Ursolic acid increases strength in mdx mice model and may decrease fibrosis deposition by tgf-ß downregulation / El ácido ursólico aumenta la resistencia en el modelo de ratones mdx y podría disminuir la deposición de fibrosis mediante la regulación decreciente de tgf-ß

SUMMARY: Dystrophin disfunction results in sarcolemma destabilization, leading muscle cell damage by continuous degeneration cycles and limited regeneration. In muscle dystrophy, caused by dystrophin dysfunction, inflammation, necrosis and fibrosis are pathophysiological muscle function loss characteristics. As a genetic disease, this muscle dystrophy has no cure, however, advances in drug therapy using glucocorticoids can decrease the disease progression. Subsequently, alternative therapies were studied, such as ursolic acid (UA), that inhibits muscle atrophy and increases muscle mass and strength. Herein, we used 10 mg/kg daily supplementation in mdx mice for 4 weeks to evaluate serum creatine phosphokinase (CPK), muscle strength (Kondziela test), muscular organization (histology) and expression of fibrosis related genes (TGF-ß, TNF-α, mstn and ostn). UA supplementation increased muscle morphological organization, motor strength and decreased muscular TGF-ß expression. Altogether, the gene expression profile, histological organization and strength could suggest that UA treatment did not stop the fibrogenesis but decreased its progress.

RESUMEN: La disfunción de la distrofina resulta en la desestabilización del sarcolema, llevando al daño de las células musculares por ciclos continuos de degeneración y regeneración limitada. En la distrofia muscular, debido a la disfunción de la distrofina, la inflamación, la necrosis y la fibrosis, son características fisiopatológicas de la pérdida de la función muscular. Como enfermedad genetica no es possible remediar esta distrofia muscular, sin embargo, los avances en la terapia de medicamentos con glucocorticoides pueden disminuir la progresión de la enfermedad. Se estudiaron terapias alternativas, como el ácido ursólico (UA), que inhibe la atrofia muscular y aumenta la masa y la fuerza muscular. En este estudio, utilizamos una suplementación diaria de 10 mg / kg en ratones mdx durante 4 semanas para evaluar la creatina fosfoquinasa (CPK) sérica, la fuerza muscular (prueba de Kondziela), la organización muscular (histología) y la expresión de genes relacionados con la fibrosis (TGF-ß, TNF- α, mstn y ostn). La suplementación con AU aumentó la organización morfológica muscular, la fuerza motora y la disminución de la expresión muscular de TGF-ß. El perfil de expresión génica, la organización histológica y la fuerza simultáneamente podrían sugerir que el tratamiento con AU no detuvo la fibrogénesis sino que disminuyó su progreso.

Effects of laser photobiomodulation on tgf-ß and vegf expression in burn wound: systematic review and meta-analysis in the animal model / Influencia de la fotobiomodulación por láser en la expresión de tgf-ß y vegf en heridas por quemadura: revisión sistemática y meta-análisis en modelo animal

SUMMARY: Laser photobiomodulation (laser PBM) is known to be able to accelerate burn wound healing in the animal model; however little evidence exists on the action of laser PBM on the expression of important proteins in wound healing in the animal model, such as VEGF and TGF-ß1. The aim of this study was to carry out a systematic review in order to analyse the effect of laser PBM on VEGF and TGF-ß expression during burn wound repair in the animal model. A systematic review was carried out of the EMBASE, PubMed/ MEDLINE and LILACS databases. The studies included were preclinical studies that analysed the action of laser PBM on the expression of VEGF and TGF-ß (1, 2, 3) during burn wound repair in the animal model. The SYRCLE risk of bias tool was used. Random effect models were used to estimate the combined effect. Increased VEGF expression was observed with the use of laser PBM at 4.93 J/cm2 per point in the first two weeks after induction of the burn wound, with greater size of effect in the second week (SDM = 5.72; 95% CI: 3.14 to 8.31, I2 = 0 %; very low certainty of evidence). We also observed that the effect of laser PBM on TGF-ß1 expression was greater than in the control in the first week (SDM = -0.45; 95% CI: -1.91 to 1.02, I2 = 51 %; very low certainty of evidence), but diminished in the third week after induction of the lesion (SDM = -2.50; 95% CI: 3.98 to -1.01, I2 = 0 %; very low certainty of evidence). Laser PBM has an effect on TGF-ß1 and VEGF expression, promoting burn wound repair in the animal model.

