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ORIGINAL ARTICLE
Year : 2020  |  Volume : 23  |  Issue : 1  |  Page : 46-53

PPAR-γ, RXR, VDR, and COX-2 Expressions in gingival tissue samples of healthy individuals, periodontitis and peri-implantitis patients


1 Department of Periodontology, Faculty of Dentistry, Tokat Gaziosmanpasa University, Tokat, Turkey
2 Department of Histology and Embryology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey

Date of Submission09-Jul-2019
Date of Acceptance02-Sep-2019
Date of Web Publication10-Jan-2020

Correspondence Address:
Dr. M M Taskan
Tokat Gaziosmanpaşa University, Faculty of Dentistry, Department of Periodontology, Tokat
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_349_19

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   Abstract 


Objective: Periodontitis and peri-implantitis are irreversible destructive diseases of periodontal and peri-implant tissues. This study aimed to determine the receptor expressions of peroxisome proliferative-activated receptor (PPAR)-γ, retinoid X receptor (RXR)-α, vitamin D receptor (VDR), and cyclooxygenase (COX)-2 in diseased tissues around teeth and dental implants. Subjects and Methods: The study consisted of three groups: group 1, healthy group (C, n = 15); group 2, periodontitis patients with stage 3 grade B (P, n = 15); and group 3, peri-implantitis patients (PI, n = 15). Periodontal clinical parameters such as the plaque index (PI), gingival index (GI), and probing pocket depths (PPD) were recorded. Gingival and peri-implant mucosal biopsies were obtained from all participants and biopsy samples underwent histological tissue processing. Hematoxylin–eosin (H & E) and immunohistochemistry staining were performed. Total inflammatory cell counts and fibroblast cell density were evaluated on H and E-stained slides, while PPAR-γ, RXR-α, VDR, and COX-2 were evaluated through immunohistochemistry. Results: The age of participants were similar, while PI, GI, and PPD values were higher in periodontitis and peri-implantitis groups compared with healthy group. Inflammatory cell infiltration was higher in periodontitis and peri-implantitis compared with healthy group, while fibroblast cell density exhibited a reverse pattern. PPAR-γ and also COX-2 expressions were lower in the healthy group and higher in periodontitis and peri-implantitis groups. RXR-α and VDR were higher in the healthy group and lower in the periodontitis and peri-implantitis groups. Conclusion: The results revealed that RXR-α and VDR levels were higher, while PPAR-γ and COX-2 levels were lower in the healthy group and periodontitis and peri-implantitis groups resulting in similar expressions in the tested parameters.

Keywords: COX-2, peri-implantitis, periodontitis, PPAR-γ, RXR, VDR


How to cite this article:
Taskan M M, Gevrek F. PPAR-γ, RXR, VDR, and COX-2 Expressions in gingival tissue samples of healthy individuals, periodontitis and peri-implantitis patients. Niger J Clin Pract 2020;23:46-53

How to cite this URL:
Taskan M M, Gevrek F. PPAR-γ, RXR, VDR, and COX-2 Expressions in gingival tissue samples of healthy individuals, periodontitis and peri-implantitis patients. Niger J Clin Pract [serial online] 2020 [cited 2020 Jan 26];23:46-53. Available from: http://www.njcponline.com/text.asp?2020/23/1/46/275625




   Introduction Top


Periodontitis is the chronic destructive disease of the periodontium which is initiated by dysbiotic oral microbiota.[1] Cellular and molecular components of the gingival environment contribute to the defense system against dysbiotic microbiota.[2] Once the inflammation was triggered, the gingival tissues undergo structural and biochemical alterations such as increase in inflammatory cells, decrease in collagen and fibroblast cells, upregulation of proinflammatory cytokines, activation of complement system, and formation of granulation tissue.[3] Even though periodontitis is one of the most common infectious diseases worldwide, the mechanisms leading to periodontitis have not yet been completely elucidated.

