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Ye J, Zhu W, Cui Y, Zhang Q, Xiong Y, Jin L, Wang A, Lin M, Dong H, Liang G, Hu X, Luo W. Compound J27 alleviates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease by targeting JNK. Int Immunopharmacol 2025; 154:114570. [PMID: 40188525 DOI: 10.1016/j.intimp.2025.114570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 02/12/2025] [Accepted: 03/26/2025] [Indexed: 04/08/2025]
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most characteristic form of liver diseases. As the member of MAPK family, the cJun-N-terminal-kinase (JNK) plays a crucial role in the pathogenesis of MASLD. A small molecule compound, J27, has demonstrated strong anti-inflammatory effects by inhibiting JNK phosphorylation, but its therapeutic potential in MASLD remains unclear. METHODS To evaluate the effect of J27, we used a high-fat diet (HFD)-induced MASLD mouse model with or without J27 treatment. Pathological changes were assessed through tissue staining, biochemical analysis, and other assays. In vitro, J27's effects were tested on macrophages, hepatocytes, and co-culture systems under palmitic acid stimulation. RESULTS J27 significantly reduced HFD-induced hepatic steatosis, liver injury, insulin resistance, and inflammatory responses by targeting JNK both in vivo and in vitro. On one hand, J27 blocked JNK activation, thereby improving insulin signaling and alleviating metabolic dysfunction in hepatocytes. On the other hand, J27 inhibited the inflammatory response in macrophages by disrupting the JNK/NF-κB axis, which, through cell-cell communication, further reduced hepatocyte injury. CONCLUSIONS J27, as a potent JNK inhibitor, markedly reduced HFD-induced MASLD, suggesting it as a promising therapeutic candidate for this disease.
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Affiliation(s)
- Jiaxi Ye
- Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Weiwei Zhu
- Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou 325000, China
| | - Yaqian Cui
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Qianhui Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Yongqiang Xiong
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Leiming Jin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Ao Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Mengsha Lin
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Hui Dong
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China
| | - Guang Liang
- Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 311399, China.
| | - Xiang Hu
- Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
| | - Wu Luo
- Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou 325000, China.
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2
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Li C, Syed MU, Nimbalkar A, Shen Y, Vieira MD, Fraser C, Inde Z, Qin X, Ouyang J, Kreuzer J, Clark SE, Kelley G, Hensley EM, Morris R, Lazaro R, Belmonte B, Oh A, Walcott M, Nabel CS, Caenepeel S, Saiki AY, Rex K, Lipford JR, Heist RS, Lin JJ, Haas W, Sarosiek K, Hughes PE, Hata AN. LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers. Nat Commun 2025; 16:4112. [PMID: 40316540 PMCID: PMC12048556 DOI: 10.1038/s41467-025-58753-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 04/01/2025] [Indexed: 05/04/2025] Open
Abstract
The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.
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Affiliation(s)
- Chendi Li
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | | | | | - Yi Shen
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | | | - Cameron Fraser
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Zintis Inde
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Xingping Qin
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jian Ouyang
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Johannes Kreuzer
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Sarah E Clark
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Grace Kelley
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Emily M Hensley
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Robert Morris
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Raul Lazaro
- Amgen Research, Amgen Inc., Thousand Oaks, CA, USA
| | | | - Audris Oh
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Makeba Walcott
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Christopher S Nabel
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Anne Y Saiki
- Amgen Research, Amgen Inc., Thousand Oaks, CA, USA
| | - Karen Rex
- Amgen Research, Amgen Inc., Thousand Oaks, CA, USA
| | | | - Rebecca S Heist
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jessica J Lin
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Wilhelm Haas
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Kristopher Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Lab for Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
| | | | - Aaron N Hata
- Massachusetts General Hospital Cancer Center, Boston, MA, USA.
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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3
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Zhang X, Jeong H, Niu J, Holland SM, Rotanz BN, Gordon J, Einarson MB, Childers WE, Thomas GM. Inhibiting acute, axonal DLK palmitoylation is neuroprotective and avoids deleterious effects of cell-wide DLK inhibition. Nat Commun 2025; 16:3031. [PMID: 40180913 PMCID: PMC11968826 DOI: 10.1038/s41467-025-58036-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 03/05/2025] [Indexed: 04/05/2025] Open
Abstract
Inhibiting dual leucine-zipper kinase (DLK) could potentially ameliorate diverse neuropathological conditions, but a direct inhibitor of DLK's kinase domain caused unintended side effects in human patients, indicative of neuronal cytoskeletal disruption. We sought a more precise intervention and show here that axon-to-soma pro-degenerative signaling requires acute, axonal palmitoylation of DLK. To identify potential modulators of this modification, we screened >28,000 compounds using a high-content imaging readout of DLK's palmitoylation-dependent subcellular localization. Several hits alter DLK localization in non-neuronal cells, reduce DLK retrograde signaling and protect cultured dorsal root ganglion neurons from neurodegeneration. Mechanistically, the two most neuroprotective compounds selectively prevent DLK's stimulus-dependent palmitoylation and subsequent recruitment to axonal vesicles, but do not affect palmitoylation of other axonal proteins assessed and avoid the cytoskeletal disruption associated with direct DLK inhibition. Our hit compounds also reduce pro-degenerative retrograde signaling in vivo, revealing a previously unrecognized neuroprotective strategy.
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Affiliation(s)
- Xiaotian Zhang
- Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Heykyeong Jeong
- Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Jingwen Niu
- Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Sabrina M Holland
- Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - Brittany N Rotanz
- Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
| | - John Gordon
- Moulder Center for Drug Discovery, School of Pharmacy, Temple University, Philadelphia, PA, USA
| | - Margret B Einarson
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Wayne E Childers
- Moulder Center for Drug Discovery, School of Pharmacy, Temple University, Philadelphia, PA, USA
| | - Gareth M Thomas
- Center for Neural Development and Repair, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
- Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
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4
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Zhong BL, Zhang YF, Zheng HY, Chen Q, Lu HD, Chen XP. SP600125, a selective JNK inhibitor, is a potent inhibitor of NAD(P)H: quinone oxidoreductase 1 (NQO1). Acta Pharmacol Sin 2025; 46:1137-1144. [PMID: 39587283 PMCID: PMC11950408 DOI: 10.1038/s41401-024-01418-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 10/25/2024] [Indexed: 11/27/2024]
Abstract
The c-Jun N-terminal kinases (JNKs) has been identified as a critical modulator in multiple cellular processes, including stress stimulus, inflammation, cell proliferation, apoptosis, etc. SP600125 is a widely used ATP-competitive reversible JNKs inhibitor. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavoprotein mediated two or four electron-reduction of quinones. Here, we showed that SP600125 bind to the active pocket of NQO1 and inhibit NQO1 activity. SP600125 exhibits comparable inhibitory effects on NQO1-mediated quinone bioactivation, H2O2 generation, and cell death, as the specific NQO1 inhibitor dicoumarol (DIC). Importantly, the inhibitory effects of SP600125 on NQO1 are independent of JNKs inhibition. These results suggested that SP600125 is a novel NQO1 inhibitor, which provides new insights into the mechanism of action of SP600125. Furthermore, SP600125 should be used more cautiously as a JNKs inhibitor, especially when NQO1 is highly expressed. SP600125 competed with β-Lap (NQO1-bioactivated drugs) for binding to NQO1, and inhibited NQO1-dependent cell death.
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Affiliation(s)
- Bing-Ling Zhong
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Yi-Fei Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Hao-Yi Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Qiang Chen
- Faculty of Health Sciences, University of Macau, Macao, China
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao, China
| | - Hua-Dong Lu
- Department of Pathology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen Clinical Research Center for Cancer Therapy, Xiamen, 361015, China.
| | - Xiu-Ping Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
- Faculty of Health Sciences, University of Macau, Macao, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao, China.
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5
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Saleem SK, Decker S, Kissel S, Bauer M, Chernyakov D, Bräuer-Hartmann D, Aumann K, Wickenhauser C, Herling M, Skorobohatko O, Mathew N, Schmidt C, Klein C, Follo M, Dierks C. JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL. J Exp Med 2025; 222:e20230681. [PMID: 39570282 PMCID: PMC11586660 DOI: 10.1084/jem.20230681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 03/21/2024] [Accepted: 07/08/2024] [Indexed: 11/22/2024] Open
Abstract
Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV. Proximal BCR inhibition (BTK, PI3K, or SYK inhibitors) or SYK knockdown efficiently dephosphorylated JNK1, identifying JNK1 as a critical BCR downstream kinase in CLL. JNK1 inhibition induced apoptosis in primary CLL cells, resulting in the downregulation of BCL2, MCL1, and c-JUN. JNK1 inhibition in patient-derived CLL xenografted mice and Eµ-TCL1-tg mice prevented CLL progression, reduced splenic infiltration, and restored T cell function and normal hematopoiesis. JNK1 inhibitors even remained effective in ibrutinib refractory CLL. In conclusion, our study revealed JNK1 as a promising drug target in CLL downstream of the BCR, overcoming ibrutinib resistance, blocking the protective microenvironment, and improving CLL-specific immunosuppressive mechanisms.
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MESH Headings
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Humans
- Animals
- Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
- Agammaglobulinaemia Tyrosine Kinase/metabolism
- Receptors, Antigen, B-Cell/metabolism
- Drug Resistance, Neoplasm/drug effects
- Signal Transduction/drug effects
- Mice
- Mitogen-Activated Protein Kinase 8/metabolism
- Mitogen-Activated Protein Kinase 8/genetics
- Mitogen-Activated Protein Kinase 8/antagonists & inhibitors
- Adenine/analogs & derivatives
- Adenine/pharmacology
- Protein Kinase Inhibitors/pharmacology
- Piperidines/pharmacology
- Apoptosis/drug effects
- Female
- Pyrimidines/pharmacology
- Syk Kinase/metabolism
- Syk Kinase/antagonists & inhibitors
- Male
- Mice, Transgenic
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Affiliation(s)
- Shifa Khaja Saleem
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Sarah Decker
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Sandra Kissel
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Marcus Bauer
- Institute of Pathology, University Hospital Halle, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Dmitry Chernyakov
- Department of Hematology/Oncology and Stem Cell Transplantation, KIM IV, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - Daniela Bräuer-Hartmann
- Department of Hematology/Oncology and Stem Cell Transplantation, KIM IV, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - Konrad Aumann
- Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Claudia Wickenhauser
- Institute of Pathology, University Hospital Halle, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Marco Herling
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig, Leipzig, Germany
| | - Oleksandra Skorobohatko
- Department of Hematology/Oncology and Stem Cell Transplantation, KIM IV, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - Nimitha Mathew
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Cornelius Schmidt
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Claudius Klein
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
- Department of Nuclear Medicine, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Marie Follo
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
| | - Christine Dierks
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Breisgau, Germany
- Department of Hematology/Oncology and Stem Cell Transplantation, KIM IV, Martin-Luther University Halle-Wittenberg, Halle, Germany
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Wang D, Zheng Y, Zhang J, Cao Y, Cheng J, Geng M, Li K, Yang J, Wei X. The TAK1/JNK axis participates in adaptive immunity by promoting lymphocyte activation in Nile tilapia. FISH & SHELLFISH IMMUNOLOGY 2024; 151:109747. [PMID: 38969154 DOI: 10.1016/j.fsi.2024.109747] [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: 04/15/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/07/2024]
Abstract
The transforming growth factor beta-activated kinase 1 (TAK1)/c-Jun N-terminal kinase (JNK) axis is an essential MAPK upstream mediator and regulates immune signaling pathways. However, whether the TAK1/JNK axis harnesses the strength in regulation of signal transduction in early vertebrate adaptive immunity is unclear. In this study, by modeling on Nile tilapia (Oreochromis niloticus), we investigated the potential regulatory function of TAK1/JNK axis on lymphocyte-mediated adaptive immune response. Both OnTAK1 and OnJNK exhibited highly conserved sequences and structures relative to their counterparts in other vertebrates. Their mRNA was widely expressed in the immune-associated tissues, while phosphorylation levels in splenic lymphocytes were significantly enhanced on the 4th day post-infection by Edwardsiella piscicida. In addition, OnTAK1 and OnJNK were significantly up-regulated in transcriptional level after activation of lymphocytes in vitro by phorbol 12-myristate 13-acetate plus ionomycin (P + I) or PHA, accompanied by a predominant increase in phosphorylation level. More importantly, inhibition of OnTAK1 activity by specific inhibitor NG25 led to a significant decrease in the phosphorylation level of OnJNK. Furthermore, blocking the activity of OnJNK with specific inhibitor SP600125 resulted in a marked reduction in the expression of T-cell activation markers including IFN-γ, CD122, IL-2, and CD44 during PHA-induced T-cell activation. In summary, these findings indicated that the conserved TAK1/JNK axis in Nile tilapia was involved in adaptive immune responses by regulating the activation of lymphocytes. This study enriched the current knowledge of adaptive immunity in teleost and provided a new perspective for understanding the regulatory mechanism of fish immunity.
