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1.
Methods Mol Biol ; 2109: 67-74, 2020.
Article in English | MEDLINE | ID: mdl-31309518

ABSTRACT

The application of immunohistological methods provides an invaluable contribution in revealing the protein colocalization, which may reflect the occurrence of molecular interaction processes.This chapter describes comprehensive protocols for detection of S100A7/JAB1 colocalization by immunohistochemistry in archival formalin-fixed and paraffin-embedded skin biopsies from healthy and psoriatic subjects. In addition, we provide a protocol for immunocytochemical detection of S100A7/JAB1 colocalization in S100A7 CRISPR-activated human keratinocyte cell line.


Subject(s)
COP9 Signalosome Complex/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Peptide Hydrolases/metabolism , Psoriasis/pathology , S100 Calcium Binding Protein A7/metabolism , Biopsy , CRISPR-Cas Systems , Case-Control Studies , Cell Line , Humans , Immunohistochemistry , Keratinocytes/metabolism , Psoriasis/metabolism , S100 Calcium Binding Protein A7/genetics , Tissue Embedding , Tissue Fixation
2.
Methods Mol Biol ; 1929: 729-738, 2019.
Article in English | MEDLINE | ID: mdl-30710307

ABSTRACT

Psoriasis, an inflammatory autoimmune skin disease, is the result of a chronic interaction between hyperproliferative keratinocytes and infiltrating activated immune cells. The mechanisms underlying psoriasis pathogenesis remain largely unknown, although a combination of genetic and environmental factors plays an important role in its development. S100A7 is overexpressed in psoriasis, and there is growing evidence that S100A7 may be involved in the pathogenesis of psoriasis. Since the mechanisms underlying S100A7 regulation and function remain elusive, a better understanding of these mechanisms may be useful to uncover additional treatment approaches for psoriasis. Immunohistology provides invaluable tools for a better understanding of the pathogenetic mechanisms of psoriasis. Here, we describe basic methods for immunofluorescence and immunohistochemistry analysis of S100A7 expression in psoriatic patients as well as in S100A7 CRISPR-activated human keratinocyte cell line.


Subject(s)
Keratinocytes/cytology , Psoriasis/metabolism , S100 Calcium Binding Protein A7/genetics , S100 Calcium Binding Protein A7/metabolism , COP9 Signalosome Complex/metabolism , CRISPR-Cas Systems , Cell Line , Fluorescent Antibody Technique , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Keratinocytes/metabolism , Peptide Hydrolases/metabolism , Psoriasis/genetics , Transcriptional Activation , Up-Regulation
3.
Immunobiology ; 223(1): 112-117, 2018 01.
Article in English | MEDLINE | ID: mdl-29030005

ABSTRACT

Systemic sclerosis (SSc), an autoimmune disorder, is characterized by vasculopathy, inflammation, progressive perivascular and interstitial fibrosis. Its pathogenesis is largely unknown, however strong evidences suggest that genetic predisposition may contribute to SSc development. Several gene polymorphisms involved in regulatory T cell function have been identified in many autoimmune diseases, including SSc. Moreover, dysregulation of co-stimulatory and/or co-inhibitory signals, including ICOS signalling, can lead to autoimmunity. The aim of the present study was to investigate the association of the FOXP3 rs2294020, ICOS rs6726035 and ICOSL rs378299 SNPs with both the susceptibility and the progression to SSc in an Italian case-series of patients. SNP genotyping results were successfully obtained from a total of 350 subjects including 166 individuals with SSc and 184 healthy controls. Although analysis tests did not show any significant associations between the SNPs under study and susceptibility to SSc, the occurrence of FOXP3 rs2294020 in female patients was associated with decreased time to progression from early to definite SSc (allelic model: HR=1.43; CI=1.03-1.99; p=0.03; dominant model: HR=1.54; CI=1.04-2.28; p=0.03). The inclusion of presence of ACA autoantibodies in the model did not significantly change the estimates. No conclusions can be drawn for the susceptibility to the disease or the time to progression in men due to the low statistical power. This study provides evidence of the association of rs2294020 with SSc evolution in female patients, modulating the time of progression from the diagnosis of early SSc to the diagnosis of definite SSc, while no effect on SSc susceptibility per se was found. rs2294020 may be considered a disease-modifying gene-variant rather than a disease-susceptibility SNP in SSc.


