|
1
|
Seo Y, Ryu SM, Lee J, Jeong H, Choi G, Moon BC, Lim J, Nam H, Kim J, Lee S. Protective Effect of Cast-Off Skin of Cicadidae Periostracum Water Extract in a Radiation-Induced Testicular Injury Mice Model. Food Sci Nutr 2025; 13:e70198. [PMID: 40291930 PMCID: PMC12021667 DOI: 10.1002/fsn3.70198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/30/2025] Open
Abstract
Radiation therapy has been used to treat cancer; however, the associated DNA damage and adverse effects in the surrounding tissues remain major concerns. In radiation injury, several natural remedies can effectively relieve symptoms with minimal side effects. Cicadidae Periostracum (CP, also called "Sun-Tae") is the cast-off shell of Cryptotympana pustulata Fabricius and has been traditionally used for several pharmacological actions. This study investigated the protective effects of CP water extract (CPE) on irradiated testicular tissue and spermatogenesis. The chemical constituents of CPE were analyzed using a high-performance liquid chromatography system equipped with a mass detector and were determined to be dimeric N-acetyl dopamine derivatives. The testes and epididymal tissues of male C57BL/6 mice orally pretreated with CPE (25 and 50 mg/kg) 24 h and 15 min before radiation exposure (5 Gy) were collected for analysis. CPE pretreatment ameliorated radiation-induced apoptosis in the testes and inhibited weight loss in the epididymis compared to those of the irradiated group. Treatment with high-dose CPE prevented the radiation-induced decrease in the epithelial height of seminiferous tubules. In addition, the morphology, motility, and number of damaged sperm cells following radiation exposure were alleviated by CPE treatment. Furthermore, the dose-dependent antioxidative activity of CPE was confirmed in 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) radical scavenging assays, and reactive oxygen species generation by hydrogen peroxide was reduced by CPE treatment in vitro. Our findings suggest that pretreatment with CPE can ameliorate testicular tissue damage and sperm degeneration via the antioxidative properties of CPE in radiation-injured testis tissue.
Collapse
Affiliation(s)
- Yun‐Soo Seo
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| | - Seung Mok Ryu
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| | - Jun Lee
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| | - Huiyeong Jeong
- College of Veterinary Medicine and BK21 Plus Project TeamChonnam National UniversityGwangjuRepublic of Korea
| | - Goya Choi
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| | - Byeong Cheol Moon
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| | - Je‐Oh Lim
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| | - Hyeon‐Hwa Nam
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
- Department of Crop Science & BiotechnologyJeonbuk National UniversityJeonjuRepublic of Korea
| | - Joong‐Sun Kim
- College of Veterinary Medicine and BK21 Plus Project TeamChonnam National UniversityGwangjuRepublic of Korea
| | - Sueun Lee
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuRepublic of Korea
| |
Collapse
|
|
2
|
Liu X, Zheng T, Bao Y, Li P, Zhao T, Liu Y, Wang H, Sun C. Genistein Implications in Radiotherapy: Kill Two Birds with One Stone. Molecules 2025; 30:188. [PMID: 39795243 PMCID: PMC11723059 DOI: 10.3390/molecules30010188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/27/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025] Open
Abstract
More than 70% of cancer patients receive radiotherapy during their treatment, with consequent various side effects on normal cells due to high ionizing radiation doses despite tumor shrinkage. To date, many radioprotectors and radiosensitizers have been investigated in preclinical studies, but their use has been hampered by the high toxicity to normal cells or poor tumor radiosensitization effects. Genistein is a naturally occurring isoflavone found in soy products. It selectively sensitizes tumor cells to radiation while protecting normal cells from radiation-induced damage, thus improving the efficacy of radiotherapy and consequent therapeutic outcomes while reducing adverse effects. Genistein protects normal cells by its potent antioxidant effect that reduces oxidative stress and mitigates radiation-induced apoptosis and inflammation. Conversely, genistein increases the radiosensitivity of tumor cells through specific mechanisms such as the inhibition of DNA repair, the arrest of the cell cycle in the G2/M phase, the generation of reactive oxygen species (ROS), and the modulation of apoptosis. These effects increase the cytotoxicity of radiation. Preclinical studies demonstrated genistein efficacy in various cancer models, such as breast, prostate, and lung cancer. Despite limited clinical studies, the existing evidence supports the potential of genistein in improving the therapeutic effect of radiotherapy. Future research should focus on dosage optimization and administration, the exploration of combination therapies, and long-term clinical trials to establish genistein benefits in clinical settings. Hence, the unique ability of genistein to improve the radiosensitivity of tumor cells while protecting normal cells could be a promising strategy to improve the efficacy and safety of radiotherapy.
Collapse
Affiliation(s)
- Xiongxiong Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tong Zheng
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanyu Bao
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ping Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ting Zhao
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Liu
- School of Medical Imaging, Binzhou Medical University, Yantai 264003, China;
| | - Hui Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (X.L.); (T.Z.); (Y.B.); (P.L.); (T.Z.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| |
Collapse
|
|
3
|
Sun Y, Li Q, Huang Y, Yang Z, Li G, Sun X, Gu X, Qiao Y, Wu Q, Xie T, Sui X. Natural products for enhancing the sensitivity or decreasing the adverse effects of anticancer drugs through regulating the redox balance. Chin Med 2024; 19:110. [PMID: 39164783 PMCID: PMC11334420 DOI: 10.1186/s13020-024-00982-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 08/11/2024] [Indexed: 08/22/2024] Open
Abstract
Redox imbalance is reported to play a pivotal role in tumorigenesis, cancer development, and drug resistance. Severe oxidative damage is a general consequence of cancer cell responses to treatment and may cause cancer cell death or severe adverse effects. To maintain their longevity, cancer cells can rescue redox balance and enter a state of resistance to anticancer drugs. Therefore, targeting redox signalling pathways has emerged as an attractive and prospective strategy for enhancing the efficacy of anticancer drugs and decreasing their adverse effects. Over the past few decades, natural products (NPs) have become an invaluable source for developing new anticancer drugs due to their high efficacy and low toxicity. Increasing evidence has demonstrated that many NPs exhibit remarkable antitumour effects, whether used alone or as adjuvants, and are emerging as effective approaches to enhance sensitivity and decrease the adverse effects of conventional cancer therapies by regulating redox balance. Among them are several novel anticancer drugs based on NPs that have entered clinical trials. In this review, we summarize the synergistic anticancer effects and related redox mechanisms of the combination of NPs with conventional anticancer drugs. We believe that NPs targeting redox regulation will represent promising novel candidates and provide prospects for cancer treatment in the future.
Collapse
Affiliation(s)
- Yitian Sun
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Qinyi Li
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Yufei Huang
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Zijing Yang
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Guohua Li
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Xiaoyu Sun
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Xiaoqing Gu
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Yunhao Qiao
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China.
| | - Tian Xie
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China.
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China.
| | - Xinbing Sui
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China.
- College of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, Zhejiang, China.
| |
Collapse
|
|
4
|
Bansal K, Singh V, Mishra S, Bajpai M. Articulating the Pharmacological and Nanotechnological Aspects of Genistein: Current and Future Prospectives. Curr Pharm Biotechnol 2024; 25:807-824. [PMID: 38902930 DOI: 10.2174/0113892010265344230919170611] [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: 06/02/2023] [Revised: 08/10/2023] [Accepted: 08/19/2023] [Indexed: 06/22/2024]
Abstract
Throughout the past several centuries, herbal constituents have been the subject of scientific interest and the latest research into their therapeutic potential is underway. Genistein is a soy-derived isoflavone found in huge amounts in soy, along with the plants of the Fabaceae family. Scientific studies have demonstrated the beneficial effects of genistein on various health conditions. Genistein presents a broad range of pharmacological activities, including anticancer, neuroprotective, cardioprotective, antiulcer, anti-diabetic, wound healing, anti-bacterial, antiviral, skin, and radioprotective effects. However, the hydrophobic nature of genistein results in constrained absorption and restricts its therapeutic potential. In this review, the number of nanocarriers for genistein delivery has been explored, such as polymeric nanoparticles, nanostructured lipid carriers, solid lipid nanoparticles, liposomes, micelles, transferosomes, and nanoemulsions and nanofibers. These nano-formulations of genistein have been utilized as a potential strategy for various disorders, employing a variety of ex vivo, in vitro, and in vivo models and various administration routes. This review concluded that genistein is a potential therapeutic agent for treating various diseases, including cancer, neurodegenerative disorders, cardiovascular disorders, obesity, diabetes, ulcers, etc., when formulated in suitable nanocarriers.
