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Akhigbe R, Oyedokun P, Akhigbe T, Hamed M, Fidelis F, Omole A, Adeogun A, Akangbe M, Oladipo A. The consequences of climate change and male reproductive health: A review of the possible impact and mechanisms. Biochem Biophys Rep 2025; 41:101889. [PMID: 39717849 PMCID: PMC11664087 DOI: 10.1016/j.bbrep.2024.101889] [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: 05/08/2024] [Revised: 09/20/2024] [Accepted: 11/25/2024] [Indexed: 12/25/2024] Open
Abstract
A global decline in male fertility has been reported, and climate change is considered a major cause of this. Climate change refers to long-term shifts in temperatures and weather patterns, and results from greenhouse gas emissions like carbon dioxide and methane that act as a blanket wrapped around the earth, trapping heat and elevating temperatures. Sad to say, the consequences of climatic variation are beyond the dramatic elevated temperature, they include cold stress, increased malnutrition, air pollution, cardiovascular diseases respiratory tract infections, cancer, sexually transmitted infections, mental stress, and heat waves. These negative effects of climate change impair male reproductive function through multiple pathways, like ROS-sensitive signaling, suppression of steroidogenic markers, and direct damage to testicular cells. The present study aimed to describe the impact of the consequences of climate change on male reproductive health with details of the various mechanisms involved. This will provide an in-depth understanding of the pathophysiological and molecular basis of the possible climatic variation-induced decline in male fertility, which will aid in the development of preventive measures to abate the negative effects of climate change on male reproductive function.
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Affiliation(s)
- R.E. Akhigbe
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
| | - P.A. Oyedokun
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
| | - T.M. Akhigbe
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Agronomy, Osun State Univeristy (Ejigbo Campus), Osogbo, Nigeria
| | - M.A. Hamed
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- The Brainwill Laboratory, Osogbo, Osun State, Nigeria
- Department of Medical Laboratory Science, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - F.B. Fidelis
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Biochemistry, Faculty of Life Science, Ahmadu Bello University, Zaria, Kaduna State, Nigeria
| | - A.I. Omole
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Health and Human Physiology, College of Liberal Arts and Sciences, University of Iowa, Iowa, USA
| | - A.E. Adeogun
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
| | - M.D. Akangbe
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
- Department of Nursing, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
| | - A.A. Oladipo
- Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
- Reproductive Biology and Toxicology Research Laboratory, Oasis of Grace Hospital, Osogbo, Osun State, Nigeria
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Zhang F, Zhou Y, Hamada N, Tanaka A, Yokoyama S, Yano S, Matsumoto K, Mano H, Sakurai H. Stress Response Kinase MK2 Induces Non-canonical Activation of EphA2 in EML4-ALK Lung Cancer Cells. Biol Pharm Bull 2025; 48:172-176. [PMID: 40024717 DOI: 10.1248/bpb.b24-00747] [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] [Indexed: 03/04/2025]
Abstract
The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown. We herein clarified that MK2 regulates the RSK-EphA2 axis in ERK-activated echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) lung cancer cells. In addition, an MK2 inhibitor blocked enhancements in cell motility induced by the constitutively activated RSK-EphA2 axis. The present results reveal the importance of MK2 in the ERK-activated non-canonical activation of EphA2.
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Affiliation(s)
- Fang Zhang
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | - Yue Zhou
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | - Naru Hamada
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | - Akihiro Tanaka
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | - Satoru Yokoyama
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
| | - Seiji Yano
- Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Science, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1164, Japan
| | - Kunio Matsumoto
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1164, Japan
- Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
| | - Hiroyuki Mano
- Division of Cellular Signaling, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Hiroaki Sakurai
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
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Ben Messaoud N, López JM. p38α and p38β regulate osmostress-induced apoptosis. J Biol Chem 2025; 301:108061. [PMID: 39653241 PMCID: PMC11757794 DOI: 10.1016/j.jbc.2024.108061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/24/2024] [Accepted: 11/26/2024] [Indexed: 01/07/2025] Open
Abstract
Hyperosmotic shock induces cytochrome c release and caspase-3 activation in Xenopus oocytes. Different signaling pathways engaged by osmostress converge on the mitochondria to trigger cell death. The mitogen-activated protein kinases (MAPKs) JNK1-1 and JNK1-2 are early activated by hyperosmotic shock and sustained activation of both isoforms accelerates the apoptotic program. Indeed, sustained activation of p38 accelerates osmostress-induced cell death, but the p38 isoforms involved are not well characterized. Here we study the expression and activation of Xenopus p38 isoforms in response to hyperosmotic stress. We find that p38α, p38β, and p38γ are early activated by hyperosmotic shock and sustained activation of p38α and p38β accelerates osmostress-induced apoptosis. Moreover, microinjection of cytochrome c in the oocytes induces caspase-3 activation and p38α and p38β phosphorylation suggesting that caspases and kinases are interlinked in a positive feedback loop to promote cell death. In summary, we present a more complete view of the mechanisms involved in osmostress-induced apoptosis.
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Affiliation(s)
- Nabil Ben Messaoud
- Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultad de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain
| | - José M López
- Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultad de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain.
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Kwan I, Karim R, Seeliger MA. Inhibiting p38α MAPK signaling: A balancing act in treating inflammation. J Pharmacol Exp Ther 2024; 392:100039. [PMID: 39969270 DOI: 10.1016/j.jpet.2024.100039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/24/2024] [Indexed: 02/20/2025] Open
Affiliation(s)
- Isabelle Kwan
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York; Renaissance School of Medicine, Stony Brook University, Stony Brook, New York
| | - Raisa Karim
- Renaissance School of Medicine, Stony Brook University, Stony Brook, New York
| | - Markus A Seeliger
- Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, New York; Renaissance School of Medicine, Stony Brook University, Stony Brook, New York; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York.
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Gaestel M. The enigma of small heat shock protein phosphorylation. Front Pharmacol 2024; 15:1486245. [PMID: 39508045 PMCID: PMC11538052 DOI: 10.3389/fphar.2024.1486245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 10/15/2024] [Indexed: 11/08/2024] Open
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Detka J, Płachtij N, Strzelec M, Manik A, Sałat K. p38α Mitogen-Activated Protein Kinase-An Emerging Drug Target for the Treatment of Alzheimer's Disease. Molecules 2024; 29:4354. [PMID: 39339348 PMCID: PMC11433989 DOI: 10.3390/molecules29184354] [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: 08/10/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/30/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment.
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Affiliation(s)
- Jan Detka
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland; (J.D.); (N.P.); (A.M.)
| | - Natalia Płachtij
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland; (J.D.); (N.P.); (A.M.)
| | - Martyna Strzelec
- Department of Transplantation, Institute of Pediatrics, Faculty of Medicine, Jagiellonian University Medical College, 265 Wielicka St., 30-663 Krakow, Poland;
| | - Aleksandra Manik
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland; (J.D.); (N.P.); (A.M.)
| | - Kinga Sałat
- Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland; (J.D.); (N.P.); (A.M.)
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Bommaraju S, Dhokne MD, Arun EV, Srinivasan K, Sharma SS, Datusalia AK. An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry 2024; 131:110943. [PMID: 38228244 DOI: 10.1016/j.pnpbp.2024.110943] [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: 08/05/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/18/2024]
Abstract
Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders.
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Affiliation(s)
- Sumadhura Bommaraju
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India
| | - Mrunali D Dhokne
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India
| | - E V Arun
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India
| | - Krishnamoorthy Srinivasan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab 160062, India
| | - Ashok Kumar Datusalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Uttar Pradesh (UP) 226002, India; Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Uttar Pradesh (UP) 226002, India.
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Lechuga S, Marino-Melendez A, Naydenov NG, Zafar A, Braga-Neto MB, Ivanov AI. Regulation of Epithelial and Endothelial Barriers by Molecular Chaperones. Cells 2024; 13:370. [PMID: 38474334 PMCID: PMC10931179 DOI: 10.3390/cells13050370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction-cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known regulators of protein folding and complex formation in different cellular compartments. Mammalian cells possess an elaborate chaperone network consisting of several hundred chaperones and co-chaperones. Only a small part of this network has been linked, however, to the regulation of intercellular adhesions, and the systematic analysis of chaperone functions at epithelial and endothelial barriers is lacking. This review describes the functions and mechanisms of the chaperone-assisted regulation of intercellular junctions. The major focus of this review is on heat shock protein chaperones, their co-chaperones, and chaperonins since these molecules are the focus of the majority of the articles published on the chaperone-mediated control of tissue barriers. This review discusses the roles of chaperones in the regulation of the steady-state integrity of epithelial and vascular barriers as well as the disruption of these barriers by pathogenic factors and extracellular stressors. Since cytoskeletal coupling is essential for junctional integrity and remodeling, chaperone-assisted assembly of the actomyosin cytoskeleton is also discussed.
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Affiliation(s)
- Susana Lechuga
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.L.); (A.M.-M.); (N.G.N.); (A.Z.); (M.B.B.-N.)
| | - Armando Marino-Melendez
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.L.); (A.M.-M.); (N.G.N.); (A.Z.); (M.B.B.-N.)
| | - Nayden G. Naydenov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.L.); (A.M.-M.); (N.G.N.); (A.Z.); (M.B.B.-N.)
| | - Atif Zafar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.L.); (A.M.-M.); (N.G.N.); (A.Z.); (M.B.B.-N.)
| | - Manuel B. Braga-Neto
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.L.); (A.M.-M.); (N.G.N.); (A.Z.); (M.B.B.-N.)
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Andrei I. Ivanov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.L.); (A.M.-M.); (N.G.N.); (A.Z.); (M.B.B.-N.)
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Cai E, Zeng R, Feng R, Zhang L, Li L, Jia H, Zheng W, Chen S, Yan M, Chang C. Discovery of N-Benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine as a Potential Antifungal Agent against Sporidia Growth and Teliospore Germination of Sporisorium scitamineum. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:3325-3333. [PMID: 38329286 DOI: 10.1021/acs.jafc.3c04589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
The cultivation of sugar cane using perennial roots is the primary planting method, which is one of the reasons for the serious occurrence of sugar cane smut disease caused by the basidiomycetous fungus Sporisorium scitamineum in the sugar cane perennial root planting area. Consequently, it is crucial to eliminate pathogens from perennial sugar cane buds. In this study, we found that MAP kinase Hog1 is necessary for heat stress resistance. Subsequent investigations revealed a significant reduction in the expression of the heat shock protein 104-encoding gene, SsHSP104, in the ss1hog1Δ mutant. Additionally, the overexpression of SsHSP104 partially restored colony growth in the ss1hog1Δ strain following heat stress treatment, demonstrating the crucial role of SsHsp104 in SsHog1-mediated heat stress tolerance. Hence, we constructed the ss1hsp104:eGFP fusion strain in the wild type of S. scitamineum to identify small-molecule compounds that could inhibit the heat stress response, leading to the discovery of N-benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine as a potential compound that targets the SsHog1 mediation SsHsp104 pathway during heat treatment. Furthermore, the combination of N-benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine and warm water treatment (45 °C for 15 min) inhibits the growth of S. scitamineum and teliospore germination, thereby reducing the occurrence of sugar cane smut diseases and indicating its potential for eliminating pathogens from perennial sugar cane buds. In conclusion, these findings suggest that N-benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine is promising as a targeted compound for the SsHog1-mediated SsHsp104 pathway and may enable the reduction of hot water treatment duration and/or temperature, thereby limiting the occurrence of sugar cane smut diseases caused by S. scitamineum.
