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Keleş ÖF, Bayir MH, Çiçek HA, Ahlatcı A, Yıldızhan K. The Effect of Selenium Against Cadmium-Induced Nephrotoxicity in Rats: The Role of the TRPM2 Channel. TOXICS 2025; 13:87. [PMID: 39997902 PMCID: PMC11860756 DOI: 10.3390/toxics13020087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/16/2025] [Accepted: 01/21/2025] [Indexed: 02/26/2025]
Abstract
This study investigated the protective effect of selenium (Se) in a cadmium (Cd)-induced nephrotoxicity model in rats and the role of the TRPM2 channel in this mechanism. For this purpose, Cd (25 mg/kg orally), Se (0.5 mg/kg i.p.), and 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 channel antagonist, (3 mg/kg i.p.) were administered to rats every day for 5 days. At the end of the study, kidney tissues were analysed using histological and biochemical methods. A histopathological examination revealed congestion, tubular degeneration, necrosis, and glomerular adhesion in the Cd group. However, these lesions were significantly reduced in the Cd + Se and Cd + 2-APB groups, while the Cd + Se + 2-APB group showed a histological appearance similar to the control group. Immunohistochemical analysis revealed that Caspase-3, Bax, and TRPM2 expression was higher in the Cd group, while these levels were lower in the Se and 2-APB treatment groups (p < 0.05). Among the groups that received Cd, urea, creatinine, TOS, TNF-α, and IL-1β levels were at the highest level in the Cd group, while TAS level was at the lowest level (p < 0.05). The Se and 2-APB treatment modulated these parameters; however, Se + 2-APB treatment reduced urea, creatinine, TOS, TNF-α, and IL-1β levels to the lowest level compared to the Cd groups and brought the TAS level closer to the control group (p < 0.05). These findings indicated that targeting TRPM2 channel inactivation together with the selenium treatment could alleviate Cd-induced nephrotoxicity.
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Affiliation(s)
- Ömer Faruk Keleş
- Department of Pathology, Faculty of Veterinary Medicine, Van Yuzuncu Yil University, 65080 Van, Türkiye;
| | - Mehmet Hafit Bayir
- Department of Histology, Faculty of Medicine, Van Yuzuncu Yil University, 65080 Van, Türkiye;
| | - Hacı Ahmet Çiçek
- Department of Pathology, Faculty of Veterinary Medicine, Van Yuzuncu Yil University, 65080 Van, Türkiye;
| | - Adem Ahlatcı
- Vocational School of Health Services, Van Yuzuncu Yil University, 65080 Van, Türkiye;
| | - Kenan Yıldızhan
- Department of Biophysics, Faculty of Medicine, Van Yuzuncu Yil University, 65080 Van, Türkiye;
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Cao LM, Zhong NN, Chen Y, Li ZZ, Wang GR, Xiao Y, Liu XH, Jia J, Liu B, Bu LL. Less is more: Exploring neoadjuvant immunotherapy as a de-escalation strategy in head and neck squamous cell carcinoma treatment. Cancer Lett 2024; 598:217095. [PMID: 38964728 DOI: 10.1016/j.canlet.2024.217095] [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: 04/08/2024] [Revised: 06/15/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
Head and neck squamous cell carcinoma (HNSCC) constitutes a significant global cancer burden, given its high prevalence and associated mortality. Despite substantial progress in survival rates due to the enhanced multidisciplinary approach to treatment, these methods often lead to severe tissue damage, compromised function, and potential toxicity. Thus, there is an imperative need for novel, effective, and minimally damaging treatment modalities. Neoadjuvant treatment, an emerging therapeutic strategy, is designed to reduce tumor size and curtail distant metastasis prior to definitive intervention. Currently, neoadjuvant chemotherapy (NACT) has optimized the treatment approach for a subset of HNSCC patients, yet it has not produced a noticeable enhancement in overall survival (OS). In the contemporary cancer therapeutics landscape, immunotherapy is gaining traction at an accelerated pace. Notably, neoadjuvant immunotherapy (NAIT) has shown promising radiological and pathological responses, coupled with encouraging efficacy in several clinical trials. This potentially paves the way for a myriad of possibilities in treatment de-escalation of HNSCC, which warrants further exploration. This paper reviews the existing strategies and efficacies of neoadjuvant immune checkpoint inhibitors (ICIs), along with potential de-escalation strategies. Furthermore, the challenges encountered in the context of the de-escalation strategies of NAIT are explored. The aim is to inform future research directions that strive to improve the quality of life (QoL) for patients battling HNSCC.
