ABSTRACT
MicroRNA-494 (miR-494) is a small non-coding RNA located in chromosome 14q32.31 and regulates post-transcriptional gene expression by promoting the degradation of its target mRNAs via binding to the 3' untranslated regions (3'UTR). It has been reported that miR-494 plays an important role in the occurrence, development and prognosis of various diseases. Several signaling pathways modulated by miR-494 including the PTEN/PI3K/AKT, nuclear factor κ-B (NF-κB), mitogen-activated protein kinase (MAPK), transforming growth factor-β (TGF-β)/SMAD, and Wnt/β-catenin are associated with physiological regulation and pathological process in many diseases. The stably expression of miR-494 in the blood stream suggests its potential as a biological marker for disease diagnosis, treatment, and prognosis. Based on recent research, we summarize the role and molecular mechanism of miR-494 in disease development and progression. We also discuss its potential as a marker for clinical diagnosis and prognosis of various diseases.
Subject(s)
MicroRNAs/metabolism , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolismABSTRACT
OBJECTIVE@#To explore the mechanism by which estradiol modulates the immunophenotype of macrophages through the endoplasmic reticulum stress pathway.@*METHODS@#Peritoneal macrophages isolated from C57 mice were cultured in the presence of 60 ng/mL interferon-γ (IFN-γ) followed by treatment with estradiol (1.0 nmol/L) alone, estradiol with estrogen receptor antagonist (Acolbifene, 4 nmol/L), estradiol with IRE1α inhibitor (4 μ 8 C), or estradiol with IRE1α agonist. After the treatments, the expression levels of MHC-Ⅱ, iNOS and endoplasmic reticulum stress marker proteins IRE1α, eIF2α and ATF6 in the macrophages were detected with Western blotting, and the mRNA levels of TGF-β, IL-6, IL-10 and TNF-α were detected with RT-PCR.@*RESULTS@#Estrogen treatment of the macrophages significantly decreased the expressions of M1-related proteins MHC-Ⅱ (P=0.021) and iNOS (P < 0.001) and the mRNA expressions of TNF-α (P=0.003) and IL-6 (P=0.004), increased the mRNA expression of TGF-β (P=0.002) and IL-10 (P=0.008), and up-regulated the protein expressions of IRE1α (P < 0.001) and its downstream transcription factor XBP-1 (P < 0.001). Addition of the estrogen inhibitor obviously blocked the effect of estrogen. Compared with estrogen treatment alone, combined treatment of the macrophages with estrogen and the IRE1α inhibitor 4 μ 8 C significantly up-regulated the protein expressions of MHC-Ⅱ (P=0.002) and iNOS (P=0.003) and the mRNA expressions of TNF-α (P=0.003) and IL-6 (P=0.024), and obviously down-regulated the mRNA expression of TGF-β (P < 0.001) and IL-10 (P < 0.001); these changes were not observed in cells treated with estrogen and the IRE1α agonist.@*CONCLUSION@#Estrogen can inhibit the differentiation of murine macrophages into a pro-inflammatory phenotype by up-regulating the IRE1α-XBP-1 signaling axis, thereby producing an inhibitory effect on inflammatory response.
Subject(s)
Animals , Cell Differentiation/drug effects , Endoribonucleases/metabolism , Estradiol/pharmacology , Estrogens/metabolism , Interleukin-10 , Interleukin-6/metabolism , Macrophages, Peritoneal/metabolism , Mice , Phenotype , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/metabolism , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation/drug effects , X-Box Binding Protein 1/metabolismABSTRACT
OBJECTIVE@#To explore the role of vasohibin-2 (VASH2) in regulation of proliferation and metastasis of cervical cancer cells.@*METHODS@#We analyzed the differentially expressed genes between cervical cancer cells with flotillin-1 overexpression and knockdown by RNA-seq combined with analysis of public databases. The expression levels of VASH2 were examined in normal cervical epithelial cells (HcerEpic), cervical cancer cell lines (HeLa, C-33A, Ca ski, SiHa and MS751) and fresh cervical cancer tissues with different lymph node metastasis status. We further tested the effects of lentivirus-mediated overexpression and interference of VASH2 on proliferation, migration, invasion and lymphatic vessel formation of the cervical cancer cells and detected the expression levels of key epithelial-mesenchymal transition (EMT) markers and TGF-β mRNA.@*RESULTS@#RNA-seq and analysis of public databases showed that VASH2 expression was significantly upregulated in cervical cancer cells exogenously overexpressing flotillin-1 (P < 0.05) and downregulated in cells with flotillin-1 knockdown (P < 0.05), and was significantly higher in cervical cancer tissues with lymph node metastasis than in those without lymph node metastasis (P < 0.01). In cervical cancer cell lines Ca Ski, SiHa, and MS751 and cervical cancer tissue specimens with lymph node metastasis, VASH2 expression was also significantly upregulated as compared with HcerEpic cells and cervical cancer tissues without lymph node metastasis (P < 0.05). Exogenous overexpression of VASH2 significantly promoted proliferation, migration, invasion and lymphatic vessel formation of cervical cancer cells, whereas these abilities were significantly inhibited in cells with VASH2 knockdown (P < 0.05). The cervical cancer cells overexpressing VASH2 showed significant down- regulation of e-cadherin and up- regulation of N-cadherin, Vimentin and VEGF-C, while the reverse changes were detected in cells with VASH2 knockdown (P < 0.05). TGF-β mRNA expression was significantly up-regulated in cervical cancer cells overexpressing VASH2 and down-regulated in cells with VASH2 knockdown (P < 0.001).@*CONCLUSION@#Flotillin-1 may participate in TGF-β signaling pathway-mediated EMT through its down-stream target gene VASH2 to promote the proliferation, migration, invasion and lymphatic vessel formation of cervical cancer cells in vitro.
