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1
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Hamadmad S, Heisler-Taylor T, Goswami S, Hawthorn E, Chaurasia S, Martini D, Summitt D, Zatari A, Shalash R, Sohail M, Urbanski EG, Bernstein K, Racine J, Satoskar A, El-Hodiri HM, Fischer AJ, Cebulla CM. Ibudilast Protects Retinal Bipolar Cells From Excitotoxic Retinal Damage and Activates the mTOR Pathway. Glia 2025; 73:905-927. [PMID: 39916387 PMCID: PMC11920683 DOI: 10.1002/glia.24657] [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: 03/04/2024] [Revised: 10/09/2024] [Accepted: 11/24/2024] [Indexed: 02/12/2025]
Abstract
Ibudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography (SD-OCT), and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.
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Affiliation(s)
- Sumaya Hamadmad
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Tyler Heisler-Taylor
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Sandeep Goswami
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Evan Hawthorn
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Sameer Chaurasia
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Dena Martini
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Diana Summitt
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Ali Zatari
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Rahaf Shalash
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Misha Sohail
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Elizabeth G Urbanski
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Kayla Bernstein
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Julie Racine
- Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Abhay Satoskar
- Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
| | - Heithem M El-Hodiri
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Andy J Fischer
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Colleen M Cebulla
- Department of Ophthalmology and Visual Sciences, Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio, USA
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Wang B, Zhou X, Wu D, Gao L, Wan Z, Wu R. Development and validation of M2 macrophage-related genes in a prognostic model of lung adenocarcinoma based on bulk RNA and ScRNA datasets. Discov Oncol 2025; 16:352. [PMID: 40100580 PMCID: PMC11920479 DOI: 10.1007/s12672-025-02123-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 03/11/2025] [Indexed: 03/20/2025] Open
Abstract
OBJECTIVE This study aimed to investigate the correlation between M2 macrophages activity with the prognosis of lung adenocarcinoma (LUAD). We sought to identify key genes associated with M2 macrophage activity and examine their relationship with clinicopathological features to elucidate the underlying mechanism. METHODS Published datases were analyzed for differentially expressed genes. After quality control, batch effect removal, and annotation, the scRNA dataset identified M2 macrophage-associated differentially expressed genes in the LUAD group, which were cross-analyzed and referred to as M2 macrophage-linked genes. A risk model was generated using machine learing for these genes. Thereafter, two bulk RNA-seq datasets were used to evaluate the model. We computed risk scores for all samples and grouped them into low and high risk, aiding in the comparison of clinical characteristics, immune and stromal infiltration, and drug sensitivity. Finally, key genes were validated through immunohistochemistry in IPA samples. RESULTS We identified four key M2 macrophage-linked genes: TIMP1, CAV2, MIF, and SELENBP1. Survival durations in the high-riskscore cluster were lower across the TCGA-LUAD (P = 1.2 × 10-4), GSE14814 (P = 0.02), and GSE37745 (P = 0.01) data sets. The stromal score, fibroblast infiltration, and cytokinesis activation were increased in the high-risk subgroup. Neutrophil and endothelial cell infiltration and activation of the linolenic acid pathway occurred in the low-risk group. IHC confirmed that CAV2 and SELENBP1 expression was significantly reduced, while TIMP1 and MIF were significantly increased in LUAD, which was consistent with the bioinformatics findings. CONCLUSION The role of M2 macrophages in tumor progression could anticipate the prognosis of LUAD and develop novel immunotherapy strategies.
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Affiliation(s)
- Bolin Wang
- Graduate School of Chengde Medical College, Chengde, Hebei, China
- Department of Chest Surgery, Baoding First Central Hospital, Baoding, Hebei, China
| | - Xiaofeng Zhou
- Department of Chest Surgery, Baoding First Central Hospital, Baoding, Hebei, China
| | - Di Wu
- Department of Chest Surgery, Baoding First Central Hospital, Baoding, Hebei, China
| | - Lu Gao
- Department of Chest Surgery, Baoding First Central Hospital, Baoding, Hebei, China
| | - Zhihua Wan
- Department of Chest Surgery, Baoding First Central Hospital, Baoding, Hebei, China
| | - Ruifeng Wu
- Department of Chest Surgery, Baoding First Central Hospital, Baoding, Hebei, China.
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Molnár AÁ, Birgés K, Surman A, Merkely B. The Complex Connection Between Myocardial Dysfunction and Cancer Beyond Cardiotoxicity: Shared Risk Factors and Common Molecular Pathways. Int J Mol Sci 2024; 25:13185. [PMID: 39684895 DOI: 10.3390/ijms252313185] [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: 11/21/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
Cardiovascular diseases and cancer represent the largest disease burden worldwide. Previously, these two conditions were considered independent, except in terms of cardiotoxicity, which links cancer treatment to subsequent cardiovascular issues. However, recent studies suggest that there are further connections between cancer and heart disease beyond cardiotoxicity. It has been revealed that myocardial dysfunction may promote carcinogenesis, indicating that additional common pathophysiological mechanisms might be involved in the relationship between cardiology and oncology, rather than simply a connection through cardiotoxic effects. These mechanisms may include shared risk factors and common molecular pathways, such as persistent inflammation and neurohormonal activation. This review explores the connection between myocardial dysfunction and cancer, emphasizing their shared risk factors, similar biological mechanisms, and causative factors like cardiotoxicity, along with their clinical implications.
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Affiliation(s)
| | - Kristóf Birgés
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
| | - Adrienn Surman
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary
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4
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Praharaj MR, Budamgunta H, Ambati T, Khan RIN, Dey B, Gandham RK, Sharma GT, Majumdar SS. Proteome modulation triggers potent antiviral response in Japanese Encephalitis Virus infected human macrophages. Arch Microbiol 2024; 206:464. [PMID: 39520552 DOI: 10.1007/s00203-024-04167-1] [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: 07/11/2024] [Revised: 09/26/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024]
Abstract
Japanese encephalitis virus (JEV) is a mosquito-borne neurotropic virus that claims thousands of children's lives globally every year, causing neuropsychiatric sequelae. While neuronal cell pathogenesis is a terminal consequence of JEV infection, the virus hijacks macrophages during initial replication and propagation, making macrophages critical cells of host immune defense that dictate the outcomes of infection. Though a plethora of studies have been reported using various neuronal and immune cells, a global response of human macrophages to JEV infection is yet to be explored. In this study, we assessed the kinetics of global proteome dysregulation employing an in vitro JEV infection model using human monocyte-derived macrophages (THP-1). A comparative assessment of the proteome of the infected THP-1 cells revealed differential regulation of 428 proteins at 24 h post-infection (hpi), which was later increased to 443 by 48 h post-infection. Global gene ontology analysis of the differentially expressed proteins highlighted several critical pathways related to immune and metabolic processes that are known to play either proviral or antiviral effects during infection. Notably, several antiviral proteins, including STAT2, OAS1, MX1, MX2, RIG-I, ISG15, and ISG20, were significantly upregulated at both time points post-infection. In contrast, a considerable downregulation of BCL-2, an anti-apoptotic protein at 48hpi indicates the activation of cell death pathways. Further, gene set enrichment analysis identified the type I interferon signaling pathway as one of the top upregulated pathways following JEV infection in human macrophages. Altogether, this study demonstrates human macrophage responses to JEV infection at the proteome level for the first time, highlighting several critical and novel antiviral proteins and pathways that not only advance our understanding of anti-JEV immunity but also aid in developing strategies to control this acute global public health menace.
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Affiliation(s)
- Manas Ranjan Praharaj
- DBT-National Institute of Animal Biotechnology, Hyderabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | | | - Tejaswi Ambati
- DBT-National Institute of Animal Biotechnology, Hyderabad, India
- Regional Centre for Biotechnology, Faridabad, India
| | - Raja Ishaq Nabi Khan
- DBT-National Institute of Animal Biotechnology, Hyderabad, India
- Washington University School of Medicine, St. Louis, USA
| | - Bappaditya Dey
- DBT-National Institute of Animal Biotechnology, Hyderabad, India.
- Regional Centre for Biotechnology, Faridabad, India.
| | - Ravi Kumar Gandham
- DBT-National Institute of Animal Biotechnology, Hyderabad, India.
- ICAR-National Bureau of Animal Genetic Resources, Karnal, India.
| | - G Taru Sharma
- DBT-National Institute of Animal Biotechnology, Hyderabad, India.
- Regional Centre for Biotechnology, Faridabad, India.
| | - Subeer S Majumdar
- DBT-National Institute of Animal Biotechnology, Hyderabad, India.
- Gujarat Biotechnology University, Gandhinagar, India.
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5
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Rezaeian AH, Wei W. Molecular signaling and clinical implications in the human aging-cancer cycle. Semin Cancer Biol 2024; 106-107:28-42. [PMID: 39197809 PMCID: PMC11625621 DOI: 10.1016/j.semcancer.2024.08.003] [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: 07/17/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 09/01/2024]
Abstract
It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also retard cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.
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Affiliation(s)
- Abdol-Hossein Rezaeian
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
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Roi C, Riviș M, Roi A, Raica M, Ceaușu RA, Motofelea AC, Gaje PN. CD34 and Ki-67 Immunoexpression in Periapical Granulomas: Implications for Angiogenesis and Cellular Proliferation. Diagnostics (Basel) 2024; 14:2446. [PMID: 39518412 PMCID: PMC11545815 DOI: 10.3390/diagnostics14212446] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/18/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES The main mechanism of the formation of granulation tissue is the progression of an infection from the tooth to the periapical bone. At this level, the immune system tries to localize and annihilate the microorganism's injury. Ki-67 is a protein directly associated with the cell proliferation rate, while CD34 is a biomarker involved in angiogenesis, and studies suggest that they both have a positive correlation with the intensity of the local inflammatory infiltrate. This study will determine the immunoexpression of CD34 and Ki-67 in periapical granulomas and assess their impact on the growth and development of this tissue, as well as consider their roles in the proliferative process and aggressiveness of evolution. METHODS In the present study, 35 periapical granulomas obtained after a tooth extraction were included. The specimens were analyzed via histopathology and immunohistochemistry. RESULTS A positive reaction for the Ki-67 antibody was observed in 32 (86.5%) of the 35 periapical granuloma cases included in our study. We identified the overexpression of Ki-67 and CD34 and further calculated the Ki-67 index to evaluate and correlate the proliferation potential and angiogenesis with regard to the presence of an inflammatory infiltrate. CONCLUSIONS These findings suggest that the persistence of an inflammatory environment directly influences Ki-67 and CD34 expression, sustaining the proliferative capacity of cells and abnormal angiogenesis. This study is the first to evaluate the presence of the CD34+ and Ki-67+ proliferating vessels in periapical granulomas.
