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1.
Expert Rev Mol Med ; 23: e11, 2021 09 01.
Article in English | MEDLINE | ID: mdl-34470679

ABSTRACT

Epigenetic modifications have been well documented in autoimmune diseases. MicroRNAs (miRNAs), in particular, have long intrigued scientists in the field of autoimmunity. Owing to its central role in the development of the immune system, microRNA-155 (miR-155) is deeply involved in systemic lupus erythematosus (SLE). Despite the advancements made in treating SLE, the disease still remains incurable. Therefore, recent attention has been drawn to the manipulation of epigenetics in the development of curative treatments. In fact, it is a widely held view that miRNA-targeted therapy is a new glimmer of hope in the treatment of autoimmune diseases. However, the duplicity of miRNAs should not be overlooked. A single miRNA can target several mRNAs, and some mRNAs may possess opposing functions. In this review, we highlight the role of miR-155 as a biomarker and review its functions in SLE patients and animal models while discussing possible reasons behind inconsistencies across studies.


Subject(s)
Autoimmune Diseases , Lupus Erythematosus, Systemic , MicroRNAs , Animals , Biomarkers , Humans , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/therapy , MicroRNAs/genetics
2.
Nat Prod Res ; 32(18): 2217-2220, 2018 Sep.
Article in English | MEDLINE | ID: mdl-28817968

ABSTRACT

Insulin-like growth factor-2 binding proteins (IGF2BPs) are oncogenic RNA-binding proteins, highly up-regulated in HCC, and were recently validated as direct targets of the tumour suppressor miR-1275. It is worth noting that around 47% of FDA approved anticancer drugs are derived from plants. Modulation by miRNAs and their cellular signalling cascades could constitute new pathways by which these phytochemicals exert their effects. This study aimed to investigate the potential use of Tamarix articulata, quercetin and epigallocatechin gallate (EGCG) in HCC and how these phytochemicals could epigenetically modulate the IGF axis using their impact on miR-1275. T. articulata ethyl acetate fraction significantly reduced the viability of Huh-7 cells compared to control cells. Treatment with T. articulata ethyl acetate fraction, quercetin and EGCG significantly enhanced miR-1275, while suppressed IGF2BP1 and IGF2BP3 mRNA expression levels. In summary, T. articulata, quercetin and EGCG have important implications for HCC molecular-targeted therapy through destabilizing the interplay between miR-1275 and the IGF axis.


Subject(s)
Carcinoma, Hepatocellular/therapy , Insulin-Like Growth Factor Binding Protein 2/metabolism , Liver Neoplasms/therapy , MicroRNAs/metabolism , Quercetin/therapeutic use , Tamaricaceae/chemistry , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Catechin/analogs & derivatives , Catechin/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Humans , Liver Neoplasms/pathology
3.
Growth Factors ; 35(2-3): 49-60, 2017 06.
Article in English | MEDLINE | ID: mdl-28683581

ABSTRACT

microRNA-155 (miR-155) is implicated in regulating B-cell activation and survival that is important in systemic lupus erythematosus (SLE) pathogenesis. PU.1, a target for miR-155, is a crucial regulator of B-cell development and enhances Tumour-Necrosis-factor-alpha (TNF-α) expression. TNF-α induces the expression of B-cell-activating-factor (BAFF). BAFF is reported to increase the expression of the autoimmunity marker; CD19. This study aimed to investigate the regulation of expression of PU.1 in pediatric-systemic-lupus-erythematosus (pSLE) patients by miR-155, and hence evaluate its impact on TNF-α/BAFF/CD19 signalling pathway. Screening revealed that PU.1 is upregulated in PBMCs and B-cells of pSLE patients. PU.1 expression directly correlated with systemic-lupus-erythematosus disease-activity-index-2 K SLEDAI-2K. Ectopic expression of miR-155 and knockdown of PU.1 suppressed PU.1, TNF-α and BAFF. Finally, miR-155 decreased the proportion of BAFF-expressing-B-cells and CD19 protein expression. These findings suggest that miR-155 suppresses autoimmunity through transcriptional repression of PU.1 and TNF-α, which in turn suppresses BAFF and CD19 protein expression.


