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1
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Wang Y, Qin J, Dong L, He C, Zhang D, Wu X, Li T, Yue H, Mu L, Wang Q, Yang J. Suppression of mir-150-5p attenuates the anti-inflammatory effect of glucocorticoids in mice with ulcerative colitis. Mol Immunol 2023; 163:28-38. [PMID: 37729776 DOI: 10.1016/j.molimm.2023.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 08/08/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023]
Abstract
Glucocorticoids have been widely used in the treatment of ulcerative colitis, but not all patients benefit from this therapy due to hormone resistance. Mir-150-5p has been reported to enhance the efficacy of glucocorticoids, and low serum mir-150-5p expression has been linked to glucocorticoid resistance in ulcerative colitis patients. The aim of this study was to elucidate the mechanisms of mir-150-5p regulation on glucocorticoid resistance. An ulcerative colitis mouse model was used to evaluate changes in ulcerative colitis symptoms, inflammatory factors, and glucocorticoid resistance-related gene expression. The results showed that mir-150-5p suppression with antagomirs did not significantly interfere with or enhance the induction of ulcerative colitis symptoms by dextran sulfate sodium, but it did attenuate the inflammation inhibitory effect of dexamethasone by abnormally regulating the expression of IL-17a, IL-10, IL-2 and IL-6 levels and myeloperoxidase activity. Mir-150-5p inhibition also induced a glucocorticoid-resistant gene expression profile in colon tissues of ulcerative colitis mice, with upregulation of p-ERK, p-JNK, and HSP90 and downregulation of p-GRa, FKBP4, and HDAC2 expression. Our results indicate that mir-150-5p suppression attenuates the anti-inflammatory effect of glucocorticoids and may function as a driver element in ulcerative colitis glucocorticoid resistance. AVAILABILITY OF DATA AND MATERIALS: All data and figures analyzed in this study are available from the corresponding author by request.
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Affiliation(s)
- Yijie Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
| | - Jiahong Qin
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lihong Dong
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chen He
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Dapeng Zhang
- Department of Internal Medicine, Kunming Meizhao Physical Examination Center, Kunming, China
| | - Xue Wu
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ting Li
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Haidong Yue
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lingjie Mu
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qiang Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jilin Yang
- Department of Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
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2
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Huang H, Wang W, Cui Y, Hu CX, Du M. Correlation between nuclear expression of heat shock protein 90 in dermis and glucocorticoid resistance in bullous dermatosis. Steroids 2023; 194:109223. [PMID: 36948346 DOI: 10.1016/j.steroids.2023.109223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/24/2023]
Abstract
BACKGROUND bullous dermatosis is a group of skin diseases that occur on the skin and mucous membrane, with blister and bulla as basic damage, mainly including pemphigus and bullous pemphigoid. Glucocorticoid (GC) is still the preferred drug for its treatment, but some patients respond poorly to GC and even develop glucocorticoid resistance (GCR). However, at present about the disease the understanding of the mechanisms for GCR is limited. OBJECTIVE This study attempted to investigate the molecular mechanism of GCR in bullous dermatosis with heat shock proteins 90 (HSP90) and glucocorticoid receptor (GR) as molecular targets. METHODS In this study, flow cytometry was used to measure and analyze the expression of HSP90 and GR in the lesions of patients with glucocorticoid-resistant bullosa dermatosis. Immunohistochemistry and immunofluorescence were used to observe the expression distribution and cell localization of HSP90 and GR. RESULTS The expression of HSP90 in skin lesions of GCR group was significantly higher than that of glucocorticoid-sensitive (GCS) group, while the expression level of GR was lower than that of GCS group. In the epidermis, the expression and distribution of HSP90 were not different between the GCR group and the GCS group. And in the dermis, HSP90 and GR were more likely to be expressed in the nucleus in the GCR group. CONCLUSION The overexpression and nuclear distribution of HSP90 may be related to the occurrence of GCR in patients with bullous dermatosis. And this correlation is more likely to occur in the dermis than in the epidermis.