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Affiliation(s)
- Ciprian Roi
- Department of Anesthesiology and Oral Surgery, Multidisciplinary Center for Research, Evaluation, Diagnosis and Therapies in Oral Medicine, “Victor Babeș” University of Medicine and Pharmacy, Eftimie Murgu Sq. no. 2, 300041 Timisoara, Romania; (C.R.); (M.R.)
| | - Mircea Riviș
- Department of Anesthesiology and Oral Surgery, Multidisciplinary Center for Research, Evaluation, Diagnosis and Therapies in Oral Medicine, “Victor Babeș” University of Medicine and Pharmacy, Eftimie Murgu Sq. no. 2, 300041 Timisoara, Romania; (C.R.); (M.R.)
| | - Alexandra Roi
- Department of Oral Pathology, Multidisciplinary Center for Research, Evaluation, Diagnosis and Therapies in Oral Medicine, “Victor Babeș” University of Medicine and Pharmacy, Eftimie Murgu Sq. no. 2, 300041 Timisoara, Romania
| | - Marius Raica
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (M.R.); (R.A.C.); (P.N.G.)
| | - Raluca Amalia Ceaușu
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (M.R.); (R.A.C.); (P.N.G.)
| | - Alexandru Cătălin Motofelea
- Department of Internal Medicine, Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Pușa Nela Gaje
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (M.R.); (R.A.C.); (P.N.G.)
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7
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Tanese K, Ogata D. The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma. Exp Dermatol 2024; 33:e15122. [PMID: 38884501 DOI: 10.1111/exd.15122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 06/18/2024]
Abstract
Melanoma is an aggressive tumour with poor prognosis that arises from the malignant transformation of melanocytes. Over the past few decades, intense research into the pathogenesis of melanoma has led to the development of BRAF and immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which have shown clinically significant efficacy. However, some tumours do not respond to these therapies initially or become treatment resistant. Most melanoma tissues appear to possess biological characteristics that allow them to evade these treatments, and identifying these characteristics is one of the major challenges facing cancer researchers. One such characteristic that has recently gained attention is the role of macrophage migration inhibitory factor (MIF) and its receptor CD74. This review outlines the cellular and molecular functions of CD74, MIF and their family of proteins. We then review their roles in tumours based on previous reports, highlight their pathological significance in melanoma and discuss their potential as therapeutic targets.
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Affiliation(s)
- Keiji Tanese
- Department of Dermatology, Toho University School of Medicine, Tokyo, Japan
| | - Dai Ogata
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
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8
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Valdez CN, Sánchez-Zuno GA, Bucala R, Tran TT. Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities. Int J Mol Sci 2024; 25:4849. [PMID: 38732068 PMCID: PMC11084905 DOI: 10.3390/ijms25094849] [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: 03/28/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Discovered as inflammatory cytokines, MIF and DDT exhibit widespread expression and have emerged as critical mediators in the response to infection, inflammation, and more recently, in cancer. In this comprehensive review, we provide details on their structures, binding partners, regulatory mechanisms, and roles in cancer. We also elaborate on their significant impact in driving tumorigenesis across various cancer types, supported by extensive in vitro, in vivo, bioinformatic, and clinical studies. To date, only a limited number of clinical trials have explored MIF as a therapeutic target in cancer patients, and DDT has not been evaluated. The ongoing pursuit of optimal strategies for targeting MIF and DDT highlights their potential as promising antitumor candidates. Dual inhibition of MIF and DDT may allow for the most effective suppression of canonical and non-canonical signaling pathways, warranting further investigations and clinical exploration.
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Affiliation(s)
- Caroline Naomi Valdez
- School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA; (C.N.V.); (R.B.)
| | - Gabriela Athziri Sánchez-Zuno
- Section of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA;
| | - Richard Bucala
- School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA; (C.N.V.); (R.B.)
- Section of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA;
- Yale Cancer Center, Yale University, 333 Cedar St., New Haven, CT 06510, USA
| | - Thuy T. Tran
- School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA; (C.N.V.); (R.B.)
- Yale Cancer Center, Yale University, 333 Cedar St., New Haven, CT 06510, USA
- Section of Medical Oncology, Department of Internal Medicine, Yale University, 333 Cedar St., New Haven, CT 06510, USA
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Antonucci L, Karin M. The Past and Future of Inflammation as a Target to Cancer Prevention. Cancer Prev Res (Phila) 2024; 17:141-155. [PMID: 38271694 PMCID: PMC10987280 DOI: 10.1158/1940-6207.capr-23-0423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/21/2023] [Accepted: 01/23/2024] [Indexed: 01/27/2024]
Abstract
Inflammation is an essential defense mechanism in which innate immune cells are coordinately activated on encounter of harmful stimuli, including pathogens, tissue injury, and toxic compounds and metabolites to neutralize and eliminate the instigator and initiate healing and regeneration. Properly terminated inflammation is vital to health, but uncontrolled runaway inflammation that becomes chronic begets a variety of inflammatory and metabolic diseases and increases cancer risk. Making damaged tissues behave as "wounds that do not heal" and sustaining the production of growth factors whose physiologic function is tissue healing, chronic inflammation accelerates cancer emergence from premalignant lesions. In 1863, Rudolf Virchow, a leading German pathologist, suggested a possible association between inflammation and tumor formation, but it took another 140 years to fully elucidate and appreciate the tumorigenic role of inflammation. Key findings outlined molecular events in the inflammatory cascade that promote cancer onset and progression and enabled a better appreciation of when and where inflammation should be inhibited. These efforts triggered ongoing research work to discover and develop inflammation-reducing chemopreventive strategies for decreasing cancer risk and incidence.
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Affiliation(s)
- Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine; La Jolla, CA 92093, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine; La Jolla, CA 92093, USA
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10
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Hamadmad S, Heisler-Taylor T, Goswami S, Hawthorn E, Chaurasia S, Martini D, Summitt D, Zaatari A, Urbanski EG, Bernstein K, Racine J, Satoskar A, El-Hodiri HM, Fischer AJ, Cebulla CM. Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.18.585556. [PMID: 38562805 PMCID: PMC10983953 DOI: 10.1101/2024.03.18.585556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Ibudilast, an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), has been recently shown to have neuroprotective effects in a variety of neurologic diseases. We utilize a chick excitotoxic retinal damage model to investigate ibudilast's potential to protect retinal neurons. Using single cell RNA-sequencing (scRNA-seq), we find that MIF, putative MIF receptors CD74 and CD44, and several PDEs are upregulated in different retinal cells during damage. Intravitreal ibudilast is well tolerated in the eye and causes no evidence of toxicity. Ibudilast effectively protects neurons in the inner nuclear layer from NMDA-induced cell death, restores retinal layer thickness on spectral domain optical coherence tomography, and preserves retinal neuron function, particularly for the ON bipolar cells, as assessed by electroretinography. PDE inhibition seems essential for ibudilast's neuroprotection, as AV1013, the analogue that lacks PDE inhibitor activity, is ineffective. scRNA-seq analysis reveals upregulation of multiple signaling pathways, including mTOR, in damaged Müller glia (MG) with ibudilast treatment compared to AV1013. Components of mTORC1 and mTORC2 are upregulated in both bipolar cells and MG with ibudilast. The mTOR inhibitor rapamycin blocked accumulation of pS6 but did not reduce TUNEL positive dying cells. Additionally, through ligand-receptor interaction analysis, crosstalk between bipolar cells and MG may be important for neuroprotection. We have identified several paracrine signaling pathways that are known to contribute to cell survival and neuroprotection and might play essential roles in ibudilast function. These findings highlight ibudilast's potential to protect inner retinal neurons during damage and show promise for future clinical translation.
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11
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Harada M, Su-Harada K, Kimura T, Ono K, Ashida N. Sustained activation of NF-κB through constitutively active IKKβ leads to senescence bypass in murine dermal fibroblasts. Cell Cycle 2024; 23:308-327. [PMID: 38461418 PMCID: PMC11057680 DOI: 10.1080/15384101.2024.2325802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Although the transcription factor nuclear factor κB (NF-κB) plays a central role in the regulation of senescence-associated secretory phenotype (SASP) acquisition, our understanding of the involvement of NF-κB in the induction of cellular senescence is limited. Here, we show that activation of the canonical NF-κB pathway suppresses senescence in murine dermal fibroblasts. IκB kinase β (IKKβ)-depleted dermal fibroblasts showed ineffective NF-κB activation and underwent senescence more rapidly than control cells when cultured under 20% oxygen conditions, as indicated by senescence-associated β-galactosidase (SA-β-gal) staining and p16INK4a mRNA levels. Conversely, the expression of constitutively active IKKβ (IKKβ-CA) was sufficient to drive senescence bypass. Notably, the expression of a degradation-resistant form of inhibitor of κB (IκB), which inhibits NF-κB nuclear translocation, abolished senescence bypass, suggesting that the inhibitory effect of IKKβ-CA on senescence is largely mediated by NF-κB. We also found that IKKβ-CA expression suppressed the derepression of INK4/Arf genes and counteracted the senescence-associated loss of Ezh2, a catalytic subunit of the Polycomb repressive complex 2 (PRC2). Moreover, pharmacological inhibition of Ezh2 abolished IKKβ-CA-induced senescence bypass. We propose that NF-κB plays a suppressive role in the induction of stress-induced senescence through sustaining Ezh2 expression.
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Affiliation(s)
- Masayuki Harada
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kanae Su-Harada
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takeshi Kimura
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koh Ono
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Noboru Ashida
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Fu Z, Li Q, Jiang P, Song X, Yang J, Chen G, Gong X, Yang L. Macrophage migration inhibitory factor reversed senescent phenotype in human chondrocytes in vitro. Mol Biol Rep 2024; 51:154. [PMID: 38245877 DOI: 10.1007/s11033-023-09101-0] [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: 09/26/2023] [Accepted: 12/04/2023] [Indexed: 01/23/2024]
Abstract
BACKGROUND The senescence of chondrocytes, which is closely linked to the development of osteoarthritis (OA), has been found to be influenced by the inflammatory environment of joint cavity. However, there remains a lack of comprehensive understanding regarding the specific mechanisms through which cytokine impacts chondrocytes senescence. PURPOSE To investigate the effects of MIF on the chondrocytes senescence and explore the underlying mechanism. METHODS Human cytokine array and ELISA were used for the level of MIF in synovium fluid. CCK-8 was used for chondrocytes viability. IF, WB, SA-β-gal staining and flow cytometry were used for the chondrogenic, apoptotic and senescent phenotype of chondrocytes. RESULTS The level of MIF was significantly increased in OA patients. MIF significantly reversed the senescent phenotype induced by LPS pretreatment in human chondrocytes. MIF significantly enhanced the expression of Col II, SOX9, and ACAN in LPS pre-treated human chondrocytes. Furthermore, MIF significantly inhibited the apoptosis of LPS-induced senescent chondrocytes. CONCLUSION Increased level of MIF in osteoarthritic joint cavity might effectively suppress the senescent phenotype and simultaneously improve the chondrogenic phenotype in chondrocytes, the underlying mechanism was likely to be independent of apoptosis.
