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Sakurai M, Takenaka M, Mitsui Y, Sakai Y, Morimoto M. Prednisolone improves hippocampal regeneration after trimethyltin-induced neurodegeneration in association with prevention of T lymphocyte infiltration. Neuropathology 2024; 44:21-30. [PMID: 37288771 DOI: 10.1111/neup.12926] [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: 11/24/2022] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 06/09/2023]
Abstract
The endogenous regenerative capacity of the brain is quite weak; however, a regenerative reaction, the production of new neurons (neurogenesis), has been reported to occur in brain lesions. In addition, leukocytes are well known to infiltrate brain lesions. Therefore, leukocytes would also have a link with regenerative neurogenesis; however, their role has not been fully elucidated. In this study, we investigated leukocyte infiltration and its influence on brain tissue regeneration in a trimethyltin (TMT)-injected mouse model of hippocampal regeneration. Immunohistochemically, CD3-positive T lymphocytes were found in the hippocampal lesion of TMT-injected mice. Prednisolone (PSL) treatment inhibited T lymphocyte infiltration and increased neuronal nuclei (NeuN)-positive mature neurons and doublecortin (DCX)-positive immature neurons in the hippocampus. Investigation of bromodeoxyuridine (BrdU)-labeled newborn cells revealed the percentage of BrdU/NeuN- and BrdU/DCX-positive cells increased by PSL treatment. These results indicate that infiltrated T lymphocytes prevent brain tissue regeneration by inhibiting hippocampal neurogenesis.
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Affiliation(s)
- Masashi Sakurai
- Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Miki Takenaka
- Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Yuki Mitsui
- Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Yusuke Sakai
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masahiro Morimoto
- Department of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
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Boekstegers A, Schmidt H, Kurzay M, Vallée T, Jung E, Dubinski I, Maxwell R, Schmid I. Cortisol response in children with cancer and fever during chemotherapy: A prospective, observational study using random serum cortisol levels. Cancer Med 2023; 12:9247-9259. [PMID: 36734317 PMCID: PMC10166925 DOI: 10.1002/cam4.5667] [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: 07/06/2022] [Revised: 12/19/2022] [Accepted: 01/20/2023] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Glucocorticoids are crucial components of the treatment of leukemia and lymphoma. High doses can lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis and be causative for an impaired stress response during infection. This study aims to evaluate the cortisol response in pediatric oncologic patients during febrile episodes. METHODS Totally, 75 children and adolescents (5 months-18 years) with fever during chemotherapy were consecutively enrolled in this study. In total, 47 patients received glucocorticoids as part of their treatment. Random serum cortisol and adrenocorticotropic hormone (ACTH) were analyzed in every patient. A low cortisol response (LCR) was defined as a cortisol level < 14.6 μg/dL. RESULTS In total, 52 (69%) patients had a cortisol level < 14.6 μg/dL during fever. There was no significant difference between patients who received glucocorticoids and those who did not. Significantly lower cortisol levels were measured ≤7 days after last glucocorticoid intake compared to later time points. Nearly all patients treated with dexamethasone or prophylactic posaconazole demonstrated a LCR under stress (fever). CONCLUSION The incidence of an impaired HPA axis in pediatric cancer patients might be underestimated since 69% of the children in our study had a LCR during fever. Intake of dexamethasone, posaconazole and a time period of ≤7 days from the last glucocorticoid intake were additional risk factors for an LCR. However, we could not confirm that patients with a LCR fared worse than patients with a high cortisol response (HCR). Therefore, a different cortisol threshold may be necessary for defining an impaired HPA axis in febrile oncologic patients without concomitant symptoms of AI.
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Affiliation(s)
- Ann Boekstegers
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Heinrich Schmidt
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Mathias Kurzay
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Tanja Vallée
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Eva Jung
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Ilja Dubinski
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Rebecca Maxwell
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Irene Schmid
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
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3
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Stubbs FE, Flynn BP, Rivers CA, Birnie MT, Herman A, Swinstead EE, Baek S, Fang H, Temple J, Carroll JS, Hager GL, Lightman SL, Conway-Campbell BL. Identification of a novel GR-ARID1a-P53BP1 protein complex involved in DNA damage repair and cell cycle regulation. Oncogene 2022; 41:5347-5360. [PMID: 36344675 PMCID: PMC9734058 DOI: 10.1038/s41388-022-02516-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/02/2022] [Accepted: 10/17/2022] [Indexed: 11/09/2022]
Abstract
ARID1a (BAF250), a component of human SWI/SNF chromatin remodeling complexes, is frequently mutated across numerous cancers, and its loss of function has been putatively linked to glucocorticoid resistance. Here, we interrogate the impact of siRNA knockdown of ARID1a compared to a functional interference approach in the HeLa human cervical cancer cell line. We report that ARID1a knockdown resulted in a significant global decrease in chromatin accessibility in ATAC-Seq analysis, as well as affecting a subset of genome-wide GR binding sites determined by analyzing GR ChIP-Seq data. Interestingly, the specific effects on gene expression were limited to a relatively small subset of glucocorticoid-regulated genes, notably those involved in cell cycle regulation and DNA repair. The vast majority of glucocorticoid-regulated genes were largely unaffected by ARID1a knockdown or functional interference, consistent with a more specific role for ARID1a in glucocorticoid function than previously speculated. Using liquid chromatography-mass spectrometry, we have identified a chromatin-associated protein complex comprising GR, ARID1a, and several DNA damage repair proteins including P53 binding protein 1 (P53BP1), Poly(ADP-Ribose) Polymerase 1 (PARP1), DNA damage-binding protein 1 (DDB1), DNA mismatch repair protein MSH6 and splicing factor proline and glutamine-rich protein (SFPQ), as well as the histone acetyltransferase KAT7, an epigenetic regulator of steroid-dependent transcription, DNA damage repair and cell cycle regulation. Not only was this protein complex ablated with both ARID1a knockdown and functional interference, but spontaneously arising DNA damage was also found to accumulate in a manner consistent with impaired DNA damage repair mechanisms. Recovery from dexamethasone-dependent cell cycle arrest was also significantly impaired. Taken together, our data demonstrate that although glucocorticoids can still promote cell cycle arrest in the absence of ARID1a, the purpose of this arrest to allow time for DNA damage repair is hindered.
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Affiliation(s)
- Felicity E Stubbs
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
- Laboratory of Receptor Biology and Gene Expression, The National Cancer Institute, US National Institutes of Health, 41 Medlars Drive, Bethesda, MD, 20892, USA
| | - Benjamin P Flynn
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Caroline A Rivers
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Matthew T Birnie
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Andrew Herman
- Flow Cytometry Facility, Faculty of Life Sciences, School of Cellular & Molecular Medicine, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK
| | - Erin E Swinstead
- Laboratory of Receptor Biology and Gene Expression, The National Cancer Institute, US National Institutes of Health, 41 Medlars Drive, Bethesda, MD, 20892, USA
| | - Songjoon Baek
- Laboratory of Receptor Biology and Gene Expression, The National Cancer Institute, US National Institutes of Health, 41 Medlars Drive, Bethesda, MD, 20892, USA
| | - Hai Fang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jillian Temple
- Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Jason S Carroll
- Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
| | - Gordon L Hager
- Laboratory of Receptor Biology and Gene Expression, The National Cancer Institute, US National Institutes of Health, 41 Medlars Drive, Bethesda, MD, 20892, USA
| | - Stafford L Lightman
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Becky L Conway-Campbell
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
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Schwed-Gross A, Hamiel H, Faber GP, Angel M, Ben-Yishay R, Benichou JIC, Ishay-Ronen D, Shav-Tal Y. Glucocorticoids enhance chemotherapy-driven stress granule assembly and impair granule dynamics leading to cell death. J Cell Sci 2022; 135:276097. [PMID: 35713120 PMCID: PMC9450892 DOI: 10.1242/jcs.259629] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
Abstract
Stress granules (SGs) can assemble in cancer cells upon chemotoxic stress. Glucocorticoids function during stress responses and are administered with chemotherapies. The roles of glucocorticoids in SG assembly and disassembly pathways are unknown. We examined whether combining glucocorticoids such as cortisone with chemotherapies from the vinca alkaloid family, which dismantle the microtubule network, affects SG assembly and disassembly pathways and influences cell viability in cancer cells and human-derived organoids. Cortisone augmented SG formation when combined with vinorelbine (VRB). Live-cell imaging showed that cortisone increased SG assembly rates but reduced SG clearance rates after stress, by increasing protein residence times within the SGs. Mechanistically, VRB and cortisone signaled through the integrated stress response mediated by eIF2α (also known as EIF2S1), yet induced different kinases, with cortisone activating the GCN2 kinase (also known as EIF2AK4). Cortisone increased VRB-induced cell death and reduced the population of cells trapped in mitotic catastrophe. These effects were mediated by the core SG proteins G3BP1 and G3BP2. In conclusion, glucocorticoids induce SG assembly and cell death when administered with chemotherapies, suggesting that combining glucocorticoids with chemotherapies can enhance cancer cell chemosensitivity. Summary: Combining cortisone with the chemotherapy vinorelbine enhances the assembly of stress granules that are less likely to be cleared from the cells, augmenting vinorelbine-induced cell death.
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Affiliation(s)
- Avital Schwed-Gross
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Hila Hamiel
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Gabriel P Faber
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Mor Angel
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Rakefet Ben-Yishay
- Oncology Institute, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Jennifer I C Benichou
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
| | - Dana Ishay-Ronen
- Oncology Institute, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Yaron Shav-Tal
- The Mina & Everard Goodman Faculty of Life Sciences & Institute of Nanotechnology, Bar-Ilan University, Ramat Gan 5290002, Israel
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Kalfeist L, Galland L, Ledys F, Ghiringhelli F, Limagne E, Ladoire S. Impact of Glucocorticoid Use in Oncology in the Immunotherapy Era. Cells 2022; 11:770. [PMID: 35269392 PMCID: PMC8909189 DOI: 10.3390/cells11050770] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/18/2022] [Accepted: 02/18/2022] [Indexed: 12/11/2022] Open
Abstract
Thanks to their anti-inflammatory, anti-oedema, and anti-allergy properties, glucocorticoids are among the most widely prescribed drugs in patients with cancer. The indications for glucocorticoid use are very wide and varied in the context of cancer and include the symptomatic management of cancer-related symptoms (compression, pain, oedema, altered general state) but also prevention or treatment of common side effects of anti-cancer therapies (nausea, allergies, etc.) or immune-related adverse events (irAE). In this review, we first give an overview of the different clinical situations where glucocorticoids are used in oncology. Next, we describe the current state of knowledge regarding the effects of these molecules on immune response, in particular anti-tumour response, and we summarize available data evaluating how these effects may interfere with the efficacy of immunotherapy using immune checkpoint inhibitors.
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Affiliation(s)
- Laura Kalfeist
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
| | - Loïck Galland
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
- Department of Medical Oncology, Georges-François Leclerc Center, 21000 Dijon, France
| | - Fanny Ledys
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
| | - François Ghiringhelli
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
- Department of Medical Oncology, Georges-François Leclerc Center, 21000 Dijon, France
- School of Medicine, University of Burgundy Franche-Comté, 21000 Dijon, France
| | - Emeric Limagne
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
| | - Sylvain Ladoire
- Platform of Transfer in Cancer Biology, Georges-Francois Leclerc Center, 21000 Dijon, France; (L.K.); (L.G.); (F.L.); (F.G.); (E.L.)
