scholarly journals Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts

2020 ◽  
Vol 21 (2) ◽  
pp. 595 ◽  
Author(s):  
Dorina Lauritano ◽  
Annalisa Palmieri ◽  
Alberta Lucchese ◽  
Dario Di Stasio ◽  
Giulia Moreo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Cyclosporine A ◽  
Matrix Metalloproteases ◽  
Gingival Hyperplasia ◽  
Gingival Fibroblasts ◽  
Down Regulation ◽  
Gingival Overgrowth ◽  
Expression Levels

Background: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. Materials and methods: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control. Results: Expression levels of different genes were significantly de-regulated. The gene CDH1, which codes for the cell adhesion protein E-cadherin, showed up-regulation. Almost all the extracellular matrix metalloproteases showed down-regulation (MMP8, MMP11, MMP15, MMP16, MMP24, MMP26). The administration of cyclosporine A was followed by down-regulation of other genes: COL7A1, the transmembrane receptors ITGB2 and ITGB4, and the basement membrane constituents LAMA2 and LAMB1. Conclusion: Data collected demonstrate that cyclosporine inhibits the secretion of matrix proteases, contributing to the accumulation of extracellular matrix components in the gingival connective tissue, causing gingival overgrowth. Patients affected by gingival overgrowth caused by cyclosporine A need to be further investigated in order to determine the role of this drug on fibroblasts.

scholarly journals Drug-Induced Gingival Overgrowth: A Pilot Study on the Effect of Diphenylhydantoin and Gabapentin on Human Gingival Fibroblasts

2020 ◽  
Vol 17 (21) ◽  
pp. 8229
Author(s):  
Dorina Lauritano ◽  
Giulia Moreo ◽  
Luisa Limongelli ◽  
Elena Tregambi ◽  
Annalisa Palmieri ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Direct Action ◽  
Human Fibroblasts ◽  
Matrix Metalloproteases ◽  
Channel Blockers ◽  
Gingival Hyperplasia ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition

Introduction. The administration of several classes of drugs can lead to the onset of gingival overgrowth: anticonvulsants, immunosuppressants, and calcium channel blockers. Among the anticonvulsants, the main drug associated with gingival overgrowth is diphenylhydantoin. Materials and Methods. In this study, we compared the effects of diphenylhydantoin and gabapentin on 57 genes belonging to the “Extracellular Matrix and Adhesion Molecule” pathway, present in human fibroblasts of healthy volunteers. Results. Both molecules induce the same gene expression profile in fibroblasts as well as a significant upregulation of genes involved in extracellular matrix deposition like COL4A1, ITGA7, and LAMB3. The two treatments also induced a significant downregulation of genes involved in the expression of extracellular matrix metalloproteases like MMP11, MMP15, MMP16, MMP24, and transmembrane receptor ITGB4. Conclusions. Data recorded in our study confirmed the hypothesis of a direct action of these drugs at the periodontium level, inducing an increase in matrix production, a reduction in its degradation, and consequently resulting in gingival hyperplasia.

Evaluation of inductive effects of different concentrations of cyclosporine A on MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2 in fetal and adult human gingival fibroblasts

2019 ◽  
Vol 30 (3) ◽  
Author(s):  
Bahareh Nazemisalman ◽  
Neda Sajedinejad ◽  
Shayan Darvish ◽  
Surena Vahabi ◽  
Hoda Gudarzi
Keyword(s):  
Cyclosporine A ◽  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
Adult Group ◽  
Gelatinase Activity ◽  
Gingival Overgrowth ◽  
Adult Human ◽  
Single Donor ◽  
Inductive Effects