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Affiliation(s)
- Zhenlan Fu
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Qingqing Li
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Peiyao Jiang
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xiongbo Song
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Junjun Yang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Guangxing Chen
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Xiaoyuan Gong
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Liu Yang
- Center for Joint Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
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13
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Matejuk A, Benedek G, Bucala R, Matejuk S, Offner H, Vandenbark AA. MIF contribution to progressive brain diseases. J Neuroinflammation 2024; 21:8. [PMID: 38178143 PMCID: PMC10765708 DOI: 10.1186/s12974-023-02993-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 12/12/2023] [Indexed: 01/06/2024] Open
Abstract
Progressive brain diseases create a huge social and economic burden on modern societies as a major cause of disability and death. Incidence of brain diseases has a significantly increasing trend and merits new therapeutic strategies. At the base of many progressive brain malfunctions is a process of unresolved, chronic inflammation. Macrophage migration inhibitory factor, MIF, is an inflammatory mediator that recently gained interest of neuro-researchers due to its varied effects on the CNS such as participation of nervous system development, neuroendocrine functions, and modulation of neuroinflammation. MIF appears to be a candidate as a new biomarker and target of novel therapeutics against numerous neurologic diseases ranging from cancer, autoimmune diseases, vascular diseases, neurodegenerative pathology to psychiatric disorders. In this review, we will focus on MIF's crucial role in neurological diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) and glioblastoma (GBM).
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Affiliation(s)
- Agata Matejuk
- Department of Immunology, Collegium Medicum, University of Zielona Góra, Zielona Góra, Poland.
| | - Gil Benedek
- Tissue Typing and Immunogenetics Unit, Department of Genetics, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Richard Bucala
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | | | - Halina Offner
- Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd., Portland, OR, 97239, USA
- Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA
- Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA
| | - Arthur A Vandenbark
- Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd., Portland, OR, 97239, USA.
- Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA.
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14
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Ghosh I, Dey Ghosh R, Mukhopadhyay S. Identification of genes associated with gall bladder cell carcinogenesis: Implications in targeted therapy of gall bladder cancer. World J Gastrointest Oncol 2023; 15:2053-2063. [PMID: 38173427 PMCID: PMC10758643 DOI: 10.4251/wjgo.v15.i12.2053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/11/2023] [Accepted: 11/10/2023] [Indexed: 12/14/2023] Open
Abstract
Gall bladder cancer (GBC) is becoming a very devastating form of hepatobiliary cancer in India. Every year new cases of GBC are quite high in India. Despite recent advanced multimodality treatment options, the survival of GBC patients is very low. If the disease is diagnosed at the advanced stage (with local nodal metastasis or distant metastasis) or surgical resection is inoperable, the prognosis of those patients is very poor. So, perspectives of targeted therapy are being taken. Targeted therapy includes hormone therapy, proteasome inhibitors, signal transduction and apoptosis inhibitors, angiogenesis inhibitors, and immunotherapeutic agents. One such signal transduction inhibitor is the specific short interfering RNA (siRNA) or short hairpin RNA (shRNA). For developing siRNA-mediated therapy shRNA, although several preclinical studies to evaluate the efficacy of these key molecules have been performed using gall bladder cells, many more clinical trials are required. To date, many such genes have been identified. This review will discuss the recently identified genes associated with GBC and those that have implications in its treatment by siRNA or shRNA.
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Affiliation(s)
- Ishita Ghosh
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India
| | - Ruma Dey Ghosh
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India
| | - Soma Mukhopadhyay
- Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata 700094, India
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15
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Olajuyin AM, Olajuyin AK, Zhang X, Hu Q. Immunomodulatory macrophages and Treg in pulmonary hypertension. COMPARATIVE CLINICAL PATHOLOGY 2023; 33:163-173. [DOI: 10.1007/s00580-023-03540-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2025]
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16
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Gupta A, Skjefte M, Muppidi P, Sikka R, Pandey M, Bharti PK, Gupta H. Unravelling the Influence of Host Genetic Factors on Malaria Susceptibility in Asian Populations. Acta Trop 2023; 249:107055. [PMID: 39491156 DOI: 10.1016/j.actatropica.2023.107055] [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: 08/08/2023] [Revised: 10/21/2023] [Accepted: 10/26/2023] [Indexed: 11/05/2024]
Abstract
Malaria is a deadly blood-borne disease caused by a Plasmodium parasite. Infection results in various forms of malaria, including an asymptomatic state, uncomplicated disease, or severe disease. Severe malaria (SM) is particularly prevalent among young children and is a significant cause of mortality. SM is associated with the sequestration of parasitized erythrocytes in the microvasculature of vital host organs, disrupting the normal functioning of the immune system. Although the exact mechanisms of malaria pathogenesis are yet to be fully understood, researchers have been investigating the role of host genetics in determining the severity of the disease and the outcome of infection. The objective of this study is to identify specific host genes that have been examined for their association with malaria in Asian populations and pinpoint those most likely to influence susceptibility. Through an extensive screening process, a total of 982 articles were initially identified, and after careful review, 40 articles discussing 68 genes were included in this review. By constructing a network of protein-protein interactions (PPIs), we identified six key proteins (TNF, IL6, TLR4, IL1β, IL10, and IL8) that exhibited substantial interactions (more than 30 edges), suggesting their potential as significant targets for influencing malaria susceptibility. Notably, these six proteins have been previously identified as crucial components of the immune response, associated with malaria susceptibility, and capable of affecting different clinical forms of the disease. Identifying genes that contribute to malaria susceptibility or resistance holds the promise of enhancing the diagnosis and treatment of this debilitating illness. Such knowledge has the potential to pave the way for more targeted and effective strategies in combating malaria, particularly in Asian populations where controlling Plasmodium vivax is challenging, and India contributes the highest number of cases. By understanding the genetic factors underlying malaria vulnerability, we can develop interventions that are tailored to the specific needs of Asian populations, ultimately leading to better outcomes in the fight against this disease.
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Affiliation(s)
- Aditi Gupta
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura, Uttar Pradesh, India
| | - Malia Skjefte
- Population Services International, Malaria Department, Washington, DC, USA
| | - Pranavi Muppidi
- GKT School of Medical Education, King's College London, London, UK
| | - Ruhi Sikka
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura, Uttar Pradesh, India.
| | - Manju Pandey
- Department of Medicine, K. D. Medical College Hospital & Research Center, Mathura, Uttar Pradesh, India
| | - Praveen Kumar Bharti
- ICMR- National Institute of Malaria Research (ICMR-NIMR), Dwarka, New Delhi, India
| | - Himanshu Gupta
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura, Uttar Pradesh, India.
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17
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Munkácsy G, Santarpia L, Győrffy B. Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer. Int J Mol Sci 2023; 24:ijms24086945. [PMID: 37108109 PMCID: PMC10138520 DOI: 10.3390/ijms24086945] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/28/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell-cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.
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Affiliation(s)
- Gyöngyi Munkácsy
- National Laboratory for Drug Research and Development, Magyar Tudósok Körútja 2, 1117 Budapest, Hungary
- Oncology Biomarker Research Group, Research Centre for Natural Sciences, Institute of Enzymology, Magyar Tudósok Körútja 2, 1117 Budapest, Hungary
| | | | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, Tűzoltó u. 5-7, 1094 Budapest, Hungary
- Department of Pediatrics, Semmelweis University, Tűzoltó u. 5-7, 1094 Budapest, Hungary
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18
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Yoon K. Gastric Cancer: H. pylori and Macrophage Migration Inhibitory Factor. HELICOBACTER PYLORI 2023:321-326. [DOI: 10.1007/978-981-97-0013-4_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Al-Marzouki L, Stavrakos VS, Pal S, Giannias B, Bourdeau F, Rayes R, Bertos N, Najmeh S, Spicer JD, Cools-Lartigue J, Bailey SD, Ferri L, Sangwan V. Soluble factors in malignant ascites promote the metastatic adhesion of gastric adenocarcinoma cells. Gastric Cancer 2023; 26:55-68. [PMID: 36059037 DOI: 10.1007/s10120-022-01338-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 08/25/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America. It is commonly associated with peritoneal accumulation of malignant ascites (MA), a fluid containing cancer and inflammatory cells and soluble proteins. Peritoneal metastasis (PM) is the most common site of gastric cancer (GC) progression after curative-intent surgery and is the leading cause of death among GC patients. METHODS/RESULTS Using a panel of gastric adenocarcinoma cell lines (human: MKN 45, SNU-5; murine: NCC-S1M), we demonstrate that prior incubation of GC cells with MA results in a significant (> 1.7-fold) increase in the number of cells capable of adhering to human peritoneal mesothelial cells (HPMC) (p < 0.05). We then corroborate these findings using an ex vivo PM model and show that MA also significantly enhances the ability of GC cells to adhere to strips of human peritoneum (p < 0.05). Using a multiplex ELISA, we identify MIF and VEGF as consistently elevated across MA samples from GC patients (p < 0.05). We demonstrate that agents that block the effects of MIF or VEGF abrogate the ability of MA to stimulate the adhesion of GC cells to adhere to human peritoneum and promote both ex vivo and in vivo metastases. CONCLUSION Agents targeting MIF or VEGF may be relevant to the treatment or prevention of PM in GC patients.
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Affiliation(s)
- Luai Al-Marzouki
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Vivian S Stavrakos
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Sanjima Pal
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Betty Giannias
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - France Bourdeau
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Roni Rayes
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Nicholas Bertos
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Sara Najmeh
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada
- Division of Thoracic and Upper GI Surgery, Montreal General Hospital, 1650 Cedar Avenue, Room L8-325, Montreal, QC, H3G 1A4, Canada
| | - Jonathan D Spicer
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada
- Division of Thoracic and Upper GI Surgery, Montreal General Hospital, 1650 Cedar Avenue, Room L8-325, Montreal, QC, H3G 1A4, Canada
| | - Jonathan Cools-Lartigue
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada
- Division of Thoracic and Upper GI Surgery, Montreal General Hospital, 1650 Cedar Avenue, Room L8-325, Montreal, QC, H3G 1A4, Canada
| | - Swneke D Bailey
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Lorenzo Ferri
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada.