- UMR INSERM 1231 “Lipides Nutrition Cancer”, 21000 Dijon, France
- Department of Medical Oncology, Georges-François Leclerc Center, 21000 Dijon, France
- School of Medicine, University of Burgundy Franche-Comté, 21000 Dijon, France
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6
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Yang W, Xu X, Xia D, Wang H, Jiang J, Yang G. Toxic epidermal necrolysis associated with chemoimmunotherapy for lymphoma: case report and literature review. Immunotherapy 2022; 14:275-282. [PMID: 35128931 DOI: 10.2217/imt-2021-0074] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Aim: The emergence of antitumor immunotherapy has been beneficial for patients with tumors, but more attention should be paid to the toxic side effects of chemoimmunotherapy. Here we describe a patient with NK/T-cell lymphoma who developed toxic epidermal necrolysis (TEN) during treatment with a regimen consisting of sintilimab combined with pegaspargase, gemcitabine and oxaliplatin (P-GemOx). Case presentation: A patient received six cycles of P-GemOx chemotherapy as first-line treatment; 1 year later, he received the same dose of P-GemOx combined with sintilimab as chemoimmunotherapy due to recurrence of NK/T-cell lymphoma. He developed a massive rash that quickly developed into TEN after the fourth chemoimmunotherapy. Conclusion: Although rare, cases of fatal TEN caused by single-agent PD-1 inhibitor or gemcitabine have been reported. Careful attention to drug-related cutaneous toxicities is needed when these two agents are combined. This report highlights the significance of TEN as a rapid and serious adverse event induced by chemoimmunotherapy.
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Affiliation(s)
- Wei Yang
- Department of Oncology, Hangzhou Red Cross Hospital, Hangzhou, China
| | - Xiaofeng Xu
- Department of Hematology, Hangzhou Red Cross Hospital, Hangzhou
| | - Dajing Xia
- Department of Toxicology of School of Public Health, & Center of Immunology & Infection, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huaichong Wang
- Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, China
| | - Jing Jiang
- Department of Oncology, Hangzhou Red Cross Hospital, Hangzhou, China
| | - Guoliang Yang
- Department of Hematology, Hangzhou Red Cross Hospital, Hangzhou
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Zhang W, Qi R, Li T, Zhang X, Shi Y, Xu M, Zhu T. Kidney Organoids as a Novel Platform to Evaluate Lipopolysaccharide-Induced Oxidative Stress and Apoptosis in Acute Kidney Injury. Front Med (Lausanne) 2021; 8:766073. [PMID: 34912825 PMCID: PMC8666666 DOI: 10.3389/fmed.2021.766073] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/29/2021] [Indexed: 12/22/2022] Open
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening syndrome. Lipopolysaccharide (LPS) is a widely used inducer for modeling SA-AKI both in vivo and in vitro. However, due to the innate complexity of the kidney architecture, the mechanisms underlying the pathogenesis of SA-AKI, as well as those involved in LPS-induced kidney injury remain to be clarified. Kidney organoids derived from human pluripotent stem cells (hPSCs) act as a model of multiple types of kidney cells in vitro and eliminate potential confounders in vivo. In the current study, we established LPS-induced kidney injury models both in vivo and in human kidney organoids. Kidney function, pathological changes, and markers of oxidative stress were evaluated with/without the presence of methylprednisolone (MP) treatment both in vivo and in vitro. The extent of LPS-induced oxidative stress and apoptosis in kidney organoids was further investigated in vitro. LPS-induced acute kidney injury in mice, together with pathological changes and increased oxidative stress, as well as enhanced apoptosis in kidney cells were evaluated. These phenomena were ameliorated by MP treatment. Experiments in kidney organoids showed that the LPS-induced apoptotic effects occurred mainly in podocytes and proximal tubular cells. Our experiments demonstrated the efficacy of using kidney organoids as a solid platform to study LPS-induced kidney injury. LPS induced oxidative stress as well as apoptosis in kidney cells independently of changes in perfusion or immune cell infiltration. MP treatment partially alleviated LPS-induced injury by reducing kidney cell oxidative stress and apoptosis.
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Affiliation(s)
- Weitao Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruochen Qi
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Tingting Li
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xuepeng Zhang
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Shi
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ming Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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8
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Homeostatic Regulation of Glucocorticoid Receptor Activity by Hypoxia-Inducible Factor 1: From Physiology to Clinic. Cells 2021; 10:cells10123441. [PMID: 34943949 PMCID: PMC8699886 DOI: 10.3390/cells10123441] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/02/2021] [Accepted: 12/04/2021] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoids (GCs) represent a well-known class of lipophilic steroid hormones biosynthesised, with a circadian rhythm, by the adrenal glands in humans and by the inter-renal tissue in teleost fish (e.g., zebrafish). GCs play a key role in the regulation of numerous physiological processes, including inflammation, glucose, lipid, protein metabolism and stress response. This is achieved through binding to their cognate receptor, GR, which functions as a ligand-activated transcription factor. Due to their potent anti-inflammatory and immune-suppressive action, synthetic GCs are broadly used for treating pathological disorders that are very often linked to hypoxia (e.g., rheumatoid arthritis, inflammatory, allergic, infectious, and autoimmune diseases, among others) as well as to prevent graft rejections and against immune system malignancies. However, due to the presence of adverse effects and GC resistance their therapeutic benefits are limited in patients chronically treated with steroids. For this reason, understanding how to fine-tune GR activity is crucial in the search for novel therapeutic strategies aimed at reducing GC-related side effects and effectively restoring homeostasis. Recent research has uncovered novel mechanisms that inhibit GR function, thereby causing glucocorticoid resistance, and has produced some surprising new findings. In this review we analyse these mechanisms and focus on the crosstalk between GR and HIF signalling. Indeed, its comprehension may provide new routes to develop novel therapeutic targets for effectively treating immune and inflammatory response and to simultaneously facilitate the development of innovative GCs with a better benefits-risk ratio.
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9
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Stress Axis in the Cancer Patient: Clinical Aspects and Management. ENDOCRINES 2021. [DOI: 10.3390/endocrines2040044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Hypothalamus–pituitary–adrenal (HPA) axis alterations are common in cancer patients, mainly due to the different antitumoral therapies, which lead to several acute and late endocrine side effects. This review summarizes the most recent evidence regarding HPA derangement, both in patients with active neoplasms and in cancer survivors, with particular attention to the impact of the different antitumoral treatments, focusing on the major clinical aspects. While acute hormone failure usually results from injury caused directly by tumor burden or surgical interventions, short- and long-term effects are generally due to chemotherapy, radiotherapy and, as more recently shown, to different types of targeted- and immuno-therapy. Adrenal insufficiency (AI) is mostly caused by pituitary or hypothalamic injury rather than a direct damage of the adrenal gland. Moreover, other treatments commonly employed as supportive therapy or in the context of palliative care (i.e., glucocorticoids, opioids) can lead to HPA dysfunction. Epidemiology and pathophysiology of stress axis alterations in cancer patients still require clarification. Since AI may represent a life-threatening condition, monitoring adrenal function in cancer patients is mandatory, especially in subjects who experience fatigue or during stress conditions, in order to promptly start replacement treatment when needed.
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10
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The long noncoding RNA HOTAIRM1 controlled by AML1 enhances glucocorticoid resistance by activating RHOA/ROCK1 pathway through suppressing ARHGAP18. Cell Death Dis 2021; 12:702. [PMID: 34262023 PMCID: PMC8280127 DOI: 10.1038/s41419-021-03982-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 11/08/2022]
Abstract
Acquired resistance to glucocorticoids (GCs) is an obstacle to the effective treatment of leukemia, but the molecular mechanisms of steroid insensitivity have not been fully elucidated. In this study, we established an acquired GC-resistant leukemia cell model and found a long noncoding RNA, HOTAIRM1, was overexpressed in the resistant cells by transcriptional profiling, and was higher expressed in patients with poor prognosis. The whole-genome-binding sites of HOTAIRM1 were determined by ChIRP-seq (chromatin isolation by RNA purification combined with sequencing) analysis. Further study determined that HOTAIRM1 bound to the transcriptional inhibitory region of ARHGAP18 and repressed the expression of ARHGAP18, which led to the increase of RHOA/ROCK1 signaling pathway and promoted GC resistance through antiapoptosis of leukemia cells. The inhibition of ROCK1 in GC-resistant cells could restore GCs responsiveness. In addition, HOTAIRM1 could also act as a protein sequester to prevent transcription factor AML1(acute myeloid leukemia 1) from binding to the regulatory region of ARHGAP18 by interacting with AML1. At last, we also proved AML1 could directly activate the expression of HOTAIRM1 through binding to the promoter of HOTAIRM1, which enriched the knowledge on the regulation of lncRNAs. This study revealed epigenetic causes of glucocorticoid resistance from the perspective of lncRNA, and laid a foundation for the optimization of glucocorticoid-based leukemia treatment strategy in clinic.
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11
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Manera M. Exploratory Factor Analysis of Rainbow Trout Serum Chemistry Variables. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18041537. [PMID: 33562845 PMCID: PMC7914411 DOI: 10.3390/ijerph18041537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/29/2021] [Accepted: 02/03/2021] [Indexed: 11/25/2022]
Abstract
Clinical chemistry offers a valuable, affordable, moderately invasive, and nondisruptive way to assess animal physiological status and wellness within defined ranges and is widely used as a diagnostic clinical tool. Because of physiological differences between mammals, clinical correlates of blood chemistry variables are not known in detail in fish, in which tissue/organ function tests are inferred from mammal-derived clinical chemistry data. The aim of the present study was to apply exploratory factor analysis on a serum chemistry dataset from clinically healthy, reared rainbow trout Oncorhynchusmykiss (Walbaum, 1792) to select the most correlated variables and to test for possible underlying factors explaining the observed correlations as possible physiological status estimates in trout. The obtained factors were tested for correlation with hepatosomatic and splenosomatic indexes. Thirteen highly correlated variables were selected out of 18 original serum chemistry variables, and three underlying factors (Factors 1, 2, and 3) were identified that explained the observed correlations among variables. Moreover, Factor 1 correlated negatively with the hepatosomatic index and Factors 2 and 3 negatively with the splenosomatic index. The obtained factors were tentatively associated with: protein (liver) metabolism (Factor 1), cell turnover (Factor 2), and lipid (muscle) metabolism (Factor 3).