Subject(s)
Forkhead Transcription Factors/genetics , Genotype , Scleroderma, Systemic/genetics , Case-Control Studies , Disease Progression , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Inducible T-Cell Co-Stimulator Ligand/genetics , Inducible T-Cell Co-Stimulator Protein/genetics , Italy , Middle Aged , Polymorphism, Single Nucleotide
4.
Pathobiology ; 84(2): 71-79, 2017.
Article in English | MEDLINE | ID: mdl-27639922

ABSTRACT

Obesity, type 1 diabetes, and psoriasis are wide-ranging health problems. Genetics, epigenetics, and environmental factors together with immune disturbances are involved in these diseases. The white adipose tissue is an active endocrine organ, secreting a wide variety of soluble mediators called adipokines that have a central role in the relationship between adipose tissue and immune system. Inflammatory cytokines, including the IL-23/IL-17 and IL-18 axes, and microRNAs are involved in many processes, including immunity and inflammation, thus having a major role in the onset of these three diseases. In this review, we present an overview of the roles of adipokines, cytokines, and microRNAs in the pathogenesis and the progression of these three diseases.


Subject(s)
Adipose Tissue, White/immunology , Autoimmune Diseases/immunology , Diabetes Mellitus, Type 1/immunology , Obesity/immunology , Psoriasis/immunology , Adipokines/immunology , Cytokines/immunology , Humans , MicroRNAs/immunology
5.
Immunol Lett ; 181: 58-62, 2017 01.
Article in English | MEDLINE | ID: mdl-27888057

ABSTRACT

Autoimmune diseases often share common susceptibility genes. Most genetic variants associated with susceptibility to systemic lupus erythematosus are also associated with other autoimmune diseases. The X-linked variant rs2294020 is positioned in exon 7 of the CCDC22 gene. The encoded protein functions in the regulation of NF-κB, a master regulator in immune response. The aim of this study is to investigate whether the rs2294020 polymorphism may be a general susceptibility factor for autoimmunity. We evaluated case-control association between the occurrence of rs2294020 and different autoimmune diseases, including new data for systemic lupus erythematosus and previous genome-wide association studies (GWAS) (though most did not analyse the X chromosome) of psoriasis, celiac disease, Crohn's disease, ulcerative colitis, multiple sclerosis, vitiligo, type-1 diabetes, rheumatoid arthritis, and ankylosing spondylitis. Cases from patients affected by amyotrophic lateral sclerosis and type-2 diabetes were also included in the study. We detected nominal significant associations of rs2294020 with systemic lupus erythematosus (additive model test: p=0.01), vitiligo (p=0.016), psoriasis (p=0.038), and in only one of two studies of multiple sclerosis (p=0.03). Our results suggest that rs2294020 is associated with the risk of several autoimmune diseases in European populations, specifically with diseases that present themselves, among else, in the skin.


Subject(s)
Alleles , Autoimmune Diseases/genetics , Genes, X-Linked , Genetic Association Studies , Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Proteins/genetics , Adult , Autoimmune Diseases/diagnosis , Case-Control Studies , Exons , Female , Genotype , Humans , Lupus Erythematosus, Systemic/diagnosis , Male , Odds Ratio , Phenotype , Polymorphism, Single Nucleotide
6.
Cytokine Growth Factor Rev ; 32: 97-104, 2016 12.
Article in English | MEDLINE | ID: mdl-26872860

ABSTRACT

S100A7 (psoriasin), an EF-hand type calcium binding protein localized in epithelial cells, regulates cell proliferation and differentiation. An S100A7 overexpression may occur in response to inflammatory stimuli, such in psoriasis, a chronic inflammatory autoimmune-mediated skin disease. Increasing evidence suggests that S100A7 plays critical roles in amplifying the inflammatory process in psoriatic skin, perpetuating the disease phenotype. This review will discuss the interactions between S100A7 and cytokines in psoriatic skin. Furthermore, we will focus our discussion on regulation and functions of S100A7 in psoriasis. Finally, we will discuss the possible use of S100A7 as therapeutic target in psoriasis.


