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1
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Zhong R, He H, Wang X. Novel neutrophil targeting platforms in treating Glioblastoma: Latest evidence and therapeutic approaches. Int Immunopharmacol 2025; 150:114173. [PMID: 39938169 DOI: 10.1016/j.intimp.2025.114173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
Glioblastoma (GBM) is the most aggressive and lethal type of primary brain tumor, characterized by its rapid growth, resistance to conventional therapies, and a highly immunosuppressive tumor microenvironment (TME). Recent studies have highlighted the critical role of neutrophils in the progression of GBM, where they contribute to tumor growth, invasion, and treatment resistance. As a result, neutrophils have emerged as a promising target for therapeutic intervention in GBM. Various strategies are being investigated to specifically target neutrophils within the GBM environment, including using small molecules, antibodies, and nanoparticle-based methods. These approaches aim to regulate neutrophils' recruitment, activation, and functions. This study reviews the latest findings regarding the involvement of neutrophils in GBM, explores potential techniques targeting neutrophils for therapeutic purposes, and discusses current clinical studies and prospects in this rapidly evolving field. By studying the diverse functions of neutrophils in GBM, these innovative therapeutic strategies can help address some of the most significant challenges in treating this malignancy.
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Affiliation(s)
- Rui Zhong
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China
| | - Hongmei He
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China
| | - Xiande Wang
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China.
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2
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Mathew DJ, Maurya S, Ho J, Livne-Bar I, Chan D, Buys Y, Sit M, Trope G, Flanagan JG, Gronert K, Sivak JM. Lipidomic Analysis Reveals Drug-Induced Lipoxins in Glaucoma Treatment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.24.634771. [PMID: 39975338 PMCID: PMC11838192 DOI: 10.1101/2025.01.24.634771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Synthetic prostaglandin analogues, such as latanoprost, are first-line treatments to reduce intraocular pressure (IOP) in the management of glaucoma, treating millions of patients daily. Glaucoma is a leading cause of blindness, characterized by progressive optic neuropathy, with elevated IOP being the sole modifiable risk factor. Despite this importance, the underlying latanoprost mechanism is still not well defined, being associated with both acute and long term activities, and ocular side effects. Prostaglandins are eicosanoid lipid mediators. Yet, there has not been a comprehensive assessment of small lipid mediators in glaucomatous eyes. Here we performed a lipidomic screen of aqueous humour sampled from glaucoma patients or healthy control eyes. The resulting signature was surprisingly focused on significantly elevated levels of arachidonic acid (AA) and the potent proresolving mediator, lipoxin A4 (LXA4) in glaucoma eyes. Subsequent experiments revealed that this response is due to latanoprost actions, rather than a consequence of elevated IOP. We demonstrated that increased LXA4 inhibits pro-inflammatory cues and promotes TGF-β3 mediated tissue remodeling in the anterior chamber. In concert, an autocrine prostaglandin circuit mediates rapid IOP-lowering. This work reveals parallel mechanisms underlying acute and long-term latanoprost activities during the treatment of glaucoma.
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Affiliation(s)
- D J Mathew
- Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto School of Medicine, Toronto, Canada
| | - S Maurya
- Herbert Wertheim School of Optometry & Vision Science, University of California Berkeley, Berkeley, California, United States
- Vision Science Program, University of California Berkeley, Berkeley, California, United States
| | - J Ho
- Herbert Wertheim School of Optometry & Vision Science, University of California Berkeley, Berkeley, California, United States
- Vision Science Program, University of California Berkeley, Berkeley, California, United States
| | - I Livne-Bar
- Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto School of Medicine, Toronto, Canada
| | - D Chan
- Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto School of Medicine, Toronto, Canada
| | - Y Buys
- Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
| | - M Sit
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
| | - G Trope
- Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
| | - J G Flanagan
- Herbert Wertheim School of Optometry & Vision Science, University of California Berkeley, Berkeley, California, United States
- Vision Science Program, University of California Berkeley, Berkeley, California, United States
| | - K Gronert
- Herbert Wertheim School of Optometry & Vision Science, University of California Berkeley, Berkeley, California, United States
- Vision Science Program, University of California Berkeley, Berkeley, California, United States
- Infectious Disease and Immunity Program, University of California Berkeley, Berkeley, California, United States
| | - J M Sivak
- Donald K Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, Canada
- Department of Ophthalmology and Vision Science, University of Toronto School of Medicine, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto School of Medicine, Toronto, Canada
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3
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Amoah AS, Pestov NB, Korneenko TV, Prokhorenko IA, Kurakin GF, Barlev NA. Lipoxygenases at the Intersection of Infection and Carcinogenesis. Int J Mol Sci 2024; 25:3961. [PMID: 38612771 PMCID: PMC11011848 DOI: 10.3390/ijms25073961] [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: 01/31/2024] [Revised: 03/08/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
The persisting presence of opportunistic pathogens like Pseudomonas aeruginosa poses a significant threat to many immunocompromised cancer patients with pulmonary infections. This review highlights the complexity of interactions in the host's defensive eicosanoid signaling network and its hijacking by pathogenic bacteria to their own advantage. Human lipoxygenases (ALOXs) and their mouse counterparts are integral elements of the innate immune system, mostly operating in the pro-inflammatory mode. Taking into account the indispensable role of inflammation in carcinogenesis, lipoxygenases have counteracting roles in this process. In addition to describing the structure-function of lipoxygenases in this review, we discuss their roles in such critical processes as cancer cell signaling, metastases, death of cancer and immune cells through ferroptosis, as well as the roles of ALOXs in carcinogenesis promoted by pathogenic infections. Finally, we discuss perspectives of novel oncotherapeutic approaches to harness lipoxygenase signaling in tumors.
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Affiliation(s)
- Abdul-Saleem Amoah
- Institute of Biomedical Chemistry, Moscow 119121, Russia; (A.-S.A.); (N.A.B.)
- Laboratory of Molecular Oncology, Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Nikolay B. Pestov
- Institute of Biomedical Chemistry, Moscow 119121, Russia; (A.-S.A.); (N.A.B.)
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (T.V.K.); (I.A.P.)
- Laboratory of Tick-Borne Encephalitis and Other Viral Encephalitides, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow 108819, Russia
- Vavilov Institute of General Genetics, Moscow 119991, Russia
| | - Tatyana V. Korneenko
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (T.V.K.); (I.A.P.)
| | - Igor A. Prokhorenko
- Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (T.V.K.); (I.A.P.)
| | - Georgy F. Kurakin
- Department of Biochemistry, Pirogov Russian National Research Medical University, Moscow 117513, Russia;
| | - Nickolai A. Barlev
- Institute of Biomedical Chemistry, Moscow 119121, Russia; (A.-S.A.); (N.A.B.)
- Laboratory of Tick-Borne Encephalitis and Other Viral Encephalitides, Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow 108819, Russia
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4
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Tajbakhsh A, Yousefi F, Farahani N, Savardashtaki A, Reiner Ž, Jamialahmadi T, Sahebkar A. Molecular Mechanisms and Therapeutic Potential of Resolvins in Cancer - Current Status and Perspectives. Curr Med Chem 2024; 31:5898-5917. [PMID: 37497711 DOI: 10.2174/0929867331666230727100123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 05/26/2023] [Accepted: 06/15/2023] [Indexed: 07/28/2023]
Abstract
Resolvins are specialized pro-resolving mediators derived from omega-3 fatty acids that can suppress several cancer-related molecular pathways, including important activation of transcription parameters in the tumor cells and their microenvironment, inflammatory cell infiltration, cytokines as well as chemokines. Recently, an association between resolvins and an important anti-inflammatory process in apoptotic tumor cell clearance (efferocytosis) was shown. The inflammation status or the oncogene activation increases the risk of cancer development via triggering the transcriptional agents, including nuclear factor kappa-light-chain-enhancer of activated B cells by generating the pro-inflammatory lipid molecules and infiltrating the tumor cells along with the high level of pro-inflammatory signaling. These events can cause an inflammatory microenvironment. Resolvins might decrease the leukocyte influx into the inflamed tissues. It is widely accepted that resolvins prohibit the development of debris-triggered cancer via increasing the clearance of debris, especially by macrophage phagocytosis in tumors without any side effects. Resolvins D2, D1, and E1 might suppress tumor-growing inflammation by activation of macrophages clearance of cell debris in the tumor. Resolvin D5 can assist patients with pain during treatment. However, the effects of resolvins as anti-inflammatory mediators in cancers are not completely explained. Thus, based on the most recent studies, we tried to summarize the most recent knowledge on resolvins in cancers.
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Affiliation(s)
- Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Yousefi
- Department of Biological Sciences, Faculty of Genetics, Tarbiat Modares University, Tehran, Iran
| | - Najmeh Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amir Savardashtaki
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Center Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
- Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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5
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Torres W, Pérez JL, Díaz MP, D’Marco L, Checa-Ros A, Carrasquero R, Angarita L, Gómez Y, Chacín M, Ramírez P, Villasmil N, Durán-Agüero S, Cano C, Bermúdez V. The Role of Specialized Pro-Resolving Lipid Mediators in Inflammation-Induced Carcinogenesis. Int J Mol Sci 2023; 24:12623. [PMID: 37628804 PMCID: PMC10454572 DOI: 10.3390/ijms241612623] [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: 03/02/2023] [Revised: 04/10/2023] [Accepted: 04/15/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer is a process involving cell mutation, increased proliferation, invasion, and metastasis. Over the years, this condition has represented one of the most concerning health problems worldwide due to its significant morbidity and mortality. At present, the incidence of cancer continues to grow exponentially. Thus, it is imperative to open new avenues in cancer research to understand the molecular changes driving DNA transformation, cell-to-cell interaction derangements, and immune system surveillance decay. In this regard, evidence supports the relationship between chronic inflammation and cancer. In light of this, a group of bioactive lipids derived from polyunsaturated fatty acids (PUFAs) may have a position as novel anti-inflammatory molecules known as the specialized pro-resolving mediators (SPMs), a group of pro-resolutive inflammation agents that could improve the anti-tumor immunity. These molecules have the potential role of chemopreventive and therapeutic agents for various cancer types, and their effects have been documented in the scientific literature. Thus, this review objective centers around understanding the effect of SPMs on carcinogenesis and their potential therapeutic effect.