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Affiliation(s)
- Ding Wang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yuying Zheng
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jiansong Zhang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yi Cao
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jie Cheng
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Ming Geng
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Kang Li
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jialong Yang
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China; Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China.
| | - Xiumei Wei
- State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
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7
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Wang TH, Watanabe K, Hamada N, Tani-Ishii N. Role of MAPKs in TGF-β1-induced maturation and mineralization in human osteoblast-like cells. J Oral Biosci 2024; 66:61-67. [PMID: 38110177 DOI: 10.1016/j.job.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/14/2023] [Accepted: 12/14/2023] [Indexed: 12/20/2023]
Abstract
OBJECTIVES Our study aimed to clarify the role of mitogen-activated protein kinases (MAPKs) in transforming growth factor (TGF)-β1-stimulated mineralization in the human osteoblast-like MG63 cells. METHODS The viability of MG63 cells under TGF-β1 stimulation was assessed by MTS assay. Western blotting determined TGF-β1-mediated activation of extracellular signal-related protein kinase (ERK), p38, and c-Jun amino-terminal kinase (JNK). Mineralization-related gene expression was examined by quantitative real-time PCR, and mineral deposition levels were evaluated by alizarin red S staining. RESULTS TGF-β1 had no effect on MG63 cell proliferation. Activation of p38 was observed at 3 h post TGF-β1 stimulation. Moreover, JNK phosphorylation was upregulated by TGF-β1 from 1 to 6 h post stimulation, but had no activation on ERK phosphorylation throughout the experimental period. Treatment with JNK inhibitor diminished the alizarin red S-stained area in a dose-dependent manner. Mineral deposition was unaffected by MEK inhibitor, whereas p38 inhibitor increased the red-stained area. Gene expression levels of ALP and BSP were significantly decreased under treatment with JNK inhibitor and p38 inhibitor. The MEK inhibitor had no effect on the TGF-β1-mediated upregulation of ALP and BSP. Although all three inhibitors suppressed expression of COL I, none were found to stimulate expression of OCN. CONCLUSIONS Human osteoblast-like MG63 cells maturation and mineralization are induced through JNK activation of MAPK signaling in response to TGF-β1.
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Affiliation(s)
- Ting-Hsuan Wang
- Department of Pulp Biology and Endodontics, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, 238-8580, Japan
| | - Kiyoko Watanabe
- Department of Liberal Arts Education, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, 238-8580, Japan
| | - Nobushiro Hamada
- Department of Oral Microbiology, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, 238-8580, Japan
| | - Nobuyuki Tani-Ishii
- Department of Pulp Biology and Endodontics, Graduate School of Dentistry, Kanagawa Dental University, 82 Inaoka-cho, Yokosuka, 238-8580, Japan.
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8
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Yan H, He L, Lv D, Yang J, Yuan Z. The Role of the Dysregulated JNK Signaling Pathway in the Pathogenesis of Human Diseases and Its Potential Therapeutic Strategies: A Comprehensive Review. Biomolecules 2024; 14:243. [PMID: 38397480 PMCID: PMC10887252 DOI: 10.3390/biom14020243] [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: 12/06/2023] [Revised: 02/12/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions.
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Affiliation(s)
- Huaying Yan
- Department of Ultrasound, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; (H.Y.); (L.H.)
| | - Lanfang He
- Department of Ultrasound, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; (H.Y.); (L.H.)
| | - De Lv
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Jun Yang
- Cancer Center and State Key Laboratory of Biotherapy, Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;
| | - Zhu Yuan
- Cancer Center and State Key Laboratory of Biotherapy, Department of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;
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9
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Hasan I, Rainsford KD, Ross JS. Salsalate: a pleotropic anti-inflammatory drug in the treatment of diabetes, obesity, and metabolic diseases. Inflammopharmacology 2023; 31:2781-2797. [PMID: 37758933 DOI: 10.1007/s10787-023-01242-9] [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: 03/17/2023] [Accepted: 04/12/2023] [Indexed: 09/29/2023]
Abstract
Type two Diabetes Mellitus (T2DM) is a rising epidemic. Available therapeutic strategies have provided glycaemic control via HbA1c reduction but fail to provide clinically meaningful reduction in microvascular and macrovascular (cardiac, renal, ophthalmological, and neurological) complications. Inflammation is strongly linked to the pathogenesis of T2DM. Underlying inflammatory mechanisms include oxidative stress, endoplasmic reticulum stress amyloid deposition in the pancreas, lipotoxicity, and glucotoxicity. Molecular signalling mechanisms in chronic inflammation linked to obesity and diabetes include JANK, NF-kB, and AMPK pathways. These activated pathways lead to a production of various inflammatory cytokines, such as Interleukin (IL-6), tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP), which create a chronic low-grade inflammation and ultimately dysregulation of glucose homeostasis in the liver, skeletal muscle, and smooth muscle. Anti-inflammatory agents are being tested as anti-diabetic agents such as the IL-1b antagonist, Anakinra, the IL-1b inhibitor, Canakinuma, the IL-6 antagonists such as Tocilizumab, Rapamycin (Everolimus), and the IKK-beta kinase inhibitor, Salsalate. Salsalate is a century old safe anti-inflammatory drug used in the treatment of arthritis. Long-term safety and efficacy of Salsalate in the treatment of T2DM have been evaluated, which showed improved fasting plasma glucose and reduced HbA1C levels as well as reduced pro-inflammatory markers in T2DM patients. Current publication summarizes the literature review of pathophysiology of role of inflammation in T2DM and clinical efficacy and safety of Salsalate in the treatment of T2DM.
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Affiliation(s)
- I Hasan
- RH Nanopharmaceuticals LLC, 140 Ocean Ave, Monmouth Beach, New Jersey, 07750, USA.
| | - K D Rainsford
- Emeritus Professor of Biomedical Sciences, Department of Biosciences and Chemistry, BMRC, Sheffield Hallam University, Howard Street, Sheffield, S1 1WB, UK
| | - Joel S Ross
- RH Nanopharmaceuticals LLC, 140 Ocean Ave, Monmouth Beach, New Jersey, 07750, USA
- J & D Pharmaceuticals LLC, Monmouth County, USA
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10
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Nguyen HT, Martin LJ. Classical cadherins in the testis: how are they regulated? Reprod Fertil Dev 2023; 35:641-660. [PMID: 37717581 DOI: 10.1071/rd23084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/31/2023] [Indexed: 09/19/2023] Open
Abstract
Cadherins (CDH) are crucial intercellular adhesion molecules, contributing to morphogenesis and creating tissue barriers by regulating cells' movement, clustering and differentiation. In the testis, classical cadherins such as CDH1, CDH2 and CDH3 are critical to gonadogenesis by promoting the migration and the subsequent clustering of primordial germ cells with somatic cells. While CDH2 is present in both Sertoli and germ cells in rodents, CDH1 is primarily detected in undifferentiated spermatogonia. As for CDH3, its expression is mainly found in germ and pre-Sertoli cells in developing gonads until the establishment of the blood-testis barrier (BTB). This barrier is made of Sertoli cells forming intercellular junctional complexes. The restructuring of the BTB allows the movement of early spermatocytes toward the apical compartment as they differentiate during a process called spermatogenesis. CDH2 is among many junctional proteins participating in this process and is regulated by several pathways. While cytokines promote the disassembly of the BTB by enhancing junctional protein endocytosis for degradation, testosterone facilitates the assembly of the BTB by increasing the recycling of endocytosed junctional proteins. Mitogen-activated protein kinases (MAPKs) are also mediators of the BTB kinetics in many chemically induced damages in the testis. In addition to regulating Sertoli cell functions, follicle stimulating hormone can also regulate the expression of CDH2. In this review, we discuss the current knowledge on regulatory mechanisms of cadherin localisation and expression in the testis.
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Affiliation(s)
- Ha Tuyen Nguyen
- Biology Department, Université de Moncton, Moncton, NB E1A 3E9, Canada
| | - Luc J Martin
- Biology Department, Université de Moncton, Moncton, NB E1A 3E9, Canada
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11
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Li CH, Lim SH, Jeong YI, Ryu HH, Jung S. Synergistic Effects of Radiotherapy With JNK Inhibitor-Incorporated Nanoparticle in an Intracranial Lewis Lung Carcinoma Mouse Models. IEEE Trans Nanobioscience 2023; 22:845-854. [PMID: 37022021 DOI: 10.1109/tnb.2023.3238687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Radiosurgery has been recognized as a reasonable treatment for metastatic brain tumors. Increasing the radiosensitivity and synergistic effects are possible ways to improve the therapeutic efficacy of specific regions of tumors. c-Jun-N-terminal kinase (JNK) signaling regulates H2AX phosphorylation to repair radiation-induced DNA breakage. We previously showed that blocking JNK signaling influenced radiosensitivity in vitro and in an in vivo mouse tumor model. Drugs can be incorporated into nanoparticles to produce a slow-release effect. This study assessed JNK radiosensitivity following the slow release of the JNK inhibitor SP600125 from a poly (DL-lactide-co-glycolide) (LGEsese) block copolymer in a brain tumor model. MATERIALS AND METHODS A LGEsese block copolymer was synthesized to fabricate SP600125-incorporated nanoparticles by nanoprecipitation and dialysis methods. The chemical structure of the LGEsese block copolymer was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. The physicochemical and morphological properties were observed by transmission electron microscopy (TEM) imaging and measured with particle size analyzer. The blood-brain barrier (BBB) permeability to the JNK inhibitor was estimated by BBBflammaTM 440-dye-labeled SP600125. The effects of the JNK inhibitor were investigated using SP600125-incorporated nanoparticles and by optical bioluminescence, magnetic resonance imaging (MRI), and a survival assay in a mouse brain tumor model for Lewis lung cancer (LLC)-Fluc cells. DNA damage was estimated by histone γ H2AX expression and apoptosis was assessed by the immunohistochemical examination of cleaved caspase 3. RESULTS The SP600125-incorporated nanoparticles of the LGEsese block copolymer were spherical and released SP600125 continuously for 24h. The use of BBBflammaTM 440-dye-labeled SP600125 demonstrated the ability of SP600125 to cross the BBB. The blockade of JNK signaling with SP600125-incorporated nanoparticles significantly delayed mouse brain tumor growth and prolonged mouse survival after radiotherapy. γ H2AX, which mediates DNA repair protein, was reduced and the apoptotic protein cleaved-caspase 3 was increased by the combination of radiation and SP600125-incorporated nanoparticles.
