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Lu Q, Wang H, Zhang X, Yuan T, Wang Y, Feng C, Li Z, Sun S. Corydaline attenuates osteolysis in rheumatoid arthritis via mitigating reactive oxygen species production and suppressing calcineurin-Nfatc1 signaling. Int Immunopharmacol 2024; 142:113158. [PMID: 39293314 DOI: 10.1016/j.intimp.2024.113158] [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: 06/20/2024] [Revised: 09/04/2024] [Accepted: 09/09/2024] [Indexed: 09/20/2024]
Abstract
AIM OF THE STUDY Osteolysis in Rheumatoid arthritis (RA) is principally provoked by osteoclast hyperactivity. This study aims to employ Corydaline (Cory), a plant extract, as an osteoclast inhibitor in treating RA-inflicted osteolysis while unveiling the corresponding mechanism. MATERIALS AND METHODS Osteoclasts were derived from mouse bone marrow-derived monocytes (BMMs) stimulated with M-CSF and RANKL. Subsequently, utilizing network pharmacology, we performed a thorough analysis of Cory's molecular structure and discerned its preliminary therapeutic potential. Subsequently, LPS was used to simulate and establish an in vitro model of RA, and the biological effect of Cory on osteoclast behaviors was evaluated through various staining methods, RT-qPCR, and Western blot. In addition, a collagen-induced arthritis (CIA) mouse model was developed to evaluate the therapeutic effects of Cory in vivo. RESULTS The results from network pharmacology indicated a significant correlation between Cory, oxidative stress, and calcium signaling. Subsequent in vitro experiments demonstrated Cory's capacity to inhibit the formation and function of osteoclast under inflammatory stimuli, thereby protecting against abnormal bone resorption. This effect is achieved by activating the Nrf2 signaling pathway, mitigating the generation of reactive oxygen species (ROS), and modulating the calcineurin-Nfatc1 signaling. Furthermore, this therapeutic effect of Cory on RA-associated osteolysis was proved in CIA mice models. CONCLUSIONS Cory demonstrates the potential to activate the Nrf2 signaling pathway, effectively countering oxidative stress, and simultaneously inhibit the calcineurin-Nfatc1 signaling pathway to regulate the terminals of calcium signaling. These dual effects collectively reduce osteoclast activity, ultimately contributing to a therapeutic role in RA osteolysis. Therefore, our study presents Cory as a novel pharmaceutical candidate for the prevention and treatment of RA.
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Affiliation(s)
- Qizhen Lu
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Haojue Wang
- Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xin Zhang
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Tao Yuan
- Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yi Wang
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Changgong Feng
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Ziqing Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
| | - Shui Sun
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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Tucker SK, Eberhart JK. The convergence of mTOR signaling and ethanol teratogenesis. Reprod Toxicol 2024; 130:108720. [PMID: 39306261 DOI: 10.1016/j.reprotox.2024.108720] [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: 07/01/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 10/04/2024]
Abstract
Ethanol is one of the most common teratogens and causes of human developmental disabilities. Fetal alcohol spectrum disorders (FASD), which describes the wide range of deficits due to prenatal ethanol exposure, are estimated to affect between 1.1 % and 5.0 % of births in the United States. Ethanol dysregulates numerous cellular mechanisms such as programmed cell death (apoptosis), protein synthesis, autophagy, and various aspects of cell signaling, all of which contribute to FASD. The mechanistic target of rapamycin (mTOR) regulates these cellular mechanisms via sensing of nutrients like amino acids and glucose, DNA damage, and growth factor signaling. Despite an extensive literature on ethanol teratogenesis and mTOR signaling, there has been less attention paid to their interaction. Here, we discuss the impact of ethanol teratogenesis on mTORC1's ability to coordinate growth factor and amino acid sensing with protein synthesis, autophagy, and apoptosis. Notably, the effect of ethanol exposure on mTOR signaling depends on the timing and dose of ethanol as well as the system studied. Overall, the overlap between the functions of mTORC1 and the phenotypes observed in FASD suggest a mechanistic interaction. However, more work is required to fully understand the impact of ethanol teratogenesis on mTOR signaling.
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Affiliation(s)
- Scott K Tucker
- Department of Molecular Biosciences, Waggoner Center for Alcohol and Addiction Research and Institute for Neuroscience, University of Texas, Austin, TX, USA
| | - Johann K Eberhart
- Department of Molecular Biosciences, Waggoner Center for Alcohol and Addiction Research and Institute for Neuroscience, University of Texas, Austin, TX, USA.
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Zhai P, Ouyang XH, Yang ML, Lin L, Li JY, Li YM, Cheng X, Zhu R, Hu DS. Luteolin protects against myocardial ischemia/reperfusion injury by reducing oxidative stress and apoptosis through the p53 pathway. JOURNAL OF INTEGRATIVE MEDICINE 2024; 22:652-664. [PMID: 39343710 DOI: 10.1016/j.joim.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 08/13/2024] [Indexed: 10/01/2024]
Abstract
OBJECTIVE Myocardial ischemia/reperfusion injury (MIRI) is an obstacle to the success of cardiac reperfusion therapy. This study explores whether luteolin can mitigate MIRI by regulating the p53 signaling pathway. METHODS Model mice were subjected to a temporary surgical ligation of the left anterior descending coronary artery, and administered luteolin. The myocardial infarct size, myocardial enzyme levels, and cardiac function were measured. Latent targets and signaling pathways were screened using network pharmacology and molecular docking. Then, proteins related to the p53 signaling pathway, apoptosis and oxidative stress were measured. Hypoxia/reoxygenation (HR)-incubated HL1 cells were used to validate the effects of luteolin in vitro. In addition, a p53 agonist and an inhibitor were used to investigate the mechanism. RESULTS Luteolin reduced the myocardial infarcted size and myocardial enzymes, and restored cardiac function in MIRI mice. Network pharmacology identified p53 as a hub target. The bioinformatic analyses showed that luteolin had anti-apoptotic and anti-oxidative properties. Additionally, luteolin halted the activation of p53, and prevented both apoptosis and oxidative stress in myocardial tissue in vivo. Furthermore, luteolin inhibited cell apoptosis, JC-1 monomer formation, and reactive oxygen species elevation in HR-incubated HL1 cells in vitro. Finally, the p53 agonist NSC319726 downregulated the protective attributes of luteolin in the MIRI mouse model, and both luteolin and the p53 inhibitor pifithrin-α demonstrated a similar therapeutic effect in the MIRI mice. CONCLUSION Luteolin effectively treats MIRI and may ameliorate myocardial damage by regulating apoptosis and oxidative stress through its targeting of the p53 signaling pathway. Please cite this article as: Zhai P, Ouyang XH, Yang ML, Lin L, Li JY, Li YM, Cheng X, Zhu R, Hu DS. Luteolin protects against myocardial ischemia/reperfusion injury by reducing oxidative stress and apoptosis through the p53 pathway. J Integr Med. 2024; 22(6): 652-664.
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Affiliation(s)
- Pan Zhai
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiao-Hu Ouyang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Meng-Ling Yang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Lan Lin
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jun-Yi Li
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yi-Ming Li
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Rui Zhu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
| | - De-Sheng Hu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China; China-Russia Medical Research Center for Stress Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
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Liu D, Youssef MM, Grace JA, Sinclair M. Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care. World J Hepatol 2024; 16:650-660. [PMID: 38689747 PMCID: PMC11056899 DOI: 10.4254/wjh.v16.i4.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/30/2024] [Accepted: 03/19/2024] [Indexed: 04/24/2024] Open
Abstract
BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients. AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation. METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms "solid organ transplantation", "tacrolimus", "mycophenolic acid", and "carcinogenicity", in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria. RESULTS A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients. CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.
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Affiliation(s)
- Dorothy Liu
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Victorian Liver Transplant Unit, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia.
| | - Mark M Youssef
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
| | - Josephine A Grace
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
| | - Marie Sinclair
- Department of Gastroenterology, Austin Health, Melbourne 3084, Victoria, Australia
- Victorian Liver Transplant Unit, Austin Health, Melbourne 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3084, Victoria, Australia
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Xu X, Zhang G, Chen Y, Xu W, Liu Y, Ji G, Xu H. Can proline dehydrogenase-a key enzyme involved in proline metabolism-be a novel target for cancer therapy? Front Oncol 2023; 13:1254439. [PMID: 38023181 PMCID: PMC10661406 DOI: 10.3389/fonc.2023.1254439] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Emerging evidence suggests that proline metabolism is important for regulating the survival and death of different types of cancer cells. Proline dehydrogenase (PRODH), an enzyme catalyzing proline catabolism, and the degradation products of proline by PRODH, such as ATP and ROS, are known to play critical roles in cancer progression. Notably, the role of PRODH in cancer is still complicated and unclear, and primarily depends on the cancer type and tumor microenvironment. For instance, PRODH induces apoptosis and senescence through ROS signaling in different types of cancers, while as a protumor factor, PRODH promotes malignant phenotypes of certain tumors under stresses such as hypoxia. In order to assess whether PRODH can serve as a novel target for cancer therapy, we will provide an overview of the biological functions of PRODH and its double-edged role in cancer in this article.