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Affiliation(s)
- Maurizio Manera
- Faculty of Biosciences, Food and Environmental Technologies, University of Teramo, St. R. Balzarini 1, 64100 Teramo, Italy
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12
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Marinelli D, Giusti R, Mazzotta M, Filetti M, Krasniqi E, Pizzuti L, Landi L, Tomao S, Cappuzzo F, Ciliberto G, Barba M, Vici P, Marchetti P. Palliative- and non-palliative indications for glucocorticoids use in course of immune-checkpoint inhibition. Current evidence and future perspectives. Crit Rev Oncol Hematol 2020; 157:103176. [PMID: 33276183 DOI: 10.1016/j.critrevonc.2020.103176] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 11/08/2020] [Accepted: 11/09/2020] [Indexed: 12/17/2022] Open
Abstract
Immune-checkpoint inhibitors significantly reshaped treatment landscapes in several solid tumors. Concurrently with disease-oriented therapies, cancer patients often require proper management of drug-related adverse events and/or cancer-related symptoms. Glucocorticoids (GC) are a cornerstone of symptom management in advanced cancer care and in the management of immune-related adverse events (irAEs) due to immune-modulating therapies. Moreover, GC are often administered in patients with autoimmune diseases (AID), either alone or in combination with other treatments. While handling of irAEs with GC is supported by multiple guidelines, it is unclear whether GC administration because of pre-existing AID or because of palliative needs is associated with inferior outcomes in cancer patients treated with immune-checkpoint inhibitors (ICIs). When globally considered, the available evidence seems to orient towards less favorable survival outcomes when GC administration is driven by a palliative intent. Conversely, steroid administration for non-palliative intent seems to be associated with stable or negligibly reduced survival outcomes.
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Affiliation(s)
- Daniele Marinelli
- Department of Clinical and Molecular Medicine, Sapienza - University of Rome, Sant'Andrea Hospital, Rome, Italy; Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | | | - Marco Mazzotta
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Marco Filetti
- Department of Clinical and Molecular Medicine, Sapienza - University of Rome, Sant'Andrea Hospital, Rome, Italy
| | - Eriseld Krasniqi
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Laura Pizzuti
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Lorenza Landi
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Silverio Tomao
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, Policlinico Umberto I, 'Sapienza' University of Rome, Rome, Italy
| | - Federico Cappuzzo
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Gennaro Ciliberto
- Scientific Direction, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Maddalena Barba
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy.
| | - Patrizia Vici
- Division of Medical Oncology 2, IRCCS Regina Elena, National Cancer Institute, Rome, Italy
| | - Paolo Marchetti
- Department of Clinical and Molecular Medicine, Sapienza - University of Rome, Sant'Andrea Hospital, Rome, Italy
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13
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Ahmad N, Abosoudah IF, Sobaihi MM, Algiraigri AH, Roujouleh F, Ghurab F, Chanoine JP. Adrenal function following acute discontinuation of glucocorticoids in children with acute lymphocytic leukemia: A prospective study. Pediatr Hematol Oncol 2019; 36:422-431. [PMID: 31429623 DOI: 10.1080/08880018.2019.1652710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Background: Children with acute lymphocytic leukemia (ALL) are enrolled in advanced treatment protocols involving high doses of glucocorticoids (GCs). Current protocols do not advocate tapering of GCs doses postinduction phase. Prolonged administration of supra-physiologic doses of GCs can induce transient suppression of the hypothalamic pituitary adrenal axis (HPA). Timely recognition of adrenal insufficiency is important in order to ensure that children at risk receive the necessary treatment and follow-up including stress coverage during illness and surgical procedures. Methods: 21 newly diagnosed patients with ALL aged 3-10 years old were prospectively enrolled in the study over a 2-year period. All enrolled patients received high doses of GCs as part of a chemotherapy treatment protocol. The HPA axis was assessed prior to the induction phase of chemotherapy and 1-2 weeks after un-tapered discontinuation of GCs. Results: All children had normal HPA axis at baseline. Postinduction 1 mcg ACTH stimulation test result was normal (cortisol > 500 nmol/L) in 75% of children and partially responsive in 25% (cortisol 300-500 nmol/L). None of the participants demonstrated clinically significant adrenal insufficiency following abrupt cessation of GCs. Conclusion: All children in our cohort had either normal or subnormal cortisol response during a low dose ACTH stimulation test 1 to 2 weeks following abrupt discontinuation of GCs, suggesting that any inhibition of the HPA axis is of short duration. We suggest that future studies investigate the timing of adrenal function recovery following GC discontinuation as well as whether tapering of the GC should be recommended.
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Affiliation(s)
- Noman Ahmad
- Consultant Pediatric Endocrinology, King Faisal Specialist Hospital and Research Center , Jeddah , Saudi Arabia
| | - Ibraheem Faisal Abosoudah
- Consultant Pediatric Oncology, King Faisal Specialist Hospital and Research Center , Jeddah , Saudi Arabia
| | - Mrouge Mohamed Sobaihi
- Consultant Pediatric Endocrinology, King Faisal Specialist Hospital and Research Center , Jeddah , Saudi Arabia
| | - Ali Hassan Algiraigri
- Consultant Pediatric Oncology, King Faisal Specialist Hospital and Research Center , Jeddah , Saudi Arabia.,King Abdulaziz university hospital , Jeddah , Saudi Arabia
| | - Farh Roujouleh
- Resident General Pediatrics, King Faisal Specialist Hospital and Research Center , Jeddah , Saudi Arabia
| | - Fatima Ghurab
- Resident General Pediatrics, King Faisal Specialist Hospital and Research Center , Jeddah , Saudi Arabia
| | - Jean-Pierre Chanoine
- Clinical Professor and Head, Endocrinology and Diabetes Unit, British Columbia Children's Hospital , Vancouver Canada
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14
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The relationship between neutrophil-lymphocyte ratio and onset of lactation among postpartum women: A prospective observational cohort study. Int J Nurs Stud 2019; 97:55-62. [PMID: 31181412 DOI: 10.1016/j.ijnurstu.2019.05.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 05/05/2019] [Accepted: 05/05/2019] [Indexed: 01/29/2023]
Abstract
BACKGROUND Delayed onset of lactation is a key factor in the low rate of exclusive breast-feeding in 6 months after caesarean section. The mechanism of delayed onset of lactation is not clear. Milk production depends largely on mitochondrial adenosine triphosphate synthesis, and the neutrophil-lymphocyte ratio is closely related to mitochondrial deoxyribonucleic acid copy number and adenosine triphosphate production. Presently, it is unclear whether a difference in the neutrophil-lymphocyte ratio exists between those undergoing vaginal delivery and those undergoing caesarean delivery and, if so, whether the difference correlates to the time of onset of lactation. OBJECTIVES To identify whether the neutrophil-lymphocyte ratio at 24 hours after delivery is different between mothers delivering by caesarean section and those giving birth vaginally and whether the neutrophil-lymphocyte ratio is related to the delayed onset of lactation. DESIGN The study adopted a prospective cohort study design. SETTINGS Maternity units of an Obstetrics & Gynecology Hospital. PARTICIPANTS 327 mother-infant pairs who met inclusion/exclusion criteria and were followed up to the time of onset of lactation. METHODS Mother-infant pairs were allocated to the vaginal birth group or the caesarean section group according to birth method. The neutrophil-lymphocyte ratio was calculated as the absolute value of neutrophils divided by the absolute value of lymphocytes based on full blood counts. Before delivery, full blood counts were obtained from medical records. After delivery, blood samples were drawn 24 hours postpartum, and blood cells were classified and counted. The onset of lactation was confirmed by the maternal perception of breast fullness. The neutrophil-lymphocyte ratio and its relationship with lactation onset were analyzed by multivariable regression. RESULTS The neutrophil-lymphocyte ratios of both groups were elevated after delivery. Based on the covariance analysis, after adjusting for baseline full blood counts before delivery, the neutrophil-lymphocyte ratio in the caesarean group was higher than the ratio in the vaginal group after delivery (p = .000). In addition, after adjustment for confounding factors, multivariable regression analyses showed that an increased neutrophil-lymphocyte ratio was correlated with delayed onset of lactation (95% confidence interval 0.285-1.646). CONCLUSIONS The neutrophil-lymphocyte ratio in the caesarean section group was higher than that in the vaginal delivery group and was related to a delayed onset of lactation. Given the decreased mitochondrial copy number in the elevated neutrophil-lymphocyte ratio and therefore the associated reduction in adenosine triphosphate synthesis, these findings may elucidate the mechanism for delayed onset of lactation in caesarean section births.
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15
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Draghi A, Borch TH, Radic HD, Chamberlain CA, Gokuldass A, Svane IM, Donia M. Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses: implications for the management of irAEs. Int J Cancer 2019; 145:1408-1413. [PMID: 30575963 DOI: 10.1002/ijc.32080] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/03/2018] [Accepted: 10/22/2018] [Indexed: 12/19/2022]
Abstract
Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti-TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10-125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high doses impaired the activation (-46 and -62%, respectively) and tumor-killing ability (-48 and -53%, respectively) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (-20%) and tumor killing (-10%). A 72-hr resting period after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid-sparing strategies and early initiation of anti-TNF therapy for the treatment of irAEs in immuno-oncology.
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Affiliation(s)
- Arianna Draghi
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Troels Holz Borch
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Haja Dominike Radic
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Christopher Aled Chamberlain
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Aishwarya Gokuldass
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Inge Marie Svane
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
| | - Marco Donia
- Department of Hematology, Center for Cancer Immune Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Herlev, Denmark
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16
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Scicchitano BM, Dobrowolny G, Sica G, Musarò A. Molecular Insights into Muscle Homeostasis, Atrophy and Wasting. Curr Genomics 2018; 19:356-369. [PMID: 30065611 PMCID: PMC6030854 DOI: 10.2174/1389202919666180101153911] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Muscle homeostasis is guaranteed by a delicate balance between synthesis and degradation of cell proteins and its alteration leads to muscle wasting and diseases. In this review, we describe the major anabolic pathways that are involved in muscle growth and homeostasis and the proteolytic systems that are over-activated in muscle pathologies. Modulation of these pathways comprises an attractive target for drug intervention.
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Affiliation(s)
- Bianca Maria Scicchitano
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo Francesco Vito 1-00168, Roma, Italy
| | - Gabriella Dobrowolny
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
| | - Gigliola Sica
- Istituto di Istologia e Embriologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo Francesco Vito 1-00168, Roma, Italy
| | - Antonio Musarò
- Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
- DAHFMO-Unit of Histology and Medical Embryology, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy
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17
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Tong J, Yu Y, Zheng L, Zhang C, Tu Y, Liu Y, Wu J, Li H, Wang S, Jiang C, Zhou EM, Wang G, Cai X. Hypothalamus-pituitary-adrenal axis involves in anti-viral ability through regulation of immune response in piglets infected by highly pathogenic porcine reproductive and respiratory syndrome virus. BMC Vet Res 2018. [PMID: 29540178 PMCID: PMC5853143 DOI: 10.1186/s12917-018-1414-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND The highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has been responsible for several viral attacks in the Asian porcine industry, since the first outbreak in China in 2006. During the early stages of the HP-PRRSV infection, high levels of proinflammatory cytokines are noted in the host peripheral blood, which are accompanied by severe lesions in the lungs and immune system organs; these are considered as the greatest contributors to the overall disease burden. We hypothesized that the anti-PRRSV response in piglets might be mediated by the hypothalamus-pituitary-adrenal (HPA) axis, which led to a decrease in the psycho-neuroendocrinological manifestation of HP-PRRSV etiology via immune response regulation. RESULTS We investigated the regulation of the HPA axis in HP-PRRSV-infected piglets that were treated with 1 mg/kg body weight (b. w.)/day mifepristone (RU486) or 2 mg/kg b.w./day dexamethasone (DEX). Both RU486 and DEX enhanced the disease status of the piglets infected by the HP-PRRSV HuN4 strain, resulting in high mortality and more severe pathological changes in the lungs. CONCLUSIONS HP-PRRSV infection activates the HPA axis, and artificial regulation of the immune-endocrine system enhances disease severity in HP-PRRSV-infected piglets. Thus, DEX and RU486 should be avoided in the clinical treatment of HP-PRRS.