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12
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Du J, Zhang X, Zhang J, Huo S, Li B, Wang Q, Song M, Shao B, Li Y. Necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl 3-induced kidney damage. Food Chem Toxicol 2023; 178:113915. [PMID: 37393014 DOI: 10.1016/j.fct.2023.113915] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/18/2023] [Accepted: 06/21/2023] [Indexed: 07/03/2023]
Abstract
Aluminum (Al) is a common environmental pollutant that can induce kidney damage. However, the mechanism is not clear. In the present study, to explored the exact mechanism of AlCl3-induced nephrotoxicity, C57BL/6 N male mice and HK-2 cells were used as experimental subjects. Our results showed that Al induced reactive oxygen species (ROS) overproduction, c-Jun N-terminal kinase (JNK) signaling activation, RIPK3-dependent necroptosis, NLRP3 inflammasome activation, and kidney damage. In addition, inhibiting JNK signaling could downregulate the protein expressions of necroptosis and NLRP3 inflammasome, thereby alleviating kidney damage. Meanwhile, clearing ROS effectively inhibited JNK signaling activation, which in turn inhibited necroptosis and NLRP3 inflammasome activation, ultimately alleviating kidney damage. In conclusion, these findings suggest that necroptosis and NLPR3 inflammasome activation mediated by ROS/JNK pathway participate in AlCl3-induced kidney damage.
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Affiliation(s)
- Jiayu Du
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Xuliang Zhang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Jian Zhang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Siming Huo
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Bo Li
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Qi Wang
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Miao Song
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Bing Shao
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Yanfei Li
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
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13
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Liu HF, Pan XW, Li HQ, Zhang XN, Zhao XH. Amino Acid Composition of a Chum Salmon ( Oncorhynchus keta) Skin Gelatin Hydrolysate and Its Antiapoptotic Effects on Etoposide-Induced Osteoblasts. Foods 2023; 12:2419. [PMID: 37372630 DOI: 10.3390/foods12122419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/09/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
A gelatin hydrolysate with a hydrolysis degree of 13.7% was generated using the skin gelatin of chum salmon (Oncorhynchus keta) and papain-catalyzed enzymatic hydrolysis. The results of analysis demonstrated that four amino acids, namely Ala, Gly, Pro, and 4-Hyp, were the most abundant in the obtained gelatin hydrolysate with measured molar percentages ranging from 7.2% to 35.4%; more importantly, the four amino acids accounted for 2/3 of the total measured amino acids. However, two amino acids, Cys and Tyr, were not detected in the generated gelatin hydrolysate. The experimental results indicated that the gelatin hydrolysate at a dose of 50 µg/mL could combat etoposide-induced apoptosis in human fetal osteoblasts (hFOB 1.19 cells), causing a decrease in the total apoptotic cells from 31.6% to 13.6% (via apoptotic prevention) or 13.3% to 11.8% (via apoptotic reversal). Meanwhile, the osteoblasts exposed to the gelatin hydrolysate showed expression changes for 157 genes (expression folds > 1.5-fold), among which JNKK, JNK1, and JNK3 were from the JNK family with a 1.5-2.7-fold downregulated expression. Furthermore, the protein expressions of JNKK, JNK1, JNK3, and Bax in the treated osteoblasts showed a 1.25-1.41 fold down-regulation, whereas JNK2 expression was not detected in the osteoblasts. It is thus suggested that gelatin hydrolysate is rich in the four amino acids and has an in vitro antiapoptotic effect on etoposide-stimulated osteoblasts via mitochondrial-mediated JNKK/JNK(1,3)/Bax downregulation.
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Affiliation(s)
- Hong-Fang Liu
- Harbin Comprehensive Inspection and Detection Centre for Product Quality, Harbin 150036, China
| | - Xiao-Wen Pan
- School of Biology and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
| | - Hua-Qiang Li
- School of Biology and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
| | - Xiao-Nan Zhang
- School of Life Science, Jiaying University, Meizhou 514015, China
| | - Xin-Huai Zhao
- School of Biology and Food Engineering, Guangdong University of Petrochemical Technology, Maoming 525000, China
- Key Laboratory of Dairy Science, Ministry of Education, Northeast Agricultural University, Harbin 150030, China
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14
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Prasad S, Kumar V, Singh C, Singh A. Crosstalk between phytochemicals and inflammatory signaling pathways. Inflammopharmacology 2023; 31:1117-1147. [PMID: 37022574 DOI: 10.1007/s10787-023-01206-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 03/21/2023] [Indexed: 04/07/2023]
Abstract
Novel bioactive constituents from natural sources are actively being investigated. The phytochemicals in these phenolic compounds are believed to have a variety of beneficial effects on human health. Several phenolic compounds have been found in plants. The antioxidant potential of phenols has been discussed in numerous studies along with their anti-inflammatory effects on pro-inflammatory cytokine, inducible cyclooxygenase-2, and nitric oxide synthase. Through current study, an attempt is made to outline and highlight a wide variety of inflammation-associated signaling pathways that have been modified by several natural compounds. These signaling pathways include nuclear factor-kappa B (NF-кB), activator protein (AP)-1, protein tyrosine kinases (PTKs), mitogen-activated protein kinases (MAPKs), nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factors, tyrosine phosphatidylinositol 3-kinase (PI3K)/AKT, and the ubiquitin-proteasome system. In light of the influence of natural substances on signaling pathways, their impact on the production of inflammatory mediator is highlighted in this review.
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Affiliation(s)
- Sonima Prasad
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Vishal Kumar
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Charan Singh
- Department of Pharmaceutical Sciences, School of Pharmacy, H.N.B. Garhwal University, Srinagar, Garhwal, 246174, Uttarakhand, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
- Affiliated to IK Gujral Punjab Technical University, Jalandhar, Punjab, 144603, India.
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15
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Gay RD, Enke YL, Kirk JR, Goldman DR. Therapeutics for hearing preservation and improvement of patient outcomes in cochlear implantation—Progress and possibilities. Hear Res 2022; 426:108637. [DOI: 10.1016/j.heares.2022.108637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 10/11/2022] [Accepted: 10/18/2022] [Indexed: 11/04/2022]
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16
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Oki K, Henderson CG, Ward SM, Ward JA, Plamper ML, Mayer TA, Caldwell AR, Leon LR. Identification of therapeutic targets in a murine model of severe exertional heat stroke. Am J Physiol Regul Integr Comp Physiol 2022; 323:R935-R950. [PMID: 36283086 PMCID: PMC9722257 DOI: 10.1152/ajpregu.00150.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 11/22/2022]
Abstract
Exertional heat stroke (EHS) is a potentially lethal condition resulting from high core body temperatures (TC) in combination with a systemic inflammatory response syndrome (SIRS) with varying degrees of severity across victims, and limited understanding of the underlying mechanism(s). We established a mouse model of severe EHS to identify mechanisms of hyperthermia/inflammation that may be responsible for organ damage. Mice were forced to run on a motorized wheel in a 37.5°C chamber until loss of consciousness and were either removed immediately (exertional heat injury or EHI; TCMax = 42.4 ± 0.2°C) or remained in the chamber an additional 20 min (EHS; TCMax = 42.5 ± 0.4°C). Exercise control mice (ExC) experienced identical procedures to EHS at 25°C. At 3 h post-EHS, there was evidence for an immune/inflammatory response as elevated blood chemokine [interferon γ-induced protein 10 (IP-10), keratinocytes-derived chemokine (KC), macrophage inflammatory proteins (MIP-1α), MIP-1β, MIP-2] and cytokine [granulocyte colony-stimulating factor (G-CSF), interleukins (IL-10), IL-6] levels peaked and were highest in EHS mice compared with EHI and ExC mice. Immunoblotting of organs susceptible to EHS damage indicated that several kinases were sensitive to stress associated with heat/inflammation and exercise; specifically, phosphorylation of liver c-Jun NH2-terminal kinase (JNK) at threonine 183/tyrosine 185 immediately (0 h) postheating related to heat illness severity. We have established a mouse EHS model, and JNK [or its downstream target(s)] could underlie EHS symptomatology, allowing the identification of molecular pathways or countermeasure targets to mitigate heat illness severity, enable complete recovery, and decrease overall EHS-related fatalities.
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Affiliation(s)
- Kentaro Oki
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Chloe G Henderson
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
- Oak Ridge Institute of Science and Education, Oak Ridge, Tennessee
| | - Shauna M Ward
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Jermaine A Ward
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Mark L Plamper
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Thomas A Mayer
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
| | - Aaron R Caldwell
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
- Oak Ridge Institute of Science and Education, Oak Ridge, Tennessee
| | - Lisa R Leon
- Thermal and Mountain Medicine Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts
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17
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Brennan CM, Hill AS, St. Andre M, Li X, Madeti V, Breitkopf S, Garren S, Xue L, Gilbert T, Hadjipanayis A, Monetti M, Emerson CP, Moccia R, Owens J, Christoforou N. DUX4 expression activates JNK and p38 MAP kinases in myoblasts. Dis Model Mech 2022; 15:dmm049516. [PMID: 36196640 PMCID: PMC10655719 DOI: 10.1242/dmm.049516] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 09/28/2022] [Indexed: 11/20/2022] Open
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of the DUX4 transcription factor in skeletal muscle that results in transcriptional alterations, abnormal phenotypes and cell death. To gain insight into the kinetics of DUX4-induced stresses, we activated DUX4 expression in myoblasts and performed longitudinal RNA sequencing paired with proteomics and phosphoproteomics. This analysis revealed changes in cellular physiology upon DUX4 activation, including DNA damage and altered mRNA splicing. Phosphoproteomic analysis uncovered rapid widespread changes in protein phosphorylation following DUX4 induction, indicating that alterations in kinase signaling might play a role in DUX4-mediated stress and cell death. Indeed, we demonstrate that two stress-responsive MAP kinase pathways, JNK and p38, are activated in response to DUX4 expression. Inhibition of each of these pathways ameliorated DUX4-mediated cell death in myoblasts. These findings uncover that the JNK pathway is involved in DUX4-mediated cell death and provide additional insights into the role of the p38 pathway, a clinical target for the treatment of FSHD.
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Affiliation(s)
- Christopher M. Brennan
- Rare Disease Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
- WRDM Postdoctoral Program, Pfizer Inc., Cambridge, MA 02139, USA
| | - Abby S. Hill
- Rare Disease Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | | | - Xianfeng Li
- Rare Disease Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Vijaya Madeti
- NGS Technology Center, Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139, USA
| | - Susanne Breitkopf
- Proteomics Technology Center, Internal Medicine Research Unit, Pfizer, Cambridge, MA 02139, USA
| | - Seth Garren
- NGS Technology Center, Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139, USA
| | - Liang Xue
- Machine Learning and Computational Science, Pfizer Inc., Cambridge, MA 02139, USA
| | - Tamara Gilbert
- High Content Imaging Technology Center, Internal Medicine Research Unit, Pfizer, Cambridge, MA 02139, USA
| | - Angela Hadjipanayis
- NGS Technology Center, Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA 02139, USA
| | - Mara Monetti
- Proteomics Technology Center, Internal Medicine Research Unit, Pfizer, Cambridge, MA 02139, USA
| | - Charles P. Emerson
- Rare Disease Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
- Wellstone Muscular Dystrophy Program, Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Robert Moccia
- Rare Disease Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
| | - Jane Owens
- Rare Disease Research Unit, Pfizer Inc., Cambridge, MA 02139, USA
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18
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Varga D, Hajdinák P, Makk-Merczel K, Szarka A. The Possible Connection of Two Dual Function Processes: The Relationship of Ferroptosis and the JNK Pathway. Int J Mol Sci 2022; 23:ijms231911004. [PMID: 36232313 PMCID: PMC9570426 DOI: 10.3390/ijms231911004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Ferroptosis represents a typical process that has dual functions in cell fate decisions since the reduction and/or inhibition of ferroptosis is desirable for the therapies of diseases such as neurological disorders, localized ischemia-reperfusion, kidney injury, and hematological diseases, while the enhanced ferroptosis of cancer cells may benefit patients with cancer. The JNK pathway also has a real dual function in the fate of cells. Multiple factors suggest a potential link between the ferroptotic and JNK pathways; (i) both processes are ROS mediated; (ii) both can be inhibited by lipid peroxide scavengers; (iii) RAS mutations may play a role in the initiation of both pathways. We aimed to investigate the possible link between ferroptosis and the JNK pathway. Interestingly, JNK inhibitor co-treatment could enhance the cancer cytotoxic effect of the ferroptosis inducers in NRAS and KRAS mutation-harboring cells (HT-1080 and MIA PaCa-2). Since cancer’s cytotoxic effect from the JNK inhibitors could only be suspended by the ferroptosis inhibitors, and that sole JNK-inhibitor treatment did not affect cell viability, it seems that the JNK inhibitors “just” amplify the effect of the ferroptosis inducers. This cancer cell death amplifying effect of the JNK inhibitors could not be observed in other oxidative stress-driven cell deaths. Hence, it seems it is specific to ferroptosis. Finally, our results suggest that GSH content/depletion could be an important candidate for switching the anti-cancer effect of JNK inhibitors.