RESUMEN: Es sabido que la fotobiomodulación por láser (FBM láser) puede acelerar el proceso de curación de heridas por quemadura en modelo animal, sin embargo aún se carece de mayor evidencia sobre la acción de la FBM láser en la expresión de proteínas importantes en el proceso de curación de heridas en modelo animal, como VEGF y TGF-ß1. Así, el objetivo de este estudio fue realizar una revisión sistemática a fin de analizar el efecto de la FBM láser sobre la expresión de VEGF, TGF-ß durante el proceso de reparación de heridas por quemadura en modelo animal. Se realizó una búsqueda sistemática en las bases de datos EMBASE, PubMed/MEDLINE y LILACS. Se incluyeron estudios preclínicos que analizaron la acción de la FBM láser en la expresión de VEGF, TGF-ß (1, 2, 3) durante el proceso de reparación de heridas por quemadura en modelo animal. Se utilizó la herramienta de riesgo de sesgo SYRCLE. Se utilizaron modelos de efectos aleatorios para estimar el efecto combinado. Observamos aumento de la expresión de VEGF con el uso de FBM láser 4.93 J/cm2 por punto, en las dos primeras semanas tras inducción de la herida por quemadura, con mayor tamaño de efecto en la segunda semana (SDM = 5,72; IC del 95%: 3,14 a 8,31, I2 = 0 %; certeza de la evidencia muy baja). También se observó el efecto de la FBM láser en la expresión del TGF- ß1 que fue mayor que el control en la primera semana (SDM = - 0,45; IC del 95%: -1,91 a 1,02, I2 = 51 %; certeza de la evidencia muy baja), disminuyendo en la tercera semana tras inducción de la lesión (SDM = -2,50; IC del 95%: -3,98 a -1,01; I2 = 0 %; certeza de la evidencia baja). La TFB por láser ejerce influencia en la expresión de TGF-ß1 y VEGF favoreciendo el proceso de reparación de heridas por quemadura en modelo animal.

O papel de proteínas das vias WNT/ß-Catenina, TGF-ß/BMP4 e SHH na odontogênese e odontomas / The role of proteins from the WNT/ß-Catenin, TGF-ß/BMP4 and SHH pathways in odontogenesis and odontomas

O desenvolvimento do dente depende de uma série de interações sinalizadoras recíprocas entre o epitélio oral (EO) e o ectomesênquima derivado da crista neural, a via WNT com o TGF-ß e BMP4 tem sido implicada na tumorigênese. A via de sinalização tipo Wingless (Wnt) / ß-catenina é essencial para a ativação precoce da odontogênese e no desenvolvimento de tumores odontogênicos. O TGF-ß e as BMPs tem sido associadas aos processos de dentinogênese reacionária e reparadora. A sinalização de Shh pode regular a proliferação celular no ectomesênquima dentário, controlando assim a morfogênese dentária. O objetivo da pesquisa foi investigar a atuação de algumas proteínas das vias na odontogênese e na formação de odontomas e tumores odontogênicos mistos benignos, para isto, foi desenvolvido um estudo seccional restrospectivo e imuno-histoquímico contendo 23 odontomas compostos, 21 odontomas complexos, 17 germes dentários, 05 fibro-odontomas ameloblásticos e 01 fibroma ameloblástico. Os resultados encontrados demonstraram maiores imunoexpressões da via WNT/ß-catenina no epitélio dos germes dentários (p<0,001) e no fibroma ameloblástico, enquanto que, esteve no ectomesênquima dos odontomas (p<0,001) e fibro-odontomas ameloblásticos. A via WNT/ßcatenina correlacionou-se moderadamente e significativamente com a CK14 no epitélio (p = 0,007) dos odontomas. A BMP4 foi imunoexpressa, especialmente, no ectomesênquima dos odontomas complexos (mediana = 33,7; p<0,001). A via Shh foi mais imunoexpressa no epitélio dos germes dentários (p<0,001) e no ectomesênquima dos odontomas complexos (p=0,029). De forma similar, o TGFß apresentou maior imunoexpressão no epitélio dos germes dentários (p<0,001) e no ectomesênquima dos odontomas complexos (p = 0,002). O dente em desenvolvimento exibiu maiores concentrações para estas proteínas no epitélio odontogênico nas fases de botão e capuz e a expressão diferencial ocorreu, principalmente, no ectomesênquima dos tumores, o que indica que esse componente é de fato mais proliferativo (AU).