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Affiliation(s)
- Huanming Huang
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; Hebei Medical University, Shijiazhuang, China
| | - Wenqing Wang
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
| | - Yu Cui
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Cai-Xia Hu
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ming Du
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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3
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Huang H, Wang W. Molecular mechanisms of glucocorticoid resistance. Eur J Clin Invest 2023; 53:e13901. [PMID: 36346177 DOI: 10.1111/eci.13901] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/29/2022] [Accepted: 10/04/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND As a powerful anti-inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined. METHODS The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included 'glucocorticoid resistance/insensitive', 'steroid resistance/insensitive', 'NR3C1', and 'glucocorticoid receptor'. RESULTS Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported. CONCLUSION The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated.
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Affiliation(s)
- Huanming Huang
- The Fourth Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang, China
| | - Wenqing Wang
- The Fourth Hospital of Hebei Medical University, Hebei Medical University, Shijiazhuang, China
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4
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Giudice A, Aliberti SM, Barbieri A, Pentangelo P, Bisogno I, D'Arena G, Cianciola E, Caraglia M, Capunzo M. Potential Mechanisms by which Glucocorticoids Induce Breast Carcinogenesis through Nrf2 Inhibition. FRONT BIOSCI-LANDMRK 2022; 27:223. [PMID: 35866405 DOI: 10.31083/j.fbl2707223] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 01/03/2025]
Abstract
Breast cancer is the most common malignancy among women worldwide. Several studies indicate that, in addition to established risk factors for breast cancer, other factors such as cortisol release related to psychological stress and drug treatment with high levels of glucocorticoids may also contribute significantly to the initiation of breast cancer. There are several possible mechanisms by which glucocorticoids might promote neoplastic transformation of breast tissue. Among these, the least known and studied is the inhibition of the nuclear erythroid factor 2-related (Nrf2)-antioxidant/electrophile response element (ARE/EpRE) pathway by high levels of glucocorticoids. Specifically, Nrf2 is a potent transcriptional activator that plays a central role in the basal and inducible expression of many cytoprotective genes that effectively protect mammalian cells from various forms of stress and reduce the propensity of tissues and organisms to develop disease or malignancy including breast cancer. Consequently, a loss of Nrf2 in response to high levels of gluco-corticoids may lead to a decrease in cellular defense against oxidative stress, which plays an important role in the initiation of human mammary carcinogenesis. In the present review, we provide a comprehensive overview of the current state of knowledge of the cellular mechanisms by which both glucocorticoid pharmacotherapy and endogenous GCs (cortisol in humans and corticosterone in rodents) may contribute to breast cancer development through inhibition of the Nrf2-ARE/EpRE pathway and the protective role of melatonin against glucocorticoid-induced apoptosis in the immune system.
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Affiliation(s)
- Aldo Giudice
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Silvana Mirella Aliberti
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Antonio Barbieri
- Animal Facility, Istituto Nazionale Tumori - "Fondazione G. Pascale" - IRCCS, 80131 Naples, Italy
| | - Paola Pentangelo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
| | - Ilaria Bisogno
- Department of Radiological, Oncological and Anatomo-Pathological Science, University of Rome "Sapienza", 00161 Rome, Italy
| | - Giovanni D'Arena
- Hematology Service, San Luca Hospital, ASL Salerno, 84124 Salerno, Italy
| | - Emidio Cianciola
- Anesthesia and Intensive Care Unit, "Immacolata di Sapri" Hospital- ASL Salerno, 84073 Salerno, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Mario Capunzo
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy
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Yang G, Wan L, Zhang S, Shi X, Wang J, Hu L, Zou L. CLOCK, SIRT1, and HDAC2 Knockdown along with Melatonin Intervention Significantly Decreased the Level Glucocorticoid Receptor. RUSS J GENET+ 2022. [DOI: 10.1134/s1022795422010148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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6
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Li H, Gao Y, Xie L, Wang R, Duan R, Li Z, Chen B, Zhu L, Wang X, Su W. Prednisone Reprograms the Transcriptional Immune Cell Landscape in CNS Autoimmune Disease. Front Immunol 2021; 12:739605. [PMID: 34484247 PMCID: PMC8414592 DOI: 10.3389/fimmu.2021.739605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/29/2021] [Indexed: 11/13/2022] Open
Abstract
Glucocorticoids (GCs) are widely used immunosuppressive drugs for autoimmune diseases, although considerable gaps exist between current knowledge of the mechanisms of GCs and their conclusive immune-regulatory effects. Here we generated a single-cell transcriptional immune cell atlas based on prednisone-treated or untreated experimental autoimmune uveitis (EAU) mice. Immune cells were globally activated in EAU, and prednisone partially reversed this effect in terms of cell composition, gene expression, transcription factor regulation, and cell-cell communication. Prednisone exerted considerable rescue effects on T and B cells and increased the proportion of neutrophils. Besides commonly regulated transcriptional factors (Fosb, Jun, Jund), several genes were only regulated in certain cell types (e.g. Cxcr4 and Bhlhe40 in T cells), suggesting cell-type-dependent immunosuppressive properties of GC. These findings provide new insights into the mechanisms behind the properties and cell-specific effects of GCs and can potentially benefit immunoregulatory therapy development.