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Affiliation(s)
- Dóra Varga
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
| | - Péter Hajdinák
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
| | - Kinga Makk-Merczel
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
| | - András Szarka
- Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
- Biotechnology Model Laboratory, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, Szent Gellért tér 4, H-1111 Budapest, Hungary
- Correspondence:
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19
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Zhao Y, Li L, Wang X, He S, Shi W, Chen S. Temporal Proteomic and Phosphoproteomic Analysis of EV-A71-Infected Human Cells. J Proteome Res 2022; 21:2367-2384. [DOI: 10.1021/acs.jproteome.2c00237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Yue Zhao
- College of Biological Sciences, China Agricultural University, Beijing 100193, China
- Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
| | - Lin Li
- Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
| | - Xinhui Wang
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, Jiangsu, China
- Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China
| | - Sudan He
- CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, Jiangsu, China
- Suzhou Institute of Systems Medicine, Suzhou 215123, Jiangsu, China
| | - Weifeng Shi
- Department of Laboratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China
| | - She Chen
- Proteomics Center, National Institute of Biological Sciences, Beijing 102206, China
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China
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20
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Schepetkin IA, Kovrizhina AR, Stankevich KS, Khlebnikov AI, Kirpotina LN, Quinn MT, Cook MJ. Design, synthesis and biological evaluation of novel O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase inhibitors. Front Pharmacol 2022; 13:958687. [PMID: 36172181 PMCID: PMC9510750 DOI: 10.3389/fphar.2022.958687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
The c-Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNK represents an attractive target for therapeutic intervention. Herein, a panel of novel tryptanthrin oxime analogs were synthesized and evaluated for JNK1-3 binding (Kd) and inhibition of cellular inflammatory responses (IC50). Several compounds exhibited submicromolar JNK binding affinity, with the most potent inhibitor being 6-(acetoxyimino)indolo[2,1-b]quinazolin-12(6H)-one (1j), which demonstrated high JNK1-3 binding affinity (Kd = 340, 490, and 180 nM for JNK1, JNK2, and JNK3, respectively) and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcription activity in THP-1Blue cells and interleukin-6 (IL-6) production in MonoMac-6 monocytic cells (IC50 = 0.8 and 1.7 μM, respectively). Compound 1j also inhibited LPS-induced production of several other proinflammatory cytokines, including IL-1α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF) in MonoMac-6 cells. Likewise, 1j inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of selected compounds in the JNK3 catalytic site that were in agreement with the experimental JNK3 binding data. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems.
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Affiliation(s)
- Igor A. Schepetkin
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United States
| | | | - Ksenia S. Stankevich
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, United States
| | | | - Liliya N. Kirpotina
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United States
| | - Mark T. Quinn
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United States
- *Correspondence: Mark T. Quinn, ; Matthew J. Cook,
| | - Matthew J. Cook
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, United States
- *Correspondence: Mark T. Quinn, ; Matthew J. Cook,
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Gene Correlation Network Analysis to Identify Biomarkers of Peri-Implantitis. Medicina (B Aires) 2022; 58:medicina58081124. [PMID: 36013591 PMCID: PMC9416455 DOI: 10.3390/medicina58081124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/01/2022] [Accepted: 08/14/2022] [Indexed: 12/02/2022] Open
Abstract
Background and Objectives: The histopathological and clinical conditions for transforming peri-implant mucositis into peri-implantitis (PI) are not fully clarified. We aim to uncover molecular mechanisms and new potential biomarkers of PI. Materials and Methods: Raw GSE33774 and GSE57631 datasets were obtained from the Gene Expression Omnibus (GEO) database. The linear models for microarray data (LIMMA) package in R software completes differentially expressed genes (DEGs). We conducted a weighted gene co-expression network analysis (WGCNA) on the top 25% of altered genes and identified the key modules associated with the clinical features of PI. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the R software. We constructed a protein–protein interaction (PPI) network through the STRING database. After that we used Cytohubba plug-ins of Cytoscape to screen out the potential hub genes, which were subsequently verified via receiver operating characteristic (ROC) curves in another dataset, GSE178351, and revalidation of genes through the DisGeNET database. Results: We discovered 632 DEGs (570 upregulated genes and 62 downregulated genes). A total of eight modules were screened by WGCNA, among which the turquoise module was most correlated with PI. The Cytohubba plug-ins were used for filtering hub genes, which are highly linked with PI development, from the candidate genes in the protein–protein interaction (PPI) network. Conclusions: We found five key genes from PI using WGCNA. Among them, ICAM1, CXCL1, and JUN are worthy of further study of new target genes, providing the theoretical basis for further exploration of the occurrence and development mechanism of PI.
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22
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Signaling pathway(s) of TNFR2 required for the immunoregulatory effect of CD4 +Foxp3 + regulatory T cells. Int Immunopharmacol 2022; 108:108823. [PMID: 35623290 DOI: 10.1016/j.intimp.2022.108823] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 11/23/2022]
Abstract
CD4+Foxp3+ regulatory T cells (Tregs), a subpopulation of CD4+ T cells, are engaged in maintaining the periphery tolerance and preventing autoimmunity. Recent studies showed that tumor necrosis factor receptor 2 (TNFR2) is preferentially expressed by Tregs and the expression of this receptor identifies the maximally suppressive Tregs. That is, TNFR2 is a liable phenotypic and functional surface marker of Tregs. Moreover, TNF activates and expands Tregs through TNFR2. However, it is very interesting which signaling pathway(s) of TNFR2 is required for the inhibitory effect of Tregs. Compelling evidence shows three TNFR2 signaling pathways in Tregs, including NF-κB, MAPK and PI3K-Akt pathways. Here, we summarize and discuss the latest progress in the studies on the downstream signaling pathways of TNF-TNFR2 for controlling Treg homeostasis, differentiation and proliferation.
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Tanshinone Protects against Spinal Cord Ischemia-Reperfusion Injury by Inhibiting JNK Activity. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:7619797. [PMID: 35602615 PMCID: PMC9117045 DOI: 10.1155/2022/7619797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/17/2022] [Accepted: 03/22/2022] [Indexed: 01/06/2023]
Abstract
Spinal cord reperfusion injury as a secondary damage after primary spinal cord injury is an important factor causing nerve cell damage. In this study, we aim to investigate the effects and mechanisms of tanshinone (TAE) in the rabbit spinal cord during ischemia-reperfusion. New Zealand white rabbits were randomly divided into 3 groups: sham-operated group (5 rabbits), ischemia-reperfusion group (0.9% TAE was administered intraperitoneally 30 min before ischemia, and 4 groups of 5 rabbits each according to different time periods of reperfusion: group A reperfused for 0.5 h, group B reperfused for 2 h, group C reperfused for 8 h, and group D reperfused for 24 h), and TAE group (an ischemia-reperfused for 24 h). Group A was reperfused for 0.5 h, group B for 2 h, group C for 8 h, group D for 24 h, and group TAE (TAE was applied 30 min before ischemia reperfusion, grouped as ischemia-reperfusion group). The expression of JNK (c-Jun NH2-terminal Kinase) and phosphorylation-JNK (p-JNK) in spinal cord tissues of each group were detected by Western blot. Light and electron microscopy showed that early apoptosis started in group B in the ischemia-reperfusion group, while early apoptosis appeared only in group D in the tanshinone intervention group. Western blot showed that p-JNK expression started in group B in the ischemia-reperfusion group and gradually increased with the prolongation of ischemia time, while p-JNK expression only increased in group D in the tanshinone intervention group. In the tanshinone intervention group, p-JNK was activated only in group D and its activity was less than that in the ischemia-reperfusion group; the protein expression of JNK did not change significantly in both groups. Spinal cord ischemia-reperfusion can cause spinal cord injury by activating the signaling molecule JNK (MRPKs family), and early tanshinone intervention can partially inhibit this injury. Our finding provides a new idea and theoretical basis for clinical treatment of spinal cord ischemia-reperfusion injury.
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Marinho MAG, Marques MDS, Cordeiro MF, de Moraes Vaz Batista Filgueira D, Horn AP. Combination of Curcumin and Photodynamic Therapy Based on the Use of Red Light or Near-Infrared Radiation in Cancer: a Systematic Review. Anticancer Agents Med Chem 2022; 22:2985-2997. [PMID: 35469576 DOI: 10.2174/1871520622666220425093657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 01/13/2022] [Accepted: 02/18/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Photodynamic therapy (PDT) is a therapeutic intervention that can be applied to the treatment of cancer. The interaction between a photosensitizer (PS), ideal wavelength radiation and tissue molecular oxygen, triggers a series of photochemical reactions that are responsible for the production of reactive oxygen species. These highly reactive species can decrease proliferation and induce tumor cell death. The search for PS of natural origin extracted from plants becomes relevant, as they have photoactivation capacity, preferentially targeting tumor cells and because they do not present any or little toxicity to healthy cells. OBJECTIVE Our work aimed to carry out a qualitative systematic review to investigate the effects of curcumin (CUR), a molecule considered as PS of natural origin, on PDT, using red light or near infrared radiation, in tumor models. METHODS A systematic search was performed in three databases (PubMed, Scopus, and Web of Science) using the PICOT method, retrieving a total of 1,373 occurrences. At the end of the peer screening, using inclusion, exclusion, and eligibility criteria, 25 eligible articles were included in this systematic review. RESULTS CUR, whether in its free state, associated with metal complexes or other PS, and in a nanocarrier system, was considered a relevant PS for PDT using red light or near-infrared against tumoral models in vitro and in vivo, acting by increasing cytotoxicity, inhibiting proliferation, inducing cell death mainly by apoptosis, and changing oxidative parameters. CONCLUSION The results found in this systematic review suggest the potential use of CUR as a PS of natural origin to be applied in PDT against many neoplasms, encouraging further search in the field of PDT against cancer and serving as an investigative basis for upcoming pre-clinical and clinical applications.
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Affiliation(s)
- Marcelo Augusto Germani Marinho
- Programa de Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil.,Laboratório de Neurociências, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil.,Laboratório de Cultura Celular, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil
| | - Magno da Silva Marques
- Programa de Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil.,Laboratório de Neurociências, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil
| | - Marcos Freitas Cordeiro
- Programa de Pós-Graduação em Biociências e Saúde, Universidade do Oeste de Santa Catarina-UNOESC, Joaçaba, SC, 89600-000, Brasil
| | - Daza de Moraes Vaz Batista Filgueira
- Programa de Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil.,Laboratório de Cultura Celular, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil
| | - Ana Paula Horn
- Programa de Pós-Graduação em Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil.,Laboratório de Neurociências, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande-FURG, Rio Grande, RS, 96210-900, Brasil
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25
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Myc-Interacting Zinc Finger Protein 1 (Miz-1) Is Essential to Maintain Homeostasis and Immunocompetence of the B Cell Lineage. BIOLOGY 2022; 11:biology11040504. [PMID: 35453704 PMCID: PMC9027237 DOI: 10.3390/biology11040504] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 11/16/2022]
Abstract
Aging of the immune system is described as a progressive loss of the ability to respond to immunologic stimuli and is commonly referred to as immunosenescence. B cell immunosenescence is characterized by a decreased differentiation rate in the bone marrow and accumulation of antigen-experienced and age-associated B cells in secondary lymphoid organs (SLOs). A specific deletion of the POZ-domain of the transcription factor Miz-1 in pro-B cells, which is known to be involved in bone marrow hematopoiesis, leads to premature aging of the B cell lineage. In mice, this causes a severe reduction in bone marrow-derived B cells with a drastic decrease from the pre-B cell stage on. Further, mature, naïve cells in SLOs are reduced at an early age, while post-activation-associated subpopulations increase prematurely. We propose that Miz-1 interferes at several key regulatory checkpoints, critical during B cell aging, and counteracts a premature loss of immunocompetence. This enables the use of our mouse model to gain further insights into mechanisms of B cell aging and it can significantly contribute to understand molecular causes of impaired adaptive immune responses to counteract loss of immunocompetence and restore a functional immune response in the elderly.
