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Tumor resistance remains an obstacle to successfully treating oral squamous cell carcinoma (OSCC). Cisplatin is widely used as a cytotoxic drug to treat solid tumors, including advanced OSCC, but with low efficacy due to chemoresistance. Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor-alpha (TNF-alpha)/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF-alpha/NFkB signaling pathway, and RNA-Seq confirmed the upregulation of TNF-alpha/NFkB signaling in cisplatin-resistant cell lines. NFkB was accumulated in cisplatin-resistant cell lines and in cancer stem cells (CSC), and the administration of TNF-alpha increased the CSC, suggesting that TNF-alpha/NFkB signaling is involved in the accumulation of CSC. TNF-alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin-resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin-resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin-resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF-alpha/NFkB/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin-resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Emetina/metabolismo , Emetina/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Histonas/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Células-Tronco Neoplásicas/patologia , Sirtuína 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
Oral potentially malignant disorders (OPMD) are clinical presentations that carry an increased risk of cancer development. Currently, epithelial dysplasia grade is based on architectural and cytological epithelial changes and is used to predict the malignant transformation of these lesions. However, predicting which OPMD will progress to a malignant tumor is very challenging. Inflammatory infiltrates can favor cancer development, and recent studies suggest that this association with OPMD lesions may be related to the etiology and/or aggressive clinical behavior of these lesions. Epigenetic changes such as histone modifications may mediate chronic inflammation and also favor tumor cells in immune resistance and evasion. This study aimed to evaluate the relationship between histone acetylation (H3K9ac) and DNA damage in the context of dysplastic lesions with prominent chronic inflammation. Immunofluorescence of "low-risk" and "high-risk" OPMD lesions (n = 24) and inflammatory fibrous hyperplasia (n = 10) as the control group was performed to assess histone acetylation levels and DNA damage through the phosphorylation of H2AX (γH2AX). Cell co-culture assays with PBMCs and oral keratinocyte cell lines (NOK-SI, DOK, and SCC-25) were performed to assess proliferation, adhesion, migration, and epithelial-mesenchymal transition (EMT). Oral dysplastic lesions showed a hypoacetylation of H3K9 and low levels of γH2AX compared to control. The contact of dysplastic oral keratinocytes with PBMCs favored EMT and the loss of cell-cell adhesion. On the other hand, p27 levels increased and cyclin E decreased in DOK, indicating cell cycle arrest. We conclude that the presence of chronic inflammation associated to dysplastic lesions is capable of promoting epigenetic alterations, which in turn can favor the process of malignant transformation.
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Cinnamaldehyde is a natural product with anti-inflammatory and immune-modulatory properties, known to regulate host responses to bacterial stimuli. This study aimed to investigate the effects of cinnamaldehyde on ligature-induced periodontitis in rats, and its impact on the modulation of human peripheral blood mononuclear cells (PBMC). Male Wistar rats were assigned into three groups:i) control: no ligature + vehicle; ii) ligature: ligature + vehicle; and iii) ligature + cinnamaldehyde (50 mg/kg); all treatments by daily oral gavage. After 14 days of induced periodontitis, the hemimandibles were collected for bone loss evaluation. The gingival levels of IL-1ß, MMP-9 and iNOS mRNA were evaluated. Nitric oxide (NO) was measured in both rat saliva and plasma. PBMC were stimulated with Aggregatibacter actinomycetemcomitans (Aa) in the presence or absence of cinnamaldehyde (5, 20 e 40 µM), and cytokine production was quantified in cell supernatant. Proliferating lymphocytes were taken for flow cytometer reading, while culture supernatants were used for IFN-γ and IL-10 assessment. The ligature group had both increased alveolar bone loss and gingival expression of IL-1ß, MMP-9 and iNOS compared to the control group. All parameters were attenuated by cinnamaldehyde treatment. Lower salivary but not plasma NO was detected in the cinnamaldehyde compared to the ligature group. Aa-stimulated PBMCs treated with cinnamaldehyde produced less IL-1ß; the compound also attenuated lymphocyte proliferation in a dose-dependent manner, as well as cell IL-10 production. Cinnamaldehyde treatment reduced periodontal bone loss, and downregulated key inflammatory mediators and human PBMC responses, pointing to novel potential therapeutic effects of this compound.