- Division of Thoracic and Upper GI Surgery, Montreal General Hospital, 1650 Cedar Avenue, Room L8-325, Montreal, QC, H3G 1A4, Canada.
| | - Veena Sangwan
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
- Division of Experimental Surgery, Department of Medicine, McGill University, Montreal, QC, Canada.
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20
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Dharshini LCP, Rasmi RR, Kathirvelan C, Kumar KM, Saradhadevi KM, Sakthivel KM. Regulatory Components of Oxidative Stress and Inflammation and Their Complex Interplay in Carcinogenesis. Appl Biochem Biotechnol 2022; 195:2893-2916. [PMID: 36441404 DOI: 10.1007/s12010-022-04266-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2022] [Indexed: 11/29/2022]
Abstract
Cancer progression is closely linked to oxidative stress (OS) inflammation. OS is caused by an imbalance between the amount of reactive oxygen species produced and antioxidants present in the body. Excess ROS either oxidizes biomolecules or activates the signaling cascade, resulting in inflammation. Immune cells secrete cytokines and chemokines when inflammation is activated. These signaling molecules attract a wide range of immune cells to the site of infection or oxidative stress. Similarly, increased ROS production by immune cells at the inflamed site causes oxidative stress in the affected area. A review on the role of oxidative stress and inflammation in cancer-related literature was conducted to obtain data. All of the information gathered was focused on the current state of oxidative stress and inflammation in various cancers. After gathering all relevant information, a narrative review was created to provide a detailed note on oxidative stress and inflammation in cancer. Proliferation, differentiation, angiogenesis, migration, invasion, metabolic changes, and evasion of programmed cell death are all aided by OS and inflammation in cancer. Imbalance between reactive oxygen species (ROS) and antioxidants lead to oxidative stress that damages macromolecules (nucleic acids, lipids and proteins). It causes breakdown of the biological signaling cascade. Prolonged oxidative stress causes inflammation by activating transcription factors (NF-κB, p53, HIF-1α, PPAR-γ, Nrf2, AP-1) that alter the expression of many other genes and proteins, including growth factors, tumor-suppressor genes, oncogenes, and pro-inflammatory cytokines, resulting in cancer cell survival. The present review article examines the complex relationship between OS and inflammation in certain types of cancer (colorectal, breast, lung, bladder, and gastric cancer).
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Affiliation(s)
| | - Rajan Radha Rasmi
- Department of Biotechnology, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore, 641 014, Tamil Nadu, India
| | - Chinnadurai Kathirvelan
- Department of Animal Nutrition, Veterinary College and Research Institute, Tamil Nadu Veterinary and Animal Sciences University (TANUVAS), Namakkal, 637 002, Tamil Nadu, India
| | - Kalavathi Murugan Kumar
- School of Lifescience, Department of Bioinformatics, Pondicherry University, Pondicherry, 605014, India
| | - K M Saradhadevi
- Department of Biochemistry, Bharathiar University, Coimbatore, 641046, Tamil Nadu, India
| | - Kunnathur Murugesan Sakthivel
- Department of Biochemistry, PSG College of Arts and Science, Civil Aerodrome Post, Coimbatore, 641 014, Tamil Nadu, India.
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21
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Thavayogarajah T, Sinitski D, Bounkari OE, Torres-Garcia L, Lewinsky H, Harjung A, Chen HR, Panse J, Vankann L, Shachar I, Bernhagen J, Koschmieder S. CXCR4 and CD74 together enhance cell survival in response to macrophage migration-inhibitory factor in chronic lymphocytic leukemia. Exp Hematol 2022; 115:30-43. [PMID: 36096455 DOI: 10.1016/j.exphem.2022.08.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/16/2022] [Accepted: 08/29/2022] [Indexed: 11/04/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of small, mature CD5+ B lymphocytes in the blood, marrow, and lymphoid organs. Cell survival depends on interaction with the leukemic microenvironment. However, the mechanisms controlling CLL cell survival are still incompletely understood. Macrophage migration-inhibitory factor (MIF), a pro-inflammatory and immunoregulatory chemokine-like cytokine, interacts with CXCR4, a major chemokine receptor, as well as with CD74/invariant chain, a single-pass type II receptor. In this study, we analyzed the roles of CXCR4, CD74, and MIF in CLL. Mononuclear cells from patients with hematological malignancies were analyzed for coexpression of CXCR4 and CD74 by flow cytometry. Strong co- and overexpression of CXCR4 and CD74 were observed on B cells of CLL patients (n = 10). Survival and chemotaxis assays indicated that CXCR4 and CD74 work together to enhance the survival and migration of malignant cells in CLL. Blockade of the receptors, either individually or in combination, promoted cell death and led to an abrogation of MIF-driven migration responses in murine and human CLL cells, suggesting that joint activation of both receptors is crucial for CLL cell survival and mobility. These findings indicate that the MIF/CXCR4/CD74 axis represents a novel therapeutic target in CLL.
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Affiliation(s)
- Tharshika Thavayogarajah
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany; Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany; Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Dzmitry Sinitski
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Omar El Bounkari
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Laura Torres-Garcia
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Hadas Lewinsky
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Alexander Harjung
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Hong-Ru Chen
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany
| | - Jens Panse
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany
| | - Lucia Vankann
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany
| | - Idit Shachar
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Jürgen Bernhagen
- Department of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany; SyNergy Excellence Cluster, Munich, Germany.
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, Rheinisch-Westfälische Technische (RWTH) Aachen University, Aachen, Germany.
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22
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Thiele M, Donnelly SC, Mitchell RA. OxMIF: a druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases. J Immunother Cancer 2022; 10:e005475. [PMID: 36180072 PMCID: PMC9528626 DOI: 10.1136/jitc-2022-005475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2022] [Indexed: 11/04/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of cancer and inflammatory diseases. MIF is constitutively present in several cell types and non-lymphoid tissues and is secreted after acute stress or inflammation. MIF triggers the release of proinflammatory cytokines, overrides the anti-inflammatory effects of glucocorticoids, and exerts chemokine function, resulting in increased migration and recruitment of leukocytes into inflamed tissue. Despite this, MIF is a challenging target for therapeutic intervention because of its ubiquitous nature and presence in the circulation and tissue of healthy individuals. Oxidized MIF (oxMIF) is an immunologically distinct disease-related structural isoform found in the plasma and tissues of patients with inflammatory diseases and in solid tumor tissues. MIF converts to oxMIF in an oxidizing, inflammatory environment. This review discusses the biology and activity of MIF and the potential for autoimmune disease and cancer modification by targeting oxMIF. Anti-oxMIF antibodies reduce cancer cell invasion/migration, angiogenesis, proinflammatory cytokine production, and ERK and AKT activation. Anti-oxMIF antibodies also elicit apoptosis and alter immune cell function and/or migration. When co-administered with a glucocorticoid, anti-oxMIF antibodies produced a synergistic response in inflammatory models. Anti-oxMIF antibodies therefore counterregulate biological activities attributed to MIF. oxMIF expression has been observed in inflammatory diseases (eg, sepsis, psoriasis, asthma, inflammatory bowel disease, and systemic lupus erythematosus) and oxMIF has been detected in ovarian, colorectal, lung, and pancreatic cancers. In contrast to MIF, oxMIF is specifically detected in plasma and/or tissues of diseased patients, but not in healthy individuals. Therefore, as a druggable isoform of MIF, oxMIF represents a potential new therapeutic target in inflammatory diseases and cancer. Fully human, monoclonal anti-oxMIF antibodies have been shown to selectively bind oxMIF in preclinical and phase I studies; however, additional clinical assessments are necessary to validate their use as either a monotherapy or in combination with standard-of-care regimens (ie, immunomodulatory agents/checkpoint inhibitors, anti-angiogenic drugs, chemotherapeutics, and glucocorticoids).
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Affiliation(s)
- Michael Thiele
- Biology Research, OncoOne Research & Development GmbH, Vienna, Austria
| | - Seamas C Donnelly
- Department of Medicine, Tallaght University Hospital & Trinity College Dublin, Dublin, Ireland
| | - Robert A Mitchell
- Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, USA
- Department of Surgery, J.G. Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
- Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA
- Division of Immunotherapy, Department of Surgery, University of Louisville, Louisville, Kentucky, USA
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23
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Rojas A, Schneider I, Lindner C, Gonzalez I, Morales M. The RAGE/multiligand axis: a new actor in tumor biology. Biosci Rep 2022; 42:BSR20220395. [PMID: 35727208 PMCID: PMC9251583 DOI: 10.1042/bsr20220395] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/02/2022] [Accepted: 06/21/2022] [Indexed: 01/06/2023] Open
Abstract
The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ivan Schneider
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Cristian Lindner
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ileana Gonzalez
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Miguel A. Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Universidad de Chile, Santiago 8320000, Chile, Santiago, Chile
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24
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Berisha A, Shutkind K, Borniger JC. Sleep Disruption and Cancer: Chicken or the Egg? Front Neurosci 2022; 16:856235. [PMID: 35663547 PMCID: PMC9160986 DOI: 10.3389/fnins.2022.856235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
Sleep is a nearly ubiquitous phenomenon across the phylogenetic tree, highlighting its essential role in ensuring fitness across evolutionary time. Consequently, chronic disruption of the duration, timing, or structure of sleep can cause widespread problems in multiple physiological systems, including those that regulate energy balance, immune function, and cognitive capacity, among others. Many, if not all these systems, become altered throughout the course of cancer initiation, growth, metastatic spread, treatment, and recurrence. Recent work has demonstrated how changes in sleep influence the development of chronic diseases, including cancer, in both humans and animal models. A common finding is that for some cancers (e.g., breast), chronic disruption of sleep/wake states prior to disease onset is associated with an increased risk for cancer development. Additionally, sleep disruption after cancer initiation is often associated with worse outcomes. Recently, evidence suggesting that cancer itself can affect neuronal circuits controlling sleep and wakefulness has accumulated. Patients with cancer often report difficulty falling asleep, difficulty staying asleep, and severe fatigue, during and even years after treatment. In addition to the psychological stress associated with cancer, cancer itself may alter sleep homeostasis through changes to host physiology and via currently undefined mechanisms. Moreover, cancer treatments (e.g., chemotherapy, radiation, hormonal, and surgical) may further worsen sleep problems through complex biological processes yet to be fully understood. This results in a "chicken or the egg" phenomenon, where it is unclear whether sleep disruption promotes cancer or cancer reciprocally disrupts sleep. This review will discuss existing evidence for both hypotheses and present a framework through which the interactions between sleep and cancer can be dissociated and causally investigated.