Subject(s)
Cytokines/immunology , Psoriasis/immunology , S100 Calcium Binding Protein A7/immunology , Animals , Antimicrobial Cationic Peptides/immunology , Humans
7.
G Ital Nefrol ; 32(5)2015.
Article in Italian | MEDLINE | ID: mdl-26480254

ABSTRACT

Clinical genetics plays a central role in the diagnostic practice, mainly due to both the hereditary and non-hereditary genetic component, which characterizes most of the diseases. This branch of medicine has been characterized by a rapid technological growth since 2003, when the entire human genome was sequenced. We need to consider the reduction in terms of both time and costs that the gene sequencing has gone through. Before, 13 years and about three billion dollars were needed, now it takes only a few weeks and about ten thousand dollars to sequence the entire human genome. The applicability of clinical genetics in nephrology is due to the fact that many kidney diseases are characterized by genetic mutations (e.g., von-Hippel Lindau syndrome, MYH9 related disorders, Fabry's syndrome, Liddle's and Bartter's Syndrome, and others). Clinical genetics plays, therefore, a crucial role since many of these diseases are often not properly diagnosed. In this review, we examine the new technologies that are available to the nephrologist for the molecular diagnosis of renal diseases.


Subject(s)
Genetic Testing , Kidney Diseases/diagnosis , Kidney Diseases/genetics , Chromosome Mapping , Genomics , Humans , Polymerase Chain Reaction
8.
J Dermatol Sci ; 80(1): 38-44, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26276441

ABSTRACT

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. It is characterized by immune cell activation and altered epidermal differentiation. S100A7 (psoriasin) is overexpressed in psoriasis, suggesting a determinant role of this protein in inflammation and keratinocyte differentiation. OBJECTIVE: The purpose of this study was to investigate the expression of S100A7 in the skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. METHODS: S100A7 expression and distribution were analyzed by immunohistochemistry. RESULTS: S100A7, overexpressed in epidermal keratinocytes of psoriatic lesions, was downregulated, under the biological therapy with adalimumab, etanercept or ustekinumab, only in patients achieving a PASI score<15. CONCLUSIONS: Dysregulation of S100A7 may represent a non-negligible player in the maintenance of psoriasis and the relative epidermal changes. Blockage of S100A7 may represent an additional therapeutic approach in the treatment of psoriasis.


Subject(s)
Adalimumab/therapeutic use , Etanercept/therapeutic use , Psoriasis/drug therapy , S100 Proteins/metabolism , Ustekinumab/therapeutic use , Adalimumab/pharmacology , Adult , Aged , Etanercept/pharmacology , Female , Humans , Immunohistochemistry , Male , Middle Aged , Psoriasis/metabolism , S100 Calcium Binding Protein A7 , Skin/drug effects , Skin/metabolism , Ustekinumab/pharmacology , Young Adult
9.
Arch Dermatol Res ; 307(10): 863-73, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26319047

ABSTRACT

Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/biosynthesis , Biological Therapy/methods , Calcium-Binding Proteins/biosynthesis , Homeodomain Proteins/biosynthesis , Intercellular Signaling Peptides and Proteins/biosynthesis , Membrane Proteins/biosynthesis , Psoriasis/physiopathology , Receptor, Notch1/biosynthesis , Receptor, Notch2/biosynthesis , Adalimumab/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/therapeutic use , Basic Helix-Loop-Helix Transcription Factors/genetics , Calcium-Binding Proteins/genetics , Etanercept/therapeutic use , Female , Homeodomain Proteins/genetics , Humans , Intercellular Signaling Peptides and Proteins/genetics , Interleukin-12 Subunit p40/antagonists & inhibitors , Jagged-1 Protein , Keratinocytes/metabolism , Male , Membrane Proteins/genetics , Middle Aged , Psoriasis/drug therapy , RNA, Messenger/biosynthesis , Receptor, Notch1/genetics , Receptor, Notch2/genetics , Serrate-Jagged Proteins , Skin/pathology , Transcription Factor HES-1 , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Ustekinumab/therapeutic use
10.
Clin Rev Allergy Immunol ; 47(3): 334-43, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24126759

ABSTRACT

Systemic sclerosis is a multifactorial and heterogeneous disease. Genetic and environmental factors are known to interplay in the onset and progression of systemic sclerosis. Sex plays an important and determinant role in the development of such a disorder. Systemic sclerosis shows a significant female preponderance. However, the reason for this female preponderance is incompletely understood. Hormonal status, genetic and epigenetic differences, and lifestyle have been considered in order to explain female preponderance in systemic sclerosis. Sex chromosomes play a determinant role in contributing to systemic sclerosis onset and progression, as well as in its sex-biased prevalence. It is known, in fact, that X chromosome contains many sex- and immuno-related genes, thus contributing to immuno tolerance and sex hormone status. This review focuses mainly on the recent progress on epigenetic mechanisms--exclusively linked to the X chromosome--which would contribute to the development of systemic sclerosis. Furthermore, we report also some hypotheses (dealing with skewed X chromosome inactivation, X gene reactivation, acquired monosomy) that have been proposed in order to justify the female preponderance in autoimmune diseases. However, despite the intensive efforts in elucidating the mechanisms involved in the pathogenesis of systemic sclerosis, many questions remain still unanswered.