Subject(s)
Angiogenic Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Lymphatic Metastasis , RNA, Messenger , Transforming Growth Factor beta/metabolism , Uterine Cervical Neoplasms/pathologyABSTRACT
Renal fibrosis is one of the most significant pathological changes after ureteral obstruction. Transforming growth factor-β (TGF-β) signaling pathway plays essential roles in kidney fibrosis regulation. The aims of the present study were to investigate effects of microRNA-302b (miR-302b) on renal fibrosis, and interaction between miR-302b and TGF-β signaling pathway in murine unilateral ureteral obstruction (UUO) model. Microarray dataset GSE42716 was downloaded by retrieving Gene Expression Omnibus database. In accordance with bioinformatics analysis results, miR-302b was significantly down-regulated in UUO mouse kidney tissue and TGF-β1-treated HK-2 cells. Masson's trichrome staining showed that miR-302b mimics decreased renal fibrosis induced by UUO. The increased mRNA expression of collagen I and α-smooth muscle actin (α-SMA) and decreased expression of E-cadherin were reversed by miR-302b mimics. In addition, miR-302b up-regulation also inhibited TGF-β1-induced epithelial mesenchymal transition (EMT) of HK-2 cells by restoring E-cadherin expression and decreasing α-SMA expression. miR-302b mimics suppressed both luciferase activity and protein expression of TGF-βR2. However, miR-302b inhibitor increased TGF-βR2 luciferase activity and protein expression. Meanwhile, miR-302b mimics inhibited TGF-βR2 mRNA expression and decreased Smad2 and Smad3 phosphorylation in vivo and in vitro. Furthermore, over-expression of TGF-βR2 restored the miR-302b-induced decrease of collagen I and α-SMA expression. In conclusion, this study demonstrated that miR-302b attenuated renal fibrosis by targeting TGF-βR2 to suppress TGF-β/Smad signaling activation. Our findings showed that elevating renal miR-302b levels may be a novel therapeutic strategy for preventing renal fibrosis.
Subject(s)
Humans , Animals , Rats , Ureteral Obstruction/pathology , Signal Transduction , Transforming Growth Factor beta/metabolism , MicroRNAs/genetics , Smad Proteins , Kidney Diseases/genetics , Fibrosis , Cell Line , Epithelial-Mesenchymal Transition , Kidney/pathology , Kidney Diseases/pathologyABSTRACT
The purpose of this study was to investigate the anti-cancer effect of melittin on growth, migration, invasion, and apoptosis of non-small-cell lung cancer (NSCLC) cells. This study also explored the potential anti-cancer mechanism of melittin in NSCLC cells. The results demonstrated that melittin suppressed growth, migration, and invasion, and induced apoptosis of NSCLC cells in vitro. Melittin increased pro-apoptotic caspase-3 and Apaf-1 gene expression. Melittin inhibited tumor growth factor (TGF)-β expression and phosphorylated ERK/total ERK (pERK/tERK) in NSCLC cells. However, TGF-β overexpression (pTGF-β) abolished melittin-decreased TGF-β expression and pERK/tERK in NSCLC cells. Treatment with melittin suppressed tumor growth and prolonged mouse survival during the 120-day observation in vivo. Treatment with melittin increased TUNEL-positive cells and decreased expression levels of TGF-β and ERK in tumor tissue compared to the control group. In conclusion, the findings of this study indicated that melittin inhibited growth, migration, and invasion, and induced apoptosis of NSCLC cells through down-regulation of TGF-β-mediated ERK signaling pathway, suggesting melittin may be a promising anti-cancer agent for NSCLC therapy.
Subject(s)
Animals , Rabbits , Apoptosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , MAP Kinase Signaling System , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Melitten/pharmacology , Down-Regulation , Gene Expression Regulation, Neoplastic , Cell Movement , Transforming Growth Factor beta/metabolism , Cell Line, Tumor , Caspase 3 , Apoptotic Protease-Activating Factor 1 , Neoplasm InvasivenessABSTRACT
ABSTRACT Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogene-modulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network - thus establishing a new layer of regulation. In this context, TGFβ signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition, cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFβ. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.