Collapse
Affiliation(s)
- Keshav Bansal
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Vanshita Singh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Samiksha Mishra
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India
| | - Meenakshi Bajpai
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, Uttar Pradesh, India
| |
Collapse
|
|
5
|
Prades-Sagarra È, Yaromina A, Dubois LJ. Polyphenols as Potential Protectors against Radiation-Induced Adverse Effects in Patients with Thoracic Cancer. Cancers (Basel) 2023; 15:cancers15092412. [PMID: 37173877 PMCID: PMC10177176 DOI: 10.3390/cancers15092412] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Radiotherapy is one of the standard treatment approaches used against thoracic cancers, occasionally combined with chemotherapy, immunotherapy and molecular targeted therapy. However, these cancers are often not highly sensitive to standard of care treatments, making the use of high dose radiotherapy necessary, which is linked with high rates of radiation-induced adverse effects in healthy tissues of the thorax. These tissues remain therefore dose-limiting factors in radiation oncology despite recent technological advances in treatment planning and delivery of irradiation. Polyphenols are metabolites found in plants that have been suggested to improve the therapeutic window by sensitizing the tumor to radiotherapy, while simultaneously protecting normal cells from therapy-induced damage by preventing DNA damage, as well as having anti-oxidant, anti-inflammatory or immunomodulatory properties. This review focuses on the radioprotective effect of polyphenols and the molecular mechanisms underlying these effects in the normal tissue, especially in the lung, heart and esophagus.
Collapse
Affiliation(s)
- Èlia Prades-Sagarra
- The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ala Yaromina
- The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ludwig J Dubois
- The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| |
Collapse
|
|
6
|
Nam H, Kang S, Seo Y, Lee J, Moon BC, Lee HJ, Lee JH, Kim B, Lee S, Kim J. Protective effects of an aqueous extract of Protaetia brevitarsis seulensis larvae against radiation-induced testicular injury in mice. Food Sci Nutr 2022; 10:3969-3978. [PMID: 36348800 PMCID: PMC9632216 DOI: 10.1002/fsn3.2992] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022] Open
Abstract
The larvae of Protaetia brevitarsis seulensis have been used as a food ingredient and are known for their nutritional value and anti-inflammatory properties. However, whether P. brevitarsis seulensis larvae demonstrate protective effects against radiation-induced testicular injury has not been investigated. In this study, the protective effects of an aqueous extract of P. brevitarsis seulensis larvae (PBE) against radiation-induced testicular injury were tested. Male C57BL/6 mice were administered PBE (5 or 10 mg/kg) orally for 14 days before exposure to focal pelvic irradiation. Histopathological examinations were conducted at 8 h and 30 d after radiation exposure. PBE pretreatment reduced the radiation-induced apoptosis of germ cells at 8 h after irradiation and significantly increased testis and epididymis weights relative to those of the irradiated control mice at 30 days. PBE protected against histopathological damage and decreased the radiation-induced effects on the epithelium height and seminiferous tubule diameter. Furthermore, the extract ameliorated the radiation-induced morphological abnormalities of sperm cells and improved their motility. It also prevented a decrease in the epididymal sperm count caused by irradiation. Moreover, the extract alleviated the generation of reactive oxygen species, and its antioxidative activity increased in a dose-dependent manner. Among the six major compounds isolated from PBE, benzoic acid and uridine showed the highest antioxidant activities. These results suggest that PBE protects against radiation-induced testicular injury via its antioxidative properties. Thus, it has potential clinical applicability as a neoadjuvant therapy for the prevention of testicular damage caused by cancer radiotherapy.
Collapse
Affiliation(s)
- Hyeon‐Hwa Nam
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuKorea
| | - Sohi Kang
- College of Veterinary Medicine and BK21 Plus Project TeamChonnam National UniversityGwangjuKorea
| | - Yun‐Soo Seo
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuKorea
| | - Jun Lee
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuKorea
| | - Byeong Cheol Moon
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuKorea
| | - Hae June Lee
- Divison of Radiation Biomedical ResearchKorea Institute of Radiological and Medicinal SciencesSeoulKorea
| | - Ji Hye Lee
- College of Korean MedicineSemyung UniversityJecheonKorea
| | - Bohye Kim
- College of Veterinary Medicine and BK21 Plus Project TeamChonnam National UniversityGwangjuKorea
| | - Sueun Lee
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuKorea
| | - Joong‐Sun Kim
- Herbal Medicine Resources Research CenterKorea Institute of Oriental MedicineNajuKorea
- College of Veterinary Medicine and BK21 Plus Project TeamChonnam National UniversityGwangjuKorea
| |
Collapse
|
|
7
|
Ivashkevich A. The role of isoflavones in augmenting the effects of radiotherapy. Front Oncol 2022; 12:800562. [PMID: 36936272 PMCID: PMC10016616 DOI: 10.3389/fonc.2022.800562] [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: 10/23/2021] [Accepted: 08/31/2022] [Indexed: 03/05/2023] Open
Abstract
Cancer is one of the major health problems and the second cause of death worldwide behind heart disease. The traditional soy diet containing isoflavones, consumed by the Asian population in China and Japan has been identified as a protective factor from hormone-related cancers. Over the years the research focus has shifted from emphasizing the preventive effect of isoflavones from cancer initiation and promotion to their efficacy against established tumors along with chemo- and radiopotentiating effects. Studies performed in mouse models and results of clinical trials emphasize that genistein or a mixture of isoflavones, containing in traditional soy diet, could be utilized to both potentiate the response of cancer cells to radiotherapy and reduce radiation-induced toxicity in normal tissues. Currently ongoing clinical research explores a potential of another significant isoflavone, idronoxil, also known as phenoxodiol, as radiation enhancing agent. In the light of the recent clinical findings, this article reviews the accumulated evidence which support the clinically desirable interactions of soy isoflavones with radiation therapy resulting in improved tumor treatment. This review discusses important aspects of the development of isoflavones as anticancer agents, and mechanisms potentially relevant to their activity in combination with radiation therapy of cancer. It gives a critical overview of studies characterizing isoflavone targets such as topoisomerases, ENOX2/PMET, tyrosine kinases and ER receptor signaling, and cellular effects on the cell cycle, DNA damage, cell death, and immune responses.
Collapse
Affiliation(s)
- Alesia Ivashkevich
- Faculty of Engineering and Information Sciences, University of Wollongong, Wollongong, NSW, Australia
- Noxopharm, Gordon, NSW, Australia
- *Correspondence: Alesia Ivashkevich,
| |
Collapse
|
|
8
|
Evaluation of Global DNA Methylation and Gene Expression of Izumo1 and Izumo1r in Gonads after High- and Low-Dose Radiation in Neonatal Mice. BIOLOGY 2021; 10:biology10121270. [PMID: 34943185 PMCID: PMC8698457 DOI: 10.3390/biology10121270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/11/2021] [Accepted: 12/01/2021] [Indexed: 11/17/2022]
Abstract
The intergenerational effects from chronic low-dose exposure are matters of concern. It is thus important to elucidate the radiation-induced effects of germ cell maturation, fertilization and embryonic development. It is well known that DNA methylation levels in CpG sites in gametes are reprogrammed in stages during their maturity. Furthermore, the binding of Izumo on the surface of sperm and Juno on the surface of oocytes is essential for fertilization. Thus, there is a possibility that these genes are useful indicators to evaluate fertility in mice after irradiation exposure. Therefore, in this study, we analyzed global DNA methylation patterns in the testes and gene expression of Izumo1 and Izumo1r (Juno) in the gonads of mice after neonatal acute high-dose ionizing radiation (HDR) and chronic low-dose ionizing radiation (LDR). One-week-old male and female mice were irradiated with a total dose of 4 Gy, with acute HDR at 7 days at a dose rate of 30 Gy/h and LDR continuously at a dose rate of 6 mGy/h from 7 to 35 days. Their gonads were subsequently analyzed. The results of global DNA methylation patterns in the testes showed that methylation level increased with age in the control group, the LDR group maintained its DNA methylation level, and the HDR group showed decreased DNA methylation levels with age. In the control group, the gene expression level of Izumo1 in the testis did not show age-related changes, although there was high expression at 100 days of age. However, in the LDR group, the expression level recovered after the end of irradiation, while it remained low regardless of age in the HDR group. Conversely, gene expression of Izumo1r (Izumo1 receptor) in the ovary decreased with age in the control group. Although the gene expression of Izumo1r decreased with age in the LDR group, it remained low in the HDR group. Our results indicate that LDR can induce different DNA methylation patterns, and both high- and low-dose radiation before sexual maturity might affect gametogenesis and fertility.