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Affiliation(s)
- Wheeler Torres
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - José Luis Pérez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - María P. Díaz
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Luis D’Marco
- Grupo de Investigación en Enfermedades Cardiorrenales y Metabólicas, Departamento de Medicina y Cirugía, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, 46115 Valencia, Spain
| | - Ana Checa-Ros
- Grupo de Investigación en Enfermedades Cardiorrenales y Metabólicas, Departamento de Medicina y Cirugía, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, 46115 Valencia, Spain
| | - Rubén Carrasquero
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Lissé Angarita
- Escuela de Nutrición y Dietética, Facultad de Medicina, Universidad Andres Bello, Concepción 4260000, Chile
| | - Yosselin Gómez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Maricarmen Chacín
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080022, Colombia
| | - Paola Ramírez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Nelson Villasmil
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Samuel Durán-Agüero
- Facultad de Ciencias Para el Cuidado de la Salud, Universidad San Sebastián, Los Leones 8420524, Chile
| | - Clímaco Cano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Valmore Bermúdez
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080022, Colombia
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6
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Yang H, Rothenberger E, Zhao T, Fan W, Kelly A, Attaya A, Fan D, Panigrahy D, Deng J. Regulation of inflammation in cancer by dietary eicosanoids. Pharmacol Ther 2023:108455. [PMID: 37257760 DOI: 10.1016/j.pharmthera.2023.108455] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived from dietary polyunsaturated fatty acids, such as arachidonic acid (AA), and are mainly produced by a series of enzymatic pathways that include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenase (CYP). Eicosanoids consist of at least several hundred individual molecules and play important roles in the inflammatory response and inflammation-related cancers. SCOPE AND APPROACH Dietary sources of AA and biosynthesis of eicosanoids from AA through different metabolic pathways are summarized. The bioactivities of eicosanoids and their potential molecular mechanisms on inflammation and cancer are revealed. Additionally, current challenges and limitations in eicosanoid research on inflammation-related cancer are discussed. KEY FINDINGS AND CONCLUSIONS Dietary AA generates a large variety of eicosanoids, including prostaglandins, thromboxane A2, leukotrienes, cysteinyl leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Eicosanoids exert different bioactivities and mechanisms involved in the inflammation and related cancer developments. A deeper understanding of eicosanoid biology may be advantageous in cancer treatment and help to define cellular targets for further therapeutic development.
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Affiliation(s)
- Haixia Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
| | - Eva Rothenberger
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Tong Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Wendong Fan
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Abigail Kelly
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ahmed Attaya
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Jianjun Deng
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi'an 710069, China; State Key Laboratory of Vegetable Biobreeding, Institute of Vegetables and Flowers, Chinese Academy of Agricultural Sciences, Beijing 100081, China.
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Zhao Y, Zhang X, Wang G, Wu H, Chen R, Zhang Y, Yang S, Liu L. LXA4 inhibits TGF-β1-induced airway smooth muscle cells proliferation and migration by suppressing the Smad/YAP pathway. Int Immunopharmacol 2023; 118:110144. [PMID: 37030120 DOI: 10.1016/j.intimp.2023.110144] [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: 01/26/2023] [Revised: 03/29/2023] [Accepted: 03/31/2023] [Indexed: 04/10/2023]
Abstract
The aims of the present study were to examine the signaling mechanisms for transforming growth factor-β1 (TGF-β1)-induced rat airway smooth muscle cells (ASMCs) proliferation and migration and to determine the effect of lipoxin A4 (LXA4) on TGF-β1-induced rat ASMCs proliferation and migration and its underlying mechanisms. TGF-β1 upregulated transcriptional coactivator Yes-associated protein (YAP) expression by activating Smad2/3 and then upregulated cyclin D1, leading to rat ASMCs proliferation and migration. This effect was reversed after treatment with the TGF-β1 receptor inhibitor SB431542. YAP is a critical mediator of TGF-β1-induced ASMCs proliferation and migration. Knockdown of YAP disrupted the pro-airway remodeling function of TGF-β1. Preincubation of rat ASMCs with LXA4 blocked TGF-β1-induced activation of Smad2/3 and changed its downstream targets, YAP and cyclin D1, resulting in the inhibition of rat ASMCs proliferation and migration. Our study suggests that LXA4 suppresses Smad/YAP signaling to inhibit rat ASMCs proliferation and migration and therefore has potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.
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Affiliation(s)
- Yali Zhao
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Xiangli Zhang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Guizuo Wang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Hua Wu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Ruilin Chen
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Yongqing Zhang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Shumei Yang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China
| | - Lu Liu
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, No. 256, West Youyi Road, Xi'an, Shaanxi 710068, PR China.
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8
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Fuller H, Race AD, Fenton H, Burke L, Downing A, Williams EA, Rees CJ, Brown LC, Loadman PM, Hull MA. Plasma and rectal mucosal oxylipin levels during aspirin and eicosapentaenoic acid treatment in the seAFOod polyp prevention trial. Prostaglandins Leukot Essent Fatty Acids 2023; 192:102570. [PMID: 37003144 DOI: 10.1016/j.plefa.2023.102570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/03/2023]
Abstract
BACKGROUND Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months. METHODS Resolvin (Rv) E1, 15-epi-lipoxin (LX) A4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants. RESULTS Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21-1.95] ng/ml at baseline versus 0.95 [0.46-4.06] ng/ml at 6 months [P<0.0001] in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin. CONCLUSION Analysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15‑epi-LXA4. We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation.
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Affiliation(s)
- H Fuller
- Leeds Institute of Medical Research, University of Leeds, UK
| | - A D Race
- Institute of Cancer Therapeutics, University of Bradford, UK
| | - H Fenton
- Leeds Institute of Medical Research, University of Leeds, UK
| | - L Burke
- Institute of Cancer Therapeutics, University of Bradford, UK
| | - A Downing
- Leeds Institute of Medical Research, University of Leeds, UK
| | - E A Williams
- Department of Oncology and Metabolism, University of Sheffield, UK
| | - C J Rees
- Population Health Science Institute, Newcastle University, UK
| | - L C Brown
- MRC Clinical Trials Unit at University College, London, UK
| | - P M Loadman
- Institute of Cancer Therapeutics, University of Bradford, UK
| | - M A Hull
- Leeds Institute of Medical Research, University of Leeds, UK.
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9
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Hoxha M, Zappacosta B. A review on the role of fatty acids in colorectal cancer progression. Front Pharmacol 2022; 13:1032806. [PMID: 36578540 PMCID: PMC9791100 DOI: 10.3389/fphar.2022.1032806] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/30/2022] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of mortality in cancer patients. The role of fatty acids (FA) and their metabolism in cancer, particularly in CRC raises a growing interest. In particular, dysregulation of synthesis, desaturation, elongation, and mitochondrial oxidation of fatty acids are involved. Here we review the current evidence on the link between cancer, in particular CRC, and fatty acids metabolism, not only to provide insight on its pathogenesis, but also on the development of novel biomarkers and innovative pharmacological therapies that are based on FAs dependency of cancer cells.
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10
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Burke ND, Nixon B, Roman SD, Schjenken JE, Walters JLH, Aitken RJ, Bromfield EG. Male infertility and somatic health - insights into lipid damage as a mechanistic link. Nat Rev Urol 2022; 19:727-750. [PMID: 36100661 DOI: 10.1038/s41585-022-00640-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2022] [Indexed: 11/08/2022]
Abstract
Over the past decade, mounting evidence has shown an alarming association between male subfertility and poor somatic health, with substantial evidence supporting the increased incidence of oncological disease, cardiovascular disease, metabolic disorders and autoimmune diseases in men who have previously received a subfertility diagnosis. This paradigm is concerning, but might also provide a novel window for a crucial health reform in which the infertile phenotype could serve as an indication of potential pathological conditions. One of the major limiting factors in this association is the poor understanding of the molecular features that link infertility with comorbidities across the life course. Enzymes involved in the lipid oxidation process might provide novel clues to reconcile the mechanistic basis of infertility with incident pathological conditions. Building research capacity in this area is essential to enhance the early detection of disease states and provide crucial information about the disease risk of offspring conceived through assisted reproduction.
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Affiliation(s)
- Nathan D Burke
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia
| | - Brett Nixon
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia
| | - Shaun D Roman
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia
- Priority Research Centre for Drug Development, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
| | - John E Schjenken
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia
| | - Jessica L H Walters
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia
| | - R John Aitken
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia
| | - Elizabeth G Bromfield
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, Discipline of Biological Sciences, University of Newcastle, Callaghan, New South Wales, Australia.
- Hunter Medical Research Institute, Infertility and Reproduction Research Program, New Lambton Heights, New South Wales, Australia.