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Affiliation(s)
- Enping Cai
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Rong Zeng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Ruqing Feng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Li Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Lei Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Huan Jia
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Wenqiang Zheng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Shaofang Chen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
| | - Meixin Yan
- Sugarcane Research Institute, Guangxi Academy of Agricultural Sciences, Nanning 530000, China
| | - Changqing Chang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou 510642, Guangdong, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou 510642, China
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Kumar M, Kaur S, Kaur S. c-Jun N-terminal Kinase (JNK), p38, and Caspases: Promising Therapeutic
Targets for the Regulation of Apoptosis in Cancer Cells by Phytochemicals. CURRENT CANCER THERAPY REVIEWS 2024; 20:200-211. [DOI: 10.2174/1573394719666230817094831] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 04/29/2023] [Accepted: 06/21/2023] [Indexed: 01/04/2025]
Abstract
Abstract:
Carcinogenesis is a process in which uncontrolled cell proliferation forms preneoplastic
nodules which precede the appearance of cancer. In normal cells, growth and proliferation are regulated
by certain growth and hormonal stimulation, while mutational alterations in these signals render
the cells independent and resistant to these signals. In cancer, the critical homeostatic balance between
cell growth and apoptosis is lost and the cells continue to survive beyond their normal life
span. The activation of c-Jun N-terminal kinase (JNK), p38 and caspases are involved in potential
proapoptotic signaling pathways. JNK, p38 MAPK pathway and caspases play a crucial role in the
control of apoptosis in response to stress. The most recent and up-to-date literature was evaluated in
this study, which describes the role of JNK, p38 MAPK pathway and caspases as therapeutic target in
cancer. Chemotherapy uses drugs that are cytotoxic to highly proliferating tumor cells but also kills
the non-tumor rapidly proliferating cells in the hair, skin and gastrointestinal tract epithelium, thereby
accounting the side effects of these types of treatments. Recently, chemopreventive modalities derived
from phytoconstituents present in plants provide a broad-spectrum strategy to overcome the
incidence of cancer. Non-toxic, safe and affordable bioavailabilities of chemopreventive agents provide
credence support in the field of cancer research compared to conventional therapies that cause
serious consequences. Chemoprevention envisages the basic mechanisms like modulating the activity
of xenobiotic-metabolizing enzymes, induction of apoptosis, immune system activation, suppressing
angiogenesis and the formation of metastasis, antioxidant and anti-inflammatory properties. The present
review highlighted the role of phytoconstituents derived from food, vegetables and medicinal
plants in the induction of apoptosis in cancer cells, which in turn is mediated by the activation of
JNK, p38 MAPK pathways, and caspases.
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Affiliation(s)
| | - Satwinderjeet Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev
University, Amritsar- 143005, Punjab, India
| | - Sandeep Kaur
- Department of Botanical and Environmental Sciences, Guru Nanak Dev
University, Amritsar- 143005, Punjab, India
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Abi Nahed R, Safwan-Zaiter H, Gemy K, Lyko C, Boudaud M, Desseux M, Marquette C, Barjat T, Alfaidy N, Benharouga M. The Multifaceted Functions of Prion Protein (PrP C) in Cancer. Cancers (Basel) 2023; 15:4982. [PMID: 37894349 PMCID: PMC10605613 DOI: 10.3390/cancers15204982] [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: 08/04/2023] [Revised: 09/23/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
The cellular prion protein (PrPC) is a glycoprotein anchored to the cell surface by glycosylphosphatidylinositol (GPI). PrPC is expressed both in the brain and in peripheral tissues. Investigations on PrPC's functions revealed its direct involvement in neurodegenerative and prion diseases, as well as in various physiological processes such as anti-oxidative functions, copper homeostasis, trans-membrane signaling, and cell adhesion. Recent findings have revealed the ectopic expression of PrPC in various cancers including gastric, melanoma, breast, colorectal, pancreatic, as well as rare cancers, where PrPC promotes cellular migration and invasion, tumor growth, and metastasis. Through its downstream signaling, PrPC has also been reported to be involved in resistance to chemotherapy and tumor cell apoptosis. This review summarizes the variance of expression of PrPC in different types of cancers and discusses its roles in their development and progression, as well as its use as a potential target to treat such cancers.
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Affiliation(s)
- Roland Abi Nahed
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Hasan Safwan-Zaiter
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Kevin Gemy
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Camille Lyko
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Mélanie Boudaud
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Morgane Desseux
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Christel Marquette
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Tiphaine Barjat
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Nadia Alfaidy
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
| | - Mohamed Benharouga
- U1292, Laboratoire de BioSanté, Institut National de la Santé et de la Recherche Médicale (INSERM), F-38058 Grenoble, France; (R.A.N.); (H.S.-Z.); (K.G.); (C.L.); (M.B.); (M.D.); (C.M.); (T.B.); (N.A.)
- Commissariat à l’Energie Atomique (CEA), DSV-IRIG, F-38054 Grenoble, France
- University of Grenoble Alpes (UGA), F-38058 Grenoble, France
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12
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Boyd RA, Majumder S, Stiban J, Mavodza G, Straus AJ, Kempelingaiah SK, Reddy V, Hannun YA, Obeid LM, Senkal CE. The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation. Cell Rep 2023; 42:113081. [PMID: 37689067 PMCID: PMC10591768 DOI: 10.1016/j.celrep.2023.113081] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/24/2023] [Accepted: 08/18/2023] [Indexed: 09/11/2023] Open
Abstract
Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.
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Affiliation(s)
- Rowan A Boyd
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA
| | - Saurav Majumder
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA
| | - Johnny Stiban
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA; Department of Biology and Biochemistry, Birzeit University, Ramallah, Palestine
| | - Grace Mavodza
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA
| | - Alexandra J Straus
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA
| | - Sachin K Kempelingaiah
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA
| | - Varun Reddy
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Yusuf A Hannun
- Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Lina M Obeid
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Northport Veterans Affairs Medical Center, Northport, NY 11768, USA
| | - Can E Senkal
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23398, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23398, USA.
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13
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Melamed Kadosh D, Beenstock J, Engelberg D, Admon A. Differential Modulation of the Phosphoproteome by the MAP Kinases Isoforms p38α and p38β. Int J Mol Sci 2023; 24:12442. [PMID: 37569817 PMCID: PMC10419006 DOI: 10.3390/ijms241512442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
The p38 members of the mitogen-activated protein kinases (MAPKs) family mediate various cellular responses to stress conditions, inflammatory signals, and differentiation factors. They are constitutively active in chronic inflammatory diseases and some cancers. The differences between their transient effects in response to signals and the chronic effect in diseases are not known. The family is composed of four isoforms, of which p38α seems to be abnormally activated in diseases. p38α and p38β are almost identical in sequence, structure, and biochemical and pharmacological properties, and the specific unique effects of each of them, if any, have not yet been revealed. This study aimed to reveal the specific effects induced by p38α and p38β, both when transiently activated in response to stress and when chronically active. This was achieved via large-scale proteomics and phosphoproteomics analyses using stable isotope labeling of two experimental systems: one, mouse embryonic fibroblasts (MEFs) deficient in each of these p38 kinases and harboring either an empty vector or vectors expressing p38αWT, p38βWT, or intrinsically active variants of these MAPKs; second, induction of transient stress by exposure of MEFs, p38α-/-, and p38β-/- MEFs to anisomycin. Significant differences in the repertoire of the proteome and phosphoproteome between cells expressing active p38α and p38β suggest distinct roles for each kinase. Interestingly, in both cases, the constitutive activation induced adaptations of the cells to the chronic activity so that known substrates of p38 were downregulated. Within the dramatic effect of p38s on the proteome and phosphoproteome, some interesting affected phosphorylation sites were those found in cancer-associated p53 and Hspb1 (HSP27) proteins and in cytoskeleton-associated proteins. Among these, was the stronger direct phosphorylation by p38α of p53-Ser309, which was validated on the Ser315 in human p53. In summary, this study sheds new light on the differences between chronic and transient p38α and p38β signaling and on the specific targets of these two kinases.
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Affiliation(s)
| | - Jonah Beenstock
- Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel;
| | - David Engelberg
- Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel;
- Singapore-HUJ Alliance for Research and Enterprise, Mechanisms of Liver Inflammatory Diseases Program, National University of Singapore, Singapore 138602, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Arie Admon
- Faculty of Biology, Technion—Israel Institute of Technology, Haifa 3200003, Israel;
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14
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Raghavan B, Paulikat M, Ahmad K, Callea L, Rizzi A, Ippoliti E, Mandelli D, Bonati L, De Vivo M, Carloni P. Drug Design in the Exascale Era: A Perspective from Massively Parallel QM/MM Simulations. J Chem Inf Model 2023; 63:3647-3658. [PMID: 37319347 PMCID: PMC10302481 DOI: 10.1021/acs.jcim.3c00557] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Indexed: 06/17/2023]
Abstract
The initial phases of drug discovery - in silico drug design - could benefit from first principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, yet many applications are currently limited by the short time scales that this approach can cover. Developing scalable first principle QM/MM MD interfaces fully exploiting current exascale machines - so far an unmet and crucial goal - will help overcome this problem, opening the way to the study of the thermodynamics and kinetics of ligand binding to protein with first principle accuracy. Here, taking two relevant case studies involving the interactions of ligands with rather large enzymes, we showcase the use of our recently developed massively scalable Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework (currently using DFT to describe the QM region) to investigate reactions and ligand binding in enzymes of pharmacological relevance. We also demonstrate for the first time strong scaling of MiMiC-QM/MM MD simulations with parallel efficiency of ∼70% up to >80,000 cores. Thus, among many others, the MiMiC interface represents a promising candidate toward exascale applications by combining machine learning with statistical mechanics based algorithms tailored for exascale supercomputers.