Collapse
|
|
9
|
Singh VK, Fatanmi OO, Wise SY, Carpenter A, Nakamura-Peek S, Serebrenik AA, Kaytor MD. A novel oral formulation of BIO 300 confers prophylactic radioprotection from acute radiation syndrome in mice. Int J Radiat Biol 2021; 98:958-967. [PMID: 34554032 DOI: 10.1080/09553002.2021.1981556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE). There is no radiation medical countermeasure (MCM) approved by the U.S. Food and Drug Administration which can be used prior to radiation exposure to protect exposed individuals. Different formulations containing synthetic genistein (BIO 300) are being developed to counter the harmful effects of radiation exposure. MATERIALS AND METHODS We investigated the efficacy of a BIO 300 oral powder (OP) formulation as a prophylactic radiation MCM against a lethal dose of cobalt-60 gamma-radiation in CD2F1 male mice while comparing to other formulations of BIO 300 and Neulasta (PEGylated filgrastim), a standard of care drug for H-ARS. RESULTS BIO 300 OP provided significant radioprotection against ionizing radiation in mice when administered twice per day for six days prior to total-body radiation exposure. Its radioprotective efficacy in the murine model was comparable to the efficacy of a single subcutaneous (sc) injection of Neulasta administered after total-body radiation exposure. CONCLUSIONS Our results demonstrate that BIO 300 OP, which can be administered orally, is a promising prophylactic radiation countermeasure for H-ARS.
Collapse
Affiliation(s)
- Vijay K Singh
- Department of Pharmacology and Molecular Therapeutics, Division of Radioprotectants, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Oluseyi O Fatanmi
- Department of Pharmacology and Molecular Therapeutics, Division of Radioprotectants, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Stephen Y Wise
- Department of Pharmacology and Molecular Therapeutics, Division of Radioprotectants, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Alana Carpenter
- Department of Pharmacology and Molecular Therapeutics, Division of Radioprotectants, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Sara Nakamura-Peek
- Department of Pharmacology and Molecular Therapeutics, Division of Radioprotectants, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | | | | |
Collapse
|
|
10
|
Chico-Sordo L, Córdova-Oriz I, Polonio AM, S-Mellado LS, Medrano M, García-Velasco JA, Varela E. Reproductive aging and telomeres: Are women and men equally affected? Mech Ageing Dev 2021; 198:111541. [PMID: 34245740 DOI: 10.1016/j.mad.2021.111541] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023]
Abstract
Successful reproduction is very important for individuals and for society. Currently, the human health span and lifespan are the object of intense and productive investigation with great achievements, compared to the last century. However, reproduction span does not progress concomitantly with lifespan. Reproductive organs age, decreasing the levels of sexual hormones, which are protectors of health through their action on several organs of the body. Thus, this is the starting point of the organismal decay and infertility. This starting point is easily detected in women. In men, it goes under the surface, undetected, but it goes, nevertheless. Regarding fertility, aging alters the hormonal equilibrium, decreases the potential of reproductive organs, diminishes the quality of the gametes and worsen the reproductive outcomes. All these events happen at a different pace and affecting different organs in women and men. The question is what molecular pathways are involved in reproductive aging and if there is a possible halting or even reversion of the aging events. Answers to all these points will be explained in the present review.
Collapse
Affiliation(s)
- Lucía Chico-Sordo
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
| | - Isabel Córdova-Oriz
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
| | - Alba María Polonio
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
| | - Lucía Sánchez S-Mellado
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
| | - Marta Medrano
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; IVIRMA Madrid, Spain.
| | - Juan Antonio García-Velasco
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Madrid, Spain; Rey Juan Carlos University, Madrid, Spain.
| | - Elisa Varela
- IVI Foundation, Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain; Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Rey Juan Carlos University, Madrid, Spain.
| |
Collapse
|
|
11
|
Yi J, Zhu J, Zhao C, Kang Q, Zhang X, Suo K, Cao N, Hao L, Lu J. Potential of natural products as radioprotectors and radiosensitizers: opportunities and challenges. Food Funct 2021; 12:5204-5218. [PMID: 34018510 DOI: 10.1039/d1fo00525a] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Natural products can be used as natural radiosensitizers and radioprotectors, showing promising effects in cancer treatments in combination with radiotherapy, while reducing ionizing radiation (IR) damage to normal cells/tissues. The different effects of natural products on irradiated normal and tumor cells/tissues have attracted more and more researchers' interest. Nonetheless, the clinical applications of natural products in radiotherapy are few, which may be related to their low bioavailability in the human body. Here, we displayed the radiation protection and radiation sensitization of major natural products, highlighted the related molecular mechanisms of these bioactive substances combined with radiotherapy to treat cancer, and critically reviewed their deficiency and improved measures. Lastly, several clinical trials were presented to verify the clinical application of natural products as radiosensitizers and radioprotectors. Further clinical evaluation is still needed. This review provides a reference for the utilization of natural products as radiosensitizers and radioprotectors.
Collapse
Affiliation(s)
- Juanjuan Yi
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Jiaqing Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Changcheng Zhao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Qiaozhen Kang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Xiaomiao Zhang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Keke Suo
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Nana Cao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Limin Hao
- Institute of Quartermaster Engineering and Technology, Academy of Military Sciences PLA China, Beijing, 100010, China.
| | - Jike Lu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China.
| |
Collapse
|
|
12
|
Comparative proteomic analysis of serum from nonhuman primates administered BIO 300: a promising radiation countermeasure. Sci Rep 2020; 10:19343. [PMID: 33168863 PMCID: PMC7653926 DOI: 10.1038/s41598-020-76494-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 10/28/2020] [Indexed: 11/12/2022] Open
Abstract
Hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE) are detrimental health effects that occur after exposure to high doses of ionizing radiation. BIO 300, a synthetic genistein nanosuspension, was previously proven safe and effective against H-ARS when administered (via the oral (po) or intramuscular (im) route) prior to exposure to lethal doses of total-body radiation. In this study, we evaluated the proteomic changes in serum of nonhuman primates (NHP) after administering BIO 300 by different routes (po and im). We utilized nanoflow-ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (NanoUPLC-MS/MS) methods for comprehensive global profiling and quantification of serum proteins. The results corroborate previous findings that suggest a very similar metabolic profile following both routes of drug administration. Furthermore, we observed minor alterations in protein levels, 2 hours after drug administration, which relates to the Cmax of BIO 300 for both routes of administration. Taken together, this assessment may provide an insight into the mechanism of radioprotection of BIO 300 and a reasonable illustration of the pharmacodynamics of this radiation countermeasure.
Collapse
|
|
13
|
Haddad YH, Said RS, Kamel R, Morsy EME, El-Demerdash E. Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-β, TGF-β, and FOXL-2. Sci Rep 2020; 10:13551. [PMID: 32782329 PMCID: PMC7419553 DOI: 10.1038/s41598-020-70309-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 07/14/2020] [Indexed: 01/17/2023] Open
Abstract
Radiotherapy is a well-known cause of premature ovarian failure (POF). Therefore, we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to ϒ-radiation. Female Sprague Dawley rats were exposed to a 3.2 Gy γ-radiation to induce POF and/or treated with either GEN (5 mg/kg, i.p.) or Ethinyl estradiol (E2; 0.1 mg/kg, s.c.), once daily for 10 days. GEN was able to conserve primordial follicles stock and population of growing follicles accompanied with reduction in atretic follicles. GEN restored the circulating estradiol and anti-Müllerian hormone levels which were diminished after irradiation. GEN has potent antioxidant activity against radiation-mediated oxidative stress through upregulating endogenous glutathione levels and glutathione peroxidase activity. Mechanistically, GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. On the molecular basis, GEN reversed ovarian apoptosis through up-regulation of ER-β and FOXL-2 with downregulation of TGF-β expression, therefore inhibiting transition of primordial follicles to more growing follicles. GEN may constitute a novel therapeutic modality for safeguarding ovarian function of females' cancer survivors.