Tooth development depends on a series of reciprocal signaling interactions between oral epithelium (EO) and neural crest-derived ectomesenchyme, the WNT pathway with TGF-ß and BMP4 has been implicated in tumorigenesis. The Wingless (Wnt)/ß-catenin signaling pathway is essential for the early activation of odontogenesis and the development of odontogenic tumors. TGF-ß and BMPs have been associated with reactionary and reparative dentinogenesis processes. Shh signaling can regulate cell proliferation in dental ectomesenchyme, thus controlling dental morphogenesis. The objective of the research was to investigate the role of some proteins in the pathways in odontogenesis and in the formation of odontomas and benign mixed odontogenic tumors. tooth germs, 05 ameloblastic fibro-odontomas and 01 ameloblastic fibroma. The results found showed higher immunoexpressions of the WNT/ß-catenin pathway in the epithelium of tooth germs (p<0.001) and in ameloblastic fibroma, while it was in the ectomesenchyme of odontomas (p<0.001) and ameloblastic fibroodontomas. The WNT/ß-catenin pathway correlated moderately and significantly with CK14 in the epithelium (p = 0.007) of odontomas. BMP4 was immunoexpressed, especially in the ectomesenchyme of complex odontomas (median = 33.7; p<0.001). The Shh pathway was more immunoexpressed in the epithelium of tooth germs (p<0.001) and in the ectomesenchyme of complex odontomas (p=0.029). Similarly, TGF-ß showed higher immunoexpression in the epithelium of tooth germs (p<0.001) and in the ectomesenchyme of complex odontomas (p = 0.002). The developing tooth exhibited higher concentrations of these proteins in the odontogenic epithelium in the bud and cap phases and the differential expression occurred mainly in the ectomesenchyme of the tumors, which indicates that this component is in fact more proliferative (AU).

Resveratrol as an anti-asthmatic agent: could this stilbenoid help against COVID-19 in any way? a meta-analysis / Resveratrol como agente antiasmático: ¿podría este estilbenoide ayudar contra el COVID-19 de alguna manera? un metaanálisis

Resveratrol is a phenolic phytoconstituent found in many plants. This molecule has always caught the attention of scientists because of biological potentials such as inhibition of inflammation, oxidative stress and platelet aggregation as well as to prevent/protect against cardiovascular and neurodegenerative disease/disorders. Literature search have been conducted over resveratrol in covid-19 and asthma studies published in Pubmed and Google Scholars until 30 September 2020. The criteria used in the literature review were determined and were reviewed works on resveratrol including 368 articles and 47 articles on covid-19 and asthma, respectively. As a result of meta-analysis, TNF-α values of the studies showed a significant difference (heterogeneity) of I2=68.39% from each other in total (Cohran Q:6.33, p<0.0423). This study shows that resveratrol would have a potential to reduce ARDS symptoms, by suppressing the cytokine storm and severe inflammation caused by SARS-CoV-2, and by showing strong activity against various types of DNA/RNA viruses.

El resveratrol es un fitoconstituyente fenólico que se encuentra en muchas plantas. Esta molécula siempre ha llamado la atención de los científicos debido a sus potenciales biológicos como la inhibición de la inflamación, el estrés oxidativo y la agregación plaquetaria, así como para prevenir/proteger contra enfermedades/trastornos cardiovasculares y neurodegenerativos. Se han realizado búsquedas bibliográficas sobre resveratrol en covid-19 y estudios sobre asma publicados en Pubmed y Google Scholars hasta el 30 de septiembre de 2020. Se determinaron los criterios utilizados en la revisión bibliográfica y se revisaron trabajos sobre resveratrol que incluyen 368 artículos y 47 artículos sobre covid-19 y asma, respectivamente. Como resultado del metanálisis, los valores de TNF-α de los estudios mostraron una diferencia significativa (heterogeneidad) de I2=68,39% entre sí en total (Cohran Q: 6,33, p<0,0423). Este estudio muestra que el resveratrol podría reducir los síntomas del ARDS al suprimir la tormenta de citocinas y la inflamación severa causada por el SARS-CoV-2, y al mostrar una fuerte actividad contra varios tipos de virus de ADN/ARN.