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Affiliation(s)
- Adrian Berisha
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
| | - Kyle Shutkind
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
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25
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Garofalo M, Payros D, Oswald E, Nougayrède JP, Oswald IP. The foodborne contaminant deoxynivalenol exacerbates DNA damage caused by a broad spectrum of genotoxic agents. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 820:153280. [PMID: 35066032 DOI: 10.1016/j.scitotenv.2022.153280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/14/2022] [Accepted: 01/16/2022] [Indexed: 06/14/2023]
Abstract
Humans are exposed to different contaminants including mycotoxins. Deoxynivalenol (DON), a potent ribosome inhibitor, is a highly prevalent mycotoxin in the food chain worldwide. Although DON is not genotoxic, we previously showed that it exacerbates the genotoxicity of colibactin, a DNA-crosslinking toxin produced by bacteria in the gut. In the present study, we investigated whether this phenotype can be extended to other genotoxic compounds with different modes of action. Our data showed that, at a dose that can be found in food, DON exacerbated the DNA damage caused by etoposide, cisplatin and phleomycin. In contrast, de-epoxy-deoxynivalenol (DOM-1), a modified form of DON that does not induce ribotoxic stress, did not exacerbate DNA damage. The effect of DON was mimicked with other ribosome inhibitors such as anisomycin and cycloheximide, suggesting that ribotoxicity plays a key role in exacerbating DNA damage. In conclusion, a new effect of DON was identified, this toxin aggravates the DNA damage induced by a broad spectrum of genotoxic agents with different modes of action. These results are of utmost importance as our food can be co-contaminated with DON and DNA-damaging agents.
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Affiliation(s)
- Marion Garofalo
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France
| | - Delphine Payros
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France
| | - Eric Oswald
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, France; CHU Toulouse, Hôpital Purpan, Service de Bactériologie-Hygiène, Toulouse, France
| | | | - Isabelle P Oswald
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.
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26
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Chihanga T, Vicente-Muñoz S, Ruiz-Torres S, Pal B, Sertorio M, Andreassen PR, Khoury R, Mehta P, Davies SM, Lane AN, Romick-Rosendale LE, Wells SI. Head and Neck Cancer Susceptibility and Metabolism in Fanconi Anemia. Cancers (Basel) 2022; 14:cancers14082040. [PMID: 35454946 PMCID: PMC9025423 DOI: 10.3390/cancers14082040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/05/2022] [Accepted: 04/11/2022] [Indexed: 02/06/2023] Open
Abstract
Fanconi anemia (FA) is a rare inherited, generally autosomal recessive syndrome, but it displays X-linked or dominant negative inheritance for certain genes. FA is characterized by a deficiency in DNA damage repair that results in bone marrow failure, and in an increased risk for various epithelial tumors, most commonly squamous cell carcinomas of the head and neck (HNSCC) and of the esophagus, anogenital tract and skin. Individuals with FA exhibit increased human papilloma virus (HPV) prevalence. Furthermore, a subset of anogenital squamous cell carcinomas (SCCs) in FA harbor HPV sequences and FA-deficient laboratory models reveal molecular crosstalk between HPV and FA proteins. However, a definitive role for HPV in HNSCC development in the FA patient population is unproven. Cellular metabolism plays an integral role in tissue homeostasis, and metabolic deregulation is a known hallmark of cancer progression that supports uncontrolled proliferation, tumor development and metastatic dissemination. The metabolic consequences of FA deficiency in keratinocytes and associated impact on the development of SCC in the FA population is poorly understood. Herein, we review the current literature on the metabolic consequences of FA deficiency and potential effects of resulting metabolic reprogramming on FA cancer phenotypes.
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Affiliation(s)
- Tafadzwa Chihanga
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (T.C.); (S.R.-T.); (B.P.)
| | - Sara Vicente-Muñoz
- Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (S.V.-M.); (L.E.R.-R.)
| | - Sonya Ruiz-Torres
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (T.C.); (S.R.-T.); (B.P.)
| | - Bidisha Pal
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (T.C.); (S.R.-T.); (B.P.)
| | - Mathieu Sertorio
- Department of Radiation Oncology, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA;
| | - Paul R. Andreassen
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Ruby Khoury
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (R.K.); (P.M.); (S.M.D.)
| | - Parinda Mehta
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (R.K.); (P.M.); (S.M.D.)
| | - Stella M. Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (R.K.); (P.M.); (S.M.D.)
| | - Andrew N. Lane
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA;
| | - Lindsey E. Romick-Rosendale
- Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (S.V.-M.); (L.E.R.-R.)
| | - Susanne I. Wells
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (T.C.); (S.R.-T.); (B.P.)
- Correspondence: ; Tel.: +1-513-636-5986
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27
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Nematode Orthologs of Macrophage Migration Inhibitory Factor (MIF) as Modulators of the Host Immune Response and Potential Therapeutic Targets. Pathogens 2022; 11:pathogens11020258. [PMID: 35215200 PMCID: PMC8877345 DOI: 10.3390/pathogens11020258] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/03/2022] [Accepted: 02/14/2022] [Indexed: 01/27/2023] Open
Abstract
One of the adaptations of nematodes, which allows long-term survival in the host, is the production of proteins with immunomodulatory properties. The parasites secrete numerous homologs of human immune mediators, such as macrophage migration inhibitory factor (MIF), which is a substantial regulator of the inflammatory immune response. Homologs of mammalian MIF have been recognized in many species of nematode parasites, but their role has not been fully understood. The application of molecular biology and genetic engineering methods, including the production of recombinant proteins, has enabled better characterization of their structure and properties. This review provides insight into the current state of knowledge on MIF homologs produced by nematodes, as well as their structure, enzymatic activity, tissue expression pattern, impact on the host immune system, and potential use in the treatment of parasitic, inflammatory, and autoimmune diseases.
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Skeens E, Pantouris G, Shah D, Manjula R, Ombrello MJ, Maluf NK, Bhandari V, Lisi GP, Lolis EJ. A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies. Front Mol Biosci 2022; 9:783669. [PMID: 35252348 PMCID: PMC8893199 DOI: 10.3389/fmolb.2022.783669] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 01/12/2022] [Indexed: 11/15/2022] Open
Abstract
Macrophage migration inhibitory factor (MIF) is an inflammatory protein with various non-overlapping functions. It is not only conserved in mammals, but it is found in parasites, fish, and plants. Human MIF is a homotrimer with an enzymatic cavity between two subunits with Pro1 as a catalytic base, activates the receptors CD74, CXCR2, and CXCR4, has functional interactions in the cytosol, and is reported to be a nuclease. There is a solvent channel down its 3-fold axis with a recently identified gating residue as an allosteric site important for regulating, to different extents, the enzymatic activity and CD74 binding and signaling. In this study we explore the consequence of converting the allosteric residue Tyr99 to cysteine (Y99C) and characterize its crystallographic structure, NMR dynamics, stability, CD74 function, and enzymatic activity. In addition to the homotrimeric variant, we develop strategies for expressing and purifying a heterotrimeric variant consisting of mixed wild type and Y99C for characterization of the allosteric site to provide more insight.
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Affiliation(s)
- Erin Skeens
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
| | - Georgios Pantouris
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
- Department of Chemistry, University of the Pacific, Stockton, CA, United States
| | - Dilip Shah
- Section of Neonatology, Department of Pediatrics, Cooper University Hospital, Camden, NJ, United States
| | - Ramu Manjula
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
| | - Michael J. Ombrello
- Translational Genetics and Genomic Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States
| | | | - Vineet Bhandari
- Section of Neonatology, Department of Pediatrics, Cooper University Hospital, Camden, NJ, United States
| | - George P. Lisi
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
- *Correspondence: George P. Lisi, ; Elias J. Lolis,
| | - Elias J. Lolis
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
- *Correspondence: George P. Lisi, ; Elias J. Lolis,
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29
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Song S, Xiao Z, Dekker FJ, Poelarends GJ, Melgert BN. Macrophage migration inhibitory factor family proteins are multitasking cytokines in tissue injury. Cell Mol Life Sci 2022; 79:105. [PMID: 35091838 PMCID: PMC8799543 DOI: 10.1007/s00018-021-04038-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 02/06/2023]
Abstract
The family of macrophage migration inhibitory factor (MIF) proteins in humans consist of MIF, its functional homolog D-dopachrome tautomerase (D-DT, also known as MIF-2) and the relatively unknown protein named DDT-like (DDTL). MIF is a pleiotropic cytokine with multiple properties in tissue homeostasis and pathology. MIF was initially found to associate with inflammatory responses and therefore established a reputation as a pro-inflammatory cytokine. However, increasing evidence demonstrates that MIF influences many different intra- and extracellular molecular processes important for the maintenance of cellular homeostasis, such as promotion of cellular survival, antioxidant signaling, and wound repair. In contrast, studies on D-DT are scarce and on DDTL almost nonexistent and their functions remain to be further investigated as it is yet unclear how similar they are compared to MIF. Importantly, the many and sometimes opposing functions of MIF suggest that targeting MIF therapeutically should be considered carefully, taking into account timing and severity of tissue injury. In this review, we focus on the latest discoveries regarding the role of MIF family members in tissue injury, inflammation and repair, and highlight the possibilities of interventions with therapeutics targeting or mimicking MIF family proteins.
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30
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Rogers MP, Mi Z, Li NY, Wai PY, Kuo PC. Tumor: Stroma Interaction and Cancer. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:59-87. [PMID: 35165860 DOI: 10.1007/978-3-030-91311-3_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor β and osteopontin, and their roles in cancer metastasis will be highlighted.
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Affiliation(s)
- Michael P Rogers
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Zhiyong Mi
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Neill Y Li
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Philip Y Wai
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Paul C Kuo
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
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31
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Cui JY, Lisi GP. Molecular Level Insights Into the Structural and Dynamic Factors Driving Cytokine Function. Front Mol Biosci 2021; 8:773252. [PMID: 34760929 PMCID: PMC8573031 DOI: 10.3389/fmolb.2021.773252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/06/2021] [Indexed: 11/16/2022] Open
Abstract
Cytokines are key mediators of cellular communication and regulators of biological advents. The timing, quantity and localization of cytokines are key features in producing specific biological outcomes, and thus have been thoroughly studied and reviewed while continuing to be a focus of the cytokine biology community. Due to the complexity of cellular signaling and multitude of factors that can affect signaling outcomes, systemic level studies of cytokines are ongoing. Despite their small size, cytokines can exhibit structurally promiscuous and dynamic behavior that plays an equally important role in biological activity. In this review using case studies, we highlight the recent insight gained from observing cytokines through a molecular lens and how this may complement a system-level understanding of cytokine biology, explain diversity of downstream signaling events, and inform therapeutic and experimental development.
