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Su W, Wang W, Zhang G, Yang L. Epigenetic regulatory protein chromobox family regulates multiple signalling pathways and mechanisms in cancer. Clin Epigenetics 2025; 17:48. [PMID: 40083014 PMCID: PMC11907984 DOI: 10.1186/s13148-025-01852-w] [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: 10/02/2024] [Accepted: 02/20/2025] [Indexed: 03/16/2025] Open
Abstract
Signal transduction plays a pivotal role in modulating a myriad of critical processes, including the tumour microenvironment (TME), cell cycle arrest, proliferation and apoptosis of tumour cells, as well as their migration, invasion, and the epithelial-mesenchymal transition (EMT). Epigenetic mechanisms are instrumental in the genesis and progression of tumours. The Chromobox (CBX) family proteins, which serve as significant epigenetic regulators, exhibit tumour-specific expression patterns and biological functionalities. These proteins are influenced by a multitude of factors and could modulate the activation of diverse signalling pathways within tumour cells through alterations in epigenetic modifications, thereby acting as either oncogenic agents or tumour suppressors. This review aims to succinctly delineate the composition, structure, function, and expression of CBXs within tumour cells, with an emphasis on synthesizing and deliberating the CBXs-mediated activation of intracellular signalling pathways and the intricate mechanisms governing tumourigenesis and progression. Moreover, a plethora of contemporary studies have substantiated that CBXs might represent a promising target for the diagnosis and therapeutic intervention of tumour patients. We have also compiled and scrutinized the current research landscape concerning inhibitors targeting CBXs, aspiring to aid researchers in gaining a deeper comprehension of the biological roles and mechanisms of CBXs in the malignant evolution of tumours, and to furnish novel perspectives for the innovation of targeted tumour therapeutics.
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Affiliation(s)
- Weiyu Su
- Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China
| | - Weiwen Wang
- Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China
| | - Guanghui Zhang
- Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China.
| | - Lianhe Yang
- Medical College, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China.
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2
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Rudalska R, Harbig J, Forster M, Woelffing P, Esposito A, Kudolo M, Botezatu A, Haller V, Janssen N, Holzmayer S, Nahidino P, Trompak O, Pantsar T, Kronenberger T, Yurttas C, Rist E, Weber ANR, Dahlke MH, Ott G, Koenigsrainer A, Rothbauer U, Maerklin M, Muerdter T, Schwab M, Singer S, Zender L, Laufer S, Dauch D. First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer. NATURE CANCER 2025; 6:259-277. [PMID: 39820127 PMCID: PMC11864979 DOI: 10.1038/s43018-024-00899-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 12/12/2024] [Indexed: 01/19/2025]
Abstract
Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes. ULTR-p38i monotherapy triggers an uncontrolled mitotic entry by activating Cdc25 and simultaneously blocking Wee1. Consequently, CRC cells undergo mitotic catastrophe, resulting in apoptosis or senescence. ULTR-p38i exhibit high selectivity, good pharmaco-kinetic properties and no measurable toxicity with strong therapeutic effects in patient-derived CRC organoids and syngeneic CRC mouse models. Conceptually, our study suggests ultralong-target-residence-time kinase inhibitors as an alternative to covalent inhibitors, which, because of the lack of cysteine residues, cannot be generated for many kinase cancer targets.
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Affiliation(s)
- Ramona Rudalska
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Jule Harbig
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Michael Forster
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
| | - Pascal Woelffing
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Aylin Esposito
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Mark Kudolo
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
| | - Adelina Botezatu
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Vanessa Haller
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
| | - Nicole Janssen
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany
| | - Samuel Holzmayer
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Philipp Nahidino
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
| | - Omelyan Trompak
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Tatu Pantsar
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Thales Kronenberger
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Can Yurttas
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Elke Rist
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Alexander N R Weber
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Marc H Dahlke
- Department of General and Visceral Surgery, Robert Bosch Hospital, Stuttgart, Germany
| | - German Ott
- Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany
| | - Alfred Koenigsrainer
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Ulrich Rothbauer
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
- Department of Pharmaceutical Biotechnology, University of Tübingen, Tübingen, Germany
| | - Melanie Maerklin
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Thomas Muerdter
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany
| | - Matthias Schwab
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany
- Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University of Tübingen, Tübingen, Germany
- German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephan Singer
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany
| | - Lars Zender
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany
| | - Stefan Laufer
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
- Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany
- Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany
| | - Daniel Dauch
- Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
- IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
- Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany.
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Camilleri‐Robles C, Climent‐Cantó P, Llorens‐Giralt P, Klein CC, Serras F, Corominas M. A shift in chromatin binding of phosphorylated p38 precedes transcriptional changes upon oxidative stress. FEBS Lett 2024; 598:2926-2938. [PMID: 39218622 PMCID: PMC11627000 DOI: 10.1002/1873-3468.15006] [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: 06/17/2024] [Revised: 07/24/2024] [Accepted: 08/02/2024] [Indexed: 09/04/2024]
Abstract
P38 mitogen-activated protein kinases are key in the regulation of the cellular response to stressors. P38 is known to regulate transcription, mRNA processing, stability, and translation. The transcriptional changes mediated by phosphorylated p38 (P-p38) in response to extracellular stimuli have been thoroughly analyzed in many tissues and organisms. However, the genomic localization of chromatin-associated P-p38 remains poorly understood. Here, we analyze the chromatin binding of activated P-p38 and its role in the response to reactive oxygen species (ROS) in Drosophila S2 cells. We found that P-p38 is already bound to chromatin in basal conditions. After ROS exposure, chromatin-associated P-p38 relocates towards genes involved in the recovery process. Our findings highlight the role of P-p38 dynamic chromatin binding in orchestrating gene expression responses to oxidative stress.
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Affiliation(s)
- Carlos Camilleri‐Robles
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB)Universitat de BarcelonaSpain
| | - Paula Climent‐Cantó
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB)Universitat de BarcelonaSpain
- Present address:
Hereditary Cancer Program, IDIBELLL'Hospitalet de LlobregatBarcelonaSpain
| | - Palmira Llorens‐Giralt
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB)Universitat de BarcelonaSpain
| | - Cecilia C. Klein
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB)Universitat de BarcelonaSpain
| | - Florenci Serras
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB)Universitat de BarcelonaSpain
| | - Montserrat Corominas
- Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB)Universitat de BarcelonaSpain
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Shin YJ, Chae SY, Lee H, Fang X, Cui S, Lim SW, Lee KI, Lee JY, Li C, Yang CW, Chung BH. CRISPR/Cas9-mediated suppression of A4GALT rescues endothelial cell dysfunction in a fabry disease vasculopathy model derived from human induced pluripotent stem cells. Atherosclerosis 2024; 397:118549. [PMID: 39141976 DOI: 10.1016/j.atherosclerosis.2024.118549] [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: 11/07/2023] [Revised: 07/08/2024] [Accepted: 07/31/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND AND AIMS The objective of this study was to investigate the efficacy of CRISPR/Cas9-mediated A4GALT suppression in rescuing endothelial dysfunction in Fabry disease (FD) endothelial cells (FD-ECs) derived from human induced pluripotent stem cells (hiPSCs). METHODS We differentiated hiPSCs (WT (wild-type), WTC-11), GLA-mutant hiPSCs (GLA-KO, CMC-Fb-002), and CRISPR/Cas9-mediated A4GALT-KO hiPSCs (GLA/A4GALT-KO, Fb-002-A4GALT-KO) into ECs and compared FD phenotypes and endothelial dysfunction. We also analyzed the effect of A4GALT suppression on reactive oxygen species (ROS) formation and transcriptome profiles through RNA sequencing. RESULTS GLA-mutant hiPSC-ECs (GLA-KO and CMC-Fb-002) showed downregulated expression of EC markers and significantly reduced α-GalA expression with increased Gb-3 deposition and intra-lysosomal inclusion bodies. However, CRISPR/Cas9-mediated A4GALT suppression in GLA/A4GALT-KO and Fb-002-A4GALT-KO hiPSC-ECs increased expression levels of EC markers and rescued these FD phenotypes. GLA-mutant hiPSC-ECs failed to form tube-like structure in tube formation assays, showing significantly decreased migration of cells into the scratched wound area. In contrast, A4GALT suppression improved tube formation and cell migration capacity. Western blot analysis revealed that MAPK and AKT phosphorylation levels were downregulated while SOD and catalase were upregulated in GLA-KO hiPSC-ECs. However, suppression of A4GALT restored these protein alterations. RNA sequencing analysis demonstrated significant transcriptome changes in GLA-mutant EC, especially in angiogenesis, cell death, and cellular response to oxidative stress. However, these were effectively restored in GLA/A4GALT-KO hiPSC-ECs. CONCLUSIONS CRISPR/Cas9-mediated A4GALT suppression rescued FD phenotype and endothelial dysfunction in GLA-mutant hiPSC-ECs, presenting a potential therapeutic approach for FD-vasculopathy.
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Affiliation(s)
- Yoo Jin Shin
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung Yun Chae
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, South Korea
| | - Hanbi Lee
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, South Korea
| | - Xianying Fang
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sheng Cui
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sun Woo Lim
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | | | | | - Can Li
- Department of Nephrology, Yanbian University Hospital, Yanji, China
| | - Chul Woo Yang
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, South Korea
| | - Byung Ha Chung
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea; Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, South Korea.
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5
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Pantho AF, Mohamed S, Govande JV, Rane R, Vora N, Kelso KR, Kuehl TJ, Lindheim SR, Uddin MN. Pravastatin Protects Cytotrophoblasts from Hyperglycemia-Induced Preeclampsia Phenotype. Cells 2024; 13:1534. [PMID: 39329718 PMCID: PMC11430553 DOI: 10.3390/cells13181534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 09/28/2024] Open
Abstract
There are no effective therapies to prevent preeclampsia (PE). Pravastatin shows promise by attenuating processes associated with PE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction. METHODS Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 h. Some cells were pretreated with pravastatin (1 µg/mL), while others were cotreated with pravastatin and glucose. The expression of urokinase plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) mRNA, vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) were measured. CTB migration was assayed using a CytoSelect migration assay kit. Statistical comparisons were performed using an analysis of variance with Duncan's post hoc test. RESULTS The hyperglycemia-induced downregulation of uPA was attenuated in CTB cells pretreated with pravastatin at glucose levels > 200 mg/dL and cotreated at glucose levels > 300 mg/dL (p < 0.05). Hyperglycemia-induced decreases in VEGF and PlGF and increases in sEng and sFlt-1 were attenuated in both the pretreatment and cotreatment samples regardless of glucose dose (p < 0.05). Pravastatin attenuated hyperglycemia-induced dysfunction of CTB migration. CONCLUSIONS Pravastatin mitigates stress signaling responses in hyperglycemic conditions, weakening processes leading to abnormal CTB migration and invasion associated with PE in pregnancy.
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Affiliation(s)
- Ahmed F. Pantho
- Artemis Biotechnologies LLC, Temple, TX 76504, USA; (A.F.P.); (T.J.K.)
| | - Sara Mohamed
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | | | - Riddhi Rane
- Texas A&M University College of Medicine, College Station, TX 77807, USA;
| | - Niraj Vora
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | - Kelsey R. Kelso
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | - Thomas J. Kuehl
- Artemis Biotechnologies LLC, Temple, TX 76504, USA; (A.F.P.); (T.J.K.)
| | - Steven R. Lindheim
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
| | - Mohammad N. Uddin
- Artemis Biotechnologies LLC, Temple, TX 76504, USA; (A.F.P.); (T.J.K.)
- Baylor Scott & White Health, Temple, TX 76508, USA; (S.M.); (N.V.); (K.R.K.); (S.R.L.)