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Affiliation(s)
- Jie Tong
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Ying Yu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Linlin Zheng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Chong Zhang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Yabin Tu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Yonggang Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Jianan Wu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Hai Li
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Shujie Wang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - Chenggang Jiang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China
| | - En-Min Zhou
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
| | - Gang Wang
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China.
| | - Xuehui Cai
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agriculture Science, Harbin, 150001, People's Republic of China.
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18
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Stubbs FE, Birnie MT, Biddie SC, Lightman SL, Conway-Campbell BL. SKOV3 cells containing a truncated ARID1a protein have a restricted genome-wide response to glucocorticoids. Mol Cell Endocrinol 2018; 461:226-235. [PMID: 28942102 DOI: 10.1016/j.mce.2017.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 08/07/2017] [Accepted: 09/13/2017] [Indexed: 12/11/2022]
Abstract
AT-rich interacting domain subunit 1a (ARID1a) is an essential SWI/SNF component frequently mutated in human cancers. ARID1a mutations have also been associated with glucocorticoid resistance, potentially related to the well-established role of the SWI/SNF complex in glucocorticoid target gene regulation. Glucocorticoids are steroid hormones important for regulating many physiological processes through the activation of the glucocorticoid receptor (GR). As GR interacts directly with ARID1a, we hypothesized that a truncating ARID mutation would interfere with GR-dependent gene regulation. Using high throughput RNA sequencing (RNA-SEQ) we show a restricted glucocorticoid response in SKOV3 cells, which contain an inactivating ARID1a mutation. We also show a lack of GR binding at the GR-dependent regulatory site in the Period 1 gene, which has previously been shown to require chromatin remodelling. Taken together, our data suggests that ARID1a may be required for regulation of a subset of glucocorticoid responsive genes. In the case of SKOV3 cells, in which ARID1a is mutated, glucocorticoid-dependent transcriptional regulation of these genes is significantly impaired.
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Affiliation(s)
- F E Stubbs
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK.
| | - M T Birnie
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK.
| | - S C Biddie
- West Hertfordshire NHS Trust, Watford General Hospitals, Vicarage Road, Watford, Hertfordshire WD18 0HB, UK.
| | - S L Lightman
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK.
| | - B L Conway-Campbell
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK.
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19
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Rensen N, Gemke RJBJ, van Dalen EC, Rotteveel J, Kaspers GJL, Cochrane Childhood Cancer Group. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev 2017; 11:CD008727. [PMID: 29106702 PMCID: PMC6486149 DOI: 10.1002/14651858.cd008727.pub4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. OBJECTIVES To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. SELECTION CRITERIA All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. DATA COLLECTION AND ANALYSIS Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. MAIN RESULTS We identified 10 studies (total of 298 children; we identified two studies for this update) including two randomised controlled trials (RCTs) that assessed adrenal function. None of the included studies assessed the HPA axis at the level of the hypothalamus, the pituitary, or both. Owing to substantial differences between studies, we could not pool results. All studies had risk of bias issues. Included studies demonstrated that adrenal insufficiency occurs in nearly all children during the first days after cessation of glucocorticoid treatment for childhood ALL. Most children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks.Included studies evaluated several risk factors for (prolonged) adrenal insufficiency. First, three studies including two RCTs investigated the difference between prednisone and dexamethasone in terms of occurrence and duration of adrenal insufficiency. The RCTs found no differences between prednisone and dexamethasone arms. In the other (observational) study, children who received prednisone recovered earlier than children who received dexamethasone. Second, treatment with fluconazole appeared to prolong the duration of adrenal insufficiency, which was evaluated in two studies. One of these studies reported that the effect was present only when children received fluconazole at a dose higher than 10 mg/kg/d. Finally, two studies evaluated the presence of infection, stress episodes, or both, as a risk factor for adrenal insufficiency. In one of these studies (an RCT), trial authors found no relationship between the presence of infection/stress and adrenal insufficiency. The other study found that increased infection was associated with prolonged duration of adrenal insufficiency. AUTHORS' CONCLUSIONS We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. No data were available on the levels of the hypothalamus and the pituitary; therefore, we could draw no conclusions regarding these outcomes. Clinicians may consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, additional high-quality research is needed to inform evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as these treatments may prolong the duration of adrenal insufficiency, especially when administered at a dose higher than 10 mg/kg/d.Finally, it would be relevant to investigate further the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.
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Affiliation(s)
- Niki Rensen
- VU University Medical CenterDepartment of Pediatrics, Division of Oncology/HematologyDe Boelelaan 1117AmsterdamNetherlands1081 HZ
| | - Reinoud JBJ Gemke
- VU University Medical CenterDepartment of Pediatrics, Division of General Pediatrics and other subspecialtiesPO Box 7057AmsterdamNetherlands1007 MB
| | - Elvira C van Dalen
- Emma Children's Hospital/Academic Medical CenterDepartment of Paediatric OncologyPO Box 22660 (room H4‐139)AmsterdamNetherlands1100 DD
| | - Joost Rotteveel
- VU University Medical CenterDepartment of Pediatrics, Division of EndocrinologyPO Box 7057AmsterdamNetherlands1007 MB
| | - Gertjan JL Kaspers
- VU University Medical CenterDepartment of Pediatrics, Division of Oncology/HematologyDe Boelelaan 1117AmsterdamNetherlands1081 HZ
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20
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Pazdrak K, Moon Y, Straub C, Stafford S, Kurosky A. Eosinophil resistance to glucocorticoid-induced apoptosis is mediated by the transcription factor NFIL3. Apoptosis 2016; 21:421-31. [PMID: 26880402 DOI: 10.1007/s10495-016-1226-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The mainstay of asthma therapy, glucocorticoids (GCs) exert their therapeutic effects through the inhibition of inflammatory signaling and induction of eosinophil apoptosis. However, laboratory and clinical observations of GC-resistant asthma suggest that GCs' effects on eosinophil viability may depend on the state of eosinophil activation. In the present study we demonstrate that eosinophils stimulated with IL-5 show impaired pro-apoptotic response to GCs. We sought to determine the contribution of GC-mediated transactivating (TA) and transrepressing (TR) pathways in modulation of activated eosinophils' response to GC by comparing their response to the selective GC receptor (GR) agonist Compound A (CpdA) devoid of TA activity to that upon treatment with Dexamethasone (Dex). IL-5-activated eosinophils showed contrasting responses to CpdA and Dex, as IL-5-treated eosinophils showed no increase in apoptosis compared to cells treated with Dex alone, while CpdA elicited an apoptotic response regardless of IL-5 stimulation. Proteomic analysis revealed that both Nuclear Factor IL-3 (NFIL3) and Map Kinase Phosphatase 1 (MKP1) were inducible by IL-5 and enhanced by Dex; however, CpdA had no effect on NFIL3 and MKP1 expression. We found that inhibiting NFIL3 with specific siRNA or by blocking the IL-5-inducible Pim-1 kinase abrogated the protective effect of IL-5 on Dex-induced apoptosis, indicating crosstalk between IL-5 anti-apoptotic pathways and GR-mediated TA signaling occurring via the NFIL3 molecule. Collectively, these results indicate that (1) GCs' TA pathway may support eosinophil viability in IL-5-stimulated cells through synergistic upregulation of NFIL3; and (2) functional inhibition of IL-5 signaling (anti-Pim1) or the use of selective GR agonists that don't upregulate NFIL3 may be effective strategies for the restoring pro-apoptotic effect of GCs on IL-5-activated eosinophils.
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Affiliation(s)
- Konrad Pazdrak
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA. .,Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA.
| | - Young Moon
- Undergraduate Summer Research Program, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Christof Straub
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA
| | - Susan Stafford
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA
| | - Alexander Kurosky
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA.,Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA
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21
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Pazdrak K, Straub C, Maroto R, Stafford S, White WI, Calhoun WJ, Kurosky A. Cytokine-Induced Glucocorticoid Resistance from Eosinophil Activation: Protein Phosphatase 5 Modulation of Glucocorticoid Receptor Phosphorylation and Signaling. THE JOURNAL OF IMMUNOLOGY 2016; 197:3782-3791. [PMID: 27742828 DOI: 10.4049/jimmunol.1601029] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/21/2016] [Indexed: 01/01/2023]
Abstract
The mechanisms contributing to persistent eosinophil activation and poor eosinopenic response to glucocorticoids in severe asthma are poorly defined. We examined the effect of cytokines typically overexpressed in the asthmatic airways on glucocorticoid signaling in in vitro activated eosinophils. An annexin V assay used to measure eosinophil apoptosis showed that cytokine combinations of IL-2 plus IL-4 as well as TNF-α plus IFN-γ, or IL-3, GM-CSF, and IL-5 alone significantly diminished the proapoptotic response to dexamethasone. We found that IL-2 plus IL-4 resulted in impaired phosphorylation and function of the nuclear glucocorticoid receptor (GCR). Proteomic analysis of steroid sensitive and resistant eosinophils identified several differentially expressed proteins, namely protein phosphatase 5 (PP5), formyl peptide receptor 2, and annexin 1. Furthermore, increased phosphatase activity of PP5 correlated with impaired phosphorylation of the GCR. Importantly, suppression of PP5 expression with small interfering RNA restored proper phosphorylation and the proapoptotic function of the GCR. We also examined the effect of lipoxin A4 on PP5 activation by IL-2 plus IL-4. Similar to PP5 small interfering RNA inhibition, pretreatment of eosinophils with lipoxin A4 restored GCR phosphorylation and the proaptoptotic function of GCs. Taken together, our results showed 1) a critical role for PP5 in cytokine-induced resistance to GC-mediated eosinophil death, 2) supported the dependence of GCR phosphorylation on PP5 activity, and 3) revealed that PP5 is a target of the lipoxin A4-induced pathway countering cytokine-induced resistance to GCs in eosinophils.