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26
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Yang J, Do-Umehara HC, Zhang Q, Wang H, Hou C, Dong H, Perez EA, Sala MA, Anekalla KR, Walter JM, Liu S, Wunderink RG, Budinger GRS, Liu J. miR-221-5p-Mediated Downregulation of JNK2 Aggravates Acute Lung Injury. Front Immunol 2021; 12:700933. [PMID: 34899681 PMCID: PMC8656235 DOI: 10.3389/fimmu.2021.700933] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 09/13/2021] [Indexed: 12/24/2022] Open
Abstract
Sepsis and acute lung injury (ALI) are linked to mitochondrial dysfunction; however, the underlying mechanism remains elusive. We previously reported that c-Jun N-terminal protein kinase 2 (JNK2) promotes stress-induced mitophagy by targeting small mitochondrial alternative reading frame (smARF) for ubiquitin-mediated proteasomal degradation, thereby preventing mitochondrial dysfunction and restraining inflammasome activation. Here we report that loss of JNK2 exacerbates lung inflammation and injury during sepsis and ALI in mice. JNK2 is downregulated in mice with endotoxic shock or ALI, concomitantly correlated inversely with disease severity. Small RNA sequencing revealed that miR-221-5p, which contains seed sequence matching to JNK2 mRNA 3’ untranslated region (3’UTR), is upregulated in response to lipopolysaccharide, with dynamically inverse correlation with JNK2 mRNA levels. miR-221-5p targets the 3’UTR of JNK2 mRNA leading to its downregulation. Accordingly, miR-221-5p exacerbates lung inflammation and injury during sepsis in mice by targeting JNK2. Importantly, in patients with pneumonia in medical intensive care unit, JNK2 mRNA levels in alveolar macrophages flow sorted from non-bronchoscopic broncholaveolar lavage (BAL) fluid were inversely correlated strongly and significantly with the percentage of neutrophils, neutrophil and white blood cell counts in BAL fluid. Our data suggest that miR-221-5p targets JNK2 and thereby aggravates lung inflammation and injury during sepsis.
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Affiliation(s)
- Jing Yang
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Hanh Chi Do-Umehara
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Qiao Zhang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Huashan Wang
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Changchun Hou
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Huali Dong
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Edith A Perez
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
| | - Marc A Sala
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Kishore R Anekalla
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - James M Walter
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Shuwen Liu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Richard G Wunderink
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.,Simpson Querrey Institute for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - G R Scott Budinger
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Jing Liu
- Department of Surgery, College of Medicine and University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, United States
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27
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Zepeda-Peña AC, Gurrola-Díaz CM, Domínguez-Rosales JA, García-López PM, Pizano-Andrade JC, Hernández-Nazará ZH, Vargas-Guerrero B. Effect of Lupinus rotundiflorus gamma conglutin treatment on JNK1 gene expression and protein activation in a rat model of type 2 diabetes. PHARMACEUTICAL BIOLOGY 2021; 59:374-380. [PMID: 33784492 PMCID: PMC8018548 DOI: 10.1080/13880209.2021.1893757] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 01/05/2021] [Accepted: 02/17/2021] [Indexed: 06/12/2023]
Abstract
CONTEXT Gamma conglutin (Cγ) from lupine species represents a potential complementary treatment for type 2 diabetes mellitus (T2DM) because of its hypoglycaemic effect. However, its underlying mechanism of action is not fully known. OBJECTIVE To evaluate whether Cγ from Lupinus rotundiflorus M. E. Jones (Fabaceae) modulates c-Jun N-terminal kinase 1 (JNK1) expression and activation in a T2DM rat model. MATERIALS AND METHODS Gamma conglutin isolated from L. rotundiflorus seeds was characterized by SDS-PAGE. Fifteen Wistar rats with streptozotocin-induced T2DM (HG) were randomized into three groups (n = 5): vehicle administration (HG-Ctrl), oral treatment with Cγ (120 mg/kg/day) (HG-Lr) for one week, and treatment with metformin (300 mg/kg/day) (HG-Met); a healthy group (Ctrl, n = 5) was included as control. The levels of glucose and biomarkers of renal and hepatic function were measured pre- and post-treatment. Hepatic Jnk1 expression and phosphorylation of JNK1 were evaluated by qRT-PCR and western blot, respectively. RESULTS Oral treatment with either Cγ or metformin reduced serum glucose level to 86.30 and 74.80 mg/dL, respectively (p ˂ 0.05), from the basal levels. Jnk1 expression was 0.65- and 0.54-fold lower (p ˂ 0.05) in the HG-Lr and HG-Met groups, respectively, than in HG-Ctrl. Treatment with Cγ decreased JNK1 phosphorylation. However, Cγ did not change the levels of kidney and liver biomarkers. DISCUSSION AND CONCLUSIONS Treatment with Cγ from L. rotundiflorus inhibited Jnk1 expression, in vivo, suggesting JNK1 as a potential therapeutic target in diabetes and revealing one mechanism underlying the hypoglycaemic effect of lupine Cγ. Nevertheless, further studies are required.
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Affiliation(s)
- Andrea Catalina Zepeda-Peña
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - Carmen Magdalena Gurrola-Díaz
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - José Alfredo Domínguez-Rosales
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - Pedro Macedonio García-López
- Departamento de Botánica y Zoología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan, México
| | - Juan Carlos Pizano-Andrade
- Departamento de Botánica y Zoología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan, México
| | - Zamira Helena Hernández-Nazará
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - Belinda Vargas-Guerrero
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
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28
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Nguyen HT, Najih M, Martin LJ. The AP-1 family of transcription factors are important regulators of gene expression within Leydig cells. Endocrine 2021; 74:498-507. [PMID: 34599696 DOI: 10.1007/s12020-021-02888-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/16/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Members of the AP-1 family of transcription factors are immediate early genes being modulated by different extracellular signals. The aim of this review is to highlight the important roles of AP-1 members in transcriptional regulation of genes important for testicular Leydig cell function and male testosterone production. METHODS A search of the relevant literature was performed in Google Scholar and NCBI Pubmed for AP-1 members and Leydig cells. Additional information was accessed from references of relevant articles. Only primary data from original peer-reviewed articles was considered for this review. RESULTS Different signaling pathways important for Leydig cells' functions are involved in the regulation of the activity of AP-1 members. These transcription factors participate in the regulation of genes related to different biological processes important for Leydig cells. CONCLUSIONS We conclude that members of the AP-1 family of transcription factors play critical roles in the regulation of Leydig cell proliferation, steroidogenesis, and cell-to-cell communication.
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Affiliation(s)
- Ha Tuyen Nguyen
- Biology Department, Université de Moncton, Moncton, NB, E1A 3E9, Canada
| | - Mustapha Najih
- Biology Department, Université de Moncton, Moncton, NB, E1A 3E9, Canada
| | - Luc J Martin
- Biology Department, Université de Moncton, Moncton, NB, E1A 3E9, Canada.
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Karkali K, Martin-Blanco E. Dissection of the Regulatory Elements of the Complex Expression Pattern of Puckered, a Dual-Specificity JNK Phosphatase. Int J Mol Sci 2021; 22:ijms222212205. [PMID: 34830088 PMCID: PMC8623796 DOI: 10.3390/ijms222212205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/19/2021] [Accepted: 11/09/2021] [Indexed: 11/16/2022] Open
Abstract
For developmental processes, we know most of the gene networks controlling specific cell responses. We still have to determine how these networks cooperate and how signals become integrated. The JNK pathway is one of the key elements modulating cellular responses during development. Yet, we still know little about how the core components of the pathway interact with additional regulators or how this network modulates cellular responses in the whole organism in homeostasis or during tissue morphogenesis. We have performed a promoter analysis, searching for potential regulatory sequences of puckered (puc) and identified different specific enhancers directing gene expression in different tissues and at different developmental times. Remarkably, some of these domains respond to the JNK activity, but not all. Altogether, these analyses show that puc expression regulation is very complex and that JNK activities participate in non-previously known processes during the development of Drosophila.
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30
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Li S, Chen T. Colorectal Carcinoma Growth Inhibition by Dietary Care Combined with Probiotic Intervention through Targeting NRP2 Expression. DOKL BIOCHEM BIOPHYS 2021; 500:354-359. [PMID: 34697743 DOI: 10.1134/s1607672921050161] [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: 05/06/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 11/22/2022]
Abstract
The present study investigated the effect of probiotics on inhibition of colorectal tumor growth in vivo and as anti-proliferative agent in vitro. Viability changes were measured by MTT assay whereas protein expression was assessed using western blotting. The study demonstrated that tumor growth was delayed significantly (P < 0.05) in probiotic administered mice from 2nd week compared to the control group. The difference in body weight of the mice in probiotic administered, 5-fluorouracil treated and untreated groups of the mice showed no significant differences during 5-weeks of the study. In probiotic administered mice the expression of miR-331-3p was significantly promoted and that of NRP2 effectively alleviated. Probiotic administration of the mice led to a significant (P < 0.05) increase in p53 and p-c-Jun expression and reduction in Bcl-2 level. Probiotic treatment of SW480 and HCT116 cells led to a significant (P < 0.05) reduction in viability after 48 h compared to the control cells. However, no changes were observed in FHC cell viability after 48 h of treatment with probiotics. The expression of miR-331-3p in SW480 and HCT116 cells was significantly promoted on treatment with probiotics after 48 h. Additionally, probiotic treatment for 48 h led to a remarkable reduction in NRP2 expression in SW480 and HCT116 cells. Thus, probiotic administration inhibited colorectal tumor growth in vivo in mice possibly by upregulation of miR-331-3p expression and down-regulation of NRP2 level. Therefore, probiotics may be used for the treatment of colorectal cancer growth.
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Affiliation(s)
- Shanshan Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 215000, Suzhou, Jiangsu Province, China
| | - Ting Chen
- Department of General Surgery, The First Affiliated Hospital of Soochow University, 215000, Suzhou, Jiangsu Province, China.
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31
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Liu T, Li X, Cui Y, Meng P, Zeng G, Wang Y, Wang Q. Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Intracerebral Hemorrhage. Front Neurosci 2021; 15:661663. [PMID: 34163322 PMCID: PMC8215678 DOI: 10.3389/fnins.2021.661663] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/14/2021] [Indexed: 12/20/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a dangerous neurological disease. The mechanism of ferroptosis in ICH remains unclear. Using bioinformatics analysis, we aimed to identify the key molecules involved in ferroptosis and provide treatment targets for ICH to further explore the mechanism of ferroptosis in ICH. GSE24265 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes. A total of 45 differentially expressed genes (DEGs) were selected, most of which were involved in the TNF signaling pathway and oxidative stress response. Key modules constructed by the protein–protein interaction (PPI) network analysis and screening of genes related to the TNF signaling pathway led to the confirmation of the following genes of interest: MAPK1, MAPK8, TNFAIP3, ATF4, and SLC2A1. Moreover, MAPK1 was one of the key genes related to TNF signaling and oxidative stress, and it may play an important role in ferroptosis after cerebral hemorrhage. The MAPK1-related molecules included hsa-miR-15b-5P, hsa-miR-93-5P, miR-20b-5p, SNHG16, XIST, AC084219.4, RP11-379K17.11, CTC-444N24.11, GS1-358P8.4, CTB-89H12.4, RP4-773N10.5, and FGD5-AS1. We also generated a hemorrhage rat model, which was used to conduct exercise intervention in ICH rats, and qRT-PCR was used to assess the expression levels of our genes of interest. The mRNA levels after cerebral hemorrhage showed that MAPK1, ATF4, SLC2A1, and TNFAIP3 were upregulated, whereas MAPK8 was downregulated. Treadmill training increased the expression of anti-inflammatory molecules TNFAIP3 and SLC2A1 and reduced the expression of MAPK1, ATF4, and MAPK8, indicating that treadmill training may be utilized as antioxidant therapy to decrease neuronal ferroptosis. The results of this study indicated that the MAPK1-related mRNA–miRNA–lncRNA interaction chain could be potentially employed as a biomarker of the inception and progression of ferroptosis after cerebral hemorrhage.