Subject(s)
Antigens, CD19/blood , Autoimmunity , B-Lymphocytes/immunology , Lupus Erythematosus, Systemic/immunology , MicroRNAs/genetics , B-Cell Activating Factor/genetics , B-Cell Activating Factor/metabolism , Biomarkers/blood , Cells, Cultured , Child , Female , Humans , Lupus Erythematosus, Systemic/blood , Male , MicroRNAs/metabolism , Monocytes/immunology , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Signal Transduction , Trans-Activators/genetics , Trans-Activators/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
4.
Lupus ; 24(3): 240-7, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25253569

ABSTRACT

MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.


Subject(s)
Interleukin-2/metabolism , Leukocytes, Mononuclear/metabolism , Lupus Erythematosus, Systemic/metabolism , MicroRNAs/metabolism , Protein Phosphatase 2/metabolism , Arthritis, Juvenile/metabolism , Case-Control Studies , Cells, Cultured , Child , Familial Mediterranean Fever/metabolism , Female , Humans , Male
5.
Biochem Biophys Res Commun ; 434(3): 421-7, 2013 May 10.
Article in English | MEDLINE | ID: mdl-23583198

ABSTRACT

E2F-1, c-MYC, and miR-17-5p is a triad of two regulatory loops: a negative and a positive loop, where c-MYC induces the expression of E2F-1 that induces the expression of miR-17-5p which in turn reverses the expression of E2F-1 to close the loop. In this study, we investigated this triad for the first time in hepatocellular carcinoma (HCC), where miR-17-5p showed a significant down-regulation in 23 non-metastatic HCC biopsies compared to 10 healthy tissues; however, E2F-1 and c-MYC transcripts were markedly elevated. Forced over-expression of miR-17-5p in HuH-7 cells resulted in enhanced cell proliferation, growth, migration and clonogenicity with concomitant inhibition of E2F-1 and c-MYC transcripts expressions, while antagomirs of miR-17-5p reversed these events. In conclusion, this study revealed a unique pattern of expression for miR-17-5p in non-metastatic HCC patients in contrast to metastatic HCC patients. In addition we show that miR-17-5p is the key player among the triad that tumor growth and spread.


Subject(s)
Carcinoma, Hepatocellular/genetics , E2F1 Transcription Factor/genetics , Genes, myc , Liver Neoplasms/genetics , MicroRNAs/genetics , Adult , Carcinoma, Hepatocellular/pathology , Case-Control Studies , Cell Division , Cell Line , Female , Humans , Liver Neoplasms/pathology , Male , Middle Aged
6.
Photodiagnosis Photodyn Ther ; 10(1): 87-94, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23465377

ABSTRACT

BACKGROUND: Although several treatment options are available for hepatocellular carcinoma (HCC), their application is mostly restricted to early diagnosed cases or includes liver transplantation, which is rarely available due to donor scarcity. The attractiveness of PDT as a cancer treatment does not only come from its minimal invasiveness, but also from the high selectivity due to tumor localization that can be applied. Precise focusing of light on tumor lesions will result in tumor-specific PDT activation. Novel photosensitizers can be applied in such low concentrations that cells not subjected to irradiation remain healthy. The lethal effect and mechanism of death induction of the photosensitizer Fospeg has never been studied on hepatocellular carcinoma. The aim of the present study is to functionally analyze the impact of PDT on Huh-7 HCC cell line, as well as to analyze its impact on cell cycle protein expression. METHODS: Cellular viability, and proliferation assays were conducted via MTT and BrdU assay, respectively. Transfected cell models of Huh7 with different constructs harboring cell cycle genes and downstream reporter luciferase gene were generated. RESULTS: Our results show a statistically significant decrease in both viability and proliferation of Huh-7 cells following PDT, while maintaining Fospeg and laser concentrations far below toxic levels. Proliferative cell cycle genes show a tendency of inhibition, while p53 levels show a significant increase following PDT. CONCLUSION: Fospeg-mediated PDT is a promising strategy for treatment of hepatocellular carcinoma and needs to be further explored in vivo.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cell Cycle Proteins/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Mesoporphyrins/administration & dosage , Photochemotherapy/methods , Animals , Carcinoma, Hepatocellular/pathology , Cell Cycle Checkpoints/drug effects , Cell Cycle Checkpoints/radiation effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Cell Survival/drug effects , Cell Survival/radiation effects , Humans , Liver Neoplasms/pathology , Photosensitizing Agents/administration & dosage
7.
J Viral Hepat ; 19(12): 854-61, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23121363