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Affiliation(s)
- Xiangyuan Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai, China
| | - Guangtao Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yijia Chen
- Department of Gynecology, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weina Xu
- Shanghai Pudong New Area Zhoujiadu Community Health Service Center, Shanghai, China
| | - Yujing Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai, China
| | - Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai, China
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6
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Wójcik-Piotrowicz K, Kaszuba-Zwoińska J, Piszczek P, Nowak B, Guzdek P, Gil K, Rokita E. Low-frequency electromagnetic fields influence the expression of calcium metabolism related proteins in leukocytic cell lines. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 104:104320. [PMID: 37984675 DOI: 10.1016/j.etap.2023.104320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 11/11/2023] [Accepted: 11/15/2023] [Indexed: 11/22/2023]
Abstract
Our study aimed to verify the hypothesis concerning low-frequency magnetic fields (LF-MFs)-related changes in cell viability through the biomechanism(s) based on calcineurin (CaN)-mediated signaling pathways triggered via ROS-like molecules. For experiments, Mono Mac 6 and U937 leukocytic cell lines were chosen and exposed to various LF-MFs and/or puromycin (PMC). The protein expression level of key regulatory proteins of calcium metabolism was examined by Western Blot analysis. In turn, the reactive oxygen species (ROS) and cell viability parameters were evaluated by cytochrome C reduction assay and flow cytometry, respectively. The simultaneous action of applied MF and PMC influenced cell viability in a MF-dependent manner. The changes in cell viability were correlated with protein expression and ROS levels. It was verified experimentally that applied stress stimuli influence cell susceptibility to undergo cell death. Moreover, the evoked bioeffects might be recognized as specific to both types of leukocyte populations.
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Affiliation(s)
- Karolina Wójcik-Piotrowicz
- Department of Biophysics, Jagiellonian University Medical College, Łazarza street 16, 31-530 Cracow, Poland.
| | - Jolanta Kaszuba-Zwoińska
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta street 18, 31-121 Cracow, Poland
| | - Piotr Piszczek
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta street 18, 31-121 Cracow, Poland
| | - Bernadeta Nowak
- Department of Immunology, Jagiellonian University Medical College, Czysta street 18, 31-121 Cracow, Poland
| | - Piotr Guzdek
- Łukasiewicz Research Network - Institute of Microelectronics and Photonics, Lotników street 32/46, 02-668 Warsaw, Poland
| | - Krzysztof Gil
- Department of Pathophysiology, Jagiellonian University Medical College, Czysta street 18, 31-121 Cracow, Poland
| | - Eugeniusz Rokita
- Department of Biophysics, Jagiellonian University Medical College, Łazarza street 16, 31-530 Cracow, Poland
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7
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Wang F, Dezfouli AB, Khosravi M, Sievert W, Stangl S, Schwab M, Wu Z, Steiger K, Ma H, Multhoff G. Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70. Cell Death Discov 2023; 9:286. [PMID: 37542074 PMCID: PMC10403543 DOI: 10.1038/s41420-023-01578-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 07/12/2023] [Accepted: 07/25/2023] [Indexed: 08/06/2023] Open
Abstract
Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood. This study provides new insights into the potential mechanisms of CBD-induced mutual antagonism of apoptosis and macroautophagy using wild type (HCT116 p53wt, LS174T p53wt), knockout (HCT116 p53-/-) and mutant (SW480 p53mut) human colorectal cancer cells (CRC). CBD causes a more pronounced loss in the viability of p53wt cells than p53-/- and p53mut cells, and a 5-week treatment with CBD reduced the volume of HCT116 p53wt xenografts in mice, but had no effect on the volume of HCT116 p53-/- tumors. Mechanistically, we demonstrate that CBD only significantly elevates ROS production in cells harboring wild-type p53 (HCT116, LS174T) and that this is associated with an accumulation of PARP1. CBD-induced elevated ROS levels trigger G0/G1 cell cycle arrest, a reduction in CDK2, a p53-dependent caspase-8/9/3 activation and macroautophagy in p53wt cells. The ROS-induced macroautophagy which promotes the activation of keap1/Nrf2 pathway might be positively regulated by p53wt, since inhibition of p53 by pifithrin-α further attenuates autophagy after CBD treatment. Interestingly, an inhibition of heat shock protein 70 (Hsp70) expression significantly enhances caspase-3 mediated programmed cell death in p53wt cells, whereas autophagy-which is associated with a nuclear translocation of Nrf2-was blocked. Taken together, our results demonstrate an intricate interplay between apoptosis and macroautophagy in CBD-treated colorectal cancer cells, which is regulated by the complex interactions of p53wt and Hsp70.
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Affiliation(s)
- Fei Wang
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - Ali Bashiri Dezfouli
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Mohammad Khosravi
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Wolfgang Sievert
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Stefan Stangl
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Melissa Schwab
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Zhiyuan Wu
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Katja Steiger
- Institute for General Pathology and Pathological Anatomy, Technische Universität München, Munich, Germany
| | - Hu Ma
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Gabriele Multhoff
- Radiation Immuno-Oncology Project Group, TranslaTUM-Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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8
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Marques MA, de Andrade GC, Silva JL, de Oliveira GAP. Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53. Front Mol Biosci 2022; 9:944955. [PMID: 36090037 PMCID: PMC9452956 DOI: 10.3389/fmolb.2022.944955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/18/2022] [Indexed: 12/30/2022] Open
Abstract
The p53 protein is a pleiotropic regulator working as a tumor suppressor and as an oncogene. Depending on the cellular insult and the mutational status, p53 may trigger opposing activities such as cell death or survival, senescence and cell cycle arrest or proliferative signals, antioxidant or prooxidant activation, glycolysis, or oxidative phosphorylation, among others. By augmenting or repressing specific target genes or directly interacting with cellular partners, p53 accomplishes a particular set of activities. The mechanism in which p53 is activated depends on increased stability through post-translational modifications (PTMs) and the formation of higher-order structures (HOS). The intricate cell death and metabolic p53 response are reviewed in light of gaining stability via PTM and HOS formation in health and disease.
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Affiliation(s)
- Mayra A. Marques
- *Correspondence: Mayra A. Marques, ; Guilherme A. P. de Oliveira,
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9
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Song YC, Kuo CC, Liu CT, Wu TC, Kuo YT, Yen HR. Combined Effects of Tanshinone IIA and an Autophagy Inhibitor on the Apoptosis of Leukemia Cells via p53, Apoptosis-Related Proteins and Oxidative Stress Pathways. Integr Cancer Ther 2022; 21:15347354221117776. [PMID: 35996358 PMCID: PMC9421224 DOI: 10.1177/15347354221117776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background: Acute myeloid leukemia (AML) is a kind of hematopoietic malignancy with
limited response and acquired resistance to therapy. Inducing apoptosis and
inhibiting autophagy in tumor cells is a combinational strategy for the
development of anticancer therapeutics. Tanshinone IIA (TAIIA) is one of the
major ingredients in Salvia miltiorrhiza, which is the most
prescribed herb for the treatment of AML in Taiwan. Therefore, this study
aimed to delineate the anticancer effects of TAIIA and its effect when
combined with an autophagy inhibitor to treat AML. Methods: The anticancer effects of a combination of TAIIA and the autophagy inhibitor
3-methladenine (3MA) on the human monocytic leukemia cell line THP-1 were
explored. The apoptosis and cell cycle of the leukemia cells were examined
by Annexin V and propidium iodide staining and analyzed by flow cytometry.
The oxidative stress level was determined by a malondialdehyde (MDA)
colorimetric assay, nitric oxide colorimetric assay and glutathione
peroxidase (GPx) colorimetric assay. The expression of apoptosis-related
proteins was determined by western blotting. Results: TAIIA treatment significantly induced apoptosis via increased p53, Bax/Bcl,
PARP, and caspase-3 signals and oxidative stress by enhancing MDA and
nitrate/nitrite production and reducing GPx activity in THP-1 cells in a
dose-dependent and time-dependent manner. The combination of the autophagy
inhibitor 3MA enhanced TAIIA-induced apoptosis via the p53, Bax/Bcl, PARP,
caspase-3, and oxidative stress pathways in THP-1 cells. Conclusion: The results suggest that TAIIA and autophagy inhibitors have combined effects
on the apoptosis of leukemia cells, thus representing a novel and effective
combination with the potential for application as a clinical therapy for
AML.
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Affiliation(s)
- Ying-Chyi Song
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.,Research Center of Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Chieh Kuo
- Research Center of Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chuan-Teng Liu
- Research Center of Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Tsai-Chen Wu
- Research Center of Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Yi-Ting Kuo
- Research Center of Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
| | - Hung-Rong Yen
- Research Center of Traditional Chinese Medicine, Department of Medical Research, and Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan.,School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.,Department of Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
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Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax. Metabolites 2021; 11:metabo11110755. [PMID: 34822413 PMCID: PMC8620300 DOI: 10.3390/metabo11110755] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 10/26/2021] [Accepted: 10/30/2021] [Indexed: 12/20/2022] Open
Abstract
Oxidative metabolism is fine-tuned machinery that combines two tightly coupled fluxes of glucose and glutamine-derived carbons. Hypoxia interrupts the coordination between the metabolism of these two nutrients and leads to a decrease of the system efficacy and may eventually cause cell death. The subterranean blind mole rat, Spalax, is an underexplored, underground, hypoxia-tolerant mammalian group which spends its life under sharply fluctuating oxygen levels. Primary Spalax cells are an exceptional model to study the metabolic strategies that have evolved in mammals inhabiting low-oxygen niches. In this study we explored the metabolic frame of glutamine (Gln) homeostasis in Spalax skin cells under normoxic and hypoxic conditions and their impacts on the metabolism of rat cells. Targeted metabolomics employing liquid chromatography and mass spectrometry (LC-MS) was used to track the fate of heavy glutamine carbons (13C5 Gln) after 24 h under normoxia or hypoxia (1% O2). Our results indicated that large amounts of glutamine-originated carbons were detected as proline (Pro) and hydroxyproline (HPro) in normoxic Spalax cells with a further increase under hypoxia, suggesting a strategy for reduced Gln carbons storage in proteins. The intensity of the flux and the presence of HPro suggests collagen as a candidate protein that is most abundant in animals, and as the primary source of HPro. An increased conversion of αKG to 2 HG that was indicated in hypoxic Spalax cells prevents the degradation of hypoxia-inducible factor 1α (HIF-1α) and, consequently, maintains cytosolic and mitochondrial carbons fluxes that were uncoupled via inhibition of the pyruvate dehydrogenase complex. A strong antioxidant defense in Spalax cells can be attributed, at least in part, to the massive usage of glutamine-derived glutamate for glutathione (GSH) production. The present study uncovers additional strategies that have evolved in this unique mammal to support its hypoxia tolerance, and probably contribute to its cancer resistance, longevity, and healthy aging.