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Affiliation(s)
- Lei-Ming Cao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Nian-Nian Zhong
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Yang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Zi-Zhan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Guang-Rui Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Yao Xiao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Xuan-Hao Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China
| | - Jun Jia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China; Department of Oral & Maxillofacial Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
| | - Bing Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China; Department of Oral & Maxillofacial Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
| | - Lin-Lin Bu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Somatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China; Department of Oral & Maxillofacial Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
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El-Gendy HF, El-Bahrawy A, Mansour DA, Sheraiba NI, Abdel-Megeid NS, Selim S, Alhotan RA, Ayyoub A, El Hanbally S. Unraveling the Potential of Saccharum officinarum and Chlorella vulgaris towards 5-Fluorouracil-Induced Nephrotoxicity in Rats. Pharmaceuticals (Basel) 2024; 17:885. [PMID: 39065736 PMCID: PMC11279568 DOI: 10.3390/ph17070885] [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: 06/22/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
5-Fluorouracil (5-FU) is often used as a chemotherapeutic agent in treating tumors and is said to have adverse effects, including nephrotoxicity. Therefore, the present study aimed to evaluate the protective effects of Chlorella vulgaris (VL) and Saccharum officinarum L. (SOL) against 5-FU-induced nephrotoxicity in rats through the measurement of renal histology, kidney damage indicators, and antioxidant measures. A total of forty-eight male rats were allotted into six groups: group 1 acted as a control negative group (control), group 2 received 5-FU and worked as a control positive group (FU), group 3 received SOL 15 mL/kg (SOL), group 4 received VL 400 mg/kg (VL), group 5 received 5-FU+SOL (5-FU+SOL), and group 6 received 5-FU+VL (5-FU+VL). After fifteen days, blood and renal tissue specimens were collected for hematological, biochemical, molecular, and histopathological examinations. Findings of the current investigation showed that 5-FU leads to hematological alterations and kidney injury evinced by elevated serum concentrations of uric acid, creatinine, and urea (p < 0.01), and a marked increase in kidney MDA and NO levels with a reduction in kidney CAT, SOD and GSH activities (p < 0.05). Alterations of the histopathological structure of kidney tissue in the FU group were noticed compared to the other groups. 5-FU administration elevated expression levels of TNF-α, lipocalin 2, and KIM1 (p < 0.01) compared to the control ones. 5-FU-induced nephrotoxicity was ameliorated after treatment with SOL and VL via their free radical scavenging, potent antioxidant, and anti-inflammatory effects. In conclusion, our findings demonstrate that the treatment with SOL and VL significantly improved nephrotoxicity induced by 5-FU in rats.