Bone destruction is the inevitable result of the inflammatory process in the periodontal tissues and decreased osteoblastic activity, increased osteoclastic activity, or both can modify the bone metabolism and affect the periodontal disease development and progress. This process can be regulated by certain receptor activations mainly nuclear factor κB (NF-κB).[4] Osteoclastic differentiation requires receptor activator of NF-κB (RANKL) and another nuclear transcription factor which was reported to decrease osteoblastic cell differentiation and activity is the peroxisome proliferator-activated receptor (PPAR).[5] PPAR, especially the PPAR-γ, regulates glucose metabolism and adipogenic differentiation.[6] PPAR-γ forms heterodimers with retinoid X receptor (RXR) and plays significant roles in development of chronic inflammatory diseases and conditions such as obesity, diabetes, and atherosclerosis.[5] PPAR-γ/c-Fos pathway participates in RANKL-induced osteoclastogenesis.[7] PPAR-γ agonists are commonly used in these situations and successfully prevent the inflammation and destructive process.[8],[9]

Another nuclear receptor which is closely associated with RXR is the vitamin D receptor (VDR), and VDR and PPAR-γ were both suggested to induce autophagy which is considered a major contributor to periodontal disease development.[10] Furthermore, a VDR-PPAR-γ autophagy functional module was suggested to induce inflammation and contribute to pathogenesis of inflammatory disease such as rheumatoid arthritis.[11] Apart from autophagy, PPAR-γ also induces M2 macrophage maturation. PPAR-γ is highly expressed in macrophage cells and plays significant roles in macrophage-driven inflammation.[12] In bacterial infection, PPAR-γ exhibits significant anti-inflammatory activity through inhibition of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α.[13],[14] PPAR-γ was also reported to induce apoptosis of leucocyte cells which accelerate the progress of inflammatory reactions.[15] Reduced chemotaxis with decreased neutrophil adhesion and migration was also demonstrated with PPAR-γ activation.[16] The cyclooxygenase (COX) is a critical enzyme in arachidonic acid metabolism. There are two isoforms of COX, COX-1 and COX-2. Especially COX-2 has an important role in the development of periodontitis and peri-implantitis by mediating inflammatory reactions in periodontal tissues.[17]

PPAR-γ receptor activation can either be protective or provocative in the disease progress and inflammatory process, and the role in the periodontal diseases was not revealed yet. Dental implants also exhibit an inflammatory destructive chronic disease which is similar to periodontitis. However, there are several histological differences in tissues surrounding the teeth and dental implants, a major one being the lack of periodontal ligament. (PDL).[18],[19] PDL has a particular importance because it contributes to the defense mechanisms of periodontium.[20] In this regard, peri-implant tissues, which lack periodontal ligament and vascular plexus, might exhibit higher levels of inflammation compared with the teeth. Therefore, the aim of this study was to evaluate the expressions of nuclear transcription proteins PPAR-γ, RXR-α, VDR, and COX-2 in inflamed periodontal and peri-implant tissues.


   Subjects and Methods Top


This study is designed as a cross-sectional clinical study and the study protocol was approved by the local ethical committee of the Medical Ethics Committee of Tokat Gaziosmanpasa University. The study was conducted at Tokat Gaziosmanpaşa University Faculty of Dentistry Department of Periodontology and Tokat Gaziosmanpasa University Faculty of Medicine Department of Histology and Embriology. All participants were informed regarding the procedure, and written informed consent was obtained and they underwent overall oral examination and radiographic evaluation by an experienced clinician (M.M.T.).