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Perda do Osso Alveolar , Periodontite , Humanos , Ratos , Masculino , Animais , Ratos Wistar , Leucócitos Mononucleares/metabolismo , Interleucina-10/uso terapêutico , Metaloproteinase 9 da Matriz , Periodontite/metabolismo , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/metabolismo , Modelos Animais de DoençasRESUMO
Chemoresistance is associated with tumor recurrence, metastases, and short survival. Cisplatin is one of the most used chemotherapies in cancer treatment, including head and neck squamous cell carcinoma (HNSCC), and many patients develop resistance. Here, we established cell lines resistant to cisplatin to better understand epigenetics and biological differences driving the progression of HNSCC after treatment. Cisplatin resistance was established in CAL-27 and SCC-9 cell lines. Gene expression of HDAC1, HDAC2, SIRT1, MTA1, KAT2B, KAT6A, KAT6B, and BRD4 indicated the cisplatin activates the epigenetic machinery. Increases in tumor aggressiveness were detected by BMI-1 and KI-67 in more resistant cell lines. Changes in cellular shape and epithelial-mesenchymal transition (EMT) activation were also observed. HDAC1 and ZEB1 presented an opposite distribution with down-regulation of HDAC1 and up-regulation of ZEB1 in the course of chemoresistance. Up-regulation of ZEB1 and BMI-1 in patients with HNSCC is also associated with a poor response to therapy. Cancer stem cells (CSC) population increased significantly with chemoresistance. Down-regulation of HDAC1, HDAC2, and SIRT1 and accumulation of Vimentin and ZEB1 were observed in the CSC population. Our results suggest that in the route to cisplatin chemoresistance, epigenetic modifications can be associated with EMT activation and CSC accumulation which originate more aggressive tumors.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Cisplatino/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 1/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal/genética , Proteínas Nucleares/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases/metabolismoRESUMO
Oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL) are oral potentially malignant disorders (OPMDs) that microscopically show no or varying degrees of dysplasia. Even sharing clinical and microscopic aspects, PVL shows a more aggressive clinical behaviour, with a malignant transformation rate greater than 40%. Inflammatory infiltrate associated with dysplastic lesions may favour malignant transformation of OPMDs. This study aimed to evaluate the density of T cells and cytokines in dysplastic lesions from OL and PVL patients. Additionally, we evaluated whether soluble products produced in vitro by dysplastic keratinocytes are capable of modulating apoptosis rates and Th phenotype (Th1, Th2, Th17 and Treg) of peripheral blood mononuclear cells. The density of CD3, CD4 and CD8 T cells was assessed by immunohistochemistry. Cytokines and chemokines profile from frozen tissue samples were analysed using the LUMINEX system. Apoptosis rates and Th phenotype modulation were evaluated by flow cytometry. Our results showed an increase in the number of CD8 T cell in the subepithelial region from PVL dysplastic lesions in relation to OL samples. PVL showed increased levels of IL-5 and a decrease in IL-1ß and IFN-γ levels compared to OL. Soluble products of PVL and oral carcinoma cell cultures were able to reduce apoptosis rate and promote an imbalance of Th1/Th2 and Th17/Treg. The high-subepithelial density of CD8 T cells and immune imbalance of T lymphocytes subsets probably play an important role in the pathogenesis of PVL and may explain its more aggressive behaviour in relation to OL.