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11
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Jakoube P, Cutano V, González-Morena JM, Keckesova Z. Mitochondrial Tumor Suppressors-The Energetic Enemies of Tumor Progression. Cancer Res 2021; 81:4652-4667. [PMID: 34183354 PMCID: PMC9397617 DOI: 10.1158/0008-5472.can-21-0518] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/09/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023]
Abstract
Tumor suppressors represent a critical line of defense against tumorigenesis. Their mechanisms of action and the pathways they are involved in provide important insights into cancer progression, vulnerabilities, and treatment options. Although nuclear and cytosolic tumor suppressors have been extensively investigated, relatively little is known about tumor suppressors localized within the mitochondria. However, recent research has begun to uncover the roles of these important proteins in suppressing tumorigenesis. Here, we review this newly developing field and summarize available information on mitochondrial tumor suppressors.
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Affiliation(s)
- Pavel Jakoube
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Valentina Cutano
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Juan M. González-Morena
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Keckesova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Corresponding Author: Zuzana Keckesova, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Namesti 2, Prague 16000, Czech Republic. Phone: 420-2201-83584; E-mail:
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12
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Activation of proline metabolism maintains ATP levels during cocaine-induced polyADP-ribosylation. Amino Acids 2021; 53:1903-1915. [PMID: 34417893 PMCID: PMC8651605 DOI: 10.1007/s00726-021-03065-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/06/2021] [Indexed: 01/30/2023]
Abstract
Cocaine is a commonly abused drug worldwide. Acute as well as repeated exposure to cocaine activates persistent cellular and molecular changes in the brain reward regions. The effects of cocaine are predominantly mediated via alterations in neuronal gene expression by chromatin remodeling. Poly(ADP-ribose) polymerase-1 (PARP-1) catalyzed PARylation of chromatin has been reported as an important regulator of cocaine-mediated gene expression. PARP-1 dependent ADP-ribosylation is an energy-dependent process. In this study, we investigated the cellular energy response to cocaine-induced upregulation of PARP-1 expression. Exposure of differentiated SH-SY5Y cells to varying concentrations of cocaine resulted in the induction of PARP-1 dependent PARylation of p53 tumor suppressor. Further analysis revealed that PARylation of p53 by cocaine treatment resulted in nuclear accumulation of p53. However, induction and nuclear accumulation of p53 did not correlate with neuronal apoptosis/cell death upon cocaine exposure. Interestingly, cocaine-induced p53 PARylation resulted in the induction of proline oxidase (POX)—a p53 responsive gene involved in cellular metabolism. Given that cocaine-induced p53 PARylation is an energy-dependent process, we observed that cocaine-induced PARP-1/p53/POX axes alters cellular energy metabolism. Accordingly, using pharmacological and genetic studies of PARP-1, p53, and POX, we demonstrated the contribution of POX in maintaining cellular energy during neuronal function. Collectively, these studies highlight activation of a novel metabolic pathway in response to cocaine treatment.
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Astaxanthin-s-allyl cysteine diester against high glucose-induced neuronal toxicity in vitro and diabetes-associated cognitive decline in vivo: Effect on p53, oxidative stress and mitochondrial function. Neurotoxicology 2021; 86:114-124. [PMID: 34339762 DOI: 10.1016/j.neuro.2021.07.007] [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: 05/07/2021] [Revised: 06/24/2021] [Accepted: 07/28/2021] [Indexed: 02/08/2023]
Abstract
Neuroprotective effect of astaxanthin-s-allyl cysteine diester (AST-SAC) against high glucose (HG)-induced oxidative stress in in vitro and cognitive decline under diabetes conditions in in vivo has been explored. Pretreatment of AST-SAC (5, 10 and 15 μM) dose-dependently preserved the neuronal cells (SH-SY5Y) viability against HG toxicity through i) decreasing oxidative stress (decreasing reactive oxygen species generation and increasing endogenous antioxidants level); ii) protecting mitochondrial function [oxidative phosphorylation (OXPHOS) complexes activity and mitochondrial membrane potential (MMP)]; and iii) decreasing p53 level thereby subsequently decreasing the level of apoptotic marker proteins. Male Spraque-Dawley rats were orally administered AST-SAC (1 mg/kg/day) for 45 days in streptozotocin-induced diabetes mellitus (DM) rats. AST-SAC administration prevented the loss of spatial memory in DM rats as determined using the novel object location test. AST-SAC administration alleviated the DM-induced injury in brain such as increased cholinesterases activity, elevated oxidative stress and mitochondrial dysfunction. Altogether, the results from the present study demonstrated that AST-SAC averted the neuronal apoptosis and preserved the cognitive function against HG toxicity under DM conditions.
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14
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Liu Y, Mao C, Liu S, Xiao D, Shi Y, Tao Y. Proline dehydrogenase in cancer: apoptosis, autophagy, nutrient dependency and cancer therapy. Amino Acids 2021; 53:1891-1902. [PMID: 34283310 DOI: 10.1007/s00726-021-03032-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/27/2021] [Indexed: 01/03/2023]
Abstract
L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.
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Affiliation(s)
- Yating Liu
- Postdoctoral Research Station of Clinical Medicine & Department of Hematology and Critical Care Medicine, Central South University, the 3rd Xiangya Hospital, Changsha, 410000, People's Republic of China.,Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078, China.,NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China
| | - Chao Mao
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078, China.,NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, Center for Geriatric Disorders, National Clinical Research, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Desheng Xiao
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078, China. .,NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China.
| | - Ying Shi
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078, China. .,NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China.
| | - Yongguang Tao
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Hunan, 410078, China. .,NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China. .,Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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15
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McGinity CL, Palmieri EM, Somasundaram V, Bhattacharyya DD, Ridnour LA, Cheng RYS, Ryan AE, Glynn SA, Thomas DD, Miranda KM, Anderson SK, Lockett SJ, McVicar DW, Wink DA. Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment. Int J Mol Sci 2021; 22:7068. [PMID: 34209132 PMCID: PMC8268115 DOI: 10.3390/ijms22137068] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 02/07/2023] Open
Abstract
The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes.
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Affiliation(s)
- Christopher L. McGinity
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Erika M. Palmieri
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Veena Somasundaram
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Dibyangana D. Bhattacharyya
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
- Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland; (A.E.R.); (S.A.G.)
| | - Lisa A. Ridnour
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Robert Y. S. Cheng
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Aideen E. Ryan
- Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland; (A.E.R.); (S.A.G.)
| | - Sharon A. Glynn
- Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway, H91 TK33 Galway, Ireland; (A.E.R.); (S.A.G.)
| | - Douglas D. Thomas
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA;
| | | | - Stephen K. Anderson
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - Stephen J. Lockett
- Optical Microscopy and Analysis Laboratory, LEIDO Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;
| | - Daniel W. McVicar
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
| | - David A. Wink
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; (C.L.M.); (E.M.P.); (V.S.); (D.D.B.); (L.A.R.); (R.Y.S.C.); (S.K.A.); (D.W.M.)
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Yen C, Curran SP. Incomplete proline catabolism drives premature sperm aging. Aging Cell 2021; 20:e13308. [PMID: 33480139 PMCID: PMC7884046 DOI: 10.1111/acel.13308] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/19/2020] [Accepted: 12/27/2020] [Indexed: 12/20/2022] Open
Abstract
Infertility is an increasingly common health issue, with rising prevalence in advanced parental age. Environmental stress has established negative effects on reproductive health, however, the impact of altering cellular metabolism and its endogenous reactive oxygen species (ROS) on fertility remains unclear. Here, we demonstrate the loss of proline dehydrogenase, the first committed step in proline catabolism, is relatively benign. In contrast, disruption of alh-6, which facilitates the second step of proline catabolism by converting 1-pyrroline-5-carboxylate (P5C) to glutamate, results in premature reproductive senescence, specifically in males. The premature reproductive senescence in alh-6 mutant males is caused by aberrant ROS homeostasis, which can be countered by genetically limiting the first committed step of proline catabolism that functions upstream of ALH-6 or by pharmacological treatment with antioxidants. Taken together, our work uncovers proline metabolism as a critical component of normal sperm function that can alter the rate of aging in the male reproductive system.