- Texas A&M University College of Medicine, College Station, TX 77807, USA;
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6
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Golmohammadi M, Meibodi SAA, Al-Hawary SIS, Gupta J, Sapaev IB, Najm MAA, Alwave M, Nazifi M, Rahmani M, Zamanian MY, Moriasi G. Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review. Animal Model Exp Med 2024; 7:195-207. [PMID: 38808561 PMCID: PMC11228121 DOI: 10.1002/ame2.12438] [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: 02/12/2024] [Accepted: 04/22/2024] [Indexed: 05/30/2024] Open
Abstract
Glaucoma, an irreversible optic neuropathy, primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness. The damage to RGCs in glaucoma occurs by various mechanisms, including elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, the loss of RGCs leads to vision loss. Therefore, protecting RGCs from damage and promoting their survival are important goals in managing glaucoma. In this regard, resveratrol (RES), a polyphenolic phytoalexin, exerts antioxidant effects and slows down the evolution and progression of glaucoma. The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina. Additionally, RES plays protective roles in RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H2O2-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways. RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway. Therefore, RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.
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Affiliation(s)
- Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Ibrohim B Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers, Tashkent, Uzbekistan
- New Uzbekistan University, Tashkent, Uzbekistan
| | - Mazin A A Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Marim Alwave
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Mozhgan Nazifi
- Department of Neurology, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammadreza Rahmani
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Gervason Moriasi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Mount Kenya University, Thika, Kenya
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7
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Mohamed S, Kundysek W, Vora N, Govande V, Bajwa R, Uddin MN. Diabetic pregnancy: A literature review of maternal and neonatal adverse outcomes. Int J Reprod Biomed 2024; 23:131-140. [PMID: 40371362 PMCID: PMC12070054 DOI: 10.18502/ijrm.v23i2.18482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 12/24/2024] [Accepted: 01/25/2025] [Indexed: 05/16/2025] Open
Abstract
Of all pregnant women in the United States an average of 1.5% reported to have type 1 or type 2 diabetes mellitus. Our review article will discuss and explore the relationship between pre-pregnancy diabetes and its adverse outcomes in mothers and neonates. Diabetes in pregnancy can cause a myriad of complications, many of which are related to microvascular changes, including diabetic nephropathy and retinopathy associated with preterm delivery, cesarean sections, and intrauterine growth restriction. Pregnant patients with diabetes also have an increased risk of pre-eclampsia, likely due to complications related to abnormal structure and function of the placenta. In addition, cardiovascular complications are more common and may present antepartum, intrapartum, or postpartum. Adverse neonatal outcomes that have been observed in diabetic pregnancies include fetal stillbirth and perinatal death, macrosomia, congenital malformations, respiratory distress, and neurological impairments. These complications explain the increased morbidity and mortality rate of infants of diabetic mothers, and the increased frequency of neonatal intensive care unit hospitalizations after birth. Diabetes in pregnancy causes a spectrum of changes in the maternal-fetal interface. This review addresses the placental changes during pregnancy and its adverse maternal and neonatal outcomes. We strongly believe the material discussed in this article can help in understanding the effects of diabetes during pregnancy which will ultimately aid in designing interventions to prevent these adverse outcomes.
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Affiliation(s)
- Sara Mohamed
- Department of Neonatology, Baylor Scott & White Health, Temple, Texas, USA
| | - Waverly Kundysek
- Texas A&M University School of Medicine, College Station, Texas, USA
| | - Niraj Vora
- Department of Neonatology, Baylor Scott & White Health, Temple, Texas, USA
| | - Vinayak Govande
- Department of Neonatology, Baylor Scott & White Health, Temple, Texas, USA
| | - Raza Bajwa
- Department of Neonatology, Baylor Scott & White Health, Temple, Texas, USA
| | - Mohammad Nasir Uddin
- Department of Neonatology, Baylor Scott & White Health, Temple, Texas, USA
- Texas A&M University School of Medicine, College Station, Texas, USA
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8
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Zhong R, Rua MT, Wei-LaPierre L. Targeting mitochondrial Ca 2+ uptake for the treatment of amyotrophic lateral sclerosis. J Physiol 2024; 602:1519-1549. [PMID: 38010626 PMCID: PMC11032238 DOI: 10.1113/jp284143] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/31/2023] [Indexed: 11/29/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non-cell autonomous condition with pathology detected in both MNs and non-neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed.
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Affiliation(s)
- Renjia Zhong
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32611
- Department of Emergency Medicine, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China, 110001
| | - Michael T. Rua
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32611
| | - Lan Wei-LaPierre
- Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, 32611
- Myology Institute, University of Florida, Gainesville, FL 32611
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9
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Lan T, Chen B, Hu X, Cao J, Chen S, Ding X, Li S, Fu Y, Liu H, Luo D, Rong X, Guo J. Tianhuang formula ameliorates liver fibrosis by inhibiting CCL2-CCR2 axis and MAPK/NF-κB signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117516. [PMID: 38042390 DOI: 10.1016/j.jep.2023.117516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/07/2023] [Accepted: 11/25/2023] [Indexed: 12/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In the progression of chronic liver diseases, liver fibrosis is a reversible pathophysiologic event for liver diseases prognosis and risk of cirrhosis. Liver injury factors of different etiologies mediate this process. There is still a lack of effective medications for treating liver fibrosis. Additionally, the ameliorative effects of traditional herbs on liver fibrosis have been commonly reported. Tianhuang formula (THF) is a drug combination consisting of 2 traditional Chinese herbs, which has been showing significant improvement in metabolic liver diseases. However, the hepatoprotective effect and mechanism of THF in ameliorating liver fibrosis are still unclear. AIM OF THE STUDY This study aimed to investigate the effects of THF on carbon tetrachloride (CCl4)-induced and methionine-choline-deficient (MCD) diet-induced liver fibrosis model and to reveal the potential mechanisms. It can provide experimental evidence for THF as a therapeutic candidate for liver fibrosis. MATERIALS AND METHODS In this study, CCl4-induced mice were treated with THF (80 mg/kg, 160 mg/kg) or Fuzheng Huayu (FZHY) capsules (4.8 g/kg) for 6 weeks. MCD-induced mice received the same doses of THF or FZHY for 4 weeks. FZHY is used as a comparative study in these two models. Following that, using kit reagents detected changes in relevant serum and liver biochemical indicators. Histological changes in mouse liver were measured by staining of H&E and Sirius Red. The markers expression of liver fibrosis and inflammation were detected using qRT-PCR, western blotting and immunohistochemical staining analysis. The potential regulatory mechanism of THF to ameliorate liver fibrosis was performed by RNA-sequencing analysis. Finally, the analysis results were verified by immunofluorescence co-staining, qRT-PCR and western blotting. RESULTS Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic triglyceride (TG) levels in CCl4 and MCD-induced liver fibrosis mice were significantly improved after THF treatment. Meanwhile, the expression of fibrosis and inflammation markers were significantly suppressed. Furthermore, THF downregulated the expression of the macrophage marker CD68. According to RNA-sequencing analysis, we found the CCL2-CCR2 axis and MAPK/NF-κB as the potential signaling pathway for THF against liver fibrosis. CONCLUSION This study revealed that THF ameliorated liver injury, inflammation and fibrotic process by inhibiting CCL2-CCR2 axis and its downstream MAPK/NF-κB signaling pathway.
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Affiliation(s)
- Tian Lan
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Bo Chen
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
| | - Xianzhe Hu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
| | - Jiafan Cao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Shiyun Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Xin Ding
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
| | - Shengwen Li
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
| | - Yanfang Fu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Huanle Liu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Duosheng Luo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
| | - Xianglu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou Higher Education Mega Center, Institute of Chinese Medicine, Guangdong Pharmaceutical University, 280 Wai Huan Dong Road, Guangzhou, 510006, China.
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10
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Rahman SMT, Zhou W, Deiters A, Haugh JM. Dissection of MKK6 and p38 Signaling Using Light-Activated Protein Kinases. Chembiochem 2024; 25:e202300551. [PMID: 37856284 DOI: 10.1002/cbic.202300551] [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: 08/04/2023] [Revised: 10/18/2023] [Accepted: 10/18/2023] [Indexed: 10/21/2023]
Abstract
Stress-activated signaling pathways orchestrate cellular behaviors and fates. Studying the precise role(s) of stress-activated protein kinases is challenging, because stress conditions induce adaptation and impose selection pressure. To meet this challenge, we have applied an optogenetic system with a single plasmid to express light-activated p38α or its upstream activator, MKK6, in conjunction with live-cell fluorescence microscopy. In starved cells, decaging of constitutively active p38α or MKK6 by brief exposure to UV light elicits rapid p38-mediated signaling, release of cytochrome c from mitochondria, and apoptosis with different kinetics. In parallel, light activation of p38α also suppresses autophagosome formation, similarly to stimulation with growth factors that activate PI3K/Akt/mTORC1 signaling. Active MKK6 negatively regulates serum-induced ERK activity, which is p38-independent as previously reported. Here, we reproduce that result with the one plasmid system and show that although decaging active p38α does not reduce basal ERK activity in our cells, it can block growth factor-stimulated ERK signaling in serum-starved cells. These results clarify the roles of MKK6 and p38α in dynamic signaling programs, which act in concert to actuate apoptotic death while suppressing cell survival mechanisms.
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Affiliation(s)
- Shah Md Toufiqur Rahman
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, 911 Partners Way, Raleigh, NC, 27695, USA
| | - Wenyuan Zhou
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Alexander Deiters
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Jason M Haugh
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, 911 Partners Way, Raleigh, NC, 27695, USA
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11
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Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther 2023; 8:455. [PMID: 38105263 PMCID: PMC10725898 DOI: 10.1038/s41392-023-01705-z] [Citation(s) in RCA: 203] [Impact Index Per Article: 101.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/03/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023] Open
Abstract
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
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Affiliation(s)
- Md Entaz Bahar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea.
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Al Amin M, Emran TB, Khan J, Zehravi M, Sharma I, Patil A, Gupta JK, Jeslin D, Krishnan K, Das R, Nainu F, Ahmad I, Wilairatana P. Research Progress of Indole Alkaloids: Targeting MAP Kinase Signaling Pathways in Cancer Treatment. Cancers (Basel) 2023; 15:5311. [PMID: 38001572 PMCID: PMC10670446 DOI: 10.3390/cancers15225311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/25/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted.
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Affiliation(s)
- Md. Al Amin
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh;
| | - Talha Bin Emran
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh;
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
| | - Jishan Khan
- Department of Pharmacy, International Islamic University Chittagong, Kumira, Chittagong 4318, Bangladesh
| | - Mehrukh Zehravi
- Department of Clinical Pharmacy, College of Dentistry & Pharmacy, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia;
| | - Indu Sharma
- Department of Physics, Career Point University, Hamirpur 176041, Himachal Pradesh, India
| | - Anasuya Patil
- Department of Pharmaceutics, KLE College of Pharmacy, Bengaluru 560010, Karnataka, India
| | - Jeetendra Kumar Gupta
- Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura 281406, Uttar Pradesh, India;
| | - D. Jeslin
- Department of Pharmaceutics, Sree Balaji Medical College and Hospital Campus, Bharath Institute of Higher Education and Research, Chromepet, Chennai 600044, Tamil Nadu, India
| | - Karthickeyan Krishnan
- Department of Pharmacy Practice, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS), Pallavaram, Chennai 600117, Tamil Nadu, India;
| | - Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
| | - Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia;
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61411, Saudi Arabia
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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13
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Kim JH, Irfan M, Hossain MA, Shin S, George A, Chung S. LPS-induced inflammation potentiates dental pulp stem cell odontogenic differentiation through C5aR and p38. Connect Tissue Res 2023; 64:505-515. [PMID: 37247252 PMCID: PMC10524681 DOI: 10.1080/03008207.2023.2218944] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 04/24/2023] [Accepted: 05/23/2023] [Indexed: 05/31/2023]
Abstract
AIM Inflammation is a complex host response to harmful infection or injury, and it seems to play a crucial role in tissue regeneration both positively and negatively. We have previously demonstrated that the activation of the complement C5a pathway affects dentin-pulp regeneration. However, limited information is available to understand the role of the complement C5a system related to inflammation-mediated dentinogenesis. The aim of this study was to determine the role of complement C5a receptor (C5aR) in regulating lipopolysaccharide (LPS)-induced odontogenic differentiation of dental pulp stem cells (DPSCs). MATERIAL AND METHODS Human DPSCs were subjected to LPS-stimulated odontogenic differentiation in dentinogenic media treated with the C5aR agonist and antagonist. A putative downstream pathway of the C5aR was examined using a p38 mitogen-activated protein kinase (p38) inhibitor (SB203580). RESULTS Our data demonstrated that inflammation induced by the LPS treatment potentiated DPSC odontogenic differentiation and that this is C5aR dependent. C5aR signaling controlled the LPS-stimulated dentinogenesis by regulating the expression of odontogenic lineage markers like dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP-1). Moreover, the LPS treatment increased the total p38, and the active form of p38 expression, and treatment with SB203580 abolished the LPS-induced DSPP and DMP-1 increase. CONCLUSIONS These data suggest a significant role of C5aR and its putative downstream molecule p38 in the LPS-induced odontogenic DPSCs differentiation. This study highlights the regulatory pathway of complement C5aR/p38 and a possible therapeutic approach for improving the efficiency of dentin regeneration during inflammation.