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Affiliation(s)
- Bharath Raghavan
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
- Department
of Physics, RWTH Aachen University, Aachen 52074, Germany
| | - Mirko Paulikat
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
| | - Katya Ahmad
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
| | - Lara Callea
- Department
of Earth and Environmental Sciences, University
of Milano-Bicocca, Piazza della Scienza 1, 20126 Milan, Italy
| | - Andrea Rizzi
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
- Atomistic
Simulations, Italian Institute of Technology, Genova 16163, Italy
| | - Emiliano Ippoliti
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
| | - Davide Mandelli
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
| | - Laura Bonati
- Department
of Earth and Environmental Sciences, University
of Milano-Bicocca, Piazza della Scienza 1, 20126 Milan, Italy
| | - Marco De Vivo
- Molecular
Modelling and Drug Discovery, Italian Institute
of Technology, Genova 16163, Italy
| | - Paolo Carloni
- Computational
Biomedicine, Institute of Advanced Simulations IAS-5/Institute for
Neuroscience and Medicine INM-9, Forschungszentrum
Jülich GmbH, Jülich 52428, Germany
- Department
of Physics and Universitätsklinikum, RWTH Aachen University, Aachen 52074, Germany
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15
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Yuan PP, Li M, Zhang Q, Zeng MN, Ke YY, Wei YX, Fu Y, Zheng XK, Feng WS. 2-phenylacetamide Separated from the seed of Lepidium apetalum Willd. inhibited renal fibrosis via MAPK pathway mediated RAAS and oxidative stress in SHR Rats. BMC Complement Med Ther 2023; 23:207. [PMID: 37353787 DOI: 10.1186/s12906-023-04012-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 05/25/2023] [Indexed: 06/25/2023] Open
Abstract
BACKGROUND Renal fibrosis with Renin-angiotensin-aldosterone system (RAAS) activation and oxidative stress are one of the major complications in hypertension. 2-phenylacetamide (PA), a major active component of Lepidium apetalum Willd. (L.A), has numerous pharmacological effects. Its analogues have the effect of anti-renal fibrosis and alleviating renal injury. This study aims to explore the underlying mechanism of PA for regulating the renal fibrosis in SHR based on the MAPK pathway mediated RAAS and oxidative stress. METHODS The SHR rats were used as the hypertension model, and the WKY rats were used as the control group. The blood pressure (BP), urine volume were detected every week. After PA treatment for 4 weeks, the levels of RAAS, inflammation and cytokines were measured by Enzyme-Linked Immunosorbnent Assay (ELISA). Hematoxylin-Eosin staining (HE), Masson and Immunohistochemistry (IHC) were used to observe the renal pathology, collagen deposition and fibrosis. Western blot was used to examine the MAPK pathway in renal. Finally, the SB203580 (p38 MAPK inhibitor) antagonism assay in the high NaCl-induced NRK52e cells was used, together with In-Cell Western (ICW), Flow Cytometry (FCM), High Content Screening (HCS) and ELISA to confirm the potential pharmacological mechanism. RESULTS PA reduced the BP, RAAS, inflammation and cytokines, promoted the urine, and relieved renal pathological injury and collagen deposition, repaired renal fibrosis, decreased the expression of NADPH Oxidase 4 (NOX4), transforming growth factor-β (TGF-β), SMAD3 and MAPK signaling pathway in SHR rats. Meanwhile,,the role of PA could be blocked by p38 antagonist SB203580 effectively in the high NaCl-induced NRK52e cells. Moreover, molecular docking indicated that PA occupied the ligand binding sites of p38 MAPK. CONCLUSION PA inhibited renal fibrosis via MAPK signalling pathway mediated RAAS and oxidative stress in SHR Rats.
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Affiliation(s)
- Pei-Pei Yuan
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China
| | - Meng Li
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China
| | - Qi Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Meng-Nan Zeng
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China
| | - Ying-Ying Ke
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China
| | - Ya-Xin Wei
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Yang Fu
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xiao-Ke Zheng
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Wei-Sheng Feng
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
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16
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Fernandez A, Monsen PJ, Platanias LC, Schiltz GE. Medicinal chemistry approaches to target the MNK-eIF4E axis in cancer. RSC Med Chem 2023; 14:1060-1087. [PMID: 37360400 PMCID: PMC10285747 DOI: 10.1039/d3md00121k] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/08/2023] [Indexed: 06/28/2023] Open
Abstract
Aberrant translation of proteins that promote cell proliferation is an essential factor that defines oncogenic processes and cancer. The process for ribosomal translation of proteins from mRNA requires an essential initiation step which is controlled by the protein eIF4E, which binds the RNA 5'-cap and forms the eIF4F complex that subsequently translates protein. Typically, eIF4E is activated by phosphorylation on Ser209 by MNK1 and MNK2 kinases. Substantial work has shown that eIF4E and MNK1/2 are dysregulated in many cancers and this axis has therefore become an active area of interest for developing new cancer therapeutics. This review summarizes and discusses recent work to develop small molecules that target different steps in the MNK-eIF4E axis as potential cancer therapeutics. The aim of this review is to cover the breadth of different molecular approaches being taken and the medicinal chemistry basis for their optimization and testing as new cancer therapeutics.
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Affiliation(s)
- Ann Fernandez
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
| | - Paige J Monsen
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
| | - Leonidas C Platanias
- Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago IL 60611 USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center Chicago IL 60612 USA
| | - Gary E Schiltz
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
- Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA
- Department of Pharmacology, Northwestern University Feinberg School of Medicine Chicago IL 60611 USA
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17
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Sularz O, Koronowicz A, Smoleń S, Boycott C, Stefanska B. Iodine-Biofortified Lettuce Can Promote Mitochondrial Dependent Pathway of Apoptosis in Human Gastrointestinal Cancer Cells. Int J Mol Sci 2023; 24:9869. [PMID: 37373017 PMCID: PMC10298746 DOI: 10.3390/ijms24129869] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 05/31/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Previously, our research provided evidence that exposure of gastric and colon cancer cells to extracts from iodine-biofortified lettuce leads to a reduction of cell viability and proliferation through cell cycle arrest and upregulation of pro-apoptotic genes. The aim of the present study was to determine the potential cellular mechanisms of induction of cell death in human gastrointestinal cancer cell lines after treatment with iodine-biofortified lettuce. We demonstrated that extracts from lettuce enriched with iodine induce apoptosis in gastric AGS and colon HT-29 cancer cells and the mechanism of programmed cell death may be triggered and executed through different signaling pathways, depending on the type of cells. Western blot analysis revealed that iodine-fortified lettuce leads to cell death through the release of cytochrome c to the cytosolic fraction and activation of the primary drivers of apoptosis: caspase-3, caspase-7, and caspase-9. Furthermore, we have reported that apoptotic effects of lettuce extracts may be mediated by poly (ADP-ribose) polymerase (PARP) and activation of pro-apoptotic Bcl-2 family proteins such as Bad, Bax, and BID. We also observed mitochondrial dysfunction with the dissipation of the mitochondrial membrane potential in cells exposed to lettuce extracts. Taken together, these results indicate that the organic form of iodine such as 5-ISA and 3,5-diISA is an important factor in the activation of intrinsic mitochondrial apoptotic pathway in AGS and HT-29 cancer cells in a p53-independent manner.
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Affiliation(s)
- Olga Sularz
- Department of Human Nutrition and Dietetics, Faculty of Food Technology, University of Agriculture in Krakow, Balicka 122, 31-149 Krakow, Poland;
| | - Aneta Koronowicz
- Department of Human Nutrition and Dietetics, Faculty of Food Technology, University of Agriculture in Krakow, Balicka 122, 31-149 Krakow, Poland;
| | - Sylwester Smoleń
- Department of Plant Biology and Biotechnology, Faculty of Biotechnology and Horticulture, University of Agriculture in Krakow, Al. 29 Listopada 54, 31-425 Krakow, Poland;
| | - Cayla Boycott
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC V6T 1Z4, Canada;
| | - Barbara Stefanska
- Food, Nutrition and Health Program, Faculty of Land and Food Systems, The University of British Columbia, 2205 East Mall, Vancouver, BC V6T 1Z4, Canada;
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18
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Shnayder NA, Ashkhotov AV, Trefilova VV, Nurgaliev ZA, Novitsky MA, Petrova MM, Narodova EA, Al-Zamil M, Chumakova GA, Garganeeva NP, Nasyrova RF. Molecular Basic of Pharmacotherapy of Cytokine Imbalance as a Component of Intervertebral Disc Degeneration Treatment. Int J Mol Sci 2023; 24:ijms24097692. [PMID: 37175399 PMCID: PMC10178334 DOI: 10.3390/ijms24097692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Intervertebral disc degeneration (IDD) and associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. With age, IDD progresses, leading to spondylosis, spondylarthrosis, herniated disc, spinal canal stenosis. One of the leading mechanisms in the development of IDD and chronic back pain is an imbalance between pro-inflammatory and anti-inflammatory cytokines. However, classical therapeutic strategies for correcting cytokine imbalance in IDD do not give the expected response in more than half of the cases. The purpose of this review is to update knowledge about new and promising therapeutic strategies based on the correction of the molecular mechanisms of cytokine imbalance in patients with IDD. This review demonstrates that knowledge of the molecular mechanisms of the imbalance between pro-inflammatory and anti-inflammatory cytokines may be a new key to finding more effective drugs for the treatment of IDD in the setting of acute and chronic inflammation.
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Affiliation(s)
- Natalia A Shnayder
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Azamat V Ashkhotov
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
| | - Vera V Trefilova
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Zaitun A Nurgaliev
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Maxim A Novitsky
- Department of Neurology, Hospital for War Veterans, 193079 Saint Petersburg, Russia
| | - Marina M Petrova
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Ekaterina A Narodova
- Shared Core Facilities "Molecular and Cell Technologies", V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia
| | - Mustafa Al-Zamil
- Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples' Friendship University of Russia, 117198 Moscow, Russia
| | - Galina A Chumakova
- Department of Therapy and General Medical Practice with a Course of Postgraduate Professional Education, Altai State Medical University, 656038 Barnaul, Russia
| | - Natalia P Garganeeva
- Department of General Medical Practice and Outpatient Therapy, Siberian State Medical University, 634050 Tomsk, Russia
| | - Regina F Nasyrova
- Institute of Personalized Psychiatry and Neurology, Shared Core Facilities, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, 443016 Samara, Russia
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19
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Zhou Y, Oki R, Tanaka A, Song L, Takashima A, Hamada N, Yokoyama S, Yano S, Sakurai H. Cellular stress induces non-canonical activation of the receptor tyrosine kinase EphA2 through the p38-MK2-RSK signaling pathway. J Biol Chem 2023; 299:104699. [PMID: 37059179 DOI: 10.1016/j.jbc.2023.104699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/16/2023] Open
Abstract
The receptor tyrosine kinase EphA2 is overexpressed in malignant tumors. We previously reported that non-canonical EphA2 phosphorylation at Ser-897 was catalyzed by p90 ribosomal S6 kinase (RSK) via the MEK-ERK pathway in ligand- and tyrosine kinase-independent manners. Non-canonical EphA2 activation plays a key role in tumor progression; however, its activation mechanism remains unclear. In the present study, we focused on cellular stress signaling as a novel inducer of non-canonical EphA2 activation. p38, instead of ERK in the case of epidermal growth factor signaling, activated RSK-EphA2 under cellular stress conditions, including anisomycin, cisplatin and high osmotic stress. Notably, p38 activated the RSK-EphA2 axis via downstream MAPK-activated protein kinase 2 (MK2). Furthermore, MK2 directly phosphorylated both RSK1 Ser-380 and RSK2 Ser-386, critical residues for the activation of their N-terminal kinases, which is consistent with the result showing that the C-terminal kinase domain of RSK1 was dispensable for MK2-mediated EphA2 phosphorylation. Moreover, the p38-MK2-RSK-EphA2 axis promoted glioblastoma cell migration induced by temozolomide, a chemotherapeutic agent for the treatment of glioblastoma patients. Collectively, the present results reveal a novel molecular mechanism for non-canonical EphA2 activation under stress conditions in the tumor microenvironment.