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Affiliation(s)
- Chia‐An Yen
- Leonard Davis School of Gerontology University of Southern California Los Angeles CA USA
- Department of Molecular and Computation Biology Dornsife College of Letters, Arts, and Sciences University of Southern California Los Angeles CA USA
| | - Sean P. Curran
- Leonard Davis School of Gerontology University of Southern California Los Angeles CA USA
- Department of Molecular and Computation Biology Dornsife College of Letters, Arts, and Sciences University of Southern California Los Angeles CA USA
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17
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Infante B, Coviello N, Troise D, Gravina M, Bux V, Castellano G, Stallone G. Rapamycin Inhibitors for Eye Squamous Cell Carcinoma after Renal Transplantation: A Case Report. Kidney Blood Press Res 2021; 46:121-125. [PMID: 33508825 DOI: 10.1159/000512364] [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] [Received: 04/07/2020] [Accepted: 10/17/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION The immunosuppressive efficiency obtained in the last decades in kidney transplantation significantly improved graft survival. However, there is still a high risk and incidence of cancer in transplant patients strongly and directly related to the type of immunosuppression. An increasing body of evidence suggests that the PI3K/Akt/mTOR pathway may play a pivotal role in the development and progression of several neoplastic diseases. CASE PRESENTATION We describe a 47-year-old male patient who received a cadaveric primary renal transplant in November 2008 developing a poorly differentiated infiltrating and ulcerated squamous cell carcinoma (SCC) at the eye level. In this patient, the modification of an immunosuppressive regimen with introduction of rapamycin (mTOR) inhibitors and withdrawal of calcineurin inhibitors (CNIs) led to the resolution of this severe condition. CONCLUSION The introduction of mTOR inhibitors and withdrawal of CNIs in kidney-transplanted patients with de novo eye SCC should be considered in this clinical setting.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Nicola Coviello
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Dario Troise
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Matteo Gravina
- Department of Medical and Surgical Sciences, Radiology Unit, University of Foggia, Foggia, Italy
| | - Valeria Bux
- Department of Medical and Surgical Sciences, Ophthalmology Unit, University of Foggia, Foggia, Italy
| | - Giuseppe Castellano
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy,
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18
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Role of calcineurin biosignaling in cell secretion and the possible regulatory mechanisms. Saudi J Biol Sci 2021; 28:116-124. [PMID: 33424288 PMCID: PMC7783665 DOI: 10.1016/j.sjbs.2020.08.042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/02/2020] [Accepted: 08/30/2020] [Indexed: 11/22/2022] Open
Abstract
Cyclic adenosine monophosphate (cAMP) and calcium ions (Ca2+) are two chemical molecules that play a central role in the stimulus-dependent secretion processes within cells. Ca2+ acts as the basal signaling molecule responsible to initiate cell secretion. cAMP primarily acts as an intracellular second messenger in a myriad of cellular processes by activating cAMP-dependent protein kinases through association with such kinases in order to mediate post-translational phosphorylation of those protein targets. Put succinctly, both Ca2+ and cAMP act by associating or activating other proteins to ensure successful secretion. Calcineurin is one such protein regulated by Ca2+; its action depends on the intracellular levels of Ca2+. Being a phosphatase, calcineurin dephosphorylate and other proteins, as is the case with most other phosphatases, such as protein phosphatase 2A (PP2A), PP2C, and protein phosphatase-1 (PP1), will likely be activated by phosphorylation. Via this process, calcineurin is able to affect different intracellular signaling with clinical importance, some of which has been the basis for development of different calcineurin inhibitors. In this review, the cAMP-dependent calcineurin bio-signaling, protein-protein interactions and their physiological implications as well as regulatory signaling within the context of cellular secretion are explored.
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Ferreira AGK, Biasibetti-Brendler H, Sidegum DSV, Loureiro SO, Figueiró F, Wyse ATS. Effect of Proline on Cell Death, Cell Cycle, and Oxidative Stress in C6 Glioma Cell Line. Neurotox Res 2020; 39:327-334. [PMID: 33196952 DOI: 10.1007/s12640-020-00311-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/08/2020] [Accepted: 11/09/2020] [Indexed: 01/24/2023]
Abstract
Since proline metabolism has been implicated to play an underlying role in apoptotic signaling and cancer, and hyperprolinemic patients present susceptibility to tumors development, this study investigated the effect of proline on cell death, cell cycle, antioxidant enzymes activities, and immunocontent/activity of proteins involved in cell death/survival signaling pathways in C6 glioma cells. C6 cells were incubated with proline (0-5 mM) for 1 h, 24 h, 48 h, 72 h, or 7 days. Proline in high concentrations slightly decreased LDH release, and no cytotoxic effect was seen by Annexin-PI staining. Superoxide dismutase and catalase activities were increased by proline (1 mM) after 72 h, suggesting an increase in reactive species levels. Acetylcholinesterase activity was inhibited by proline at 1, 3, and 5 mM. The cell cycle progression was not altered. Results from Western blot analyses showed that proline at 1 mM after 72 h increased p-NF-ĸB and decreased acetylcholinesterase immunocontent but did not altered AKT, p-AKT, GSK3β, and p-GSK3β. Taken together, the data suggest that high proline levels seems to favor the signaling pathways towards cell proliferation, since acetylcholinesterase, which may act as tumor suppressor, is inhibited by proline. Also, p-NF-κB is increased by proline treatment and its activation is related to tumor cell proliferation and cellular response to oxidants. Proline also induced oxidative stress, but it appears to be insufficient to induce a significant change in cell cycle progression. These data may be related, at least in part, to the increased susceptibility to tumor development in hyperprolinemic individuals.
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Affiliation(s)
- Andréa Gisiane Kurek Ferreira
- Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, ICBS, UFRGS Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
| | - Helena Biasibetti-Brendler
- Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, ICBS, UFRGS Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Daniele Susana Volkart Sidegum
- Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, ICBS, UFRGS Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Samanta Oliveira Loureiro
- Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, ICBS, UFRGS Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Fabrício Figueiró
- Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Angela T S Wyse
- Laboratório de Neuroproteção e Doenças Neurometabólicas, Departamento de Bioquímica, ICBS, UFRGS Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
- Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
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Chowdhury AR, Zielonka J, Kalyanaraman B, Hartley RC, Murphy MP, Avadhani NG. Mitochondria-targeted paraquat and metformin mediate ROS production to induce multiple pathways of retrograde signaling: A dose-dependent phenomenon. Redox Biol 2020; 36:101606. [PMID: 32604037 PMCID: PMC7327929 DOI: 10.1016/j.redox.2020.101606] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/11/2020] [Indexed: 01/12/2023] Open
Abstract
The mitochondrial electron transport chain is a major source of reactive oxygen species (ROS) and is also a target of ROS, with an implied role in the stabilization of hypoxia-inducible factor (HIF) and induction of the AMPK pathway. Here we used varying doses of two agents, Mito-Paraquat and Mito-Metformin, that have been conjugated to cationic triphenylphosphonium (TPP+) moiety to selectively target them to the mitochondrial matrix compartment, thereby resulting in the site-specific generation of ROS within mitochondria. These agents primarily induce superoxide (O2•-) production by acting on complex I. In Raw264.7 macrophages, C2C12 skeletal myocytes, and HCT116 adenocarcinoma cells, we show that mitochondria-targeted oxidants can induce ROS (O2•- and H2O2). In all three cell lines tested, the mitochondria-targeted agents disrupted membrane potential and activated calcineurin and the Cn-dependent retrograde signaling pathway. Hypoxic culture conditions also induced Cn activation and HIF1α activation in a temporally regulated manner, with the former appearing at shorter exposure times. Together, our results indicate that mitochondrial oxidant-induced retrograde signaling is driven by disruption of membrane potential and activation of Ca2+/Cn pathway and is independent of ROS-induced HIF1α or AMPK pathways.
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Affiliation(s)
- Anindya Roy Chowdhury
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jacek Zielonka
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Balaraman Kalyanaraman
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Michael P Murphy
- MRC-Mitochondrial Biology Unit, University of Cambridge, Hills Road, Cambridge, CB2 OXY, UK
| | - Narayan G Avadhani
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Yang L, Zhou J, Meng F, Fu C, Zou X, Liu J, Zhang C, Tan R, Li Z, Guo Q, Wei L. G1 phase cell cycle arrest in NSCLC in response to LZ-106, an analog of enoxacin, is orchestrated through ROS overproduction in a P53-dependent manner. Carcinogenesis 2019; 40:131-144. [PMID: 30239617 DOI: 10.1093/carcin/bgy124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/16/2018] [Accepted: 09/13/2018] [Indexed: 01/09/2023] Open
Abstract
LZ-106, a newly synthetized analog of quinolone, has been shown to be highly effective in non-small cell lung cancer (NSCLC) in both cultured cells and xenograft mouse model with low toxicity, yet the molecular mechanisms still require exploration. Here, we substantiated the involvement of P53 activation in intracellular reactive oxygen species (ROS) generation upon LZ-106 treatment and related P53 to the ROS-induced viability inhibition and apoptosis, which was exhibited in the previous research. P53 was shown to play an indispensable role in the elevated levels of intracellular ROS in LZ-106-treated NSCLC cells through ROS detection. We further identified the anti-proliferation effect of LZ-106 in NSCLC cells through G1 phase cell cycle arrest by cell cycle analysis, with the expression analysis of the key proteins, and discovered that the cell cycle arrest effect is also mediated by induction of ROS in a P53-dependent manner. In addition, the tumor suppression effect exhibited in vivo was demonstrated to be similar to that in vitro, which requires the participation of P53. Thus, LZ-106 is a potent antitumor drug possessing potent proliferation inhibition and apoptosis induction ability through the P53-dependent ROS modulation both in vitro and in vivo.