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Affiliation(s)
- Hanem F. El-Gendy
- Department of Pharmacology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
| | - Amanallah El-Bahrawy
- Department of Pathology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
| | - Doaa A. Mansour
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
| | - Nagwa I. Sheraiba
- Department of Husbandry and Animal Wealth Development, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
| | - Nazema S. Abdel-Megeid
- Department of Cytology and Histology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
| | - Shaimaa Selim
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Menoufia University, Shibin El-Kom 32514, Egypt
| | - Rashed A. Alhotan
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Anam Ayyoub
- College of Life Sciences, Northwest A & F University, Yangling District, Xianyang 712100, China
| | - Saber El Hanbally
- Department of Pharmacology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City 32897, Egypt
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Sharma A, Chorawala MR, Rawal RM, Shrivastava N. Integrated blood and organ profile analysis to evaluate ameliorative effects of kaempferol on 5-fluorouracil-induced toxicity. Sci Rep 2024; 14:2363. [PMID: 38287048 PMCID: PMC10824726 DOI: 10.1038/s41598-024-52915-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 01/25/2024] [Indexed: 01/31/2024] Open
Abstract
Colorectal cancer (CRC) treatment strategies encompass a triad of medical interventions: surgery, radiotherapy, and chemotherapy. Among these, the use of chemotherapy, specifically 5-fluorouracil (5-FU), has become a cornerstone in CRC management. However, it is imperative to explore novel approaches that harness the synergistic potential of chemotherapy agents alongside adjunctive compounds to mitigate the severe adverse effects that often accompany treatment. In light of this pressing need, this study focuses on evaluating Kaempferol (KMP) in combination with 5-FU in a DMH-induced CRC animal model, scrutinizing its impact on haematological indices, organ health, and gastrointestinal, hepatotoxic, and nephrotoxic effects. Remarkably, KMP demonstrated haemato-protective attributes and exerted an immunomodulatory influence, effectively counteracting 5-FU-induced damage. Furthermore, organ assessments affirm the safety profile of the combined treatments while suggesting KMP's potential role in preserving the structural integrity of the intestine, and spleen. Histopathological assessments unveiled KMP's capacity to ameliorate liver injury and mitigate CRC-induced renal impairment. These multifaceted findings underscore KMP's candidacy as a promising adjunctive therapeutic option for CRC, underlining the pivotal need for personalized therapeutic strategies that concurrently optimize treatment efficacy and safeguard organ health. KMP holds tremendous promise in elevating the paradigm of CRC management.
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Affiliation(s)
- Abhilasha Sharma
- Department of Life Science, University School of Sciences, Gujarat University, Ahmedabad, 380009, Gujarat, India
| | | | - Rakesh M Rawal
- Department of Life Science, University School of Sciences, Gujarat University, Ahmedabad, 380009, Gujarat, India
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Aghababaei F, Nejati M, Karami H, Darvish M, Mirzaei H. The Combination of 5-FU and Resveratrol Can Suppress the Growth of Glioblastoma Cells Through Downregulation of TRPM2 and β-Catenin. J Mol Neurosci 2024; 74:7. [PMID: 38193979 DOI: 10.1007/s12031-023-02174-3] [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: 08/30/2023] [Accepted: 12/05/2023] [Indexed: 01/10/2024]
Abstract
Glioblastoma multiforme (GBM) is the most common as well as the most fatal primary malignant tumor of the central nervous system (CNS), which still lacks a definitive cure. 5-FU is an anti-metabolite anti-cancer agent which has shown promising results for GBM treatment. Resveratrol (Res) is a phytochemical anti-oxidant that has also been effective in suppressing the progression of GBM. The combination of 5-FU and Res has been studied in a variety of cancers, but no study has assessed this combination in GBM. In this study, we investigated how 5-FU and Res, in combination and alone, may affect the growth and apoptosis of GBM cells and also the potential of TRPM2 and β-catenin as the mediator of their effects. U87 cells were cultured as the in vitro model. MTT assay was used for measuring cellular growth, and RT-qPCR was used to measure the level of caspase-3, TRPM2, and β-catenin; caspase-3 level served as the indicator of apoptotic rate. 5-FU and Res, in combination and alone, suppressed the growth while promoting the apoptosis of U87 cells; these effects were significantly greater when they were used in combination. RT-qPCR showed downregulation of TRPM-2 and β-catenin in response to this combination, which suggested that these two molecules may mediate the cited anti-oncogenic effects. In conclusion, our study confirmed the synergism between 5-FU and Res in suppressing the progression of GBM and suggested the putative axis of TRPM2/ β-catenin as the downstream mediator of this therapeutic regime. Future studies may be able to approve the eligibility of this therapeutic regime for GBM treatment and also the underlying mechanism.