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Affiliation(s)
- He Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yuehan Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lihui Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Rong Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Runping Duan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhaohuai Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Binyao Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lei Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xianggui Wang
- Eye Center of Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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Cazzola M, Rogliani P, Calzetta L, Matera MG. Pharmacogenomic Response of Inhaled Corticosteroids for the Treatment of Asthma: Considerations for Therapy. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2020; 13:261-271. [PMID: 32801837 PMCID: PMC7414974 DOI: 10.2147/pgpm.s231471] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/27/2020] [Indexed: 12/14/2022]
Abstract
There is a large interindividual variability in response to ICSs in asthma. About 70% of the variance in ICS response is likely due at least partially to genetically determined characteristics of target genes. In this article, we examine the effects on the ICS response of gene variations in the corticosteroid pathway, and in the pharmacokinetics of corticosteroids, and also those outside the corticosteroid pathway, which have the potential to influence corticosteroid activity. Although the available evidence indicates that responses to ICSs in asthma are influenced by different genetic variants, there are still deep uncertainties as to whether a real association between these genetic variants and corticosteroid response could also possibly exist because there are difficulties in reproducing pharmacogenetic findings. This explains at least partly the insufficient use of pharmacogenomic data when treating asthmatic patients, which creates a real limitation to the proper use of ICSs in an era of precision medicine that links the right patient to the right treatment. Knowing and dealing with the genetic factors that influence the therapeutic ICS response is a fundamental condition for prescribing the right dose of ICS to the right patient at the right time.
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Affiliation(s)
- Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Luigino Calzetta
- Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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8
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Schijvens AM, Ter Heine R, de Wildt SN, Schreuder MF. Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome. Pediatr Nephrol 2019; 34:389-403. [PMID: 29549463 PMCID: PMC6349812 DOI: 10.1007/s00467-018-3929-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/19/2018] [Accepted: 02/19/2018] [Indexed: 01/29/2023]
Abstract
Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice.