In all, 45 participants were enrolled in this study and three study groups were created as follows:

Healthy group: healthy individuals (C, mean age 45.05 ± 2.50 years, eight men, seven women)

Periodontitis group: periodontitis patients with stage 3 grade B, (P, mean age 46.47 ± 1.89 years, nine women, six men)

Peri-implantitis group: patients with peri-implantitis (PI peri-implantitis, mean age 45.73 ± 2.14 years, nine women, six men)

After oral examination, a diagnosis based on the criteria defined by the 2017 International World Workshop for a Classification of Periodontal Diseases and Conditions[21] was made. In the healthy group, one biopsy from each participant was obtained by either gingivectomy or crown lengthening procedure in the routine treatment protocol or before orthodontically indicated tooth extraction. In the periodontitis and peri-implantitis groups, one biopsy sample from the inflamed gingival or peri-implant mucosal tissue was obtained during the nonsurgical periodontal treatment. All biopsies were obtained from posterior maxillary teeth or dental implants placed in the posterior maxilla region (tooth #4, #5, #6, or #7).

All participants were never smokers and systemically healthy. Patients with any systemic disease or condition which might affect the inflammatory state, had less than 10 or over missing teeth, used tobacco or any drugs, pregnant or lactating patients, and patients who underwent antibiotic or periodontal therapy within previous 6 months were excluded.

Periodontal clinical parameters

Full mouth periodontal clinical parameters such as plaque index (PI), gingival index (GI), and probing pocket depths (PPD) were evaluated, and the PI, GI, and PPD of the tooth or dental implant to be chosen were recorded.[22],[23] All clinical measurements were performed from six points, three from buccal aspect and three from the palatinal aspect as mesial, middle, and distal sites for both teeth and dental implants. A mean value of six measurements was recorded. PPD was measured as the distance from the gingival margin to the bottom of the pocket through a periodontal probe (Williams-type periodontal probe; Hu-Friedy Co., Chicago, IL, USA). For dental implants, measurements were performed through plastic periodontal probe of Williams type (Hu-Friedy Co.).

Collection of gingival samples

First, local anesthesia was performed and a gingival sample was dissected with a tissue scissor from an area requiring either gingivectomy or crown lengthening procedures from patients with impaired gingival topography or before tooth extraction indicated for orthodontic treatment in healthy individuals. As for the periodontitis and peri-implantitis patients, a gingival or peri-implant mucosal sample was dissected using a tissue scissor during the scaling and root planning procedure or mechanical debridement from the gingival/peri-implant mucosal areas with severe inflammation. Samples were immediately placed in 10% neutral buffered formalin for 48 h and underwent histological tissue processing.

Histopathological evaluation

Hematoxylin–eosin (H and E) and immunohistochemistry staining were performed on histological slides. For histological tissue processing, tissues were dehydrated with alcohol series and cleared with xylene and then embedded in paraffin. An experienced blind examiner performed the histological procedures (F.G.). Serial sections were obtained from paraffin blocks, and three sections from each block were chosen for each staining procedure. Fibroblast and inflammatory cell infiltration were evaluated from H and E-stained slides under 1000 × magnification through a light microscope (Nikon Eclipse, E 600, Tokyo, Japan).

For fibroblast and inflammatory cell evaluation, the gingival area at the connective tissue border neighboring gingival epithelium was evaluated. A cell counting frame of 10,000 μm2 area was selected under 1000 × magnification. The total inflammatory cells (neutrophil, lymphocyte, eosinophil, and macrophage cells) within the frame were counted as inflammatory cell counting. The fibroblasts were also counted similarly. The measurements were performed from three different points, and the mean of these three measurements was recorded.[24]

PPAR-γ, RXR-α, VDR, and COX-2 immunohistochemistry

Immunohistochemistry was performed as reported in previous studies.[24],[25],[26] Three sections were chosen for each immunohistochemistry staining from each participant. First, all slides were deparaffinized and dehydrated with alcohol series. After washing with distilled water, antigen retrieval was performed through sodium citrate buffer (pH 6.0) for 2 h at 70 C, and then endogenous peroxidase activity was suppressed with 3% hydrogen peroxide treatment. After hydrogen peroxide treatment, all slides were incubated with normal rabbit serum for 30 min. After normal serum incubation, primary antibody diluents were prepared and applied to the samples overnight at a humidified chamber at 4°C. The primary antibodies were goat polyclonal anti-PPAR-γ antibody (Abcam plc, Cambridge, UK) (1:250), anti-RXR-α antibody (Abcam plc) (1:250), and anti-VDR antibody (Abcam plc) (1:250). After primary antibody incubation, all slides were washed with phosphate buffer solution (PBS) three times for 5 min (3 × 5) and biotinylated immunoglobulin G was applied for 30 min. After a wash of 3 × 5 PBS, all samples were exposed to a streptavidin–horseradish peroxidase-conjugated reagent for another 30 min. After washing with 3 × 5 PBS, all sections were treated with AEC chromogen to visualize staining. Counterstaining was performed with Meyer's hematoxylin, and sections were mounted. After being dried for 2 days, the samples were examined under 400 × magnification using light microscopy (Nikon Eclipse, E 600).[24],[25]