ABSTRACT

Summary. Hepatitis C virus (HCV) is a major health concern in Egypt being highly prevalent among Egyptians. The two genders experience different responses to HCV infection and show variations in response to interferon (IFN)-based therapy that may be attributed to sex hormones. We previously demonstrated the suppressive effect of 17ß-estradiol (E2) on the expression of the IFN-stimulated gene MxA in HCV-infected peripheral blood mononuclear cells (PBMCs). The selective oestrogen receptor (ER) modulator Tamoxifen has been shown to have an antiviral effect against HCV, but its effect on the host immune response is unknown. We investigated the effect of Tamoxifen on the IFN signalling pathways in PBMCs of HCV-infected Egyptian females. We pooled PBMCs and treated then with exogenous interferon alpha (IFNα) or the TLR7 ligand, Imiquimod, and quantified the relative expressions of MxA using RTqPCR. Studies were performed with and without Tamoxifen pretreatment. Pretreatment with Tamoxifen reversed the suppressive effect of E2 on the JAK-STAT pathway in IFNα-treated PBMCs as indicated by a significant increase in MxA expression (P = 0.05*). Tamoxifen pretreatment also significantly upregulated MxA expression in Imiquimod-treated PBMCs (P = 0.0011**), an effect not ascribed to ER blocking nor to an upregulation in TLR7 expression because Tamoxifen showed no potentiating effect on the expression of the receptor. In conclusion, our findings reveal that Tamoxifen has immunomodulatory effects whereby it enhances the host IFN signalling pathways during HCV infection.


Subject(s)
Hepacivirus/pathogenicity , Immunologic Factors/pharmacology , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Tamoxifen/pharmacology , Toll-Like Receptor 7/metabolism , Adult , Cells, Cultured , Egypt , Female , GTP-Binding Proteins/biosynthesis , Gene Expression Profiling , Hepacivirus/immunology , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Middle Aged , Myxovirus Resistance Proteins
8.
Intervirology ; 55(3): 210-8, 2012.
Article in English | MEDLINE | ID: mdl-21597279

ABSTRACT

AIMS: To investigate the myxovirus-resistance protein A (MxA) and double-stranded RNA-activated protein kinase (PKR) genetic response to interferon (IFN) therapy in hepatitis C virus (HCV) genotype 4-infected patients. Moreover, we studied the association between suppressor of cytokine signaling 3 (SOCS3) gene expression and therapy resistance in genotype 4. Finally, we investigated the novel link between p53 and IFN-stimulated genes (ISGs) in humans. METHODS: Gene expression analyses were performed in peripheral blood using TaqMan real-time PCR. Virologic response was assessed with a branched-DNA assay. Genotyping was confirmed. RESULTS: Early virologic responders (EVRs, n = 23) but not non-EVRs (n = 7) showed strong upregulation of PKR at week 12 of therapy compared to baseline. Both EVRs and non-EVRs showed MxA upregulation at week 12 compared to baseline. Baseline SOCS3 expression did not distinguish EVRs from non-EVRs in genotype 4. An association was found between p53 and MxA and PKR gene expression. CONCLUSION: Measurement of MxA and PKR transcriptional induction during treatment may distinguish EVRs from non-EVRs in genotype 4. SOCS3 gene does not seem to be implicated in therapy resistance in genotype 4. An association between p53 and ISGs expression was shown for the first time in HCV-infected patients, further supporting the contribution of p53 to host antiviral response.