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Affiliation(s)
- Farzaneh Aghababaei
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Majid Nejati
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hadi Karami
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Tambe PK, Qsee HS, Bharati S. Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study. Inflammopharmacology 2023:10.1007/s10787-023-01261-6. [PMID: 37338659 DOI: 10.1007/s10787-023-01261-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 05/31/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND Recent evidences highlight role of mitochondria in the development of 5-fluorouracil (5-FU)-induced intestinal toxicity. Mitochondria-targeted antioxidants are well-known for their protective effects in mitochondrial oxidative stress- mediated diseases. In the present study, we investigated protective effect of Mito-TEMPO in 5-FU-induced intestinal toxicity. METHODS Mito-TEMPO (0.1 mg/kg b.w.) was administered intraperitoneally to male BALB/c mice for 7 days, followed by co-administration of 5-FU for next 4 days (intraperitoneal 12 mg/kg b.w.). Protective effect of Mito-TEMPO on intestinal toxicity was assessed in terms of histopathological alterations, modulation in inflammatory markers, apoptotic cell death, expression of 8-OhDG, mitochondrial functional status and oxidative stress. RESULTS 5-FU administered animals showed altered intestinal histoarchitecture wherein a shortening and atrophy of the villi was observed. The crypts were disorganized and inflammatory cell infiltration was noted. Mito-TEMPO pre-protected animals demonstrated improved histoarchitecture with normalization of villus height, better organized crypts and reduced inflammatory cell infiltration. The inflammatory markers and myeloperoxidase activity were normalized in mito-TEMPO protected group. A significant reduction in intestinal apoptotic cell death and expression of 8-OhDG was also observed in mito-TEMPO group as compared to 5-FU group. Further, mtROS, mtLPO and mitochondrial antioxidant defense status were improved by mito-TEMPO. CONCLUSION Mito-TEMPO exerted significant protective effect against 5-FU-induced intestinal toxicity. Therefore, it may be used as an adjuvant in 5-FU chemotherapy.
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Affiliation(s)
- Prasad Kisan Tambe
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - H S Qsee
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sanjay Bharati
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India.
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Wang H, Wang ZL, Zhang S, Kong DJ, Yang RN, Cao L, Wang JX, Yoshida S, Song ZL, Liu T, Fan SL, Ren JS, Li JH, Shen ZY, Zheng H. Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients’ T cell ferroptosis. World J Gastroenterol 2023; 29:3084-3102. [PMID: 37346150 PMCID: PMC10280797 DOI: 10.3748/wjg.v29.i20.3084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/19/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation.
AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP.
METHODS A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy.
RESULTS With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells.
CONCLUSION Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.
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Affiliation(s)
- Hao Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zheng-Lu Wang
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
| | - Sai Zhang
- School of Medicine, Nankai University, Tianjin 300190, China
| | - De-Jun Kong
- School of Medicine, Nankai University, Tianjin 300190, China
| | - Rui-Ning Yang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Lei Cao
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jian-Xi Wang
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
| | - Zhuo-Lun Song
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Tao Liu
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Shun-Li Fan
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Jia-Shu Ren
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Jiang-Hong Li
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zhong-Yang Shen
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Hong Zheng
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
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Zhang XM, Song Y, Zhu XY, Wang WJ, Fan XL, El-Aziz TMA. MITOCHONDRIA: The dual function of the transient receptor potential melastatin 2 channels from cytomembrane to mitochondria. Int J Biochem Cell Biol 2023; 157:106374. [PMID: 36708986 DOI: 10.1016/j.biocel.2023.106374] [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: 09/16/2022] [Revised: 12/20/2022] [Accepted: 01/24/2023] [Indexed: 01/26/2023]
Abstract
Mitochondria are closely related to oxidative stress and play an important role in maintaining cell functional homeostasis and meeting cell energy demand. The transient receptor potential melastatin 2 (TRPM2) channel affects the occurrence and progression of diseases by regulating mitochondrial function. TRPM2 channel promotes Ca2+ influx to affect 18 kDa translocator protein (TSPO), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), adenosine triphosphate (ATP) production, and mitochondrial autophagy. The mechanism of Ca2+ influx into the mitochondria by TRPM2 is abundant. Interestingly, the TRPM2 channel inhibits the production of mitochondrial ROS in cancer cells and promotes the production of mitochondrial ROS in normal cells, which induces cell death in normal cells but proliferation in cancer cells. TRPM2 can be a potential target for the treatment of various diseases due to its role as a molecular link between mitochondria and Ca2+ signals.