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Affiliation(s)
- Jennifer Y Cui
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States
| | - George P Lisi
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States
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32
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Hasenburg A, Eichkorn D, Vosshagen F, Obermayr E, Geroldinger A, Zeillinger R, Bossart M. Biomarker-based early detection of epithelial ovarian cancer based on a five-protein signature in patient's plasma - a prospective trial. BMC Cancer 2021; 21:1037. [PMID: 34530759 PMCID: PMC8447799 DOI: 10.1186/s12885-021-08682-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 08/13/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Trial on five plasma biomarkers (CA125, HE4, OPN, leptin, prolactin) and their possible role in differentiating benign from malignant ovarian tumors. METHODS In this unicentric prospective trial preoperative blood samples of 43 women with ovarian masses determined for ovarian surgery were analyzed. 25 patients had pathologically confirmed benign, 18 malignant ovarian tumors. Blood plasma was analyzed for CA125, HE4, OPN, leptin, prolactin and MIF by multiplex immunoassay analysis. Each single protein and a logistical regression model including all the listed proteins were tested as preoperative predictive marker for suspect ovarian masses. RESULTS Plasma CA125 was confirmed as a highly accurate tumor marker in ovarian cancer. HE4, OPN, leptin and prolactin plasma levels differed significantly between benign and malignant ovarian masses. With a logistical regression model a formula including CA125, HE4, OPN, leptin and prolactin was developed to predict malignant ovarian tumors. With a discriminatory AUC of 0.96 it showed to be a highly sensitive and specific diagnostic test for a malignant ovarian tumor. CONCLUSIONS The calculated formula with the combination of CA125, HE4, OPN, leptin and prolactin plasma levels surpasses each single marker in its diagnostic value to discriminate between benign and malignant ovarian tumors. The formula, applied to our patient population was highly accurate but should be validated in a larger cohort. TRIAL REGISTRATION Clinical Trials.gov under NCT01763125 , registered Jan. 8, 2013.
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Affiliation(s)
- A Hasenburg
- Department of Obstetrics and Gynecology, University Medical Center, Mainz, Germany
| | - D Eichkorn
- Department of Obstetrics and Gynecology, Schwarzwald-Baar Clinics, Villingen-Schwenningen, Germany
| | - F Vosshagen
- Department of Anesthesiology, Ortenau Clinics, Lahr-Ettenheim, Germany
| | - E Obermayr
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - A Geroldinger
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - R Zeillinger
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - M Bossart
- Department of Obstetrics and Gynecology, University Medical Center, Freiburg, Germany.
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Zhao M, Chang Q, Liu Y, Sang P, Kang Z, Wang X. Functional Characterization of the Wheat Macrophage Migration Inhibitory Factor TaMIF1 in Wheat-Stripe Rust ( Puccinia striiformis) Interaction. BIOLOGY 2021; 10:biology10090878. [PMID: 34571757 PMCID: PMC8470491 DOI: 10.3390/biology10090878] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 01/03/2023]
Abstract
Simple Summary There have been many breakthroughs in MIF function and mechanism investigation in vertebrates, but it has rarely been studied in plants. Here, we aimed to characterize the function of MIF in wheat and its potential role in Wheat-Stripe rust interaction. We showed that wheat MIF has some similarities with that MIF in vertebrates, such as subcellular localization in both the cytosol and nuclei, as well as significant tautomerase activity, and both can inhibit Bax-induced programmed cell death. In the wheat–Pst interaction, TaMIF1 is upregulated during Pst infection. Silencing TaMIF1 decreased Pst infection of wheat tissues, and the accumulation of ROS was increased in TaMIF1-silenced wheat leaves, which hinted that TaMIF1 mainly modulates the ROS signaling and then alters the subsequent immune responses. The function characterization of TaMIF1 provides significant insight into the role of MIFs across kingdoms and helpful in-depth functional mechanism analysis on these proteins. Abstract Macrophage migration inhibitory factor (MIF), named for its role in inhibiting macrophage/monocyte migration, has multiple functions in modulation of inflammation, cell proliferation, angiogenesis, and tumorigenesis in vertebrates. Although homologs of this gene can be found in plants, the function of MIF in plants remains obscure. Here, we characterized TaMIF1 in Triticum aestivum resembling the MIF secreted from Homo sapiens. Transcript analysis revealed that TaMIF1 responded to stripe rust infection of wheat and was upregulated during the infection stage. TaMIF1 was localized to both the cytosol and nuclei in wheat mesophyll protoplast. Additionally, TaMIF1 possessed significant tautomerase activity, indicating conservation of MIFs across kingdoms. Agrobacterium tumefaciens infiltration assay demonstrated that TaMIF1 was capable of suppressing programmed cell death hinting its role in plant immunity. Heterologous expression of TaMIF1 increased fission yeast sensitivity to oxidative stress. Silencing TaMIF1 decreased the susceptibility of wheat to Pst seemingly through increasing reactive oxygen species accumulation. In conclusion, functions of the TaMIF1 were investigated in this study, which provides significant insight into understanding the role of MIFs across kingdoms.
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Affiliation(s)
- Mengxin Zhao
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Xianyang 712100, China; (M.Z.); (Y.L.); (P.S.)
| | - Qing Chang
- Bio-Agriculture Institute of Shaanxi, Xi’an 710043, China;
| | - Yueni Liu
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Xianyang 712100, China; (M.Z.); (Y.L.); (P.S.)
| | - Peng Sang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Xianyang 712100, China; (M.Z.); (Y.L.); (P.S.)
| | - Zhensheng Kang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Xianyang 712100, China; (M.Z.); (Y.L.); (P.S.)
- Correspondence: (Z.K.); (X.W.); Tel./Fax: +86-29-87080061 (Z.K.); +86-29-87080063 (X.W.)
| | - Xiaojie Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Xianyang 712100, China; (M.Z.); (Y.L.); (P.S.)
- Correspondence: (Z.K.); (X.W.); Tel./Fax: +86-29-87080061 (Z.K.); +86-29-87080063 (X.W.)
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34
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Ives A, Le Roy D, Théroude C, Bernhagen J, Roger T, Calandra T. Macrophage migration inhibitory factor promotes the migration of dendritic cells through CD74 and the activation of the Src/PI3K/myosin II pathway. FASEB J 2021; 35:e21418. [PMID: 33774873 DOI: 10.1096/fj.202001605r] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/14/2021] [Accepted: 01/21/2021] [Indexed: 12/18/2022]
Abstract
Constitutively expressed by innate immune cells, the cytokine macrophage migration inhibitory factor (MIF) initiates host immune responses and drives pathogenic responses in infectious, inflammatory, and autoimmune diseases. Dendritic cells (DCs) express high levels of MIF, but the role of MIF in DC function remains poorly characterized. As migration is critical for DC immune surveillance, we investigated whether MIF promoted the migration of DCs. In classical transwell experiments, MIF-/- bone marrow-derived DCs (BMDCs) or MIF+/+ BMDCs treated with ISO-1, an inhibitor of MIF, showed markedly reduced spontaneous migration and chemotaxis. CD74-/- BMDCs that are deficient in the ligand-binding component of the cognate MIF receptor exhibited a migration defect similar to that of MIF-/- BMDCs. Adoptive transfer experiments of LPS-matured MIF+/+ and MIF-/- and of CD74+/+ and CD74-/- BMDCs injected into the hind footpads of homologous or heterologous mice showed that the autocrine and paracrine MIF activity acting via CD74 contributed to the recruitment of DCs to the draining lymph nodes. Mechanistically, MIF activated the Src/PI3K signaling pathway and myosin II complexes, which were required for the migration of BMDCs. Altogether, these data show that the cytokine MIF exerts chemokine-like activity for DC motility and trafficking.
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Affiliation(s)
- Annette Ives
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Didier Le Roy
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Charlotte Théroude
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jürgen Bernhagen
- Chair of Vascular Biology, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München (KUM), Ludwig-Maximilians-University (LMU), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thierry Calandra
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes. Immunol Res 2021; 69:225-238. [PMID: 33983569 DOI: 10.1007/s12026-021-09202-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022]
Abstract
P53 is a transcription factor that regulates many signaling pathways like apoptosis, cell cycle, DNA repair, and cellular stress responses. P53 is involved in inflammatory responses through the regulation of inflammatory signaling pathways, induction of cytokines, and matrix metalloproteinase expression. Also, p53 regulates immune responses through modulating Toll-like receptors expression and innate and adaptive immune cell differentiation and maturation. P53 is a modulator of the apoptosis and proliferation processes through regulating multiple anti and pro-apoptotic genes. Rheumatoid arthritis (RA) is categorized as an invasive inflammatory autoimmune disease with irreversible deformity of joints and bone resorption. Different immune and non-immune cells contribute to RA pathogenesis. Fibroblast-like synoviocytes (FLSs) have been recently introduced as a key player in the pathogenesis of RA. These cells in RA synovium produce inflammatory cytokines and matrix metalloproteinases which results in synovitis and joint destruction. Besides, hyper proliferation and apoptosis resistance of FLSs lead to synovial hyperplasia and bone and cartilage destruction. Given the critical role of p53 in inflammation, apoptosis, and cell proliferation, lack of p53 function (due to mutation or low expression) exerts a prominent role for this gene in the pathogenesis of RA. This review focuses on the role of p53 in different mechanisms and cells (specially FLSs) that involved in RA pathogenesis.