Collapse
Affiliation(s)
| | - Riham S Said
- Department of Drug Radiation Research, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt
| | - Rehab Kamel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Engy M El Morsy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
| |
Collapse
|
|
14
|
Khani HM, Shariati M, Forouzanfar M, Hosseini SE. Protective effects of Ceratonia siliqua extract on protamine gene expression, testicular function, and testicular histology in doxorubicin-treated adult rats: An experimental study. Int J Reprod Biomed 2020; 18:667-682. [PMID: 32923932 PMCID: PMC7457156 DOI: 10.18502/ijrm.v13i8.7507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 12/14/2019] [Accepted: 04/27/2020] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Spermatogenesis is a complex process that takes place under the influence of many different genes. OBJECTIVE The aim of this study was to investigate the possible effects of Ceratonia siliqua hydroalcoholic extract (CSHAE) on protamine gene expression, testicular function, and testicular histology in doxorubicin-treated rats. MATERIALS AND METHODS 56 adult male rats with a age range of 2.5 to 3 months (210 ± 10 gr) were divided into seven groups (n = 8/each). A) Control group was left untreated; B) Sham group received 0.3 ml distilled water intraperitoneally, C) Negative control group received 3 mg/kg doxorubicin, intraperitoneally once a week for 28 days; and D) Positive control group received 600 mg/kg of CSHAE orally for 48 days; E, F, G) the experimental groups 1, 2, and 3 received 150, 300, and 600 mg/kg of CSHAE respectively orally, for 48 days, as well as 3 mg/kg doxorubicin once a week for 28 days. Hematoxylin-eosin staining was used in the histological study of testes, and enzyme-linked immunosorbent assay method was used in measuring serum levels of testosterone. Protamine gene expression was determined by real-Time PCR method. RESULTS The mean body weight, testicular weight, testicular volume, testosterone level (p = 0.022), the count of Leydig, spermatogonia, spermatocyte, and spermatid cells, as well as protamine gene expression (p = 0.008) were significantly increased in the experimental group 2 compared to the negative control group. The regeneration of testicular tissue was observed in the experimental group 2. CONCLUSION CSHAE has protective effect on doxorubicin-induced testicular injuries.
Collapse
Affiliation(s)
| | - Mehrdad Shariati
- Department of Biology, Kazerun Branch, Islamic Azad University, Kazerun, Iran
| | - Mohsen Forouzanfar
- Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | | |
Collapse
|
|
15
|
Said RS, Mohamed HA, Kamal MM. Coenzyme Q10 mitigates ionizing radiation-induced testicular damage in rats through inhibition of oxidative stress and mitochondria-mediated apoptotic cell death. Toxicol Appl Pharmacol 2019; 383:114780. [PMID: 31618661 DOI: 10.1016/j.taap.2019.114780] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/05/2019] [Accepted: 10/10/2019] [Indexed: 12/24/2022]
Abstract
Radiotherapy is a common treatment modality for cancer patients; however, its use is limited by decreasing the probability of fertility in male cancer survivors. Therefore, this study aimed to define the capability of coenzyme Q10 (CoQ10), a potent stimulator of mitochondrial function, in attenuating ionizing radiation (IR)-induced spermatogenesis impairments. Male Sprague Dawley rats were exposed to a single dose of ϒ-rays (10 Gy) and/or treated with CoQ10 (10 mg/kg, orally, for 2 consecutive weeks). IR mediated irregular seminiferous tubules, which were emerged with typical morphological characteristics of apoptosis, and nuclear condensation, while CoQ10 significantly preserved the testicular structure and maintained spermatogenesis, which was displayed by higher levels of serum estradiol and testosterone. CoQ10 remarkably augmented sperm count, motility, and viability while diminished the rate of sperm-defects relatively to their counterparts after IR exposure. CoQ10 modulations in reproductive parameters were underpinned by attenuating IR-induced oxidative stress as evidenced by decreasing lipid peroxidation and increasing the antioxidant enzymes glutathione peroxidase and glutathione-s-transferase activities, and glutathione level. Supporting the involvement of CoQ10 in the anti-apoptotic response, the reduced mRNA expression levels of p53, Puma, and Bax accompanied by the increased Bcl-2 mRNA expression were observed. Subsequently, CoQ10 ameliorated the mitochondria dependent apoptotic pathway through diminishing Bax/Bcl-2 ratio, caspase-3 protein expression, and DNA fragmentation in testes of irradiated rats. Taken together, our findings showed that CoQ10 conserved against IR-induced steroidogenesis disruption through subsiding mitochondria-mediated oxidative stress injury in germinal cells.
Collapse
Affiliation(s)
- Riham S Said
- Drug Radiation Research Department, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt.
| | - Heba A Mohamed
- Drug Radiation Research Department, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt
| | - Mohamed M Kamal
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| |
Collapse
|
|
16
|
Landauer MR, Harvey AJ, Kaytor MD, Day RM. Mechanism and therapeutic window of a genistein nanosuspension to protect against hematopoietic-acute radiation syndrome. JOURNAL OF RADIATION RESEARCH 2019; 60:308-317. [PMID: 31038675 PMCID: PMC6530628 DOI: 10.1093/jrr/rrz014] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/08/2019] [Indexed: 05/17/2023]
Abstract
There are no FDA-approved drugs that can be administered prior to ionizing radiation exposure to prevent hematopoietic-acute radiation syndrome (H-ARS). A suspension of synthetic genistein nanoparticles was previously shown to be an effective radioprotectant against H-ARS when administered prior to exposure to a lethal dose of total body radiation. Here we aimed to determine the time to protection and the duration of protection when the genistein nanosuspension was administered by intramuscular injection, and we also investigated the drug's mechanism of action. A single intramuscular injection of the genistein nanosuspension was an effective radioprotectant when given prophylactically 48 h to 12 h before irradiation, with maximum effectiveness occurring when administered 24 h before. No survival advantage was observed in animals administered only a single dose of drug after irradiation. The dose reduction factor of the genistein nanosuspension was determined by comparing the survival of treated and untreated animals following different doses of total body irradiation. As genistein is a selective estrogen receptor beta agonist, we also explored whether this was a central component of its radioprotective mechanism of action. Mice that received an intramuscular injection of an estrogen receptor antagonist (ICI 182,780) prior to administration of the genistein nanosuspension had significantly lower survival following total body irradiation compared with animals only receiving the nanosuspension (P < 0.01). These data define the time to and duration of radioprotection following a single intramuscular injection of the genistein nanosuspension and identify its likely mechanism of action.
Collapse
Affiliation(s)
- Michael R Landauer
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, 4555 South Palmer Road, Building 42, Bethesda, MD, USA
| | - Adam J Harvey
- Humanetics Corporation, 7650 Edinborough Way, Suite 620, Edina, MN, USA
| | - Michael D Kaytor
- Humanetics Corporation, 7650 Edinborough Way, Suite 620, Edina, MN, USA
| | - Regina M Day
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Building C, Roomm 2023, 4301 Jones Bridge Road, Bethesda, MD, USA
- Corresponding author. Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Building C, Room 2023, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA. Tel: +301-295-3236; fax: +301-295-3220;
| |
Collapse
|
|
17
|
Cavalim Vale AP, Dos Santos G, da Silva TP, Mansano NDS, Chies AB, Chagas EFB, Spadella MA. Influence of the AT1 Receptor Antagonists Telmisartan and Losartan on Reproduction and Offspring After Paternal Exposure to Ionizing Radiation. Reprod Sci 2018; 26:639-648. [PMID: 29938606 DOI: 10.1177/1933719118783251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
This study evaluated the repercussions of paternal exposure to radiation on reproduction and offspring in rats, as well as whether treatment with the angiotensin II type 1 (AT1) receptor antagonists telmisartan and losartan has a mitigating effect. Rats were randomly divided into 6 groups: control, radiation, telmisartan, losartan, radiation + telmisartan, and radiation + losartan. A single 5 Gy dose of radiation was administered directly into the scrotum, followed by treatment with telmisartan (12 mg/kg/d) or losartan (34 mg/kg/2 times per day) for 60 days in the groups receiving these medications. The reproductive ability of the test animals was assessed before and after exposure to radiation via fertility tests. The resulting offspring were analyzed for the presence of external and internal anomalies. Ionizing radiation significantly affected the rates of fertility, pre- and postimplantation losses, and implantation. Telmisartan and losartan did not significantly prevent this radiation-induced damage. The frequency of fetal anomalies was similar in offspring produced before and after paternal radiation exposure. Moreover, irradiated rats that received treatments and were able to generate offspring did not produce fetuses with morphological changes; this may represent a possible radioprotective effect AT1 antagonists have on offspring development, although few fetuses survived and were evaluated for malformations. Although the study findings indicate that these medications have a positive effect, further studies with longer treatment periods (extending beyond 1 rat spermatogenic cycle) are needed to determine whether these drugs significantly improve reproductive rates after paternal exposure to radiation, which may also reflect an increase in the number of viable fetuses.