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Affiliation(s)
- Yue Zhou
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Ryota Oki
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Akihiro Tanaka
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Leixin Song
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Atsushi Takashima
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Naru Hamada
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Satoru Yokoyama
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Takara-Machi, Kanazawa, Ishikawa 920-0934, Japan
| | - Hiroaki Sakurai
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama; Toyama 930-0194, Japan.
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20
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Mager CE, Mormol JM, Shelton ED, Murphy PR, Bowman BA, Barley TJ, Wang X, Linn SC, Liu K, Nelin LD, Hafner M, Liu Y. p38 MAPK and MKP-1 control the glycolytic program via the bifunctional glycolysis regulator PFKFB3 during sepsis. J Biol Chem 2023; 299:103043. [PMID: 36803959 PMCID: PMC10025163 DOI: 10.1016/j.jbc.2023.103043] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 02/10/2023] [Accepted: 02/11/2023] [Indexed: 02/19/2023] Open
Abstract
Hyperlactatemia often occurs in critically ill patients during severe sepsis/septic shock and is a powerful predictor of mortality. Lactate is the end product of glycolysis. While hypoxia due to inadequate oxygen delivery may result in anaerobic glycolysis, sepsis also enhances glycolysis under hyperdynamic circulation with adequate oxygen delivery. However, the molecular mechanisms involved are not fully understood. Mitogen-activated protein kinase (MAPK) families regulate many aspects of the immune response during microbial infections. MAPK phosphatase (MKP)-1 serves as a feedback control mechanism for p38 and JNK MAPK activities via dephosphorylation. Here, we found that mice deficient in Mkp-1 exhibited substantially enhanced expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) 3, a key enzyme that regulates glycolysis following systemic Escherichia coli infection. Enhanced PFKFB3 expression was observed in a variety of tissues and cell types, including hepatocytes, macrophages, and epithelial cells. In bone marrow-derived macrophages, Pfkfb3 was robustly induced by both E. coli and lipopolysaccharide, and Mkp-1 deficiency enhanced PFKFB3 expression with no effect on Pfkfb3 mRNA stability. PFKFB3 induction was correlated with lactate production in both WT and Mkp-1-/- bone marrow-derived macrophage following lipopolysaccharide stimulation. Furthermore, we determined that a PFKFB3 inhibitor markedly attenuated lactate production, highlighting the critical role of PFKFB3 in the glycolysis program. Finally, pharmacological inhibition of p38 MAPK, but not JNK, substantially attenuated PFKFB3 expression and lactate production. Taken together, our studies suggest a critical role of p38 MAPK and MKP-1 in the regulation of glycolysis during sepsis.
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Affiliation(s)
- Carli E Mager
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Justin M Mormol
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Evan D Shelton
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Parker R Murphy
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Bridget A Bowman
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Timothy J Barley
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Xiantao Wang
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, Maryland, USA
| | - Sarah C Linn
- Combined Anatomic Pathology Residency/Graduate Program, Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA; Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kevin Liu
- The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Leif D Nelin
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Markus Hafner
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, Maryland, USA
| | - Yusen Liu
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
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21
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Mondru AK, Aljasir MA, Alrumayh A, Nithianandarajah GN, Ahmed K, Muller J, Goldring CEP, Wilm B, Cross MJ. VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells. Cells 2023; 12:967. [PMID: 36980305 PMCID: PMC10047687 DOI: 10.3390/cells12060967] [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: 02/01/2023] [Revised: 03/02/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival.
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Affiliation(s)
- Anil Kumar Mondru
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Mohammad A. Aljasir
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Ahmed Alrumayh
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Gopika N. Nithianandarajah
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Katie Ahmed
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Jurgen Muller
- Cardiovascular Research Group, School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Christopher E. P. Goldring
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK
| | - Michael J. Cross
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GE, UK
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22
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Dan Y, Radic N, Gay M, Fernández-Torras A, Arauz G, Vilaseca M, Aloy P, Canovas B, Nebreda A. Characterization of p38α signaling networks in cancer cells using quantitative proteomics and phosphoproteomics. Mol Cell Proteomics 2023; 22:100527. [PMID: 36894123 PMCID: PMC10105487 DOI: 10.1016/j.mcpro.2023.100527] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023] Open
Abstract
p38α (encoded by MAPK14) is a protein kinase that regulates cellular responses to almost all types of environmental and intracellular stresses. Upon activation, p38α phosphorylates many substrates both in the cytoplasm and nucleus, allowing this pathway to regulate a wide variety of cellular processes. While the role of p38α in the stress response has been widely investigated, its implication in cell homeostasis is less understood. To investigate the signaling networks regulated by p38α in proliferating cancer cells, we performed quantitative proteomic and phosphoproteomic analyses in breast cancer cells in which this pathway had been either genetically targeted or chemically inhibited. Our study identified with high confidence 35 proteins and 82 phosphoproteins (114 phosphosites) that are modulated by p38α, and highlighted the implication of various protein kinases, including MK2 and mTOR, in the p38α-regulated signaling networks. Moreover, functional analyses revealed an important contribution of p38α to the regulation of cell adhesion, DNA replication and RNA metabolism. Indeed, we provide experimental evidence supporting that p38α facilitates cancer cell adhesion, and showed that this p38α function is likely mediated by the modulation of the adaptor protein ArgBP2. Collectively, our results illustrate the complexity of the p38α regulated signaling networks, provide valuable information on p38α-dependent phosphorylation events in cancer cells, and document a mechanism by which p38α can regulate cell adhesion.
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Affiliation(s)
- Yuzhen Dan
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Nevenka Radic
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Marina Gay
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Adrià Fernández-Torras
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Gianluca Arauz
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Marta Vilaseca
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - Patrick Aloy
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
| | - Begoña Canovas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
| | - AngelR Nebreda
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain.
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23
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Bolat N, Erzurumlu Y, Aşcı H, Özmen Ö, Üreyen Kaya B. Selenium ameliorates inflammation by decreasing autophagic flux and mitogen-activated protein kinase signalling on experimentally induced rat periapical lesions. Int Endod J 2023; 56:227-244. [PMID: 36314140 DOI: 10.1111/iej.13861] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 11/05/2022]
Abstract
AIM To reveal the molecular mechanisms that targets mitogen-activated protein kinase (MAPK) signalling and the autophagic flux and to investigate the possible effects of the systemic administration of selenium (Se) on experimentally induced rat periapical lesions. METHODOLOGY Thirty adult Sprague-Dawley rats were divided equally into negative control, positive control and Se groups. In the positive control and Se groups, the pulp chambers of their mandibular first molars were exposed to the oral environment to induce periapical lesions The Se group received daily intraperitoneal injections of Se at a dose of 0.1 mg kg-1 . After 28 days, the amount of bone destruction; severity of inflammation; penetration of microorganisms along the root canal; collagen degradation in periodontal ligament; interleukin (IL)-6, hypoxia-inducible factor-1 (HIF-1), cyclooxygenase-2 (COX-2) and caspase-3 expression; autophagic flux; and p38 MAPK signalling were evaluated using radiographic, histopathological, Gram staining, picrosirius red stain, immunohistochemical, quantitative real-time polymerase chain (qRT-PCR) and Western blot methods, respectively. These data were analysed through the Kruskal-Wallis and Dunnett's tests (p < .05). RESULTS The area of radiographic periapical bone loss, histopathological scores, the area of periapical bone loss and the scores for the bacteria localisation, the intensity of immunohistochemical staining for IL-6, HIF-1, COX-2 and caspase-3 in the Se group was significantly less than those of the positive control group (p < .01). The mRNA expression levels of Beclin-1, Atg3, Atg5, Atg7 and Atg16L1 were lower in the Se group than in the positive control group (p < .01). The protein expressions of Beclin-1, Atg5 and LC3-II, the phosphorylation ratio of the p38 MAPK and the ratios of LC3II/LC3I were significantly higher (p < .05) in the positive control and Se groups. On the contrary, the expression of the p62/SQSTM1 protein was significantly lower (p < .05) in the positive control and Se groups than in the negative control group. CONCLUSION The induction of periapical lesions in rats increased autophagic flux and activated p38 MAPK signal transduction processes. Se suppressed the inflammatory process, reduced bone destruction and both the autophagic flux and p38 MAPK activation.
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Affiliation(s)
- Nergiz Bolat
- Department of Endodontics, Faculty of Dentistry, Suleyman Demirel University, Isparta, Turkey
| | - Yalçin Erzurumlu
- Department of Biochemistry, Faculty of Pharmacy, Suleyman Demirel University, Isparta, Turkey
| | - Halil Aşcı
- Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey
| | - Özlem Özmen
- Department of Pathology, Faculty of Veterinary, Mehmet Akif Ersoy University, Burdur, Turkey
| | - Bulem Üreyen Kaya
- Department of Endodontics, Faculty of Dentistry, Suleyman Demirel University, Isparta, Turkey
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24
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García-Flores N, Jiménez-Suárez J, Garnés-García C, Fernández-Aroca DM, Sabater S, Andrés I, Fernández-Aramburo A, Ruiz-Hidalgo MJ, Belandia B, Sanchez-Prieto R, Cimas FJ. P38 MAPK and Radiotherapy: Foes or Friends? Cancers (Basel) 2023; 15:861. [PMID: 36765819 PMCID: PMC9913882 DOI: 10.3390/cancers15030861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/16/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Over the last 30 years, the study of the cellular response to ionizing radiation (IR) has increased exponentially. Among the various signaling pathways affected by IR, p38 MAPK has been shown to be activated both in vitro and in vivo, with involvement in key processes triggered by IR-mediated genotoxic insult, such as the cell cycle, apoptosis or senescence. However, we do not yet have a definitive clue about the role of p38 MAPK in terms of radioresistance/sensitivity and its potential use to improve current radiotherapy. In this review, we summarize the current knowledge on this family of MAPKs in response to IR as well as in different aspects related to radiotherapy, such as their role in the control of REDOX, fibrosis, and in the radiosensitizing effect of several compounds.