Presentación atípica de síndrome de CamuratiEngelmann en una paciente femenina colombiana. Reporte de caso / Atypical presentation of Camurati-Engelmann syndrome in a colombian female patient. Case report

Resumen El síndrome de Camurati-Engelmann, también conocido como displasia diafisaria progresiva, es una enfermedad rara, autosómica dominante y con una prevalencia de uno por cada millón de habitantes. Genera mutaciones del factor de crecimiento transformante beta, que participa en la proliferación ósea. Son frecuentes las manifestaciones osteomusculares y neurológicas, con escasas expresiones de laboratorio. El diagnóstico se basa en la clínica, los hallazgos radiológicos y la confirmación genética; el tratamiento se dirige al control sintomático y el pronóstico es incierto. La presente publicación tiene como objetivo compartir con la comunidad médica el tercer caso de síndrome de Camurati-Engelmann conocido en Colombia. Se trata de una paciente femenina de 33 años con cuadro clínico de distonías intensas y signos y síntomas característicos de este síndrome, cuyo diagnóstico fue confirmado por prueba molecular, encontrando la presencia de la variante patogénica p.Arg156Cys en el gen TGF-β1, con presentación de novo. MÉD.UIS.2021;34(1): 119-27.

Abstract Camurati-Engelmann syndrome, also known as progressive diaphyseal dysplasia, is a rare, autosomal dominant disease with a prevalence of one per million inhabitants. It generates mutations of the transforming growth factor beta, which participates in bone proliferation. Osteomuscular and neurological manifestations are frequent, with few laboratory expressions. The diagnosis is based on the clinic, radiological findings, and genetic confirmation, treatment is aimed at symptom control and prognosis is uncertain. The objective of this publication is to share with the medical community the third case of Camurati-Engelmann syndrome known in Colombia. This is a 33-year- old female patient with a clinical picture of intense dystonia and characteristic signs and symptoms of this syndrome, whose diagnosis was confirmed by molecular testing, finding the presence of the pathogenic variant p.Arg156Cys in the TGF-β1 gene, with de novo presentation. MÉD.UIS.2021;34(1): 119-27.

The effect of mild hypothermia plus rutin on the treatment of spinal cord injury and inflammatory factors by repressing TGF-β/smad pathway

ABSTRACT Purpose To probe the mechanism of mild hypothermia combined with rutin in the treatment of spinal cord injury (SCI). Methods Thirty rats were randomized into the following groups: control, sham, model, mild hypothermia (MH), and mild hypothermia plus rutin (MH+Rutin). We used modified Allen's method to injure the spinal cord (T10) in rats, and then treated it with MH or/and rutin immediately. BBB scores were performed on all rats. We used HE staining for observing the injured spinal cord tissue; ELISA for assaying TNF-α, IL-1β, IL-8, Myeloperoxidase (MPO), and Malondialdehyde (MDA) contents; Dihydroethidium (DHE) for measuring the reactive oxygen species (ROS) content; flow cytometry for detecting apoptosis; and both RT-qPCR and Western blot for determining the expression levels of TGF-β/Smad pathway related proteins (TGF-β, Smad2, and Smad3). Results In comparison with model group, the BBB score of MH increased to a certain extent and MH+Rutin group increased more than MH group (p < 0.05). After treatment with MH and MH+Rutin, the inflammatory infiltration diminished. MH and MH+Rutin tellingly dwindled TNF-β, MDA and ROS contents (p < 0.01), and minified spinal cord cell apoptosis. MH and MH+Rutin could patently diminished TGF-β1, Smad2, and Smad3 expression (p < 0.01). Conclusions MH+Rutin can suppress the activation of TGF-β/Smad pathway, hence repressing the cellular inflammatory response after SCI.

Emodin alleviates hypertrophic scar formation by suppressing macrophage polarization and inhibiting the Notch and TGF-β pathways in macrophages

Hypertrophic scar (HS) formation is a common complication that develops after skin injury; however, there are few effective and specific therapeutic approaches for HS. Emodin has previously been reported to inhibit mechanical stress-induced HS inflammation. Here, we investigated the molecular mechanisms underlying the inhibitory effects of emodin on HS formation. First, we conducted in vitro assays that revealed that emodin inhibited M1 and M2 polarization in rat macrophages. We subsequently established a combined rat model of tail HS and dorsal subcutaneous polyvinyl alcohol (PVA) sponge-induced wounds. Rats were treated with emodin or vehicle (DMEM). Tail scar specimens were harvested at 14, 28, and 42 days post-incision and subjected to H&E staining and Masson's trichrome staining. Histopathological analyses confirmed that emodin attenuated HS formation and fibrosis. Macrophages were separated from wound cells collected from the PVA sponge at 3 and 7 days after implantation. Flow cytometry analysis demonstrated that emodin suppressed in vivo macrophage recruitment and polarization at the wound site. Finally, we explored the molecular mechanisms of emodin in modulating macrophage polarization by evaluating the expression levels of selected effectors of the Notch and TGF-β pathways in macrophages isolated from PVA sponges. Western blot and qPCR assays showed that Notch1, Notch4, Hes1, TGF-β, and Smad3 were downregulated in response to emodin treatment. Taken together, our findings suggested that emodin attenuated HS formation and fibrosis by suppressing macrophage polarization, which is associated with the inhibition of the Notch and TGF-β pathways in macrophages.