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Affiliation(s)
- Xiao-Min Zhang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
| | - Xin-Yi Zhu
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Wen-Jun Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Xu-Li Fan
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Tarek Mohamed Abd El-Aziz
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA; Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
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Yang Y, Zhang M, Zhang Y, Liu K, Lu C. 5-Fluorouracil Suppresses Colon Tumor through Activating the p53-Fas Pathway to Sensitize Myeloid-Derived Suppressor Cells to FasL + Cytotoxic T Lymphocyte Cytotoxicity. Cancers (Basel) 2023; 15:1563. [PMID: 36900354 PMCID: PMC10001142 DOI: 10.3390/cancers15051563] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients. The molecular mechanism underlying 5-FU's suppression of MDSCs is currently unknown. We aimed at testing the hypothesis that 5-FU suppresses MDSCs through enhancing MDSC sensitivity to Fas-mediated apoptosis. We observed that, although FasL is highly expressed in T cells, Fas is weakly expressed in myeloid cells in human colon carcinoma, indicating that downregulation of Fas is a mechanism underlying myeloid cell survival and accumulation in human colon cancer. 5-FU treatment upregulated expression of both p53 and Fas, and knocking down p53 diminished 5-FU-induced Fas expression in MDSC-like cells, in vitro. 5-FU treatment also increased MDSC-like cell sensitivity to FasL-induced apoptosis in vitro. Furthermore, we determined that 5-FU therapy increased expression of Fas on MDSCs, suppressed MDSC accumulation, and increased CTL tumor infiltration in colon tumor-bearing mice. In human colorectal cancer patients, 5-FU chemotherapy decreased MDSC accumulation and increased CTL level. Our findings determine that 5-FU chemotherapy activates the p53-Fas pathway, to suppress MDSC accumulation, to increase CTL tumor infiltration.
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Affiliation(s)
- Yingcui Yang
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Mingqing Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Yongdan Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta, GA 30912, USA
| | - Chunwan Lu
- School of Life Sciences, Tianjin University, Tianjin 300072, China
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Gadekar GJ, Bhandare PA, Bandawane DD. Amelioration of 5-Fluorouracil Induced Nephrotoxicity by Acacia catechu through Overcoming Oxidative Damage and Inflammation in Wistar Rats. Cardiovasc Hematol Disord Drug Targets 2023; 23:189-201. [PMID: 37946347 DOI: 10.2174/011871529x274030231102065433] [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: 08/15/2023] [Revised: 10/03/2023] [Accepted: 10/13/2023] [Indexed: 11/12/2023]
Abstract
AIM The research intended to explore the possible nephroprotective potential of the ethyl acetate fraction derived from Acacia catechu leaves against nephrotoxicity brought about by 5-fluorouracil (5-FU) in Wistar rats. BACKGROUND While possessing strong anticancer properties, 5-FU is hindered in its therapeutic application due to significant organ toxicity linked to elevated oxidative stress and inflammation. OBJECTIVE The study is undertaken to conduct an analysis of the ethyl acetate fraction of A. catechu leaves both in terms of quality and quantity, examining its impact on different biochemical and histopathological parameters within the context of 5-FU-induced renal damage in rats and elucidation of the mechanism behind the observed outcomes. METHODOLOGY Intraperitoneal injection of 5-FU at a dosage of 20 mg/kg/day over 5 days was given to induce nephrotoxicity in rats. The evaluation of nephrotoxicity involved quantifying serum creatinine, urea, uric acid, and electrolyte concentrations. Furthermore, superoxide dismutase, catalase antioxidant enzymes, and TNF-α concentration in serum were also measured. RESULTS 5-FU injection led to the initiation of oxidative stress within the kidneys, leading to modifications in renal biomarkers (including serum creatinine, urea, uric acid, and Na+, K+ levels), and a reduction in antioxidant enzymes namely superoxide dismutase and catalase. Notably, the presence of the inflammatory cytokine TNF-α was significantly elevated due to 5-FU. Microscopic examination of renal tissue revealed tubular degeneration and congestion. However, treatment involving the ethyl acetate fraction derived from A. catechu leaves effectively and dose-dependently reversed the changes observed in renal biomarkers, renal antioxidant enzymes, inflammatory mediators, and histopathological features, bringing them closer to normal conditions. The observed recuperative impact was mainly attributed to the antioxidant and antiinflammatory properties of the fraction. CONCLUSION The ethyl acetate fraction of A. catechu leaves exhibited a mitigating influence on the renal impairment caused by 5-FU, showcasing its potential as a nephroprotective agent capable of preventing and ameliorating 5-FU-induced nephrotoxicity.