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Affiliation(s)
- Natalia García-Flores
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Jaime Jiménez-Suárez
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Cristina Garnés-García
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Diego M. Fernández-Aroca
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Sebastia Sabater
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Ignacio Andrés
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - Antonio Fernández-Aramburo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, 02006 Albacete, Spain
| | - María José Ruiz-Hidalgo
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Borja Belandia
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
| | - Ricardo Sanchez-Prieto
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC-UAM), Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, 28029 Madrid, Spain
- Departamento de Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
| | - Francisco J. Cimas
- Laboratorio de Oncología Molecular, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
- Departamento de Química Inorgánica, Orgánica y Bioquímica, Área de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Castilla-La Mancha, 02008 Albacete, Spain
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25
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Tan T, Wu C, Liu B, Pan BF, Hawke DH, Su Z, Liu S, Zhang W, Wang R, Lin SH, Kuang J. Revisiting the multisite phosphorylation that produces the M-phase supershift of key mitotic regulators. Mol Biol Cell 2022; 33:ar115. [PMID: 35976701 PMCID: PMC9635296 DOI: 10.1091/mbc.e22-04-0118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 07/11/2022] [Accepted: 08/10/2022] [Indexed: 11/11/2022] Open
Abstract
The term M-phase supershift denotes the phosphorylation-dependent substantial increase in the apparent molecular weight of numerous proteins of varied biological functions during M-phase induction. Although the M-phase supershift of multiple key mitotic regulators has been attributed to the multisite phosphorylation catalyzed by the Cdk1/cyclin B/Cks complex, this view is challenged by multiple lines of paradoxical observations. To solve this problem, we reconstituted the M-phase supershift of Xenopus Cdc25C, Myt1, Wee1A, APC3, and Greatwall in Xenopus egg extracts and characterized the supershift-producing phosphorylations. Our results demonstrate that their M-phase supershifts are each due to simultaneous phosphorylation of a considerable portion of S/T/Y residues in a long intrinsically disordered region that is enriched in both S/T residues and S/TP motifs. Although the major mitotic kinases in Xenopus egg extracts, Cdk1, MAPK, Plx1, and RSK2, are able to phosphorylate the five mitotic regulators, they are neither sufficient nor required to produce the M-phase supershift. Accordingly, inhibition of the four major mitotic kinase activities in Xenopus oocytes did not inhibit the M-phase supershift in okadaic acid-induced oocyte maturation. These findings indicate that the M-phase supershift is produced by a previously unrecognized category of mitotic phosphorylation that likely plays important roles in M-phase induction.
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Affiliation(s)
- Tan Tan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
- Department of Biochemistry and Molecular Biology, Hengyang Medical School, The University of South China, Hengyang, Hunan 421001, China
| | - Chuanfen Wu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Boye Liu
- Key Laboratory for Biodiversity and Ecological Engineering of Ministry of Education
| | - Bih-Fang Pan
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - David H. Hawke
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Zehao Su
- Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Shuaishuai Liu
- Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Wei Zhang
- Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Ruoning Wang
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Sue-Hwa Lin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Jian Kuang
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
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26
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Oldach L. A Bona Fide MAP Kinase. J Biol Chem 2022; 298:102432. [PMID: 36037971 PMCID: PMC9513259 DOI: 10.1016/j.jbc.2022.102432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/21/2022] Open
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Jiménez-Andrade Y, Hillette KR, Yoshida T, Kashiwagi M, Choo MK, Liang Y, Georgopoulos K, Park JM. The Developmental Transcription Factor p63 Is Redeployed to Drive Allergic Skin Inflammation through Phosphorylation by p38α. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:2613-2621. [PMID: 35623662 PMCID: PMC9308733 DOI: 10.4049/jimmunol.2101160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/03/2022] [Indexed: 06/15/2023]
Abstract
Keratinocytes, the epithelial cells of the skin, reprogram their gene expression and produce immune effector molecules when exposed to environmental and endogenous triggers of inflammation. It remains unclear how keratinocytes process physiological signals generated during skin irritation and switch from a homeostatic to an inflammatory state. In this article, we show that the stress-activated protein kinase p38α is crucial for keratinocytes to prompt changes in their transcriptome upon cytokine stimulation and drive inflammation in allergen-exposed skin. p38α serves this function by phosphorylating p63, a transcription factor essential for the lineage identity and stemness of the skin epithelium. Phosphorylation by p38α alters the activity of p63 and redeploys this developmental transcription factor to a gene expression program linked to inflammation. Genetic ablation and pharmacological inhibition of p38α or the p38α-p63 target gene product MMP13 attenuate atopic dermatitis-like disease in mice. Our study reveals an epithelial molecular pathway promoting skin inflammation and actionable through treatment with topical small-molecule therapeutics.
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Affiliation(s)
- Yanek Jiménez-Andrade
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Kathryn R Hillette
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Toshimi Yoshida
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan; and
| | - Mariko Kashiwagi
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Min-Kyung Choo
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Yinming Liang
- School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Katia Georgopoulos
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - Jin Mo Park
- Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA;
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Small Molecule Arranged Thermal Proximity Co aggregation (smarTPCA)-A Novel Approach to Characterize Protein-Protein Interactions in Living Cells by Similar Isothermal Dose-Responses. Int J Mol Sci 2022; 23:ijms23105605. [PMID: 35628420 PMCID: PMC9147192 DOI: 10.3390/ijms23105605] [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: 03/31/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 11/17/2022] Open
Abstract
Chemical biology and the application of small molecules has proven to be a potent perturbation strategy, especially for the functional elucidation of proteins, their networks, and regulators. In recent years, the cellular thermal shift assay (CETSA) and its proteome-wide extension, thermal proteome profiling (TPP), have proven to be effective tools for identifying interactions of small molecules with their target proteins, as well as off-targets in living cells. Here, we asked the question whether isothermal dose-response (ITDR) CETSA can be exploited to characterize secondary effects downstream of the primary binding event, such as changes in post-translational modifications or protein-protein interactions (PPI). By applying ITDR-CETSA to MAPK14 kinase inhibitor treatment of living HL-60 cells, we found similar dose-responses for the direct inhibitor target and its known interaction partners MAPKAPK2 and MAPKAPK3. Extension of the dose-response similarity comparison to the proteome wide level using TPP with compound concentration range (TPP-CCR) revealed not only the known MAPK14 interaction partners MAPKAPK2 and MAPKAPK3, but also the potentially new intracellular interaction partner MYLK. We are confident that dose-dependent small molecule treatment in combination with ITDR-CETSA or TPP-CCR similarity assessment will not only allow discrimination between primary and secondary effects, but will also provide a novel method to study PPI in living cells without perturbation by protein modification, which we named "small molecule arranged thermal proximity coaggregation" (smarTPCA).
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G-protein Biased Signaling Agonists of Dopamine D3 Receptor Promote Distinct Activation Patterns of ERK1/2. Pharmacol Res 2022; 179:106223. [DOI: 10.1016/j.phrs.2022.106223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/31/2022] [Accepted: 04/10/2022] [Indexed: 01/11/2023]
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Niu J, Holland SM, Ketschek A, Collura KM, Hesketh NL, Hayashi T, Gallo G, Thomas GM. Palmitoylation couples the kinases DLK and JNK3 to facilitate prodegenerative axon-to-soma signaling. Sci Signal 2022; 15:eabh2674. [PMID: 35349303 DOI: 10.1126/scisignal.abh2674] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Dual leucine-zipper kinase (DLK; a MAP3K) mediates neuronal responses to diverse injuries and insults through the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs). Here, we identified two ways through which DLK is coupled to the neural-specific isoform JNK3 to control prodegenerative signaling. JNK3 catalyzed positive feedback phosphorylation of DLK that further activated DLK and locked the DLK-JNK3 module in a highly active state. Neither homologous MAP3Ks nor a homologous MAPK could support this positive feedback loop. Unlike the related JNK1 isoform JNK2 and JNK3 promote prodegenerative axon-to-soma signaling and were endogenously palmitoylated. Moreover, palmitoylation targeted both DLK and JNK3 to the same axonal vesicles, and JNK3 palmitoylation was essential for axonal retrograde signaling in response to optic nerve crush injury in vivo. These findings provide previously unappreciated insights into DLK-JNK signaling relevant to neuropathological conditions and answer long-standing questions regarding the selective prodegenerative roles of JNK2 and JNK3.
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Affiliation(s)
- Jingwen Niu
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
| | - Sabrina M Holland
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
| | - Andrea Ketschek
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
| | - Kaitlin M Collura
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
| | - Natasha L Hesketh
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA
| | - Takashi Hayashi
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central6 (6-10), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan
| | - Gianluca Gallo
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.,Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USA
| | - Gareth M Thomas
- Shriners Hospitals Pediatric Research Center (Center for Neurorehabilitation and Neural Repair), Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA.,Department of Neural Sciences, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA 19140, USA
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31
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Weighted correlation network analysis revealed novel long non-coding RNAs for colorectal cancer. Sci Rep 2022; 12:2990. [PMID: 35194111 PMCID: PMC8863977 DOI: 10.1038/s41598-022-06934-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 02/07/2022] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, which after breast, lung and, prostate cancers, is the fourth prevalent cancer in the United States. Long non-coding RNAs (lncRNAs) have an essential role in the pathogenesis of CRC. Therefore, bioinformatics studies on lncRNAs and their target genes have potential importance as novel biomarkers. In the current study, publicly available microarray gene expression data of colorectal cancer (GSE106582) was analyzed with the Limma, Geoquery, Biobase package. Afterward, identified differentially expressed lncRNAs and their target genes were inserted into Weighted correlation network analysis (WGCNA) to obtain modules and hub genes. A total of nine differentially expressed lncRNAs (LINC01018, ITCH-IT, ITPK1-AS1, FOXP1-IT1, FAM238B, PAXIP1-AS1, ATP2B1-AS1, MIR29B2CHG, and SNHG32) were identified using microarray data analysis. The WGCNA has identified several hub genes for black (LMOD3, CDKN2AIPNL, EXO5, ZNF69, BMS1P5, METTL21A, IL17RD, MIGA1, CEP19, FKBP14), blue (CLCA1, GUCA2A, UGT2B17, DSC2, CA1, AQP8, ITLN1, BEST4, KLF4, IQCF6) and turquoise (PAFAH1B1, LMNB1, CACYBP, GLO1, PUM3, POC1A, ASF1B, SDCCAG3, ASNS, PDCD2L) modules. The findings of the current study will help to improve our understanding of CRC. Moreover, the hub genes that we have identified could be considered as possible prognostic/diagnostic biomarkers. This study led to the determination of nine lncRNAs with no previous association with CRC development.