- Department of Biomolecular Health Sciences, Utrecht University, Utrecht, Netherlands.
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11
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Udumula MP, Poisson LM, Dutta I, Tiwari N, Kim S, Chinna-Shankar J, Allo G, Sakr S, Hijaz M, Munkarah AR, Giri S, Rattan R. Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo. Cancers (Basel) 2022; 14:cancers14061504. [PMID: 35326656 PMCID: PMC8946838 DOI: 10.3390/cancers14061504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/07/2022] [Accepted: 03/12/2022] [Indexed: 02/01/2023] Open
Abstract
Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.
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Affiliation(s)
- Mary P. Udumula
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Laila M. Poisson
- Center for Bioinformatics, Department of Public Health Services, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (L.M.P.); (I.D.)
| | - Indrani Dutta
- Center for Bioinformatics, Department of Public Health Services, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (L.M.P.); (I.D.)
| | - Nivedita Tiwari
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Seongho Kim
- Biostatistics and Bioinformatics Core, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA;
| | - Jasdeep Chinna-Shankar
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Ghassan Allo
- Department of Pathology, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA;
| | - Sharif Sakr
- Department of Gynecology Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA;
| | - Miriana Hijaz
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Adnan R. Munkarah
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
| | - Shailendra Giri
- Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA;
| | - Ramandeep Rattan
- Department of Women’s Health Services, Henry Ford Hospital, Henry Ford Cancer Institute, Detroit, MI 48202, USA; (M.P.U.); (N.T.); (J.C.-S.); (M.H.); (A.R.M.)
- Department of Oncology, Wayne State School of Medicine, Detroit, MI 48201, USA
- Correspondence: ; Tel.: +313-876-7381; Fax: +313-876-3415
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12
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Schneider Alves AC, Cardoso RS, de Oliveira Neto XA, Kawano DF. Uncovering the Potential of Lipid Drugs: A Focus on Transient Membrane Microdomain-Targeted Lipid Therapeutics. Mini Rev Med Chem 2022; 22:2318-2331. [PMID: 35264091 DOI: 10.2174/1389557522666220309162203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/27/2021] [Accepted: 01/27/2022] [Indexed: 11/22/2022]
Abstract
Membrane lipids are generally viewed as inert physical barriers, but many vital cellular processes greatly rely on the interaction with these structures, as expressed by the membrane hypothesis that explain the genesis of schizophrenia, Alzheimer's and autoimmune diseases, chronic fatigue or cancer, among others. The concept that the cell membrane displays transient membrane microdomains with distinct lipid composition provide the basis for the development of selective lipid-targeted therapies, the membrane-lipid therapies (MLTs). In this concern, medicinal chemists may design therapeutically valuable compounds 1) with a higher affinity for the lipids in these microdomains to restore the normal physiological conditions, 2) that can directly or 3) indirectly (via enzyme inhibition/activation) replace damaged lipids or restore the regular lipid levels in the whole membrane or microdomain, 4) that alter the expression of genes related to lipid genesis/metabolism or 5) that modulate the pathways related to the membrane binding affinity of lipid-anchored proteins. In this context, this mini-review aims to explore the structural diversity and clinical applications of some of the main membrane and microdomain-targeted lipid drugs.
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Affiliation(s)
- Anna Carolina Schneider Alves
- Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP 200 Cândido Portinari Street, Campinas, SP 13083871. Brazil
| | - Raquel Soares Cardoso
- Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP. 200 Cândido Portinari Street, Campinas, SP 13083871. Brazil
| | - Xisto Antonio de Oliveira Neto
- Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP. 200 Cândido Portinari Street, Campinas, SP 13083871. Brazil
| | - Daniel Fábio Kawano
- Faculty of Pharmaceutical Sciences, University of Campinas - UNICAMP. 200 Cândido Portinari Street, Campinas, SP 13083871. Brazil
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13
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Kolawole OR, Kashfi K. NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 2022; 23:1432. [PMID: 35163356 PMCID: PMC8836048 DOI: 10.3390/ijms23031432] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
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Affiliation(s)
- Oluwafunke R. Kolawole
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10091, USA
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14
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Abstract
Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell “debris” which can promote tumor progression. Thus, therapy can be a double-edged sword. Specifically, injury and debris generated by cancer therapies, including chemotherapy, radiation, and surgery, may offset their benefit by promoting the secretion of pro-tumorigenic factors (e.g., eicosanoid-driven cytokines) that stimulate regrowth and metastasis of surviving cells. The debris produced by cytotoxic cancer therapy can also contribute to a tumor microenvironment that promotes tumor progression and recurrence. Although not well understood, several molecular mechanisms have been implicated in debris-stimulated tumor growth that we review here, such as the involvement of extracellular vesicles, exosomal miR-194-5p, Bax, Bak, Smac, HMGB1, cytokines, and caspase-3. We discuss the cases of pancreatic and other cancer types where debris promotes postoperative tumor recurrence and metastasis, thus offering a new opportunity to prevent cancer progression intrinsically linked to treatment by stimulating resolution of tumor-promoting debris.
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Affiliation(s)
- Victoria M Haak
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
| | - Sui Huang
- Institute for Systems Biology, Seattle, WA, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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15
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Abstract
Metabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.
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Affiliation(s)
- Huakan Zhao
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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16
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Volpato M, Ingram N, Perry SL, Spencer J, Race AD, Marshall C, Hutchinson JM, Nicolaou A, Loadman PM, Coletta PL, Hull MA. Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. Cancer Chemother Pharmacol 2020; 87:173-184. [PMID: 33040178 PMCID: PMC7870614 DOI: 10.1007/s00280-020-04157-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/24/2020] [Indexed: 01/05/2023]
Abstract
Purpose The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. Methods A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. Results Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. Conclusion Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies. Electronic supplementary material The online version of this article (10.1007/s00280-020-04157-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Milene Volpato
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK.
| | - Nicola Ingram
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Sarah L Perry
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Jade Spencer
- Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK
| | - Amanda D Race
- Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK
| | - Catriona Marshall
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - John M Hutchinson
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Anna Nicolaou
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT, UK.,Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, M13 9PT, UK
| | - Paul M Loadman
- Institute of Cancer Therapeutics, University of Bradford, Bradford, BD7 1DP, UK
| | - P Louise Coletta
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
| | - Mark A Hull
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, LS9 7TF, UK
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17
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D’Angelo S, Motti ML, Meccariello R. ω-3 and ω-6 Polyunsaturated Fatty Acids, Obesity and Cancer. Nutrients 2020; 12:nu12092751. [PMID: 32927614 PMCID: PMC7551151 DOI: 10.3390/nu12092751] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/01/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022] Open
Abstract
Recently, nutraceutical bioactive compounds in foods have been discovered for their potential health benefits regarding the prevention of chronic disorders, such as cancer, and inflammatory, cardiovascular, and metabolic diseases. Dietary omega-3 polyunsaturated fatty acids (ω-3PUFAs), including alpha-linolenic acid, docosapentaenoic acid, and eicosapentaenoic acid, are mostly attractive. They are available for the customers worldwide from commonly used foods and/or as components of commercial food supplements. The anti-inflammatory and hypotriglyceridemic effects of these fatty acids are well known, whereas pro-inflammatory properties have been recognized in their dietary counterparts, the ω-6PUFAs. Both ω-3 and ω-6PUFAs contribute to the production of lipid mediators such as endocannabinoids that are notably involved in control of food intake, energy sensing, and food-related disorders. In this review, we present ω-3 and ω-6PUFAs and their derivatives, endocannabinoids; discuss the anti-obesity effects of ω-3PUFAs; their roles in inflammation and colorectal cancer development; and how their action can be co-preventative and co-therapeutic.
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18
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Fu T, Mohan M, Brennan EP, Woodman OL, Godson C, Kantharidis P, Ritchie RH, Qin CX. Therapeutic Potential of Lipoxin A 4 in Chronic Inflammation: Focus on Cardiometabolic Disease. ACS Pharmacol Transl Sci 2020; 3:43-55. [PMID: 32259087 DOI: 10.1021/acsptsci.9b00097] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Indexed: 02/07/2023]
Abstract
Several studies have shown that failure to resolve inflammation may contribute to the progression of many chronic inflammatory disorders. It has been suggested targeting the resolution of inflammation might be a novel therapeutic approach for chronic inflammatory diseases, including inflammatory bowel disease, diabetic complications, and cardiometabolic disease. Lipoxins [LXs] are a class of endogenously generated mediators that promote the resolution of inflammation. Biological actions of LXs include inhibition of neutrophil infiltration, promotion of macrophage polarization, increase of macrophage efferocytosis, and restoration of tissue homeostasis. Recently, several studies have demonstrated that LXs and synthetic analogues protect tissues from acute and chronic inflammation. The mechanism includes down-regulation of pro-inflammatory cytokines and chemokines (e.g., interleukin-1β and tumor necrosis factor-α), inhibition of the activation of the master pro-inflammatory pathway (e.g., nuclear factor κ-light-chain-enhancer of activated B cells pathway) and increased release of the pro-resolving cytokines (e.g., interleukin-10). Three generations of LXs analogues are well described in the literature, and more recently a fourth generation has been generated that appears to show enhanced potency. In this review, we will briefly discuss the potential therapeutic opportunity provided by lipoxin A4 as a novel approach to treat chronic inflammatory disorders, focusing on cardiometabolic disease and the current drug development in this area.
