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Background and Objective: Previous systematic reviews have reported that the use of a coronally advanced flap (CAF) combined with a connective tissue graft (CTG) or enamel matrix derivative (EMD) is more likely to achieve complete root coverage (CRC) than other modalities. However, the details of periodontal parameters and comparisons among a variety of combinations of CAF with CTG and/or EMD are left to be investigated. This study aimed to analyze the differences in periodontal parameters between these treatment modalities., Material and Methods: A literature search was performed using the Cochrane library and MEDLINE (PubMed) for studies focused on the treatment of gingival recession (Miller Class I, II and III) with CAF alone or combined with CTG, EMD or both up to December 2011. Randomized controlled clinical trials with a follow-up duration ≥ 6 mo were included. The outcome analysis included changes in periodontal probing depth (PPD), clinical attachment level, recession depth (RED) and keratinized tissue width (KTW)., Results: Thirteen randomized controlled clinical trials, including 529 Miller Class I-III defects from 321 patients were included. For an increase in KTW, CAF + CTG significantly improved more than CAF alone. CAF + EMD also gained more KTW than CAF alone. EMD reduced PPD, however, a significant difference was not found. Furthermore, the effects on changes of RED and clinical attachment level were not identified in the study., Conclusion: When combined with CAF, CTG contributed more in the increase of KTW, while EMD seemed helpful for wound healing by its potential in PPD reduction. However, further research is needed to clarify the effects on changes in RED and clinical attachment level., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cyclosporine A (CsA) increases β-catenin messenger RNA (mRNA) and protein expression. The present study demonstrates that Wnt/β-catenin signaling inhibits β-catenin degradation in the gingiva., Methods: Forty 5-week-old male Sprague-Dawley rats were assigned to two study groups after healing from right maxillary molar extractions. The rats in the experimental group were fed 30 mg/kg CsA daily for 4 weeks, whereas the control rats were fed mineral oil. At the end of the study, all rats were sacrificed, and the gingivae were obtained. The gingival morphology after CsA treatment was evaluated by histology, and the genes related to Wnt/β-catenin signaling were initially screened by microarray. Polymerase chain reaction, Western blotting, and immunohistochemistry were used to examine the mRNA and protein expression of proliferating cell nuclear antigen, cyclin D1, E-cadherin, β-catenin, Dvl-1, glycogen synthase kinase-3β, axin-1, and adenomatous polyposis coli (APC). Phosphoserine and ubiquitinylated β-catenin were detected after immunoprecipitation., Results: In rats treated with CsA, overgrowth of gingivae was observed, and altered expression of genes related to Wnt/β-catenin signaling was detected by the microarray. The gingival mRNA and protein expression profiles for genes associated with Wnt/β-catenin signaling further confirmed the effect of CsA: β-catenin and Dvl-1 expression increased, but APC and axin-1 expression decreased. Western blotting and immunohistochemistry showed decreases in β-catenin serine phosphorylation (33/37) and ubiquitinylation in the gingivae of CsA-treated rats., Conclusion: CsA-enhanced gingival β-catenin stability may be involved in gene upregulation or β-catenin degradation via the Wnt/β-catenin pathway.