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Neoplasias Bucais , Lesões Pré-Cancerosas , Humanos , Leucócitos Mononucleares/patologia , Leucoplasia Oral/patologia , Neoplasias Bucais/patologia , Lesões Pré-Cancerosas/patologia , Linfócitos T CD8-Positivos/patologia , Citocinas , Transformação Celular NeoplásicaRESUMO
Background: Despite the gain in life expectancy that people living with HIV (PLHIV) have had in the past few years, the disease is accompanied by an increase in the prevalence of noninfectious chronic diseases. PLHIV have a higher prevalence of osteoporosis, fracture, diabetes mellitus, and insulin resistance than the general population. It is unknown if insulin resistance is associated with osteoporosis and fractures in PLHIV. Our study aimed to assess the association between insulin resistance and osteoporosis in PLHIV. Methods: A cross-sectional study was carried out in southern Brazil. PLHIV ages 50â years or older on antiretroviral treatment were included. Insulin resistance was considered present when the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was higher than expected for the Brazilian population (>2.7). The triglyceride-glucose (TyG) index was also calculated. Results: Of the 101 PLHIV who agreed to participate, 84 underwent insulin and bone mineral density measurements. The prevalence of osteoporosis was 19%. The frequency of insulin resistance calculated by HOMA-IR was 68.2%. Participants with osteoporosis had lower body mass index (BMI) and triglyceride values than those without it. HOMA-IR [4.8(6.6) vs 8.68(9.6), P = 0.013] and TyG [5.0(0.3) vs 5.2 (0.4), P = 0.029]. The association between the total femur t-score disappeared after correction for BMI in the linear regression model. There was no association between vertebral fractures and insulin resistance. Conclusion: In our study, PLHIV with osteoporosis have lower insulin resistance than PLHIV without it. However, this finding appears to be related to lower BMI. The association between insulin resistance and bone in PLHIV appears to be somewhat similar to that of the general population.
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BACKGROUND: Chemoresistance is associated with recurrence and metastasis in oral squamous cell carcinoma (OSCC). The cancer stem cell (CSC) subpopulation is highly resistant to therapy, and they are regulated by epigenetic mechanisms. HDACs are histone deacetylase enzymes that epigenetically regulate gene expression. HDAC6 acts on several physiological processes, including oxidative stress, autophagy and DNA damage response, and its accumulation is associated with cancer. Here, we investigate the role of HDAC6 in CSC-mediated chemoresistance in oral carcinoma in addition to its application as a therapeutic target to reverse chemoresistance. METHODS: Wild-type oral carcinoma cell lines (CAL27 WT and SCC9 WT), cisplatin-resistant (CAL27 CisR and SCC9 CisR), and the subpopulations of cancer stem cells (CSC+) and non-stem (CSC-) derived from CisR cells were investigated. HDAC6 accumulation was analyzed by Western blot and immunofluorescence; DNA damage was evaluated by immunofluorescence of phospho-H2A.X; the qPCR for PRDX2, PRDX6, SOD2, and TXN and ROS assay assessed oxidative stress. Apoptosis and CSC accumulation were investigated by flow cytometry. RESULTS: We identified the accumulation of HDAC6 in CisR cell lines and CSC. Cisplatin-resistant cell lines and CSC demonstrated a reduction in DNA damage and ROS and elevated expression of PRDX2. The administration of tubastatin A (a specific HDAC6 inhibitor) increased oxidative stress and DNA damage and decreased PRDX2. Tubastatin A as a monotherapy induced apoptosis in CisR and CSC and reduced the stemness phenotype. CONCLUSION: High levels of HDAC6 sustain CSC subpopulation and chemoresistance in OSCC, suggesting HDAC6 as a pharmacological target to overcome resistance and perhaps prevent recurrence in OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/patologia , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Histona Desacetilases/metabolismo , Humanos , Neoplasias Bucais/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
To perform a systematic review focusing on the prognosis of oral cavity squamous cell carcinoma (OSCC) in young patients (≤40 years old) compared to older (>40 years old). Four databases were used in our search strategy. First, all titles were systematically organized using the Covidence platform online. In the second phase, 118 full texts of potentially eligible studies were analyzed by reviewers independently and in pairs. Twelve studies were considered eligible for data extraction. The relapse was higher in the young than in controls (pooled relative risk (RR) = 1.31; 95% CI [1.10-1.56]). The 5-year disease-free survival (DFS) was worse in young group (pooled hazard ratio (HR) = 0.73; 95% CI [0.63-0.85]) but the 5-year overall survival (OS) estimate was similar between the groups (pooled HR = 0.84; 95% CI [0.70-1.00]). While the 5-year OS was similar between groups, the number of relapses and 5-year DFS were worse in patients with OSCC ≤40 years old.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Adolescente , Adulto , Carcinoma de Células Escamosas/terapia , Humanos , Neoplasias Bucais/terapia , Recidiva Local de Neoplasia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Adulto JovemRESUMO
BACKGROUND/AIM: Antimony is a chemical element used in the therapy of parasitic diseases with a promising anticancer potential. The aim of this study was to evaluate in vitro activity of free or liposomal vesicle-packed antimony trioxide (AT or LAT) in the t(15;17)(q22;q21) translocation-positive acute promyelocytic leukemia (APL) cell line NB4. MATERIALS AND METHODS: Cytotoxicity was analysed with trypan blue exclusion, the MTT assay and neutral red exclusion assay; cell proliferation with PicoGreen®; and reactive oxygen species (ROS) production with DCFDA. RESULTS: Liposomal particles did not change the pH of the cell culture medium and entered the cells. Both formulations resulted in a time- and concentration-dependent cytotoxicity and production of ROS. LAT showed higher toxicity at lower concentrations compared to AT. CONCLUSION: LAT may be used to decrease drug dosage and maintain high anti-tumoral effects on APL cells.