Subject(s)
Humans , Thyroid Gland/pathology , Thyroid Neoplasms/pathology , Transforming Growth Factor beta/metabolism , MicroRNAs/metabolism , Thyroid Neoplasms/metabolism , Signal Transduction , Cell Transformation, Neoplastic , Disease Progression , Neoplasm Invasiveness , Neoplasm MetastasisABSTRACT
Myelofibrosis (MF) is characterized by increased circulating hematopoietic progenitor cells (HPCs), abnormal cytokine levels, and the survival advantage of neoplastic progenitors over their normal counterparts, which leads to progressive disappearance of polyclonal hematopoiesis. CD47 is a surface glycoprotein with many functions, such as acting as a phagocytosis inhibitor of the expressing cell, that is increased in normal hematopoietic stem and progenitor cells mobilized into the blood and several human cancer-initiating cells, such as in acute myeloid leukemia. We compared CD47 expression in hematopoietic stem and progenitor cells of patients with MF and controls and found it to be decreased in progenitors of MF. Exposure of control HPCs to the cytokines transforming growth factor β and stromal-derived factor 1, which are important regulators of hematopoietic stem cell cycling and are overexpressed in patients with MF, did not modulate CD47 expression.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Hematopoietic Stem Cells/metabolism , CD47 Antigen/metabolism , Primary Myelofibrosis/metabolism , Case-Control Studies , Transforming Growth Factor beta/metabolism , Chemokine CXCL12/metabolism , Primary Myelofibrosis/geneticsABSTRACT
Pregnancy-induced hypertension (PIH) causes significant maternal and fetal morbidity and mortality. A decreased number of regulatory T (Treg) cells is associated with the pathogenesis of PIH. The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is critical to normal pregnancy (NP) by promoting Treg cell development. However, the relationship between PD-1/PD-L1 and Treg differentiation in PIH has not been fully elucidated. In this study, venous blood was obtained from 20 NP and 58 PIH patients. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood. The levels of Treg-related cytokines (TGF-β, IL-10, and IL-35) in serum and PBMCs were measured by ELISA. The percentage of Treg cells in PBMCs was assessed by flow cytometry. The mRNA levels of Treg-specific transcription factor Foxp3 in PBMCs, and PD-1 and PD-L1 in Treg cells were detected by qRT-PCR. The protein levels of PD-1 and PD-L1 in Treg cells were evaluated by western blot. The serum levels of TGF-β, IL-10, IL-35, and Foxp3 mRNA expression and CD4+CD25+ Treg cell percentage in PBMCs were decreased in PIH. Furthermore, a significant increase of PD-1 in Treg cells was found in PIH compared with NP. In addition, PD-L1 Fc, an activator of PD-1/PD-L1 pathway, increased Treg cell percentage, enhanced Foxp3 mRNA expression, and elevated levels of TGF-β, IL-10, and IL-35 in PBMCs. However, anti-PD-L1 mAb exerted a reverse effect. These findings revealed that PD-L1 Fc had a favorable effect on Treg cell differentiation, indicating a potential therapeutic value of PD-1/PD-L1 pathway for PIH treatment.
Subject(s)
Humans , Female , Pregnancy , Leukocytes, Mononuclear/chemistry , Interleukins/metabolism , Interleukin-10/metabolism , Apoptosis , Hypertension, Pregnancy-Induced/metabolism , B7-H1 Antigen/metabolism , Enzyme-Linked Immunosorbent Assay , Leukocytes, Mononuclear/metabolism , Case-Control Studies , Blotting, Western , Transforming Growth Factor beta/metabolism , T-Lymphocytes, Regulatory/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
OBJECTIVE@#To investigate the effects of tetrandrine (Tet) on proliferation and activation of rat cardiac fibroblasts.@*METHODS@#Firstly, the cell counting kit-8 (cck-8) assay was applied to detect the effects of Tet with different concentrations on proliferation of cardiac fibroblasts. Secondly, transforming growth factor (TGF-β)with a concentration of 5 μg/L was used to induce the cardiac fibroblast activation, and Western blot was performed to measure the expression variation of β-catenin, vimentin (Vm), fibronectin (Fn) and smooth muscle α-actin (SMA). At last, the real-time PCR was conducted to measure the expression change of collagen-1(Col-1) and collagen-3(Col-3).@*RESULTS@#The cck-8 assay showed that the Tet with different concentrations respectively, which were 0.5 μmol/L, 1 μmol/L, 2 μmol/L, 4 μmol/L, and 8 μmol/L, significantly inhibited the proliferation of cardiac fibroblasts. The viability was decreased to 94.4%,84.9%,74.9%,63.8%and 50.3% respectively of the control group when the Tet concentration changed, and the difference was statistically significant, P=0.043, P<0.001, P<0.001, P<0.001, P<0.001 respectively. Western blot revealed that the expressions of β-catenin, Fn, SMA and Vm, were up-regulated by TGF-β(5 μg/L), the result showed that the difference was statistically significant, and the P values were 0.001,0.008,0.010,0.001 respectively. Then, the up-regulation of β-catenin, Fn and SMA was attenuated by pre-treatment of Tet, and the result also displayed that the difference was statistically significant, and the P values were 0.009, 0.005, 0.019,respectively. While there was no significant change in the expression of Vm, according to Western blotting, and P>0.05,at the same time, real-time PCR indicated that the up-regulations of Col-1 and Col-3 which were induced by TGF-β were blocked by pre-treatment of Tet, the result showed that the difference was statistically significant, P<0.001.@*CONCLUSION@#According to the experimental results, we can draw the conclusion that: the Tet can significantly inhibit the proliferation of cardiac fibroblasts, meanwhile, it can block the activation of cardiac fibroblasts, which is induced by TGF-β. It is supposed that the Tet may probably have anti myocardial fibrosis, which indicates that it may probably be a medicine which is used to block the cardiac remodeling.