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Affiliation(s)
- Anne M Schijvens
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, 804, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Rob Ter Heine
- Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Saskia N de Wildt
- Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands
- Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Michiel F Schreuder
- Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, 804, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
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9
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Associations of HSP90AA2 gene polymorphisms with disease susceptibility, glucocorticoids efficacy and health-related quality of life in Chinese systemic lupus erythematosus patients. Genes Genomics 2018; 40:1069-1079. [PMID: 29907909 DOI: 10.1007/s13258-018-0714-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 06/07/2018] [Indexed: 01/09/2023]
Abstract
Although the current glucocorticoids (GCs) treatment for systemic lupus erythematosus (SLE) is effective to a certain extent, the difference in therapeutic effect between patients is still a widespread problem. Some patients can have repeated attacks that greatly diminish their quality of life. This study was conducted to investigate the relationship between HSP90AA2 polymorphisms and disease susceptibility, GCs efficacy and health-related quality of life (HRQoL) in Chinese SLE patients. A case-control study was performed in 470 SLE patients and 470 normal controls. Then, 444 patients in the case group were followed up for 12 weeks to observe efficacy of GCs and improvement of HRQoL. Two single nucleotide polymorphisms (SNPs) of HSP90AA2 were selected for genotyping: rs1826330 and rs6484340. HRQoL was assessed using the SF-36 questionnaire. The minor T allele of rs1826330 and the TT haplotype formed by rs1826330 and rs6484340 showed associations with decreased SLE risk (T allele: PBH = 0.022; TT haplotype: PBH = 0.033). A significant association between rs6484340 and improvement of HRQoL was revealed in the follow-up study. Five subscales of SF-36 were appeared to be influenced by rs6484340: total score of SF-36 (additive model: PBH = 0.026), physical function (additive model: PBH = 0.026), role-physical (recessive model: PBH = 0.041), mental health (dominant model: PBH = 0.047), and physical component summary (additive model: PBH = 0.026). No statistical significance was found between HSP90AA2 gene polymorphisms and GCs efficacy. These results revealed a genetic association between HSP90AA2 and SLE. Remarkably, HSP90AA2 has an impact on the improvement of HRQoL in Chinese population with SLE.
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10
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Wang H, Gou X, Jiang T, Ouyang J. The effects of microRNAs on glucocorticoid responsiveness. J Cancer Res Clin Oncol 2017; 143:1005-1011. [PMID: 28286901 DOI: 10.1007/s00432-017-2388-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 02/27/2017] [Indexed: 01/19/2023]
Abstract
PURPOSE Glucocorticoids (GCs) are of wide usage in the clinical treatment of lymphoblastic malignancies such as acute lymphoblastic leukemia. However, individually distinctive responsiveness to the GC therapy may attenuate their clinical efficacy, and more reliable predictor for GC resistance is still eagerly needed. Recent studies indicate that microRNAs (miRNAs), which demonstrate regulatory functions targeting mRNAs during the post-transcription, involved in the regulation of GCs sensitivity through several mechanisms, especially adjusting the magnitude of GC receptors (GRs), which mediates the cellular effects of GCs and plays a pivotal role in GCs sensitivity, inspiring that special miRNAs pattern could serve as the biomarkers to predict GC sensitivity and bring forth potential strategies for overcoming drug resistance. In this review, we discuss related miRNAs and their diverse effects exerted on multifaceted complexity of GCs responsiveness for further exploiting the molecular mechanism of GC resistance and future construction of the molecular diagnostic method and reverse GC resistance. METHODS We have reviewed and searched for eligible literature relating to the effects of microRNAs on GC responsiveness from systematic PubMed searches. RESULTS GC response can be mediated by miRNAs through influence on GC signaling pathway, leading to diverse glucocorticoid responsiveness. Mutations in miRNA gene also influence GC response. As well, GCs regulate the function of several miRNAs, and suggesting a bidirectional influence among them. CONCLUSIONS It is possible and necessary that miRNAs serve as stable biomarkers and GC resistant patients would benefit from an effective and early screening test.
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Affiliation(s)
- Huimin Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, China
| | - Xuxu Gou
- Department of Laboratory Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, No. 74 Zhongshan Road II, Guangzhou, 510080, Guangdong, China
| | - Tang Jiang
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, China
| | - Juan Ouyang
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road II, Guangzhou, 510080, Guangdong, China.
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11
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Diagnostic value of the dual-luciferase report assay for predicting response to glucocorticoid in children with acute lymphoblastic leukemia. Clin Transl Oncol 2017; 19:1241-1246. [DOI: 10.1007/s12094-017-1661-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 04/10/2017] [Indexed: 10/19/2022]
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12
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Song QQ, Xie WY, Tang YJ, Zhang J, Liu J. Genetic variation in the glucocorticoid pathway involved in interindividual differences in the glucocorticoid treatment. Pharmacogenomics 2017; 18:293-316. [PMID: 28112586 DOI: 10.2217/pgs-2016-0151] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Glucocorticoids (GCs) are widely used for treating asthma, rheumatoid arthritis, nephrotic syndrome, acute lymphoblastic leukemia and other autoimmune diseases. However, in a subgroup of patients, failure to respond to GCs is known as GC resistance or GC insensitivity. This represents an important barrier to effective treatment and a clinical problem requiring an urgent solution. Genetic variation in the GC pathway is a significant factor in interindividual differences in GC treatment. This article reviews the pharmacogenetics of GCs in diverse diseases based on the GC pathway.