Objective: Cyclosporine-A (CsA)-induced gingival overgrowth may arise from an alteration in stoma matrix homeostasis. Sonic hedgehog (Shh) plays a key role during embryogenic development and fibrotic progression, and may be involved in CsA-altered gingival matrix homeostasis., Methods: Using the reverse transcription-polymerase chain reaction and Western blot analysis, we investigated the mRNA and protein expressions of Shh, type 1 collagen (COL1), alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) in human gingival fibroblasts after CsA treatments. The effect of Shh on CsA-induced alterations was further evaluated by the extra-supplement or inhibition of Shh or TGF-β., Results: Cyclosporine-A enhanced COL1, α-SMA, Shh and TGF-β expressions in human gingival fibroblasts. The exogenous Shh/TGF-β augmented the expression of COL1 and α-SMA, and the Shh/TGF-β inhibition suppressed the CsA-enhanced COL1 and α-SMA expressions. Moreover, Shh mRNA and protein expressions increased if extra-supplementing the exogenous TGF-β, whereas the CsA-upregulated Shh was mitigated by the TGF-β pathway inhibitor. However, neither exogenous Shh nor the Shh pathway inhibitor alters TGF-β expression or CsA-up-regulated TGF-β expression., Conclusions: Shh, regulated by TGF-β, mediates CsA-altered gingival matrix homeostasis., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cyclosporine-A (CsA) stimulates heme oxygenase-1 (HO-1) expression in the gingiva, but the regulation and the role of HO-1 in gingival overgrowth are not well-understood. HO-1 is regulated by several transcription factors, such as nuclear factor-κB (NF-κB) and nuclear factor erythroid-2-related factor 2 (Nrf-2). The aim of this study was to examine the role of Nrf-2 in the regulation of CsA-stimulated HO-1 expression in human gingival fibroblasts. Nrf-2 siRNA (siNrf-2), NF-κB, kinase inhibitors, and sulforaphane (SFN) were used to examine the nuclear translocation of Nrf-2 and expression of HO-1 and transforming growth factor-β1 (TGF-β1) in cells. Treatment with siNrf-2, but not with an NF-κB inhibitor, reduced CsA-stimulated HO-1 mRNA expression. ERK inhibition significantly decreased CsA-stimulated Nrf-2 nuclear translocation and HO-1 mRNA expression. Pre-treatment with SFN showed that HO-1 plays a role in attenuating CsA-mediated TGF-β1 expressions. These findings suggest that CsA-stimulated HO-1 expression is mediated through the activation of ERK, and that Nrf-2 plays a protective role against CsA-induced gingival fibrosis by modulating collagen turnover-related genes.

Background and Objective: This study aimed to evaluate the expression and bioactivities of endothelin-1 (ET-1) in gingiva during cyclosporine A (CsA) treatment., Material and Methods: After establishing edentulous ridges, experimental rats were fed 30 mg/kg/day CsA while control animals received mineral oil for 4 weeks, after which a reverse transcription-polymerase chain reaction (RT-PCR) and/or immunohistochemistry was used to examine the expression of ET-1, its receptors, proliferating cell nuclear antigen (PCNA) and inducible nitric oxide synthase (iNOS) in gingivae. The roles of the endothelin receptors A and B (ET(A) and ET(B)) in CsA-enhanced expression of PCNA and iNOS were examined in cultured human gingival fibroblasts pretreated with receptor antagonists, by immunocytochemistry and RT-PCR, respectively., Results: The mRNA expression of ET-1, ET(A) and ET(B), as well as of PCNA and iNOS, was significantly greater in edentulous gingiva that received CsA compared with control gingiva. Immunohistochemistry revealed more cells positively stained for ET-1 and its receptors in the tissues of CsA-treated rats than in those of control rats. In fibroblast cultures, enhanced mRNA expression of ET-1, ET(A) and ET(B) was observed after CsA treatment at the concentrations of 10 and 100 ng/mL. Cyclosporine A-enhanced PCNA expression was somewhat reduced by blockade of ET(A), but not ET(B), whereas iNOS expression was somewhat reduced by blockade of ET(B)., Conclusion: Based on the present findings, we suggest that: (1) CsA upregulates the gingival expression of ET-1 and its receptors; and (2) ET(A) and ET(B) have different bioactivities, ET(A) being involved in cell proliferation and ET(B) being associated with iNOS expression.