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Affiliation(s)
- Ji-Hyun Kim
- Department of Oral Biology, University of Illinois Chicago, Chicago, IL, USA
| | - Muhammad Irfan
- Department of Oral Biology, University of Illinois Chicago, Chicago, IL, USA
| | - Md Akil Hossain
- Department of Oral Biology, University of Illinois Chicago, Chicago, IL, USA
| | - Susie Shin
- Department of Oral Biology, University of Illinois Chicago, Chicago, IL, USA
| | - Anne George
- Department of Oral Biology, University of Illinois Chicago, Chicago, IL, USA
| | - Seung Chung
- Department of Oral Biology, University of Illinois Chicago, Chicago, IL, USA
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14
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Begum F, Manandhar S, Kumar G, Keni R, Sankhe R, Gurram PC, Beegum F, Teja MS, Nandakumar K, Shenoy RR. Dehydrozingerone promotes healing of diabetic foot ulcers: a molecular insight. J Cell Commun Signal 2023; 17:673-688. [PMID: 36280629 PMCID: PMC10409929 DOI: 10.1007/s12079-022-00703-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION One of the most common problems of diabetes are diabetic foot ulcers (DFUs). According to National Institute for Health, initial management of DFUs can decrease the complication of limb amputations and can improve the patient's quality of life. DFU treatment can be optimized with the help of multidisciplinary approach. Based on many studies, control of glucose levels in blood, antioxidant activity, reduction in cytokine levels, re-epithelialization, collagen formation, migration of fibroblasts are major phases involved in managing DFU. Dehydrozingerone (DHZ), has been known for its anti-inflammatory, antioxidant and wound healing properties. METHODOLOGY Three months high-fat diet and low dose of streptozotocin-induced type-II diabetic foot ulcer model was used to evaluate the effectiveness of dehydrozingerone. DHZ was given orally to rats for 15 days post wounding. TNF-α, IL-1β and antioxidant parameters like lipid peroxidation, glutathione reductase were estimated. Immunoblotting was done to investigate the effect of DHZ on the expression of ERK, JNK, HSP-27, P38, SIRT-1, NFκB, SMA, VEGF and MMP-9 in skin tissue. Histopathology was performed for analyzing DHZ effect on migration of fibroblasts, formation of epithelium, granulation tissue formation, angiogenesis and collagen formation. RESULTS DHZ decreased the levels of malondialdehyde, TNF-α, IL-1β and increased glutathione levels in wound tissue. Western blotting results suggested that DHZ activated ERK1/2/JNK/p38 signaling, increased expression of HSP-27, SIRT-1, VEGF, SMA thus facilitating the migration and proliferation of fibroblasts, angiogenesis and decreased inflammation. Masson Trichrome & histopathology showed an increase in collagen, epithelial and granulation tissue formation. CONCLUSION DHZ significantly accelerates the healing of diabetic foot ulcers in high fat diet fed plus low dose streptozotocin induced type-II diabetic Wistar rats.
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Affiliation(s)
- Farmiza Begum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Suman Manandhar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Gautam Kumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Raghuvir Keni
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Runali Sankhe
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Prasada Chowdari Gurram
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Fathima Beegum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Meka Sai Teja
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Rekha R Shenoy
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Natarajan P, Manne M, Koduru SK, Bokkasam TS. 3-deazaadenosine: A promising novel p38γ antagonist with potential as a breast cancer therapeutic agent. Cancer Treat Res Commun 2023; 36:100744. [PMID: 37481995 DOI: 10.1016/j.ctarc.2023.100744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/07/2023] [Accepted: 07/13/2023] [Indexed: 07/25/2023]
Abstract
Human p38γ protein kinase, or MAPK12, is a crucial signaling protein that is important in channelizing membrane signals to the nucleus in the MAPK cascade pathway, associated with breast and colorectal cancer, besides other forms of malignancies and atherosclerotic lesions too. P38γ has a significant contribution to the progression of breast carcinoma due to its multifaceted functions. Targeting p38γ for defining potent antagonists against p38γ can turn out to be an attractive and novel means of breast cancer therapeutics. Novel and potent lead molecules were designed utilizing computational drug design methodologies. Using high-throughput virtual screening, 1909 geometrically similar analogs of known inhibitors were generated, primarily using BIRB796, SB202190, ANP, CHEBI: 620708, and CHEBI: 524699. Chemical correctness was ensured using LigPrep for the standalone library, and Prep Wizard for p38γ using Maestro v.11.5. Using the Glide v5.5 flexible docking procedure on a standalone library of p38γ binding sites, we defined 18 potential leads and assessed their ADMET properties. Lead "1", among the proposed four p38γ antagonists with high-scoring and favorable interactions, was considered for 100 ns molecular dynamics simulations. Among the four proposed leads, Lead '1' displayed consistent and stable bonding interactions with p38γ throughout the 100 ns molecular dynamics (MD) simulations. Additionally, it formed water bridges, contributing to its strong association with the protein. Notably, Lead '1' (3-deazaadenosine) exhibited favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) within the acceptable range of pharmacological properties. Thus, 3-deazaadenosine and its mimetic might be promising new directions for developing a novel class of antagonists for breast cancer treatment.
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Affiliation(s)
- Pradeep Natarajan
- Bioinformatics Center, Department of Biotechnology, Anna University, Chennai, Tamil Nadu 600025, India.
| | - Munikumar Manne
- Clinical Division, ICMR-National Institute of Nutrition, Jamai-Osmania (Post), Hyderabad, 500007 Telangana, India.
| | - Swetha Kumari Koduru
- Department of Bio-sciences and Sericulture, Sri Padmavati Mahila Visvavidyalayam Women's University, Tirupati, Andhra Pradesh 517502, India
| | - Teja Sree Bokkasam
- Department of Biotechnology, Sri Padmavati Mahila Visvavidyalayam Women's University, Tirupati, Andhra Pradesh 517502, India
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Liu T, Sun Z, Yang Z, Qiao X. Microbiota-derived short-chain fatty acids and modulation of host-derived peptides formation: Focused on host defense peptides. Biomed Pharmacother 2023; 162:114586. [PMID: 36989711 DOI: 10.1016/j.biopha.2023.114586] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/12/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
The byproducts of bacterial fermentation known as short-chain fatty acids (SCFAs) are chemically comprised of a carboxylic acid component and a short hydrocarbon chain. Recent investigations have demonstrated that SCFAs can affect intestinal immunity by inducing endogenous host defense peptides (HDPs) and their beneficial effects on barrier integrity, gut health, energy supply, and inflammation. HDPs, which include defensins, cathelicidins, and C-type lectins, perform a significant function in innate immunity in gastrointestinal mucosal membranes. SCFAs have been demonstrated to stimulate HDP synthesis by intestinal epithelial cells via interactions with G protein-coupled receptor 43 (GPR43), activation of the Jun N-terminal kinase (JNK) and Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways, and the cell growth pathways. Furthermore, SCFA butyrate has been demonstrated to enhance the number of HDPs released from macrophages. SCFAs promote monocyte-to-macrophage development and stimulate HDP synthesis in macrophages by inhibiting histone deacetylase (HDAC). Understanding the etiology of many common disorders might be facilitated by studies into the function of microbial metabolites, such as SCFAs, in the molecular regulatory processes of immune responses (e.g., HDP production). This review will focus on the current knowledge of the role and mechanism of microbiota-derived SCFAs in influencing the synthesis of host-derived peptides, particularly HDPs.
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Nam MW, Lee HK, Kim CW, Choi Y, Ahn D, Go RE, Choi KC. Effects of CCN6 overexpression on the cell motility and activation of p38/bone morphogenetic protein signaling pathways in pancreatic cancer cells. Biomed Pharmacother 2023; 163:114780. [PMID: 37105075 DOI: 10.1016/j.biopha.2023.114780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/17/2023] [Accepted: 04/23/2023] [Indexed: 04/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancer types that is highly resistant to conventional treatments, such as chemotherapy and radiotherapy. As the demand for more effective therapeutics for PDAC treatment increases, various approaches have been studied to develop novel targets. The cellular communication network (CCN) family is a matricellular protein that modulates various cellular functions, including cell adhesion, proliferation, migration, and invasiveness. Despite this, little is known about the role of CCN6 in PDAC. The current study investigated the role of CCN6 in PDAC by generating CCN6-overexpressing PANC-1 cells (PANC-1-CCN6) by infecting lentivirus particles containing CCN6. PANC-1-CCN6 induces cell viability and tumorigenesis than PANC-1 cells with empty vector (control). The PANC-1-CCN6 formed more colonies, and the size of spheroids increased compared to the control. The upregulation of CCN6 enhances the expression of bone morphogenetic proteins (BMPs) genes and the upregulation of p38 mitogen-activated protein kinases (MAPKs). In PANC-1-CCN6 cells, the levels of N-cadherin, VEGF, and Snail expression were higher than the control, while E-cadherin expression was lower, which is associated with upregulation of epithelial-to-mesenchymal transition (EMT). Consistent with the changes in EMT-related proteins in PANC-1-CCN6, the migratory ability and invasiveness were enhanced in PANC-1-CCN6. Xenografted PANC-1-CCN6 in immunocompromised mice exhibited accelerated tumor growth than the control group. In immunohistochemistry (IHC), the PANC-1-CCN6 xenografted tumor showed an increased positive area of PCNA and Ki-67 than the control. These results suggest that CCN6 plays a tumorigenic role and induces the metastatic potential by the p38 MAPK and BMPs signaling pathways. Although the role of CCN6 has been introduced as an antitumor factor, there was evidence of CCN6 acting to cause tumorigenesis and invasion in PANC-1.
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Affiliation(s)
- Min-Woo Nam
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Hong Kyu Lee
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Cho-Won Kim
- Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
| | - Youngdong Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Dohee Ahn
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Ryeo-Eun Go
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, the Republic of Korea.
