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Jiang T, Gong Y, Zhang W, Qiu J, Zheng X, Li Z, Yang G, Hong Z. PD0325901, an ERK inhibitor, attenuates RANKL-induced osteoclast formation and mitigates cartilage inflammation by inhibiting the NF-κB and MAPK pathways. Bioorg Chem 2023; 132:106321. [PMID: 36642020 DOI: 10.1016/j.bioorg.2022.106321] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 12/04/2022] [Accepted: 12/09/2022] [Indexed: 01/01/2023]
Abstract
Osteoarthritis (OA), a degenerative disease affecting the joint, is characterized by degradation of the joint edge, cartilage injury, and subchondral bone hyperplasia. Treatment of early subchondral bone loss in OA can inhibit subsequent articular degeneration and improve the prognosis of OA. PD0325901, a specific inhibitor of ERK, is widely used in oncology and has potential as a therapeutic agent for osteoarthritis In this study, we investigated the biological function of PD0325901 in bone marrow monocytes/macrophages (BMMs)treated with RANKL and found that it inhibited osteoclast differentiation in vitro in a time- and dose-dependent manner. PD0325901 restrained the expression of osteoclast marker genes, such as c-Fos and NFATc1 induced by RANKL. We tested the biological effects of PD035901 on ATDC5 cells stimulated by IL-1β and found that it had protective effects on ATDC5 cells. In animal studies, we used a destabilization of the medial meniscus (DMM) model and injected 5 mg/kg or 10 mg/kg of PD0325901 compound into each experimental group of mice. We found that PD0325901 significantly reduced osteochondral pathological changes in post-OA subchondral bone destruction.Finally, we found that PD0325901 down-regulated the pyroptosis level in chondrocytes to rescue cartilage degeneration. Therefore, PD0325901 is expected to be a new generation alternative therapy for OA.
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Affiliation(s)
- Ting Jiang
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Yuhang Gong
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Wekang Zhang
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Jianxin Qiu
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Xiaohang Zheng
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Ze Li
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Guangyong Yang
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China.
| | - Zhenghua Hong
- Department of Orthopedics, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China; Bone Development and Metabolism Research Center of Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China.
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Yao Z, Zhao M, Gao G, Yang J, Wang Z, Liu Y. Prognostic Role of IL-18 in Various Human Cancers and Radiation Injuries: A Meta-Analysis. Dose Response 2020; 18:1559325820931360. [PMID: 32636720 PMCID: PMC7323287 DOI: 10.1177/1559325820931360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 04/18/2020] [Accepted: 05/10/2020] [Indexed: 01/19/2023] Open
Abstract
Background: In recent years, more and more studies have shown that various inflammatory factors have predictive effects on the prognosis of various human tumors. However, the prognostic role of interleukin 18 (IL-18) remains controversial. Furthermore, its role in radiation-induced injuries relating to radiotherapy (RT) is also unclear. In this study, we conducted the meta-analysis to clarify its roles in prognosis of human tumors and radiation-induced injuries relating to RT. Methods: We comprehensively searched PubMed, Embase, and Cochrane Library to identify studies published before November 2019 involving patients with cancer expressing IL-18 and which reported overall survival (OS) during the follow-up period. Results: A total of 1376 samples from 16 studies showed that high expression of IL-18 is closely related to prognosis and OS for patients with carcinoma (hazard ratio [HR]: 2.12; 95% CI: 1.81-2.49; P = .04; random-effect model). In addition, subgroup analysis proved that high expression of IL-18 was related to poor OS of hematologic tumor (HR: 2.03, 95% CI: 1.44-2.86, P < .00001), hepatocellular carcinoma (HR: 1.99, 95% CI: 1.38-2.86, P = .0002), and gastric cancer (HR: 2.00, 95% CI: 1.12-3.57, P = .02). Conclusions: High expression of IL-18 is related with poor prognosis of carcinoma.
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Affiliation(s)
- Zhen Yao
- Department of Nuclear Accident Medical Emergency, the Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Minyan Zhao
- Department of Nuclear Accident Medical Emergency, the Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guangyu Gao
- Department of Nuclear Accident Medical Emergency, the Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiawen Yang
- Department of Ultrasound, Xingtang Hospital, Suzhou, Jiangsu, People's Republic of China
| | - Zhenzhen Wang
- Department of Nuclear Accident Medical Emergency, the Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yulong Liu
- Department of Nuclear Accident Medical Emergency, the Second Affiliated Hospital of Soochow University, Suzhou, China.,State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China.,Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, China
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Shi X, Li S, Wang L, Li H, Li Z, Wang W, Bai J, Sun Y, Li J, Li X. RalB degradation by dihydroartemisinin induces autophagy and IFI16/caspase-1 inflammasome depression in the human laryngeal squamous cell carcinoma. Chin Med 2020; 15:64. [PMID: 32577124 PMCID: PMC7304197 DOI: 10.1186/s13020-020-00340-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/26/2020] [Indexed: 02/04/2023] Open
Abstract
Background Interferon-inducible 16 (IFI16)/caspase-1 inflammasome activates and secretes IL-1β. However, it is still unclear whether the IFI16 inflammasome is involved in human laryngeal squamous cell carcinoma. Autophagy directly removed inflammasome components and limited early IL-1β production. RalB is required for the crosstalk between inflammasome and autophagy in macrophages. Dihydroartemisinin (DHA), the main derived ingredient of artemisinin, has a variety of biological activities. The mechanism of DHA in regulating the crosstalk between IFI16 inflammasome and autophagy by inhibiting RalB expression was analyzed in order to provide clues for new therapeutic methods in laryngeal cancer. Methods The expression of IFI16 was analyzed by Oncomine and GEPIA databases and detected by Western blot and immunohistochemistry. The relationship between IFI16 inflammasome and autophagy was investigated by transmission electron microscopy, immunofluorescence assay, etc. in Hep-2, Cal-27 and HeLa cells treated with DHA. The xenograft tumor of hep-2 cell in nude mice were used to assess the effect of DHA on laryngeal cancer. Results It was reported for the first time in this study that IFI16 was overexpressed and positively correlated with caspase-1 in laryngeal carcinoma tissues. DHA significantly inhibited the activation of inflammasome and reduced IL-1β production in the microenvironment of Hep-2 cell xenograft tumor in nude mice. Mechanistically, we found that DHA degraded RalB, inhibited USP33 expression, and triggered autophagy. Meanwhile, enhanced autophagy can reduce the expression of RalB and USP33. Furthermore, DHA promotes autophagy, which suppresses the activation of IFI16/caspase-1 inflammasome and IL-1β production. Conclusions Therefore, our findings demonstrate that DHA may act as a RalB inhibitor to regulate the crosstalk between autophagy and IFI16/caspase-1 inflammasome, which inhibits IL-1β production in tumor microenvironment.