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Affiliation(s)
- Lin Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Jieying Zhou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Fei Meng
- Department of Clinical Laboratory, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Chengyu Fu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Xiaoqian Zou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Jinfeng Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Chengwan Zhang
- The Central Laboratory of Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu Province, China
| | - Renxiang Tan
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhiyu Li
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
| | - Libin Wei
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Tongjiaxiang, Nanjing, China
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Benzo[a]pyrene mediated time- and dose-dependent alteration in cellular metabolism of primary pig bladder cells with emphasis on proline cycling. Arch Toxicol 2019; 93:2593-2602. [DOI: 10.1007/s00204-019-02521-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 07/18/2019] [Indexed: 12/16/2022]
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Lunde‐Young R, Ramirez J, Naik V, Orzabal M, Lee J, Konganti K, Hillhouse A, Threadgill D, Ramadoss J. Hippocampal transcriptome reveals novel targets of FASD pathogenesis. Brain Behav 2019; 9:e01334. [PMID: 31140755 PMCID: PMC6625466 DOI: 10.1002/brb3.1334] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/01/2019] [Accepted: 05/06/2019] [Indexed: 01/26/2023] Open
Abstract
INTRODUCTION Prenatal alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), characterized by a myriad of developmental impairments affecting behavior and cognition. Studies show that many of these functional impairments are associated with the hippocampus, a structure exhibiting exquisite vulnerability to developmental alcohol exposure and critically implicated in learning and memory; however, mechanisms underlying alcohol-induced hippocampal deficits remain poorly understood. By utilizing a high-throughput RNA-sequencing (RNA-seq) approach to address the neurobiological and molecular basis of prenatal alcohol-induced hippocampal functional deficits, we hypothesized that chronic binge prenatal alcohol exposure alters gene expression and global molecular pathways in the fetal hippocampus. METHODS Timed-pregnant Sprague-Dawley rats were randomly assigned to a pair-fed control (PF) or binge alcohol (ALC) treatment group on gestational day (GD) 4. ALC dams acclimatized from GDs 5-10 with a daily treatment of 4.5 g/kg alcohol and subsequently received 6 g/kg on GDs 11-20. PF dams received a once daily maltose dextrin gavage on GDs 5-20, isocalorically matching ALC counterparts. On GD 21, bilateral hippocampi were dissected, flash frozen, and stored at -80° C. Total RNA was then isolated from homogenized tissues. Samples were normalized to ~4nM and pooled equally. Sequencing was performed by Illumina NextSeq 500 on a 75 cycle, single-end sequencing run. RESULTS RNA-seq identified 13,388 genes, of these, 76 genes showed a significant difference (p < 0.05, log2 fold change ≥2) in expression between the PF and ALC groups. Forty-nine genes showed sex-dependent dysregulation; IPA analysis showed among female offspring, dysregulated pathways included proline and citrulline biosynthesis, whereas in males, xenobiotic metabolism signaling and alaninine biosynthesis etc. were altered. CONCLUSION We conclude that chronic binge alcohol exposure during pregnancy dysregulates fetal hippocampal gene expression in a sex-specific manner. Identification of subtle, transcriptome-level dysregulation in hippocampal molecular pathways offers potential mechanistic insights underlying FASD pathogenesis.
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Affiliation(s)
- Raine Lunde‐Young
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Josue Ramirez
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Vishal Naik
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Marcus Orzabal
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Jehoon Lee
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Kranti Konganti
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Andrew Hillhouse
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - David Threadgill
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
| | - Jayanth Ramadoss
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTexas
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Hashimoto N, Nagano H, Tanaka T. The role of tumor suppressor p53 in metabolism and energy regulation, and its implication in cancer and lifestyle-related diseases. Endocr J 2019; 66:485-496. [PMID: 31105124 DOI: 10.1507/endocrj.ej18-0565] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The tumor suppressor gene p53 is mutated in approximately more than 50% of human cancers. p53 is also referred to as the "cellular gatekeeper" or "guardian of the genome" because it protects the body from spreading mutated genome induced by various stress. When the cells receives stimuli such as DNA damage, oncogene activation, oxidative stress or undernutrition, p53 gives rise to a number of cellular responses, including cell cycle arrest, apoptosis, cellular senescence and metabolic adaptation. Related to energy metabolisms, it has been reported that p53 reduces glycolysis and enhances mitochondrial respiration. p53 is also involved in the regulation of other cellular metabolism and energy production systems: amino acid metabolism, fatty acid metabolism, nucleic acid metabolism, anti-oxidation, mitochondrial quality control, and autophagy. Moreover, recent studies have shown that p53 gene polymorphisms affect life expectancy and lifestyle-related disease such as type 2 diabetes, suggesting that there is a certain relationship between p53 function and metabolic disorders. In addition, mutant p53 protein does not only lose the tumor suppressor function, but it also gains novel oncogenic function and contributes to tumor development, involving cellular metabolism modification. Therefore, the importance of multifunctionality of p53, particularly with regard to intracellular metabolisms, arouses therapeutic interest and calls attention as the key molecule among cancer, lifestyle-related diseases and life expectancy.
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Affiliation(s)
- Naoko Hashimoto
- Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hidekazu Nagano
- Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Tomoaki Tanaka
- Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan
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Labuschagne CF, Zani F, Vousden KH. Control of metabolism by p53 - Cancer and beyond. Biochim Biophys Acta Rev Cancer 2018; 1870:32-42. [PMID: 29883595 PMCID: PMC6102416 DOI: 10.1016/j.bbcan.2018.06.001] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/04/2018] [Accepted: 06/04/2018] [Indexed: 12/18/2022]
Abstract
p53 is an important tumour suppressor gene, with loss of p53 contributing to the development of most human cancers. However, the activation of p53 in response to stress signals underpins a role for p53 in diverse aspects of health and disease. Activities of p53 that regulate metabolism can play a role in maintaining homeostasis and protecting cells from damage - so preventing disease development. By contrast, either loss or over-activation of p53 can contribute to numerous metabolic pathologies, including aging, obesity and diabetes.
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Affiliation(s)
| | - Fabio Zani
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Karen H Vousden
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
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Simabuco FM, Morale MG, Pavan IC, Morelli AP, Silva FR, Tamura RE. p53 and metabolism: from mechanism to therapeutics. Oncotarget 2018; 9:23780-23823. [PMID: 29805774 PMCID: PMC5955117 DOI: 10.18632/oncotarget.25267] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/06/2018] [Indexed: 11/25/2022] Open
Abstract
The tumor cell changes itself and its microenvironment to adapt to different situations, including action of drugs and other agents targeting tumor control. Therefore, metabolism plays an important role in the activation of survival mechanisms to keep the cell proliferative potential. The Warburg effect directs the cellular metabolism towards an aerobic glycolytic pathway, despite the fact that it generates less adenosine triphosphate than oxidative phosphorylation; because it creates the building blocks necessary for cell proliferation. The transcription factor p53 is the master tumor suppressor; it binds to more than 4,000 sites in the genome and regulates the expression of more than 500 genes. Among these genes are important regulators of metabolism, affecting glucose, lipids and amino acids metabolism, oxidative phosphorylation, reactive oxygen species (ROS) generation and growth factors signaling. Wild-type and mutant p53 may have opposing effects in the expression of these metabolic genes. Therefore, depending on the p53 status of the cell, drugs that target metabolism may have different outcomes and metabolism may modulate drug resistance. Conversely, induction of p53 expression may regulate differently the tumor cell metabolism, inducing senescence, autophagy and apoptosis, which are dependent on the regulation of the PI3K/AKT/mTOR pathway and/or ROS induction. The interplay between p53 and metabolism is essential in the decision of cell fate and for cancer therapeutics.
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Affiliation(s)
- Fernando M. Simabuco
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Mirian G. Morale
- Center for Translational Investigation in Oncology/LIM24, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
- Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Isadora C.B. Pavan
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Ana P. Morelli
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Fernando R. Silva
- Laboratory of Functional Properties in Foods, School of Applied Sciences (FCA), Universidade de Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Rodrigo E. Tamura
- Center for Translational Investigation in Oncology/LIM24, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil
- Department of Radiology and Oncology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Yan J, Zhang F, Huang Q. FTIR Microspectroscopy Probes Particle-Radiation Effect on HCT116 cells (p53+/+, p53–/–). Radiat Res 2018; 189:156-164. [DOI: 10.1667/rr14883.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Jingwen Yan
- Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Fengqiu Zhang
- Henan Key Laboratory of Ion Beam Bioengineering, School of Physical Engineering, Zhengzhou University, Zhengzhou, China; and
| | - Qing Huang
- Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
- University of Science and Technology of China, Hefei, China
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28
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Altered auditory and vestibular functioning in individuals with low bone mineral density: a systematic review. Eur Arch Otorhinolaryngol 2017; 275:1-10. [DOI: 10.1007/s00405-017-4768-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 10/04/2017] [Indexed: 12/21/2022]
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Regulation of Metabolic Activity by p53. Metabolites 2017; 7:metabo7020021. [PMID: 28531108 PMCID: PMC5487992 DOI: 10.3390/metabo7020021] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 05/16/2017] [Accepted: 05/16/2017] [Indexed: 12/20/2022] Open
Abstract
Metabolic reprogramming in cancer cells is controlled by the activation of multiple oncogenic signalling pathways in order to promote macromolecule biosynthesis during rapid proliferation. Cancer cells also need to adapt their metabolism to survive and multiply under the metabolically compromised conditions provided by the tumour microenvironment. The tumour suppressor p53 interacts with the metabolic network at multiple nodes, mostly to reduce anabolic metabolism and promote preservation of cellular energy under conditions of nutrient restriction. Inactivation of this tumour suppressor by deletion or mutation is a frequent event in human cancer. While loss of p53 function lifts an important barrier to cancer development by deleting cell cycle and apoptosis checkpoints, it also removes a crucial regulatory mechanism and can render cancer cells highly sensitive to metabolic perturbation. In this review, we will summarise the major concepts of metabolic regulation by p53 and explore how this knowledge can be used to selectively target p53 deficient cancer cells in the context of the tumour microenvironment.