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Affiliation(s)
- Konrad Pazdrak
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555.,National Heart, Lung, and Blood Institute Proteomics Center Program in Airway Inflammation, The University of Texas Medical Branch, Galveston, TX 77555
| | - Christof Straub
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555
| | - Rosario Maroto
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555.,National Heart, Lung, and Blood Institute Proteomics Center Program in Airway Inflammation, The University of Texas Medical Branch, Galveston, TX 77555
| | - Susan Stafford
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555.,National Heart, Lung, and Blood Institute Proteomics Center Program in Airway Inflammation, The University of Texas Medical Branch, Galveston, TX 77555
| | | | - William J Calhoun
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555.,National Heart, Lung, and Blood Institute Proteomics Center Program in Airway Inflammation, The University of Texas Medical Branch, Galveston, TX 77555
| | - Alexander Kurosky
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555; .,National Heart, Lung, and Blood Institute Proteomics Center Program in Airway Inflammation, The University of Texas Medical Branch, Galveston, TX 77555
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22
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Bühler S, Frahm J, Tienken R, Kersten S, Meyer U, Huber K, Dänicke S. Influence of energy level and nicotinic acid supplementation on apoptosis of blood leukocytes of periparturient dairy cows. Vet Immunol Immunopathol 2016; 179:36-45. [DOI: 10.1016/j.vetimm.2016.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 07/06/2016] [Accepted: 07/07/2016] [Indexed: 01/21/2023]
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DuRant SE, Arciniega ML, Bauer CM, Romero LM. A test of reactive scope: Reducing reactive scope causes delayed wound healing. Gen Comp Endocrinol 2016; 236:115-120. [PMID: 27432814 DOI: 10.1016/j.ygcen.2016.07.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 07/14/2016] [Indexed: 12/18/2022]
Abstract
Reactive scope predicts that all animals have an adaptive ability to respond to stressors in their environment, termed reactive homeostasis, and that only when an animal's response to stressful stimuli exceeds a certain threshold (homeostatic overload) will stress have pathological effects. While this framework has successfully helped interpret effects of stressors on wildlife, no study has designed an experiment to directly test this framework. This study was designed to expose house sparrows (Passer domesticus) to treatments that would result in varying ranges of reactive homeostasis during chronic stress, which based on the reactive scope model should cause birds with the lowest reactive homeostasis range to exhibit signs of pathology during a subsequent challenge. To modulate the reactive homeostasis range, we altered allostatic load of birds by exposing them to chronic stress while either elevating, blocking, or not manipulating corticosterone. After concluding chronic stress treatments, birds were exposed to the subsequent challenge of a superficial wound. Individuals treated with corticosterone during chronic stress (high allostatic load) experienced the most pathology, including both weight loss and slower wound healing. Unmanipulated birds (medium allostatic load) also experienced weight loss but had normal healing rates, while birds with blocked corticosterone (low allostatic load) had minimal weight loss and normal healing rates. Our results indicate that increased allostatic load reduces the reactive homeostasis range, thereby causing individuals to cross the homeostatic overload threshold sooner, and thus support the reactive scope framework.
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Affiliation(s)
- S E DuRant
- Department of Integrative Biology, Oklahoma State University, Stillwater OK, 74078, United States; Department of Biology, Tufts University, Medford, MA 02144, United States.
| | - M L Arciniega
- Department of Biology, Tufts University, Medford, MA 02144, United States
| | - C M Bauer
- Department of Biology, Tufts University, Medford, MA 02144, United States
| | - L M Romero
- Department of Biology, Tufts University, Medford, MA 02144, United States
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24
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Zhang YJ, Qi RQ, Gao XH. Local hyperthermia cleared multiple cutaneous warts on a nephrotic syndrome patient. World J Dermatol 2016; 5:125-128. [DOI: 10.5314/wjd.v5.i3.125] [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: 02/15/2016] [Revised: 03/15/2016] [Accepted: 05/11/2016] [Indexed: 02/06/2023] Open
Abstract
Cutaneous warts are caused by human papillomavirus infection. Immunosuppressive state is one of the risk factors of human papillomavirus infection. A girl diagnosed of nephrotic syndrome and on immunosuppressive therapy developed multiple common warts. We treated her on a single lesion by local hyperthermia therapy at 44 °C for 3 consecutive days, each therapy lasted for 30 min. Ten days later, the patient received another 2 consecutive therapy. All lesions are completely resolved at the 9th week after the treatment. No recurrent sign was observed in a 3-mo follow-up. Side effects included burning sensation, stabbing pain at the target site during treatment.
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25
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Some GCR Polymorphisms (N363S, ER22/23EK, and Bcl-1) May Influence Steroid-induced Toxicities and Survival Rates in Children With ALL. J Pediatr Hematol Oncol 2016; 38:334-40. [PMID: 27050122 DOI: 10.1097/mph.0000000000000535] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We investigated whether an altered individual glucocorticoid sensitivity due to particular glucocorticoid receptor single-nucleotide polymorphisms (SNPs) (N363S, ER22/23EK, and Bcl-1) influences the susceptibility to steroid-related toxicities, prognostic factors, and survival rates in children with acute lymphoblastic leukemia. In total, 346 pediatric patients with acute lymphoblastic leukemia were enrolled in our study. Their carrier status was investigated by allele-specific polymerase chain reaction analysis. Clinical and laboratory signs of glucocorticoid-related toxicities, day-8 prednisone response, 5-year event-free survival, and 5-year overall survival rates were analyzed and compared retrospectively. Hepatotoxicity occurred significantly more often in 363S carriers (P=0.004), and glucose metabolism abnormalities were more common in 363S carriers (P=0.001), but did not occur in patients with the ER22/23EK SNP. Hypertension and central nervous system/behavioral changes did not occur in patients with the ER22/23EK SNP. None of the patients with the N363S SNP, the ER22/23EK polymorphism, or the GG genotype for the Bcl-1 polymorphism had a poor prednisone response. The 363S carriers had significantly better 5-year event-free survival (P=0.012) and 5-year overall survival (P=0.013) rates compared with noncarriers. The Bcl-1 SNP was not associated with any of the toxicities investigated or survival. Children with the N363S polymorphism in the glucocorticoid receptor gene were more prone to steroid-related toxicities, whereas those with the ER22/23EK polymorphism were less susceptible. Children with the N363S polymorphism may have more favorable survival rates.
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26
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Rautava S, Walker WA, Lu L. Hydrocortisone-induced anti-inflammatory effects in immature human enterocytes depend on the timing of exposure. Am J Physiol Gastrointest Liver Physiol 2016; 310:G920-9. [PMID: 27056727 PMCID: PMC4935478 DOI: 10.1152/ajpgi.00457.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 03/28/2016] [Indexed: 01/31/2023]
Abstract
The immature human gut has a propensity to exaggerated inflammatory responses that are thought to play a role in the pathogenesis of necrotizing enterocolitis (NEC). Prenatal exposure to corticosteroids has been reported to reduce the risk of NEC, while postnatal dexamethasone treatment is associated with adverse neurodevelopmental outcomes in preterm infants. The aim of this study was to investigate the direct role of hydrocortisone in gene expression patterns and inflammatory responses in immature human enterocytes. Time-dependent hydrocortisone effects in nontransformed primary human fetal intestinal epithelial cell line H4 were investigated by cDNA microarray. Fetal intestinal organ culture and cell culture experiments were conducted. Inflammatory responses were induced by stimulation with IL-1β and TNF-α with and without hydrocortisone. IL-8 and IL-6 expression and secretion were measured as functional readout. Here we report time-dependent hydrocortisone-induced changes in gene expression patterns detected by cDNA microarray. Hydrocortisone significantly attenuated IL-1β-induced inflammatory responses in the immature human gut when administered at the time of the proinflammatory insult: IL-1β-induced IL-8 and IL-6 secretion in the fetal ileum as well as H4 cells were significantly reduced. Hydrocortisone also inhibited IL-8 secretion in response to TNF-α. In contrast, TNF-α-induced IL-8 secretion was not reduced in cells treated with hydrocortisone for 48 h before stimulation. Our observations provide a physiological basis for understanding the differential clinical effects of corticosteroids in the immature human gut depending on the timing of treatment.
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Affiliation(s)
- Samuli Rautava
- 1Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; ,2Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, Massachusetts; and
| | - W. Allan Walker
- 2Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, Massachusetts; and
| | - Lei Lu
- 2Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, Massachusetts; and ,3Section of Neonatology, Department of Pediatrics, University of Chicago, Chicago, Illinois
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27
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Choi IY, Piccio L, Childress P, Bollman B, Ghosh A, Brandhorst S, Suarez J, Michalsen A, Cross AH, Morgan TE, Wei M, Paul F, Bock M, Longo VD. A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep 2016; 15:2136-2146. [PMID: 27239035 DOI: 10.1016/j.celrep.2016.05.009] [Citation(s) in RCA: 351] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 02/20/2016] [Accepted: 04/26/2016] [Indexed: 01/20/2023] Open
Abstract
Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).
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Affiliation(s)
- In Young Choi
- Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Laura Piccio
- Department of Neurology and Neurosurgery and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Patra Childress
- Global Medicine Program, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Bryan Bollman
- Department of Neurology and Neurosurgery and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Arko Ghosh
- Department of Neuroscience, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Sebastian Brandhorst
- Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Jorge Suarez
- Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Andreas Michalsen
- Institute of Social Medicine, Epidemiology and Health Economics, Charité University Medicine Berlin, 10117 Berlin, Germany
| | - Anne H Cross
- Department of Neurology and Neurosurgery and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Todd E Morgan
- Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Min Wei
- Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Friedemann Paul
- NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité University Medicine Berlin, 10117 Berlin, Germany; Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, 10117 Berlin, Germany
| | - Markus Bock
- NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité University Medicine Berlin, 10117 Berlin, Germany; Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, 10117 Berlin, Germany
| | - Valter D Longo
- Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Neuroscience, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
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28
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DuRant SE, de Bruijn R, Tran MN, Romero LM. Wound-healing ability is conserved during periods of chronic stress and costly life history events in a wild-caught bird. Gen Comp Endocrinol 2016; 229:119-26. [PMID: 26965949 DOI: 10.1016/j.ygcen.2016.03.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 02/29/2016] [Accepted: 03/06/2016] [Indexed: 12/31/2022]
Abstract
Chronic stress, potentially through the actions of corticosterone, is thought to directly impair the function of immune cells. However, chronic stress may also have an indirect effect by influencing allocation of energy, ultimately shifting resources away from the immune system. If so, the effects of chronic stress on immune responses may be greater during energetically-costly life history events. To test whether the effects of chronic stress on immune responses differ during expensive life history events we measured wound healing rate in molting and non-molting European starlings (Sturnus vulgaris) exposed to control or chronic stress conditions. To determine whether corticosterone correlated with wound healing rates before starting chronic stress, we measured baseline and stress-induced corticosterone and two estimates of corticosterone release and regulation, negative feedback (using dexamethasone injection), and maximal capacity of the adrenals to secrete corticosterone (using adrenocorticotropin hormone [ACTH] injection). After 8days of exposure to chronic stress, we wounded both control and chronically stressed birds and monitored healing daily. We monitored nighttime heart rate, which strongly correlates with energy expenditure, and body mass throughout the study. Measures of corticosterone did not differ with molt status. Contrary to work on lizards and small mammals, all birds, regardless of stress or molt status, fully-healed wounds at similar rates. Although chronic stress did not influence healing rates, individuals with low baseline corticosterone or strong negative feedback had faster healing rates than individuals with high baseline corticosterone or weak negative feedback. In addition, wound healing does appear to be linked to energy expenditure and body mass. Non-molting, chronically stressed birds decreased nighttime heart rate during healing, but this pattern did not exist in molting birds. Additionally, birds of heavier body mass at the start of the experiment healed wounds more rapidly than lighter birds. Finally, chronically stressed birds lost body mass at the start of chronic stress, but after wounding all birds regardless of stress or molt status started gaining weight, which continued for the remainder of the study. Increased body mass could suggest compensatory feeding to offset energetic or resource demands (e.g., proteins) of wound healing. Although chronic stress did not inhibit healing, our data suggest that corticosterone may play an important role in mediating healing processes and that molt could influence energy saving tactics during periods of chronic stress. Although the experiment was designed to test allostasis, interpretation of data through reactive scope appears to be a better fit.