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Antimônio/administração & dosagem , Antimônio/farmacologia , Lipossomos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos , Humanos , Leucemia Promielocítica Aguda , Sistemas de Liberação de Fármacos por Nanopartículas , Espécies Reativas de Oxigênio/metabolismoRESUMO
In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.
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PURPOSE: To report a case of central retinal artery (CRA) occlusion secondary to prepapillary loop in a 13-year-old girl. METHODS: A 13-year-old girl presented with a history of sudden visual loss in her left eye. RESULTS: Fundus examination confirmed thrombosis in a prepapillary arterial loop causing CRA occlusion and extensive retinal ischemia. Macular region was watered by an anomalous macular branch, which explained her 20/20 vision central vision. CONCLUSION: Congenital prepapillary vascular loops are rare and usually asymptomatic. We report a case of central artery occlusion confirmed by multimodal imaging.
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Squamous odontogenic tumor (SOT) is a rare benign neoplasm of the jaw that likely arises from remnants of the dental lamina. It is a slow-growing lesion, with a radiolucent appearance in the central variant. Microscopically, SOT shows islands of squamous epithelium supported by fibrous stroma. In rare cases, squamous odontogenic tumor-like proliferation (SOT-LP) can be observed arising from odontogenic cysts (SOT-LPOC). Herein, we describe the case of a 42-year-old man who presented with discreet bleeding in the maxillary gingiva. Imaging revealed a well-defined, ovoid-shaped lesion with sclerotic margins involving tooth #18 in the intraosseous location. Fine needle aspiration supported the cystic nature of the lesion. After surgery, microscopy revealed a dentigerous cyst showing SOT-LP features. There was no recurrence after a 3-year follow-up. To the best of our knowledge, this is the first report of a dentigerous cyst showing SOT-LP features in the maxilla. Such cysts should be identified to avoid misdiagnosis, with the finding having therapeutic and prognostic implications.
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OBJECTIVE: the aim of this study was to evaluate the density of Langerhans cells in oral lichen planus (OLP) and oral lichenoid lesions (OLL). DESIGN: 14 cases of OLP, 15 cases of OLL and 14 cases of oral inflammatory fibrous hyperplasia (OIFH), were selected for immunohistochemical analysis of CD1a, CD207 and S100 expression. The OIFH group was subdivided according to the presence (OIFHL nâ¯=â¯14) or absence (OIFHNL nâ¯=â¯14) of lichenoid inflammatory infiltrate. Positive cells were counted in intraepithelial and subepithelial areas. Results were analyzed by multivariate comparative analysis, correlation analysis, linear regression models and Student's T-test. RESULTS: A significantly higher amount of CD207+ cells in OLL vs OLP was observed (pâ¯=â¯0.015). The prevailing reticular pattern observed was CD207high for OLP (pâ¯=â¯0.0329). A statistically significant difference in the expression of CD1a and CD207 was observed for intraepithelial vs subepithelial areas (pâ¯=â¯0.024 and p=0.015, for CD1a and CD207, respectively). Significant correlations were also observed between the expression of CD1aâ¯+â¯and CD207+ cells in the pathogenesis of OLP and OLL. CONCLUSION: High levels of CD207+cells in OLP compared with OLL may help explain the differences in the immunopathogenesis of both diseases. Additionally, CD1aâ¯+â¯and CD207+ cells appear to be more essential to immunopathogenesis of OLL than to the pathogenesis of OLP.