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30
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Bian M, Zhang Y, Du X, Xu J, Cui J, Gu J, Zhu W, Zhang T, Chen Y. Apigenin-7-diglucuronide protects retinas against bright light-induced photoreceptor degeneration through the inhibition of retinal oxidative stress and inflammation. Brain Res 2017; 1663:141-150. [PMID: 28336272 DOI: 10.1016/j.brainres.2017.03.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 03/10/2017] [Accepted: 03/17/2017] [Indexed: 11/27/2022]
Abstract
Vision impairment in retinal degenerative diseases such as age-related macular degeneration is primarily associated with photoreceptor degeneration, in which oxidative stress and inflammatory responses are mechanistically involved as central players. Therapies with photoreceptor protective properties remain to be developed. Apigenin-7-diglucuronide (A7DG), a flavonoid glycoside, is present in an assortment of medicinal plants with anti-inflammatory or ant-oxidant activities. However, the pharmacological significance of A7DG remains unknown in vivo. The current study isolated A7DG from Glechoma longituba (Nakai) Kuprian and investigated the retinal protective effect A7DG in mice characterized by bright light-induced photoreceptor degeneration. The results showed that A7DG treatment led to remarkable photoreceptor protection in bright light-exposed BALB/c mice. Moreover, A7DG treatment alleviated photoreceptor apoptosis, mitigated oxidative stress, suppressed reactive gliosis and microglial activation and attenuated the expression of proinflammatory genes in bright light-exposed retinas. The results demonstrated for the first time remarkable photoreceptor protective activities of A7DG in vivo. Inhibition of bright light-induced retinal oxidative stress and retinal inflammatory responses was associated with the retinal protection conferred by A7DG. The work here warrants further evaluation of A7DG as a pharmacological candidate for the treatment of vision-threatening retinal degenerative disorders. Moreover, given the general implication of oxidative stress and inflammation in the pathogenesis of neurodegeneration, A7DG could be further tested for the treatment of other neurodegenerative disorders.
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Affiliation(s)
- Minjuan Bian
- Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yong Zhang
- Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaoye Du
- Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Jing Xu
- East China University of Science and Technology School of Pharmacy, Shanghai 200237, China
| | - Jingang Cui
- Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Jiangping Gu
- East China University of Science and Technology School of Pharmacy, Shanghai 200237, China
| | - Weiliang Zhu
- Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Teng Zhang
- Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
| | - Yu Chen
- Yueyang Hospital and Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
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Abstract
Unlike the rather stereotypic image by which it was portrayed until not too many years ago, p53 is now increasingly emerging as a multifaceted transcription factor that can sometimes exert opposing effects on biological processes. This includes pro-survival activities that seem to contradict p53's canonical proapoptotic features, as well as opposing effects on cell migration, metabolism, and differentiation. Such antagonistic bifunctionality (balancing both positive and negative signals) bestows p53 with an ideal attribute to govern homeostasis. The molecular mechanisms underpinning the paradoxical activities of p53 may be related to a protein conformational spectrum (from canonical wild-type to "pseudomutant"), diversity of DNA response elements, and/or higher-order chromatin configuration. Altogether, this functional flexibility positions p53 as a transcriptional "super hub" that dictates cell homeostasis, and ultimately cell fate, by governing a hierarchy of other functional hubs. Deciphering the mechanisms by which p53 determines which hubs to engage, and how one might modulate the preferences of p53, remains a major challenge for both basic science and translational cancer medicine.
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Affiliation(s)
- Yael Aylon
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel
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Jiang L, Hickman JH, Wang SJ, Gu W. Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle 2016. [PMID: 26218928 DOI: 10.1080/15384101.2015.1068479] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The p53 tumor suppressor is a multifaceted polypeptide that impedes tumorigenesis by regulating a diverse array of cellular processes. Triggered by a wide variety of stress stimuli, p53 transcriptionally regulates genes involved in the canonical tumor suppression pathways of apoptosis, cell-cycle arrest, and senescence. We recently discovered a novel mechanism whereby p53 inhibits cystine uptake through repression of the SLC7A11 gene to mediate ferroptosis. Importantly, this p53-SLC7A11 axis is preserved in the p53(3KR) mutant, and contributes to its ability to suppress tumorigenesis in the absence of the classical tumor suppression mechanisms. Here, we report that wild type p53 can induce both apoptosis and ferroptosis upon reactive oxygen species (ROS)-induced stress. Furthermore, we demonstrate that p53's functional N-terminal domain is required for its capacity to regulate oxidative stress responses and ferroptosis. Notably, activated p53 dynamically modulates intracellular ROS, causing an initial reduction and a subsequent increase of ROS levels. Taken together, these data implicate ferroptosis as an additional component of the cell death program induced by wild type p53 in human cancer cells, and reveal a complex and dynamic role of p53 in oxidative stress responses.
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Affiliation(s)
- Le Jiang
- a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA
| | - Justin H Hickman
- a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA
| | - Shang-Jui Wang
- a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA
| | - Wei Gu
- a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA.,b Herbert Irving Comprehensive Cancer Center; College of Physicians & Surgeons; Columbia University ; New York , NY USA
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Yu B, Meng F, Yang Y, Liu D, Shi K. NOX2 Antisense Attenuates Hypoxia-Induced Oxidative Stress and Apoptosis in Cardiomyocyte. Int J Med Sci 2016; 13:646-652. [PMID: 27499697 PMCID: PMC4974913 DOI: 10.7150/ijms.15177] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 06/25/2016] [Indexed: 01/12/2023] Open
Abstract
Heart ischemia is a hypoxia related disease. NOX2 and HIF-1α proteins were increased in cardiomyocytes after acute myocardial infarction. However, the relationship of the hypoxia-induced HIF-1α. NOX2-derived oxidative stress and apoptosis in cardiomyocyte remains unclear. In the current study, we use NOX2 antisense strategy to investigate the role of NOX2 in hypoxia-induced oxidative stress and apoptosis in rat cardiomyocytes. Here, we show that transduction of ADV-NOX2-AS induces potent silencing of NOX2 in cardiomyocytes, and resulting in attenuation of hypoxia-induced oxidative stress and apoptosis. This study indicates the potential of antisense-based therapies and validates NOX2 as a potent therapeutic candidate for heart ischemia.
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Affiliation(s)
| | | | | | | | - Kaiyao Shi
- Department of cardiology, China-Japan union hospital of Jilin University, Changchun, Jilin, 130033, P.R. China
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Banerjee A, Thyagarajan K, Chatterjee S, Chakraborty P, Kesarwani P, Soloshchenko M, Al-Hommrani M, Andrijauskaite K, Moxley K, Janakiraman H, Scheffel MJ, Helke K, Armenson K, Palanisamy V, Rubinstein MP, Mayer EG, Cole DJ, Paulos CM, Christina-Voelkel-Johnson, Nishimura MI, Mehrotra S. Lack of p53 Augments Antitumor Functions in Cytolytic T Cells. Cancer Res 2016; 76:5229-5240. [PMID: 27466285 DOI: 10.1158/0008-5472.can-15-1798] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 07/08/2016] [Indexed: 01/10/2023]
Abstract
Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and antitumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS-dependent JNK activation that leads to its activation-induced cell death. Because tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor-mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor-reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope-reactive T cells developed on p53 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-β signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells. Pharmacological inhibition of human TCR-transduced T cells using a combination of p53 inhibitors also potentiated the T-cell effector function and improved persistence. Thus, our data highlight the key role of p53 in regulating the tumor-reactive T-cell response and that targeting this pathway could have potential translational significance in adoptive T-cell therapy. Cancer Res; 76(18); 5229-40. ©2016 AACR.
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Affiliation(s)
- Anirban Banerjee
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | | | - Shilpak Chatterjee
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | - Paramita Chakraborty
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | - Pravin Kesarwani
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | | | - Mazen Al-Hommrani
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | | | - Kelly Moxley
- Department of Surgery, Oncology Institute, Loyola University, Maywood, IL 60153
| | | | - Matthew J Scheffel
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425
| | - Kristi Helke
- Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC 29425
| | - Kent Armenson
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425
| | - Viswanathan Palanisamy
- Department of Oral Health Research, Medical University of South Carolina, Charleston, SC 29425
| | - Mark P Rubinstein
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | - Elizabeth-Garrett Mayer
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425
| | - David J Cole
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
| | - Chrystal M Paulos
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425
| | | | - Michael I Nishimura
- Department of Surgery, Oncology Institute, Loyola University, Maywood, IL 60153
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425
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Redox Homeostasis and Cellular Antioxidant Systems: Crucial Players in Cancer Growth and Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:6235641. [PMID: 27418953 PMCID: PMC4932173 DOI: 10.1155/2016/6235641] [Citation(s) in RCA: 199] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 05/18/2016] [Indexed: 02/07/2023]
Abstract
Reactive oxygen species (ROS) and their products are components of cell signaling pathways and play important roles in cellular physiology and pathophysiology. Under physiological conditions, cells control ROS levels by the use of scavenging systems such as superoxide dismutases, peroxiredoxins, and glutathione that balance ROS generation and elimination. Under oxidative stress conditions, excessive ROS can damage cellular proteins, lipids, and DNA, leading to cell damage that may contribute to carcinogenesis. Several studies have shown that cancer cells display an adaptive response to oxidative stress by increasing expression of antioxidant enzymes and molecules. As a double-edged sword, ROS influence signaling pathways determining beneficial or detrimental outcomes in cancer therapy. In this review, we address the role of redox homeostasis in cancer growth and therapy and examine the current literature regarding the redox regulatory systems that become upregulated in cancer and their role in promoting tumor progression and resistance to chemotherapy.