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Tsuruyama T. Kullback-Leibler Divergence of an Open-Queuing Network of a Cell-Signal-Transduction Cascade. ENTROPY (BASEL, SWITZERLAND) 2023; 25:326. [PMID: 36832692 PMCID: PMC9955153 DOI: 10.3390/e25020326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 02/07/2023] [Accepted: 02/07/2023] [Indexed: 06/18/2023]
Abstract
Queuing networks (QNs) are essential models in operations research, with applications in cloud computing and healthcare systems. However, few studies have analyzed the cell's biological signal transduction using QN theory. This study entailed the modeling of signal transduction as an open Jackson's QN (JQN) to theoretically determine cell signal transduction, under the assumption that the signal mediator queues in the cytoplasm, and the mediator is exchanged from one signaling molecule to another through interactions between the signaling molecules. Each signaling molecule was regarded as a network node in the JQN. The JQN Kullback-Leibler divergence (KLD) was defined using the ratio of the queuing time (λ) to the exchange time (μ), λ/μ. The mitogen-activated protein kinase (MAPK) signal-cascade model was applied, and the KLD rate per signal-transduction-period was shown to be conserved when the KLD was maximized. Our experimental study on MAPK cascade supported this conclusion. This result is similar to the entropy-rate conservation of chemical kinetics and entropy coding reported in our previous studies. Thus, JQN can be used as a novel framework to analyze signal transduction.
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Affiliation(s)
- Tatsuaki Tsuruyama
- Department of Physics, Graduate School of Science, Tohoku University, Sendai 980-8577, Japan;
- Department of Drug and Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
- Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan
- Department of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
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The Soluble Fms-like Tyrosine Kinase-1 Contributes to Structural and Functional Changes in Endothelial Cells in Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms232416059. [PMID: 36555698 PMCID: PMC9787493 DOI: 10.3390/ijms232416059] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Endothelial cells are a critical target of the soluble Fms-like tyrosine kinase-1 (sFlt-1), a soluble factor increased in different diseases with varying degrees of renal impairment and endothelial dysfunction, including chronic kidney disease (CKD). Although the mechanisms underlying endothelial dysfunction are multifactorial and complex, herein, we investigated the damaging effects of sFlt-1 on structural and functional changes in endothelial cells. Our results evidenced that sera from patients with CKD stiffen the endothelial cell cortex in vitro, an effect correlated with sFlt-1 levels and prevented by sFlt-1 neutralization. Besides, we could show that recombinant sFlt-1 leads to endothelial stiffening in vitro and in vivo. This was accompanied by cytoskeleton reorganization and changes in the endothelial barrier function, as observed by increased actin polymerization and endothelial cell permeability, respectively. These results depended on the activation of the p38 MAPK and were blocked by the specific inhibitor SB203580. However, sFlt-1 only minimally affected the expression of stiffness-sensitive genes. These findings bring new insight into the mechanism of action of sFlt-1 and its biological effects that cannot be exclusively ascribed to the regulation of angiogenesis.
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Panteli N, Demertzioglou M, Feidantsis K, Karapanagiotis S, Tsele N, Tsakoniti K, Gkagkavouzis K, Mylonas CC, Kormas KA, Mente E, Antonopoulou E. Advances in understanding the mitogenic, metabolic, and cell death signaling in teleost development: the case of greater amberjack (Seriola dumerili, Risso 1810). FISH PHYSIOLOGY AND BIOCHEMISTRY 2022; 48:1665-1684. [PMID: 36459361 DOI: 10.1007/s10695-022-01146-5] [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: 07/25/2022] [Accepted: 11/16/2022] [Indexed: 06/17/2023]
Abstract
Cell growth and differentiation signals of insulin-like growth factor-1 (IGF-1), a key regulator in embryonic and postnatal development, are mediated through the IGF-1 receptor (IGF-1R), which activates several downstream pathways. The present study aims to address crucial organogenesis and development pathways including Akt, MAPKs, heat shock response, apoptotic and autophagic machinery, and energy metabolism in relation to IGF-1R activation during five developmental stages of reared Seriola dumerili: 1 day prior to hatching fertilized eggs (D-1), hatching day (D0), 3 days post-hatching larvae (D3), 33 (D33) and 46 (D46) days post-hatching juveniles. During both the fertilized eggs stage and larval-to-juvenile transition, IGF-1R/Akt pathway activation may mediate the hypertrophic signaling, while p44/42 MAPK phosphorylation was apparent at S. dumerili post-hatching processes and juvenile organs completion. On the contrary, apoptosis was induced during embryogenesis and autophagy at hatching day indicating a potential involvement in morphogenetic rearrangements and yolk-sac reserves depletion. Larvae morphogenesis was accompanied by a metabolic turnover with increased substantial energy consumption. The findings of the present study demonstrate the developmental stages-specific shift in critical signaling pathways during the ontogeny of reared S. dumerili.
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Affiliation(s)
- Nikolas Panteli
- Laboratory of Animal Physiology, Department of Zoology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Maria Demertzioglou
- Laboratory of Animal Physiology, Department of Zoology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Konstantinos Feidantsis
- Laboratory of Animal Physiology, Department of Zoology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | | | | | | | - Konstantinos Gkagkavouzis
- Department of Genetics, Development and Molecular Biology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
- Genomics and Epigenomics Translational Research (GENeTres), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, Buildings A & B 10th km Thessaloniki-Thermi Rd, P.O. Box 8318, 57001, Thessaloniki, Greece
| | - Constantinos C Mylonas
- Institute of Marine Biology, Biotechnology and Aquaculture, Hellenic Center for Marine Research, P.O. Box 2214, 71003, Heraklion, Crete, Greece
| | - Konstantinos Ar Kormas
- Department of Ichthyology and Aquatic Environment, School of Agricultural Sciences, University of Thessaly, 38446, Volos, Greece
| | - Eleni Mente
- School of Veterinary Medicine, Laboratory of Ichthyology-Culture and Pathology of Aquatic Animals, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Efthimia Antonopoulou
- Laboratory of Animal Physiology, Department of Zoology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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Duan Y, Zhang W, Chen X, Wang M, Zhong L, Liu J, Bian W, Zhang S. Genome-wide identification and expression analysis of mitogen-activated protein kinase (MAPK) genes in response to salinity stress in channel catfish (Ictalurus punctatus). JOURNAL OF FISH BIOLOGY 2022; 101:972-984. [PMID: 35818162 DOI: 10.1111/jfb.15158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
The mitogen-activated protein kinase (MAPK) gene family has been systematically described in several fish species, but less so in channel catfish (Ictalurus punctatus), which is an important global aquaculture species. In this study, 16 MAPK genes were identified in the channel catfish genome and classified into three subfamilies based on phylogenetic analysis, including six extracellular signal regulated kinase (ERK) genes, six p38-MAPK genes and four C-Jun N-terminal kinase (JNK) genes. All MAPK genes were distributed unevenly across 10 chromosomes, of which three (IpMAPK8, IpMAPK12 and IpMAPK14) underwent teleost-specific whole genome duplication during evolution. Gene expression profiles in channel catfish during salinity stress were analysed using transcriptome sequencing and qRT-PCR (quantitative reverse transcription PCR). Results from reads per kilobase million (RPKM) analysis showed IpMAPK13, IpMAPK14a and IpMAPK14b genes were differentially expressed when compared with other genes between treatment and control groups. Furthermore, three of these genes were validated by qRT-PCR, of which IpMAPK14a expression levels were significantly upregulated in treatment groups (high and low salinity) when compared with the control group, with the highest expression levels in the low salinity group (P < 0.05). Therefore, IpMAPK14a may have important response roles to salinity stress in channel catfish.
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Affiliation(s)
- Yongqiang Duan
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Wenping Zhang
- College of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, China
| | - Xiaohui Chen
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
- The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing, China
| | - Minghua Wang
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
- The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing, China
| | - Liqiang Zhong
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
- The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing, China
| | - Ju Liu
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
| | - Wenji Bian
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
- College of Marine Science and Fisheries, Jiangsu Ocean University, Lianyungang, China
- The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing, China
| | - Shiyong Zhang
- National Genetic Breeding Center of Channel Catfish, Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing, China
- The Jiangsu Provincial Platform for Conservation and Utilization of Agricultural Germplasm, Nanjing, China
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Li R, Shu M, Liu X, Nei Z, Ye B, Wang H, Gong Y. Genome-wide identification of mitogen-activated protein kinase (MAPK) gene family in yellow catfish (Pelteobagrus fulviadraco) and their expression profiling under the challenge of Aeromonas hydrophila. JOURNAL OF FISH BIOLOGY 2022; 101:699-710. [PMID: 35751135 DOI: 10.1111/jfb.15141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/19/2022] [Indexed: 06/15/2023]
Abstract
As serine/threonine protein kinases, mitogen-activated protein kinases (MAPK) take part in cellular metabolism. This work found 14 MAPK genes in the yellow catfish (Pelteobagrus fulviadraco) genome and evaluated their taxonomy, conserved domains and evolutionary linkages for a better understanding of the MAPK gene family's evolutionary relationship and antibacterial immune response. The findings revealed that several MAPK genes are activated in response to immunological and inflammatory responses. Collinearity research revealed that in yellow catfish and zebrafish, there are six pairs of highly similar MAPK genes, indicating that these genes have been more conserved throughout evolution. The MAPK gene quantification findings revealed that JNK1a, JNK1b, p38delta and p38alpha b expression levels were considerably upregulated, indicating that they act in fish innate immunity. The findings implied that MAPK genes may involve in defence against detrimental microbe in yellow catfish, which will help researchers better understand how MAPK genes work in the innate immune system.
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Affiliation(s)
- Ronghui Li
- Key Laboratory of Marine Biotechnology of Zhejiang Province, School of Marine Sciences, Ningbo University, Ningbo, China
| | - Mingyu Shu
- Key Laboratory of Marine Biotechnology of Zhejiang Province, School of Marine Sciences, Ningbo University, Ningbo, China
| | - Xuanxuan Liu
- Key Laboratory of Marine Biotechnology of Zhejiang Province, School of Marine Sciences, Ningbo University, Ningbo, China
| | - Zhiwei Nei
- Key Laboratory of Marine Biotechnology of Zhejiang Province, School of Marine Sciences, Ningbo University, Ningbo, China
| | - Ben Ye
- Key Laboratory of Marine Biotechnology of Zhejiang Province, School of Marine Sciences, Ningbo University, Ningbo, China
| | - Heyu Wang
- College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China
| | - Yifu Gong
- Key Laboratory of Marine Biotechnology of Zhejiang Province, School of Marine Sciences, Ningbo University, Ningbo, China
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Tanshinone IIA Accomplished Protection against Radiation-Induced Cardiomyocyte Injury by Regulating the p38/p53 Pathway. Mediators Inflamm 2022; 2022:1478181. [PMID: 36046762 PMCID: PMC9424041 DOI: 10.1155/2022/1478181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/20/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Background Radiotherapy is one of the major strategies for treating tumors, and it inevitably causes damage to relevant tissues and organs during treatment. Radiation-induced heart disease (RIHD) refers to radiation-induced cardiovascular adverse effects caused by thoracic radiotherapy. Currently, there is no uniform standard in the treatment of RIHD. Methods In our group study, by administering a dose of 4 Gy radiation, we established a radiation injured cardiomyocyte model and explored the regulatory relationship between tanshinone IIA and p38 MAPK in cardiomyocyte injury. We assessed cell damage and proliferation using clonogenic assay and lactate dehydrogenase (LDH) release assay. The measures of antioxidant activity and oxidative stress were conducted using superoxide dismutase (SOD) and reactive oxygen species (ROS). The apoptosis rate and the relative expression of apoptotic proteins were conducted using flow cytometry and western blot. To assess p38 and p53 expressions and phosphorylation levels, western blot was performed. Results Experimental results suggested that tanshinone IIA restored cell proliferation in radiation-induced cardiomyocyte injury (∗∗P < 0.01), and the level of LDH release decreased (∗P < 0.05). Meanwhile, tanshinone IIA could decrease the ROS generation induced by radiation (∗∗P < 0.01) and upregulate the SOD level (∗∗P < 0.01). Again, tanshinone IIA reduced radiation-induced cardiomyocyte apoptosis (∗∗P < 0.01). Finally, tanshinone IIA downregulated radiation-induced p38/p53 overexpression (∗∗∗P < 0.001). Conclusions The treatment effects of tanshinone IIA against radiation-induced myocardial injury may be through the regulation of the p38/p53 pathway.