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Affiliation(s)
- S E DuRant
- Department of Biology, Tufts University, Medford, MA 02155, United States; Department of Zoology, Oklahoma State University, Stillwater, OK 74078, United States.
| | - R de Bruijn
- Department of Biology, Tufts University, Medford, MA 02155, United States
| | - M N Tran
- Department of Biology, Tufts University, Medford, MA 02155, United States
| | - L M Romero
- Department of Biology, Tufts University, Medford, MA 02155, United States
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Divyashree S, Sarjan H, Yajurvedi H. Effects of long-term chronic stress on the lymphoid organs and blood leukocytes of the rat (Rattus norvegicus). CAN J ZOOL 2016. [DOI: 10.1139/cjz-2015-0150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Exposure of adult female rats (Rattus norvegicus (Berkenhout,1769)) to restraint (1 h) and after a gap of 4 h to forced swimming exercise for 15 min daily for 12 weeks resulted in a significant decrease in (i) weight of the body and lymphoid organs (spleen, thymus, and axillary lymph node), (ii) counts of total leukocytes and their subpopulation (lymphocytes, neutrophils, monocytes, eosinophils, and basophils), and (iii) healthy cells of all lymphoid organs and a significant increase in the count of apoptotic cells in all the lymphoid organs. One month after cessation of exposure to stressors (recovery group), all the parameters did not significantly differ from stress-group rats. The results may indicate that either deleterious effects of long-term chronic exposure to stress are not reversible or the 4-week recovery period is not sufficient to restore normalcy.
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Affiliation(s)
- S. Divyashree
- Department of Zoology, University of Mysore, Manasagangotri, Mysore 570 006, India
- Department of Zoology, University of Mysore, Manasagangotri, Mysore 570 006, India
| | - H.N. Sarjan
- Department of Zoology, University of Mysore, Manasagangotri, Mysore 570 006, India
- Department of Zoology, University of Mysore, Manasagangotri, Mysore 570 006, India
| | - H.N. Yajurvedi
- Department of Zoology, University of Mysore, Manasagangotri, Mysore 570 006, India
- Department of Zoology, University of Mysore, Manasagangotri, Mysore 570 006, India
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30
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Bergquist M, Huss F, Hästbacka J, Lindholm C, Martijn C, Rylander C, Hedenstierna G, Fredén F. Glucocorticoid receptor expression and binding capacity in patients with burn injury. Acta Anaesthesiol Scand 2016; 60:213-21. [PMID: 26338204 DOI: 10.1111/aas.12604] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 05/25/2015] [Accepted: 06/25/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Burn injuries are associated with strong inflammation and risk of secondary sepsis which both may affect the function of the glucocorticoid receptor (GR). The aim of this study was to determine GR expression and binding capacity in leucocytes from patients admitted to a tertiary burn center. METHODS Blood was sampled from 13 patients on admission and days 7, 14 and 21, and once from 16 healthy subjects. Patients were grouped according to the extent of burn and to any sepsis on day 7. Expression and binding capacity of GR were determined as arbitrary units using flow cytometry. RESULTS GR expression and binding capacity were increased compared to healthy subjects in most circulating leucocyte subsets on admission irrespective of burn size. Patients with sepsis on day 7 displayed increased GR expression in T lymphocytes (51.8%, P < 0.01) compared to admission. There was a negative correlation between GR binding capacity in neutrophils and burn size after 14 days (P < 0.05). CONCLUSIONS GR expression and binding capacity are increased in most types of circulating leucocytes of severely burned patients on their admission to specialized burn care. If sepsis is present after 1 week, it is associated with higher GR expression in T lymphocytes and NK cells.
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Affiliation(s)
- M. Bergquist
- Department of Medical Sciences, Clinical Physiology; Uppsala University; Uppsala Sweden
- Department of Rheumatology and Inflammation Research; Sahlgrenska Academy; University of Gothenburg; Gothenburg Sweden
| | - F. Huss
- Uppsala Burn Center; Uppsala University Hospital; Uppsala Sweden
- Department of Surgical Sciences, Plastic Surgery; Uppsala University; Uppsala Sweden
| | - J. Hästbacka
- Department of Anaesthesia and Intensive Care Medicine; Helsinki University Central Hospital; Helsinki Finland
| | - C. Lindholm
- Department of Rheumatology and Inflammation Research; Sahlgrenska Academy; University of Gothenburg; Gothenburg Sweden
| | - C. Martijn
- Department of Chemistry; Biomedical Center; Uppsala University; Uppsala Sweden
| | - C. Rylander
- Department of Anaesthesia and Intensive Care; Sahlgrenska University Hospital; Gothenburg Sweden
| | - G. Hedenstierna
- Department of Medical Sciences, Clinical Physiology; Uppsala University; Uppsala Sweden
| | - F. Fredén
- Uppsala Burn Center; Uppsala University Hospital; Uppsala Sweden
- Department of Surgical Sciences, Anaesthesiology and Intensive Care; Uppsala University; Uppsala Sweden
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31
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Gordijn MS, Rensen N, Gemke RJBJ, van Dalen EC, Rotteveel J, Kaspers GJL. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev 2015:CD008727. [PMID: 26282194 DOI: 10.1002/14651858.cd008727.pub3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infections, which remains a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is an update of a previously published Cochrane review. OBJECTIVES To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 6, 2014), MEDLINE/PubMed (from 1945 to June 2014), and EMBASE/Ovid (from 1980 to June 2014). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 to 2013), and ongoing trial databases (the ISRCTN register and the NIH register via http://www.controlled-trials.com in June 2014). SELECTION CRITERIA All study designs, except case reports and patient series with fewer than 10 children, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which another review author checked. MAIN RESULTS We identified eight studies (total of 218 children), including two randomised controlled trials (RCTs), that assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. Due to substantial differences between studies, we could not pool results. All of the studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all children in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCTs, the occurrence and duration of adrenal insufficiency did not differ between the prednisone and dexamethasone arms. In one study, it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency. Furthermore, one of the studies evaluated the presence of infections or stress episodes, or both as a risk factor for adrenal insufficiency. The authors found no relationship between the presence of infection/stress and adrenal insufficiency. AUTHORS' CONCLUSIONS We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available, we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.Finally, it would be relevant to further investigate the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.
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Affiliation(s)
- Maartje S Gordijn
- Department of Pediatrics, Division of Oncology/Hematology, VU University Medical Center, PO Box 7057, Amsterdam, Netherlands, 1007 MB
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Nagahama K, Eto N, Shimojo T, Kondoh T, Nakahara K, Sakakibara Y, Fukui K, Suiko M. Effect of kumquat (Fortunella crassifolia) pericarp on natural killer cell activity in vitro and in vivo. Biosci Biotechnol Biochem 2015; 79:1327-36. [PMID: 25849817 DOI: 10.1080/09168451.2015.1025033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Natural killer (NK) cells play a key role in innate immune defense against infectious disease and cancer. A reduction of NK activity is likely to be associated with increased risk of these types of disease. In this study, we investigate the activation potential of kumquat pericarp acetone fraction (KP-AF) on NK cells. It is shown to significantly increase IFN-γ production and NK cytotoxic activity in human KHYG-1 NK cells. Moreover, oral administration of KP-AF significantly improves both suppressed plasma IFN-γ levels and NK cytotoxic activity per splenocyte in restraint-stressed mice. These results indicate that raw kumquat pericarp activates NK cells in vitro and in vivo. To identify the active constituents, we also examined IFN-γ production on KHYG-1 cells by the predicted active components. Only β-cryptoxanthin increased IFN-γ production, suggesting that NK cell activation effects of KP-AF may be caused by carotenoids such as β-cryptoxanthin.
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Affiliation(s)
- Kiyoko Nagahama
- a Interdisciplinary Graduate School of Agriculture and Engineering , University of Miyazaki , Miyazaki , Japan
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Knapp CM, Whitehead KA. In pursuit of a moving target: nanotherapeutics for the treatment of non-Hodgkin B-cell lymphoma. Expert Opin Drug Deliv 2014; 11:1923-37. [DOI: 10.1517/17425247.2014.945419] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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de Ruiter RD, Gordijn MS, Gemke RJBJ, van den Bos C, Bierings MB, Rotteveel J, Koper JW, van Rossum EFC, Kaspers GL. Adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia is associated with glucocorticoid receptor polymorphisms ER22/23EK and BclI. Haematologica 2014; 99:e136-7. [PMID: 24816241 DOI: 10.3324/haematol.2014.105056] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Ruben D de Ruiter
- Department of Pediatrics, Division Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - M Suzanne Gordijn
- Department of Pediatrics, Division Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
| | - Reinoud J B J Gemke
- Department of Pediatrics, Division of General Pediatrics and other subspecialties, VU University Medical Center, Amsterdam, the Netherlands
| | - Cor van den Bos
- Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, the Netherlands
| | - Marc B Bierings
- Department of Pediatric Hemato/Oncology, University Medical Center Utrecht, Amsterdam, the Netherlands
| | - Joost Rotteveel
- Department of Pediatrics, Division of Endocrinology, VU University Medical Center, Amsterdam, the Netherlands
| | - Jan W Koper
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | | | - Gertjan L Kaspers
- Department of Pediatrics, Division Oncology/Hematology, VU University Medical Center, Amsterdam, the Netherlands
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Broos CE, van Nimwegen M, Hoogsteden HC, Hendriks RW, Kool M, van den Blink B. Granuloma formation in pulmonary sarcoidosis. Front Immunol 2013; 4:437. [PMID: 24339826 PMCID: PMC3857538 DOI: 10.3389/fimmu.2013.00437] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 11/23/2013] [Indexed: 01/14/2023] Open
Abstract
Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs, but mainly the lungs. The exact order of immunological events remains obscure. Reviewing current literature, combined with careful clinical observations, we propose a model for granuloma formation in pulmonary sarcoidosis. A tight collaboration between macrophages, dendritic cells, and lymphocyte subsets, initiates the first steps toward granuloma formation, orchestrated by cytokines and chemokines. In a substantial part of pulmonary sarcoidosis patients, granuloma formation becomes an on-going process, leading to debilitating disease, and sometimes death. The immunological response, determining granuloma sustainment is not well understood. An impaired immunosuppressive function of regulatory T cells has been suggested to contribute to the exaggerated response. Interestingly, therapeutical agents commonly used in sarcoidosis, such as glucocorticosteroids and anti-TNF agents, interfere with granuloma integrity and restore the immune homeostasis in autoimmune disorders. Increasing insight into their mechanisms of action may contribute to the search for new therapeutical targets in pulmonary sarcoidosis.