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LIANG LEI, ZHANG XUHUI, JI BO, YAO HUI, LING XIAOMEI, GUO ZHIJIAN, DENG HONGZHU, WU XINRONG. Yifuning postpones ovarian aging through antioxidant mechanisms and suppression of the Rb/p53 signal transduction pathway. Mol Med Rep 2016; 14:888-96. [DOI: 10.3892/mmr.2016.5322] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 04/18/2016] [Indexed: 11/06/2022] Open
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Hu Z, Lv G, Li Y, Li E, Li H, Zhou Q, Yang B, Cao W. Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:71. [PMID: 27102814 PMCID: PMC4840943 DOI: 10.1186/s13046-016-0349-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 04/17/2016] [Indexed: 01/16/2023]
Abstract
Background Hepatocellular carcinoma (HCC) accounts for 75 % of liver cancers and is the second most lethal cancer, associated with its multiple etiologies, poor prognosis and resistance to chemotherapy drugs. Chemotherapy treatment on HCC suffers low efficacy of drug uptake and can produce a range of side effects. Here we report an investigation on the effect of a combined treatment on human hepatocellular carcinoma BEL-7402 cells using low-intensity ultrasound (US) and 5-fluorouracil (5-FU). Methods The uptake of 5-FU was measured by the high-performance liquid chromatography (HPLC). DNA damage was detected by the comet assay. MTT assay was used to examine cell viability. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) were respectively detected by the fluorescent probes DCFH-DA or JC-1. Endogenous apoptosis-associated proteins were analyzed by the western blot and immunohistochemistry. Histopathological changes were evaluated by the hematoxylin and eosin (H&E) staining. Cell apoptosis was evaluated by the TUNEL and flow cytometry assays. Cell proliferation was measured using the immunohistochemical staining of PCNA. Results Our results showed that low-intensity US (1.1 MHz, 1.0 W/cm2, 10 % duty cycle) significantly enhanced the uptake of 5-FU, 5-FU-mediated DNA damage and reactive oxygen species (ROS) generation. The increased ROS production up-regulated the p53 protein level, which led to the up-regulation of Bax and down-regulation of Bcl-2. The enhancement of ROS generation and the activation of the apoptosis-associated proteins further triggered the collapse of mitochondrial membrane potential, released cytochrome c from mitochondria into cytosol and activated the mitochondria-caspase pathway, and cell apoptosis. Such enhanced effects could be partially blocked by the ROS scavenger N-acetylcysteine (NAC). Overall, low-intensity US combined with 5-FU led to an effective inhibition of tumor growth and prolonged overall survival of BEL-7402 HCC-bearing nude mice by more than 15 % compared with 5-FU treatment alone. Conclusions Our results showed that low-intensity ultrasound combined with 5-FU produced much enhanced synergistic anti-tumor effects via enhanced ROS production in treating HCC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0349-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zheng Hu
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China
| | - Guixiang Lv
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150086, China
| | - Yongning Li
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China
| | - Enze Li
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China
| | - Haixia Li
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150086, China
| | - Qi Zhou
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China
| | - Bin Yang
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China
| | - Wenwu Cao
- Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, 150080, China. .,Department of Mathematics, and Materials Research Institute, The Pennsylvania State University, University Park, 16802, PA, USA.
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Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat Med 2016; 22:506-15. [PMID: 27043494 PMCID: PMC5570457 DOI: 10.1038/nm.4072] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/29/2016] [Indexed: 02/06/2023]
Abstract
Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.
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Abstract
Since both reactive oxygen species (ROS) production and microRNAs expression signature have been associated with tumor development, progression, metastasis and therapeutic response, it is important to understand the crosstalk between ROS and microRNAs. Indeed, growing evidence suggests a reciprocal connection between ROS signaling and microRNAs pathway, resulting in diverse biological effects in cancer cells. In this mini review, we discussed the ROS-responsive microRNAs that have implications in cancer and the possible mechanisms in which ROS regulate microRNAs. We also highlighted the microRNAs which are able to modify cellular ROS homeostasis during tumorigenesis, their biological targets and subsequent functions. As the use of antioxidants is limited due to the diverse or even opposing roles of ROS signaling in cancer, the discovery of ROS-responsive microRNAs provides a potential new strategy to specifically overcome ROS-mediated tumor progression or benefit from ROS-induced apoptosis.
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Affiliation(s)
- Jun He
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA
| | - Bing-Hua Jiang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA
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Stallone G, Infante B, Grandaliano G. Management and prevention of post-transplant malignancies in kidney transplant recipients. Clin Kidney J 2015; 8:637-44. [PMID: 26413294 PMCID: PMC4581374 DOI: 10.1093/ckj/sfv054] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 06/11/2015] [Indexed: 12/27/2022] Open
Abstract
The central issue in organ transplantation remains suppression of allograft rejection. Thus, the development of immunosuppressive drugs has been the key to successful allograft function. The increased immunosuppressive efficiency obtained in the last two decades in kidney transplantation dramatically reduced the incidence of acute rejection. However, the inevitable trade-off was an increased rate of post-transplant infections and malignancies. Since the incidence of cancer in immunosuppressed transplant recipients becomes greater over time, and the introduction of new immunosuppressive strategies are expected to extend significantly allograft survival, the problem might grow exponentially in the near future. Thus, cancer is becoming a major cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. There are at least four distinct areas requiring consideration, which have a potentially serious impact on recipient outcome after transplantation: (i) the risk of transmitting a malignancy to the recipient within the donor organ; (ii) the problems of previously diagnosed and treated malignancy in the recipient; (iii) the prevention of de novo post-transplant malignant diseases and (iv) the management of these complex and often life-threatening clinical problems. In this scenario, the direct and indirect oncogenic potential of immunosuppressive therapy should be always carefully considered.
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Affiliation(s)
- Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Giuseppe Grandaliano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
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Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 2015; 16:393-405. [PMID: 26122615 DOI: 10.1038/nrm4007] [Citation(s) in RCA: 805] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The function of p53 as a tumour suppressor has been attributed to its ability to promote cell death or permanently inhibit cell proliferation. However, in recent years, it has become clear that p53 can also contribute to cell survival. p53 regulates various metabolic pathways, helping to balance glycolysis and oxidative phosphorylation, limiting the production of reactive oxygen species, and contributing to the ability of cells to adapt to and survive mild metabolic stresses. Although these activities may be integrated into the tumour suppressive functions of p53, deregulation of some elements of the p53-induced response might also provide tumours with a survival advantage.
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Affiliation(s)
- Flore Kruiswijk
- 1] Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK. [2]
| | | | - Karen H Vousden
- Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK
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Latina A, Viticchiè G, Lena AM, Piro MC, Annicchiarico-Petruzzelli M, Melino G, Candi E. ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer. Oncogene 2015; 35:1493-503. [PMID: 26096935 DOI: 10.1038/onc.2015.222] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 02/17/2015] [Accepted: 03/08/2015] [Indexed: 12/13/2022]
Abstract
During physiological aerobic metabolism, the epidermis undergoes significant oxidative stress as a result of the production of reactive oxygen species (ROS). To maintain a balanced oxidative state, cells have developed protective antioxidant systems, and preliminary studies suggest that the transcriptional factor p63 is involved in cellular oxidative defence. Supporting this hypothesis, the ΔNp63α isoform of p63 is expressed at high levels in the proliferative basal layer of the epidermis. Here we identify the CYGB gene as a novel transcriptional target of ΔNp63 that is involved in maintaining epidermal oxidative defence. The CYGB gene encodes cytoglobin, a member of the globin protein family, which facilitates the diffusion of oxygen through tissues and acts as a scavenger for nitric oxide or other ROS. By performing promoter activity assays and chromatin immunoprecipitation, reverse transcriptase quantitative PCR and western blotting analyses, we confirm the direct regulation of CYGB by ΔNp63α. We also demonstrate that CYGB has a protective role in proliferating keratinocytes grown under normal conditions, as well as in cells treated with exogenous hydrogen peroxide. These results indicate that ΔNp63, through its target CYGB has an important role in the cellular antioxidant system and protects keratinocytes from oxidative stress-induced apoptosis. The ΔNp63-CYGB axis is also present in lung and breast cancer cell lines, indicating that CYGB-mediated ROS-scavenging activity may also have a role in epithelial tumours. In human lung cancer data sets, the p63-CYGB interaction significantly predicts reduction of patient survival.
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Affiliation(s)
- A Latina
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - G Viticchiè
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - A M Lena
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | - M C Piro
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy
| | | | - G Melino
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.,Medical Research Council Toxicology Unit, Leicester, UK
| | - E Candi
- Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.,IDI-IRCCS, Biochemistry Laboratory, Rome, Italy
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Abstract
Oxygen is the basic molecule which supports life and it truly is "god's gift to life." Despite its immense importance, research on "oxygen biology" has never received the light of the day and has been limited to physiological and biochemical studies. It seems that in modern day biology, oxygen research is summarized in one word "hypoxia." Scientists have focused on hypoxia-induced transcriptomics and molecular-cellular alterations exclusively in disease models. Interestingly, the potential of oxygen to control the basic principles of biology like homeostatic maintenance, transcription, replication, and protein folding among many others, at the molecular level, has been completely ignored. Here, we present a perspective on the crucial role played by oxygen in regulation of basic biological phenomena. Our conclusion highlights the importance of establishing novel research areas like oxygen biology, as there is great potential in this field for basic science discoveries and clinical benefits to the society.