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Abstract
Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the cross talk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Natalia Ronkina
- Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany;
| | - Matthias Gaestel
- Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany;
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Kumar A, Joishy T, Das S, Kalita MC, Mukherjee AK, Khan MR. A Potential Probiotic Lactobacillus plantarum JBC5 Improves Longevity and Healthy Aging by Modulating Antioxidative, Innate Immunity and Serotonin-Signaling Pathways in Caenorhabditis elegans. Antioxidants (Basel) 2022; 11:268. [PMID: 35204151 PMCID: PMC8868178 DOI: 10.3390/antiox11020268] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 12/19/2022] Open
Abstract
Since the hypothesis of Dr. Elie Metchnikoff on lactobacilli-mediated healthy aging, several microbes have been reported to extend the lifespan with different features of healthy aging. However, a microbe affecting diverse features of healthy aging is of choice for broader acceptance and marketability as a next-generation probiotic. We employed Caenorhabditis elegans as a model to understand the potential of Lactobacillus plantarum JBC5 (LPJBC5), isolated from fermented food sample on longevity and healthy aging as well as their underlying mechanisms. Firstly, LPJBC5 enhanced the mean lifespan of C. elegans by 27.81% compared with control (untreated). LPBC5-induced longevity was accompanied with better aging-associated biomarkers, such as physical functions, fat, and lipofuscin accumulation. Lifespan assay on mutant worms and gene expression studies indicated that LPJBC5-mediated longevity was due to upregulation of the skinhead-1 (skn-1) gene activated through p38 MAPK signaling cascade. Secondly, the activated transcription factor SKN-1 upregulated the expression of antioxidative, thermo-tolerant, and anti-pathogenic genes. In support, LPJBC5 conferred resistance against abiotic and biotic stresses such as oxidative, heat, and pathogen. LPJBC5 upregulated the expression of intestinal tight junction protein ZOO-1 and improved gut integrity. Thirdly, LPJBC5 improved the learning and memory of worms trained on LPJBC5 compared with naive worms. The results showed upregulation of genes involved in serotonin signaling (ser-1, mod-1, and tph-1) in LPJBC5-fed worms compared with control, suggesting that serotonin-signaling was essential for LPJBC5-mediated improved cognitive function. Fourthly, LPJBC5 decreased the fat accumulation in worms by reducing the expression of genes encoding key substrates and enzymes of fat metabolism (i.e., fat-5 and fat-7). Lastly, LPJBC5 reduced the production of reactive oxygen species and improved mitochondrial function, thereby reducing apoptosis in worms. The capability of a single bacterium on pro-longevity and the features of healthy aging, including enhancement of gut integrity and cognitive functions, makes it an ideal candidate for promotion as a next-generation probiotic.
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Affiliation(s)
- Arun Kumar
- Molecular Biology and Microbial Biotechnology Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Guwahati 781035, Assam, India; (A.K.); (T.J.); (S.D.); (A.K.M.)
| | - Tulsi Joishy
- Molecular Biology and Microbial Biotechnology Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Guwahati 781035, Assam, India; (A.K.); (T.J.); (S.D.); (A.K.M.)
| | - Santanu Das
- Molecular Biology and Microbial Biotechnology Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Guwahati 781035, Assam, India; (A.K.); (T.J.); (S.D.); (A.K.M.)
| | - Mohan C. Kalita
- Department of Biotechnology, Gauhati University, Guwahati 781014, Assam, India;
| | - Ashis K. Mukherjee
- Molecular Biology and Microbial Biotechnology Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Guwahati 781035, Assam, India; (A.K.); (T.J.); (S.D.); (A.K.M.)
- Department of Molecular Biology and Biotechnology, School of Sciences, Tezpur University, Tezpur 784028, Assam, India
| | - Mojibur R. Khan
- Molecular Biology and Microbial Biotechnology Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Guwahati 781035, Assam, India; (A.K.); (T.J.); (S.D.); (A.K.M.)
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34
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Jia Y, Li C, Yin M, Lin J, Zhang L, Li N, Jiang N, Xu Q, Wang Q, Gu L, Yu B, Zhao G. Kaempferol ameliorate the prognosis of Aspergillus fumigatus keratitis by reducing fungal load and inhibiting the Dectin-1 and p38 MAPK pathway. Exp Eye Res 2022; 216:108960. [DOI: 10.1016/j.exer.2022.108960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 11/04/2022]
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35
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Caliz AD, Vertii A, Fisch V, Yoon S, Yoo HJ, Keaney JF, Kant S. Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases. Front Cell Dev Biol 2022; 10:979673. [PMID: 36340039 PMCID: PMC9630596 DOI: 10.3389/fcell.2022.979673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
Stress-activated mitogen-activated protein kinase kinase 7 (MKK7) is a member of the dual-specificity mitogen-activated protein kinase family. In the human body, MKK7 controls essential physiological processes, including but not limited to proliferation and differentiation in multiple tissues and organs. MKK7, along with the MKK4 pathway, has been implicated in stress-activated activities and biological events that are mediated by c-Jun N-terminal kinase (JNK) signaling. Although numerous studies have been performed to identify the role of JNK in multiple biological processes, there are limited publications that focus on dissecting the independent role of MKK7. Recent research findings have spurred testing via in vivo genetically deficient models, uncovering previously undocumented JNK-independent functions of MKK7. Here we discuss both JNK-dependent and-independent functions of MKK7 in vivo. This review summarizes the role of MKK7 in inflammation, cytokine production, cancer, and neurological diseases.
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Affiliation(s)
- Amada D Caliz
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Anastassiia Vertii
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, United States
| | - Vijay Fisch
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Soonsang Yoon
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Hyung-Jin Yoo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - John F Keaney
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Shashi Kant
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
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Berman R, Rose CS, Downey GP, Day BJ, Chu HW. Role of Particulate Matter from Afghanistan and Iraq in Deployment-Related Lung Disease. Chem Res Toxicol 2021; 34:2408-2423. [PMID: 34808040 DOI: 10.1021/acs.chemrestox.1c00090] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Approximately 3 million United States military personnel and contractors were deployed to Southwest Asia and Afghanistan over the past two decades. After returning to the United States, many developed persistent respiratory symptoms, including those due to asthma, rhinosinusitis, bronchiolitis, and others, which we collectively refer to as deployment-related lung diseases (DRLD). The mechanisms of different DRLD have not been well defined. Limited studies from us and others suggest that multiple factors and biological signaling pathways contribute to the onset of DRLD. These include, but are not limited to, exposures to high levels of particulate matter (PM) from sandstorms, burn pit combustion products, improvised explosive devices, and diesel exhaust particles. Once inhaled, these hazardous substances can activate lung immune and structural cells to initiate numerous cell-signaling pathways such as oxidative stress, Toll-like receptors, and cytokine-driven cell injury (e.g., interleukin-33). These biological events may lead to a pro-inflammatory response and airway hyperresponsiveness. Additionally, exposures to PM and other environmental hazards may predispose military personnel and contractors to more severe disease due to the interactions of those hazardous materials with subsequent exposures to allergens and cigarette smoke. Understanding how airborne exposures during deployment contribute to DRLD may identify effective targets to alleviate respiratory diseases and improve quality of life in veterans and active duty military personnel.
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Affiliation(s)
- Reena Berman
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Cecile S Rose
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Gregory P Downey
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Brian J Day
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
| | - Hong Wei Chu
- Department of Medicine, National Jewish Health, 1400 Jackson Street, Denver, Colorado 80206, United States
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The Combination of AHCC and ETAS Decreases Migration of Colorectal Cancer Cells, and Reduces the Expression of LGR5 and Notch1 Genes in Cancer Stem Cells: A Novel Potential Approach for Integrative Medicine. Pharmaceuticals (Basel) 2021; 14:ph14121325. [PMID: 34959725 PMCID: PMC8705140 DOI: 10.3390/ph14121325] [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: 12/06/2021] [Accepted: 12/11/2021] [Indexed: 11/18/2022] Open
Abstract
The AHCC standardized extract of cultured Lentinula edodes mycelia, and the standardized extract of Asparagus officinalis stem, trademarked as ETAS, are well known supplements with immunomodulatory and anticancer potential. Several reports have described their therapeutic effects, including antioxidant and anticancer activity and improvement of immune response. In this study we aimed at investigating the effects of a combination of AHCC and ETAS on colorectal cancer cells and biopsies from healthy donors to assess the possible use in patients with colorectal cancer. Our results showed that the combination of AHCC and ETAS was synergistic in inducing a significant decrease in cancer cell growth, compared with single agents. Moreover, the combined treatment induced a significant increase in apoptosis, sparing colonocytes from healthy donors, and was able to induce a strong reduction in migration potential, accompanied by a significant modulation of proteins involved in invasiveness. Finally, combined treatment was able to significantly downregulate LGR5 and Notch1 in SW620 cancer stem cell (CSC) colonospheres. Overall, these findings support the potential therapeutic benefits of the AHCC and ETAS combinatorial treatment for patients with colorectal cancer.
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38
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Braun LM, Zeiser R. Kinase Inhibition as Treatment for Acute and Chronic Graft- Versus-Host Disease. Front Immunol 2021; 12:760199. [PMID: 34868001 PMCID: PMC8635802 DOI: 10.3389/fimmu.2021.760199] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/28/2021] [Indexed: 01/25/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies via the donor immune system driven graft-versus-leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft-versus-host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient’s tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT.
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Affiliation(s)
- Lukas M Braun
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), University of Freiburg, Freiburg, Germany.,Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
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39
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Li M, Liu Y, Liu Y, Yang L, Xu Y, Wang W, Jiang Z, Liu Y, Wang S, Wang C. Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype. Front Oncol 2021; 11:724435. [PMID: 34552875 PMCID: PMC8451478 DOI: 10.3389/fonc.2021.724435] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/17/2021] [Indexed: 11/13/2022] Open
Abstract
Background The prognosis of acute myeloid leukemia (AML) with a normal karyotype is highly heterogonous, and the current risk stratification is still insufficient to differentiate patients from high-risk to standard-risk. Changes in some genetic profiles may contribute to the poor prognosis of AML. Although the prognostic value of G protein subunit alpha 15 (GNA15) in AML has been reported based on the GEO (Gene Expression Omnibus) database, the prognostic significance of GNA15 has not been verified in clinical samples. The biological functions of GNA15 in AML development remain open to investigation. This study explored the clinical significance, biological effects and molecular mechanism of GNA15 in AML. Methods Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression level of GNA15 in blasts of bone marrow specimens from 154 newly diagnosed adult AML patients and 26 healthy volunteers. AML cell lines, Kasumi-1 and SKNO-1, were used for lentiviral transfection. Cell Counting Kit-8 (CCK8) and colony formation assays were used to determine cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. The relevant signaling pathways were evaluated by Western blot. The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. Xenograft tumor mouse model was used for in vivo experiments. Results The expression of GNA15 in adult AML was significantly higher than that in healthy individuals. Subjects with high GNA15 expression showed lower overall survival and relapse-free survival in adult AML with normal karyotype. High GNA15 expression was independently correlated with a worse prognosis in multivariate analysis. Knockdown of GNA15 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. GNA15-knockdown induced down-regulation of p-P38 MAPK and its downstream p-MAPKAPK2 and p-CREB. Rescue assays confirmed that P38 MAPK signaling pathway was involved in the inhibition of proliferation mediated by GNA15 knockdown. Conclusions In summary, GNA15 was highly expressed in adult AML, and high GNA15 expression was independently correlated with a worse prognosis in adult AML with normal karyotype. Knockdown of GNA15 inhibited the proliferation of AML regulated by the P38 MAPK signaling pathway. Therefore, GNA15 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
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Affiliation(s)
- Mengya Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yu Liu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yajun Liu
- Department of Orthopaedics, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Lu Yang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Xu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weiqiong Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanfang Liu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shujuan Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chong Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Morgan D, Berggren KL, Spiess CD, Smith HM, Tejwani A, Weir SJ, Lominska CE, Thomas SM, Gan GN. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) and its role in cell survival, inflammatory signaling, and migration in promoting cancer. Mol Carcinog 2021; 61:173-199. [PMID: 34559922 DOI: 10.1002/mc.23348] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/19/2022]
Abstract
Cancer and the immune system share an intimate relationship. Chronic inflammation increases the risk of cancer occurrence and can also drive inflammatory mediators into the tumor microenvironment enhancing tumor growth and survival. The p38 MAPK pathway is activated both acutely and chronically by stress, inflammatory chemokines, chronic inflammatory conditions, and cancer. These properties have led to extensive efforts to find effective drugs targeting p38, which have been unsuccessful. The immediate downstream serine/threonine kinase and substrate of p38 MAPK, mitogen-activated-protein-kinase-activated-protein-kinase-2 (MK2) protects cells against stressors by regulating the DNA damage response, transcription, protein and messenger RNA stability, and motility. The phosphorylation of downstream substrates by MK2 increases inflammatory cytokine production, drives an immune response, and contributes to wound healing. By binding directly to p38 MAPK, MK2 is responsible for the export of p38 MAPK from the nucleus which gives MK2 properties that make it unique among the large number of p38 MAPK substrates. Many of the substrates of both p38 MAPK and MK2 are separated between the cytosol and nucleus and interfering with MK2 and altering this intracellular translocation has implications for the actions of both p38 MAPK and MK2. The inhibition of MK2 has shown promise in combination with both chemotherapy and radiotherapy as a method for controlling cancer growth and metastasis in a variety of cancers. Whereas the current data are encouraging the field requires the development of selective and well tolerated drugs to target MK2 and a better understanding of its effects for effective clinical use.