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Affiliation(s)
- Ting Fu
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Muthukumar Mohan
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
| | - Eoin P Brennan
- UCD Diabetes Complications Research Centre, UCD Conway Institute, UCD School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Owen L Woodman
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, UCD Conway Institute, UCD School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Phillip Kantharidis
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
| | - Rebecca H Ritchie
- Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia.,Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | - Cheng Xue Qin
- Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria 3800, Australia
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19
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Sanfilippo C, Paterna A, Biondi DM, Patti A. Lyophilized extracts from vegetable flours as valuable alternatives to purified oxygenases for the synthesis of oxylipins. Bioorg Chem 2019; 93:103325. [PMID: 31586707 DOI: 10.1016/j.bioorg.2019.103325] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/25/2019] [Accepted: 09/26/2019] [Indexed: 12/31/2022]
Abstract
In this work, the whole aqueous extracts of soybean flour and oat flour have been used as valuable alternatives to purified oxygenase enzymes for the preparation of oxylipins derived from (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoic acid (EPA). The lipoxygenase activity in the aqueous extracts of soybean (Glycine max. L.) flour was monitored with linoleic acid as substrate and compared with the commercially available purified enzyme (LOX-1). Oat flour extracts (Avena sativa L.) were evaluated for their peroxygenase activity by comparing different enzyme preparations in the epoxidation of methyl oleate. It was found that lyophilization of the aqueous extracts from these vegetable flours offers advantages in terms of enzyme stability, reproducibility and applicability to preparative organic synthesis. The lyophilized enzyme preparations were tested for the oxyfunctionalization of EPA and the formed products were isolated in satisfactory yields. In the presence of lyophilized extract from soybean, EPA gave 15S-hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic acid in enantiopure form as exclusive product. Peroxygenase from oat flour was less selective and catalyzed the formation of different epoxides of EPA. However, the biocatalyzed epoxidation of EPA under controlled conditions allowed to obtain optically active (17R,18S)-epoxy-(5Z,8Z,11Z,14Z)-eicosatetraenoic acid (65% ee) as the main monoepoxide, among the five possible ones.
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Affiliation(s)
- Claudia Sanfilippo
- CNR - Istituto di Chimica Biomolecolare, Via Paolo Gaifami 18, I-95126 Catania, Italy
| | - Angela Paterna
- CNR - Istituto di Chimica Biomolecolare, Via Paolo Gaifami 18, I-95126 Catania, Italy
| | - Daniela M Biondi
- CNR - Istituto di Chimica Biomolecolare, Via Paolo Gaifami 18, I-95126 Catania, Italy
| | - Angela Patti
- CNR - Istituto di Chimica Biomolecolare, Via Paolo Gaifami 18, I-95126 Catania, Italy.
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20
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Liu H, Zeng J, Huang W, Xu Q, Ye D, Sun R, Zhang D. Colorectal Cancer Is Associated with a Deficiency of Lipoxin A 4, an Endogenous Anti-inflammatory Mediator. J Cancer 2019; 10:4719-4730. [PMID: 31528237 PMCID: PMC6746129 DOI: 10.7150/jca.32456] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 07/17/2019] [Indexed: 01/01/2023] Open
Abstract
Unresolved inflammation, due to insufficient production of proresolving anti-inflammatory lipid mediators, can lead to tumorigenesis. Among these mediators, lipoxin A4 (LXA4) has potent anti-carcinogenic properties, and may serve as key target for modulating inflammation-associated cancer like colorectal cancer. The purpose of present study was to clarify the roles of LXA4 in colorectal cancer. We investigated the effects and underlying mechanisms of LXA4 in colorectal cancer and its relationship with tumor-associated inflammation and immune microenvironment by employing clinical samples and mouse colorectal cancer cell line CT26-bearing tumor model as well as colorectal cancer cells. It was found that colorectal cancer is associated with dysregulation of immune microenvironment and deficiency of LXA4 that could play different roles at different stages of tumor growth: inhibiting early but promoting late tumor growth. Analysis of peripheral immune cells in subcutaneous xenograft mice model disclosed that early LXA4 treatment induced lymphocytes and inhibited neutrophils and monocytes, while late LXA4 treatment induced neutrophils but inhibited lymphocytes. Detailed analysis of tumor microenvironment revealed that early LXA4 treatment could inhibit inflammatory mediators expressions and leukocytes infiltration into tumor. Furthermore, LXA4 could suppress the expressions of p-ERK, p-P38 and NF-κB in subcutaneous xenograft. Additionally, LXA4 could inhibit the proliferation and migration of colorectal cancer cells, and, meanwhile, inhibit the proliferation and migration of colorectal cancer cells stimulated by activated macrophage-conditioned media. These findings suggest that colorectal cancer is associated with a deficiency of LXA4 that could suppress colorectal cancer via modulating tumor-associated inflammation and immune microenvironment as well as inhibiting colorectal cancer cell development.
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Affiliation(s)
- Haojing Liu
- Department of Internal Medicine, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China
| | - Ji Zeng
- Department of Clinical Laboratory, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China
| | - Wei Huang
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Qiang Xu
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Duyun Ye
- Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
| | - Rui Sun
- Department of Oncology, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China
| | - Dongxin Zhang
- Department of Clinical Laboratory, Wuhan Fourth Hospital; Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430033, People's Republic of China.,Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China
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21
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Li J, Chen CY, Arita M, Kim K, Li X, Zhang H, Kang JX. An omega-3 polyunsaturated fatty acid derivative, 18-HEPE, protects against CXCR4-associated melanoma metastasis. Carcinogenesis 2018; 39:1380-1388. [PMID: 30184109 PMCID: PMC7191087 DOI: 10.1093/carcin/bgy117] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/23/2018] [Accepted: 09/03/2018] [Indexed: 12/28/2022] Open
Abstract
Melanoma has a high propensity to metastasize and exhibits a poor response to classical therapies. Dysregulation of the chemokine receptor gene CXCR4 is associated with melanoma progression, and although n-3 polyunsaturated fatty acids (PUFAs) are known to be beneficial for melanoma prevention, the underlying mechanism of this effect is unclear. Here, we used the n-3 fatty acid desaturase (Fat-1) transgenic mouse model of endogenous n-3 PUFA synthesis to investigate the influence of elevated n-3 PUFA levels in a mouse model of metastatic melanoma. We found that relative to wild-type (WT) mice, Fat-1 mice exhibited fewer pulmonary metastatic colonies and improved inflammatory indices, including reduced serum tumor necrosis factor alpha (TNF-α) levels and pulmonary myeloperoxidase activity. Differential PUFA metabolites in serum were considered a key factor to alter cancer cell travelling to lung, and we found that n-6 PUFAs such as arachidonic acid induced CXCR4 protein expression although n-3 PUFAs such as eicosapentaenoic acid (EPA) decreased CXCR4 levels. In addition, serum levels of the bioactive EPA metabolite, 18-HEPE, were elevated in Fat-1 mice relative to WT mice, and 18-HEPE suppressed CXCR4 expression in B16-F0 cells. Moreover, relative to controls, numbers of pulmonary metastatic colonies were reduced in WT mice receiving intravenous injections either of 18-HEPE or 18-HEPE-pretreated melanoma cells. Our results indicate that 18-HEPE is a potential anticancer metabolite that mediates, at least in part, the preventive effect of n-3 PUFA on melanoma metastasis.
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Affiliation(s)
- Jieping Li
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Clinic Medical Laboratory, General Hospital of Fujian Corps of CAPF, Fuzhou, China
| | - Chih-Yu Chen
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Makoto Arita
- Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Kuijin Kim
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Xiangyong Li
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hongman Zhang
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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22
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Philpott JD, Witard OC, Galloway SD. Applications of omega-3 polyunsaturated fatty acid supplementation for sport performance. Res Sports Med 2018; 27:219-237. [DOI: 10.1080/15438627.2018.1550401] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Jordan D. Philpott
- Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK
| | - Oliver C. Witard
- Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK
| | - Stuart D.R. Galloway
- Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK
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23
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Lee HJ, Han YM, An JM, Kang EA, Park YJ, Cha JY, Hahm KB. Role of omega-3 polyunsaturated fatty acids in preventing gastrointestinal cancers: current status and future perspectives. Expert Rev Anticancer Ther 2018; 18:1189-1203. [DOI: 10.1080/14737140.2018.1524299] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Ho-Jae Lee
- Department of Biochemistry, Gachon University College of Medicine, Incheon, Korea
| | - Young-Min Han
- Western Seoul Center, Korea Basic Science Institute, Seoul, Korea
| | - Jeong Min An
- CHA Cancer Preventive Research Center, CHA Bio Complex, Pangyo, Korea
| | - Eun A. Kang
- CHA Cancer Preventive Research Center, CHA Bio Complex, Pangyo, Korea
| | | | - Ji-Young Cha
- Department of Biochemistry, Gachon University College of Medicine, Incheon, Korea
| | - Ki Baik Hahm
- CHA Cancer Preventive Research Center, CHA Bio Complex, Pangyo, Korea
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea
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24
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Shen Y, Wang C, Ren Y, Ye J. A comprehensive look at the role of hyperlipidemia in promoting colorectal cancer liver metastasis. J Cancer 2018; 9:2981-2986. [PMID: 30123367 PMCID: PMC6096362 DOI: 10.7150/jca.25640] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most malignant cancers, and it tends to migrate to the liver and has a high mortality rate. Several mechanisms behind the metastasis of CRC have been identified, including hyperlipidemia. For example, hyperlipidemia can lead to enhanced stemness and neutrophil infiltration, which increases CRC metastasis. There are three primary aspects to the relationship between hyperlipidemia and CRC metastasis: hyperlipidemia (1) promotes the initial metastatic properties of CRC, (2) stimulates CRC cells to leave the vasculature, and (3) facilitates the development of CRC metastasis. In this study, we provide a comprehensive overview of the role that hyperlipidemia played in CRC metastasis to help reduce the mortality associated with CRC metastasis from the standpoint of metabolic. We also review cancer metastasis.