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Affiliation(s)
- Xinli Shi
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China.,Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, 050200 China
| | - Shenghao Li
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, 050200 China
| | - Li Wang
- Laboratory of Organ Fibrosis Prophylaxis and Treatment by Combine Traditional Chinese and Western Medicine, Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, 646000 China
| | - Hui Li
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China
| | - Zhen Li
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China
| | - Weiyi Wang
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China.,Department of Neurology, Children's Hospital of Hebei Province, Shijiazhuang, 050000 China
| | - Jing Bai
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China
| | - Yajing Sun
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China
| | - Jianchun Li
- Laboratory of Organ Fibrosis Prophylaxis and Treatment by Combine Traditional Chinese and Western Medicine, Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, 646000 China
| | - Xiaoming Li
- Department of Otolaryngology Head and Neck Surgery, Bethune International Peace Hospital, Shijiazhuang, 050081 China
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Joffre C, Dinel AL, Chataigner M, Pallet V, Layé S. n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging. Nutrients 2020; 12:nu12030647. [PMID: 32121189 PMCID: PMC7146513 DOI: 10.3390/nu12030647] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 12/15/2022] Open
Abstract
: Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging.
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Affiliation(s)
- Corinne Joffre
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.C.); (V.P.); (S.L.)
- Correspondence:
| | - Anne-Laure Dinel
- NutriBrain Research and Technology Transfer, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France
| | - Mathilde Chataigner
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.C.); (V.P.); (S.L.)
- Abyss Ingredients, 56850 Caudan, France
| | - Véronique Pallet
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.C.); (V.P.); (S.L.)
| | - Sophie Layé
- Université de Bordeaux, INRAE, Bordeaux INP, NutriNeuro, 146 rue Léo Saignat, 33076 Bordeaux, France; (M.C.); (V.P.); (S.L.)
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Neagu M, Constantin C, Popescu ID, Zipeto D, Tzanakakis G, Nikitovic D, Fenga C, Stratakis CA, Spandidos DA, Tsatsakis AM. Inflammation and Metabolism in Cancer Cell-Mitochondria Key Player. Front Oncol 2019; 9:348. [PMID: 31139559 PMCID: PMC6527883 DOI: 10.3389/fonc.2019.00348] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/15/2019] [Indexed: 12/17/2022] Open
Abstract
Cancer metabolism is an essential aspect of tumorigenesis, as cancer cells have increased energy requirements in comparison to normal cells. Thus, an enhanced metabolism is needed in order to accommodate tumor cells' accelerated biological functions, including increased proliferation, vigorous migration during metastasis, and adaptation to different tissues from the primary invasion site. In this context, the assessment of tumor cell metabolic pathways generates crucial data pertaining to the mechanisms through which tumor cells survive and grow in a milieu of host defense mechanisms. Indeed, various studies have demonstrated that the metabolic signature of tumors is heterogeneous. Furthermore, these metabolic changes induce the exacerbated production of several molecules, which result in alterations that aid an inflammatory milieu. The therapeutic armentarium for oncology should thus include metabolic and inflammation regulators. Our expanding knowledge of the metabolic behavior of tumor cells, whether from solid tumors or hematologic malignancies, may provide the basis for the development of tailor-made cancer therapies.
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Affiliation(s)
- Monica Neagu
- Immunology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania.,Doctoral School, Biology Faculty, University of Bucharest, Bucharest, Romania.,Pathology Department, Colentina Clinical Hospital, Bucharest, Romania
| | - Carolina Constantin
- Immunology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania.,Pathology Department, Colentina Clinical Hospital, Bucharest, Romania
| | - Iulia Dana Popescu
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Donato Zipeto
- Department Neuroscience, Biomedicine and Movement Science, School of Medicine, University of Verona, Verona, Italy
| | - George Tzanakakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| | - Dragana Nikitovic
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, Heraklion, Greece
| | - Concettina Fenga
- Biomedical, Odontoiatric, Morphological and Functional Images Department, Occupational Medicine Section, University of Messina, Messina, Italy
| | - Constantine A Stratakis
- Section on Genetics & Endocrinology (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), NIH, Bethesda, MD, United States
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion, Greece
| | - Aristidis M Tsatsakis
- Department of Forensic Sciences and Toxicology, University of Crete, Heraklion, Greece
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