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24
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Lu Y, Liu Y, Zheng M. The role and regulation of apoptosis signal-regulated kinase 1 in liver disease. Mol Biol Rep 2022; 49:10905-10914. [DOI: 10.1007/s11033-022-07783-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 07/06/2022] [Accepted: 07/07/2022] [Indexed: 10/15/2022]
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Zhao Y, Dai J, Jiang Y, Wu H, Cui Y, Li X, Mao H, Wang B, Ju S, Peng XG. Reducing White Adipose Tissue Browning Using p38α MAPK Inhibitors Ameliorates Cancer-Associated Cachexia as Assessed by Magnetic Resonance Imaging. Nutrients 2022; 14:nu14153013. [PMID: 35893867 PMCID: PMC9331061 DOI: 10.3390/nu14153013] [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: 06/13/2022] [Revised: 07/13/2022] [Accepted: 07/20/2022] [Indexed: 11/30/2022] Open
Abstract
Background: Up to 80% of pancreatic cancer patients suffer from cachexia. White adipose tissue (WAT) browning caused by the tumorigenicity and progression aggravates the cancer-associated cachexia (CAC). Cancer-initiated changes in the protein-38 mitogen-activated protein kinases (p38 MAPK) pathway are likely involved in the development of CAC. Methods: p38 MAPK inhibitors, VCP979 or SB203580, were used in the in vitro and in vivo models of pancreatic cancer cachexia. Expression of uncoupling protein 1 (UCP1) in the p38 MARK pathway and the properties and level of white adipocytes were analyzed and correlated to browning, followed by immunohistochemistry and Western blotting validations. Changes in the volume and fat fraction of WAT in animals were monitored by magnetic resonance imaging (MRI). Results: The size of white adipocytes was increased after being treated with the p38 MAPK inhibitors, along with increase in the MRI-measured volume and fat fraction of WAT. Comparing two p38 MAPK inhibitors, the p38α subunit-specific inhibitor VCP979 had a better therapeutic effect than SB203580, which targets both p38α and β subunits. Conclusions: Blockade of p38 MAPK reduced the WAT browning that contributes to CAC. Thus, p38 MARK inhibitors can potentially be used as a therapy for treating CAC. Non-invasive MRI can also be applied to assess the progression and treatment responses of CAC.
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Affiliation(s)
- Yufei Zhao
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Jingyue Dai
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Yang Jiang
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Honghong Wu
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Ying Cui
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Xinxiang Li
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Hui Mao
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30329, USA;
| | - Binghui Wang
- Monash Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia;
| | - Shenghong Ju
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
| | - Xin-Gui Peng
- Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, China; (Y.Z.); (J.D.); (Y.J.); (H.W.); (Y.C.); (X.L.); (S.J.)
- People’s Hospital of Lishui District, 86 Chongwen Road, Yongyang Town, Lishui District, Nanjing 211299, China
- Correspondence: ; Tel.: +86-025-83272115
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Wang J, Chen S, Pan C, Li G, Tang Z. Application of Small Molecules in the Central Nervous System Direct Neuronal Reprogramming. Front Bioeng Biotechnol 2022; 10:799152. [PMID: 35875485 PMCID: PMC9301571 DOI: 10.3389/fbioe.2022.799152] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 06/09/2022] [Indexed: 11/13/2022] Open
Abstract
The lack of regenerative capacity of neurons leads to poor prognoses for some neurological disorders. The use of small molecules to directly reprogram somatic cells into neurons provides a new therapeutic strategy for neurological diseases. In this review, the mechanisms of action of different small molecules, the approaches to screening small molecule cocktails, and the methods employed to detect their reprogramming efficiency are discussed, and the studies, focusing on neuronal reprogramming using small molecules in neurological disease models, are collected. Future research efforts are needed to investigate the in vivo mechanisms of small molecule-mediated neuronal reprogramming under pathophysiological states, optimize screening cocktails and dosing regimens, and identify safe and effective delivery routes to promote neural regeneration in different neurological diseases.
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Affiliation(s)
| | | | | | - Gaigai Li
- *Correspondence: Gaigai Li, ; Zhouping Tang,
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Chan SKN, Suresh S, Munday P, Ravasi T, Bernal MA, Schunter C. The alternative splicing landscape of a coral reef fish during a marine heatwave. Ecol Evol 2022; 12:e8738. [PMID: 35342554 PMCID: PMC8933327 DOI: 10.1002/ece3.8738] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 11/09/2022] Open
Abstract
Alternative splicing is a molecular mechanism that enables a single gene to encode multiple transcripts and proteins by post-transcriptional modification of pre-RNA molecules. Changes in the splicing scheme of genes can lead to modifications of the transcriptome and the proteome. This mechanism can enable organisms to respond to environmental fluctuations. In this study, we investigated patterns of alternative splicing in the liver of the coral reef fish Acanthochromis polyacanthus in response to the 2016 marine heatwave on the Great Barrier Reef. The differentially spliced (DS; n = 40) genes during the onset of the heatwave (i.e., 29.49°C or +1°C from average) were related to essential cellular functions such as the MAPK signaling system, Ca(2+) binding, and homeostasis. With the persistence of the heatwave for a period of one month (February to March), 21 DS genes were detected, suggesting that acute warming during the onset of the heatwave is more influential on alternative splicing than the continued exposure to elevated temperatures. After the heatwave, the water temperature cooled to ~24.96°C, and fish showed differential splicing of genes related to cyto-protection and post-damage recovery (n = 26). Two-thirds of the DS genes detected across the heatwave were also differentially expressed, revealing that the two molecular mechanisms act together in A. polyacanthus to cope with the acute thermal change. This study exemplifies how splicing patterns of a coral reef fish can be modified by marine heatwaves. Alternative splicing could therefore be a potential mechanism to adjust cellular physiological states under thermal stress and aid coral reef fishes in their response to more frequent acute thermal fluctuations in upcoming decades.
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Affiliation(s)
- Stanley Kin Nok Chan
- Swire Institute of Marine ScienceSchool of Biological SciencesThe University of Hong KongHong Kong SARChina
| | - Sneha Suresh
- Swire Institute of Marine ScienceSchool of Biological SciencesThe University of Hong KongHong Kong SARChina
| | - Phillip Munday
- Australian Research Council Centre of Excellence for Coral Reef StudiesJames Cook UniversityTownsvilleQueenslandAustralia
| | - Timothy Ravasi
- Australian Research Council Centre of Excellence for Coral Reef StudiesJames Cook UniversityTownsvilleQueenslandAustralia
- Marine Climate Change UnitOkinawa Institute of Science and Technology Graduate UniversityOnna‐sonJapan
| | - Moisés A. Bernal
- Department of Biological SciencesCollege of Science and MathematicsAuburn UniversityAuburnAlabamaUSA
| | - Celia Schunter
- Swire Institute of Marine ScienceSchool of Biological SciencesThe University of Hong KongHong Kong SARChina
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Er H, Tas GG, Soygur B, Ozen S, Sati L. Acute and Chronic Exposure to 900 MHz Radio Frequency Radiation Activates p38/JNK-mediated MAPK Pathway in Rat Testis. Reprod Sci 2022; 29:1471-1485. [PMID: 35015292 DOI: 10.1007/s43032-022-00844-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 01/01/2022] [Indexed: 10/19/2022]
Abstract
The use of electronic devices such as mobile phones has had a long stretch of rapid growth all over the world. Therefore, exposure to radio frequency radiation (RFR) has increased enormously. Here, we aimed to assess the balance between cell death and proliferation and also investigate the involvement of the JNK/p38 MAPK signaling pathway in the testis of rats exposed to 900 MHz RFR in acute and chronic periods (2 h/day, 5 days/week) for 1 or 10 weeks, respectively. The expression of proliferating cell nuclear antigen (PCNA), Bcl-xL, cleaved caspase-3, phosphorylated-JNK (p-JNK), and phosphorylated-p38 (p-p38) was analyzed in line with histopathology and TUNEL analysis in rat testis. There were no histopathological differences between sham and RFR groups in the acute and chronic groups. PCNA expression was not altered between groups in both periods. However, alterations for cleaved caspase-3 and Bcl-xL were observed depending on the exposure period. TUNEL analysis showed a significant increase in the RFR group in the acute period, whereas no difference in the chronic groups for the apoptotic index was reported. In addition, both p-p38 and p-JNK protein expressions increased significantly in RFR groups in both periods. Our study indicated that 900 MHz RFR might result in alterations during acute period exposure for several parameters, but this can be ameliorated in the chronic period in rat testis. Here, we also report the involvement of the p38/JNK-mediated MAPK pathway after exposure to 900 MHz RFR. Hence, this information might shed light in future studies toward detailed molecular mechanisms in male reproduction and infertility.
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Affiliation(s)
- Hakan Er
- Department of Biophysics, Akdeniz University School of Medicine, Akdeniz University, Antalya, Turkey.,Department of Medical Imaging Techniques, Vocational School of Health Services, Akdeniz University, Antalya, Turkey
| | - Gizem Gamze Tas
- Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey
| | - Bikem Soygur
- Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey.,Department of Obstetrics, Gynecology and Reproductive Sciences, Center for Reproductive Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA
| | - Sukru Ozen
- Department of Electrical and Electronics Engineering, Faculty of Engineering, Akdeniz University, Antalya, Turkey
| | - Leyla Sati
- Department of Histology and Embryology, Akdeniz University School of Medicine, Campus, 07070, Antalya, Turkey.
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Accumulation of acetaldehyde in aldh2.1 zebrafish causes increased retinal angiogenesis and impaired glucose metabolism. Redox Biol 2022; 50:102249. [PMID: 35114580 PMCID: PMC8818574 DOI: 10.1016/j.redox.2022.102249] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/03/2022] [Accepted: 01/21/2022] [Indexed: 01/22/2023] Open
Abstract
Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1−/− animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1−/− zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c-Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1−/− zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase (gck) and glucose-6-phosphatase (g6pc), which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.
ALDH2.1 was compensatory upregulated in glyoxalase 1 zebrafish mutants. Loss of ALDH2.1 increases acetaldehyde leading to vascular retinal alterations. Acetaldehyde controls glucose metabolism via glucose-6-phosphate and glucokinase. Altered JNK and p38 cause microvascular complications.
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Zhao L, Zhang K, He H, Yang Y, Li W, Liu T, Li J. The Relationship Between Mesenchymal Stem Cells and Tumor Dormancy. Front Cell Dev Biol 2021; 9:731393. [PMID: 34712663 PMCID: PMC8545891 DOI: 10.3389/fcell.2021.731393] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor dormancy, a state of tumor, is clinically undetectable and the outgrowth of dormant tumor cells into overt metastases is responsible for cancer-associated deaths. However, the dormancy-related molecular mechanism has not been clearly described. Some researchers have proposed that cancer stem cells (CSCs) and disseminated tumor cells (DTCs) can be seen as progenitor cells of tumor dormancy, both of which can remain dormant in a non-permissive soil/niche. Nowadays, research interest in the cancer biology field is skyrocketing as mesenchymal stem cells (MSCs) are capable of regulating tumor dormancy, which will provide a unique therapeutic window to cure cancer. Although the influence of MSCs on tumor dormancy has been investigated in previous studies, there is no thorough review on the relationship between MSCs and tumor dormancy. In this paper, the root of tumor dormancy is analyzed and dormancy-related molecular mechanisms are summarized. With an emphasis on the role of the MSCs during tumor dormancy, new therapeutic strategies to prevent metastatic disease are proposed, whose clinical application potentials are discussed, and some challenges and prospects of the studies of tumor dormancy are also described.