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Affiliation(s)
- Gayatri Jaising Gadekar
- Department of Pharmacology, P. E. Society's Modern College of Pharmacy, Nigdi, Pune- 44, India
| | | | - Deepti Dinesh Bandawane
- Department of Pharmacology, P. E. Society's Modern College of Pharmacy, Nigdi, Pune- 44, India
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Biosynthetic Silver Nanoparticles Inhibit the Malignant Behavior of Gastric Cancer Cells and Enhance the Therapeutic Effect of 5-Fluorouracil by Promoting Intracellular ROS Generation and Apoptosis. Pharmaceutics 2022; 14:pharmaceutics14102109. [PMID: 36297544 PMCID: PMC9609819 DOI: 10.3390/pharmaceutics14102109] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/21/2022] [Accepted: 09/27/2022] [Indexed: 11/25/2022] Open
Abstract
(1) Background: Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Silver nanoparticles (Ag-NPs) have been increasingly used in the diagnosis and treatment of cancer due to their physicochemical properties. This study investigated the role of a kind of biosynthetic silver nanoparticle (b-Ag) in the development of GC, the enhancement of 5-fluorouracil (5F), and its mechanism. (2) Methods: X-ray, transmission electron microscopy (TEM), and UV absorbance were used to detect the characterizations of AgNPs. CCK8, Colony formation and a Transwell assay were performed to confirm the malignant behaviors of GC. DCFH-DA and DHE were used to detect intracellular reactive oxygen species (ROS). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of apoptosis-related genes. (3) Results: Compared with the chemosynthetic silver nanoparticles (c-Ag), b-Ag had a stronger cytokilling effect, and it had a better inhibition on the malignant phenotype of GC when combined with 5F. The b-Ag increased the expression of Bax and P53 while decreasing the expression of Bcl2. It also promoted the generation of intracellular ROS. (4) Conclusions: By promoting cell apoptosis and increasing intracellular ROS, b-Ag inhibited the development of GC and enhanced the inhibition of 5F on GC.
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Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans. Expert Rev Mol Med 2022; 24:e9. [PMID: 35098910 PMCID: PMC9884763 DOI: 10.1017/erm.2022.3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and clinicians. 5-Fluorouracil (5-FU) has been widely used as a chemotherapeutic agent in the clinical treatment of various cancers, but several studies showed its adverse effects on reproduction. Reproductive toxicity of 5-FU often associates with developmental block, malformation and ovarian damage in the females. In males, 5-FU administration alters the morphology of sexual organs, the levels of reproductive endocrine hormones and the progression of spermatogenesis, ultimately reducing sperm numbers. Mechanistically, 5-FU exerts its effect through incorporating the active metabolites into nucleic acids directly, or inhibiting thymidylate synthase to disrupt the function of DNA and RNA, leading to profound effects on cellular metabolism and viability. However, some studies suggested that the toxicity of 5-FU on reproduction is reversible and certain drugs used in combination with 5-FU during chemotherapy could protect reproductive systems from 5-FU damage both in females and males. Herein, we summarise the recent findings and discuss underlying mechanisms of the 5-FU-induced reproductive toxicity, providing a reference for future research and clinical treatments.
