injury (RILI) in mice and the possible underlying mechanism. Methods: A total of 45 mice were divided into five groups using the random number table method, namely, blank group, drug group alone (75 mg/kg DIM by peritoneal perfusion), simple irradiation group (one-time irradiation of 16 Gy), irradiation + drug group (one-time irradiation of 16 Gy + intraperitoneal perfusion of 75 mg/kg DIM 30 min before irradiation), and irradiation + prednisone group (one-time irradiation of 16 Gy + intraperitoneal perfusion of 5 mg/kg prednisone 30 min before irradiationas a positive control group). The whole lung was irradiated with a single dose of 16 Gy X-ray. Mice were killed by cervical dislocation at 24 h, 1 week, 2 weeks, and 4 weeks after irradiation, following which the lung tissue samples were subjected to hematoxylin and eosin (HE) staining. In addition, the expression of transforming growth factor (TGF)-β1/vascular endothelial growth factor (VEGF) pathway-related proteins was studied. Results: Under the same irradiation dose, the degree of lung injury in model mice after the intervention of DIM drugs was significantly lower than that in mice in the simple irradiation group. DIM significantly reduced the expression of TGF-β/VEGF-1 (PConclusion: 3-3'diindolyl methane (DIM) can be downregulated by TGF-β1 signaling pathway, thereby reducing the expression of VEGF in lung tissue, inhibiting radiation-induced oxidative stress and inflammatory factor release in mouse lung tissue, and reducing the degree of RILI. These prospective experimental research results provide necessary experimental and theoretical basis for the application of 3-3'diindolemethane and its derivatives as new radiation protective drugs in clinical tumor radiotherapy.
    
    VL  - 11
    IS  - 4
    ER  - 

    Copy | Download

Author Information
  • Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, China

  • Sections