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Affiliation(s)
- Linxian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Hongyu He
- Operating Theater and Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China
| | - Yongping Yang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Wei Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
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31
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Seo SA, Park HJ, Han MG, Lee R, Kim JS, Park JH, Lee WY, Song H. Fermented Colostrum Whey Upregulates Aquaporin-3 Expression in, and Proliferation of, Keratinocytes via p38/c-Jun N-Terminal Kinase Activation. Food Sci Anim Resour 2021; 41:749-762. [PMID: 34632396 PMCID: PMC8460327 DOI: 10.5851/kosfa.2021.e33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/07/2021] [Accepted: 06/12/2021] [Indexed: 01/03/2023] Open
Abstract
Colostrum, which contains various immune and growth factors, aids wound healing by promoting keratinocyte proliferation. Aquaporins (AQPs) are small, hydrophobic membrane proteins that regulate cellular water retention. However, few studies have examined the effect of processed colostrum whey on AQP-3 expression in human skin cells. Here, we investigated the effect of milk, colostrum, fermented milk, and fermented colostrum whey on AQP-3 expression in keratinocyte HaCaT cells. Concentrations of 100-400 μg/mL of fermented colostrum whey were found to induce HaCaT cell proliferation. AQP-3 was found to be expressed exclusively in HaCaT cells. AQP-3 expression was significantly increased in 100 μg/mL fermented colostrum whey-treated cells compared with that in controls. Moreover, fermented colostrum increased p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, but not ERK1/2 phosphorylation. Thus, our results suggest that fermented colostrum whey increased AQP-3 expression in, and the proliferation of, keratinocytes via JNK and p38 MAPK activation.
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Affiliation(s)
- Sang-Ah Seo
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea
| | - Hyun-Jung Park
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea.,Department of Animal Biotechnology, College of Life Science and Natural Resources, Sangji University, Wonju 26339, Korea
| | - Min-Gi Han
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea
| | - Ran Lee
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea
| | - Ji-Soo Kim
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea
| | - Ji-Hoo Park
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea
| | - Won-Young Lee
- Department of Beef & Dairy Science, Korea National College of Agricultures and Fisheries, Jeonbuk 54874, Korea
| | - Hyuk Song
- Department of Stem Cells and Regenerative Technology, KIT, Konkuk University, Seoul 05029, Korea
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32
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Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways. Biomolecules 2021; 11:biom11101444. [PMID: 34680077 PMCID: PMC8533283 DOI: 10.3390/biom11101444] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/23/2021] [Accepted: 09/30/2021] [Indexed: 12/18/2022] Open
Abstract
Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein-protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein-protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways.
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33
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Genome-Wide Association Study Identifies 12 Loci Associated with Body Weight at Age 8 Weeks in Korean Native Chickens. Genes (Basel) 2021; 12:genes12081170. [PMID: 34440344 PMCID: PMC8394794 DOI: 10.3390/genes12081170] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
Meat from Korean native chickens (KNCs) has high consumer demand; however, slow growth performance and high variation in body weight (BW) of KNCs remain an issue. Genome-wide association study (GWAS) is a powerful method to identify quantitative trait-associated genomic loci. A GWAS, based on a large-scale KNC population, is needed to identify underlying genetic mechanisms related to its growth traits. To identify BW-associated genomic regions, we performed a GWAS using the chicken 60K single nucleotide polymorphism (SNP) panel for 1328 KNCs. BW was measured at 8 weeks of age, from 2018 to 2020. Twelve SNPs were associated with BW at the suggestive significance level (p < 2.95 × 10−5) and located near or within 11 candidate genes, including WDR37, KCNIP4, SLIT2, PPARGC1A, MYOCD and ADGRA3. Gene set enrichment analysis based on the GWAS results at p < 0.05 (1680 SNPs) showed that 32 Gene Ontology terms and two Kyoto Encyclopedia of Genes and Genomes pathways, including regulation of transcription, motor activity, the mitogen-activated protein kinase signaling pathway, and tight junction, were significantly enriched (p < 0.05) for BW-associated genes. These pathways are involved in cell growth and development, related to BW gain. The identified SNPs are potential biomarkers in KNC breeding.
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34
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Brennan CM, Emerson CP, Owens J, Christoforou N. p38 MAPKs - roles in skeletal muscle physiology, disease mechanisms, and as potential therapeutic targets. JCI Insight 2021; 6:e149915. [PMID: 34156029 PMCID: PMC8262482 DOI: 10.1172/jci.insight.149915] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
p38 MAPKs play a central role in orchestrating the cellular response to stress and inflammation and in the regulation of myogenesis. Potent inhibitors of p38 MAPKs have been pursued as potential therapies for several disease indications due to their antiinflammatory properties, although none have been approved to date. Here, we provide a brief overview of p38 MAPKs, including their role in regulating myogenesis and their association with disease progression. Finally, we discuss targeting p38 MAPKs as a therapeutic approach for treating facioscapulohumeral muscular dystrophy and other muscular dystrophies by addressing multiple pathological mechanisms in skeletal muscle.
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Affiliation(s)
| | - Charles P Emerson
- Wellstone Muscular Dystrophy Program, Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Jane Owens
- Rare Disease Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA
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35
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Natani S, Dhople VM, Parveen A, Sruthi KK, Khilar P, Bhukya S, Ummanni R. AMPK/SIRT1 signaling through p38MAPK mediates Interleukin-6 induced neuroendocrine differentiation of LNCaP prostate cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119085. [PMID: 34171447 DOI: 10.1016/j.bbamcr.2021.119085] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/29/2022]
Abstract
Neuroendocrine Prostate Cancer (NEPC) is an aggressive form of androgen independent prostate cancer (AIPC), correlated with therapeutic resistance. Interleukin (IL)-6 promotes proliferation and neuroendocrine differentiation (NED) of androgen dependent LNCaP cells. We treated LNCaP cells with IL-6 and observed for in vitro NED of cells and also expression of NE markers βIII tubulin, neuron-specific enolase (NSE) and chromogranin A (ChA). Here we investigated the proteins and/or pathways involved in NED of LNCaP cells induced by IL-6 and characterized their role in NED of PCa cells. We found that the altered proteins modulated AMPK signaling pathway in NE cells. Remarkably, IL-6 induces NED of LNCaP cells through activation of AMPK and SIRT1 and also both of these are co-regulated while playing a predominant role in NED of LNCaP cells. Of the few requirements of AMPK-SIRT1 activation, increased eNOS is essential for NED by elevating Nitric oxide (NO) levels. Pleiotropic effects of NO ultimately regulate p38MAPK in IL-6 induced NED. Hence, IL-6 induced AMPK-SIRT1 activation eventually transfers its activation signals through p38MAPK for advancing NED of LNCaP cells. Moreover, inactivation of p38MAPK with specific inhibitor (SB203580) attenuated IL-6 induced NED of LNCaP cells. Therefore, IL-6 promotes NED of PCa cells via AMPK/SIRT1/p38MAPK signaling. Finally, targeting AMPK-SIRT1 or p38MAPK in androgen independent PC3 cells with neuroendocrine features reversed their neuroendocrine characteristics. Taken together these novel findings reveal that targeting p38MAPK mitigated NED of PCa cells, and thus it can be a favorable target to overcome progression of NEPC.
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Affiliation(s)
- Sirisha Natani
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Vishnu M Dhople
- Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Asha Parveen
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - K K Sruthi
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Priyanka Khilar
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Supriya Bhukya
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India
| | - Ramesh Ummanni
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Yang KM, Zhu C, Wang L, Cao ST, Yang XF, Gao KG, Jiang ZY. Early supplementation with Lactobacillus plantarum in liquid diet modulates intestinal innate immunity through toll-like receptor 4-mediated mitogen-activated protein kinase signaling pathways in young piglets challenged with Escherichia coli K88. J Anim Sci 2021; 99:6259343. [PMID: 33928383 DOI: 10.1093/jas/skab128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
This study was conducted to investigate the effects of early supplementation during 4 to 18 d of age with Lactobacillus plantarum (LP) in liquid diets on intestinal innate immune response in young piglets infected with enterotoxigenic Escherichia coli (ETEC) K88. Seventy-two barrow piglets at 4 d old were assigned to basal or LP-supplemented liquid diet (5 × 1010 CFU·kg-1). On day 15, piglets from each group were orally challenged with either ETEC K88 (1 × 108 CFU·kg-1) or the same amount of phosphate-buffered saline. The intestinal mucosa, mesenteric lymph node (MLN), and spleen samples were collected on day 18. Here, we found that LP pretreatment significantly decreased the mRNA relative expression of inflammatory cytokines (interleukin [IL]-1β, IL-8, and tumor necrosis factor-α), porcine β-defensin 2 (pBD-2), and mucins (MUC1 and MUC4) in the jejunal mucosa in piglets challenged with ETEC K88 (P < 0.05). Moreover, LP significantly decreased the ileal mucosa mRNA relative expression of IL-8 and MUC4 in young piglets challenged with ETEC K88 (P < 0.05). Furthermore, the piglets of the LP + ETEC K88 group had lower protein levels of IL-8, secretory immunoglobulin A, pBD-2, and MUC4 in the jejunal mucosa than those challenged with ETEC K88 (P < 0.05). Besides, LP supplementation reduced the percentage of gamma/delta T cells receptor (γδTCR) and CD172a+ (SWC3+) cells in MLN and the percentage of γδTCR cells in the spleen of young piglets after the ETEC K88 challenge. Supplementation with LP in liquid diets prevented the upregulated protein abundance of toll-like receptor (TLR) 4, phosphorylation-p38, and phosphorylation-extracellular signal-regulated protein kinases in the jejunal mucosa induced by ETEC K88 (P < 0.05). In conclusion, LP supplementation in liquid diet possesses anti-inflammatory activity and modulates the intestinal innate immunity during the early life of young piglets challenged with ETEC K88, which might be attributed to the suppression of TLR4-mediated mitogen-activated protein kinase signaling pathways. Early supplementation with LP in liquid diets regulates the innate immune response, representing a promising immunoregulation strategy for maintaining intestinal health in weaned piglets.
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Affiliation(s)
- Kuanmin M Yang
- State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed in South China, Ministry of Agriculture and Rural Affairs, Guangdong, China. Key Laboratory of Animal Breeding and Nutrition, Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Institute of Animal Science, China, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P.R. China
| | - Cui Zhu
- School of Life Sciences and Engineering, Foshan University, Foshan 528225, P.R. China
| | - Li Wang
- State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed in South China, Ministry of Agriculture and Rural Affairs, Guangdong, China. Key Laboratory of Animal Breeding and Nutrition, Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Institute of Animal Science, China, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P.R. China
| | - Shuting T Cao
- State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed in South China, Ministry of Agriculture and Rural Affairs, Guangdong, China. Key Laboratory of Animal Breeding and Nutrition, Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Institute of Animal Science, China, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P.R. China
| | - Xuefen F Yang
- State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed in South China, Ministry of Agriculture and Rural Affairs, Guangdong, China. Key Laboratory of Animal Breeding and Nutrition, Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Institute of Animal Science, China, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P.R. China
| | - Kaiguo G Gao
- State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed in South China, Ministry of Agriculture and Rural Affairs, Guangdong, China. Key Laboratory of Animal Breeding and Nutrition, Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Institute of Animal Science, China, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P.R. China
| | - Zongyong Y Jiang
- State Key Laboratory of Livestock and Poultry Breeding, Key Laboratory of Animal Nutrition and Feed in South China, Ministry of Agriculture and Rural Affairs, Guangdong, China. Key Laboratory of Animal Breeding and Nutrition, Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Institute of Animal Science, China, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P.R. China
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Jayawardena TU, Kim HS, Asanka Sanjeewa K, Han EJ, Jee Y, Ahn G, Rho JR, Jeon YJ. Loliolide, isolated from Sargassum horneri; abate LPS-induced inflammation via TLR mediated NF-κB, MAPK pathways in macrophages. ALGAL RES 2021. [DOI: 10.1016/j.algal.2021.102297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease. Int J Mol Sci 2021; 22:ijms22115911. [PMID: 34072862 PMCID: PMC8199025 DOI: 10.3390/ijms22115911] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 01/18/2023] Open
Abstract
Alzheimer's disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington's disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.