Subject(s)
Actins , Animals , Benzylisoquinolines/pharmacology , Blotting, Western , Calcium Channel Blockers/pharmacology , Cell Proliferation , Collagen , Collagen Type I , Fibroblasts/physiology , Fibrosis , Myocardium/cytology , Neoplasm Proteins/metabolism , Rats , Signal Transduction , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1ABSTRACT
El objetivo de este estudio fue evaluar el efecto de la radiación ultravioleta (UV) B sobre la expresión del factor de crecimiento transformante (TGF) ß1 por fibroblastos de mucosa oral, con el objetivo de dilucidar si este tipo celular puede contribuir a la expresión de TGFß1 en bermellón labial sobreexpuesto a la radiación UV. Se obtuvieron cultivos primarios de fibroblastos desde explantes de mucosa bucal, los que fueron irradiados con una dosis única de luz UVB (60 mJ/cm2). Se midió proliferación celular con el método MTT, y la expresión de TGFß1, a nivel de ARN mensajero (normalizado a GAPDH) por RT-PCR y a nivel de proteína mediante inmunofluorescencia. Se observó una disminución de la proliferación celular de los fibroblastos de mucosa oral a las 24 hrs post-irradiación en relación a los fibroblastos no irradiados (P<0,05, Mann Whitney). No se encontraron diferencias entre los fibroblastos control y los irradiados en la expresión de TGFß-1 ni a nivel de mensajero (0,5 y 6 h post-irradiación), ni de proteína (24 h post-irradiación). Los resultados sugieren que los fibroblastos de mucosa oral presentan una disminución de su proliferación en respuesta a una dosis única de radiación UVB, sin que se afecte la expresión de TGFß-1, la que fue similar a los fibroblastos no irradiados. Esto sugiere que los fibroblastos contribuirían a la producción de TGFß-1 en respuesta a la exposición crónica a UVB del bermellón labial.
The objective of this study was to characterize the effect of Ultraviolet (UV) B irradiation on the expression of transforming growth factor (TGF) ß1 by oral mucosa fibroblasts, in order to assess if these cells contribute to the production of TGFß-1 in UV-irradiated lip vermillion. Primary cultures of fibroblasts were obtained from oral mucosa explants, and were irradiated with a single dose of UVB light (60 mJ/cm2). The effects of UVB radiation on cell proliferation was evaluated by the MTT method. The effects of UVB on the expression of TGF-ß1 was analyzed by RT-PCR (normalized to GAPDH) and by immunofluorescence. The results showed a decrease in the proliferation of UVB-irradiated fibroblasts as compared to controls at 24h post-irradiation (p<0.05). No variations in the expression of TGFß1, both at the mRNA and protein level, were observed between control and UVB-irradiated fibroblasts during the first 24 h after irradiation. Oral mucosa fibroblasts have reduced proliferation in response to a single dose of UVB, but their expression of TGFß1 was not affected. This suggests that oral mucosa fibroblasts may contribute to the production of TGFß1 in the lip vermillion independent of UVB exposure.
Subject(s)
Humans , Mouth Mucosa/metabolism , Mouth Mucosa/radiation effects , Transforming Growth Factor beta/radiation effects , Ultraviolet Rays , Cell Proliferation , Fibroblasts/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
ABSTRACT PURPOSE : To evaluate the effects of platelet rich plasma (PRP) on the healing of fascia wherein peritonitis has been created. METHODS: Twenty eight Wistar Albino rats were divided into four groups. Only a primary fascial repair following laparotomy was performed on Group 1, a primary fascial repair performed and PRP treatment applied following laparotomy on Group 2, and a fecal peritonitis created following laparotomy and a primary fascial repair carried out on Group 3. A fecal peritonitis was created following laparotomy and primary fascial repair and PRP treatment on the fascia was carried out on Group 4. RESULTS: TNF-α was found to be significantly lower in the control group (Group 1). It was detected at the highest level in the group in which fecal peritonitis was created and PRP applied (Group 4). TGF-β was determined as being significantly higher only in Group 4. Histopathologically, the differences between the groups in terms of cell infiltration and collagen deposition were not found to be significant. CONCLUSION: When platelet rich plasma was given histologically and biochemicaly as wound healing parameters cellular infiltration, collagen accumulation, and tissue hydroxyiproline levels were not increased but neovascularization, fibroblast activation and TNF Alfa levels were increased and PRP accelerated wound healing.