Subject(s)
Chromosomes, Human, X/genetics , Scleroderma, Systemic/genetics , Sex Characteristics , Epigenesis, Genetic , Female , Genetic Predisposition to Disease , Humans , Male
11.
Immunol Lett ; 152(2): 109-13, 2013 May.
Article in English | MEDLINE | ID: mdl-23707908

ABSTRACT

A case control study to evaluate the possible influence of FOXP3 polymorphisms (rs3761548 and rs2280883) in the susceptibility of systemic sclerosis in an Italian Caucasian population. Subgroup analysis was also performed to test association between these SNPs and specific disease phenotypes. The study groups consisted of 467 individuals: 228 patients (194 with limited cutaneous form and 34 with diffuse cutaneous form of the disease) and 239 healthy control subjects. Genotyping was performed by high resolution melting analysis. Genotype distribution and allele frequency of the FOXP3 polymorphisms were analyzed statistically, using χ(2) or Fisher exact test. Single-marker analysis of allelic and genotype frequencies revealed that SNP rs3761548 was not associated with systemic sclerosis susceptibility. Analysis of genotype and allele distributions of the rs2280883 genetic variant was associated, only in female subjects with systemic sclerosis, its limited subtype, and anti-centromere autoantibodies. Although these findings require replication in a larger set and other populations, FOXP3 rs2280883 may represent a novel susceptibility locus for systemic sclerosis in female subjects.


Subject(s)
Forkhead Transcription Factors/genetics , Scleroderma, Systemic/genetics , Autoantibodies/immunology , Case-Control Studies , Centromere/immunology , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Italy , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide
12.
Int J Mol Med ; 31(5): 1011-6, 2013 May.
Article in English | MEDLINE | ID: mdl-23545719

ABSTRACT

In this study, we investigated the expression and localisation of the proteins, osteopontin (OPN) and prominin-1 (CD133), as well as the plasma OPN levels in the endometrium of patients with endometriosis. Samples of ectopic endometriotic lesions and normal endometrium were obtained from 31 women with endometriosis and 28 healthy control subjects. The mRNA and protein expression of OPN and CD133 was analysed by real­time RT-PCR and immunohistochemistry. The plasma levels of OPN were determined by ELISA. Our results revealed that OPN mRNA and protein expression, as well as its release in the blood, was significantly increased in the endometriotic lesions in comparison to normal tissue. Although the presence of CD133+ cells was detected in the normal endometrium, as well as in the endometriosis specimens, a significant quantitative variation of this protein was not demonstrated in the patients with endometriosis. In conclusion, our data indicate that OPN is involved in the development of endometriosis by enhancing the invasiveness, proliferation and survival of endometrial cells in ectopic lesions. CD133 cannot be used as a disease marker for endometriosis, although an involvement of this protein in the pathogenesis of endometriosis cannot be excluded.


Subject(s)
Antigens, CD/metabolism , Endometriosis/metabolism , Glycoproteins/metabolism , Osteopontin/metabolism , Peptides/metabolism , AC133 Antigen , Adult , Antigens, CD/genetics , Case-Control Studies , Demography , Endometriosis/blood , Endometriosis/genetics , Endometriosis/pathology , Female , Glycoproteins/genetics , Humans , Immunohistochemistry , Osteopontin/blood , Osteopontin/genetics , Peptides/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction
13.
Arch Oral Biol ; 58(4): 370-6, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22947212