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Affiliation(s)
- Qian-Qian Song
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P.R. China
| | - Wan-Ying Xie
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P.R. China
| | - Yong-Jun Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P.R. China
| | - Jun Zhang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China
| | - Jie Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, P.R. China.,Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, P.R. China
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Prenatal Dexamethasone Exposure Increases the Susceptibility to Autoimmunity in Offspring Rats by Epigenetic Programing of Glucocorticoid Receptor. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9409452. [PMID: 28078304 PMCID: PMC5203882 DOI: 10.1155/2016/9409452] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/22/2016] [Accepted: 11/27/2016] [Indexed: 11/18/2022]
Abstract
Objective. Prenatal glucocorticoids (GC) can induce long term effects on offspring health. However, reports and related studies regarding the prolonged effects of prenatal GC on the development of autoimmunity are limited. Here, we aimed to explore the immunological effects of dexamethasone (DEX) exposure on young adults and whether glucocorticoid receptor (GR) is involved in this process. Methods. Wistar rats were given DEX during pregnancy. Susceptibility to autoimmunity in offspring was assessed using experimental autoimmune encephalomyelitis (EAE) and adjuvant-induced arthritis (AIA) animal models. To reveal the possible mechanism, glucocorticoid response, GR expression, and methylation status were measured in peripheral blood mononuclear cells (PBMCs). Results. Our results showed that the DEX-treated rats had greater susceptibility to EAE (100% versus 62.5%, P < 0.05) and AIA (63.6% versus 0%, P < 0.05) than saline control group. Glucocorticoid response and GR expression were decreased in DEX rats. Significant difference was also found in the methylation levels of GR exon 1-10 to exon 1-11 region. Conclusions. Prenatal DEX administration increases the susceptibility to autoimmune diseases, which is potentially mediated by programming GR methylation status and glucocorticoid sensitivity.
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Singh AK, Haldar C. Melatonin modulates glucocorticoid receptor mediated inhibition of antioxidant response and apoptosis in peripheral blood mononuclear cells. Mol Cell Endocrinol 2016; 436:59-67. [PMID: 27452798 DOI: 10.1016/j.mce.2016.07.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 01/09/2023]
Abstract
Pineal melatonin is known for its immunomodulatory and anti-stress properties. It modulates stress condition by regulating antioxidant responses and apoptosis in the immune cells. Stress causes increased glucocorticoid level that acts through glucocorticoid receptor (GR) and is translocated into nucleus under regulation of HSP90 based chaperone machinery. Melatonin influences glucocorticoid and GR mediated stress condition in rodents, but till date there are no reports which could suggest the effect of melatonin treatment on GR mediated apoptosis and inhibition of Nrf-2/hemeoxygenase-1 (HO-1) induced antioxidant status in immunocompetent cells (peripheral blood mononuclear cells; PBMCs). Therefore, in the present study, we considered GR mediated inhibition of Nrf2 and HO-1 along with anti-apoptotic Bcl-2 expression in PBMCs. The PBMCs were treated with synthetic glucocorticoid; dexamethasone (Dex) and melatonin (Mel), to explore the effect of melatonin treatment in regulation of GR mediated apoptosis and inhibition of antioxidant status in immune cells. It was noted that melatonin treatment retained GR into cytoplasm by inhibiting the dissociation of HSP90 from GR-HSP90 complex and enhanced expression of Nrf2/HO-1 and Bcl-2 expression. This led to increased HO-1 expression and elevated Bcl-2 led to increased Bcl-2/Bax ratio that might ultimately enhanced the cellular antioxidant response and survival under glucocorticoid mediated stress condition. Our observations suggest that the declined GR nuclear translocation upon melatonin treatment might be responsible for the up-regulation of Nrf2 mediated HO-1 activity and increased Bcl-2/Bax ratio in PBMCs to maintain the immune homeostasis under stress condition.