Subject(s)
Animals , Peritonitis/complications , Wound Healing , Platelet-Rich Plasma , Fascia/physiology , Peritonitis/metabolism , Serine Endopeptidases/metabolism , Random Allocation , Transforming Growth Factor beta/analysis , Transforming Growth Factor beta/metabolism , Collagen/drug effects , Collagen/metabolism , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/metabolism , Rats, Wistar , Gelatinases/metabolism , Neovascularization, Physiologic , Models, Animal , Fascia/blood supply , Hydroxyproline/analysis , Hydroxyproline/metabolism , Membrane Proteins/metabolismABSTRACT
Purpose: To determine the efficacy of tranilast as an adjunctive therapy in conjunctival autograft. Methods: Twenty-nine patients were randomly allocated to the Tranilast Group (n=15) or the Control Group (n=14). The Tranilast Group received a subconjunctival injection of 0.5% tranilast 30 days prior to surgery. Conjunctival autograft was performed in both groups using fibrin sealant and 0.02% subconjunctival mitomycin C at the end of the surgery. After the resection of the pterygium, immunohistochemistry was performed with 100 cells to identify epithelial cells positive for transforming growth factor-β (TGF-β). Subjective symptoms were evaluated using a 5-point scale, and the recurrence rate was assessed. Results: Both groups showed improvements in their symptoms and similar clinical results. Compared with the Control Group, the Tranilast Group failed to show a decreased recurrence rate (p=0.59). However, the number of epithelial cells expressing TGF-β was lower in the Tranilast Group (5 cells; 95% CI: 2.56-13.15; Control Group, 16 cells, 95% CI: 11.53-24.76; p=0.01). Minimal but reversible complications, including glaucoma secondary to corticosteroids and granuloma, occurred during the study. Conclusion: Tranilast was effective in decreasing the number of pterygium epithelial cells expressing TGF-β. .
Objetivo: Determinar a eficácia do tranilast, como terapia auxiliar no transplante autólogo de conjuntiva. Métodos: Vinte e nove pacientes foram randomizados em dois grupos: Grupo Tratado (15) e Grupo Controle (14). Trinta dias antes da cirurgia, o Grupo Tratado recebeu uma injeção subconjuntival de tranilast a 0,5%. O transplante autólogo de conjuntiva foi realizado em ambos os grupos, usando-se a cola de fibrina e a mitomicina 0,02% subconjuntival, ao final da cirurgia. Cada paciente foi examinado por 12 meses de acompanhamento. A imuno-histoquímica foi realizada, mediante um total de 100 células, a fim de que se contassem as células epiteliais positivas, para o fator de crescimento transformador beta (TGF-β), após a cirurgia do pterígio. Os sintomas subjetivos foram avaliados usando-se uma escala de cinco pontos, e a taxa de recorrência foi avaliada. Resultados: Os 2 grupos apresentaram melhora dos sintomas e com resultados clínicos similares. Quando comparado com o Grupo Controle, o Grupo Tratado falhou em mostrar uma diminuição da taxa de recorrência (p=0,59). Entretanto o número de células epiteliais expressando o TGF-β foi menor no Grupo Tratado (5 células; 95% CI=2,56-13,15; Grupo Controle, 16 células; 95% CI: 11,53-24,76, p=0,01). Complicações mínimas, mas reversíveis, ocorreram durante o estudo, incluindo glaucoma secundário ao uso de corticoide e granuloma. Conclusão: O tranilast foi efetivo em diminuir o número células epiteliais do pterígio expressando o TGF-β. .