ABSTRACT

OBJECTIVE: Chronic isoproterenol treatment causes hypertrophy and hyperplasia of rodent salivary glands. Cell-extracellular matrix interactions play a critical role in salivary gland proliferation and matrix metalloproteinases (MMPs) are known to be involved in cell proliferation. The present study was undertaken to investigate the expression of MMP-2 and the tissue inhibitor metalloproteinase (TIMP)-2 in rat parotid gland following isoproterenol treatment. DESIGN: Female Wistar rats were daily treated with isoproterenol (25mg/kg body weight) for 0, 1, 3, and 7 days. Expression of parotid gland MMP-2 and its tissue inhibitor TIMP-2 was analysed by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Our results suggest that isoproterenol modulates expression of MMP-2 and TIMP-2 mRNAs, as well as their protein expression levels in a time dependent-manner. Interestingly, at day 1 of treatment, MMP-2 and TIMP-2 expression were higher in comparison to untreated gland. At days 3 and 7, we can observe a gradual decrease of mRNA and protein levels of MMP-2 and TIMP-2. CONCLUSIONS: Our results suggest the presence of a isoproterenol-dependent modulation of extracellular matrix components. Such a modulation seems to be associated with ß-adrenergic agonist-induced hyperplasy, occurring during the first 24h of agonist treatment, and hypertrophy of the parotid gland.


Subject(s)
Adrenergic beta-Agonists/pharmacology , Cell Proliferation/drug effects , Isoproterenol/pharmacology , Matrix Metalloproteinase 2/drug effects , Parotid Gland/drug effects , Tissue Inhibitor of Metalloproteinase-2/drug effects , Animals , Female , Hyperplasia/etiology , Hypertrophy/etiology , Immunohistochemistry , Matrix Metalloproteinase 2/genetics , Parotid Gland/enzymology , RNA, Messenger/metabolism , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Tissue Inhibitor of Metalloproteinase-2/genetics
14.
Cell Biochem Biophys ; 66(2): 239-47, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23152091

ABSTRACT

Macrophages as a principal component of immune system play an important role in the initiation, modulation, and final activation of the immune response against pathogens. Upon stimulation with different cytokines, macrophages can undergo classical or alternative activation to become M1 or M2 macrophages, which have different functions during infections. Although chitotriosidase is widely accepted as a marker of activated macrophages and is thought to participate in innate immunity, particularly in defense mechanisms against chitin containing pathogens, little is known about its expression during macrophages full maturation and polarization. In this study we analyzed CHIT-1 modulation during monocyte-to-macrophage maturation and during their polarization. The levels of CHIT-1 expression was investigated in human monocytes obtained from buffy coat of healthy volunteers, polarized to classically activated macrophages (or M1), whose prototypical activating stimuli are interferon-γ and lipopolysaccharide, and alternatively activated macrophages (or M2) obtained by interleukin-4 exposure by real-time PCR and by Western blot analysis. During monocyte-macrophage differentiation both protein synthesis and mRNA analysis showed that CHIT-1 rises significantly and is modulated in M1 and M2 macrophages.Our results demonstrated that variations of CHIT-1 production are strikingly associated with macrophages polarization, indicating a different rule of this enzyme in the specialized macrophages.


Subject(s)
Hexosaminidases/metabolism , Macrophages/cytology , Monocytes/metabolism , Cell Differentiation/drug effects , Cells, Cultured , Chemokine CXCL11/genetics , Chemokine CXCL11/metabolism , Chemokines, CC/genetics , Chemokines, CC/metabolism , Hexosaminidases/genetics , Humans , Interferon-gamma/pharmacology , Interleukin-4/pharmacology , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Mannose Receptor , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/metabolism , Monocytes/cytology , Monocytes/drug effects , RNA, Messenger/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
15.
Hum Immunol ; 73(9): 950-3, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22820628

ABSTRACT

A candidate gene for TIMP-1 gene located on the X-chromosome (rs4898) was selected for a control case study to investigate a possible association of this SNP with the susceptibility to systemic sclerosis and its digit ulcer manifestation. A total of 461 individuals of Italian Caucasian origin (228 SSc patients and 233 healthy control subjects) were genotyped for TIMP-1 +372 T/C single nucleotide polymorphism rs4898. Subgroups were analyzed according to the presence or absence of digital ulcers. The CC genotype and C allele frequencies were significantly lower in female SSc patients than in controls (OR 0.53, CI 0.29-0.96, p=0.03 and OR 0.72, CI 0.53-0.98 p=0.04, respectively). CC genotypes frequency was lower also in female patients with ulcers than those without ulcers (OR 0.37, CI 0.14-1.00, p=0.03). Furthermore, CC genotype and C allele frequencies were lower also in female patients with ulcers in comparison to female healthy control subjects (OR 0.27, CI 0.10-0.70, p=0.004; OR 0.60, CI 0.40-0.89, p=0.01, respectively). The TIMP-1 rs4898 polymorphism may play a protective role in the susceptibility to SSC in females, and in particular to digital ulcer formation.