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Maros ME, Balla P, Micsik T, Sapi Z, Szendroi M, Wenz H, Groden C, Forsyth RG, Picci P, Krenacs T. Cell Cycle Regulatory Protein Expression in Multinucleated Giant Cells of Giant Cell Tumor of Bone: do They Proliferate? Pathol Oncol Res 2021; 27:643146. [PMID: 34257609 PMCID: PMC8262213 DOI: 10.3389/pore.2021.643146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/01/2021] [Indexed: 12/24/2022]
Abstract
Cells of the monocyte macrophage lineage form multinucleated giant cells (GCs) by fusion, which may express some cell cycle markers. By using a comprehensive marker set, here we looked for potential replication activities in GCs, and investigated whether these have diagnostic or clinical relevance in giant cell tumor of bone (GCTB). GC rich regions of 10 primary and 10 first recurrence GCTB cases were tested using immunohistochemistry in tissue microarrays. The nuclear positivity rate of the general proliferation marker, replication licensing, G1/S-phase, S/G2/M-phase, mitosis promoter, and cyclin dependent kinase (CDK) inhibitor reactions was analyzed in GCs. Concerning Ki67, moderate SP6 reaction was seen in many GC nuclei, while B56 and Mib1 positivity was rare, but the latter could be linked to more aggressive (p = 0.012) phenotype. Regular MCM6 reaction, as opposed to uncommon MCM2, suggested an initial DNA unwinding. Early replication course in GCs was also supported by widely detecting CDK4 and cyclin E, for the first time, and confirming cyclin D1 upregulation. However, post-G1-phase markers CDK2, cyclin A, geminin, topoisomerase-2a, aurora kinase A, and phospho-histone H3 were rare or missing. These were likely silenced by upregulated CDK inhibitors p15INK4b, p16INK4a, p27KIP1, p53 through its effector p21WAF1 and possibly cyclin G1, consistent with the prevention of DNA replication. In conclusion, the upregulation of known and several novel cell cycle progression markers detected here clearly verify early replication activities in GCs, which are controlled by cell cycle arresting CDK inhibitors at G1 phase, and support the functional maturation of GCs in GCTB.
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Affiliation(s)
- Mate E. Maros
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Department of Biomedical Informatics at the Center for Preventive Medicine and Digital Health, Mannheim, Germany
- Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Peter Balla
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Tamas Micsik
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Zoltan Sapi
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Miklos Szendroi
- Department of Orthopedics, Semmelweis University, Budapest, Hungary
| | - Holger Wenz
- Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Christoph Groden
- Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ramses G. Forsyth
- Department of Anatomic Pathology and Experimental Pathology, University Ziekenhuis, Brussels, Belgium
| | - Piero Picci
- Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Tibor Krenacs
- 1 Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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Wigner P, Grębowski R, Bijak M, Saluk-Bijak J, Szemraj J. The Interplay between Oxidative Stress, Inflammation and Angiogenesis in Bladder Cancer Development. Int J Mol Sci 2021; 22:ijms22094483. [PMID: 33923108 PMCID: PMC8123426 DOI: 10.3390/ijms22094483] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 04/18/2021] [Accepted: 04/22/2021] [Indexed: 02/07/2023] Open
Abstract
In 2018, 550,000 people were diagnosed with bladder cancer (BC), of which nearly 200,000 people died. Moreover, men are 4 times more likely than women to be diagnosed with BC. The risk factors include exposure to environmental and occupational chemicals, especially tobacco smoke, benzidine and genetic factors. Despite numerous studies, the molecular basis of BC development remains unclear. A growing body of evidence suggests that inflammation, oxidant-antioxidant imbalance and angiogenesis disorders may play a significant role in the development and progression of bladder cancer. The patients with bladder cancer were characterised by an increased level of reactive oxygen species (ROS), the products of lipid peroxidation, proinflammatory cytokines and proangiogenic factors as compared to controls. Furthermore, it was shown that polymorphisms localised in genes associated with these pathways may modulate the risk of BC. Interestingly, ROS overproduction may induce the production of proinflammatory cytokines, which finally activated angiogenesis. Moreover, the available literature shows that both inflammation and oxidative stress may lead to activation of angiogenesis and tumour progression in BC patients.
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Affiliation(s)
- Paulina Wigner
- Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
- Correspondence: ; Tel.: +48-42-635-44-85; Fax: +48-42-635-44-84
| | - Radosław Grębowski
- Department of Urology, Provincial Integrated Hospital in Plock, 09-400 Plock, Poland;
- Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Michał Bijak
- Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Joanna Saluk-Bijak
- Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland;
| | - Janusz Szemraj
- Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland;
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Musashi-1 Regulates MIF1-Mediated M2 Macrophage Polarization in Promoting Glioblastoma Progression. Cancers (Basel) 2021; 13:cancers13081799. [PMID: 33918794 PMCID: PMC8069545 DOI: 10.3390/cancers13081799] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/17/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Glioblastoma (GBM) is the most lethal type of brain cancer. It is well known that the malignancy of cancers is dependent not only on the oncogenic properties of the tumor cells, but also on the composition of the tumor microenvironment, which includes macrophages of the immune system. The prevalence of M2 type macrophages usually promotes tumor progression as opposed to tumor-suppressing function of M1 type macrophages. In our previous studies, we identified Musashi-1 (MSI1) RNA-binding protein as a principal oncogenic factor in GBM. In this study, in a pursuit of finding secreted factors that may alter tumor microenvironment in GBM, we identified MIF1 cytokine to be positively regulated by MSI1. Moreover, we found that MSI1-mediated MIF1 secretion promotes differentiation of macrophages into pro-oncogenic M2 phenotype. The oncogenic role of MSI1/MIF1/M2 macrophage regulatory axis was also confirmed in GBM mouse models, which makes it a promising target for novel drug discovery. Abstract Glioblastoma (GBM) is the most malignant brain tumor which is characterized by high proliferation and migration capacity. The poor survival rate has been attributed to limitations of the current standard therapies. The search for novel biological targets that can effectively hamper tumor progression remains extremely challenging. Previous studies indicated that tumor-associated macrophages (TAMs) are the abundant elements in the tumor microenvironment that are closely implicated in glioma progression and tumor pathogenesis. M2 type TAMs are immunosuppressive and promote GBM proliferation. RNA-binding protein Musashi-1 (MSI1) has recently been identified as a marker of neural stem/progenitor cells, and its high expression has been shown to correlate with the growth of GBM. Nevertheless, the relationship between MSI1 and TAMs in GBM is still unknown. Thus, in our present study, we aimed to investigate the molecular interplay between MSI1 and TAMs in contributing to GBM tumorigenesis. Our data revealed that the secretion of macrophage inhibitory factor 1 (MIF1) is significantly upregulated by MSI1 overexpression in vitro. Importantly, M2 surface markers of THP-1-derived macrophages were induced by recombinant MIF1 and reduced by using MIF1 inhibitor (S,R)-3-(4-hHydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1). Furthermore, GBM tumor model data suggested that the tumor growth, MIF1 expression and M2 macrophage population were significantly downregulated when MSI1 expression was silenced in vivo. Collectively, our findings identified a novel role of MSI1 in the secretion of MIF1 and the consequent polarization of macrophages into the M2 phenotype in promoting GBM tumor progression.
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Wen Y, Cai W, Yang J, Fu X, Putha L, Xia Q, Windsor JA, Phillips AR, Tyndall JDA, Du D, Liu T, Huang W. Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer. Front Pharmacol 2021; 12:638950. [PMID: 33776775 PMCID: PMC7992011 DOI: 10.3389/fphar.2021.638950] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/29/2021] [Indexed: 02/05/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.
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Affiliation(s)
- Yongjian Wen
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.,Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Wenhao Cai
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.,Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Jingyu Yang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Xianghui Fu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Lohitha Putha
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Qing Xia
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China
| | - John A Windsor
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Anthony R Phillips
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | | | - Dan Du
- West China-Washington Mitochondria and Metabolism Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Liu
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Huang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.,Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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Ahn R, Ursini-Siegel J. Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors. Int J Mol Sci 2021; 22:ijms22052608. [PMID: 33807608 PMCID: PMC7961781 DOI: 10.3390/ijms22052608] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/28/2021] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors.
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Affiliation(s)
- Ryuhjin Ahn
- Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;
| | - Josie Ursini-Siegel
- Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC H3T 1E2, Canada
- Department of Experimental Medicine, McGill University, Montréal, QC H3A 0G4, Canada
- Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, QC H2W 1S6, Canada
- Correspondence: ; Tel.: +514-340-8222 (ext. 26557); Fax: +514-340-7502
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Chaudhari S, Dey Pereira S, Asare-Warehene M, Naha R, Kabekkodu SP, Tsang BK, Satyamoorthy K. Comorbidities and inflammation associated with ovarian cancer and its influence on SARS-CoV-2 infection. J Ovarian Res 2021; 14:39. [PMID: 33632295 PMCID: PMC7906086 DOI: 10.1186/s13048-021-00787-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/09/2021] [Indexed: 12/29/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide is a major public health concern. Cancer patients are considered a vulnerable population to SARS-CoV-2 infection and may develop several COVID-19 symptoms. The heightened immunocompromised state, prolonged chronic pro-inflammatory milieu coupled with comorbid conditions are shared in both disease conditions and may influence patient outcome. Although ovarian cancer (OC) and COVID-19 are diseases of entirely different primary organs, both diseases share similar molecular and cellular characteristics in their microenvironment suggesting a potential cooperativity leading to poor outcome. In COVID-19 related cases, hospitalizations and deaths worldwide are lower in women than in males; however, comorbidities associated with OC may increase the COVID-19 risk in women. The women at the age of 50-60 years are at greater risk of developing OC as well as SARS-CoV-2 infection. Increased levels of gonadotropin and androgen, dysregulated renin-angiotensin-aldosterone system (RAAS), hyper-coagulation and chronic inflammation are common conditions observed among OC and severe cases of COVID-19. The upregulation of common inflammatory cytokines and chemokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-2, IL-6, IL-10, interferon-γ-inducible protein 10 (IP-10), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage colony-stimulating factor (M-CSF), among others in the sera of COVID-19 and OC subjects suggests potentially similar mechanism(s) involved in the hyper-inflammatory condition observed in both disease states. Thus, it is conceivable that the pathogenesis of OC may significantly contribute to the potential infection by SARS-CoV-2. Our understanding of the influence and mechanisms of SARS-CoV-2 infection on OC is at an early stage and in this article, we review the underlying pathogenesis presented by various comorbidities of OC and correlate their influence on SARS-CoV-2 infection.
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Affiliation(s)
- Sima Chaudhari
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Satyajit Dey Pereira
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Meshach Asare-Warehene
- Chronic Disease Program, Ottawa Hospital Research Institute and Department of Obstetrics & Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Ritam Naha
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Benjamin K Tsang
- Chronic Disease Program, Ottawa Hospital Research Institute and Department of Obstetrics & Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Klemke L, De Oliveira T, Witt D, Winkler N, Bohnenberger H, Bucala R, Conradi LC, Schulz-Heddergott R. Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer. Cell Death Dis 2021; 12:155. [PMID: 33542244 PMCID: PMC7862487 DOI: 10.1038/s41419-021-03426-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/02/2021] [Accepted: 01/07/2021] [Indexed: 12/19/2022]
Abstract
Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.