MicroRNA-302b mitigates renal fibrosis via inhibiting TGF-ß/Smad pathway activation

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.

Melittin suppresses growth and induces apoptosis of non-small-cell lung cancer cells via down-regulation of TGF-ß-mediated ERK signal pathway

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.

Effect of rhBMP-2 applied with a 3D-printed titanium implant on new bone formation in rabbit calvarium

Abstract Objective This study sought to compare the biocompatibility of a three-dimensional (3D)-printed titanium implant with a conventional machined titanium product, as well as the effect of such implant applied with recombinant human Bone Morphogenetic Protein Type 2 (rhBMP-2) for guided bone regeneration. Methodology Disk-shaped titanium specimens fabricated either by the conventional machining technique or by the 3D-printing technique were compared by MC3T3-E1 cells cytotoxicity assay. New bone formation was evaluated using a rapid prototype titanium cap applied to the calvaria of 10 rabbits, which were divided into two groups: one including an atelopeptide collagen plug on one side of the cap (group I) and the other including a plug with rhBMP-2 on the other side (group II). At six and 12 weeks after euthanasia, rabbits calvaria underwent morphometric analysis through radiological and histological examination. Results Through the cytotoxicity assay, we identified a significantly higher number of MC3T3-E1 cells in the 3D-printed specimen when compared to the machined specimen after 48 hours of culture. Moreover, morphometric analysis indicated significantly greater bone formation at week 12 on the side where rhBMP-2 was applied when evaluating the upper portion immediately below the cap. Conclusion The results suggest that 3D-printed titanium implant applied with rhBMP-2 enables new bone formation.

Suckling by Schistosoma mansoni-infected mothers restored IgG2a and TGF-β production, but not IL-6 and delayed-type hypersensitivity in IL-12/IL-23-deficient mice

Abstract INTRODUCTION Suckling by schistosomotic mice improves anti-ovalbumin (OA) antibody production, while delayed-type hypersensitivity (DTH) remains unaffected. This property of milk from schistosomotic mice was investigated in IL-12/IL-23-deficient mice (IL-12p40KO). METHODS We compared anti-OA DTH, IgG2a and cytokines in wild-type and IL-12p40KO mice suckled by infected (SIM) or non-infected (CONTROL) mothers. RESULTS SIM mice showed similar intensity and eosinophils in the DTH, which was abolished in IL-12p40KO and IL-12p40KO-SIM mice. In IL-12p40KO-SIM, IgG2a and TGF-β levels were higher, but IL-6 levels were lower. CONCLUSIONS Milk from schistosomotic mothers may evoke IgG2a without eliciting DTH in IL-12/IL-23 deficiencies, by changing TGF-β/IL-6 levels.

Modification in clic4 expression is associated with p53, tgf-ß, tnf-α and myofibroblasts in lip carcinogenesis

Abstract Chloride intracellular channel-4 (CLIC4) is regulated by p53 and tumor necrosis factor-α (TNF-α), it is linked to the increase of transforming growth factor-β (TGF-β), and myofibroblastic differentiation in skin carcinogenesis. This study analyzed the immunoexpression of CLIC4, p53, TGF-β, TNF-α, and α-SMA in 50 actinic cheilitis (AC) and 50 lower lip squamous cell carcinoma (LLSCC). AC and LLSCC immunoexpression were categorized as score 1 (<5% positive cells), 2 (5-50%) or 3 (>50%). For CLIC4, nuclear and cytoplasmic immunostaining of epithelial cells was considered individually. For morphologic analysis, the World Health Organization criteria were used to epithelial dysplasia grade of ACs, and Bryne grading of malignancy system was applied for LLSCC. Higher nuclear CLIC4 (CLIC4n) and TGF-β were observed in ACs with low-risk of transformation, while cytoplasmic CLIC4 (CLIC4c), p53 and TNF-α were higher in the high-risk cases (p<0.05). In LLSCCs, CLIC4c was higher in cases with lymph node metastasis, advanced clinical stages, and histological high-grade malignancy. p53 expression was higher in high-grade LLSCCs, whereas TGF-β decreased as the clinical stage and morphological grade progressed (p<0.05). ACs showed an increased expression of CLIC4n and TGF-β, while CLIC4c and α-SMA were higher in LLSCCs (p<0.0001). Both lesions showed negative correlation between CLIC4n and CLIC4c, while in LLSCCs, negative correlation was also verified between CLIC4c and p53, as well as CLIC4c and TGF-β (p<0.05). Change of CLIC4 from the nucleus to cytoplasm and alterations in p53, TGF-β, TNF-α, and α-SMA expression are involved in lip carcinogenesis.