Abstract Background The etiology of gingival overgrowth due to cyclosporine A (CsA) is still unknown. The aim of this study was to determine the possible role of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) on extra-cellular matrix (ECM) homeostasis when treated with different levels of CsA and its difference between fetal and adult human gingival fibroblasts (HGFs). Methods Each group of cells (adult and fetal) was cultured in 40 wells that consisted of four different CsA treatment concentrations. Every 10 wells were treated with 0, 50, 100, and 150 ng/mL of CsA which makes a total of 80 wells. Supernatants of every well were used to determine the concentration of MMPs and TIMPs using the Elisa kits from Boster, CA, USA. Results MMP-1 level increased with the treatment of CsA when treated with 50 and 150 ng/mL of CsA (p = 0.02 and p = 0.04) as TIMP-1 decreased (p < 0.0001) in adult group; while in the fetal group, TIMP-1 level increased with treatment of 150 ng/mL (p < 0.0001). MMP-2 level increased in both adult and fetal groups (p < 0.0001). MMP-3 level decreased in adult group (p < 0.0001) but went up in fetal HGFs (p = 0.01) when treated with 150 ng/mL CsA. TIMP-2 level increased in all wells significantly when treated with CsA (p < 0.0001). The study showed that CsA affects secretion of MMPs and TIMPs. MMP-1 increment and TIMP-1 decrement were observed, which indicate more degradation of ECM. This may be due to single donor use in this study. TIMP-2 and MMP-2 were both more active when treated with CsA which may be due to the gelatinase activity of them and that in CsA gingival overgrowth. There was more inflammation rather than fibrosis.

scholarly journals Drug-induced gingival hyperplasia: An in vitro study using amlodipine and human gingival fibroblasts

2019 ◽  
Vol 33 ◽  
pp. 205873841982774 ◽  
Author(s):  
Dorina Lauritano ◽  
Marcella Martinelli ◽  
Alessandro Baj ◽  
Giada Beltramini ◽  
Valentina Candotto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Human Gingival Fibroblasts ◽  
Gingival Tissue ◽  
Gingival Fibroblast ◽  
Gingival Hyperplasia ◽  
Gingival Fibroblasts ◽  
Drug Induced ◽  
Gingival Overgrowth

Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast’s function in gingival overgrowth. To determine whether amlodipine alters the inflammatory responses, we investigated its effects on gingival fibroblast gene expression as compared with untreated cells. Fragments of gingival tissue of healthy volunteers (11 years old boy, 68 years old woman, and 20 years old men) were collected during operation. Gene expression of 29 genes was investigated in gingival fibroblast cell culture treated with amlodipine, compared with untreated cells. Among the studied genes, only 15 ( CCL1, CCL2D, CCL5, CCL8, CXCL5, CXCL10, CCR1, CCR10, IL1A, IL1B, IL5, IL7, IL8, SPP1, and TNFSF10) were significantly deregulated. In particular, the most evident overexpressed genes in treated cells were CCR10 and IL1A. These results seem to indicate a possible role of amlodipine in the inflammatory response of treated human gingival fibroblasts.

scholarly journals Molecular Aspects of Drug-Induced Gingival Overgrowth: An In Vitro Study on Amlodipine and Gingival Fibroblasts

2019 ◽  
Vol 20 (8) ◽  
pp. 2047 ◽  
Author(s):  
Dorina Lauritano ◽  
Alberta Lucchese ◽  
Dario Di Stasio ◽  
Fedora Della Vella ◽  
Francesca Cura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
In Vitro Study ◽  
Gingival Fibroblast ◽  
Gingival Hyperplasia ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Molecular Aspects ◽  
Gene Expression Levels

Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast’s function in gingival overgrowth. To determine whether amlodipine alters the fibrotic response, we investigated its effects on treated gingival fibroblast gene expression as compared with untreated cells. Materials and Methods: Fibroblasts from ATCC® Cell Lines were incubated with amlodipine. The gene expression levels of 12 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway was investigated in treated fibroblasts cell culture, as compared with untreated cells, by real time PCR. Results: Most of the significant genes were up-regulated. (CTNND2, COL4A1, ITGA2, ITGA7, MMP10, MMP11, MMP12, MMP26) except for COL7A1, LAMB1, MMP8, and MMP16, which were down-regulated. Conclusion: These results seem to demonstrate that amlodipine has an effect on the extracellular matrix of gingival fibroblast. In the future, it would be interesting to understand the possible effect of the drug on fibroblasts of patients with amlodipine-induced gingival hyperplasia.

scholarly journals Drug-Induced Gingival Overgrowth: The Effect of Cyclosporin A and Mycophenolate Mophetil on Human Gingival Fibroblasts

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 221 ◽  
Author(s):  
Dorina Lauritano ◽  
Giulia Moreo ◽  
Luisa Limongelli ◽  
Annalisa Palmieri ◽  
Francesco Carinci
Keyword(s):  
Extracellular Matrix ◽  
Cell Viability ◽  
Cyclosporin A ◽  
Chronic Administration ◽  
Immunosuppressive Drugs ◽  
Matrix Metalloproteases ◽  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
Drug Induced ◽  
Gingival Overgrowth