Subject(s)
Antiviral Agents/administration & dosage , GTP-Binding Proteins/biosynthesis , Hepatitis C/drug therapy , Interferons/administration & dosage , Suppressor of Cytokine Signaling Proteins/biosynthesis , Tumor Suppressor Protein p53/metabolism , eIF-2 Kinase/biosynthesis , Adult , Cells, Cultured , GTP-Binding Proteins/immunology , Gene Expression Profiling , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Hepacivirus/isolation & purification , Hepatitis C/virology , Humans , Middle Aged , Myxovirus Resistance Proteins , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/immunology , Treatment Outcome , Tumor Suppressor Protein p53/immunology , eIF-2 Kinase/immunology
9.
Biomarkers ; 16(4): 346-54, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21506705

ABSTRACT

BACKGROUND/AIM: Elevated relative expression of insulin-like growth factor-II (IGF-II) was observed in hepatocellular carcinoma (HCC) liver tissues with a role in neovascularization and associated with poor prognosis. IGF-II is influenced by the proteolytic cleavage of IGF-binding protein 3 and by matrix metalloproteinases (MMP), which are further regulated by their tissue inhibitors tissue inhibitor of metalloprotienase-1 (TIMP-1). Our aim is to study new molecular markers for HCC. PATIENTS/METHODS: RNA was extracted from the peripheral blood for evaluating the relative expression of IGF-II, MMP-9, and TIMP-1 in correlation with clinical staging of 39 HCC patients and 15 healthy controls using TaqMan real-time PCR. RESULTS: The relative expression of IGF-II and MMP-9 mRNA were significantly elevated in HCC patients compared with healthy controls; P-value <0.0001 for both. There was a significant correlation between MMP-9 and different HCC stages. On the other hand, TIMP-1 was significantly down-regulated in HCC patients; P = 0.0003 with the elevation of the IGF-II/TIMP-1 ratio. Significant correlation between TIMP-1 and HCC Stage III and Stage IV was found; P-value = 0.0138. CONCLUSION: These results highlight the importance of profiling the expression of IGF-II, MMP-9, and TIMP-1 in the peripheral blood as prognostic molecular biomarkers in HCC.


Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/pathology , Insulin-Like Growth Factor II/analysis , Liver Neoplasms/pathology , Matrix Metalloproteinase 9/blood , Tissue Inhibitor of Metalloproteinase-1/blood , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Matrix Metalloproteinases/blood , Middle Aged , Prognosis
10.
Clin Exp Rheumatol ; 29(2): 351-7, 2011.
Article in English | MEDLINE | ID: mdl-21385555

ABSTRACT

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease manifested by self-reactive antibodies due to failure of selection in both B and T lymphocytes leading to immune intolerance accompanied by increased rate of apoptosis and deficiency in the clearance of the apoptotic cells. Micro RNAs regulate posttranscriptional gene expression and have been recently identified to regulate cellular differentiation, establishing immunological tolerance and are involved in the pathogenesis of several diseases. miR-181-a, expressed in haematopoietic cell lineage, has shown to be an important modulator of B and T cell differentiation, maturation and function. This study aims to identify the expression signature of miR-181-a in the peripheral blood of paediatric SLE and its regulatory effect on the consequent expression of its target gene PCAF. METHODS: Twenty SLE paediatrics patients, 9 healthy controls and 4 FMF patients were enrolled in this study. The relative expression of miR-181-a, miR-223, PCAF and Hdm2 were performed using quantitative real time PCR. RESULTS: For the first time we show that miR-181-a was significantly downregulated in SLE pediatrics as compared to healthy controls. Furthermore, miR-181-a showed significant difference in its expression among groups with different SLEDAI scores. This special signature of miR-181-a expression is unique to SLE as compared to FMF samples which showed a parallel expression to healthy controls. PCAF was upregulated in SLE patients compared to healthy controls, which has an impact on the ubiquitination of Hdm2 and hence releases p53 leading to the induction of apoptosis. CONCLUSIONS: miR-181-a plays an important role in SLE pathogenesis.


Subject(s)
Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , MicroRNAs/genetics , B-Lymphocytes/immunology , Child , Female , Humans , Male , Proto-Oncogene Proteins c-mdm2/genetics , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/immunology , p300-CBP Transcription Factors/genetics
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