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Affiliation(s)
- Tongye Liu
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinhe Li
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yiteng Cui
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Pingping Meng
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guanghui Zeng
- Department of Sports Medicine, Qingdao University Medical College, Qingdao, China
| | - Yuyang Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiang Wang
- Department of Rehabilitation Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
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Kullmann MK, Pegka F, Ploner C, Hengst L. Stimulation of c-Jun/AP-1-Activity by the Cell Cycle Inhibitor p57 Kip2. Front Cell Dev Biol 2021; 9:664609. [PMID: 33928088 PMCID: PMC8076676 DOI: 10.3389/fcell.2021.664609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/10/2021] [Indexed: 11/13/2022] Open
Abstract
p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription. Here we report that p57 can stimulate AP-1 promotor activity. While transactivation by c-Jun is strongly activated by p57, it did not enhance c-Fos induced transcription. This indicates that c-Jun is the target of p57 in the canonical AP-1 heterodimeric transcription factor. We could detect endogenous p57/c-Jun containing complexes in cells by co-immunoprecipitation. The strong stimulation of c-Jun activity is not the consequence of activating phosphorylation in the transactivation domain (TAD) of c-Jun, but rather due to negative interference with c-Jun repressors and positive interference with c-Jun activators. In contrast to full-length p57, the amino- and carboxy-terminal domains of p57 are insufficient for a significant activation of c-Jun induced transcription. When expressed in presence of full length p57, the p57 C-terminus abrogated and the N-terminus enhanced c-Jun activation. This indicates that the C-terminus may bind and sequester a putative activator of c-Jun, whereas the N-terminus may sequester a c-Jun repressor. Interestingly, the p57 aminoterminus is sufficient for binding to the two c-Jun repressors HDAC1 and HDAC3. These data are consistent with a model of c-Jun activation where p57 is a part of large nuclear remodeling/transcription complexes. p57 might stimulate transcription by inhibiting transcription repressor proteins like HDACs via its N-terminus and/or attracting transcription activators through its C-terminus. These data suggest that in addition to its role as a CDK inhibitor and tumor suppressor, p57 may also exert tumor promoting functions by activation of the proto-oncoprotein c-Jun.
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Affiliation(s)
- Michael Keith Kullmann
- Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Fragka Pegka
- Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Ploner
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Ludger Hengst
- Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
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Okada M, Kawagoe Y, Sato Y, Nozumi M, Ishikawa Y, Tamada A, Yamazaki H, Sekino Y, Kanemura Y, Shinmyo Y, Kawasaki H, Kaneko N, Sawamoto K, Fujii Y, Igarashi M. Phosphorylation of GAP-43 T172 is a molecular marker of growing axons in a wide range of mammals including primates. Mol Brain 2021; 14:66. [PMID: 33832520 PMCID: PMC8034164 DOI: 10.1186/s13041-021-00755-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 02/19/2021] [Indexed: 02/07/2023] Open
Abstract
GAP-43 is a vertebrate neuron-specific protein and that is strongly related to axon growth and regeneration; thus, this protein has been utilized as a classical molecular marker of these events and growth cones. Although GAP-43 was biochemically characterized more than a quarter century ago, how this protein is related to these events is still not clear. Recently, we identified many phosphorylation sites in the growth cone membrane proteins of rodent brains. Two phosphorylation sites of GAP-43, S96 and T172, were found within the top 10 hit sites among all proteins. S96 has already been characterized (Kawasaki et al., 2018), and here, phosphorylation of T172 was characterized. In vitro (cultured neurons) and in vivo, an antibody specific to phosphorylated T172 (pT172 antibody) specifically recognized cultured growth cones and growing axons in developing mouse neurons, respectively. Immunoblotting showed that pT172 antigens were more rapidly downregulated throughout development than those of pS96 antibody. From the primary structure, this phosphorylation site was predicted to be conserved in a wide range of animals including primates. In the developing marmoset brainstem and in differentiated neurons derived from human induced pluripotent stem cells, immunoreactivity with pT172 antibody revealed patterns similar to those in mice. pT172 antibody also labeled regenerating axons following sciatic nerve injury. Taken together, the T172 residue is widely conserved in a wide range of mammals including primates, and pT172 is a new candidate molecular marker for growing axons.
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Affiliation(s)
- Masayasu Okada
- Department of Neurosurgery, Brain Research Institute, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, Japan
- Medical and Dental Hospital, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, Japan
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan
| | - Yosuke Kawagoe
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan
| | - Yuta Sato
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0810, Japan
| | - Motohiro Nozumi
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan
| | - Yuya Ishikawa
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan
- Department of Orthopedic Surgery, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, Japan
| | - Atsushi Tamada
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan
- Department of iPS Cell Applied Medicine, Faculty of Medicine, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
| | - Hiroyuki Yamazaki
- Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yuko Sekino
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Yonehiro Kanemura
- Division of Regenerative Medicine, Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Yohei Shinmyo
- Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiroshi Kawasaki
- Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Naoko Kaneko
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kazunobu Sawamoto
- Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Division of Neural Development and Regeneration, National Institute for Physiological Sciences, Okazaki, Japan
| | - Yukihiko Fujii
- Department of Neurosurgery, Brain Research Institute, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, Japan
- Medical and Dental Hospital, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, Japan
| | - Michihiro Igarashi
- Departments of Neurochemistry and Molecular Cell Biology, School of Medicine and Graduate School of Medical/Dental Sciences, Niigata University, Niigata, 951-8510, Japan.
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34
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JNK signaling as a target for anticancer therapy. Pharmacol Rep 2021; 73:405-434. [PMID: 33710509 DOI: 10.1007/s43440-021-00238-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/30/2021] [Accepted: 02/15/2021] [Indexed: 12/15/2022]
Abstract
The JNKs are members of mitogen-activated protein kinases (MAPK) which regulate many physiological processes including inflammatory responses, macrophages, cell proliferation, differentiation, survival, and death. It is increasingly clear that the continuous activation of JNKs has a role in cancer development and progression. Therefore, JNKs represent attractive oncogenic targets for cancer therapy using small molecule kinase inhibitors. Studies showed that the two major JNK proteins JNK1 and JNK2 have opposite functions in different types of cancers, which need more specification in the design of JNK inhibitors. Some of ATP- competitive and ATP non-competitive inhibitors have been developed and widely used in vitro, but this type of inhibitors lack selectivity and inhibits phosphorylation of all JNK substrates and may lead to cellular toxicity. In this review, we summarized and discussed the strategies of JNK binding inhibitors and the role of JNK signaling in the pathogenesis of different solid and hematological malignancies.
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35
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Pathak A, Clark S, Bronfman FC, Deppmann CD, Carter BD. Long-distance regressive signaling in neural development and disease. WILEY INTERDISCIPLINARY REVIEWS. DEVELOPMENTAL BIOLOGY 2021; 10:e382. [PMID: 32391977 PMCID: PMC7655682 DOI: 10.1002/wdev.382] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 03/23/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023]
Abstract
Nervous system development proceeds via well-orchestrated processes involving a balance between progressive and regressive events including stabilization or elimination of axons, synapses, and even entire neurons. These progressive and regressive events are driven by functionally antagonistic signaling pathways with the dominant pathway eventually determining whether a neural element is retained or removed. Many of these developmental sculpting events are triggered by final target innervation necessitating a long-distance mode of communication. While long-distance progressive signaling has been well characterized, particularly for neurotrophic factors, there remains relatively little known about how regressive events are triggered from a distance. Here we discuss the emergent phenomenon of long-distance regressive signaling pathways. In particular, we will cover (a) progressive and regressive cues known to be employed after target innervation, (b) the mechanisms of long-distance signaling from an endosomal platform, (c) recent evidence that long-distance regressive cues emanate from platforms like death receptors or repulsive axon guidance receptors, and (d) evidence that these pathways are exploited in pathological scenarios. This article is categorized under: Nervous System Development > Vertebrates: General Principles Signaling Pathways > Global Signaling Mechanisms Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization.
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Affiliation(s)
- Amrita Pathak
- Department of Biochemistry and Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Shayla Clark
- Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia
| | - Francisca C. Bronfman
- Institute of Biomedical Sciences (ICB), Faculty of Medicine, Faculty of Life Science, Universidad Andres Bello, Santiago, Chile
| | - Christopher D. Deppmann
- Departments of Biology, Cell Biology, Biomedical Engineering, and Neuroscience, University of Virginia, Charlottesville, Virginia
| | - Bruce D. Carter
- Department of Biochemistry and Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee
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36
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Medda A, Duca D, Chiocca S. Human Papillomavirus and Cellular Pathways: Hits and Targets. Pathogens 2021; 10:262. [PMID: 33668730 PMCID: PMC7996217 DOI: 10.3390/pathogens10030262] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/08/2021] [Accepted: 02/19/2021] [Indexed: 12/18/2022] Open
Abstract
The Human Papillomavirus (HPV) is the causative agent of different kinds of tumors, including cervical cancers, non-melanoma skin cancers, anogenital cancers, and head and neck cancers. Despite the vaccination campaigns implemented over the last decades, we are far from eradicating HPV-driven malignancies. Moreover, the lack of targeted therapies to tackle HPV-related tumors exacerbates this problem. Biomarkers for early detection of the pathology and more tailored therapeutic approaches are needed, and a complete understanding of HPV-driven tumorigenesis is essential to reach this goal. In this review, we overview the molecular pathways implicated in HPV infection and carcinogenesis, emphasizing the potential targets for new therapeutic strategies as well as new biomarkers.
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Affiliation(s)
| | | | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; (A.M.); (D.D.)
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37
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Ludwig S, Hrincius ER, Boergeling Y. The Two Sides of the Same Coin-Influenza Virus and Intracellular Signal Transduction. Cold Spring Harb Perspect Med 2021; 11:a038513. [PMID: 31871235 PMCID: PMC7778220 DOI: 10.1101/cshperspect.a038513] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling inside the cell, primarily induced by pathogen-associated molecular patterns (PAMPs) that provoke safeguard mechanisms to defend from the invader. In the constant arms race between pathogen and cellular defense, viruses not only have evolved mechanisms to suppress or misuse supposedly antiviral signaling processes for their own benefit but also actively induce signaling to promote replication. This creates viral dependencies that may be exploited for novel strategies of antiviral intervention. Here, we will summarize the current knowledge of activation and function of influenza virus-induced signaling pathways with a focus on nuclear factor (NF)-κB signaling, mitogen-activated protein kinase cascades, and the phosphatidylinositol-3-kinase pathway. We will discuss the opportunities and drawbacks of targeting these signaling pathways for antiviral intervention.