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Pancione M, Cerulo L, Remo A, Giordano G, Gutierrez-Uzquiza Á, Bragado P, Porras A. Centrosome Dynamics and Its Role in Inflammatory Response and Metastatic Process. Biomolecules 2021; 11:629. [PMID: 33922633 PMCID: PMC8146599 DOI: 10.3390/biom11050629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 02/05/2023] Open
Abstract
Metastasis is a process by which cancer cells escape from the location of the primary tumor invading normal tissues at distant organs. Chromosomal instability (CIN) is a hallmark of human cancer, associated with metastasis and therapeutic resistance. The centrosome plays a major role in organizing the microtubule cytoskeleton in animal cells regulating cellular architecture and cell division. Loss of centrosome integrity activates the p38-p53-p21 pathway, which results in cell-cycle arrest or senescence and acts as a cell-cycle checkpoint pathway. Structural and numerical centrosome abnormalities can lead to aneuploidy and CIN. New findings derived from studies on cancer and rare genetic disorders suggest that centrosome dysfunction alters the cellular microenvironment through Rho GTPases, p38, and JNK (c-Jun N-terminal Kinase)-dependent signaling in a way that is favorable for pro-invasive secretory phenotypes and aneuploidy tolerance. We here review recent data on how centrosomes act as complex molecular platforms for Rho GTPases and p38 MAPK (Mitogen activated kinase) signaling at the crossroads of CIN, cytoskeleton remodeling, and immune evasion via both cell-autonomous and non-autonomous mechanisms.
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Affiliation(s)
- Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy;
| | - Luigi Cerulo
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy;
| | - Andrea Remo
- Pathology Unit, Mater Salutis Hospital AULSS9, “Scaligera”, 37122 Verona, Italy;
| | - Guido Giordano
- Department of Medical Oncology Unit, University of Foggia, 71122 Foggia, Italy;
| | - Álvaro Gutierrez-Uzquiza
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, 28040 Madrid, Spain; (Á.G.-U.); (P.B.); (A.P.)
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Paloma Bragado
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, 28040 Madrid, Spain; (Á.G.-U.); (P.B.); (A.P.)
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Almudena Porras
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, 28040 Madrid, Spain; (Á.G.-U.); (P.B.); (A.P.)
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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Xu J, Fu C, Li T, Xia X, Zhang H, Wang X, Zhao Y. Protective effect of acorn (Quercus liaotungensis Koidz) on streptozotocin-damaged MIN6 cells and type 2 diabetic rats via p38 MAPK/Nrf2/HO-1 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 266:113444. [PMID: 33027641 DOI: 10.1016/j.jep.2020.113444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 09/18/2020] [Accepted: 09/29/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Acorn obtained from the Quercus liaotungensis Koidz tree is consumed as a Chinese folk medicine for the treatment of diarrhea, abdominal pain, and inflammation, also having strong antioxidant activity and have been utilized for the treatment of diabetes in China. However, its mechanism of action on complications of diabetes and oxidative stress is unclear. AIM OF THE STUDY The purpose of this research was to assess the effects of acorn (Quercus liaotungensis Koidz) ethanol extract (AE) on pancreatic β-cell dysfunction through a streptozotocin (STZ)-damaged mouse normal pancreatic β-cell (MIN6 cell) model in vitro, and by using a high-fat and high-sugar diet with STZ-induced diabetic rat model in vivo to explore the possible mechanism of action against diabetes. MATERIALS AND METHODS MIN6 cells were pretreated with AE (20, 40, 80 μM) for 2 h and then treated with 3 mM STZ for 24 h. Cell viability was measured by MTT assay. The amount of intracellular reactive oxygen species was measured by 2,7-dichlorodi-hydrofluorescein diacetate. The activities of insulin secretion, superoxide dismutase, catalase and glutathione were determined by kits. Sprague Dawley rats were either given normal feed or a high sugar and fat diet for four weeks, followed STZ (25 mg/kg, via i. p.) was given. Rats with fasting blood glucose ≥11.1 mmol/l after one week were deemed to be diabetic. Animals were divided into 5 groups, which received saline (10 mL/kg), metformin (200 mg/kg), or AE at doses of 200 and 400 mg/kg during 4 weeks by oral gavage. Blood samples were used to evaluate hematological and biochemical indicators, and pancreas was removed for post-analysis. Body weight and fasting blood glucose were recorded weekly. The expression levels of Bax, Bcl-2, p38, p-p38, Nrf2 and HO-1 were determined by Western blot. RESULTS Data showed that AE inhibited apoptosis and increased antioxidant level in STZ-induced MIN6 cells. In addition, the AE-administered group lowered blood glucose, increased insulin secretion, and alleviated weight loss in the diabetic rats. Histopathologically, the AE-administered group reduced pancreatic injury by significantly restoring the insulin content in β-islets. It was observed that the anti-diabetic effects of AE were associated with the suppressed the p38 MAPK pathway and actived the Nrf2 pathway. CONCLUSIONS The ameliorative impact of AE on diabetes may be attributed to protection of the function of pancreatic β islets and by improving serum insulin levels, hence reducing the blood glucose, which involved in the p38 MAPK and Nrf2 pathways.
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Affiliation(s)
- Jing Xu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Chaofan Fu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Tao Li
- College of Life Sciences and Biological Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Xiaoyan Xia
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Huixing Zhang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Xude Wang
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Yuqing Zhao
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China; Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Ali EMH, Abdel-Maksoud MS, Hassan RM, Mersal KI, Ammar UM, Se-In C, He-Soo H, Kim HK, Lee A, Lee KT, Oh CH. Design, synthesis and anti-inflammatory activity of imidazol-5-yl pyridine derivatives as p38α/MAPK14 inhibitor. Bioorg Med Chem 2021; 31:115969. [PMID: 33422910 DOI: 10.1016/j.bmc.2020.115969] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/20/2020] [Accepted: 12/21/2020] [Indexed: 01/12/2023]
Abstract
P38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, and COX-2). In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF V600E imidazol-5-yl pyridine inhibitors to inhibit P38α kinase. A group 25 reported P38α kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38α active site. Target compounds were evaluated for their potency against P38α kinase, compounds 11a and 11d were the most potent inhibitors (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokinesTNF-α, 1L-6, and 1L-1β in LPS-induced RAW 264.7 macrophages with IC50 values of 78.03 nM, 17.6 µM and 82.15 nM, respectively. The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC50 values of 0.29 µM and 0.61 µM, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38α kinase.
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Affiliation(s)
- Eslam M H Ali
- Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 12055, Egypt
| | - Mohammed S Abdel-Maksoud
- Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt
| | - Rasha Mohamed Hassan
- Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (NRC), (ID: 60014618), P.O. 12622, Dokki, Giza, Egypt
| | - Karim I Mersal
- Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea
| | - Usama M Ammar
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom
| | - Choi Se-In
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Han He-Soo
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Hee-Kwon Kim
- Department of Nuclear Medicine, Molecular Imaging & Therapeutic Medicine Research Center, Jeonbuk National University Medical School and Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Republic of Korea
| | - Anna Lee
- Department of Chemistry, Hanseo University, Seosan 31962, Republic of Korea
| | - Kyung-Tae Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
| | - Chang-Hyun Oh
- Center for Biomaterials, Korea Institute of Science & Technology (KIST School), Seoul, Seongbuk-gu, 02792, Republic of Korea; University of Science & Technology (UST), Daejeon, Yuseong-gu, 34113, Republic of Korea.
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Huang XF, Gao HW, Lee SC, Chang KF, Tang LT, Tsai NM. Juniperus indica Bertol. extract synergized with cisplatin against melanoma cells via the suppression of AKT/mTOR and MAPK signaling and induction of cell apoptosis. Int J Med Sci 2021; 18:157-168. [PMID: 33390784 PMCID: PMC7738970 DOI: 10.7150/ijms.49423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 10/15/2020] [Indexed: 01/05/2023] Open
Abstract
Juniperus indica Bertol. is an herbal plant that belongs to the genus Juniperus, which is commonly used in traditional medicine to refresh the mind and for diuretic use. However, few studies have reported the function of J. indica Bertol. Hence, this study aimed to investigate the anti-tumor and synergistic potential of J. indica Bertol. extract (JIB extract) for melanoma cells. Our results indicated the anti-melanoma activity of JIB extract. JIB extract induced cell cycle arrest at the G0/G1 phase and decreased cyclin and cdk protein expressions. In addition, AKT/mTOR signaling and MAPK signaling were inhibited by JIB extract to suppress melanoma cell growth and proliferation. Additionally, JIB extract induced B16/F10 cell apoptosis via the caspase cascade. According to the JIB extract's anti-melanoma capacity, to assess the synergistic effects of cisplatin and JIB extract. The results demonstrated that JIB extract combined with cisplatin enhanced the inhibition of cell growth, proliferation, and survival through the obstruction of cell cycle progression and AKT/mTOR and MAPK signaling as well as the induction of cell apoptosis. Collectively, our results indicate that JIB extract showed anti-tumor effects and synergized with cisplatin against B16/F10 cells, indicating the possibility of JIB extract to be developed as adjuvant therapy for melanoma.
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Affiliation(s)
- Xiao-Fan Huang
- Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC.,Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC
| | - Hong-Wei Gao
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan, ROC
| | - Shan-Chih Lee
- Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC.,Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan, ROC
| | - Kai-Fu Chang
- Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC.,Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC
| | - Li-Ting Tang
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC
| | - Nu-Man Tsai
- Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, 40201, Taiwan, ROC.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan, ROC
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Abstract
Obesity is a health condition that has reached pandemic levels and is implicated in the development and progression of type 2 diabetes mellitus, cancer and heart failure. A key characteristic of obesity is the activation of stress-activated protein kinases (SAPKs), such as the p38 and JNK stress kinases, in several organs, including adipose tissue, liver, skeletal muscle, immune organs and the central nervous system. The correct timing, intensity and duration of SAPK activation contributes to cellular metabolic adaptation. By contrast, uncontrolled SAPK activation has been proposed to contribute to the complications of obesity. The stress kinase signalling pathways have therefore been identified as potential targets for the development of novel therapeutic approaches for metabolic syndrome. The past few decades have seen intense research efforts to determine how these kinases are regulated in a cell-specific manner and to define their contribution to the development of obesity and insulin resistance. Several studies have uncovered new and unexpected functions of the non-classical members of both pathways. Here, we provide an overview of the role of SAPKs in metabolic control and highlight important discoveries in the field.
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Affiliation(s)
- Ivana Nikolic
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Magdalena Leiva
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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Battagello D, Dragunas G, Klein M, Ayub AL, Velloso F, Correa R. Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission. Clin Sci (Lond) 2020; 134:2137-2160. [PMID: 32820801 PMCID: PMC7443512 DOI: 10.1042/cs20200904] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023]
Abstract
The highly infective coronavirus disease 19 (COVID-19) is caused by a novel strain of coronaviruses - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - discovered in December 2019 in the city of Wuhan (Hubei Province, China). Remarkably, COVID-19 has rapidly spread across all continents and turned into a public health emergency, which was ultimately declared as a pandemic by the World Health Organization (WHO) in early 2020. SARS-CoV-2 presents similar aspects to other members of the coronavirus family, mainly regarding its genome, protein structure and intracellular mechanisms, that may translate into mild (or even asymptomatic) to severe infectious conditions. Although the mechanistic features underlying the COVID-19 progression have not been fully clarified, current evidence have suggested that SARS-CoV-2 may primarily behave as other β-coronavirus members. To better understand the development and transmission of COVID-19, unveiling the signaling pathways that may be impacted by SARS-CoV-2 infection, at the molecular and cellular levels, is of crucial importance. In this review, we present the main aspects related to the origin, classification, etiology and clinical impact of SARS-CoV-2. Specifically, here we describe the potential mechanisms of cellular interaction and signaling pathways, elicited by functional receptors, in major targeted tissues/organs from the respiratory, gastrointestinal (GI), cardiovascular, renal, and nervous systems. Furthermore, the potential involvement of these signaling pathways in evoking the onset and progression of COVID-19 symptoms in these organ systems are presently discussed. A brief description of future perspectives related to potential COVID-19 treatments is also highlighted.