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Affiliation(s)
- Yimin Shen
- 1 Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Caihua Wang
- 2 Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yuezhong Ren
- 1 Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jun Ye
- 2 Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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25
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26
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Jain R, Austin Pickens C, Fenton JI. The role of the lipidome in obesity-mediated colon cancer risk. J Nutr Biochem 2018; 59:1-9. [PMID: 29605789 DOI: 10.1016/j.jnutbio.2018.02.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 02/07/2018] [Accepted: 02/13/2018] [Indexed: 02/07/2023]
Abstract
Obesity is a state of chronic inflammation influenced by lipids such as fatty acids and their secondary oxygenated metabolites deemed oxylipids. Many such lipid mediators serve as potent signaling molecules of inflammation, which can further alter lipid metabolism and lead to carcinogenesis. For example, sphingosine-1-phosphate activates cyclooxygenase-2 in endothelial cells resulting in the conversion of arachidonic acid (AA) to prostaglandin E2 (PGE2). PGE2 promotes colon cancer cell growth. In contrast, the less studied path of AA oxygenation via cytochrome p450 enzymes produces epoxyeicosatetraenoic acids (EETs), whose anti-inflammatory properties cause shrinking of enlarged adipocytes, a characteristic of obesity, through the liberation of fatty acids. It is now thought that EET depletion occurs in obesity and may contribute to colon cell carcinogenesis. Meanwhile, gangliosides, a type of sphingolipid, are cell surface signaling molecules that contribute to the apoptosis of colon tumor cells. Many of these discoveries have been made recently and the mechanisms are still not fully understood, leading to an exciting new chapter of lipidomic research. In this review, mechanisms behind obesity-associated colon cancer are discussed with a focus on the role of small lipid signaling molecules in the process. Specifically, changes in lipid metabolite levels during obesity and the development of colon cancer, as well as novel biomarkers and targets for therapy, are discussed.
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Affiliation(s)
- Raghav Jain
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, USA
| | - C Austin Pickens
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, USA
| | - Jenifer I Fenton
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, USA.
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Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis. Int J Mol Sci 2017; 18:ijms18122661. [PMID: 29292756 PMCID: PMC5751263 DOI: 10.3390/ijms18122661] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/02/2017] [Accepted: 12/06/2017] [Indexed: 12/14/2022] Open
Abstract
Metastatic breast cancer (BC) (also referred to as stage IV) spreads beyond the breast to the bones, lungs, liver, or brain and is a major contributor to the deaths of cancer patients. Interestingly, metastasis is a result of stroma-coordinated hallmarks such as invasion and migration of the tumor cells from the primary niche, regrowth of the invading tumor cells in the distant organs, proliferation, vascularization, and immune suppression. Targeted therapies, when used as monotherapies or combination therapies, have shown limited success in decreasing the established metastatic growth and improving survival. Thus, novel therapeutic targets are warranted to improve the metastasis outcomes. We have been actively investigating the cytochrome P450 4 (CYP4) family of enzymes that can biosynthesize 20-hydroxyeicosatetraenoic acid (20-HETE), an important signaling eicosanoid involved in the regulation of vascular tone and angiogenesis. We have shown that 20-HETE can activate several intracellular protein kinases, pro-inflammatory mediators, and chemokines in cancer. This review article is focused on understanding the role of the arachidonic acid metabolic pathway in BC metastasis with an emphasis on 20-HETE as a novel therapeutic target to decrease BC metastasis. We have discussed all the significant investigational mechanisms and put forward studies showing how 20-HETE can promote angiogenesis and metastasis, and how its inhibition could affect the metastatic niches. Potential adjuvant therapies targeting the tumor microenvironment showing anti-tumor properties against BC and its lung metastasis are discussed at the end. This review will highlight the importance of exploring tumor-inherent and stromal-inherent metabolic pathways in the development of novel therapeutics for treating BC metastasis.
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Gkretsi V, Zacharia LC, Stylianopoulos T. Targeting Inflammation to Improve Tumor Drug Delivery. Trends Cancer 2017; 3:621-630. [PMID: 28867166 PMCID: PMC5614424 DOI: 10.1016/j.trecan.2017.07.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 07/21/2017] [Accepted: 07/24/2017] [Indexed: 12/17/2022]
Abstract
Inefficient delivery of drugs is a main cause of chemotherapy failure in hypoperfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness, and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on anti-angiogenic drugs, whereas stress alleviation is based on stroma-depleting agents. We present here an alternative approach to normalize tumor vasculature, taking into account that malignant tumors tend to develop at sites of chronic inflammation. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyperpermeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) or inflammation resolution mediators, as an alternative means to increase tumor drug delivery might prove promising.
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Affiliation(s)
- Vasiliki Gkretsi
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
| | - Lefteris C Zacharia
- Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
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29
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Kutzner L, Goloshchapova K, Heydeck D, Stehling S, Kuhn H, Schebb NH. Mammalian ALOX15 orthologs exhibit pronounced dual positional specificity with docosahexaenoic acid. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:666-675. [DOI: 10.1016/j.bbalip.2017.04.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 04/05/2017] [Accepted: 04/07/2017] [Indexed: 01/18/2023]
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30
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Wu RF, Yang HM, Zhou WD, Zhang LR, Bai JB, Lin DC, Ng TW, Dai SJ, Chen QH, Chen QX. Effect of interleukin-1β and lipoxin A 4 in human endometriotic stromal cells: Proteomic analysis. J Obstet Gynaecol Res 2016; 43:308-319. [PMID: 27987338 DOI: 10.1111/jog.13201] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 08/23/2016] [Accepted: 09/11/2016] [Indexed: 12/19/2022]
Abstract
AIM Lipoxin A4 (LXA4 ) can function as an endogenous 'breaking signal' in inflammation and plays an important role in the progression of endometriosis. The proteome responses to interleukin-1β (IL-1β) or LXA4 in human endometriotic stromal cells (ESC) are not well understood. METHODS In this study, primary ESC were cultured from ovarian endometriosis tissue. Three groups were established: the control group; the IL-1β stimulation group; and the IL-1β and LXA4 incubation group. Proteins were assessed on 2-D polyacrylamide gel electrophoresis (2D-PAGE), and differentially expressed protein spots were further identified on matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MALDI-TOF-MS). Wound healing and transwell assays were performed to assess the migration and invasion of ESC after treatment. RESULTS In total, 40 differentially expressed protein spots were identified successfully on MALDI-TOF-MS. The proteins identified were related to cell structure, metabolism, signal transduction, protein synthesis and membrane structure, processes that may be involved in the development of endometriosis. Vinculin and IL-4 were further analyzed on western blot and quantitative real-time polymerase chain reaction. Moreover, LXA4 could suppress the migration and invasion of ESC induced by IL-1β. CONCLUSION LXA4 may inhibit the progression of endometriosis partly by lowering or raising the effect of IL-1β, mediated via some inflammation-related proteins (e.g. vinculin) and immune response-related protein (e.g. IL-4) in vitro.
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Affiliation(s)
- Rong-Feng Wu
- State Key Laboratory of Cellular Stress Biology and Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, China
| | - Hui-Ming Yang
- State Key Laboratory of Cellular Stress Biology and Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, China
| | - Wei-Dong Zhou
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Li-Rong Zhang
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jian-Bing Bai
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Dian-Chao Lin
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Tai-Wei Ng
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Song-Juan Dai
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Qiong-Hua Chen
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Qing-Xi Chen
- State Key Laboratory of Cellular Stress Biology and Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, School of Life Sciences, Xiamen University, Xiamen, China
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31
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Miccadei S, Masella R, Mileo AM, Gessani S. ω3 Polyunsaturated Fatty Acids as Immunomodulators in Colorectal Cancer: New Potential Role in Adjuvant Therapies. Front Immunol 2016; 7:486. [PMID: 27895640 PMCID: PMC5108786 DOI: 10.3389/fimmu.2016.00486] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 10/21/2016] [Indexed: 12/13/2022] Open
Abstract
Diet composition may affect the onset and progression of chronic degenerative diseases, including cancer, whose pathogenesis relies on inflammatory processes. Growing evidence indicates that diet and its components critically contribute to human health, affecting the immune system, secretion of adipokines, and metabolic pathways. Colorectal cancer (CRC) is one of the leading causes of death worldwide. Antineoplastic drugs are widely used for CRC treatment, but drug resistance and/or off-target toxicity limit their efficacy. Dietary ω3 polyunsaturated fatty acids (PUFA) have been gaining great interest in recent years as possible anti-inflammatory and anticancer agents, especially in areas such as the large bowel, where the pro-inflammatory context promotes virtually all steps of colon carcinogenesis. Growing epidemiological, experimental, and clinical evidence suggests that ω3 PUFA may play a role in several stages of CRC management exhibiting antineoplastic activity against human CRC cells, improving the efficacy of radiation and chemotherapy, ameliorating cancer-associated secondary complications, and preventing CRC recurrence. These effects are most likely related to the immunomodulatory activities of ω3 PUFA that are able to influence several aspects of the inflammatory process ranging from inflammasome activation, leukocyte recruitment, production of immune mediators to differentiation, and activation of immune cells. In this review, we will focus on the potential use of ω3 PUFA as adjuvant agents together with chemo/radiotherapy, highlighting the immunomodulatory effects most likely responsible for their beneficial effects in different stages of CRC management.