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Affiliation(s)
- Stephan Ludwig
- Institute of Virology Muenster, University of Muenster, 48149 Muenster, Germany
| | - Eike R Hrincius
- Institute of Virology Muenster, University of Muenster, 48149 Muenster, Germany
| | - Yvonne Boergeling
- Institute of Virology Muenster, University of Muenster, 48149 Muenster, Germany
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38
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Delpoux A, Marcel N, Hess Michelini R, Katayama CD, Allison KA, Glass CK, Quiñones-Parra SM, Murre C, Loh L, Kedzierska K, Lappas M, Hedrick SM, Doedens AL. FOXO1 constrains activation and regulates senescence in CD8 T cells. Cell Rep 2021; 34:108674. [PMID: 33503413 DOI: 10.1016/j.celrep.2020.108674] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 10/25/2020] [Accepted: 12/29/2020] [Indexed: 12/19/2022] Open
Abstract
Naive and memory T cells are maintained in a quiescent state, yet capable of rapid response and differentiation to antigen challenge via molecular mechanisms that are not fully understood. In naive cells, the deletion of Foxo1 following thymic development results in the increased expression of multiple AP-1 family members, rendering T cells less able to respond to antigenic challenge. Similarly, in the absence of FOXO1, post-infection memory T cells exhibit the characteristics of extended activation and senescence. Age-based analysis of human peripheral T cells reveals that levels of FOXO1 and its downstream target, TCF7, are inversely related to host age, whereas the opposite is found for AP-1 factors. These characteristics of aging also correlate with the formation of T cells manifesting features of cellular senescence. Our work illustrates a role for FOXO1 in the active maintenance of stem-like properties in T cells at the timescales of acute infection and organismal life span.
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Affiliation(s)
- Arnaud Delpoux
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Nimi Marcel
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Rodrigo Hess Michelini
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Carol D Katayama
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Karmel A Allison
- Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Sergio M Quiñones-Parra
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Cornelis Murre
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA
| | - Liyen Loh
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia
| | - Katherine Kedzierska
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Parkville, VIC, Australia
| | - Martha Lappas
- Obstetrics, Nutrition, and Endocrinology Group, Department of Obstetrics & Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, VIC, Australia
| | - Stephen M Hedrick
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA.
| | - Andrew L Doedens
- Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA.
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Park HJ, Lee R, Yoo H, Hong K, Song H. Nonylphenol Induces Apoptosis through ROS/JNK Signaling in a Spermatogonia Cell Line. Int J Mol Sci 2020; 22:ijms22010307. [PMID: 33396729 PMCID: PMC7796095 DOI: 10.3390/ijms22010307] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 12/22/2022] Open
Abstract
Nonylphenol (NP) is an endocrine-disruptor chemical that negatively affects reproductive health. Testes exposure to NP results in testicular structure disruption and a reduction in testicular size and testosterone levels. However, the effects of NP on spermatogonia in testes have not been fully elucidated. In this study, the molecular mechanisms of NP in GC-1 spermatogonia (spg) cells were investigated. We found that cell viability significantly decreased and apoptosis increased in a dose-dependent manner when GC-1 spg cells were exposed to NP. Furthermore, the expression levels of the pro-apoptotic proteins increased, whereas anti-apoptosis markers decreased in NP-exposed GC-1 spg cells. We also found that NP increased reactive oxygen species (ROS) generation, suggesting that ROS-induced activation of the MAPK signaling pathway is the molecular mechanism of NP-induced apoptosis in GC-1 spg cells. Thus, NP could induce c-Jun phosphorylation; dose-dependent expression of JNK, MKK4, p53, and p38; and the subsequent inhibition of ERK1/2 and MEK1/2 phosphorylation. The genes involved in apoptosis and JNK signaling were also upregulated in GC-1 spg cells treated with NP compared to those in the controls. Our findings suggest that NP induces apoptosis through ROS/JNK signaling in GC-1 spg cells.
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Affiliation(s)
| | | | | | | | - Hyuk Song
- Correspondence: ; Tel.: +82-2-450-0562
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40
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Vind AC, Genzor AV, Bekker-Jensen S. Ribosomal stress-surveillance: three pathways is a magic number. Nucleic Acids Res 2020; 48:10648-10661. [PMID: 32941609 PMCID: PMC7641731 DOI: 10.1093/nar/gkaa757] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/28/2020] [Accepted: 09/06/2020] [Indexed: 12/15/2022] Open
Abstract
Cells rely on stress response pathways to uphold cellular homeostasis and limit the negative effects of harmful environmental stimuli. The stress- and mitogen-activated protein (MAP) kinases, p38 and JNK, are at the nexus of numerous stress responses, among these the ribotoxic stress response (RSR). Ribosomal impairment is detrimental to cell function as it disrupts protein synthesis, increase inflammatory signaling and, if unresolved, lead to cell death. In this review, we offer a general overview of the three main translation surveillance pathways; the RSR, Ribosome-associated Quality Control (RQC) and the Integrated Stress Response (ISR). We highlight recent advances made in defining activation mechanisms for these pathways and discuss their commonalities and differences. Finally, we reflect on the physiological role of the RSR and consider the therapeutic potential of targeting the sensing kinase ZAKα for treatment of ribotoxin exposure.
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Affiliation(s)
- Anna Constance Vind
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark
| | - Aitana Victoria Genzor
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark
| | - Simon Bekker-Jensen
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark
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41
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Kirsch K, Zeke A, Tőke O, Sok P, Sethi A, Sebő A, Kumar GS, Egri P, Póti ÁL, Gooley P, Peti W, Bento I, Alexa A, Reményi A. Co-regulation of the transcription controlling ATF2 phosphoswitch by JNK and p38. Nat Commun 2020; 11:5769. [PMID: 33188182 PMCID: PMC7666158 DOI: 10.1038/s41467-020-19582-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/21/2020] [Indexed: 01/26/2023] Open
Abstract
Transcription factor phosphorylation at specific sites often activates gene expression, but how environmental cues quantitatively control transcription is not well-understood. Activating protein 1 transcription factors are phosphorylated by mitogen-activated protein kinases (MAPK) in their transactivation domains (TAD) at so-called phosphoswitches, which are a hallmark in response to growth factors, cytokines or stress. We show that the ATF2 TAD is controlled by functionally distinct signaling pathways (JNK and p38) through structurally different MAPK binding sites. Moreover, JNK mediated phosphorylation at an evolutionarily more recent site diminishes p38 binding and made the phosphoswitch differently sensitive to JNK and p38 in vertebrates. Structures of MAPK-TAD complexes and mechanistic modeling of ATF2 TAD phosphorylation in cells suggest that kinase binding motifs and phosphorylation sites line up to maximize MAPK based co-regulation. This study shows how the activity of an ancient transcription controlling phosphoswitch became dependent on the relative flux of upstream signals.
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Affiliation(s)
- Klára Kirsch
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - András Zeke
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - Orsolya Tőke
- Laboratory for NMR Spectroscopy, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - Péter Sok
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - Ashish Sethi
- Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Anna Sebő
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | | | - Péter Egri
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - Ádám L Póti
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - Paul Gooley
- Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Wolfgang Peti
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA
| | - Isabel Bento
- European Molecular Biology Laboratory, Hamburg, Germany
| | - Anita Alexa
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary
| | - Attila Reményi
- Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences, H-1117, Budapest, Hungary.
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Papavassiliou AG, Musti AM. The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion. Cells 2020; 9:2470. [PMID: 33202877 PMCID: PMC7697663 DOI: 10.3390/cells9112470] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/07/2020] [Accepted: 11/11/2020] [Indexed: 12/19/2022] Open
Abstract
c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.
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Affiliation(s)
- Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Maria Musti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
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43
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Kraus S, Benard O, Naor Z, Seger R. C-Src is Activated by the EGF Receptor in a Pathway that Mediates JNK and ERK Activation by Gonadotropin-Releasing Hormone in COS7 Cells. Int J Mol Sci 2020; 21:ijms21228575. [PMID: 33202981 PMCID: PMC7697137 DOI: 10.3390/ijms21228575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/26/2022] Open
Abstract
The key participants in G-protein-coupled receptor (GPCR) signaling are the mitogen-activated protein kinase (MAPK) signaling cascades. The mechanisms involved in the activation of the above cascades by GPCRs are not fully elucidated. The prototypical GPCR is the receptor for gonadotropin-releasing hormone (GnRHR), which serves as a key regulator of the reproductive system. Here, we expressed GnRHR in COS7 cells and found that GnRHR transmits its signals to MAPKs mainly via Gαi and the EGF receptor, without the involvement of Hb-EGF or PKCs. The main pathway that leads to JNK activation downstream of the EGF receptor involves a sequential activation of c-Src and PI3K. ERK activation by GnRHR is mediated by the EGF receptor, which activates Ras either directly or via c-Src. Beside the main pathway, the dissociated Gβγ and β-arrestin may initiate additional (albeit minor) pathways that lead to MAPK activation in the transfected COS7 cells. The pathways detected are significantly different from those in other GnRHR-bearing cells, indicating that GnRH can utilize various signaling mechanisms for MAPK activation. The unique pathway elucidated here, in which c-Src and PI3K are sequentially activated downstream of the EGF receptor, may serve as a prototype of signaling mechanisms by GnRHR and additional GPCRs in various cell types.
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Affiliation(s)
- Sarah Kraus
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 7610001, Israel; (S.K.); (O.B.)
| | - Outhiriaradjou Benard
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 7610001, Israel; (S.K.); (O.B.)
| | - Zvi Naor
- Department of Biochemistry, Tel Aviv University, Ramat Aviv 69978, Israel;
| | - Rony Seger
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 7610001, Israel; (S.K.); (O.B.)
- Correspondence: ; Tel.: +972-8-9343602
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Igarashi M, Honda A, Kawasaki A, Nozumi M. Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation. Front Mol Neurosci 2020; 13:150. [PMID: 32922262 PMCID: PMC7456915 DOI: 10.3389/fnmol.2020.00150] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/16/2020] [Indexed: 12/17/2022] Open
Abstract
Neuronal polarization and growth are developmental processes that occur during neuronal cell differentiation. The molecular signaling mechanisms involved in these events in in vivo mammalian brain remain unclear. Also, cellular events of the neuronal polarization process within a given neuron are thought to be constituted of many independent intracellular signal transduction pathways (the "tug-of-war" model). However, in vivo results suggest that such pathways should be cooperative with one another among a given group of neurons in a region of the brain. Lipid rafts, specific membrane domains with low fluidity, are candidates for the hotspots of such intracellular signaling. Among the signals reported to be involved in polarization, a number are thought to be present or translocated to the lipid rafts in response to extracellular signals. As part of our analysis, we discuss how such novel molecular mechanisms are combined for effective regulation of neuronal polarization and growth, focusing on the significance of the lipid rafts, including results based on recently introduced methods.
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Affiliation(s)
- Michihiro Igarashi
- Department of Neurochemistry and Molecular Cell Biology, Niigata University School of Medicine and Graduate School of Medical/Dental Sciences, Niigata, Japan
| | - Atsuko Honda
- Department of Neurochemistry and Molecular Cell Biology, Niigata University School of Medicine and Graduate School of Medical/Dental Sciences, Niigata, Japan
| | - Asami Kawasaki
- Department of Neurochemistry and Molecular Cell Biology, Niigata University School of Medicine and Graduate School of Medical/Dental Sciences, Niigata, Japan
| | - Motohiro Nozumi
- Department of Neurochemistry and Molecular Cell Biology, Niigata University School of Medicine and Graduate School of Medical/Dental Sciences, Niigata, Japan
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Nakano R, Nakayama T, Sugiya H. Biological Properties of JNK3 and Its Function in Neurons, Astrocytes, Pancreatic β-Cells and Cardiovascular Cells. Cells 2020; 9:cells9081802. [PMID: 32751228 PMCID: PMC7464089 DOI: 10.3390/cells9081802] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 07/15/2020] [Accepted: 07/27/2020] [Indexed: 12/28/2022] Open
Abstract
JNK is a protein kinase, which induces transactivation of c-jun. The three isoforms of JNK, JNK1, JNK2, and JNK3, are encoded by three distinct genes. JNK1 and JNK2 are expressed ubiquitously throughout the body. By contrast, the expression of JNK3 is limited and observed mainly in the brain, heart, and testes. Concerning the biological properties of JNKs, the contribution of upstream regulators and scaffold proteins plays an important role in the activation of JNKs. Since JNK signaling has been described as a form of stress-response signaling, the contribution of JNK3 to pathophysiological events, such as stress response or cell death including apoptosis, has been well studied. However, JNK3 also regulates the physiological functions of neurons and non-neuronal cells, such as development, regeneration, and differentiation/reprogramming. In this review, we shed light on the physiological functions of JNK3. In addition, we summarize recent advances in the knowledge regarding interactions between JNK3 and cellular reprogramming.