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Affiliation(s)
- Deri Morgan
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Kiersten L Berggren
- Department of Internal Medicine, Division of Medical Oncology, Section of Radiation Oncology, UNM School of Medicine, The University of New Mexico, Albuquerque, New Mexico, USA
| | - Colby D Spiess
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Hannah M Smith
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ajay Tejwani
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Scott J Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Christopher E Lominska
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sufi M Thomas
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.,Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Gregory N Gan
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA.,Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
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Awasthi A, Raju MB, Rahman MA. Current Insights of Inhibitors of p38 Mitogen-Activated Protein Kinase in Inflammation. Med Chem 2021; 17:555-575. [PMID: 32106802 DOI: 10.2174/1573406416666200227122849] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 10/01/2019] [Accepted: 11/25/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND The inflammatory process is one of the mechanisms by which our body upholds us from pathogens such as parasites, bacteria, viruses, and other harmful microorganisms. Inflammatory stimuli activate many intracellular signaling pathways such as the nuclear factor-kB (NF-kB) pathway and three mitogen-activated protein kinase (MAPK) pathways, which are mediated through extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. The p38 has evolved as an enticing target in treating many persistent inflammatory diseases. Hence, designing novel p38 inhibitors targeting MAPK pathways has acquired significance. OBJECTIVE Peruse to identify the lead target to discover novel p38MAPK inhibitors with different scaffolds having improved selectivity over the prototype drugs. METHODS Structure and the binding sites of p38MAPK were focused. Various scaffolds designed for inhibition and the molecules which have entered the clinical trials are discussed. RESULTS This review aspires to present the available information on the structure and the 3D binding sites of p38MAPK, various scaffolds designed for imidazole, urea, benzamide, azoles, quinoxaline, chromone, ketone as a potent p38MAPK inhibitors and their SAR studies and the molecules which have entered the clinical trials. CONCLUSION The development of successful selective p38MAPK inhibitors in inflammatory diseases is in progress despite all challenges. It was speculated that p38MAPK also plays an important role in treating diseases such as neuroinflammation, arterial inflammation, vascular inflammation, cancer and so on, which are posing the world with treatment challenges. In this review, clinical trials of drugs are discussed related to inflammatory and its related diseases. Research is in progress to design and develop novel p38MAPK inhibitors with minimal side effects.
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Affiliation(s)
- Archana Awasthi
- Department of Pharmaceutical Chemistry, Sri Venkateshwara College of Pharmacy, Madhapur, Hyderabad, Telangana, India
| | - Mantripragada Bhagavan Raju
- Department of Pharmaceutical Chemistry, Sri Venkateshwara College of Pharmacy, Madhapur, Hyderabad, Telangana, India
| | - Md Azizur Rahman
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India
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Hossain MA, Adithan A, Alam MJ, Kopalli SR, Kim B, Kang CW, Hwang KC, Kim JH. IGF-1 Facilitates Cartilage Reconstruction by Regulating PI3K/AKT, MAPK, and NF-kB Signaling in Rabbit Osteoarthritis. J Inflamm Res 2021; 14:3555-3568. [PMID: 34335042 PMCID: PMC8318731 DOI: 10.2147/jir.s316756] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/12/2021] [Indexed: 11/30/2022] Open
Abstract
Purpose The pathogenesis of osteoarthritis (OA) is characterized by joint degeneration. The pro-inflammatory cytokine interleukin (IL)-1β plays a vital role in the pathogenesis of OA by stimulation of specific signaling pathways like NF-κB, PI3K/Akt, and MAPKs pathways. The catabolic role of growth factors in the OA may be inhibited cytokine-activated pathogen. The purpose of this study was to investigate the potential effects of insulin-like growth factor-1 (IGF-1) on IL-1β-induced apoptosis in rabbit chondrocytes in vitro and in an in vivo rabbit knee OA model. Methods In the present study, the OA developed in chondrocyte with the treatment of IL-1β and articular cartilage ruptures by removal of cartilage from the rabbit knee femoral condyle. After IGF-1 treatment, immunohistochemistry and qRT-PCR were identified OA expression with changes in MMPs (matrix metalloproteinases). The production of ROS (intracellular reactive oxygen species) in the OA was detected by flow cytometry. Further, the disease progression was microscopically investigated and pathophysiological changes were analyzed using histology. The NF-κB, PI3K/Akt and P38 (MAPK) specific pathways that are associated with disease progression were also checked using the Western blot technique. Results The expression of MMPs and various apoptotic markers are down-regulated following administration of IGF-1 in a dose-dependent fashion while significantly up-regulation of TIMP-1. The results showed that higher levels of ROS were observed upon treatment of chondrocytes and chondral OA with IL-1β. Collectively, our results indicated that IGF-1 protected NF-κB pathway by suppression of PI3K/Akt and MAPKs specific pathways. Furthermore, the macroscopic and pathological investigation showed that it has a chondroprotective effect by the formation of hyaline cartilage. Conclusion Our results indicate a protective effect of IGF-1 against OA pathogenesis by inhibition of NF-κB signaling via regulation of the MAPK and PI3K/Akt signaling pathways and prevention of apoptosis by suppression of ROS production.
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Affiliation(s)
- Mohammad Amjad Hossain
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-city, Jeollabuk-Do, Republic of Korea
| | - Aravinthan Adithan
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-city, Jeollabuk-Do, Republic of Korea
| | - Md Jahangir Alam
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-city, Jeollabuk-Do, Republic of Korea
| | - Spandana Rajendra Kopalli
- Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, 05006, Republic of Korea
| | - Bumseok Kim
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-city, Jeollabuk-Do, Republic of Korea
| | - Chang-Won Kang
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-city, Jeollabuk-Do, Republic of Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
| | - Jong-Hoon Kim
- College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Iksan-city, Jeollabuk-Do, Republic of Korea
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Chen J, Wang W, Sun H, Pang L, Bao H. Binding mechanism of inhibitors to p38α MAP kinase deciphered by using multiple replica Gaussian accelerated molecular dynamics and calculations of binding free energies. Comput Biol Med 2021; 134:104485. [PMID: 33993013 DOI: 10.1016/j.compbiomed.2021.104485] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022]
Abstract
The p38α MAP Kinase has been an important target of drug design for treatment of inflammatory diseases and cancers. This work applies multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations and the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding mechanism of inhibitors L51, R24 and 1AU to p38α. Dynamics analyses show that inhibitor bindings exert significant effect on conformational changes of the active helix α2 and the conserved DFG loop. The rank of binding free energies calculated with MM-GBSA not only agrees well with that determined by the experimental IC50 values but also suggests that mutual compensation between the enthalpy and entropy changes can improve binding of inhibitors to p38α. The analyses of free energy landscapes indicate that the L51, R24 and 1AU bound p38α display a DFG-out conformation. The residue-based free energy decomposition method is used to evaluate contributions of separate residues to the inhibitor-p38α binding and the results imply that residues V30, V38, L74, L75, I84, T106, H107, L108, M109, L167, F169 and D168 can be utilized as efficient targets of potent inhibitors toward p38α.
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Affiliation(s)
- Jianzhong Chen
- School of Science, Shandong Jiaotong University, Jinan, 250357, China.
| | - Wei Wang
- School of Science, Shandong Jiaotong University, Jinan, 250357, China
| | - Haibo Sun
- School of Science, Shandong Jiaotong University, Jinan, 250357, China
| | - Laixue Pang
- School of Science, Shandong Jiaotong University, Jinan, 250357, China
| | - Huayin Bao
- School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
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Zhang Z, Tian S, Wu C, Yan L, Wan J, Zhang J, Liu X, Zhang W. Comprehensive bioinformatics analysis reveals kinase activity profiling associated with heart failure. J Cell Biochem 2021; 122:1126-1140. [PMID: 33899242 DOI: 10.1002/jcb.29935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/22/2021] [Indexed: 01/27/2023]
Abstract
Heart failure is a complex clinical syndrome originating from cardiac injury, which leads to considerable morbidity and mortality. Among the dynamic molecular adaptations occurring in heart failure development, aggravation of the disease is often attributed to global or local abnormality of the kinase. Therefore, the overall monitoring of kinase activity is indispensable. In this study, a bioinformatics analysis method was developed to conduct deep mining of transcriptome and phosphoproteome in failing heart tissue. A total of 982 differentially expressed genes and 9781 phosphorylation sites on 3252 proteins were identified. Via upstream regulator relations and kinase-substrate relations, a dendrogram of kinases can be constructed to monitor its abnormality. The results show that, on the dendrogram, the distribution of kinases demonstrated complex kinase activity changes and certain rules that occur during heart failure. Finally, we also identified the hub kinases in heart failure and verified the expression of these kinases by reverse-transcription polymerase chain reaction and Western blot analysis. In conclusion, for the first time, we have systematically analyzed the differences in kinases during heart failure and provided an unprecedented breadth of multi-omics data. These results can bring about a sufficient data foundation and novel research perspectives.