Collapse
Affiliation(s)
| | | | | | - Naira da Silva Mansano
- 3 Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Agnaldo Bruno Chies
- 4 Laboratory of Pharmacology, Marília Medical School, Marília, São Paulo, Brazil
| | | | | |
Collapse
|
|
18
|
da Silva Mansano N, Jorge IF, Chies AB, Viani GA, Spadella MA. Effects of telmisartan and losartan on irradiated testes. Life Sci 2018; 194:157-167. [DOI: 10.1016/j.lfs.2017.12.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Revised: 12/20/2017] [Accepted: 12/23/2017] [Indexed: 12/19/2022]
|
|
19
|
Gu H, Wu W, Yuan B, Tang Q, Guo D, Chen Y, Xia Y, Hu L, Chen D, Sha J, Wang X. Genistein up-regulates miR-20a to disrupt spermatogenesis via targeting Limk1. Oncotarget 2017; 8:58728-58737. [PMID: 28938591 PMCID: PMC5601687 DOI: 10.18632/oncotarget.17637] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 04/16/2017] [Indexed: 11/25/2022] Open
Abstract
Genistein (GEN) is one of the isoflavones that has effect on male reproduction. However, the underlying mechanism remains unknown. miRNAs are a type of small non-coding RNAs that play important roles in spermatogenesis. We measured the GEN levels and miR-17-92 cluster expression in infertile subjects and found that miR-17-92 might be involved in GEN induced abnormal spermatogenesis. To clarify, we fed adult ICR mice with different doses of GEN (0, 0.5, 5, 50 and 250 mg/kg/day) for 35 days to study the underlying mechanism. We found that sperm average path velocity, straight-line velocity and eurvilinear velocity of the mice orally with GEN at 5mg/kg/day were significantly decreased, the expression levels of miR-17 and miR-20a in mice testis were higher in corresponding group. We also found miR-20a was the only miRNA that differentially expressed both in human and mice. By applying bioinformatics methods, Limk1 was predicted to be the target gene of miR-20a that is involved in spermatogenesis. Limk1 were significantly decreased in the corresponding group. Dual-luciferase report assay also proved that miR-20a could directly target Limk1. These results implied that Limk1 might be the target gene of miR-20a that is involved in GEN induced abnormal spermatogenesis.
Collapse
Affiliation(s)
- Hao Gu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Central Laboratory, Huai’an First People's Hospital, Nanjing Medical University, Huai’an 223002, China
| | - Wei Wu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- State Key Laboratory of Reproductive Medicine, Wuxi Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China
| | - Beilei Yuan
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Qiuqin Tang
- State Key Laboratory of Reproductive Medicine, Department of Obstetrics, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210004, China
| | - Dan Guo
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yiqiu Chen
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yankai Xia
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Lingqing Hu
- State Key Laboratory of Reproductive Medicine, Wuxi Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China
| | - Daozhen Chen
- State Key Laboratory of Reproductive Medicine, Wuxi Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China
| | - Jiahao Sha
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China
| | - Xinru Wang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing 211166, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| |
Collapse
|
|
20
|
Vaos G, Zavras N. Antioxidants in experimental ischemia-reperfusion injury of the testis: Where are we heading towards? World J Methodol 2017; 7:37-45. [PMID: 28706858 PMCID: PMC5489422 DOI: 10.5662/wjm.v7.i2.37] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/07/2017] [Accepted: 05/15/2017] [Indexed: 02/06/2023] Open
Abstract
Testicular torsion (TT) is a medical emergency that primary affects newborns and young adolescents. It causes testicular injury due to the torsion of the spermatic cord and its components, initially in the venous blood flow and finally in the arterial blood flow. Prompt diagnosis and early surgical management are necessary in managing this urgent situation. The process of the pathophysiological events in ischemia-reperfusion is multifactorial and deals with the perception of the oxidative stress responsible for the consequences of ischemia/reperfusion (I/R) stress following TT. Duration and severity of torsion also play a significant role in the oxidative stress. A detrimental result of the defense system of the testes takes place resulting finally in testicular atrophy and impaired function. Antioxidant factors have been experimentally studied in an effort to front this state. They have been classified as endogenous or exogenous antioxidants. Endogenous antioxidants comprise a structure of enzymic enzymatic and non-enzymic enzymatic particles presented within cytoplasm and numerous other subunits in the cells. Exogenous antioxidants include a variety of natural and pharmaceutical agents that may prevent or ameliorate the harmful effects of I/R injury. In this study we review those factors and their ability to enhance the oxidative status of the testis. A feature insight into where we are heading is attempted.
Collapse
|
|
21
|
Gao S, Li C, Chen L, Zhou X. Actions and mechanisms of reactive oxygen species and antioxidative system in semen. Mol Cell Toxicol 2017. [DOI: 10.1007/s13273-017-0015-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
22
|
Genistein Alleviates Neuroinflammation and Restores Cognitive Function in Rat Model of Hepatic Encephalopathy: Underlying Mechanisms. Mol Neurobiol 2017; 55:1762-1772. [PMID: 28224477 DOI: 10.1007/s12035-017-0454-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/13/2017] [Indexed: 01/07/2023]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome resulting from acute liver failure. Previously, we demonstrated hepatoprotective effects of genistein in D-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). In this study, we evaluated behavioural and neuroprotective effects of genistein in rat model of HE. HE was induced by intraperitonial administration of D-GalN (250 mg/kg BW) twice a week for 30 days Genistein was given as co-treatment through oral gavage daily at dose of 5 mg/kg BW. D-GalN administration significantly resulted in acute liver failure which was further associated with hyperammonemia, neurological dysfunction, as evident from behavioural and functional impairment and reduced learning ability in Morris water maze. Genistein significantly alleviated behavioural and functional impairment and restored learning ability in Morris water maze. Considerable histopathological changes, including portal inflammation, sinusoidal dilation, necrotic lesions and swelled astrocytes with pale nuclei, were seen in the liver and brain sections of D-GalN-challenged rats while genistein co-treated rats revealed normal cellular and morphological architecture as no pathological features were seen. Furthermore, pro-inflammatory markers (interleukin (IL)-10, IL-4, IL-1β and TNF-α) and membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA marked significant increase, while subunits GluR1 of AMPA receptors showed reduced expression in D-GalN-challenged rats leading to neuroinflammation and dysregulated neurotransmission. Genistein significantly normalized altered expression of pro-inflammatory cytokines and membrane receptor of GABA and GluR. Our study suggests strong therapeutic potential of genistein in animal model of HE. Genistein can be used a strong anti-oxidant to attenuate neurotoxic effects of xenobiotics.
Collapse
|
|
23
|
Ji HJ, Wang DM, Wu YP, Niu YY, Jia LL, Liu BW, Feng QJ, Feng ML. Wuzi Yanzong pill, a Chinese polyherbal formula, alleviates testicular damage in mice induced by ionizing radiation. Altern Ther Health Med 2016; 16:509. [PMID: 27927244 PMCID: PMC5142375 DOI: 10.1186/s12906-016-1481-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/08/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND Chinese medicine Wuzi Yanzong pill (WZYZP) was firstly documented in ancient Chinese medical works "She Sheng Zhong Miao Fang" by Shi-Che Zhang in 1550 AD. The traditional herbal formula is widely used in treating nephrasthenia lumbago, prospermia, erectile dysfunction and male sterility. The present study was to explore the effects of WZYZP on ionizing irradiation-induced testicular damage in mice. METHODS The pelvic region of male mice was exposed to X-rays for inducing testicular damage. The effects of WZYZP on testicular damage were evaluated in terms of testes weight, sperm quantity and motility, testes oxidative status and serum hormone levels. The alterations in testicular structure were examined by hematoxylin-eosin staining. Additionally, changes in proliferating cell nuclear antigen (PCNA) expression of testes were explored by western blot. RESULTS Pelvic exposure to x-ray induced reduction in testes weight and sperm quality, along with oxidative stress and abnormal testicular architecture in testes. Oral administration of WZYZP for 3 weeks markedly increased testes weight, sperm quantity and motility, and attenuated testicular architecture damage. Meanwhile, WZYZP treatment significantly reversed the reduction of serum testosterone, and decreased testes malondialdehyde (MDA) and Oxidative stress index (OSI) relative to the radiated mice. Additionally, WZYZP effectively prevented the downregulation of PCNA expression in testes induced by x-ray irradiation. CONCLUSION These findings suggest WZYZP exhibits ameliorating effects against ionizing irradiation-induced testicular damage in mice, which may be related to its antioxidation.