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Affiliation(s)
- Rei Nakano
- Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
- Laboratory of Veterinary Radiology, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa 252-0880, Japan; (T.N.); (H.S.)
- Correspondence:
| | - Tomohiro Nakayama
- Laboratory of Veterinary Radiology, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa 252-0880, Japan; (T.N.); (H.S.)
| | - Hiroshi Sugiya
- Laboratory of Veterinary Radiology, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa 252-0880, Japan; (T.N.); (H.S.)
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Yang Y, Liao Y, Gui YP, Zhao L, Guo LB. GL-V9 reverses adriamycin resistance in hepatocellular carcinoma cells by affecting JNK2-related autophagy. Chin J Nat Med 2020; 18:491-499. [PMID: 32616189 DOI: 10.1016/s1875-5364(20)30059-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Adriamycin resistance in HCC seriously hinders the treatment of patients, it is necessary to investigate the mechanisms. Autophagy is involved in adriamycin resistance and JNK2 is related to autophagy. However, whether JNK2 inducing drug resistance though autophagy is unknown. GL-V9, a new synthesized flavonoid derivative, has been proved of its anti-tumor effects. The aim of the study is to explore the role of JNK2-related autophagy on adriamycin-induced drug resistance and the effects of GL-V9 on reversing adriamycin resistance. We concluded that JNK2 played an important role in drug resistance induced by adriamycin. The high expression of JNK2 activated protective autophagy in Hep G2-DOXR cells under non-stress condition, which protected cells from drug attacking. Furthermore, we found that GL-V9 reversed adriamycin resistance by blocking the JNK2-related protective autophagy in HCC.
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Affiliation(s)
- Yue Yang
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China
| | - Yan Liao
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China
| | - Yan-Ping Gui
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China
| | - Li Zhao
- School of Basic Medicine and Clinical Pharmacology, China Pharmaceutical University, Nanjing 211100, China.
| | - Lu-Bo Guo
- Department of Pharmacy, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China.
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Medina MV, Sapochnik D, Garcia Solá M, Coso O. Regulation of the Expression of Heme Oxygenase-1: Signal Transduction, Gene Promoter Activation, and Beyond. Antioxid Redox Signal 2020; 32:1033-1044. [PMID: 31861960 PMCID: PMC7153632 DOI: 10.1089/ars.2019.7991] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 12/20/2019] [Indexed: 02/06/2023]
Abstract
Significance: Heme oxygenase-1 (HO-1) is a ubiquitous 32-kDa protein expressed in many tissues and highly inducible. They catalyze the degradation of the heme group and the release of free iron, carbon monoxide, and biliverdin; the latter converted to bilirubin by biliverdin reductase. Its role in the regulation of cellular homeostasis is widely documented. Studying regulation of HO-1 expression is important not only to understand the life of healthy cells but also the unbalances in cell metabolism that lead to disease. Recent Advances: The regulation of its enzymatic activity depends heavily upon changes in expression studied mainly at the transcriptional level. Current knowledge regarding HO-1 gene expression focuses primarily on transcription factors such as Nrf2 (nuclear factor erythroid 2-related factor 2), AP-1 (activator protein-1), and hypoxia-inducible factor, which collect signal transduction pathway information at the HO-1 gene promoter. Understanding of gene expression regulation is not limited to transcription factor activity but also involves an extended range of post- or cotranscriptional regulated events. Critical Issues: In addition to the regulation of gene promoter activity, alternative splicing, alternative polyadenylation, and regulation of messenger RNA stability play critical roles in changes in HO-1 gene expression levels, involving specific factors, proteins, and microRNAs. All potential targets for diagnosis or treatment of diseases are related to HO-1 dysregulation. Future Directions: Unbalances in the tightly regulated gene expression mechanisms lead to cell transformation and cancer development. Knowledge of these events and signal transduction cascades triggered by oncogenes in which HO-1 plays a critical role is of upmost importance for research in this field.
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Affiliation(s)
- María Victoria Medina
- Departamento de Fisiología, Biología Molecular y Celular (FBMC), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Daiana Sapochnik
- Departamento de Fisiología, Biología Molecular y Celular (FBMC), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Martín Garcia Solá
- Departamento de Fisiología, Biología Molecular y Celular (FBMC), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Omar Coso
- Departamento de Fisiología, Biología Molecular y Celular (FBMC), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
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The JNK inhibitor AS602801 Synergizes with Enzalutamide to Kill Prostate Cancer Cells In Vitro and In Vivo and Inhibit Androgen Receptor Expression. Transl Oncol 2020; 13:100751. [PMID: 32199273 PMCID: PMC7082632 DOI: 10.1016/j.tranon.2020.100751] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 02/26/2020] [Indexed: 01/13/2023] Open
Abstract
In our previous study, we observed that androgen deprivation therapy (ADT) may induce a compensatory increase in MAPK or JNK signaling. Here, we tested the effects of the MEK inhibitors PD0325901 and GSK1120212, ERK1/2 inhibitor GDC-0994, and the JNK inhibitor AS602801 alone and in combination with the AR inhibitor enzalutamide (ENZ) in androgen-sensitive LNCaP cells and androgen-resistant C4-2 and 22Rv1 cells. Enzalutamide combined with AS602801 synergistically killed LNCaP, C4-2, and 22Rv1 cells, and decreased migration and invasion of LNCaP and C4-2 cells. We studied the combination of enzalutamide with AS602801 in vivo using luciferase labeled LNCaP xenografts, and observed that combination of ENZ with AS602801 significantly suppressed tumor growth compared with either drug alone. Importantly, combination therapy resulted in dramatic loss of AR mRNA and protein. Surprisingly, mechanistic studies and Nanostring data suggest that AS602801 likely activates JNK signaling to induce apoptosis. Since AS602801 had sufficient safety and toxicity profile to advance from Phase I to Phase II in clinical trials, repurposing of this compound may represent an opportunity for rapid translation for clinical therapy of CRPC patients.
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Campbell A, Mohl JE, Gutierrez DA, Varela-Ramirez A, Boland T. Thermal Bioprinting Causes Ample Alterations of Expression of LUCAT1, IL6, CCL26, and NRN1L Genes and Massive Phosphorylation of Critical Oncogenic Drug Resistance Pathways in Breast Cancer Cells. Front Bioeng Biotechnol 2020; 8:82. [PMID: 32154227 PMCID: PMC7047130 DOI: 10.3389/fbioe.2020.00082] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/29/2020] [Indexed: 12/19/2022] Open
Abstract
Bioprinting technology merges engineering and biological fields and together, they possess a great translational potential, which can tremendously impact the future of regenerative medicine and drug discovery. However, the molecular effects elicited by thermal inkjet bioprinting in breast cancer cells remains elusive. Previous studies have suggested that bioprinting can be used to model tissues for drug discovery and pharmacology. We report viability, apoptosis, phosphorylation, and RNA sequence analysis of bioprinted MCF7 breast cancer cells at separate timepoints post-bioprinting. An Annexin A5-FITC apoptosis stain was used in combination with flow cytometry at 2 and 24 h post-bioprinting. Antibody arrays using a Human phospho-MAPK array kit was performed 24 h post-bioprinting. RNA sequence analysis was conducted in samples collected at 2, 7, and 24 h post-bioprinting. The post-bioprinting cell viability averages were 77 and 76% at 24 h and 48 h, with 31 and 64% apoptotic cells at 2 and 24 h after bioprinting. A total of 21 kinases were phosphorylated in the bioprinted cells and 9 were phosphorylated in the manually seeded controls. The RNA seq analysis in the bioprinted cells identified a total of 12,235 genes, of which 9.7% were significantly differentially expressed. Using a ±2-fold change as the cutoff, 266 upregulated and 206 downregulated genes were observed in the bioprinted cells, with the following 5 genes uniquely expressed NRN1L, LUCAT1, IL6, CCL26, and LOC401585. This suggests that thermal inkjet bioprinting is stimulating large scale gene alterations that could potentially be utilized for drug discovery. Moreover, bioprinting activates key pathways implicated in drug resistance, cell motility, proliferation, survival, and differentiation.
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Affiliation(s)
- Aleli Campbell
- Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, TX, United States
| | - Jonathon E Mohl
- Department of Mathematical Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, United States
| | - Denisse A Gutierrez
- Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, United States
| | - Armando Varela-Ramirez
- Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, United States
| | - Thomas Boland
- Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, TX, United States
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50
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Zhang L, Chen W, Li Y, Hong W, Li H, Cui Z, Dong X, Han X, Bao G, Xiao L, Gao P, Wang Y. Effect of 650-nm low-level laser irradiation on c-Jun, c-Fos, ICAM-1, and CCL2 expression in experimental periodontitis. Lasers Med Sci 2020; 35:31-40. [PMID: 30341668 DOI: 10.1007/s10103-018-2662-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 10/09/2018] [Indexed: 02/05/2023]
Abstract
This study was designed to investigate the effect of 650-nm low-level laser irradiation (LLLI) as an adjunctive treatment of experimental periodontitis. To investigate possible LLLI-mediated anti-inflammatory effects, we utilized an experimental periodontitis (EP) rat model and analyzed c-Jun, c-Fos, ICAM-1, and CCL2 gene expressions on PB leukocytes and in the gingival tissue. Total RNA was isolated from the gingivae and peripheral blood (PB) leukocytes of normal, EP, scaling, and root planing (SRP)-treated EP and LLLI + SRP-treated EP rats, and gene expressions were analyzed by real-time PCR. The productions of c-Jun, c-Fos, ICAM-1, and CCL2 in gingivae were analyzed immunohistochemically. Tartrate-resistant acid phosphatase (TRAP) staining was used to determine osteoclast activity in alveolar bone. The c-Jun and ICAM-1 messenger RNA (mRNA) levels were significantly decreased in the EP rat gingival tissue treated by SRP + LLLI than by SRP, the c-Jun, ICAM-1, and c-Fos mRNA levels on PB leukocytes reduced after LLLI treatment but did not show any significant differences in both groups. There was no significant difference in CCL2 mRNA levels on PB leukocytes and in gingivae between the SRP + LLLI and the SRP groups. The c-Fos mRNA levels in gingivae did not show significant difference in both groups. Immunohistochemistry showed that the CCL2, ICAM-1, c-Jun, and c-Fos productions were significantly reduced in rats of the SRP + LLLI group compared with the only SRP group. LLLI significantly decreased the number of osteoclasts as demonstrated by TRAP staining. The 650-nm LLLI might be a useful treatment modality for periodontitis.
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Affiliation(s)
- Lin Zhang
- School of Dentistry, Hospital of Stomatology, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin, 300070, China
| | - Wenlei Chen
- School of Dentistry, Hospital of Stomatology, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin, 300070, China
| | - Yingxin Li
- Institute of Biomedical Engineering, Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Wei Hong
- Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Haidong Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zhuang Cui
- School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xiaoxi Dong
- Institute of Biomedical Engineering, Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - Xiaohui Han
- Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Gang Bao
- School of Dentistry, Hospital of Stomatology, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin, 300070, China
| | - Li Xiao
- School of Dentistry, Hospital of Stomatology, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin, 300070, China
| | - Pengfei Gao
- School of Dentistry, Hospital of Stomatology, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin, 300070, China
| | - Yonglan Wang
- School of Dentistry, Hospital of Stomatology, Tianjin Medical University, 12 Qi Xiang Tai Street, Heping District, Tianjin, 300070, China.
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