Immunohistochemical semi-quantitative H score analysis

Immunohistochemistry evaluation was performed on three different areas in each section, and three sections were evaluated for each patient. Totally, nine measurements were performed for each participant. All cells were marked according to their staining as no staining “0,” low staining “1,” mild staining “2,” and dense staining “3.” Staining scores were converted to a numeric value as “H score” through a formula (ΣPi (i + l)) which is a frequently used value for immunohistochemistry.[24],[25] In this formula, i shows the staining intensity score and Pi indicates the percentage of the stained cells.

Statistical analysis

The power of the study was more than 85% based on a previous study with a similar study design.[26] IBM SPSS software (IBM SPSS; IBM Corporation, New York, NY, USA) was used for statistical analysis. One-sample Kolmogorov–Smirnov test test was used to test the normality. For the fibroblast cell counts, inflammatory cell counts, and CAL, one-way analysis of variance followed by Tukey's test was used. For other parameters, Mann–Whittney U-test and Kruskal–Wallis test were used. Data were presented as mean ± standard deviation or percentage as appropriate. P < 0.05 was considered statistically significant.


   Results Top


The results of this study are presented in the [Table 1] and [Table 2]. The age and gender of the participants were similar (P > 0.05) [Table 1]. PI, GI, and PPD values of healthy individuals were lower than those of the other groups (P < 0.05) [Table 1].
Table 1: Age, plaque index, gingival index, and clinical attachment levels of the study groups

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Table 2: Immunohistochemistry results, fibroblast, and inflammatory cell counts of the study groups

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Histological evaluation

The connective tissue composition in healthy individuals exhibited higher fibroblast cell density with lower inflammatory cell infiltration compared with the periodontitis and peri-implantitis groups (P < 0.05). Fibroblast cell density was significantly higher in the healthy group compared with the other groups (P < 0.05) [Figure 1] and [Figure 2], [Table 1]. Peri-implantitis and periodontitis groups had the lowest fibroblast cell density, while inflammatory cell density was the lowest in the healthy group (P < 0.05). Periodontitis and peri-implantitis groups had higher inflammatory cell counts compared with the healthy group (P < 0.05) but similar among each other (P > 0.05) [Figure 1] and [Figure 2], [Table 1].
Figure 1: Fibroblast and inflammatory cell counts in the study groupsaP < 0.05 vs. healthy group

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Figure 2: Hematoxylin–eosin images of the representative samples in the study groups. Interrupted black arrows indicate inflammatory cells. Ct: connective tissue, Et: epithelial tissue. A: healthy group, B: periodontitis group, C: peri-implantitis group

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   Immunohistochemistry Results Top


PPAR-γ expressions were higher in the periodontitis and peri-implantitis groups compared with the healthy group (P < 0.05) [Figure 3] and [Figure 4], [Table 2]. Peri-implantitis and periodontitis caused similarly high levels of PPAR-γ (P > 0.05).
Figure 3: Immunohistochemistry results of the PPAR-γ, RXR-α, VDR, and COX-2 in the study groups.aP < 0.05 vs. healthy group PPAR-γ: peroxisome proliferative activator receptor-γ, RXR-α: retinoid X receptor-α, VDR: vitamin D receptor, COX-2: cyclooxygenase-2