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Highly specific in vivo gene delivery for p53-mediated apoptosis and genetic photodynamic therapies of tumour. Nat Commun 2015; 6:6456. [PMID: 25739372 PMCID: PMC4366491 DOI: 10.1038/ncomms7456] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 01/29/2015] [Indexed: 12/14/2022] Open
Abstract
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments’ inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours’ acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy. Alterations of p53 are associated with more than half of all human cancers. Here the authors present a new pH-sensitive nanoparticle that is delivered via systemic circulation and combines gene delivery to restore p53 with expression of Killerred protein to induce photosensitization.
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Secchi C, Carta M, Crescio C, Spano A, Arras M, Caocci G, Galimi F, La Nasa G, Pippia P, Turrini F, Pantaleo A. T cell tyrosine phosphorylation response to transient redox stress. Cell Signal 2015; 27:777-88. [PMID: 25572700 DOI: 10.1016/j.cellsig.2014.12.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 12/09/2014] [Accepted: 12/24/2014] [Indexed: 12/29/2022]
Abstract
Reactive Oxygen Species (ROS) are crucial to multiple biological processes involved in the pathophysiology of inflammation, and are also involved in redox signaling responses. Although previous reports have described an association between oxidative events and the modulation of innate immunity, a role for redox signaling in T cell mediated adaptive immunity has not been described yet. This work aims at assessing if T cells can sense redox stress through protein sulfhydryl oxidation and respond with tyrosine phosphorylation changes. Our data show that Jurkat T cells respond to -SH group oxidation with specific tyrosine phosphorylation events. The release of T cell cytokines TNF, IFNγ and IL2 as well as the expression of a number of receptors are affected by those changes. Additionally, experiments with spleen tyrosine kinase (Syk) inhibitors showed a major involvement of Syk in these responses. The experiments described herein show a link between cysteine oxidation and tyrosine phosphorylation changes in T cells, as well as a novel mechanism by which Syk inhibitors exert their anti-inflammatory activity through the inhibition of a response initiated by ROS.
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Affiliation(s)
- Christian Secchi
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy; Istituto Nazionale Biostrutture e Biosistemi, University of Sassari, I-07100, Sassari, Italy
| | - Marissa Carta
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy
| | - Claudia Crescio
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy
| | - Alessandra Spano
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy
| | - Marcella Arras
- Haematology, Hospital Binaghi, ASL 8 Cagliari, I-09126, Cagliari, Italy
| | - Giovanni Caocci
- Haematology, Department of Medical Sciences, University of Cagliari, I-09042 Cagliari, Italy
| | - Francesco Galimi
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy; Istituto Nazionale Biostrutture e Biosistemi, University of Sassari, I-07100, Sassari, Italy
| | - Giorgio La Nasa
- Haematology, Department of Medical Sciences, University of Cagliari, I-09042 Cagliari, Italy
| | - Proto Pippia
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy
| | - Francesco Turrini
- Department of Genetics, Biology and Biochemistry, University of Turin, I-10126 Turin, Italy
| | - Antonella Pantaleo
- Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy.
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Pivotal roles of p53 transcription-dependent and -independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis. Toxicol Appl Pharmacol 2014; 281:294-302. [PMID: 25448048 DOI: 10.1016/j.taap.2014.10.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 10/15/2014] [Accepted: 10/21/2014] [Indexed: 01/14/2023]
Abstract
Chronic exposure to excessive manganese (Mn) has been known to lead to neuronal loss and a clinical syndrome resembling idiopathic Parkinson's disease (IPD). p53 plays an integral role in the development of various human diseases, including neurodegenerative disorders. However, the role of p53 in Mn-induced neuronal apoptosis and neurological deficits remains obscure. In the present study, we showed that p53 was critically involved in Mn-induced neuronal apoptosis in rat striatum through both transcription-dependent and -independent mechanisms. Western blot and immunohistochemistrical analyses revealed that p53 was remarkably upregulated in the striatum of rats following Mn exposure. Coincidentally, increased level of cleaved PARP, a hallmark of apoptosis, was observed. Furthermore, using nerve growth factor (NGF)-differentiated PC12 cells as a neuronal cell model, we showed that Mn exposure decreased cell viability and induced apparent apoptosis. Importantly, p53 was progressively upregulated, and accumulated in both the nucleus and the cytoplasm. The cytoplasmic p53 had a remarkable distribution in mitochondria, suggesting an involvement of p53 mitochondrial translocation in Mn-induced neuronal apoptosis. In addition, Mn-induced impairment of mitochondrial membrane potential (ΔΨm) could be partially rescued by pretreatment with inhibitors of p53 transcriptional activity and p53 mitochondrial translocation, Pifithrin-α (PFT-α) and Pifithrin-μ (PFT-μ), respectively. Moreover, blockage of p53 activities with PFT-α and PFT-μ significantly attenuated Mn-induced reactive oxidative stress (ROS) generation and mitochondrial H₂O₂ production. Finally, we observed that pretreatment with PFT-α and PFT-μ ameliorated Mn-induced apoptosis in PC12 cells. Collectively, these findings implicate that p53 transcription-dependent and -independent pathways may play crucial roles in the regulation of Mn-induced neuronal death.
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Ferreira AGK, Scherer EB, da Cunha AA, Manfredini V, Biancini GB, Vanzin CS, Vargas CR, Wyse ATS. Hyperprolinemia induces DNA, protein and lipid damage in blood of rats: antioxidant protection. Int J Biochem Cell Biol 2014; 54:20-5. [PMID: 24980685 DOI: 10.1016/j.biocel.2014.05.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Revised: 05/10/2014] [Accepted: 05/19/2014] [Indexed: 10/25/2022]
Abstract
The present study investigated the effects of hyperprolinemia on oxidative damage to biomolecules (protein, lipids and DNA) and the antioxidant status in blood of rats. The influence of the antioxidants on the effects elicited by proline was also examined. Wistar rats received two daily injections of proline and/or vitamin E plus C (6th-28th day of life) and were killed 12h after the last injection. Results showed that hyperprolinemia induced a significant oxidative damage to proteins, lipids and DNA demonstrated by increased carbonyl content, malondialdehyde levels and a greater damage index in comet assay, respectively. The concomitant antioxidants administration to proline treatment completely prevented oxidative damage to proteins, but partially prevented lipids and DNA damage. We also observed that the non-enzymatic antioxidant potential was decreased by proline treatment and partially prevented by antioxidant supplementation. The plasma levels of vitamins E and C significantly increased in rats treated exogenously with these vitamins but, interestingly, when proline was administered concomitantly with vitamin E plus C, the levels of these vitamins were similar to those found in plasma of control and proline rats. Our findings suggest that hyperprolinemia promotes oxidative damage to the three major classes of macromolecules in blood of rats. These effects were accomplished by decrease in non-enzymatic antioxidant potential and decrease in vitamins administered exogenously, which significantly decreased oxidative damage to biomolecules studied. These data suggest that antioxidants may be an effective adjuvant therapeutic to limit oxidative damage caused by proline.
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Affiliation(s)
- Andréa G K Ferreira
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
| | - Emilene B Scherer
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil
| | - Aline A da Cunha
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil
| | - Vanusa Manfredini
- Universidade Federal do Pampa, BR 472, Km 585, Caixa Postal 118, 97500-970 Uruguaiana, RS, Brazil
| | | | - Camila Simioni Vanzin
- Serviço de Genética Médica, HCPA, Ramiro Barcelos 2350, Porto Alegre, RS, 90035-903, Brazil
| | - Carmen R Vargas
- Serviço de Genética Médica, HCPA, Ramiro Barcelos 2350, Porto Alegre, RS, 90035-903, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Av. Ipiranga 2752, 90610-000, Porto Alegre, RS, Brazil
| | - Angela T S Wyse
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, ICBS, UFRGS, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
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Liang N, Wang P, Wang S, Li S, Li Y, Wang J, Wang M. Role of mitochondrial calcium uniporter in regulating mitochondrial fission in the cerebral cortexes of living rats. J Neural Transm (Vienna) 2014; 121:593-600. [DOI: 10.1007/s00702-014-1166-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 01/19/2014] [Indexed: 12/12/2022]
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Gallo D, Cocchietto M, Masat E, Agostinis C, Harei E, Veronesi P, Sava G. Human recombinant lysozyme downregulates advanced glycation endproduct-induced interleukin-6 production and release in an in-vitro model of human proximal tubular epithelial cells. Exp Biol Med (Maywood) 2014; 239:337-46. [PMID: 24495950 DOI: 10.1177/1535370213518281] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Diabetic nephropathy is the leading cause of chronic renal disease and one of the major causes of cardiovascular mortality. Evidence suggests that its progression is due to the chronic hyperglycemia consequent to the production and accumulation of advanced glycation endproducts (AGEs). Lysozyme was shown to posses AGE-sequestering properties and the capacity to reduce the severity of the early stage manifestations of the diabetic nephropathy. This study was aimed to contribute to the understanding the molecular mechanisms of lysozyme effectiveness in the diabetic nephropathy, using an in-vitro cellular model, represented by the HK-2 cells, human proximal tubular epithelial cells. Lysozyme significantly reduced the AGE-induced IL-6 mRNA and an ELISA assay showed also a decreased release of the functional protein with a dose-dependent trend. In addition, lysozyme prevented macrophage recruitment, suggesting its capacity to elicit an anti-inflammatory action. We may conclude that the protective action of lysozyme on the nephrotoxic effects of AGE may depend, at least in part, on its ability to prevent the production and release of inflammatory mediators, such as IL-6 and to reduce macrophage recruitment in the inflammatory sites.
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Affiliation(s)
- Davide Gallo
- Callerio Foundation Onlus, Institutes of Biological Researches, 34127 Trieste, Italy
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