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Affiliation(s)
- Caroline E Broos
- Department of Pulmonary Medicine, Erasmus MC , Rotterdam , Netherlands
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Chafin CB, Regna NL, Hammond SE, Reilly CM. Cellular and urinary microRNA alterations in NZB/W mice with hydroxychloroquine or prednisone treatment. Int Immunopharmacol 2013; 17:894-906. [PMID: 24121037 DOI: 10.1016/j.intimp.2013.09.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/06/2013] [Accepted: 09/18/2013] [Indexed: 10/26/2022]
Abstract
Determining alterations to disease-associated miRNAs induced by specific therapeutics may allow the use of tailored therapy in lupus. We determined miRNA alterations in female NZB/W lupus mice treated with hydroxychloroquine (HCQ) or prednisone (PRED) for 12 weeks beginning at 24 weeks-of-age. B cell, PBMC, and urinary miR-let-7a expression were decreased with HCQ or PRED treatment. HCQ or PRED treatment reduced miR-21 expression in mesangial cells, T cells, pDCs, PBMCs, and the urine. MiR-146a expression was reduced in mesangial cells with HCQ treatment and in pDCs with HCQ or PRED treatment. PRED treatment increased miR-155 expression in mesangial, B, and T cells and PBMCs yet decreased miR-155 expression in pDCs and the urine. In vitro studies confirmed that HCQ or PRED's anti-inflammatory actions are dependent on their ability to inhibit miRNA expression. Our studies indicate that lupus therapeutics may work, in part, by altering the expression of disease-associated miRNAs.
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Affiliation(s)
- Cristen B Chafin
- Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, United States.
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Chapman KE, Coutinho AE, Zhang Z, Kipari T, Savill JS, Seckl JR. Changing glucocorticoid action: 11β-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation. J Steroid Biochem Mol Biol 2013; 137:82-92. [PMID: 23435016 PMCID: PMC3925798 DOI: 10.1016/j.jsbmb.2013.02.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 01/22/2013] [Accepted: 02/04/2013] [Indexed: 12/18/2022]
Abstract
Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Despite the identification of 11β-HSD in liver in 1953 (which we now know to be 11β-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11β-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11β-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11β-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11β-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11β-HSD1 in inflammation. This article is part of a Special Issue entitled 'CSR 2013'.
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Affiliation(s)
- Karen E Chapman
- University/BHF Centre for Cardiovascular Sciences, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
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Iseri VJ, Klasing KC. Dynamics of the systemic components of the chicken (Gallus gallus domesticus) immune system following activation by Escherichia coli; implications for the costs of immunity. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2013; 40:248-257. [PMID: 23500513 DOI: 10.1016/j.dci.2013.02.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 02/03/2013] [Accepted: 02/12/2013] [Indexed: 06/01/2023]
Abstract
The immune response is thought to be costly and deters from growth and reproduction, but the magnitude and sources of these costs are unknown. Thus, we quantified the changes in mass of leukocytes (CD4(+) and CD8(+) T cells, Bu1(+) IgM(+) and Bu1(+) IgG(+) B cells, monocytes/macrophages, heterophils and thrombocytes) and protective plasma proteins in systemic (non-mucosal) components of adult chickens injected intravenously with dead Escherichia coli. During the first day after E. coli injection most types of blood leukocytes decreased and α-1-acid glycoprotein increased. Specific IgM, specific IgY, total IgM, Bu1(+) lymphocytes in the spleen and bone marrow and thymic CD8(+) lymphocytes increased at 5d post-injection. Quantitatively, the increases in the weight of cells and antibodies due to E. coli were dwarfed by the increase in the weight of the liver and acute phase proteins. Thus the acute phase response was markedly more costly than the subsequent adaptive response. The weight of the cells and proteins of the systemic immune system prior to challenge was 0.14% of body weight. Following E. coli injection, the additional weight of the immune components and the hypertrophy of the liver resulted in a 3.6-fold increase in weight which is equivalent to 18.5% of a large egg.
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Affiliation(s)
- V J Iseri
- Department of Animal Science, 1 Shields Avenue, Davis, CA 95616, USA
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Krishnan V, Xu X, Barwe SP, Yang X, Czymmek K, Waldman SA, Mason RW, Jia X, Rajasekaran AK. Dexamethasone-loaded block copolymer nanoparticles induce leukemia cell death and enhance therapeutic efficacy: a novel application in pediatric nanomedicine. Mol Pharm 2013; 10:2199-210. [PMID: 23194373 PMCID: PMC4162306 DOI: 10.1021/mp300350e] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Nanotechnology approaches have tremendous potential for enhancing treatment efficacy with lower doses of chemotherapeutics. Nanoparticle (NP)-based drug delivery approaches are poorly developed for childhood leukemia. Dexamethasone (Dex) is one of the most common chemotherapeutic drugs used in the treatment of childhood leukemia. In this study, we encapsulated Dex in polymeric NPs and validated their antileukemic potential in vitro and in vivo. NPs with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals (ECT2). The blank NPs were nontoxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the NPs (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to the free Dex in leukemic cells. Studies using NPs labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of the particles with time. In a preclinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice as compared to the free drug. To our knowledge, this is the first report showing the efficacy of polymeric NPs to deliver Dex to potentially treat childhood leukemia and reveals that low doses of Dex should be sufficient for inducing cell death and improving survival.
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Affiliation(s)
- Vinu Krishnan
- Department of Materials Science and Engineering, University of Delaware,
Newark, DE
- Nemours Center for Childhood Cancer Research, A.I. duPont Hospital for
Children, Wilmington, DE
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
| | - Xian Xu
- Department of Materials Science and Engineering, University of Delaware,
Newark, DE
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
| | - Sonali P. Barwe
- Nemours Center for Childhood Cancer Research, A.I. duPont Hospital for
Children, Wilmington, DE
| | - Xiaowei Yang
- Department of Materials Science and Engineering, University of Delaware,
Newark, DE
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
| | - Kirk Czymmek
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
- Department of Biological Sciences, Center for Translational Cancer Research,
University of Delaware, Newark, DE
| | - Scott A. Waldman
- Pharamcology and Experimental Therapeutics, Jefferson Medical College,
Thomas Jefferson University, Philadelphia, PA
| | - Robert W. Mason
- Nemours Center for Childhood Cancer Research, A.I. duPont Hospital for
Children, Wilmington, DE
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
- Department of Biological Sciences, Center for Translational Cancer Research,
University of Delaware, Newark, DE
| | - Xinqiao Jia
- Department of Materials Science and Engineering, University of Delaware,
Newark, DE
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
- Department of Biological Sciences, Center for Translational Cancer Research,
University of Delaware, Newark, DE
| | - Ayyappan K. Rajasekaran
- Department of Materials Science and Engineering, University of Delaware,
Newark, DE
- Nemours Center for Childhood Cancer Research, A.I. duPont Hospital for
Children, Wilmington, DE
- Delaware Biotechnology Institute, University of Delaware, Newark, DE
- Department of Biological Sciences, Center for Translational Cancer Research,
University of Delaware, Newark, DE
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Liang H, Kowalczyk P, Junco JJ, Klug-De Santiago HL, Malik G, Wei SJ, Slaga TJ. Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARα receptors. Mol Carcinog 2013; 53:753-63. [DOI: 10.1002/mc.22029] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 03/01/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Huiyun Liang
- Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
- Medical Research Division, Regional Academic Health Center at Edinburg; University of Texas Health Science Center at San Antonio; Edinburg, Texas
| | - Piotr Kowalczyk
- Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
| | - Jacob J. Junco
- Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
| | - Heather L. Klug-De Santiago
- Medical Research Division, Regional Academic Health Center at Edinburg; University of Texas Health Science Center at San Antonio; Edinburg, Texas
| | - Gunjan Malik
- Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
| | - Sung-Jen Wei
- Medical Research Division, Regional Academic Health Center at Edinburg; University of Texas Health Science Center at San Antonio; Edinburg, Texas
- Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
| | - Thomas J. Slaga
- Department of Cellular and Structural Biology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
- Department of Pharmacology; University of Texas Health Science Center at San Antonio; San Antonio, Texas
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41
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Mao Y, Triantafillou G, Hertlein E, Towns W, Stefanovski M, Mo X, Jarjoura D, Phelps M, Marcucci G, Lee LJ, Goldenberg DM, Lee RJ, Byrd JC, Muthusamy N. Milatuzumab-conjugated liposomes as targeted dexamethasone carriers for therapeutic delivery in CD74+ B-cell malignancies. Clin Cancer Res 2013; 19:347-56. [PMID: 23209030 PMCID: PMC3793126 DOI: 10.1158/1078-0432.ccr-12-2046] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
PURPOSE Corticosteroids are widely used for the treatment of B-cell malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia; however, this class of drug is associated with undesirable off-target effects. Herein, we developed novel milatuzumab-conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74(+) B-cell malignancies and explored its effect against the disease. EXPERIMENTAL DESIGN The targeting efficiency of milatuzumab-targeted liposomes to CD74(+) cells was evaluated in vitro. The effect of CD74-targeted liposomal dexamethasone was compared with free dexamethasone in primary CLL cells and cell lines in vitro. The therapeutic efficacy of CD74-targeted liposomal dexamethasone was evaluated in a Raji-severe combined immunodeficient (SCID) xenograft model in vivo. RESULTS Milatuzumab-targeted liposomes promoted selective incorporation of carrier molecules into transformed CD74-positive B cells as compared with CD74-negative T-cells. The CD74-dexamethasone-targeted liposomes (CD74-IL-DEX) promoted and increased killing in CD74-positive tumor cells and primary CLL cells. Furthermore, the targeted drug liposomes showed enhanced therapeutic efficacy against a CD74-positive B-cell model as compared with free, or non-targeted, liposomal dexamethasone in SCID mice engrafted with Raji cells in vivo. CONCLUSIONS These studies provide evidence and support for a potential use of CD74-targeted liposomal dexamethasone as a new therapy for B-cell malignancies.
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MESH Headings
- Animals
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/pharmacology
- Antigens, Differentiation, B-Lymphocyte/metabolism
- Cell Line, Tumor
- Dexamethasone/administration & dosage
- Dexamethasone/pharmacology
- Disease Models, Animal
- Female
- Histocompatibility Antigens Class II/metabolism
- Humans
- Leukemia, B-Cell/drug therapy
- Leukemia, B-Cell/metabolism
- Leukemia, B-Cell/mortality
- Liposomes
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/metabolism
- Lymphoma, B-Cell/mortality
- Mice
- Tumor Burden/drug effects
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Yicheng Mao
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Division of Pharmaceutics, The Ohio State University, Columbus, Ohio
| | - Georgia Triantafillou
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Erin Hertlein
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - William Towns
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Matthew Stefanovski
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Xiaokui Mo
- Center for Biostatistics, The Ohio State University, Columbus, Ohio
| | - David Jarjoura
- Center for Biostatistics, The Ohio State University, Columbus, Ohio
| | - Mitch Phelps
- Division of Pharmaceutics, The Ohio State University, Columbus, Ohio
| | - Guido Marcucci
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Ly James Lee
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio
| | - David M. Goldenberg
- Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, New Jersey
| | - Robert J. Lee
- Division of Pharmaceutics, The Ohio State University, Columbus, Ohio
| | - John C. Byrd
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio
| | - Natarajan Muthusamy
- Division of Hematology, The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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Mansha M, Hussain A, Kofler A, Grubbauer C, Goetsch K, Ploner C, Kofler R. "Bam," a novel glucocorticoid-induced BH3-only transcript from the BCL2L11/Bim locus, does not appear to be translated. Leuk Lymphoma 2012; 54:353-8. [PMID: 22762551 DOI: 10.3109/10428194.2012.708928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Glucocorticoids (GCs) are steroid hormones that induce cell death and cell cycle arrest in lymphoid tissues. By virtue of this property, GCs are widely exploited in the therapy of acute lymphoblastic leukemia (ALL) in children. We reported a novel BH3-only transcript, "Bam," from the BCL2L11 locus, which was first described in patients with multiple myeloma. The Bam gene consists of two exons, and became of particular interest to us when we found that it was regulated in the majority of children with ALL and many in vitro systems in which GCs induce cell death. Being a BH3-only transcript, Bam retains a BH3 domain identical to that of Bim, although Bam has a unique C-terminus that is totally different from that of its relative Bim. The present work analyzes whether Bam is translated or not. Since we could not detect Bam in the endogenous situation, we evaluated its 5' untranslated region (UTR). This revealed that there are three out-of-frame initiation codons preceding the Bam open reading frame (ORF). Experiments with constructs without out-of-frame initiation codons and constructs harboring such codons in their 5' UTR revealed that Bam translation is handicapped by their presence. Moreover, there was no Kozak translational initiation sequence surrounding any of the AUGs. Taken together, results of the present study strongly suggest that this transcript is translated at a very low rate, if at all.