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Figure 4: Immunohistochemistry images of the PPAR-γ, RXR-α, VDR, and COX-2 of the representative samples in the study groups. The first row presents PPAR-γ staining, the second row presents RXR-α staining, the third row presents VDR staining, and the fourth row presents COX-2 staining. A: healthy group, B: periodontitis group, C: peri-implantitis group Ct: connective tissue, Et: epithelial tissue PPAR-γ: peroxisome proliferative activator receptor-γ, RXR-α: retinoid X receptor-α, VDR: vitamin D receptor, COX-2: cyclooxygenase-2

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RXR-α immunohistochemistry showed a reverse pattern to the PPAR-γ expressions and was higher in the healthy individuals compared with the periodontitis and peri-implantitis patients (P < 0.05). In addition, periodontitis had similar RXR-α expressions compared with the peri-implantitis group (P > 0.05) [Figure 3] and [Figure 4], [Table 2].

Regarding VDR expressions, periodontitis and peri-implantitis groups had significantly higher levels compared with the healthy group (P < 0.05) but similar levels among each other (P > 0.05) [Figure 3] and [Figure 4], [Table 2]. The RXR-α and VDR expressions presented similar pattern in the study groups and reverse pattern compared with the PPAR-γ expressions.


   Discussion Top


Periodontitis and peri-implantitis are the chronic inflammatory destructive diseases observed in the oral cavity and are common diseases which are rather challenging to treat. Both diseases share certain ethiopathogenetic events; however, the shared underlying mechanisms were not fully enlightened. This study evaluated the three nuclear receptor proteins as PPAR-γ, RXR-α, and VDR in the healthy and diseased gingival samples to reveal any possible alterations in their expression in periodontitis and peri-implantitis. The results revealed that periodontitis and peri-implantitis lesions exhibited increased levels of PPAR-γ which play significant roles in adipose tissue metabolism and development of chronic diseases such as diabetes, atherosclerosis, and periodontitis.[6],[8],[27] RXR-α, which is also associated with PPAR activation by forming a heterodimer with PPAR-γ, presented decreased levels in periodontitis and peri-implantitis samples compared with the healthy group. VDR also forms heterodimers with RXR and activates vitamin D responsive elements.[28] Along with RXR-α, VDR levels also decreased in periodontitis and peri-implantitis patients. Furthermore, diseased connective tissue around teeth and dental implants had lower fibroblast cell and higher inflammatory cell density compared with the healthy gingival samples.

Both periodontitis and peri-implantitis are initiated by a response against dysbiotic oral microbiota; however, the disease development and progress occur differently. One of the most significant reasons is the lack of PDL which provides a significant role in immune defense.[29],[30] Furthermore, PDL is a major blood and oxygen supply in the periodontium and absence and therefore, might lead to increased risk of inflammation and a severe disease course in the peri-implant tissues.[31],[32],[33],[34],[35] The pathogenesis of periodontitis was suggested to involve the upregulation of genes related to bacterial challenge, whereas in peri-implantitis, innate immune system is more dominant with a diverse cell phenotype.[31],[32] The composition of the gingival tissues around dental implants also exhibits variations such as altered cell adhesion, disrupted wound healing, and complement activation with enhanced and prolonged proinflammatory cytokine release.[31],[33],[36] IL-1β, IL-10, TNF-α, and RANKL are among the cytokines which were reported to be upregulated in peri-implantitis lesions.[34],[37]