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Affiliation(s)
- Stefania Miccadei
- Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostic and Technological Innovation, Regina Elena National Cancer Institute , Rome , Italy
| | - Roberta Masella
- Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità , Rome , Italy
| | - Anna Maria Mileo
- Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostic and Technological Innovation, Regina Elena National Cancer Institute , Rome , Italy
| | - Sandra Gessani
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità , Rome , Italy
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32
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Colombo JS, Moore AN, Hartgerink JD, D'Souza RN. Scaffolds to control inflammation and facilitate dental pulp regeneration. J Endod 2016; 40:S6-12. [PMID: 24698696 DOI: 10.1016/j.joen.2014.01.019] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In dentistry, the maintenance of a vital dental pulp is of paramount importance because teeth devitalized by root canal treatment may become more brittle and prone to structural failure over time. Advanced carious lesions can irreversibly damage the dental pulp by propagating a sustained inflammatory response throughout the tissue. Although the inflammatory response initially drives tissue repair, sustained inflammation has an enormously destructive effect on the vital pulp, eventually leading to total necrosis of the tissue and necessitating its removal. The implications of tooth devitalization have driven significant interest in the development of bioactive materials that facilitate the regeneration of damaged pulp tissues by harnessing the capacity of the dental pulp for self-repair. In considering the process by which pulpitis drives tissue destruction, it is clear that an important step in supporting the regeneration of pulpal tissues is the attenuation of inflammation. Macrophages, key mediators of the immune response, may play a critical role in the resolution of pulpitis because of their ability to switch to a proresolution phenotype. This process can be driven by the resolvins, a family of molecules derived from fatty acids that show great promise as therapeutic agents. In this review, we outline the importance of preserving the capacity of the dental pulp to self-repair through the rapid attenuation of inflammation. Potential treatment modalities, such as shifting macrophages to a proresolving phenotype with resolvins are described, and a range of materials known to support the regeneration of dental pulp are presented.
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Affiliation(s)
- John S Colombo
- School of Dentistry, University of Utah, Salt Lake City, Utah; Department of Chemistry and Bioengineering, Rice University, Houston, Texas
| | - Amanda N Moore
- Department of Chemistry and Bioengineering, Rice University, Houston, Texas
| | | | - Rena N D'Souza
- School of Dentistry, University of Utah, Salt Lake City, Utah. RD'
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Dolowschiak T, Mueller AA, Pisan LJ, Feigelman R, Felmy B, Sellin ME, Namineni S, Nguyen BD, Wotzka SY, Heikenwalder M, von Mering C, Mueller C, Hardt WD. IFN-γ Hinders Recovery from Mucosal Inflammation during Antibiotic Therapy for Salmonella Gut Infection. Cell Host Microbe 2016; 20:238-49. [PMID: 27453483 DOI: 10.1016/j.chom.2016.06.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Revised: 05/08/2016] [Accepted: 06/14/2016] [Indexed: 12/30/2022]
Abstract
Salmonella Typhimurium (S.Tm) causes acute enteropathy resolving after 4-7 days. Strikingly, antibiotic therapy does not accelerate disease resolution. We screened for factors blocking remission using a S.Tm enterocolitis model. The antibiotic ciprofloxacin clears pathogen stool loads within 3-24 hr, while gut pathology resolves more slowly (ψ50: ∼48 hr, remission: 6-9 days). This delayed resolution is mediated by an interferon-γ (IFN-γ)-dependent response that is triggered during acute infection and continues throughout therapy. Specifically, IFN-γ production by mucosal T and NK cells retards disease resolution by maintaining signaling through the transcriptional regulator STAT1 and boosting expression of inflammatory mediators like IL-1β, TNF, and iNOS. Additionally, sustained IFN-γ fosters phagocyte accumulation and hampers antimicrobial defense mediated by IL-22 and the lectin REGIIIβ. These findings reveal a role for IFN-γ in delaying resolution of intestinal inflammation and may inform therapies for acute Salmonella enteropathy, chronic inflammatory bowel diseases, or disease resolution during antibiotic treatment.
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Affiliation(s)
| | | | | | - Rounak Feigelman
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
| | - Boas Felmy
- Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland
| | | | | | | | | | - Mathias Heikenwalder
- Institute of Virology, TU Munich, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, DKFZ, 69121 Heidelberg, Germany
| | - Christian von Mering
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
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Chandrasekharan JA, Marginean A, Sharma-Walia N. An insight into the role of arachidonic acid derived lipid mediators in virus associated pathogenesis and malignancies. Prostaglandins Other Lipid Mediat 2016; 126:46-54. [PMID: 27450483 DOI: 10.1016/j.prostaglandins.2016.07.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 06/25/2016] [Accepted: 07/18/2016] [Indexed: 12/14/2022]
Abstract
Several studies shed light on the size and diversity of the lipidome, along with its role in physiological and pathological processes in human health. Besides that, lipids also function as important signaling mediators. This review focuses on discussing the role of arachidonic acid (AA) derived lipids as mediators in diseases with special emphasis on viral infections. Structurally, arachidonic acid derived lipids, also referred to as lipid mediators, can be classified into three specific classes: Class 1-eicosanoids derived from arachidonic acid metabolism; Class 2-lysophospholipids consisting of either a glycerol or a sphingosine backbone; Class 3-AA and ω-3 polyunsaturated fatty acid (PUFA) derivatives. Class 1 and 2 lipids are commonly referred to as pro-inflammatory molecules, which are found upregulated in diseases like cancer and viral infection. Class 3 lipids are anti-inflammatory molecules, which could be potentially used in treatment of diseases associated with inflammation. The function of each class has been elucidated as unique and contributory to an overall cellular homeostasis. Current work in this field is promising and will surely usher in a new era of lipid understanding and control not only at the molecular level, but also in terms of holistic patient care.
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Affiliation(s)
- Jayashree A Chandrasekharan
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Alexandru Marginean
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Neelam Sharma-Walia
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
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Eicosopentaneoic Acid and Other Free Fatty Acid Receptor Agonists Inhibit Lysophosphatidic Acid- and Epidermal Growth Factor-Induced Proliferation of Human Breast Cancer Cells. J Clin Med 2016; 5:jcm5020016. [PMID: 26821052 PMCID: PMC4773772 DOI: 10.3390/jcm5020016] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 01/13/2016] [Accepted: 01/19/2016] [Indexed: 12/22/2022] Open
Abstract
Many key actions of ω-3 (n-3) fatty acids have recently been shown to be mediated by two G protein-coupled receptors (GPCRs) in the free fatty acid receptor (FFAR) family, FFA1 (GPR40) and FFA4 (GPR120). n-3 Fatty acids inhibit proliferation of human breast cancer cells in culture and in animals. In the current study, the roles of FFA1 and FFA4 were investigated. In addition, the role of cross-talk between GPCRs activated by lysophosphatidic acid (LPA), and the tyrosine kinase receptor activated by epidermal growth factor (EGF), was examined. In MCF-7 and MDA-MB-231 human breast cancer cell lines, both LPA and EGF stimulated proliferation, Erk activation, Akt activation, and CCN1 induction. LPA antagonists blocked effects of LPA and EGF on proliferation in MCF-7 and MDA-MB-231, and on cell migration in MCF-7. The n-3 fatty acid eicosopentaneoic acid inhibited LPA- and EGF-induced proliferation in both cell lines. Two synthetic FFAR agonists, GW9508 and TUG-891, likewise inhibited LPA- and EGF-induced proliferation. The data suggest a major role for FFA1, which was expressed by both cell lines. The results indicate that n-3 fatty acids inhibit breast cancer cell proliferation via FFARs, and suggest a mechanism involving negative cross-talk between FFARS, LPA receptors, and EGF receptor.
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Lipoxin A4 Attenuates Cell Invasion by Inhibiting ROS/ERK/MMP Pathway in Pancreatic Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2016:6815727. [PMID: 26649143 PMCID: PMC4663743 DOI: 10.1155/2016/6815727] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/27/2015] [Indexed: 12/31/2022]
Abstract
Lipoxin A4 (LXA4), an endogenous arachidonic acid metabolite, was previously considered an anti-inflammatory lipid mediator. But it also has the potential to inhibit cancer progression. To explore the therapeutic effect of LXA4 in pancreatic cancer, we used Panc-1 cells to investigate the mechanism by which LXA4 can attenuate pancreatic cancer cell invasion. Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2. Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-l-cysteine (NAC). However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204. The blocking of either intracellular ROS or ERK pathway caused the downregulation of MMP-9 and MMP-2 expression. Furthermore, tests revealed that LXA4 inhibited MMP-9 and MMP-2 at the mRNA, protein, and functional levels. Finally, LXA4 dramatically limited the invasion of CoCl2-mimic hypoxic cells and abrogated intracellular ROS levels, ERK activity, and MMPs expression. These results suggest that LXA4 attenuates cell invasion in pancreatic cancer by suppressing the ROS/ERK/MMPs pathway, which may be beneficial for preventing the invasion of pancreatic cancer.