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Affiliation(s)
- Amaresh Kumar Singh
- Pineal Research Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India.
| | - Chandana Haldar
- Pineal Research Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India.
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Zou YF, Xu JH, Gu YY, Pan FM, Tao JH, Wang DG, Xu SQ, Xiao H, Chen PL, Liu S, Cai J, Lian L, Liu SX, Liang CM, Tian G, Ye QL, Pan HF, Su H, Ye DQ. Single nucleotide polymorphisms of HSP90AA1 gene influence response of SLE patients to glucocorticoids treatment. SPRINGERPLUS 2016; 5:222. [PMID: 27026916 PMCID: PMC4771663 DOI: 10.1186/s40064-016-1911-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 02/17/2016] [Indexed: 12/26/2022]
Abstract
Heat shock protein 90 (HSP90) is an important glucocorticoid receptor (GR) chaperone protein, and is supposed to be the key factor in regulating glucocorticoids (GCs) effects. The aim of the present study was to explore whether single nucleotide polymorphisms (SNPs) within HSP90AA1 gene affect the response of systemic lupus erythematosus (SLE) patients to GCs treatment. Two hundred and forty-five SLE patients were treated with GCs (prednisone) for 12 weeks. SLE disease activity index (SLEDAI) was used to assess the response of SLE patients to GCs treatment, and patients were classified into sensitive group and insensitive group. HapMap database and Haploview software were used to select tag SNPs. Tag SNPs were genotyped by using multiplex SNaPshot method. Univariate and multivariate logistic regression analyses were used to discriminate the impact of SNPs of HSP90AA1 gene on the response of SLE patients to GCs treatment. Two hundred and thirty three SLE patients finished the 12-week follow-up. Of these patients, 128 patients were included in sensitive group, and 105 patients were included in insensitive group. Seven tag SNPs were selected within HSP90AA1 gene. We detected significant associations for rs7160651 (dominant model: crude OR 0.514, 95 % CI 0.297–0.890, P = 0.018; adjusted OR 0.518, 95 % CI 0.293–0.916, P = 0.024), rs10873531 (dominant model: crude OR 0.516, 95 % CI 0.305–0.876, P = 0.014; adjusted OR 0.522, 95 % CI 0.304–0.898, P = 0.019) and rs2298877 (dominant model: crude OR 0.543, 95 % CI 0.317–0.928, P = 0.026, adjusted OR 0.558, 95 % CI 0.323–0.967, P = 0.037) polymorphisms, but not for other polymorphisms (P > 0.05). The present study demonstrates that HSP90AA1 gene SNPs may affect the response of SLE patients to GCs treatment.
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Affiliation(s)
- Yan-Feng Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Jian-Hua Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Yuan-Yuan Gu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Fa-Ming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Jin-Hui Tao
- Department of Rheumatology and Immunology, Anhui Medical University Affiliated Provincial Hospital, Hefei, 230001 Anhui China
| | - De-Guang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601 Anhui China
| | - Sheng-Qian Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Hui Xiao
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Pei-Ling Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Shuang Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Jing Cai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Li Lian
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Sheng-Xiu Liu
- Institute of Dermatology and Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui China
| | - Chun-Mei Liang
- Department of Laboratory Medcine, School of Public Health, Anhui Medical University, Hefei, 230032 Anhui China
| | - Guo Tian
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Qian-Ling Ye
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601 Anhui China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Hong Su
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
| | - Dong-Qing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032 Anhui China
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Cuzzoni E, De Iudicibus S, Franca R, Stocco G, Lucafò M, Pelin M, Favretto D, Pasini A, Montini G, Decorti G. Glucocorticoid pharmacogenetics in pediatric idiopathic nephrotic syndrome. Pharmacogenomics 2015; 16:1631-1648. [PMID: 26419298 DOI: 10.2217/pgs.15.101] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Idiopathic nephrotic syndrome represents the most common type of primary glomerular disease in children: glucocorticoids (GCs) are the first-line therapy, even if considerable interindividual differences in their efficacy and side effects have been reported. Immunosuppressive and anti-inflammatory effects of these drugs are mainly due to the GC-mediated transcription regulation of pro- and anti-inflammatory genes. This mechanism of action is the result of a complex multistep pathway that involves the glucocorticoid receptor and several other proteins, encoded by polymorphic genes. Aim of this review is to highlight the current knowledge on genetic variants that could affect GC response, particularly focusing on children with idiopathic nephrotic syndrome.