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El-Sherbiny M, Fahmy EK, Eisa NH, Said E, Elkattawy HA, Ebrahim HA, Elsherbiny NM, Ghoneim FM. Nanogold Particles Suppresses 5-Flurouracil-Induced Renal Injury: An Insight into the Modulation of Nrf-2 and Its Downstream Targets, HO-1 and γ-GCS. Molecules 2021; 26:molecules26247684. [PMID: 34946766 PMCID: PMC8707269 DOI: 10.3390/molecules26247684] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 11/16/2022] Open
Abstract
The development of the field of nanotechnology has revolutionized various aspects in the fields of modern sciences. Nano-medicine is one of the primary fields for the application of nanotechnology techniques. The current study sheds light on the reno-protective impacts of gold nano-particles; nanogold (AuNPs) against 5-flurouracil (5-FU)-induced renal toxicity. Indeed, the use of 5-FU has been associated with kidney injury which greatly curbs its therapeutic application. In the current study, 5-FU injection was associated with a significant escalation in the indices of renal injury, i.e., creatinine and urea. Alongside this, histopathological and ultra-histopathological changes confirmed the onset of renal injury. Both gene and/or protein expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and downstream antioxidant enzymes revealed consistent paralleled anomalies. AuNPs administration induced a significant renal protection on functional, biochemical, and structural levels. Renal expression of the major sensor of the cellular oxidative status Nrf-2 escalated with a paralleled reduction in the renal expression of the other contributor to this axis, known as Kelch-like ECH-associated protein 1 (Keap-1). On the level of the effector downstream targets, heme oxygenase 1 (HO-1) and gamma-glutamylcysteine synthetase (γ-GCS) AuNPs significantly restored their gene and protein expression. Additionally, combination of AuNPs with 5-FU showed better cytotoxic effect on MCF-7 cells compared to monotreatments. Thus, it can be inferred that AuNPs conferred reno-protective impact against 5-FU with an evident modulatory impact on Nrf-2/Keap-1 and its downstream effectors, HO-1 and γ-GCS, suggesting its potential use in 5-FU regimens to improve its therapeutic outcomes and minimize its underlying nephrotoxicity.
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Affiliation(s)
- Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia; (M.E.-S.); (H.A.E.)
- Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Eslam K. Fahmy
- Medical Physiology Department, College of Medicine, Zagazig University, Zagazig 44519, Egypt;
- Medical Physiology Department, Faculty of Medicine, Northern Border University, Arar 91431, Saudi Arabia
| | - Nada H. Eisa
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Eman Said
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
- Faculty of Pharmacy, New Mansoura University, New Mansoura 7723730, Egypt
| | - Hany A. Elkattawy
- Department of Basic Medical Sciences, College of Medicine, Almaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia; (M.E.-S.); (H.A.E.)
- Medical Physiology Department, College of Medicine, Zagazig University, Zagazig 44519, Egypt;
- Zagazig Obesity Management & Research Unit, College of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Hasnaa Ali Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Nehal M. Elsherbiny
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia
- Correspondence:
| | - Fatma M. Ghoneim
- Histology and Cell Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
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Zhang S, Wang Z, Fan S, Liu T, Yoshida S, Yang S, Liu L, Hou W, Cao L, Wang J, Song Z, Li S, Zhang S, Wang H, Li J, Zheng H, Shen Z. Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect. Front Immunol 2021; 12:737849. [PMID: 34557199 PMCID: PMC8452994 DOI: 10.3389/fimmu.2021.737849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies.
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Affiliation(s)
- Sai Zhang
- School of Medicine, Nankai University, Tianjin, China
| | - Zhenglu Wang
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Shunli Fan
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Tao Liu
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Shuang Yang
- School of Medicine, Nankai University, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Lei Liu
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Wen Hou
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Lei Cao
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Jianxi Wang
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
| | - Zhuolun Song
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Shanni Li
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Sirui Zhang
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Hao Wang
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Jianghong Li
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Hong Zheng
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Zhongyang Shen
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
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