Subject(s)
Polymorphism, Single Nucleotide , Scleroderma, Systemic/complications , Scleroderma, Systemic/genetics , Skin Ulcer/etiology , Tissue Inhibitor of Metalloproteinase-1/genetics , Aged , Alleles , Case-Control Studies , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Sex Factors
16.
Int J Mol Med ; 29(6): 983-8, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22446965

ABSTRACT

In hepatitis C virus (HCV)-associated liver disease, the immune system is unable to clear the viral infection. Previous studies have raised the possibility of an involvement of regulatory T cells (Tregs). In this study, we analysed the peripheral blood from 30 patients with HCV-associated chronic liver disease and 20 healthy controls by flow cytometry for the evaluation of the Treg population [CD4⁺CD25hi forkhead box protein 3 (Foxp3)⁺], as well as the activated/effector CD4⁺ T cells (CD4⁺CD25low) and IFN-γ-secreting cells. We also analysed liver biopsies of the patients by immunohistochemical evaluation of Foxp3⁺ cells. Our results showed higher proportions of CD4⁺CD25low and IFN-γ⁺ cells in the patients than in the controls. By contrast, the proportions of peripheral CD4⁺CD25hi cells did not significantly differ. The 11 patients displaying Foxp3⁺ cells in the liver infiltrates showed significantly higher proportions of peripheral CD4⁺CD25low cells. Moreover, we found lower serum transaminase levels in the patients than in the controls, as shown by Foxp3⁺ immunohistochemistry, although these results were only statistically significant as regards alanine transaminase (ALT). In conclusion, these data suggest that the presence of Tregs infiltrating the liver is associated with high levels of activated/effector T cells in the peripheral blood and lower activity of hepatitis. Therefore, liver-infiltrating Tregs may play a role in limiting tissue damage and may thus support an effective immune response against HCV.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cell Movement , Forkhead Transcription Factors/metabolism , Hepacivirus/physiology , Interleukin-2 Receptor alpha Subunit/blood , Liver Diseases/virology , Liver/pathology , Adult , Aged , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , CD4 Antigens/blood , CD4-Positive T-Lymphocytes/drug effects , Cell Movement/drug effects , Female , Hepacivirus/drug effects , Humans , Immunohistochemistry , Interferon-gamma/metabolism , Ionomycin/pharmacology , Liver/drug effects , Liver/virology , Liver Diseases/blood , Liver Diseases/immunology , Liver Diseases/pathology , Male , Middle Aged , Tetradecanoylphorbol Acetate/pharmacology
17.
Int J Oncol ; 40(3): 605-24, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22179098

ABSTRACT

MicroRNAs (MiRNAs) are small non-coding RNAs able to regulate gene expression at a posttranscriptional level. Recent evidence indicates that they play a crucial role in the initiation and progression of human cancers. In this review we briefly describe microRNA biogenesis and function, giving a more detailed account of the current state of knowledge concerning the role of microRNAs in brain tumors and stem-like tumor cells. MicroRNAs control brain tumor development by regulating multiple biological characteristics such as proliferation, invasion, differentiation and angiogenesis. Research in this field is rapidly spreading and encourages potential applications of microRNAs as diagnostic and prognostic tools, in addition to therapeutic targets and tools, to grant clinical benefits to patients suffering of brain tumors.


Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Brain Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans
18.
Int J Mol Med ; 27(6): 873-7, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21455563

ABSTRACT

The objective of this study was to determine whether the matrix metalloproteinase-9 (MMP-9) rs3918242 single nucleotide polymorphism may confer susceptibility to systemic sclerosis (SSc) with and without ulcers in an Italian Caucasian population. The MMP-9 rs3918242 functional polymorphism was genotyped in 461 subjects of Italian Caucasian origin: 228 patients with SSc (92 with and 136 without ulcers) and 233 unrelated healthy individuals. The SNP under study was in Hardy-Weinberg equilibrium in the control population. Genotype and allele distributions between SSc patients, with or without ulcers, were not statistically significant (p>0.05). A significant increase of the genotype C/T was observed in male SSc patients without ulcers when compared to patients with ulcers (P=0.04). The MMP-9 rs3918242 functional polymorphism is not associated with susceptibility to SSc. However, the presence of the polymorphism may have a protective effect on the development of ulcers in SSc male patients.