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Líquen Plano Bucal , Erupções Liquenoides , Humanos , Células de LangerhansRESUMO
Objective: To assess salivary biomarkers for dental caries susceptibility and mental stress in young adults with perceived facial pain.Methods: Males and females who reported facial pain and pain-free controls participated in this study. Facial pain was investigated using the RDC/TMD. Unstimulated saliva was then collected for the evaluation of salivary flow rate (SFR), pH, Streptococcus mutans counts, morning cortisol, and S-IgA.Results: Women with facial pain had significantly lower SFR values, and the facial pain group showed different correlations among biomarkers for caries susceptibility and cortisol levels when compared to controls. Notably, higher SFR values were associated with a lower likelihood of having facial pain.Conclusion: Differences in SFR values, particularly in women, and markedly distinct interactions among the salivary biomarkers analyzed were observed between individuals with facial pain and pain-free controls. Hence, a connection between the dynamics of saliva, stress response, and facial pain perception might exist.
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Suscetibilidade à Cárie Dentária , Cárie Dentária , Biomarcadores , Dor Facial/etiologia , Feminino , Humanos , Masculino , Saliva , Adulto JovemRESUMO
BACKGROUND: Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported. METHODS: In this study, we followed an APL cohort (n = 17) over 7 days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method. RESULTS: In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL- 1 in D0 vs. 10.9; 0 to 26.81 pg mL- 1 in D7; p = 0.02) whereas their levels did not discriminate between DS and non-DS development during the entire induction period (all p > 0.05 in D0, D3, and D7). No significant differences were found in IL-6 levels between groups (p > 0.05 in D0-D7). Other cytokines tested were all undetectable in patients with APL or healthy controls. CONCLUSIONS: We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.
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Antineoplásicos/efeitos adversos , Diferenciação Celular/efeitos dos fármacos , Interleucina-8/sangue , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/efeitos adversos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/sangue , Feminino , Humanos , Interleucina-6/sangue , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
The prevalence of chronic diseases is increasing in people living with HIV (PLHIV) in the post ART era. Sarcopenia is prevalent in the elderly and is associated with many chronic diseases. Our study aimed to evaluate the frequency of sarcopenia in PLHIV and its association with bone mineral density and fracture. A cross-sectional study was carried out at Santa Maria, South Brazil. It included PLHV age ≥ 50 years and registered to receive antiretroviral therapy. A structured questionnaire was applied, blood samples collected, muscle strength evaluated, body composition measured, and vertebral morphometry performed. Sarcopenia and presarcopenia were defined according to the European Working Group on Sarcopenia in Older People. Of the 101 patients recruited, 83 underwent DXA and muscle strength measurements. The prevalence of sarcopenia and presarcopenia in the individuals studied was 12% and 16.9%, respectively. 66.7% of sarcopenic individuals had morphometric vertebral fractures and there was a tendency towards a higher frequency of multiple vertebral fractures when compared with non-sarcopenic subjects (44.4% vs. 16.2%, p = 0.066). BMI and total hip BMD were significantly lower in sarcopenic than non-sarcopenic individuals (p ≥ 0.035 and 0.032 respectively). In multiple regression analysis, sarcopenia was associated with age and multiple vertebral fractures. Sarcopenia was present in 12% of this population of PLHIV age ≥ 50 years and was associated with lower hip BMD and a high prevalence of vertebral fractures.