Background: The role of nitric oxide (NO) in the pathogenesis of cyclosporin A (CsA)-induced gingival overgrowth is still unknown. The purpose of this study was to evaluate the effect of CsA on the expression of nitric oxide synthases (NOS) in the gingival tissue of rats., Methods: Thirty male Sprague-Dawley rats were randomly assigned to a control and two test groups. Rats in each group received CsA (0, 10, or 30 mg/kg) daily by gastric feeding for 4 weeks. The plasma NO and the NOS enzyme activities were assayed at week 4 in the blood samples and in the gingiva and lung tissue specimens, respectively. The distribution of inducible nitric oxide synthase (iNOS) was further evaluated in tissues obtained from the gingiva and lung at the end of weeks 1 and 4 by immunohistochemistry., Results: In the CsA-treated animals, increased levels of plasma nitrites/nitrates were measured in comparison to those in control rats. Significantly greater iNOS enzyme activities were detected in lung and gingival tissues obtained from CsA-treated animals than from control animals. In addition, cells positively staining for iNOS were clearly observed in both gingival and lung tissues obtained from the CsA-treated animals by immunohistochemistry, whereas a few stained cells were found in those from the control group. The quantity of cells positively stained for iNOS was greater in tissue from week 4 than week 1., Conclusions: The effect of CsA on gingival iNOS expression was evaluated in rats for 4 weeks. A greater iNOS expression in the gingiva was observed after CsA therapy by both enzyme activities and immunohistochemica staining. Therefore, we suggest that CsA can increase gingival iNOS expression, which may play an important role in cyclosporin-induced gingival overgrowth.

Healing after tooth extraction was studied in rats treated with cyclosporine-A (CSA) for four weeks. Sixty male Sprague-Dawley rats were assigned to one of three groups of 20 rats each. The maxillary right molars were extracted from two groups; the third group served as a non-extraction control. The non-extraction group and one extraction group (vehicle control) received the solvent mineral oil daily, and the other extraction group received 15 mg/kg CSA in mineral oil. Five rats from each group were killed 5, 10, 14 and 28 days after extraction and samples analyzed histologically. On days 5 and 10, bone volume was significantly lower and marrow volume significantly higher in both extraction groups than in the non-extraction group. The fractional-formation surfaces were significantly lower in the extraction groups than in the non-extraction group on day 5 only. Osteoid volume was significantly higher in the extraction vehicle control group than in the other two groups on days 10 and 14; however, the osteoid volume was higher in the CSA group than in the other two groups on day 28. On days 14 and 28, bone volume was lower and marrow volume higher in the CSA group than in the extraction vehicle control and non-extraction groups. On day 28, bony surface areas were significantly greater in the CSA group than in the extraction vehicle control and non-extraction groups. Soft-tissue evaluation showed significantly greater epithelial areas, connective tissue areas and total tissue areas in the CSA group than in the extraction vehicle control group on day 28, but not on day 14. These data suggest that CSA may influence healing of both the gingival tissue and the alveolar bony sockets in the tooth-extraction wound. Further detailed study is needed to identify the mechanisms responsible.

The present study was carried out to investigate and compare the thickness and number of rete pegs of the sulcular epithelium histometrically in bleeding and non-bleeding gingivae with special reference to comparisons of their relationship with corresponding stereomicroscopic findings. A total of 78 biopsies (40 bleeding and 38 non-bleeding gingival specimens) was obtained from 33 patients. Tissue sections with H&E stains were performed. Each gingival section was divided into three portions (coronal, middle and apical) along the gingival sulcular epithelium horizontally. The rete pegs were counted and the thickest and thinnest parts of the epithelium in three individual portions were also measured histometrically. The results show that the epithelial thickness of bleeding gingiva at the coronal and middle portions was significantly thinner than that of non-bleeding gingiva. There were also greater numbers of rete pegs of the sulcular epithelium in bleeding gingiva than of those in non-bleeding gingiva. However, there was no specific relationship between epithelial alterations of gingiva and the visibility of vasculature by stereomicroscopy. It is suggested that epithelial alterations of gingiva to some extent might be responsible for the gingival bleeding on probing clinically and highly associated with the volumetric density of underlying infiltrated connective tissue, but might not be related to the visibility of vasculature by stereomicroscopy.