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Ivanov I, Kuhn H, Heydeck D. Structural and functional biology of arachidonic acid 15-lipoxygenase-1 (ALOX15). Gene 2015; 573:1-32. [PMID: 26216303 PMCID: PMC6728142 DOI: 10.1016/j.gene.2015.07.073] [Citation(s) in RCA: 164] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/26/2015] [Accepted: 07/21/2015] [Indexed: 12/14/2022]
Abstract
Lipoxygenases (LOX) form a family of lipid peroxidizing enzymes, which have been implicated in a number of physiological processes and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. They occur in two of the three domains of terrestrial life (bacteria, eucarya) and the human genome involves six functional LOX genes, which encode for six different LOX isoforms. One of these isoforms is ALOX15, which has first been described in rabbits in 1974 as enzyme capable of oxidizing membrane phospholipids during the maturational breakdown of mitochondria in immature red blood cells. During the following decades ALOX15 has extensively been characterized and its biological functions have been studied in a number of cellular in vitro systems as well as in various whole animal disease models. This review is aimed at summarizing the current knowledge on the protein-chemical, molecular biological and enzymatic properties of ALOX15 in various species (human, mouse, rabbit, rat) as well as its implication in cellular physiology and in the pathogenesis of various diseases.
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Affiliation(s)
- Igor Ivanov
- Institute of Biochemistry, Charité - University Medicine Berlin, Charitéplatz 1, CCO-Building, Virchowweg 6, D-10117 Berlin, Germany
| | - Hartmut Kuhn
- Institute of Biochemistry, Charité - University Medicine Berlin, Charitéplatz 1, CCO-Building, Virchowweg 6, D-10117 Berlin, Germany.
| | - Dagmar Heydeck
- Institute of Biochemistry, Charité - University Medicine Berlin, Charitéplatz 1, CCO-Building, Virchowweg 6, D-10117 Berlin, Germany
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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Abstract
An effective host defense mechanism involves inflammation to eliminate pathogens from the site of infection, followed by the resolution of inflammation and the restoration of tissue homeostasis. Lipoxins are endogenous anti-inflammatory, pro-resolving molecules that play a vital role in reducing excessive tissue injury and chronic inflammation. In this review, the mechanisms of action of lipoxins at the site of inflammation and their interaction with other cellular signaling molecules and transcription factors are discussed. Emphasis has also been placed on immune modulatory role(s) of lipoxins. Lipoxins regulate components of both the innate and adaptive immune systems including neutrophils, macrophages, T-, and B-cells. Lipoxins also modulate levels of various transcription factors such as nuclear factor κB, activator protein-1, nerve growth factor-regulated factor 1A binding protein 1, and peroxisome proliferator activated receptor γ and control the expression of many inflammatory genes. Since lipoxins and aspirin-triggered lipoxins have clinical relevance, we discuss their important role in clinical research to treat a wide range of diseases like inflammatory disorders, renal fibrosis, cerebral ischemia, and cancer. A brief overview of lipoxins in viral malignancies and viral pathogenesis especially the unexplored role of lipoxins in Kaposi’s sarcoma-associated herpes virus biology is also presented.
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Affiliation(s)
- Jayashree A Chandrasekharan
- HM Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Neelam Sharma-Walia
- HM Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
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Marventano S, Kolacz P, Castellano S, Galvano F, Buscemi S, Mistretta A, Grosso G. A review of recent evidence in human studies of n-3 and n-6 PUFA intake on cardiovascular disease, cancer, and depressive disorders: does the ratio really matter? Int J Food Sci Nutr 2015; 66:611-22. [PMID: 26307560 DOI: 10.3109/09637486.2015.1077790] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Polyunsaturated fatty acids (PUFAs) have been considered of great interest for human health due to their potential anti-inflammatory action that may protect from a number of chronic-degenerative diseases with an inflammatory pathogenesis. This review aimed to report the most updated evidence of both n-3 and n-6 PUFAs effect on cardiovascular disease, cancer, and depression in humans. Attention has been also paid to those studies exploring the effects of the ratio intake. Results from pooled analyses of human studies reported a general positive effect of n-3 PUFAs intake on all outcomes considered. In contrast, the role of n-6 PUFAs on human health needs to be better assessed in order to clearly identify which compound exerts beneficial/harmful effects. Only a limited number of clinical studies considered the n-3:n-6 PUFAs ratio, rather reporting contrasting results. A number of limitations when considering the ratio between these two families of PUFAs have risen.
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Affiliation(s)
- Stefano Marventano
- a Department of Medical, Surgical Sciences, and Advanced Technologies "G.F. Ingrassia", Section of Hygiene and Public Health , University of Catania , Catania , Italy
| | - Paulina Kolacz
- b Department of Human Nutrition , Jagiellonian University Medical College in Krakow , Krakow , Poland
| | - Sabrina Castellano
- c Department of Biomedical and Biotechnological Sciences, Section of Pharmacology and Biochemistry , University of Catania , Catania , Italy , and
| | - Fabio Galvano
- c Department of Biomedical and Biotechnological Sciences, Section of Pharmacology and Biochemistry , University of Catania , Catania , Italy , and
| | - Silvio Buscemi
- d Department of Internal Medicine , University of Palermo , Palermo , Italy
| | - Antonio Mistretta
- a Department of Medical, Surgical Sciences, and Advanced Technologies "G.F. Ingrassia", Section of Hygiene and Public Health , University of Catania , Catania , Italy
| | - Giuseppe Grosso
- a Department of Medical, Surgical Sciences, and Advanced Technologies "G.F. Ingrassia", Section of Hygiene and Public Health , University of Catania , Catania , Italy
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Marginean A, Sharma-Walia N. Lipoxins exert antiangiogenic and anti-inflammatory effects on Kaposi's sarcoma cells. Transl Res 2015; 166:111-33. [PMID: 25814167 DOI: 10.1016/j.trsl.2015.02.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 02/27/2015] [Accepted: 02/28/2015] [Indexed: 01/03/2023]
Abstract
Lipoxin A4 (LXA4) is an endogenously produced host molecule with anti-inflammatory resolution effects. Previous studies demonstrated it to be involved in anti-vascular endothelial growth factor (VEGF)-mediated angiogenesis and in a possible anticancer role via interaction with its receptor, lipoxin A 4 receptor (ALXR). Here, we examined the effects of LXA4 and its epimer 15-epi-LXA4 in inhibiting proinflammatory and angiogenic functions in a human Kaposi's sarcoma tumor-derived cell line (KS-IMM). KS-IMM cells expressed increased levels of inflammatory cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LO) pathway enzymes when compared with human microvascular dermal endothelial cells (HMVEC-d). KS-IMM cells secreted high levels of prostaglandin E2 (PGE2) and chemotactic leukotriene B4 (LTB4). Treatment with LXA4 or 15-epi-LXA4 effectively reduced the levels of COX-2, 5-LO proteins, and secretion of PGE2 and LTB4 in KS-IMM cells. LXA4 or 15-epi-LXA4 treatment also decreased secretion of proinflammatory interleukin 6 (IL-6) and IL-8 cytokines but induced the secretion of anti-inflammatory IL-10. LXA4 treatment reduced the phosphorylation of VEGF receptor (VEGFR) and ephrin family receptor tyrosine kinases. LXA4 treatment effectively induced dephosphorylation of multiple cellular kinases such as Focal Adhesion Kinase, Protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and Extracellular signal-regulated kinases (ERK)1/2, and reduced angiogenic factor VEGF-C secretion in KS cells. LX treatment drastically induced the Src-homology 2 domain-containing phosphatase tyrosine (Y542) phosphatase and reduced VEGFR-2 phosphorylation at sites Y1059, Y1175, and Y1212. Treatment of KS-IMM cells with LXA4 resulted in selective localization of VEGFR-2 in nonlipid raft (non-LR) and ALXR to LR fractions. These results demonstrated that LXA4 or 15-epi-LXA4 induce anti-inflammatory and antiangiogenic effects in KS cells and suggest that treatment with LXs is an attractive novel strategy against KS.
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Affiliation(s)
- Alexandru Marginean
- H.M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Ill
| | - Neelam Sharma-Walia
- H.M. Bligh Cancer Research Laboratories, Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Ill.
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Romano M, Cianci E, Simiele F, Recchiuti A. Lipoxins and aspirin-triggered lipoxins in resolution of inflammation. Eur J Pharmacol 2015; 760:49-63. [DOI: 10.1016/j.ejphar.2015.03.083] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/27/2015] [Accepted: 03/30/2015] [Indexed: 02/08/2023]
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Gu Z, Shan K, Chen H, Chen YQ. n-3 Polyunsaturated Fatty Acids and their Role in Cancer Chemoprevention. ACTA ACUST UNITED AC 2015; 1:283-294. [PMID: 26457243 DOI: 10.1007/s40495-015-0043-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Polyunsaturated fatty acids (PUFAs), including omega-3 (n-3) and omega-6 (n-6) PUFAs, are essential for human health. Recent research shows n-3 PUFAs and their mediators can inhibit inflammation, angiogenesis and cancer via multiple mechanisms, including reduced release of n-6 fatty acid arachidonic acid from cell membranes, inhibition of enzymatic activities, and direct competition with arachidonic acid for enzymatic conversions. In this review, we discuss inflammation-related cancer, anti-inflammatory effects of n-3 PUFA lipid mediators, antineoplastic activities of n-3 PUFA in vitro and in vivo, and present an update on recent human trials.