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Affiliation(s)
- Eva Cuzzoni
- Graduate School in Reproduction & Developmental Sciences, University of Trieste, I-34127 Trieste, Italy
| | - Sara De Iudicibus
- Institute for Maternal & Child Health IRCCS Burlo Garofolo, I-34137 Trieste, Italy
| | - Raffaella Franca
- Institute for Maternal & Child Health IRCCS Burlo Garofolo, I-34137 Trieste, Italy
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy
| | - Marianna Lucafò
- Department of Medical, Surgical and Health Sciences, University of Trieste, I-34127 Trieste, Italy
| | - Marco Pelin
- Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy
| | - Diego Favretto
- Institute for Maternal & Child Health IRCCS Burlo Garofolo, I-34137 Trieste, Italy
| | - Andrea Pasini
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliera Universitaria Sant'Orsola-Malpighi, I-40138 Bologna, Italy
| | - Giovanni Montini
- Pediatric Nephrology and Dialysis Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, I-20122 Milano, Italy
| | - Giuliana Decorti
- Department of Life Sciences, University of Trieste, I-34127 Trieste, Italy
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Allan AM, Goggin SL, Caldwell KK. Prenatal alcohol exposure modifies glucocorticoid receptor subcellular distribution in the medial prefrontal cortex and impairs frontal cortex-dependent learning. PLoS One 2014; 9:e96200. [PMID: 24755652 PMCID: PMC3995983 DOI: 10.1371/journal.pone.0096200] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 04/03/2014] [Indexed: 01/27/2023] Open
Abstract
Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice.
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Affiliation(s)
- Andrea M. Allan
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
| | - Samantha L. Goggin
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
| | - Kevin K. Caldwell
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America
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18
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Iudicibus SD, Lucafò M, Martelossi S, Pierobon C, Ventura A, Decorti G. MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases. World J Gastroenterol 2013; 19:7947-7954. [PMID: 24307788 PMCID: PMC3848142 DOI: 10.3748/wjg.v19.i44.7947] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 10/16/2013] [Accepted: 10/19/2013] [Indexed: 02/06/2023] Open
Abstract
In spite of the introduction in therapy of highly effective biological agents, glucocorticoids (GCs) are still employed to induce remission in moderate to severe inflammatory bowel diseases (IBD), but considerable inter-individual differences in their efficacy and side effects have been reported. The effectiveness of these drugs is indeed very variable and side effects, particularly severe in pediatric patients, are common and often unpredictable: the understanding of the complex gene regulation mediated by GCs could shed light on the causes of this variability. In this context, microRNAs (miRNAs) represent a new and promising field of research. miRNAs are small non-coding RNA molecules that suppress gene expression at post-transcriptional level, and are fine-tuning regulators of diverse biological processes, including the development and function of the immune system, apoptosis, metabolism and inflammation. Emerging data have implicated the deregulated expression of certain miRNA networks in the pathogenesis of autoimmune and inflammatory diseases, such as IBD. There is a great interest in the identification of the role of miRNAs in the modulation of pharmacological response; however, the association between miRNA and GC response in patients with IBD has not yet been evaluated in a prospective clinical study. The identification of miRNAs differently expressed as a consequence of GC treatment in comparison to diagnosis, represents an important innovative approach that could be translated into clinical practice. In this review we highlight the altered regulation of proteins involved in GC molecular mechanism by miRNAs, and their potential role as molecular markers useful for predicting in advance GC response.
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