Subject(s)
Matrix Metalloproteinase 9/genetics , Polymorphism, Single Nucleotide , Scleroderma, Systemic/genetics , Ulcer/genetics , Aged , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Scleroderma, Systemic/complications , Ulcer/etiology , White People/genetics
19.
Int J Mol Med ; 26(4): 505-10, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20818489

ABSTRACT

Prominin-1 (CD133) is a pentaspan cholesterol-binding membrane glycoprotein. Chronic treatment with isoproterenol, a beta-receptor agonist, induces several dramatic effects on salivary glands, such as enhanced DNA synthesis and proliferation of salivary acinar cells. In addition, the biosynthetic pathways of membrane lipids may be altered by the isoproterenol stimulation. The purpose of this study was to investigate the effect of isoproterenol administration on prominin-1 expression profiles in rat parotid gland by means of PCR and immunohistochemistry. Rats were chronically treated with the beta-adrenergic agonist for 1, 3, and 7 days. Our results showed that isoproterenol-treatment caused a down-regulation of prominin-1 on day 3 and 7 of treatment, as well as a differential immunostaining distribution pattern. This study suggests that isoproterenol-treatment may represent a useful tool to explore the molecular mechanisms involved in the synthesis and release of prominin-1. Such efforts could contribute to the development of diagnostic tools based on the detection of prominin-1 in biological fluids, such as saliva.


Subject(s)
Antigens, CD/analysis , Antigens, CD/genetics , Gene Expression Regulation/drug effects , Glycoproteins/analysis , Glycoproteins/genetics , Isoproterenol/pharmacology , Parotid Gland/drug effects , Peptides/analysis , Peptides/genetics , AC133 Antigen , Animals , Female , Isoproterenol/administration & dosage , Parotid Gland/ultrastructure , Polymerase Chain Reaction , RNA, Messenger/genetics , Rats , Rats, Wistar
20.
Haematologica ; 95(11): 1897-904, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20595097

ABSTRACT

BACKGROUND: Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome and its variant Dianzani's autoimmune lymphoproliferative disease. Analysis of the lymphocyte transcriptome from a patient with this latter condition detected striking over-expression of osteopontin and tissue inhibitor of metalloproteinases-1. Since previous work on osteopontin had detected increased serum levels in these patients, associated with variations of its gene, the aim of this work was to extend the analysis to tissue inhibitor of metalloproteinases-1. DESIGN AND METHODS: Tissue inhibitor of metalloproteinases-1 levels were evaluated in sera and culture supernatants from patients and controls by enzyme-linked immunosorbent assay. Activation- and Fas-induced cell death were induced, in vitro, using anti-CD3 and anti-Fas antibodies, respectively. RESULTS: Tissue inhibitor of metalloproteinases-1 levels were higher in sera from 32 patients (11 with autoimmune lymphoproliferative syndrome and 21 with Dianzani's autoimmune lymphoproliferative disease) than in 50 healthy controls (P<0.0001), unassociated with variations of the tissue inhibitor of metalloproteinases-1 gene. Both groups of patients also had increased serum levels of osteopontin. In vitro experiments showed that osteopontin increased tissue inhibitor of metalloproteinases-1 secretion by peripheral blood monocytes. Moreover, tissue inhibitor of metalloproteinases-1 significantly inhibited both Fas- and activation-induced cell death of lymphocytes. CONCLUSIONS: These data suggest that high osteopontin levels may support high tissue inhibitor of metalloproteinases-1 levels in autoimmune lymphoproliferative syndrome and Dianzani's autoimmune lymphoproliferative disease, and hence worsen the apoptotic defect in these diseases.


Subject(s)
Tissue Inhibitor of Metalloproteinase-1/blood , Adolescent , Apoptosis/genetics , Autoimmune Lymphoproliferative Syndrome/blood , Autoimmune Lymphoproliferative Syndrome/genetics , Child , Child, Preschool , Female , Genetic Variation , Humans , Male , Osteopontin/genetics , Osteopontin/metabolism , Tissue Inhibitor of Metalloproteinase-1/genetics
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