Collapse
|
|
24
|
Bala S, Chugh NA, Bansal SC, Garg ML, Koul A. Protective role of Aloe vera against X-ray induced testicular dysfunction. Andrologia 2016; 49. [PMID: 27620003 DOI: 10.1111/and.12697] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2016] [Indexed: 12/19/2022] Open
Abstract
The present investigation was carried out to evaluate the possible radioprotective potential of an Aloe vera extract against whole-body X-ray irradiation-induced testicular alterations in mice. Male balb/c mice were divided into four groups: control, A. vera, X-ray and A. vera pre-treated + X-ray irradiated. Histopathological examination revealed significant structural alterations in testes after X-ray exposure, which was also associated with the presence of apoptotic cells as assessed by TUNEL assay. X-ray irradiation resulted in elevation in the levels of reactive oxygen species, lipid peroxidation, a reduction in glutathione concentration and enhanced activities of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, catalase, superoxide dismutase and glutathione-S-transferase. Sperm count/motility and testosterone levels were significantly decreased in the irradiated group. Irradiated animals pre-treated with A. vera extract revealed an improvement in antioxidant status, inhibition of lipid peroxides, apoptotic cell formation and enhanced testicular parameters when compared to the X-ray-exposed group. These findings suggest that A. vera extract could ameliorate X-ray-induced damage due to its free radical scavenging properties and its potential to boost cellular antioxidant defence machinery.
Collapse
Affiliation(s)
- S Bala
- Department of Biophysics, Panjab University, Chandigarh, India
| | - N A Chugh
- Department of Biophysics, Panjab University, Chandigarh, India
| | - S C Bansal
- Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India
| | - M L Garg
- Department of Biophysics, Panjab University, Chandigarh, India
| | - A Koul
- Department of Biophysics, Panjab University, Chandigarh, India
| |
Collapse
|
|
25
|
Canyilmaz E, Uslu GH, Bahat Z, Kandaz M, Mungan S, Haciislamoglu E, Mentese A, Yoney A. Comparison of the effects of melatonin and genistein on radiation-induced nephrotoxicity: Results of an experimental study. Biomed Rep 2015; 4:45-50. [PMID: 26870332 DOI: 10.3892/br.2015.547] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 09/07/2015] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to compare the effects of melatonin and genistein on radiation-induced nephrotoxicity (RIN). A total of 70 Swiss Albino mice were divided into 7 groups. Five control groups were defined, which were sham irradiation (C, G1), radiation therapy only (RT, G2), melatonin (M, G3), genistein (G, G4) and polyethylene glycol-400 (G5), respectively. The co-treatment groups were the RT plus melatonin (RT+M, G6) and RT plus genistein (RT+G, G7) groups. Irradiation was applied using a cobalt-60 teletherapy machine (80-cm fixed source-to-surface distance, 2.5-cm depth). Melatonin was administered (100 mg/kg, intraperitoneal injection) 30 min before the single dose of irradiation, whereas genistein was administered (200 mg/kg, subcutaneous injection) 1 day before the single dose of irradiation. All the mice were sacrificed 6 months after irradiation. As an end point, the extent of renal tubular atrophy for each mouse was quantified with image analysis of histological sections of the kidney. Tissue malondialdehyde (MDA) levels were also measured in each animal. In the histopathological examination of the mouse kidneys, there was a statistically significant reduction (P<0.05) in the presence of tubular atrophy between the RT+M and RT+G groups and the RT group. There was a statistically significant increase in MDA levels in the irradiated versus sham groups (RT vs. C; P<0.05); however, MDA levels were significantly decreased by co-treatment with melatonin or genistein vs. RT alone (RT+M and RT+G vs. RT; P<0.05). In conclusion, the present experimental study showed that melatonin and genistein supplementation prior to irradiation-protected mice against RIN, which may have therapeutic implications for radiation-induced injuries.
Collapse
Affiliation(s)
- Emine Canyilmaz
- Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| | - Gonca Hanedan Uslu
- Department of Radiation Oncology, Faculty of Medicine, Kanuni Research and Education Hospital, 60080 Trabzon, Turkey
| | - Zumrut Bahat
- Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| | - Mustafa Kandaz
- Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| | - Sevdegul Mungan
- Department of Medical Pathology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| | - Emel Haciislamoglu
- Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| | - Ahmet Mentese
- Department of Medical Biochemistry, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| | - Adnan Yoney
- Department of Radiation Oncology, Faculty of Medicine, Karadeniz Technical University, 61080 Trabzon, Turkey
| |
Collapse
|
|
26
|
Son Y, Heo K, Bae MJ, Lee CG, Cho WS, Kim SD, Yang K, Shin IS, Lee MY, Kim JS. Injury to the blood-testis barrier after low-dose-rate chronic radiation exposure in mice. RADIATION PROTECTION DOSIMETRY 2015; 167:316-320. [PMID: 25948832 DOI: 10.1093/rpd/ncv270] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Exposure to ionising radiation induces male infertility, accompanied by increasing permeability of the blood-testis barrier. However, the effect on male fertility by low-dose-rate chronic radiation has not been investigated. In this study, the effects of low-dose-rate chronic radiation on male mice were investigated by measuring the levels of tight-junction-associated proteins (ZO-1 and occludin-1), Niemann-Pick disease type 2 protein (NPC-2) and antisperm antibody (AsAb) in serum. BALB/c mice were exposed to low-dose-rate radiation (3.49 mGy h(-1)) for total exposures of 0.02 (6 h), 0.17 (2 d) and 1.7 Gy (21 d). Based on histological examination, the diameter and epithelial depth of seminiferous tubules were significantly decreased in 1.7-Gy-irradiated mice. Compared with those of the non-irradiated group, 1.7-Gy-irradiated mice showed significantly decreased ZO-1, occludin-1 and NPC-2 protein levels, accompanied with increased serum AsAb levels. These results suggest potential blood-testis barrier injury and immune infertility in male mice exposed to low-dose-rate chronic radiation.
Collapse
Affiliation(s)
- Y Son
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - K Heo
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - M J Bae
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - C G Lee
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - W S Cho
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - S D Kim
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - K Yang
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea
| | - I S Shin
- College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
| | - M Y Lee
- College of Pharmacy, Kyungpook National University, Daegu, South Korea
| | - J S Kim
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jwadong-gil 40, Gijang-gun, Busan 619-953, South Korea College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea
| |
Collapse
|
|
27
|
Fountain MD, Abernathy LM, Lonardo F, Rothstein SE, Dominello MM, Yunker CK, Chen W, Gadgeel S, Joiner MC, Hillman GG. Radiation-Induced Esophagitis is Mitigated by Soy Isoflavones. Front Oncol 2015; 5:238. [PMID: 26557504 PMCID: PMC4617099 DOI: 10.3389/fonc.2015.00238] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/08/2015] [Indexed: 12/25/2022] Open
Abstract
Introduction Lung cancer patients receiving radiotherapy present with acute esophagitis and chronic fibrosis, as a result of radiation injury to esophageal tissues. We have shown that soy isoflavones alleviate pneumonitis and fibrosis caused by radiation toxicity to normal lung. The effect of soy isoflavones on esophagitis histopathological changes induced by radiation was investigated. Methods C57BL/6 mice were treated with 10 Gy or 25 Gy single thoracic irradiation and soy isoflavones for up to 16 weeks. Damage to esophageal tissues was assessed by hematoxylin–eosin, Masson’s Trichrome and Ki-67 staining at 1, 4, 10, and 16 weeks after radiation. The effects on smooth muscle cells and leukocyte infiltration were determined by immunohistochemistry using anti-αSMA and anti-CD45, respectively. Results Radiation caused thickening of esophageal tissue layers that was significantly reduced by soy isoflavones. Major radiation alterations included hypertrophy of basal cells in mucosal epithelium and damage to smooth muscle cells in muscularis mucosae as well as disruption of collagen fibers in lamina propria connective tissue with leukocyte infiltration. These effects were observed as early as 1 week after radiation and were more pronounced with a higher dose of 25 Gy. Soy isoflavones limited the extent of tissue damage induced by radiation both at 10 and 25 Gy. Conclusion Soy isoflavones have a radioprotective effect on the esophagus, mitigating the early and late effects of radiation injury in several esophagus tissue layers. Soy could be administered with radiotherapy to decrease the incidence and severity of esophagitis in lung cancer patients receiving thoracic radiation therapy.