Drug-induced gingival overgrowth may occur after a chronic administration of three classes of systemic drugs: Anticonvulsants, immunosuppressants, and calcium channel blockers. This study aimed to investigate how cyclosporin A and mycophenolate mophetil (immunosuppressive drugs) could interfere with human gingival fibroblasts functions, leading to gingival enlargement. Human gingival fibroblasts derived from the tissue of a 60-year-old female were cultured in a DMEME medium. A stock solution with 1 mg/mL of mycophenolate and 1 mg/mL of cyclosporine were prepared and dissolved in a DMEM medium to prepare a serial dilution at the concentrations of 5000, 2000, 1000, 500, and 100 ng/mL, for both treatments. Cell viability was measured using the PrestoBlue™ Reagent Protocol. Quantitative real-time RT-PCR was performed in order to analyze the expression of 57 genes coding for gingival fibroblasts “Extracellular Matrix and Adhesion Molecules”. Mycophenolate and cyclosporine had no effect on fibroblast cell viability at 1000 ng/mL. Both the treatments showed similar effects on the expression profiling of treated cells: Downregulation of most extracellular matrix metalloproteases genes (MMP8, MMP11, MMP15, MMP16, MMP24) was assessed, while CDH1, ITGA2, ITGA7, LAMB3, MMP12, and MMP13 were recorded to be upregulated in fibroblasts treated with immunosuppressive drugs. It has been demonstrated that gingival overgrowth can be caused by the chronic administration of cyclosporin A and mycophenolate mophetil. However, given the contrasting data of literature, further investigations are needed, making clear the possible effects of immunosuppressive drugs on fibroblasts.

The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis

2019 ◽  
Vol 19 (4) ◽  
pp. 255-263 ◽  
Author(s):  
Yuangang Wu ◽  
Xiaoxi Lu ◽  
Bin Shen ◽  
Yi Zeng
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Extracellular Matrix ◽  
Inflammatory Reaction ◽  
Noncoding Rna ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Translation ◽  
Cochrane Library

Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.

An analysis of culmination in Dictyostelium using prestalk and stalk-specific cell autonomous markers

Development ◽  
1991 ◽  
Vol 111 (3) ◽  
pp. 779-787 ◽  
Author(s):  
K.A. Jermyn ◽  
J.G. Williams
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Dictyostelium Discoideum ◽  
Tube Formation ◽  
Matrix Proteins ◽  
Specific Cell ◽  
Primary Role ◽  
Fusion Genes ◽  
Spore Mass

The ecmA (pDd63) and ecmB (pDd56) genes encode extracellular matrix proteins of the slime sheath and stalk tube of Dictyostelium discoideum. Using fusion genes containing the promoter of one or other gene coupled to an immunologically detectable reporter, we previously identified two classes of prestalk cells in the tip of the migrating slug; a central core of pstB cells, which express the ecmB gene, surrounded by pstA cells, which express the ecmA gene. PstB cells lie at the position where stalk tube formation is initiated at culmination and we show that they act as its founders. As culmination proceeds, pstA cells transform into pstB cells by activating the ecmB gene as they enter the stalk tube. The prespore region of the slug contains a population of cells, termed anterior-like cells (ALC), which have the characteristics of prestalk cells. We show that the ecmA and ecmB genes are expressed at a low level in ALC during slug migration and that their expression in these cells is greatly elevated during culmination. Previous observations have shown that ALC sort to surround the prespore cells during culmination (Sternfeld and David, 1982 Devl Biol. 93, 111–118) and we find just such a distribution for pstB cells. We believe that the ecmB protein plays a structural role in the stalk tube and its presence, as a cradle around the spore head, suggests that it may play a further function, perhaps in ensuring integrity of the spore mass during elevation. If this interpretation is correct, then a primary role of anterior-like cells may be to form these structures at culmination. We previously identified a third class of prestalk cells, pstO cells, which lie behind pstA cells in the slug anterior and which appeared to express neither the ecmA nor the ecmB gene. Using B-galactosidase fusion constructs, which give more sensitive detection of gene expression, we now find that these cells express the ecmA gene but at a much lower level than pstA cells. We also show that expression of the ecmA gene becomes uniformly high throughout the prestalk zone when slugs are allowed to migrate in the light. Overhead light favours culmination and it may be that increased expression of the ecmA gene in the pst ‘O’ region is a preparatory step in the process.

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