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Affiliation(s)
- Zhennan Gu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, P.R. China ; The Synergistic Innovation Center for Food Safety and Nutrition, Wuxi 214122, P.R. China ; Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Kai Shan
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, P.R. China ; The Synergistic Innovation Center for Food Safety and Nutrition, Wuxi 214122, P.R. China
| | - Haiqin Chen
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, P.R. China ; The Synergistic Innovation Center for Food Safety and Nutrition, Wuxi 214122, P.R. China
| | - Yong Q Chen
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, P.R. China ; The Synergistic Innovation Center for Food Safety and Nutrition, Wuxi 214122, P.R. China ; Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Wu R, Zhou W, Chen S, Shi Y, Su L, Zhu M, Chen Q, Chen Q. Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol 2015; 171:4927-40. [PMID: 24923883 DOI: 10.1111/bph.12816] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Revised: 04/18/2014] [Accepted: 06/06/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND AND PURPOSE Lipoxins can function as endogenous 'breaking signals' in inflammation and play important roles in the progression of endometriosis. In this study, we further investigated the molecular mechanism by which lipoxin A4 (LXA4 ) suppresses the development of endometriosis. EXPERIMENTAL APPROACH Primary endometriotic stromal cells (ESCs) were treated with IL-1β, or pre-incubated with LXA4 before incubation with IL-1β. The LXA4 receptor (ALX receptor) antagonist Boc-2 and gene-silencing approaches were used to study the involvement of the ALX receptor in anti-inflammatory signalling responses in ESCs. An animal model of endometriosis was induced in BALB/c mice by i.p. injection of an endometrium-rich fragment. KEY RESULTS Decreased levels of LXA4 and 15-LOX-2 expression but increased expression of AXL receptors were observed in endometriotic tissues. LXA4 inhibited the release of inflammatory factors and phosphorylation of p38 MAPK in IL-1β-induced ESCs, an effect mediated by ALX receptors. LXA4 inhibited the proliferation of ESCs, as indicated by reduced DNA replication, caused G0 /G1 phase cell cycle arrest and down-regulated the expression of proliferating cell nuclear antigen in ESCs. LXA4 also attenuated the invasive activity of ESCs mainly by suppressing the expression and activity of MMP-9. In vivo, we further confirmed that LXA4 could inhibit the progression of endometriosis by acting as an anti-inflammatory. CONCLUSIONS AND IMPLICATIONS LXA4 exerted anti-inflammatory, anti-proliferative and anti-invasive effects on endometriosis through a mechanism that involved down-regulating the activities of p38 MAPK, which was mediated by ALX receptors.
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Affiliation(s)
- Rongfeng Wu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China
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Serhan CN, Chiang N, Dalli J. The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin Immunol 2015; 27:200-15. [PMID: 25857211 DOI: 10.1016/j.smim.2015.03.004] [Citation(s) in RCA: 427] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/07/2015] [Accepted: 03/09/2015] [Indexed: 12/31/2022]
Abstract
Studies into the mechanisms in resolution of self-limited inflammation and acute reperfusion injury have uncovered a new genus of pro-resolving lipid mediators coined specialized pro-resolving mediators (SPM) including lipoxins, resolvins, protectins and maresins that are each temporally produced by resolving-exudates with distinct actions for return to homeostasis. SPM evoke potent anti-inflammatory and novel pro-resolving mechanisms as well as enhance microbial clearance. While born in inflammation-resolution, SPM are conserved structures with functions discovered in microbial defense, pain, organ protection and tissue regeneration, wound healing, cancer, reproduction, and neurobiology-cognition. This review covers these SPM mechanisms and other new omega-3 PUFA pathways that open their path for functions in resolution physiology.
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Affiliation(s)
- Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States.
| | - Nan Chiang
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States
| | - Jesmond Dalli
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States
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46
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Strawberry phytochemicals inhibit azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis in Crj: CD-1 mice. Nutrients 2015; 7:1696-715. [PMID: 25763529 PMCID: PMC4377876 DOI: 10.3390/nu7031696] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 01/16/2015] [Accepted: 02/26/2015] [Indexed: 01/04/2023] Open
Abstract
Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg−1 body weight). One week after injection, mice were administered 2% (w/v) dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05). The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.
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Determination of ω-6 and ω-3 PUFA metabolites in human urine samples using UPLC/MS/MS. Anal Bioanal Chem 2015; 407:1625-39. [PMID: 25577352 DOI: 10.1007/s00216-014-8412-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 12/09/2014] [Accepted: 12/13/2014] [Indexed: 12/22/2022]
Abstract
The ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are the precursors of various bioactive lipid mediators including prostaglandins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acid, isoprostanes, lipoxins, and resolvins (Rvs). These lipid mediators play important roles in various physiological and pathological processes. The quantitative determination of PUFA metabolites seems necessary for disease research and for developing biomarkers. However, there is a paucity of analytical methods for the quantification of ω-6 and ω-3 PUFA metabolites—the specialized pro-resolving mediators (SPMs) present in the human urine. We developed a method for the quantification of ω-6 and ω-3 PUFA metabolites present in human urine using ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS). The developed method shows good linearity, with a correlation coefficient >0.99 for all of the analytes. The validation results indicate that our method is adequately reliable, accurate, and precise. The method was successfully used to examine urine samples obtained from 43 healthy volunteers. We could identify 20 PUFA metabolites, and this is the first report of the quantitative determination of RvD1, 17(R)-RvD1, 11-dehydro thromboxane B3, RvE2, and 5(S)-HETE in human urine. The urinary 8-iso PGF(2α) and PGE2 levels were significantly higher in the men smokers than in the men nonsmokers (p < 0.05). In this study, we developed an accurate, precise, and novel analytical method for estimating the ω-6 and ω-3 PUFA metabolites, and this is the first report that the SPMs derived from EPA and DHA are present in human urine.
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Dileep KV, Remya C, Cerezo J, Fassihi A, Pérez-Sánchez H, Sadasivan C. Comparative studies on the inhibitory activities of selected benzoic acid derivatives against secretory phospholipase A2, a key enzyme involved in the inflammatory pathway. MOLECULAR BIOSYSTEMS 2015; 11:1973-9. [DOI: 10.1039/c5mb00073d] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Inhibitory activities of selected benzoic acid derivatives against phospholipase A2.
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Affiliation(s)
- K. V. Dileep
- Department of Biotechnology and Microbiology and Inter University Centre for Biosciences
- Thalassery Campus
- Kannur University
- India
| | - C. Remya
- Department of Biotechnology and Microbiology and Inter University Centre for Biosciences
- Thalassery Campus
- Kannur University
- India
| | - J. Cerezo
- CNR–Consiglio Nazionale delle Ricerche
- Istituto di Chimica dei Composti Organo Metallici (ICCOM-CNR)
- UOS di Pisa
- I-56124 Pisa
- Italy
| | - A. Fassihi
- Bioinformatics and High Performance Computing Research Group (BIO-HPC)
- Computer Science Department
- Universidad Católica San Antonio de Murcia (UCAM)
- 30107 Guadalupe
- Spain
| | - H. Pérez-Sánchez
- Bioinformatics and High Performance Computing Research Group (BIO-HPC)
- Computer Science Department
- Universidad Católica San Antonio de Murcia (UCAM)
- 30107 Guadalupe
- Spain
| | - C. Sadasivan
- Department of Biotechnology and Microbiology and Inter University Centre for Biosciences
- Thalassery Campus
- Kannur University
- India
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Kuhn H, Banthiya S, van Leyen K. Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta Mol Cell Biol Lipids 2014; 1851:308-30. [PMID: 25316652 DOI: 10.1016/j.bbalip.2014.10.002] [Citation(s) in RCA: 455] [Impact Index Per Article: 41.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 09/30/2014] [Accepted: 10/03/2014] [Indexed: 02/07/2023]
Abstract
Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated not only in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOXs oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in the regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".
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Affiliation(s)
- Hartmut Kuhn
- Institute of Biochemistry, University Medicine Berlin - Charite, Chariteplatz 1, CCO-Building, Virchowweg 6, D-10117 Berlin, Germany.
| | - Swathi Banthiya
- Institute of Biochemistry, University Medicine Berlin - Charite, Chariteplatz 1, CCO-Building, Virchowweg 6, D-10117 Berlin, Germany
| | - Klaus van Leyen
- Neuroprotection Research Laboratory, Department of Radiology, Massachusetts Genrel Hospital and Harvard Medical School, Charlestown, MA, USA
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50
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Loftus JP, Cavatorta D, Bushey JJ, Levine CB, Sevier CS, Wakshlag JJ. The 5-lipoxygenase inhibitor tepoxalin induces oxidative damage and altered PTEN status prior to apoptosis in canine osteosarcoma cell lines. Vet Comp Oncol 2014; 14:e17-30. [DOI: 10.1111/vco.12094] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 03/26/2014] [Accepted: 03/26/2014] [Indexed: 11/30/2022]
Affiliation(s)
- J. P. Loftus
- Department of Clinical Sciences; Cornell University College of Veterinary Medicine; Ithaca NY USA
| | - D. Cavatorta
- Department of Clinical Sciences; Cornell University College of Veterinary Medicine; Ithaca NY USA
| | - J. J. Bushey
- Department of Clinical Sciences; Cornell University College of Veterinary Medicine; Ithaca NY USA
| | - C. B. Levine
- Department of Clinical Sciences; Cornell University College of Veterinary Medicine; Ithaca NY USA
| | - C. S. Sevier
- Department of Molecular Medicine; Cornell University College of Veterinary Medicine; Ithaca NY USA
| | - J. J. Wakshlag
- Department of Clinical Sciences; Cornell University College of Veterinary Medicine; Ithaca NY USA
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