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Conjunctiva/transplantation , Epithelial Cells/drug effects , Pterygium/drug therapy , Pterygium/surgery , Transforming Growth Factor beta/metabolism , ortho-Aminobenzoates/administration & dosage , Autografts , Conjunctiva/drug effects , Conjunctiva/metabolism , Epithelial Cells/metabolism , Follow-Up Studies , Fibrin Tissue Adhesive/therapeutic use , Injections, Intraocular , Mitomycin/therapeutic use , Postoperative Period , Preoperative Care , Prospective Studies , Pterygium/metabolism , Pterygium/prevention & control , Recurrence , Secondary Prevention/methods , Transplantation, Autologous , Treatment OutcomeABSTRACT
OBJECTIVE: To determine by means of a systematic review the best treatment, whether interproximal wear or incisor extraction, to correct anterior lower crowding in Class I patients in permanent dentition. METHODS: A literature review was conducted using MEDLINE, Scopus and Web of Science to retrieve studies published between January 1950 and October 2013. In selecting the sample, the following inclusion criteria were applied: studies involving interproximal wear and/or extraction of mandibular incisors, as well as Class I cases with anterior lower crowding in permanent dentition. RESULTS: Out of a total of 943 articles found after excluding duplicates, 925 were excluded after abstract analysis. After full articles were read, 13 were excluded by the eligibility criteria and one due to methodological quality; therefore, only fours articles remained: two retrospective and two randomized prospective studies. Data were collected, analyzed and organized in tables. CONCLUSION: Both interproximal wear and mandibular incisor extraction are effective in treating Class I malocclusion in permanent dentition with moderate anterior lower crowding and pleasant facial profile. There is scant evidence to determine the best treatment option for each case. Clinical decision should be made on an individual basis by taking into account dental characteristics, crowding, dental and oral health, patient's expectations and the use of set-up models. .
OBJETIVO: determinar, por meio de uma revisão sistemática, o melhor tratamento entre desgastes interproximais e extração de incisivos para a correção de apinhamento anteroinferior em pacientes Classe I com dentição permanente. MÉTODOS: foram feitas buscas nas bases de dados eletrônicas MEDLINE, Scopus e Web of Science por artigos publicados de janeiro de 1950 até outubro de 2013. Os critérios de inclusão foram estudos que abordassem tratamentos com desgastes interproximais e/ou extração de incisivos inferiores, de casos Classe I com apinhamento anteroinferior na dentição permanente. RESULTADOS: dos 943 artigos encontrados após a remoção dos duplicados, 925 foram excluídos após a leitura dos resumos. Após leitura dos artigos completos, 13 foram excluídos pelos critérios de eligibilidade e um pela qualidade metodológica, restando quatro artigos, sendo dois retrospectivos e dois prospectivos randomizados. Os dados foram coletados, analisados e organizados em tabelas. CONCLUSÕES: tanto o desgaste interproximal quanto a extração de incisivo inferior são tratamentos eficazes em Classe I na dentição permanente, com apinhamento anteroinferior moderado e perfil facial agradável. Há fracas evidências para determinar a escolha do melhor tratamento para cada caso. A decisão clínica deve ser tomada em bases individuais, considerando as características anatômicas dentárias, da severidade do apinhamento, condições de saúde dentária e bucal, expectativas dos pacientes e ensaio em modelos (set-up). .
Subject(s)
Animals , Female , Pregnancy , Maternal Nutritional Physiological Phenomena/physiology , Myocardium/pathology , Obesity/pathology , Blotting, Western , Fibrosis , Heart/embryology , Matrix Metalloproteinase 9/metabolism , Myocardium/metabolism , Obesity/metabolism , Phosphorylation , Reverse Transcriptase Polymerase Chain Reaction , Sheep , Signal Transduction , /metabolism , Transforming Growth Factor beta/metabolism , /metabolismABSTRACT
After years of discussion by the Chilean legislature, the Law Nº 20.584, which regulates health care related rights and duties of people, entered into force in Chile in October 2012. This bill represents an important step in the recognition and protection of health care related rights, welfare, dignity and duties of persons. It also intends to protect potential participants in clinical research. However such protective measures include explicit prohibitions such as the review of clinical records or the inclusion of people with mental or psychological handicaps as research participants. We herein discuss the implications of this law in medical research.
Subject(s)
Animals , Male , Rats , Gene Expression Regulation , MicroRNAs/genetics , MicroRNAs/metabolism , Disease Models, Animal , Glomerulonephritis/metabolism , Hypertension/pathology , Kidney Glomerulus/metabolism , Kidney Tubules/metabolism , Kidney/injuries , Kidney/metabolism , Rats, Inbred WKY , Time Factors , Transforming Growth Factor beta/metabolism , Ureter/pathologyABSTRACT
PURPOSE: The expression of nerve growth factor-beta (NGF-beta) is related to cardiac nerve sprouting and sympathetic hyper innervation. We investigated the changes of plasma levels of NGF-beta and the relationship to follow-up heart rate variability (HRV) after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). MATERIALS AND METHODS: This study included 147 patients with AF (117 men, 55.8+/-11.5 years, 106 paroxysmal AF) who underwent RFCA. The plasma levels of NGF-beta were quantified using double sandwich enzyme linked immunosorbent assay method before (NGF-beta(pre)) and 1 hour after RFCA (NGF-beta(post-1hr)). HRV at pre-procedure (HRV(pre)), 3 months (HRV(post-3mo)), and 1 year post-procedure (HRV(post-1yr)) were analyzed and compared with plasma levels of NGF-beta. RESULTS: 1) The plasma levels of NGF-beta significantly increased after RFCA (20.05+/-11.09 pg/mL vs. 29.60+/-19.43 pg/mL, p18 pg/mL, low frequency components (LF)/high-frequency components (HF) (p=0.003) and the number of atrial premature contractions (APCs, p=0.045) in HRV(post-3mo) were significantly higher than those with < or =18 pg/mL. 3) The LF/HF at HRV(post-3mo) was linearly associated with the NGF-beta(pre) (B=4.240, 95% CI 1.114-7.336, p=0.008) and the NGF-beta(post-1hr) (B=7.617, 95% CI 2.106-13.127, p=0.007). 4) Both NGF-beta(pre) (OR=1.159, 95% CI 1.045-1.286, p=0.005) and NGF-beta(post-1hr) (OR=1.098, 95% CI 1.030-1.170, p=0.004) were independent predictors for the increase of LF/HF at HRV(post-3mo). CONCLUSION: AF catheter ablation increases plasma level of NGF-beta, and high plasma levels of NGF-beta(pre) was associated with higher sympathetic nerve activity and higher frequency of APCs in HRV(post-3mo).