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Affiliation(s)
- Zhen Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Saisai Tian
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Chennan Wu
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Li Yan
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Jingjing Wan
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jinbo Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Xia Liu
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Weidong Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, China
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Vahidinia Z, Mahdavi E, Talaei SA, Naderian H, Tamtaji A, Haddad Kashani H, Beyer C, Azami Tameh A. The effect of female sex hormones on Hsp27 phosphorylation and histological changes in prefrontal cortex after tMCAO. Pathol Res Pract 2021; 221:153415. [PMID: 33857717 DOI: 10.1016/j.prp.2021.153415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/13/2021] [Accepted: 03/20/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Female sex hormones are protective factors against many neurological disorders such as brain ischemia. Heat shock protein like HSP27 is activated after tissue injury. The main purpose of the present study is to determine the effect of a combined estrogen / progesterone cocktail on the morphology of astrocytes, neurons and Hsp27 phosphorylation after cerebral ischemia. METHODS One hour after the MCAO induction, a single dose of estrogen and progesterone was injected. The infarct volume was calculated by TTC staining 24 h after ischemia. Immunohistochemistry was used to show the effects of estrogen and progesterone on astrocyte and neuron morphology, as well as the Western blot technique used for the quantitation of phosphorylated Hsp27. RESULTS The combined dose of estrogen and progesterone significantly decreased astrocytosis after ischemia and increased neuron survival. There was a large increase in Hsp27 phosphorylation in the penumbra ischemic region after stroke, which was significantly reduced by hormone therapy. CONCLUSION Our results indicate that the neuroprotective effect of neurosteroids in the brain may be due to the modulation of heat shock proteins.
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Affiliation(s)
- Zeinab Vahidinia
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Elham Mahdavi
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Homayoun Naderian
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Aboutaleb Tamtaji
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Haddad Kashani
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Cordian Beyer
- Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Abolfazl Azami Tameh
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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The Anticancer Effects of Flavonoids through miRNAs Modulations in Triple-Negative Breast Cancer. Nutrients 2021; 13:nu13041212. [PMID: 33916931 PMCID: PMC8067583 DOI: 10.3390/nu13041212] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/31/2022] Open
Abstract
Triple- negative breast cancer (TNBC) incidence rate has regularly risen over the last decades and is expected to increase in the future. Finding novel treatment options with minimum or no toxicity is of great importance in treating or preventing TNBC. Flavonoids are new attractive molecules that might fulfill this promising therapeutic option. Flavonoids have shown many biological activities, including antioxidant, anti-inflammatory, and anticancer effects. In addition to their anticancer effects by arresting the cell cycle, inducing apoptosis, and suppressing cancer cell proliferation, flavonoids can modulate non-coding microRNAs (miRNAs) function. Several preclinical and epidemiological studies indicate the possible therapeutic potential of these compounds. Flavonoids display a unique ability to change miRNAs' levels via different mechanisms, either by suppressing oncogenic miRNAs or activating oncosuppressor miRNAs or affecting transcriptional, epigenetic miRNA processing in TNBC. Flavonoids are not only involved in the regulation of miRNA-mediated cancer initiation, growth, proliferation, differentiation, invasion, metastasis, and epithelial-to-mesenchymal transition (EMT), but also control miRNAs-mediated biological processes that significantly impact TNBC, such as cell cycle, immune system, mitochondrial dysregulation, modulating signaling pathways, inflammation, and angiogenesis. In this review, we highlighted the role of miRNAs in TNBC cancer progression and the effect of flavonoids on miRNA regulation, emphasizing their anticipated role in the prevention and treatment of TNBC.
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Kurogi S, Hijiya N, Hidano S, Sato S, Uchida T, Tsukamoto Y, Nakada C, Yada K, Hirashita T, Inomata M, Murakami K, Takahashi N, Kobayashi T, Moriyama M. Downregulation of ZNF395 Drives Progression of Pancreatic Ductal Adenocarcinoma through Enhancement of Growth Potential. Pathobiology 2021; 88:374-382. [PMID: 33794543 DOI: 10.1159/000514593] [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: 11/09/2020] [Accepted: 01/19/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Progression of pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma is a critical factor impacting the prognosis of patients with pancreatic tumors. However, the molecular mechanisms involved are not fully understood. We have reported that the process frequently involves loss of chromosome 8p, causing downregulation of DUSP4, thus conferring invasive ability on cancer cells. Here, we focus on ZNF395, whose expression was also found to be decreased by 8p loss and was predicted to be a growth suppressor gene. METHODS Pancreatic cancer cell lines inducibly expressing ZNF395 were established to assess the functional significance of ZNF395 in pancreatic carcinogenesis. Immunohistochemistry was also performed to analyze the expression levels of ZNF395 in pancreatic cancer tissues. RESULTS Induction of ZNF395 in pancreatic cancer cells resulted in marked activation of JNK and suppression of their proliferation through a delay in cell cycle progression. Immunohistochemistry revealed that ZNF395 was expressed ubiquitously in both normal pancreatic ducts and PanINs but was significantly reduced in invasive cancers, especially those showing poor differentiation. CONCLUSION ZNF395 acts as a novel tumor suppressor gene. Its downregulation caused by 8p loss in intraepithelial cells accelerates their proliferation through dysregulation of the cell cycle, leading to progression to invasive cancer.
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Affiliation(s)
- Shusaku Kurogi
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Naoki Hijiya
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Shinya Hidano
- Department of Infectious Disease Control, Faculty of Medicine, Oita University, Yufu, Japan
| | | | - Tomohisa Uchida
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Yoshiyuki Tsukamoto
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Chisato Nakada
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Kazuhiro Yada
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Yufu, Japan
| | - Teijiro Hirashita
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Yufu, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, Yufu, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Naohiko Takahashi
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University, Yufu, Japan
| | - Takashi Kobayashi
- Department of Infectious Disease Control, Faculty of Medicine, Oita University, Yufu, Japan
| | - Masatsugu Moriyama
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
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Abiri R, Atabaki N, Sanusi R, Malik S, Abiri R, Safa P, Shukor NAA, Abdul-Hamid H. New Insights into the Biological Properties of Eucalyptus-Derived Essential Oil: A Promising Green Anti-Cancer Drug. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.1877300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Rambod Abiri
- Department of Forestry Science and Biodiversity, Faculty of Forestry and Environment, Universiti Putra Malaysia, Serdang, Selangor DE 43400 UPM, Malaysia
| | - Narges Atabaki
- Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400 UPM, Malaysia
| | - Ruzana Sanusi
- Department of Forestry Science and Biodiversity, Faculty of Forestry and Environment, Universiti Putra Malaysia, Serdang, Selangor DE 43400 UPM, Malaysia
- Laboratory of Bioresource Management, Institute of Tropical Forestry and Forest Products (INTROP), Universiti Putra Malaysia, Serdang DE 43400 UPM, Malaysia
| | - Sonia Malik
- Health Science Graduate Program, Biological & Health Sciences Centre, Federal University of Maranhao, Sao Luis, MA, Brazil
| | - Ramin Abiri
- Department of Medical Microbiology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parastoo Safa
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor DE 43400 UPM, Malaysia
| | - Nor Aini Ab Shukor
- Department of Forestry Science and Biodiversity, Faculty of Forestry and Environment, Universiti Putra Malaysia, Serdang, Selangor DE 43400 UPM, Malaysia
- Laboratory of Bioresource Management, Institute of Tropical Forestry and Forest Products (INTROP), Universiti Putra Malaysia, Serdang DE 43400 UPM, Malaysia
| | - Hazandy Abdul-Hamid
- Department of Forestry Science and Biodiversity, Faculty of Forestry and Environment, Universiti Putra Malaysia, Serdang, Selangor DE 43400 UPM, Malaysia
- Laboratory of Bioresource Management, Institute of Tropical Forestry and Forest Products (INTROP), Universiti Putra Malaysia, Serdang DE 43400 UPM, Malaysia
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Beamer E, Corrêa SAL. The p38 MAPK-MK2 Signaling Axis as a Critical Link Between Inflammation and Synaptic Transmission. Front Cell Dev Biol 2021; 9:635636. [PMID: 33585492 PMCID: PMC7876405 DOI: 10.3389/fcell.2021.635636] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/11/2021] [Indexed: 01/04/2023] Open
Abstract
p38 is a mitogen-activated protein kinase (MAPK), that responds primarily to stress stimuli. p38 has a number of targets for phosphorylation, including MAPK-activated protein kinase 2 (MK2). MK2 primarily functions as a master regulator of RNA-binding proteins, indirectly controlling gene expression at the level of translation. The role of MK2 in regulating the synthesis of pro-inflammatory cytokines downstream of inflammation and cellular stress is well-described. A significant amount of evidence, however, now points to a role for the p38MAPK-MK2 signaling axis in mediating synaptic plasticity through control of AMPA receptor trafficking and the morphology of dendritic spines. These processes are mediated through control of cytoskeletal dynamics via the activation of cofilin-1 and possibly control of the expression of Arc/Arg3.1. There is evidence that MK2 is necessary for group I metabotropic glutamate receptors long-term depression (mGluR-LTD). Disruption of this signaling may play an important role in mediating cognitive dysfunction in neurological disorders such as fragile X syndrome and Alzheimer’s disease. To date, the role of neuronal MK2 mediating synaptic plasticity in response to inflammatory stimuli has not yet been investigated. In immune cells, it is clear that MK2 is phosphorylated following activation of a broad range of cell surface receptors for cytokines and other inflammatory mediators. We propose that neuronal MK2 may be an important player in the link between inflammatory states and dysregulation of synaptic plasticity underlying cognitive functions. Finally, we discuss the potential of the p38MAPK-MK2 signaling axis as target for therapeutic intervention in a number of neurological disorders.
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Affiliation(s)
- Edward Beamer
- Faculty of Science and Engineering, Department of Life Sciences, Manchester Metropolitan University Manchester, Manchester, United Kingdom
| | - Sonia A L Corrêa
- Faculty of Science and Engineering, Department of Life Sciences, Manchester Metropolitan University Manchester, Manchester, United Kingdom
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Canovas B, Nebreda AR. Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol 2021; 22:346-366. [PMID: 33504982 PMCID: PMC7838852 DOI: 10.1038/s41580-020-00322-w] [Citation(s) in RCA: 349] [Impact Index Per Article: 87.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
Abstract
The ability of cells to deal with different types of stressful situations in a precise and coordinated manner is key for survival and involves various signalling networks. Over the past 25 years, p38 kinases — in particular, p38α — have been implicated in the cellular response to stress at many levels. These span from environmental and intracellular stresses, such as hyperosmolarity, oxidative stress or DNA damage, to physiological situations that involve important cellular changes such as differentiation. Given that p38α controls a plethora of functions, dysregulation of this pathway has been linked to diseases such as inflammation, immune disorders or cancer, suggesting the possibility that targeting p38α could be of therapeutic interest. In this Review, we discuss the organization of this signalling pathway focusing on the diversity of p38α substrates, their mechanisms and their links to particular cellular functions. We then address how the different cellular responses can be generated depending on the signal received and the cell type, and highlight the roles of this kinase in human physiology and in pathological contexts. p38α — the best-characterized member of the p38 kinase family — is a key mediator of cellular stress responses. p38α is activated by a plethora of signals and functions through a multitude of substrates to regulate different cellular behaviours. Understanding context-dependent p38α signalling provides important insights into p38α roles in physiology and pathology.
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Affiliation(s)
- Begoña Canovas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Angel R Nebreda
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. .,ICREA, Barcelona, Spain.
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