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Affiliation(s)
- Daniella S. Battagello
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Guilherme Dragunas
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Marianne O. Klein
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Ana L.P. Ayub
- Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Fernando J. Velloso
- Department of Pharmacology, Physiology and Neurosciences, Rutgers-NJMS, Newark, NJ, U.S.A
| | - Ricardo G. Correa
- NCI-Designated Cancer Center, Sanford Burnham Prebys (SBP) Medical Discovery Institute, La Jolla, CA, U.S.A
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Jiménez J, Queralt E, Posas F, de Nadal E. The regulation of Net1/Cdc14 by the Hog1 MAPK upon osmostress unravels a new mechanism regulating mitosis. Cell Cycle 2020; 19:2105-2118. [PMID: 32794416 PMCID: PMC7513861 DOI: 10.1080/15384101.2020.1804222] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
During evolution, cells have developed a plethora of mechanisms to optimize survival in a changing and unpredictable environment. In this regard, they have evolved networks that include environmental sensors, signaling transduction molecules and response mechanisms. Hog1 (yeast) and p38 (mammals) stress-activated protein kinases (SAPKs) are activated upon stress and they drive a full collection of cell adaptive responses aimed to maximize survival. SAPKs are extensively used to learn about the mechanisms through which cells adapt to changing environments. In addition to regulating gene expression and metabolism, SAPKs control cell cycle progression. In this review, we will discuss the latest findings related to the SAPK-driven regulation of mitosis upon osmostress in yeast.
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Affiliation(s)
- Javier Jiménez
- Departament De Ciències Experimentals I De La Salut, Universitat Pompeu Fabra (UPF) , Barcelona, Spain.,Department of Ciències Bàsiques, Facultat De Medicina I Ciències De La Salut, Universitat Internacional De Catalunya , Barcelona, Spain
| | - Ethel Queralt
- Cell Cycle Group, Institut d'Investigacions Biomèdica De Bellvitge (IDIBELL), L'Hospitalet De Llobregat , Barcelona, Spain
| | - Francesc Posas
- Departament De Ciències Experimentals I De La Salut, Universitat Pompeu Fabra (UPF) , Barcelona, Spain.,Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology , 08028 Barcelona, Spain
| | - Eulàlia de Nadal
- Departament De Ciències Experimentals I De La Salut, Universitat Pompeu Fabra (UPF) , Barcelona, Spain.,Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology , 08028 Barcelona, Spain
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Terayama M, Yamada K, Hagiwara T, Inazuka F, Sezaki T, Igari T, Yokoi C, Nohara K, Soma D, Dohi T, Kawamura YI. Glutathione S-transferase omega 2 regulates cell growth and the expression of E-cadherin via post-transcriptional down-regulation of β-catenin in human esophageal squamous cells. Carcinogenesis 2020; 41:875-886. [PMID: 31738399 DOI: 10.1093/carcin/bgz189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 09/05/2019] [Accepted: 11/15/2019] [Indexed: 01/10/2023] Open
Abstract
Glutathione S-transferase omega 2 (GSTO2), which belongs to the superfamily of GST omega class, lacks any appreciable GST activity. Although GSTO2 exhibits thioltransferase and glutathione dehydrogenase activities, its precise expression and physiological functions are still unclear. In the present study, we found that GSTO2 is exclusively expressed in the basal cell layer in Ki67-negative non-proliferative cells in the human esophageal mucosa. GSTO2 overexpression in esophageal squamous cell carcinoma (ESCC) cell lines inhibited cell growth and colony formation, and GSTO2-transfected cells formed smaller tumors in nude mice compared with mock-transfected cells. Interestingly, GSTO2 induction suppressed the expressions of E-cadherin and β-catenin at the cell-cell contact site. We quantified the phosphorylation levels of key proteins of MAPK signaling pathway and identified phosphorylation of p38. Additionally, HSP27, a downstream molecule of p38, was accelerated in GSTO2-transfected cells, unlike in mock-transfected cells. When GSTO2-transfected cells were treated with a p38 inhibitor, the expression of β-catenin and the membrane localization of E-cadherin was recovered. We next examined GSTO2 expression in 61 ESCC tissues using quantitative reverse transcription polymerase chain reaction and immunostaining. The results showed that GSTO2 mRNA and protein were significantly reduced in ESCC compared with normal tissues. When human ESCC cell lines were treated with 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor, GSTO2 transcription was induced, suggesting that aberrant hypermethylation is the cause of the down-regulated expression. Our results indicate that GSTO2 expression inhibits the membrane localization of E-cadherin, probably by modulation of the p38 signaling pathway. Down-regulation of GSTO2 by DNA hypermethylation contributes to the growth and progression of ESCC.
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Affiliation(s)
- Masayoshi Terayama
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.,Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kazuhiko Yamada
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.,Course of Advanced and Specialized Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Teruki Hagiwara
- Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan
| | - Fumika Inazuka
- Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan
| | - Takuhito Sezaki
- Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan
| | - Toru Igari
- Pathology Division of Clinical Laboratory, National Center for Global Health and Medicine, Tokyo, Japan
| | - Chizu Yokoi
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kyoko Nohara
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Daisuke Soma
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Taeko Dohi
- Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan
| | - Yuki I Kawamura
- Department of Gastroenterology, The Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan
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Brown I, Lee J, Sneddon AA, Cascio MG, Pertwee RG, Wahle KWJ, Rotondo D, Heys SD. Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion. Prostaglandins Leukot Essent Fatty Acids 2020; 156:102024. [PMID: 31679810 DOI: 10.1016/j.plefa.2019.102024] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/11/2019] [Accepted: 10/15/2019] [Indexed: 12/16/2022]
Abstract
The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA). Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a). Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins. Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness. Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin β3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment. Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.
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Affiliation(s)
- Iain Brown
- Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
| | - Jisun Lee
- Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
| | - Alan A Sneddon
- Rowett Institute, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
| | - Maria G Cascio
- Translational Neuroscience Research Programme, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
| | - Roger G Pertwee
- Translational Neuroscience Research Programme, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
| | - Klaus W J Wahle
- Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK; Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, G4 0RE, UK.
| | - Dino Rotondo
- Institute of Pharmacy and Biomedical Sciences, Strathclyde University, Glasgow, G4 0RE, UK.
| | - Steven D Heys
- Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
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Yang C, Luo J, Luo X, Jia W, Fang Z, Yi S, Li L. Morusin exerts anti-cancer activity in renal cell carcinoma by disturbing MAPK signaling pathways. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:327. [PMID: 32355771 PMCID: PMC7186639 DOI: 10.21037/atm.2020.02.107] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Background Renal cell carcinoma (RCC) has gradually become a severe type of kidney malignant tumor, which warrants an urgent need for highly efficacious therapeutic agents. Morusin, a typical prenylated flavonoid, has been revealed to possess anticarcinogenic effects against several cancers by inhibiting cell proliferation and tumorigenesis. Methods Cells proliferation was examined by CCK-8. Migration assays were performed using a 24-well transwell chamber. Apoptotic cells were detected using the Annexin V PE/7-AAD apoptosis detection kit. Cell cycle analysis was carried out by flow cytometry. Western blotting and quantitative real time (qRT) PCR were used to exam the change of target gene in mRNA and protein level. Nude mouse xenograft experiments were performed to identify vivo function of morusin. Results Here, we evaluated the effect of morusin against RCC. We treated three RCC cell lines, 769-P, 786-O, and OSRC-2, with morusin to study its effects on cell growth, migration, apoptosis, cell cycle and cancer-related pathways. Additionally, we assessed the effects of morusin on tumor growth using a nude mouse model. Morusin could inhibit cell growth and migration, induce cell apoptosis and downregulate apoptosis-related proteins, and disturb the cell cycle arrest in the G1 phase. Additionally, morusin could suppress RCC tumorigenesis in vivo. Moreover, mitogen-activated protein kinase (MAPK) signal pathways were found to be involved in morusin-induced anti-cancer activity. P-p38 and P-JNK levels were up-regulated by morusin, while the ERK phosphorylation level was down-regulated. Conclusions Our results show that morusin could inhibit the growth of RCC cells in vitro and in vivo through MAPK signal pathways. Thus, morusin could be a potential anti-cancer agent for RCC.
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Affiliation(s)
- Chengfei Yang
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
| | - Jing Luo
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
| | - Xing Luo
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
| | - Weisheng Jia
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
| | - Zhenqiang Fang
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
| | - Shanhong Yi
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
| | - Longkun Li
- Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China
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New 2-amino-pyridinyl-N-acylhydrazones: Synthesis and identification of their mechanism of anti-inflammatory action. Biomed Pharmacother 2020; 123:109739. [PMID: 31918210 DOI: 10.1016/j.biopha.2019.109739] [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: 11/14/2019] [Revised: 12/06/2019] [Accepted: 12/08/2019] [Indexed: 12/18/2022] Open
Abstract
AIMS The main aim of this paper was the synthesis and the evaluation of the anti-inflammatory activity of LASSBio-1828 (an amino-pyridinyl-N-acylhydrazone) and its respective hydrochloride, based on a p38α MAPK inhibitor (LASSBio-1824) previously synthesized by our group. MAIN METHODS The compounds were tested regarding their cell viability effect and on acute models of inflammation such as formalin-induced licking test, cell migration and inflammatory mediators quantification. KEY FINDINGS Treatment with the compounds inhibited p38α, reduced inflammatory pain, cell migration and inflammatory mediators that participate on the MAPK pathway such as TNF-α and IL-1β. SIGNIFICANCE Taken together, these results suggest that the synthesis of the corresponding hydrochloride of LASSBio-1828 enhanced its potency as a p38 inhibitor, and also that this compound could be considered a good anti-inflammatory drug candidate after further studies.
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Yang L, Sun X, Ye Y, Lu Y, Zuo J, Liu W, Elcock A, Zhu S. p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma. Front Oncol 2019; 9:1294. [PMID: 31828036 PMCID: PMC6890821 DOI: 10.3389/fonc.2019.01294] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 11/07/2019] [Indexed: 12/11/2022] Open
Abstract
p38 mitogen-activated protein kinases are signaling molecules with major involvement in cancer. A detailed mechanistic understanding of how p38 MAPK family members function is urgently warranted for cancer targeted therapy. The conformational dynamics of the most common member of p38 MAPK family, p38α, are crucial for its function but poorly understood. Here we found that, unlike in other cancer types, p38α is significantly activated in pancreatic adenocarcinoma samples, suggesting its potential for anti-pancreatic cancer therapy. Using a state of the art supercomputer, Anton, long-timescale (39 μs) unbiased molecular dynamics simulations of p38α show that apo p38α has high structural flexibility in six regions, and reveal potential catalysis mechanism involving a “butterfly” motion. Moreover, in vitro studies show the low-selectivity of the current p38α inhibitors in both human and mouse pancreatic cancer cell lines, while computational solvent mapping identified 17 novel pockets for drug design. Taken together, our study reveals the conformational dynamics and potentially druggable pockets of p38α, which may potentiate p38α-targeting drug development and benefit pancreatic cancer patients.
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Affiliation(s)
- Ling Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaoting Sun
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Ye
- Department of Oral Implantology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School and Hospital of Stomatology, Tongji University, Shanghai, China
| | - Yongtian Lu
- Department of ENT, Second People's Hospital of Shenzhen, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Ji Zuo
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wen Liu
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Adrian Elcock
- Department of Biochemistry, University of Iowa, Iowa City, IA, United States
| | - Shun Zhu
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
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