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Infecções por HIV/complicações , Sarcopenia , Fraturas da Coluna Vertebral , Idoso , Composição Corporal , Densidade Óssea , Brasil , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Prevalência , Sarcopenia/complicações , Fraturas da Coluna Vertebral/complicaçõesRESUMO
Aim: Histone acetylation and methylation control gene expression. We investigated the impact of SET knockdown on histone methylation status and the consequences for the miRNAs levels in oral squamous cell carcinoma (OSCC). Methods: OSCC cells with and without SET knockdown were analyzed by quantitative real-time PCR to determine miRNA levels, and by immunoreactions to histone modifications. Results: The knockdown of SET increased the levels of histone H4K20me2 and miR-137. Still, SET protein binds to the miR-137 promoter region. The transfection of miR-137 mimic reduced the KI67 and Rb proteins and proliferation of OSCC cells. Conclusion: Our results show for the first time a relationship between SET and histone methylation associated with the control of miRNA expression and KI67 and Rb as targets of miR-137 in OSCC.
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Proteínas de Ligação a DNA/fisiologia , Chaperonas de Histonas/fisiologia , Histonas/metabolismo , MicroRNAs/genética , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Chaperonas de Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Antígeno Ki-67/metabolismo , Metilação , MicroRNAs/metabolismo , Neoplasias Bucais/patologia , Proteína do Retinoblastoma/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
BACKGROUND: Desipramine is a tricyclic antidepressant with immune-modulatory activity, whose effects on ligature-induced periodontitis are yet to be investigated. Hence, its actions on alveolar bone resorption, gingival collagen content and key inflammatory mediators were herewith analyzed. METHODS: A total of 60 male Wistar rats were randomly assigned into three groups: 1) control: rats without ligature treated with vehicle (saline); 2) ligature: rats with ligature-induced periodontitis treated with vehicle; 3) ligature + desipramine: rats with ligature-induced periodontitis treated with desipramine (20 mg/kg/d in vehicle). Mandibles and gingival tissues were collected 3 or 15 days after ligature insertion (or no ligature insertion for controls) and treatments. Alveolar bone resorption and gingival collagen fibers were histologically analyzed using either HE or picrosirius red staining. Gingival mRNA expressions of interleukin (IL)-1ß, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 were obtained through reverse transcription polymerase chain reaction. MMP-9 activity was analyzed by zymography. RESULTS: Alveolar bone loss was significantly reduced in the ligature + desipramine group (P < 0.05), whereas gingival collagen degradation was like the ligature group (P > 0.05). Desipramine administration downregulated mRNA expressions of IL-1ß, iNOS, COX-2, and TIMP-1 when compared to vehicle alone in the ligature group (P < 0.05). MMP-9 expression and MMP-9/TIMP-1 ratio were similar among rats with ligature-induced periodontitis (P > 0.05); however, MMP-9 activity was lower in the group treated with desipramine (P < 0.05). CONCLUSION: Desipramine administration reduced alveolar bone loss as histologically observed, and modulated key bone remodeling and inflammatory mediators in rats with ligature-induced periodontitis.
Assuntos
Perda do Osso Alveolar , Periodontite , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/prevenção & controle , Animais , Desipramina/farmacologia , Desipramina/uso terapêutico , Modelos Animais de Doenças , Gengiva , Masculino , Periodontite/tratamento farmacológico , Ratos , Ratos WistarRESUMO
This study aimed to histologically and radiographically evaluate the effectiveness of low-intensity laser irradiation of different wavelengths (660 or 808 nm) as an adjunct to scaling and root planing in the treatment of experimental periodontitis in rats. Periodontitis was induced by placing a ligature around the mandibular first molar of the rats. In total, 40 Wistar rats were randomly divided into five groups (n = 8 each): control (CG), periodontal disease (PD), scaling and root planing (SRP), SRP + 660 nm laser (GL660) and SRP + 808 nm laser (GL808). Groups with laser use received radiation at 6 points in the first molar. The animals were euthanized at baseline and at 7 and 14 days after the interventions. Mandibles were surgically removed for histomorphometric and radiographic assessment of periodontal tissues. The GL660 group showed lesser bone loss than the PD group (P < 0.05) and greater alveolar bone margin after 14 days, indicating a better long-term treatment response (P < 0.05). These findings suggest that SRP with the 660 nm laser as an adjunct results in more favorable radiographic and histological responses than the 808 nm laser.