Subject(s)
Aged , Atrial Fibrillation/physiopathology , Catheter Ablation/methods , Female , Heart Rate , Humans , Male , Middle Aged , Nerve Growth Factor , Nerve Growth Factors , Transforming Growth Factor beta/metabolism , Treatment OutcomeABSTRACT
Immune response plays an important role in the development of hepatic fibrosis. In the present study, we investigated the effects of quercetin on hepatitis and hepatic fibrosis induced by immunological mechanism. In the acute hepatitis model, quercetin (2.5 mg/kg) was injected iv into mice 30 min after concanavalin A (Con A) challenge. Mice were sacrificed 4 or 24 h after Con A injection, and aminotransferase tests and histopathological sections were performed. Treatment with quercetin significantly decreased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Consistent with this observation, treatment with quercetin markedly attenuated the pathologic changes in the liver. A hepatic fibrosis model was also generated in mice by Con A challenge once a week for 6 consecutive weeks. Mice in the experimental group were treated with daily iv injections of quercetin (0.5 mg/kg). Histopathological analyses revealed that treatment with quercetin markedly decreased collagen deposition, pseudolobuli development, and hepatic stellate cells activation. We also examined the effects of quercetin on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor beta (TGF-β) pathways by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). NF-κB and TGF-β production was decreased after treatment with quercetin, indicating that the antifibrotic effect of quercetin is associated with its ability to modulate NF-κB and TGF-β production. These results suggest that quercetin may be an effective therapeutic strategy in the treatment of patients with liver damage and fibrosis.
Subject(s)
Animals , Female , Antioxidants/administration & dosage , Hepatitis/drug therapy , Liver Cirrhosis/drug therapy , Quercetin/pharmacology , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Concanavalin A , Collagen/analysis , Disease Models, Animal , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Liposomes , Liver Cirrhosis/chemically induced , Mice, Inbred BALB C , Mitogens , NF-kappa B/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta/metabolismABSTRACT
Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis.
Subject(s)
Animals , Humans , Male , Actins/metabolism , Hepatic Stellate Cells/metabolism , Histone Demethylases/metabolism , Liver Cirrhosis/metabolism , /metabolism , Vimentin/metabolism , Blotting, Western , Cell Proliferation , Disease Models, Animal , Gene Expression , Gene Knockdown Techniques , Rats, Wistar , RNA, Small Interfering/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
OBJECTIVE: During the neonatal and infancy periods, some chronic liver diseases may lead to progressive hepatic fibrosis, which is a condition that can ultimately result in the loss of organ function and severe portal hypertension necessitating hepatic transplantation. In a previous report, pharmacological interventions were demonstrated to modulate hepatic fibrosis induced by bile duct ligation in young rats. The administration of pentoxifylline or prednisolone, or the combination of both, resulted in reduced fibrogenesis in portal spaces. The objectives of the present study were to evaluate the expression of transforming growth factor β and vascular endothelial growth factor after bile duct ligation in young rats and to assess the effect of those same drugs on cytokine expression. METHODS: In this experimental study, 80 young rats (21 or 22 days old) were submitted either to laparotomy and common bile duct ligation or to sham surgery. The animals were allocated into four groups according to surgical procedure, and the following treatments were administered: (1) common bile duct ligation + distilled water, (2) sham surgery + distilled water, (3) common bile duct ligation + pentoxifylline, or (4) common bile duct ligation + prednisolone. After 30 days, a hepatic fragment was collected from each animal for immunohistochemical analysis using monoclonal antibodies against transforming growth factor β and vascular endothelial growth factor. Digital morphometric and statistical analyses were performed. RESULTS: The administration of pentoxifylline reduced the transforming growth factor β-marked area and the amount of transforming growth factor β expressed in liver tissue. This effect was not observed after the administration of prednisolone. There was a significant reduction in vascular endothelial growth factor expression after the administration of either drug compared with the non-treatment group. CONCLUSIONS: The administration of pentoxifylline to cholestatic young rats resulted in the diminished expression of transforming growth factor β and vascular endothelial growth factor in liver tissue. The administration of steroids resulted in the diminished expression of vascular endothelial growth factor only. These pathways may be involved in hepatic fibrogenesis in young rats submitted to bile duct ligation and exposed to pentoxifylline or prednisolone.