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Affiliation(s)
- Muhammad Mansha
- Division of Molecular Pathophysiology, Biocenter, Medical University Innsbruck, Austria.
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Fukuyama T, Kosaka T, Miyashita L, Nishino R, Wada K, Hayashi K, Ueda H, Harada T. Role of regulatory T cells in the induction of atopic dermatitis by immunosuppressive chemicals. Toxicol Lett 2012; 213:392-401. [DOI: 10.1016/j.toxlet.2012.07.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2012] [Revised: 07/18/2012] [Accepted: 07/19/2012] [Indexed: 01/07/2023]
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Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells. Cell Death Dis 2012; 3:e349. [PMID: 22825467 PMCID: PMC3406588 DOI: 10.1038/cddis.2012.89] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. BIM (BCL-2-interacting mediator of cell death), a BCL-2 homology 3-only pro-apoptotic protein, is upregulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia cells and has an essential role in Dex-induced apoptosis. It has been indicated that Dex-induced BIM is regulated mainly by transcription, however, the molecular mechanisms including responsible transcription factors are unclear. In this study, we found that Dex treatment induced transcription factor Runx2 and c-Jun in parallel with BIM induction. Dex-induced BIM and apoptosis were decreased in cells harboring dominant-negative c-Jun and were increased in cells with c-Jun overexpression. Cells harboring short hairpin RNA for Runx2 also decreased BIM induction and apoptosis. On the Bim promoter, c-Jun bound to and activated the AP-1-binding site at about −2.7 kb from the transcription start site. Treatment with RU486, a GC receptor antagonist, blocked Dex-induced Runx2, c-Jun and BIM induction, as well as apoptosis. Furthermore, pretreatment with SB203580, a p38-mitogen-activated protein kinase (MAPK) inhibitor, decreased Dex-induced Runx2, c-Jun and BIM, suggesting that p38-MAPK activation is upstream of the induction of these molecules. In conclusion, we identified the critical signaling pathway for GC-induced apoptosis, and targeting these molecules may be an alternative approach to overcome GC-resistance in leukemia treatment.
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Gordijn MS, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers GJ. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane Database Syst Rev 2012:CD008727. [PMID: 22592733 DOI: 10.1002/14651858.cd008727.pub2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infections, which remains a cause of morbidity and death. The exact occurrence and duration of HPA axis suppression after glucocorticoid therapy for childhood ALL are unclear. OBJECTIVES To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (in The Cochrane Library, issue 3, 2010), MEDLINE/PubMed (from 1945 to July 2010) and EMBASE/Ovid (from 1980 to July 2010). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. SELECTION CRITERIA All study designs, except case reports and patient series with fewer than 10 patients, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which was checked by another review author. MAIN RESULTS We identified seven studies (total number of participants = 189), including one randomised controlled trial (RCT), which assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. Due to substantial differences between studies, results could not be pooled. All studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all patients in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of patients recovered within a few weeks, but a small amount of patients had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCT, the occurrence and duration of adrenal insufficiency did not differ between the prednisolone and dexamethasone arms. In one study included in the review it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency. AUTHORS' CONCLUSIONS Based on the available evidence, we conclude that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL, to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.
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Affiliation(s)
- Maartje S Gordijn
- Department of Pediatrics, Division of Oncology/Hematology, VU University Medical Center, Amsterdam,
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Anti-stress effects of carnosine on restraint-evoked immunocompromise in mice through spleen lymphocyte number maintenance. PLoS One 2012; 7:e33190. [PMID: 22511917 PMCID: PMC3325237 DOI: 10.1371/journal.pone.0033190] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 02/05/2012] [Indexed: 11/19/2022] Open
Abstract
Carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, has been characterized as a putative neurotransmitter and serves as a reservoir for brain histamine, which could act on histaminergic neurons system to relieve stress-induced damages. However, understanding of the role of carnosine in stress-evoked immunocompromise is limited. In this study, results showed that when mice were subjected to restraint stress, spleen index and the number of spleen lymphocytes including Natural Killer (NK) cells were obviously decreased. Results also demonstrated that restraint stress decreased the cytotoxic activity of NK cells per spleen (LU10/spleen) while the activity of a single NK cell (LU10/106 cells) was not changed. However, oral administration of carnosine (150 and 300 mg/kg) increased spleen index and number of spleen lymphocytes (including NK cells), and elevated the cytotoxic activity of NK cells per spleen in restraint-stressed mice. These results indicated that carnosine ameliorated stress-evoked immunocompromise through spleen lymphocyte number maintenance. Carnosine was further found to reduce stress-induced elevation of plasma corticosterone level. On the other hand, results showed that carnosine and RU486 (a glucocorticoids receptor antagonist) treatment prevented the reduction in mitochondrion membrane potential and the release of mitochondrial cytochrome c into cytoplasm, increased Bcl-2/Bax mRNA ratio, as well as decreased terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in spleen lymphocytes of stressed mice. The results above suggested that the maintenance of spleen lymphocyte number by carnosine was related with the inhibition of lymphocytes apoptosis caused by glucocorticoids overflow. The stimulation of lymphocyte proliferation by carnosine also contributed to the maintenance of spleen lymphocyte number in stressed mice. In view of the elevated histamine level, the anti-stress effects of carnosine on restraint-evoked immunocompromise might be via carnosine-histamine metabolic pathway. Taken together, carnosine maintained spleen lymphocyte number by inhibiting lymphocyte apoptosis and stimulating lymphocyte proliferation, thus prevented immunocompromise in restraint-stressed mice.
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Wang H, Pang B, Li Y, Zhu D, Pang T, Liu Y. Dexamethasone has variable effects on mesenchymal stromal cells. Cytotherapy 2012; 14:423-30. [PMID: 22364108 DOI: 10.3109/14653249.2011.652735] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AIMS Dexamethasone (Dex) is a potent synthetic member of the glucocorticoid class of steroid drugs. Frequently, Dex has been used to enhance osteogenic, chondrogenic and adipogenic differentiation of mesenchymal stromal cells (MSC). Recently, Dex was applied to promote MSC proliferation, because of the rare frequency of MSC in bone marrow, and could protect the cells from apoptosis. The effects of Dex on MSC cytobiology behavior needs to be investigated. METHODS MSC were obtained from human umbilical cord. The surface phenotype and functional characterization of MSC cultured with different concentrations of Dex were investigated, in comparison with a control group, including MSC proliferation, apoptosis, cytokine expression and immunosuppression. RESULTS Different concentrations of Dex exerted diverse effects on MSC proliferation and apoptosis. Dex was also able to affect the pattern of cytokine expression of MSC. Furthermore, Dex impaired immunosuppression of MSC on peripheral blood mononuclear cells. CONCLUSIONS A low dose of Dex favors MSC expansion in vitro, and protects against apoptosis. It is not suitable for MSC to be pre-treated with Dex when they are to be used to treat immunologic disease. However, when MSC are applied to promote angiogenesis, it is beneficial for them to be pre-treated with 10(-9) mol/L Dex.
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Affiliation(s)
- Hanyu Wang
- The State Key Laboratory of Experimental Hematology, Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
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Expression and glucocorticoid-regulation of “Bam”, a novel BH3-only transcript in acute lymphoblastic leukemia. Mol Biol Rep 2012; 39:6007-13. [DOI: 10.1007/s11033-011-1414-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Accepted: 12/19/2011] [Indexed: 10/14/2022]
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Jones HP. Immune cells listen to what stress is saying: neuroendocrine receptors orchestrate immune function. Methods Mol Biol 2012; 934:77-87. [PMID: 22933141 DOI: 10.1007/978-1-62703-071-7_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Over the past three decades, the field of psychoneuroimmunology research has blossomed into a major field of study, gaining interests of researchers across all traditionally accepted disciplines of scientific research. This chapter provides an overview of our current understanding in defining neuroimmune interactions with a primary focus of discussing the neuroendocrine receptor activity by immune cells. This chapter highlights the necessity of neuroimmune responses as it relates to a better understanding of the pathophysiological mechanisms of health and disease.
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Affiliation(s)
- Harlan P Jones
- Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX, USA.
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Donskow K, Drela N, Doligalska M. Heligmosomoides bakeri antigen rescues CD4-positive T cells from glucocorticoid-induced apoptosis by Bcl-2 protein expression. Parasite Immunol 2011; 33:158-69. [PMID: 21306399 DOI: 10.1111/j.1365-3024.2010.01262.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Heligmosomoides bakeri infection in mice is associated with a dominant CD4(+) T-cell response and with the activity of natural Treg cells with CD4(+) CD25(+) phenotype. The polarization of Th2 T-cell phenotype and the increase in the CD4(+) CD25(+) T cell population are regulated by glucocorticoids that induce apoptosis in CD4(+) CD25(-) T cells and inhibit apoptosis in CD4(+) CD25(+) T cells. However, exposure of mice to H. bakeri antigen induces a high glucocorticoid concentration in serum and a reduction in the number of CD4-positive; CD4(+) CD25(-) and CD4(+) CD25(+) apoptotic T cells in mesenteric lymph node cells. In this study to evaluate the in vitro effect of the anti-apoptotic property of H. bakeri antigen on T cells, apoptosis of these cells was induced by glucocorticoids-dexamethasone (Dex). Excretory-secretory (ES) antigen of the nematode prevented Dex-induced apoptosis in CD4-positive T cells with CD4(+) CD25(-) and CD4(+) CD25(High) phenotype by Bcl-2 protein expression. Contrary to the effect on CD4-positive T cells, survival of CD8(+) T cells was not connected with expression of Bcl-2 protein. This suggest that H. bakeri antigen modulates CD4-positive T cell sensitivity to glucocorticoid-induced apoptosis by induction of Bcl-2 protein.
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Affiliation(s)
- K Donskow
- Department of Parasitology, University of Warsaw, Warsaw, Poland.
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