In addition to the differences in the pathogenesis of periodontitis and peri-implantitis, there are also several similarities. Inflammation, regardless of the location, in periodontal and peri-implant tissues, results in dense inflammatory cell infiltration in the connective tissues and the connective tissue metabolism was also disrupted with an increase in the apoptosis of fibroblast cells and a decrease in the fibroblast cell proliferation, differentiation, and migration.[29],[32],[36] Irshad et al. showed similar expression profiles in the matrix degrading enzyme matrix metalloproteinase (MMP), interleukins, and chemotactic proteins in both periodontal and peri-implant lesions compared with the healthy gingiva.[37],[38],[39] Disrupted fibroblast cell functions in production of growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor (TGF) were also similar in fibroblast isolated from periodontitis and peri-implantitis lesions.[39],[40] In contrast, Bordin et al. reported that peri-implantitis lesions caused more pronounced increase in VEGF, MMP, and TGF compared with the periodontitis patients and healthy group.[41],[42] Along with increased proinflammatory mediators such as RANKL, increased inflammatory cell infiltration was also reported in peri-implantitis compared with the periodontitis with a dominant cell profile of neutrophils, macrophage, and giant cells.[34],[37],[43] However, in this study, the gingival samples obtained from periodontitis and peri-implantitis patients had a similar cell profile mainly consisting of neutrophils as the dominant cell type. Healthy gingival samples, on the other hand, exhibited significantly lower inflammatory cells and a higher density of fibroblast cells in the connective tissue. The periodontitis and peri-implantitis samples had similarly lower fibroblast cell density compared with the healthy group.

Autophagy was also suggested to participate in inflammation and take part in the decreased cell density in gingival tissues.[44],[45] Recently, Wang et al. demonstrated that PPAR-γ and VDR were associated with increased autophagy and development of rheumatoid arthritis.[11] In addition to autophagy, PPAR-γ has distinct roles in the body; one of the significant roles is the prevention of inflammation as reported by Wang et al. by activating AMPK signaling.[46] PPAR-γ was also demonstrated to stimulate apoptosis of leucocytes and fasten the inflammatory reactions.[15] On the other hand, reduction in chemotaxis with reduced neutrophil adhesion and migration was also reported after PPAR-γ activation.[16] PPAR-γ also has a close association with NF-κB pathway and RANKL-induced osteoclastic activity and therefore, might be related to ethiopathogenesis of periodontitis and peri-implantitis.[7],[8] In contrast, Takeshita et al. reported that early adipogenic factors bind to RANKL promoters and induce osteoclastic activity which occurs before late adipogenic factor, PPAR-γ.[47] Furthermore, PPAR agonist was shown to induce autophagy and inhibit IL-6, IL-8, inducible nitric oxide synthase, and COX-2.[46] PPAR agonist was also reported to reduce Porphyromonas gingivalis biofilm formation and NF-κB activation.[48] A significant role of PPAR-γ in inflammation also occurs through macrophage cells.[12] One of the most significant sources of PPAR-γ is the macrophage cells, and the maturation of macrophage cells and M2 cell phenotype was induced by PPAR-γ.[12] In infectious diseases, PPAR-γ exerts a protective role through inhibition of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α.[13],[14]

PPAR and VDR are the members of nuclear receptors and act as transcription factors to regulate significant cellular processes such as differentiation, cell death, and survival.[49] Both PPAR and VDR bind to DNA as a heterodimer with RXR.[49] This study evaluated the expressions of nuclear receptors PPAR-γ, RXR-α, and VDR and proinflammatory mediator COX-2 in healthy and diseased gingival samples. The results revealed that PPAR-γ expressions significantly increased in the diseased samples compared with the healthy gingiva. On the other hand, RXR and VDR expressions decreased in the presence of the disease, while PPAR increased. As for COX-2, it exhibited a similar pattern to PPAR-γ and was found to be higher in the periodontitis and peri-implantitis samples compared with the healthy group. All parameters were similar in the periodontitis and peri-implantitis groups indicating a possible similarity in the pathogenesis of the two diseases.


   Conclusion Top


Periodontitis and peri-implantitis were found to have similar expression levels of PPAR-γ, RXR-α, VDR, and COX-2. The connective tissue compositions were also similar, while it is quite different from the healthy group. In conclusion, the evaluated parameters in this study revealed that within the limitations of this study, periodontitis and peri-implantitis shared similar pathogenic properties. Further studies involving different parameters and analysis are necessary to reveal the underlying mechanisms of peri-implantitis pathogenesis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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