Subject(s)
Animals , Rats , Cholestasis/drug therapy , Glucocorticoids/pharmacology , Liver Cirrhosis, Experimental/prevention & control , Pentoxifylline/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Prednisolone/pharmacology , Transforming Growth Factor beta/metabolism , Vascular Endothelial Growth Factor A/metabolism , Cholestasis/metabolism , Disease Models, Animal , Immunohistochemistry , Liver Cirrhosis, Experimental/etiology , Liver Cirrhosis, Experimental/metabolism , Liver/drug effects , Liver/metabolism , Random AllocationABSTRACT
OBJECTIVE: This study sought to identify the relationship between fibroblast telomerase expression, myofibroblasts, and telomerase-mediated regulatory signals in idiopathic pulmonary fibrosis. METHODS: Thirty-four surgical lung biopsies, which had been obtained from patients with idiopathic pulmonary fibrosis and histologically classified as usual interstitial pneumonia, were examined. Immunohistochemistry was used to evaluate fibroblast telomerase expression, myofibroblast α-smooth muscle actin expression and the tissue expression of inter leu kin-4, transforming growth factor-β, and basic fibroblast growth factor. The point-counting technique was used to quantify the expression of these markers in unaffected, collapsed, mural fibrosis, and honeycombing areas. The results were correlated to patient survival. RESULTS: Fibroblast telomerase expression and basic fibroblast growth factor tissue expression were higher in collapsed areas, whereas myofibroblast expression and interleukine-4 tissue expression were higher in areas of mural fibrosis. Transforming growth factor-β expression was higher in collapsed, mural fibrosis and honeycombing areas in comparison to unaffected areas. Positive correlations were found between basic fibroblast growth factor tissue expression and fibroblast telomerase expression and between interleukin-4 tissue expression and myofibroblast α-smooth muscle actin expression. Negative correlations were observed between interleukin-4 expression and basic fibroblast growth factor tissue expression in areas of mural fibrosis. Myofibroblast α-smooth muscle actin expression and interleukin-4 tissue expression in areas of mural fibrosis were negatively associated with patient survival. CONCLUSION: Fibroblast telomerase expression is higher in areas of early remodeling in lung tissues demonstrating typical interstitial pneumonia, whereas myofibroblast α-smooth muscle actin expression predominates in areas of late remodeling. These events seem to be regulated by basic fibroblast growth factor and interleukin-4 tissue expression, respectively.
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Actins/metabolism , Idiopathic Pulmonary Fibrosis/metabolism , Lung/metabolism , Myofibroblasts/metabolism , Telomerase/metabolism , Biopsy , Biomarkers/metabolism , Cell Differentiation , Fibroblast Growth Factors/metabolism , Idiopathic Pulmonary Fibrosis/pathology , /metabolism , Lung/pathology , Proportional Hazards Models , Retrospective Studies , Survival Analysis , Transforming Growth Factor beta/metabolismABSTRACT
BACKGROUND: Cyclosporine (CyA) nephrotoxicity is partly due to some oxidative stress. Ubiquinol, the reduced form of coenzyme Q10 (rCoQ10), has recently gained attention for its anti-oxidative potential. The aim of this study is to evaluate the effect of rCoQ10 on a CyA nephrotoxic rat model. MATERIALS AND METHODS: Six-week-old male Wistar rats were divided into three groups (five animals each). Group 1 received a medium only. Group 2 received 30 mg/kg/day of CyA only. Group 3 received both the same dose of CyA and 600 mg/kg/day of rCoQ10. CyA and rCoQ10 were both given orally for four weeks. Systolic blood pressure (BP), daily urinary albumin secretion (u-Alb), serum creatinine (s-Cr) level, and super-oxide anion (SO) level in the renal tissue were measured and compared among those three groups. Immunohistochemistry using an antibody for the transforming growth factor-beta (TGF-beta) was also examined. RESULTS: BPs, u-Albs, s-Crs, and SO levels of groups 1, 2, and 3 were 114 ± 3, 132 ± 4, and 129 ± 5 mmHg, 2.6 ± 0.5, 42.1 ± 7.2, and 22.8 ± 3.4 micro-g/day, 1.1 ± 0.2, 1.7 ± 0.2, and 1.3 ± 0.2 mg/dl, and 224 ± 84, 1251 ± 138, and 512 ± 109 RLU/g kidney respectively. U-Albs, s-Crs, and SO levels were significantly ameliorated by rCoQ10. Micro-vacuolar changes and TGF-beta positive deposits in the proximal renal tubular cells of CyA group rats disappeared in those of CyA and rCoQ10 group rats. CONCLUSION: RCoQ10, an antioxidants, may have potential for preventing CyA nephrotoxicity.