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Affiliation(s)
- Luisa Klemke
- Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Tiago De Oliveira
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Daria Witt
- Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Nadine Winkler
- Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
| | | | - Richard Bucala
- Departments of Medicine, Pathology, and Epidemiology & Public Health, Yale School of Medicine and Yale Cancer Center, New Haven, CT, USA
| | - Lena-Christin Conradi
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
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The Dark Side of the Force: When the Immune System Is the Fuel of Tumor Onset. Int J Mol Sci 2021; 22:ijms22031224. [PMID: 33513730 PMCID: PMC7865698 DOI: 10.3390/ijms22031224] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 12/26/2022] Open
Abstract
Nowadays, it is well accepted that inflammation is a critical player in cancer, being, in most cases, the main character of the process. Different types of tumor arise from sites of infection or chronic inflammation. This non-resolving inflammation is responsible for tumor development at different levels: it promotes tumor initiation, as well as tumor progression, stimulating both tumor growth and metastasis. Environmental factors, lifestyle and infections are the three main triggers of chronic immune activation that promote or increase the risk of many different cancers. In this review, we focus our attention on tumor onset; in particular, we summarize the knowledge about the cause and the mechanisms behind the inflammation-driven cancer development.
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Yang F, Liu Q, Chen Y, Ye H, Wang H, Zeng S. Integrative Proteomic and Phosphoproteomic Analyses of Granulosa Cells During Follicular Atresia in Porcine. Front Cell Dev Biol 2021; 8:624985. [PMID: 33520998 PMCID: PMC7843964 DOI: 10.3389/fcell.2020.624985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/09/2020] [Indexed: 12/16/2022] Open
Abstract
Ovarian follicular atresia is a natural physiological process; however, the mechanism is not fully understood. In this study, quantitative proteomic and phosphoproteomic analyses of granulosa cells (GCs) in healthy (H), slightly atretic (SA), and atretic follicles (A) of porcine were performed by TMT labeling, enrichment of phosphopeptides, and liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. In total, 6,201 proteins were quantified, and 4,723 phosphorylation sites of 1,760 proteins were quantified. In total, 24 (11 up, 13 down) and 50 (29 up, 21 down) proteins with a fold change (FC) > 5 were identified in H/SA and H/A, respectively. In addition, there were 20 (H/SA, up) and 39 (H/A, up) phosphosites with an FC > 7 that could serve as potential biomarkers for distinguishing different quality categories of follicles. Western blotting and immunofluorescence confirmed the reliability of the proteomic analysis. Some key proteins (e.g., MIF, beta catenin, integrin β2), phosphosites (e.g., S76 of caspase6, S22 and S636 of lamin A/C), pathways (e.g., apoptosis, regulation of actin cytoskeleton pathway), transcription factors (e.g., STAT5A, FOXO1, and BCLAF1), and kinases (e.g., PBK, CDK5, CDK12, and AKT3) involved in the atresia process were revealed via further analysis of the differentially expressed proteins (DEPs) and phosphorylated proteins (DEPPs). Further study showed that mutant caspase6 Ser76 to Ala increased the ratios of cleaved caspase6/caspase6 and cleaved caspase3/caspase3 and dephosphorylation of caspase6 at Ser76 increased cell apoptotic rate, a new potential pathway of follicular atresia. Collectively, the proteomic and phosphoproteomic profiling and functional research in the current study comprehensively analyzed the dynamic changes in protein expression and phosphorylation during follicular atresia and provided some new explanations regarding the regulation of this process.
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Affiliation(s)
- Feng Yang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Qiang Liu
- Beijing Advanced Innovation Center for Genomics, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China
| | - Yanhong Chen
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Huizhen Ye
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Han Wang
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shenming Zeng
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China
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Caltabiano R, De Pasquale R, Piombino E, Campo G, Nicoletti F, Cavalli E, Mangano K, Fagone P. Macrophage Migration Inhibitory Factor (MIF) and Its Homologue d-Dopachrome Tautomerase (DDT) Inversely Correlate with Inflammation in Discoid Lupus Erythematosus. Molecules 2021; 26:molecules26010184. [PMID: 33401503 PMCID: PMC7795694 DOI: 10.3390/molecules26010184] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/25/2020] [Accepted: 12/29/2020] [Indexed: 01/12/2023] Open
Abstract
Discoid Lupus Erythematosus (DLE) is a chronic cutaneous disease of unknown etiology and of immunoinflammatory origin that is characterized by inflammatory plaques and may lead to disfiguring scarring and skin atrophy. Current treatments are limited, with a large proportion of patients either poorly or not responsive, which makes DLE an unmet medical need. Macrophage migration inhibitory factor (MIF) is the prototype of a pleiotropic family of cytokine that also includes the recently discovered homologue D-dopachrome tautomerase (DDT) or MIF2. MIF and DDT/MIF-2 exert several biological properties, primarily, but not exclusively of a proinflammatory nature. MIF and DDT have been suggested to play a key role in the pathogenesis of several autoimmune diseases, such as multiple sclerosis and type 1 diabetes, as well as in the development and progression of certain forms of cancers. In the present study, we have performed an immunohistochemistry analysis for the evaluation of MIF in DLE lesions and normal skin. We found high levels of MIF in the basal layer of the epidermis as well as in the cutaneous appendage (eccrine glands and sebocytes) of normal skin. In DLE lesions, we observed a significant negative correlation between the expression of MIF and the severity of inflammation. In addition, we performed an analysis of MIF and DDT expression levels in the skin of DLE patients in a publicly available microarray dataset. Interestingly, while these in silico data only evidenced a trend toward reduced levels of MIF, they demonstrated a significant pattern of expression and correlation of DDT with inflammatory infiltrates in DLE skins. Overall, our data support a protective role for endogenous MIF and possibly DDT in the regulation of homeostasis and inflammation in the skin and open up novel avenues for the treatment of DLE.
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Affiliation(s)
- Rosario Caltabiano
- Department of Medical, Surgical and Advanced Technologies “G.F. Ingrassia”, University of Catania, Via Santa Sofia, 87, 95123 Catania, Italy; (R.C.); (E.P.)
| | - Rocco De Pasquale
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy;
| | - Eliana Piombino
- Department of Medical, Surgical and Advanced Technologies “G.F. Ingrassia”, University of Catania, Via Santa Sofia, 87, 95123 Catania, Italy; (R.C.); (E.P.)
| | - Giorgia Campo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.C.); (E.C.); (K.M.); (P.F.)
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.C.); (E.C.); (K.M.); (P.F.)
- Correspondence:
| | - Eugenio Cavalli
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.C.); (E.C.); (K.M.); (P.F.)
| | - Katia Mangano
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.C.); (E.C.); (K.M.); (P.F.)
| | - Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (G.C.); (E.C.); (K.M.); (P.F.)
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The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:284. [PMID: 33317597 PMCID: PMC7734811 DOI: 10.1186/s13046-020-01749-x] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023]
Abstract
The enthusiasm for immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.
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Gaissmaier L, Christopoulos P. Immune Modulation in Lung Cancer: Current Concepts and Future Strategies. Respiration 2020; 99:1-27. [PMID: 33291116 DOI: 10.1159/000510385] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/10/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15-25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future.
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Affiliation(s)
- Lena Gaissmaier
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany,
- Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany,
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Fucoxanthin, a Marine-Derived Carotenoid from Brown Seaweeds and Microalgae: A Promising Bioactive Compound for Cancer Therapy. Int J Mol Sci 2020; 21:ijms21239273. [PMID: 33291743 PMCID: PMC7730715 DOI: 10.3390/ijms21239273] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 12/15/2022] Open
Abstract
Fucoxanthin is a well-known carotenoid of the xanthophyll family, mainly produced by marine organisms such as the macroalgae of the fucus genus or microalgae such as Phaeodactylum tricornutum. Fucoxanthin has antioxidant and anti-inflammatory properties but also several anticancer effects. Fucoxanthin induces cell growth arrest, apoptosis, and/or autophagy in several cancer cell lines as well as in animal models of cancer. Fucoxanthin treatment leads to the inhibition of metastasis-related migration, invasion, epithelial–mesenchymal transition, and angiogenesis. Fucoxanthin also affects the DNA repair pathways, which could be involved in the resistance phenotype of tumor cells. Moreover, combined treatments of fucoxanthin, or its metabolite fucoxanthinol, with usual anticancer treatments can support conventional therapeutic strategies by reducing drug resistance. This review focuses on the current knowledge of fucoxanthin with its potential anticancer properties, showing that fucoxanthin could be a promising compound for cancer therapy by acting on most of the classical hallmarks of tumor cells.
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Wang X, Ge P. Parthanatos in the pathogenesis of nervous system diseases. Neuroscience 2020; 449:241-250. [DOI: 10.1016/j.neuroscience.2020.09.049] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/16/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
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Wu Y, Yang D, Lin Y, Zhao Y. Identification and immunologic property of macrophage migration inhibitory factor (MIF) in grass carp (Ctenopharynogodon idella). FISH & SHELLFISH IMMUNOLOGY 2020; 104:489-496. [PMID: 32580004 DOI: 10.1016/j.fsi.2020.05.052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/13/2020] [Accepted: 05/19/2020] [Indexed: 06/11/2023]
Abstract
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, plays an important regulatory role in the activation of T cells induced by mitogenic or antigenic stimuli. However, the immunologic property of MIF in freshwater fish is limitedly known by now. In the present study, MIF gene was identified in grass carp. Bioinformatics analysis revealed that the molecular weight of grass carp MIF protein was 12.377 kDa and it could also bind to CD74. MIF gene was predominantly expressed in immune tissues including spleen and head kidney, then liver, skin, gill, intestine and blood, while a relative low level expression in heart, brain, fat and red muscle. The predicted receptor and tissues distribution of MIF implied the immunologic activity of grass carp MIF. Then grass carp MIF antigen and the polyclonal antibodies against it were prepared. Using cadmium as an immunosuppressive agent, MIF expression in spleen and head kidney was depressed in a dose-dependent manner with cadmium consumption. On the same time, white blood cell count decrease displayed a similar pattern with MIF expression, which suggested a possible positive correlation between MIF and white blood cell count. Thereafter, MIF enhanced the viability of grass carp peripheral blood leukocytes and inhibited cell apoptosis with depressed reactive oxygen species production in vitro. In addition, recombinant grass carp MIF promoted tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL1β) and interleukin 6 (IL6) secretion from peripheral blood leukocytes. These results indicated the immunologic property of grass carp MIF.
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Affiliation(s)
- Yinghuan Wu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, College of Life Science and Technology, Southwest Minzu University, Chengdu, 610041, PR China
| | - Danru Yang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, College of Life Science and Technology, Southwest Minzu University, Chengdu, 610041, PR China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, College of Life Science and Technology, Southwest Minzu University, Chengdu, 610041, PR China
| | - Yanying Zhao
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization of Ministry of Education, College of Life Science and Technology, Southwest Minzu University, Chengdu, 610041, PR China.
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