Collapse
Affiliation(s)
- Matthew D Fountain
- Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA ; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Lisa M Abernathy
- Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA ; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Fulvio Lonardo
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Shoshana E Rothstein
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Michael M Dominello
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Christopher K Yunker
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Wei Chen
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Shirish Gadgeel
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Michael C Joiner
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| | - Gilda G Hillman
- Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA ; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, MI , USA
| |
Collapse
|
|
28
|
Lee W, Son Y, Jang H, Bae MJ, Kim J, Kang D, Kim JS. Protective Effect of Administered Rolipram against Radiation-Induced Testicular Injury in Mice. World J Mens Health 2015; 33:20-9. [PMID: 25927059 PMCID: PMC4412004 DOI: 10.5534/wjmh.2015.33.1.20] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 08/04/2014] [Accepted: 08/05/2014] [Indexed: 12/22/2022] Open
Abstract
Purpose Pelvic irradiation for the treatment of cancer can affect normal cells, such as the rapidly proliferating spermatogenic cells of the testis, leading to infertility, a common post-irradiation problem. The present study investigated the radioprotective effect of rolipram, a specific phosphodiesterase type-IV inhibitor known to increase the expression and phosphorylation of the cyclic adenosine monophosphate response element-binding protein (CREB), a key factor for spermatogenesis, with the testicular system against pelvic irradiation. Materials and Methods Male C57BL/6 mice were treated with pelvic irradiation (2 Gy) and rolipram, alone or in combination, and were sacrificed at 12 hours and 35 days after irradiation. Results Rolipram protected germ cells from radiation-induced apoptosis at 12 hours after irradiation and significantly increased testis weight compared with irradiation controls at 35 days. Rolipram also ameliorated radiation-induced testicular morphological changes, such as changes in seminiferous tubular diameter and epithelial height. Additionally, seminiferous tubule repopulation and stem cell survival indices were higher in the rolipram-treated group than in the radiation group. Moreover, rolipram treatment counteracted the radiation-mediated decrease in the sperm count and mobility in the epididymis. Conclusions These protective effects of rolipram treatment prior to irradiation may be mediated by the increase in pCREB levels at 12 hours post-irradiation and the attenuated decrease in pCREB levels in the testis at 35 days post-irradiation in the rolipram-treated group. These findings suggest that activation of CREB signaling by rolipram treatment ameliorates the detrimental effects of acute irradiation on testicular dysfunction and the related male reproductive functions in mice.
Collapse
Affiliation(s)
- Wan Lee
- Department of Urology, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea. ; Medstar Washington Hospital Center, Georgetown University School of Medicine, Washington, DC, USA
| | - Yeonghoon Son
- Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | - Hyosun Jang
- Graduate School of Bio-Applications and System Engineering, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Min Ji Bae
- Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | - Jungki Kim
- Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea
| | - Dongil Kang
- Department of Urology, Inje University College of Medicine, Busan, Korea
| | - Joong Sun Kim
- Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Korea. ; College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| |
Collapse
|
|
29
|
Akdere H, Yurut Caloglu V, Tastekin E, Caloglu M, Turkkan G, Mericliler M, Mehmet Burgazli K. Acute histopathological responses of testicular tissues after different fractionated abdominal irradiation in rats. Postgrad Med 2014; 127:73-7. [PMID: 25526226 DOI: 10.1080/00325481.2015.993270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE To compare the effects of different fractionated doses of abdominal radiation therapy on acute histopathological responses of testicular tissues in rats. METHODS Thirty-three 3-week-old Wistar albino rats were randomized into 6 groups: group 1 (n = 5), control; group 2 (n = 4), hypofractionated total abdominal irradiation (TAI) of 6 Gy/1 fraction/day for 2 days; group 3 (n = 6), hypofractionated TAI of 4 Gy/1 fraction/day for 3 days; group 4 (n = 6), hypofractionated TAI of 3 Gy/1 fraction/day for 4 days; group 5 (n = 6), conventionally fractionated TAI of 2 Gy/1 fraction/day for 6 days; group 6 (n = 6), conventionally fractionated TAI of 1.7 Gy/1 fraction/day for 7 days. Mean epithelial length and diameter of seminiferous tubules of testicular tissues were determined after euthanasia. RESULTS Initially, a highly significant decrease in both the mean tubular diameter and epithelial height of the seminiferous tubules was demonstrated in all irradiated rats compared with the control group. No significant differences regarding both damage parameters were found between different hypofractionated radiation therapies. Both conventional radiation therapies reduced the epithelial height and mean diameter of the seminiferous tubules to a lesser extent when compared with 6 Gy/1 fraction/day hypofractionated therapy. It was further shown that parameter values were comparable between rats that received 3 Gy/day hypofractionated therapy and rats that received either of the two conventional therapies. Furthermore, although 4 Gy/day hypofractionation decreased tubular diameter and epithelial length to a greater degree compared with the conventional therapy of 1.7 Gy/1 fraction/day, no statistically significant difference was found when compared with conventional therapy of 2 Gy/1 fraction/day. Additionally, no statistically significant difference was demonstrated between the two types of conventional radiotherapy application. CONCLUSION The present study demonstrated that hypofractionated abdominal irradiation leads to more prominent tissue damage in the testes than conventional irradiation.
Collapse
Affiliation(s)
- Hakan Akdere
- Department of Urology, Trakya University , Edirne , Turkey
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Luo Q, Li J, Cui X, Yan J, Zhao Q, Xiang C. The effect of Lycium barbarum polysaccharides on the male rats׳ reproductive system and spermatogenic cell apoptosis exposed to low-dose ionizing irradiation. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:249-258. [PMID: 24746483 DOI: 10.1016/j.jep.2014.04.013] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Revised: 04/01/2014] [Accepted: 04/07/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Lycium barbarum, a Solanaceous defoliated shrubbery, has been used as a kind of traditional Chinese herbal medicines for thousands of years. Lycium barbarum polysaccharide (LBP) is the main bioactive component of Lycium barbarum. The aim of this study was to investigate the radioresistant effect of LBP on the damage of male rats' reproductive system and spermatogenic cells caused by low-dose (60)Co-γ irradiation. MATERIALS AND METHODS Male rats were randomly divided into 7 groups and treated with irradiation and/or LBP: normal control group, irradiation control group 1, irradiation control group 2, irradiation control group 3, LBP + irradiation group 1, LBP + irradiation group 2, and LBP + irradiation group 3. RESULTS It is found that mating function and testis organ coefficient in LBP + irradiation groups were significantly better than that of the corresponding irradiation control groups. LBP significantly up-regulates the expression of Bcl-2 while down-regulating the expression of Bax. And LBP also plays an important role in prevention mitochondrial membrane potential decrease. In addition, LBP can significantly reduce spermatogenic cells apoptosis. CONCLUSION LBP has obvious protective effect on the male rats' reproductive function and spermatogenic dysfunction induced by irradiation.
Collapse
Affiliation(s)
- Qiong Luo
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, PR China.
| | - Jingjing Li
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, PR China
| | - Xiaoyan Cui
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, PR China
| | - Jun Yan
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, PR China
| | - Qihan Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, PR China
| | - Chunyan Xiang
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University, Donghu Road 115, Wuhan 430071, Hubei, PR China
| |
Collapse
|
|
31
|
Gong EJ, Shin IS, Son TG, Yang K, Heo K, KIM JS. Low-dose-rate radiation exposure leads to testicular damage with decreases in DNMT1 and HDAC1 in the murine testis. JOURNAL OF RADIATION RESEARCH 2014; 55:54-60. [PMID: 24027299 PMCID: PMC3885123 DOI: 10.1093/jrr/rrt090] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
This study examined the effects of continuous low-dose-rate radiation exposure (3.49 mGy/h) of gamma rays on mice testicles. C57BL/6 mice were divided into sham and radiation groups (n = 8 each), and were exposed to either sham irradiation or 2 Gy for 21 days, 0.2 Gy for 2 days, or 0.02 Gy for 6 h of low-dose-rate irradiation. Testicular weight, seminiferous tubular diameter, and seminiferous epithelial depth were significantly decreased in the mice irradiated with 2 Gy at 1 and 9 days after exposure. Moreover, the low-dose-rate radiation exposure induced an increase in malondialdehyde levels, and a decrease in superoxide dismutase activity in the testis of mice irradiated with 2 Gy at 1 and 9 days after exposure. The sperm count and motility in the epididymis also decreased in mice irradiated with 2 Gy at 1 and 9 days after exposure, whereas there was no significant effect on the proportion of abnormal sperm. The expressions of DNA methlytransferases-1 and histone deacetylases 1 in testes irradiated with 2 Gy were significantly decreased compared with the sham group. In conclusion, the damage exerted on the testes and epididymis largely depended on the total dose of low-dose-rate radiation.
Collapse
Affiliation(s)
- Eun Ji Gong
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), 40 Jwadong-gil, Gijang-gun, Busan 619-953, Republic of Korea
| | - In Sik Shin
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Cheongwon-gun, Chungbuk 363-883, Republic of Korea
| | - Tae Gen Son
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), 40 Jwadong-gil, Gijang-gun, Busan 619-953, Republic of Korea
| | - Kwangmo Yang
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), 40 Jwadong-gil, Gijang-gun, Busan 619-953, Republic of Korea
| | - Kyu Heo
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), 40 Jwadong-gil, Gijang-gun, Busan 619-953, Republic of Korea
| | - Joong Sun KIM
- Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), 40 Jwadong-gil, Gijang-gun, Busan 619-953, Republic of Korea
- Corresponding author. Research Center, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), 40 Jwadong-gil, Gijang-gun, Busan 619-953, Republic of Korea. Tel: +82-51-720-5145; Fax; +82-51-720-2430;
| |
Collapse
|
|
32
|
Haeri SA, Rajabi H, Fazelipour S, Hosseinimehr SJ. Carnosine mitigates apoptosis and protects testicular seminiferous tubules from gamma-radiation-induced injury in mice. Andrologia 2013; 46:1041-6. [DOI: 10.1111/and.12193] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2013] [Indexed: 12/20/2022] Open
Affiliation(s)
- S. A. Haeri
- Faculty of Medical Sciences; Department of Medical Physics; Tarbiat Modares University; Tehran Iran
| | - H. Rajabi
- Faculty of Medical Sciences; Department of Medical Physics; Tarbiat Modares University; Tehran Iran
| | - S. Fazelipour
- Faculty of Medical Sciences; Department of Anatomy; Islamic Azad University; Tehran Iran
| | - S. J. Hosseinimehr
- Faculty of Pharmacy; Department of Radiopharmacy; Mazandaran University of Medical Sciences; Sari Iran
| |
Collapse
|
|
33
|
Romano B, Pagano E, Montanaro V, Fortunato AL, Milic N, Borrelli F. Novel Insights into the Pharmacology of Flavonoids. Phytother Res 2013; 27:1588-96. [DOI: 10.1002/ptr.5023] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 05/15/2013] [Indexed: 01/23/2023]
Affiliation(s)
- Barbara Romano
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| | - Ester Pagano
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| | - Vittorino Montanaro
- Department of Pharmacy; University of Naples Federico II; via Pansini 5 80131 Naples Italy
| | - Alfonso L. Fortunato
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| | - Natasa Milic
- Department of Pharmacy; Faculty of Medicine, University of Novi Sad; Hajduk Veljkova, 3 21000 Novi Sad Serbia
| | - Francesca Borrelli
- Department of Urology; University of Naples Federico II; via D. Montesano 49 80131 Naples Italy
| |
Collapse
|
|
34
|
Son TG, Gong EJ, Bae MJ, Kim SD, Heo K, Moon C, Yang K, Kim JS. Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 13:103. [PMID: 23672582 PMCID: PMC3671128 DOI: 10.1186/1472-6882-13-103] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 05/09/2013] [Indexed: 01/01/2023]
Abstract
BACKGROUND Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. METHODS Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. RESULTS Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. CONCLUSION Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients.
Collapse
Affiliation(s)
- Tae Gen Son
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Eun Ji Gong
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Min Ji Bae
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Sung Dae Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Kyu Heo
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Changjong Moon
- Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research Center, Chonnam National University, Gwangju, South Korea
| | - Kwangmo Yang
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| | - Joong Sun Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, Republic of Korea
| |
Collapse
|
|
35
|
Liang L, Gao C, Luo M, Zhao C, Wang W, Gu C, Yu J, Fu Y. The phytoestrogenic compound cajanol from Pigeonpea roots is associated with the activation of estrogen receptor α-dependent signaling pathway in human prostate cancer cells. Phytother Res 2013; 27:1834-41. [PMID: 23420757 DOI: 10.1002/ptr.4937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 01/07/2013] [Accepted: 01/08/2013] [Indexed: 11/10/2022]
Abstract
In the present study, the main natural estrogen-agonist/antagonist from Pigeonpea roots was studied by the estrogen receptor α-dependent signaling pathway in human prostate cancer cell. First, the natural products with estrogenic activity in Pigeonpea roots were screened by pER8-GFP transgenic Arabidopsis, and cajanol (5-hydroxy-3-(4-hydroxy-2-methoxyphenyl)-7-methoxychroman-4-one) was confirmed as the active compound. Further study showed that cajanol significantly arrested the cell cycle in the G1 and G2/M phase and induced nuclei condensation, fragmentation and the formation of apoptotic bodies. Western blotting showed that cajanol modulated the ERα-dependent PI3K pathway and induced the activation of GSK3 and CyclinD1 closely following the profile of PI3K activity. Based on above results, we proposed a mechanism through which cajanol could inhibit survival and proliferation of estrogen-responsive cells (PC-3 cells) by interfering with an ERα-associated PI3K pathway, following a process that could be dependent of the nuclear functions of the ERα. Above all, we conclude that cajanol represents a valuable natural phytoestrogen source and may potentially be applicable in health food industry.
Collapse
Affiliation(s)
- Lu Liang
- Engineering Research Center of Forest Bio-Preparation, Ministry of Education, Northeast Forestry University, Harbin, 150040, PR China; Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin, 150040, PR China
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Erkanlı Şentürk G, Ersoy Canillioĝlu Y, Umay C, Demiralp-Eksioglu E, Ercan F. Distribution of Zonula Occludens-1 and Occludin and alterations of testicular morphology after in utero radiation and postnatal hyperthermia in rats. Int J Exp Pathol 2013; 93:438-49. [PMID: 23136996 DOI: 10.1111/j.1365-2613.2012.00844.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
In utero irradiation (IR) and postnatal hyperthermia (HT) exposure cause infertility by decreasing spermatogenic colony growth and the number of sperm in rats. Four groups were used: (i) Control group, (ii) HT group (rats exposed to hyperthermia on the 10th postnatal day), (iii) IR group (rats exposed to IR on the 17th gestational day) and (iv) IR + HT group. Three and six months after the procedures testes were examined by light and electron microscopy. Some degenerated tubules in the HT group, many vacuoles in spermatogenic cells and degenerated tight junctions in the IR group, atrophic tubules and severe degeneration of tight junctions in the IR + HT group were observed. ZO-1 and occludin immunoreactivity were decreased and disorganized in the HT and IR groups and absent in the IR + HT group. The increase in the number of apoptotic cells was accompanied by a time-dependent decrease in haploid, diploid and tetraploid cells in all groups. Degenerative findings were severe after 6 months in all groups. The double-hit model may represent a Sertoli cell only model of infertility due to a decrease in spermatogenic cell and alterated blood-testis barrier proteins in rat.
Collapse
Affiliation(s)
- Gozde Erkanlı Şentürk
- Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey.
| | | | | | | | | |
Collapse
|
|
37
|
HaiRong M, HuaBo W, Zhen C, Yi Y, ZhengHua W, Madina H, Xu C, Akber AH. The estrogenic activity of isoflavones extracted from chickpea Cicer arietinum L sprouts in vitro. Phytother Res 2012; 27:1237-42. [PMID: 23065723 DOI: 10.1002/ptr.4858] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 08/24/2012] [Accepted: 09/19/2012] [Indexed: 11/10/2022]
Abstract
Isoflavones have drawn attention due to their potential therapeutic use. Isoflavones are the important chemical components of the seeds and sprouts of chickpea and higher isoflavones in sprouts than in seeds. However, there have been no previous reports of the estrogenic activity of isoflavones extracted from chickpea Cicer arietinum L sprouts (ICS) in vitro. In this study, which incorporated several in vitro bioassays methods, we systematically evaluated the estrogenic properties of ICS. MTT assay showed that ICS at the low concentration ranges (10(-3)-1 mg/L) promoted MCF-7 cell growth, while at high concentrations, (>1 mg/L) inhibited cell proliferation, indicating ICS worked at a diphasic mechanism. Flow cytometric analysis further calculated the proliferation rate of ICS at low concentration (1 mg/L). ERα/Luc trans-activation assay and then semi-quantitative RT-PCR analysis indicated that ICS at low concentrations induced ERα-mediated luciferase activity in MCF-7 cells and promoted the ER downstream target gene pS2 and PR trans-activation. These effects were inhibited by ICI 182,780, a special antagonist of ER, indicating that an ER-mediating pathway was involved. Alkaline phosphatase (AP) expression in Ishikawa cells showed that ICS at low concentrations stimulated AP expression. Our current study is the first to demonstrate that ICS has significant estrogenic activity in vitro. ICS may be useful as a supplement to hormone replacement therapy and in dietary supplements.
Collapse
Affiliation(s)
- Ma HaiRong
- Xinjiang Key Laboratory of Plant Resources and Natural Products Chemistry, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China
| | | | | | | | | | | | | | | |
Collapse
|