Resumo O canal intracelular de cloreto 4 (CLIC4) é regulado pela p53 e fator de necrose tumoral α (TNF-α) e está relacionado ao aumento do fator de crescimento transformador β (TGF-β) e na diferenciação miofibroblástica na carcinogênese cutânea. Este estudo analisou a imunoexpressão de CLIC4, p53, TGF-β, TNF-α e α-SMA em 50 queilites actínicas (QA) e 50 carcinomas de células escamosas de lábio inferior (CCELI). A imunoexpressão da QA e CCELI foram categorizadas em escore 1 (<5% de células positivas), 2 (5-50%) ou 3 (>50%). Para CLIC4, a imunomarcação nuclear e citoplasmática das células epiteliais foi considerada separadamente. Para análise morfológica, foram utilizados os critérios da Organização Mundial da Saúde para a gradação das displasias epiteliais nas QAs, e o sistema de gradação de malignidade de Bryne foi utilizado para os casos de CCELIs. Alta imunoexpressão de CLIC4 nuclear (CLIC4n) e TGF-β foi observada em QA de baixo risco de transformação, enquanto CLIC4 citoplasmática (CLIC4c), p53 e TNF-α foram elevadas nos casos de alto risco (p<0.05). No CCELI, a imunoexpressão de CLIC4c foi maior em caos com metástase linfonodal, estágio clínico avançado e alto grau histológico de malignidade. A expressão de p53 foi elevada em CCELI de alto grau, enquanto o TGF-β diminuiu à medida que o estádio clínico e o grau morfológico progrediram (p<0.05). QAs exibiram uma elevada expressão de CLIC4n e TGF-β, enquanto o CLIC4c e α-SMA foram elevados em CCELIs (p<0.0001). Ambas as lesões mostraram correlação negativa entre CLIC4n e CLIC4c, enquanto nos CCELIs, também se verificou correlação negativa entre CLIC4c e p53, assim como entre CLIC4c e TGF-β (p<0.05). Alteração do CLIC4 do núcleo para o citoplasma e alterações na expressão de p53, TGF-β, TNF-α, e α-SMA estão envolvidas na carcinogênese labial.

Evaluation of serum and salivary transforming growth factor beta, vascular endothelial growth factor and tumor necrosis factor alpha in oral lichen planus / Evaluación sérica y salival del factor de crecimiento transformante beta, factor de crecimiento endotelial vascular y factor de necrosis tumoral alfa en liquen plano oral

Introduction: Lichen planus is one of the most common oral mucosal lesions. Transforming growth factor-ß (TGF- ß) has a marked effect on epithelial­mesenchymal transition and immune cells function. Vascular Endothelial Growth Factor (VEGF) is a key regulator of vasculogenesis and angiogenesis. Tumor necrosis factor-α (TNF-α) mediates T-lymphocyte homing and apoptosis of epithelial cells. Objetive: The present study was conducted in order to compare the expression of serum and salivary TGF- ß, VEGF, TNF-α between OLP patients and control individuals to investigate if saliva can be used as an alternative to serum for diagnostic purposes and for monitoring disease. Materials and Methods: 23 OLP patients and 23 control individuals were included to evaluate serum and salivary TGF-ß, VEGF, TNF-α using ELISA kits. Five milliliters of venous blood was collected and unstimulated saliva was collected by the spitting method. Results: Serum and salivary levels of TGF- ß, VEGF, TNF-α are higher in OLP patients compared to normal controls. Mean difference is higher in saliva than serum. Moreover, there was a significant difference in serum and salivary VEGF and TNF-α between symptomatic and asymptomatic groups. Conclusions: Saliva can be a used as a substitute for serum to evaluate levels of the assessed biomarkers.

Introducción: El liquen plano oral es una de las lesiones de la mucosa oral más comunes. El factor de crecimiento transformante ß (TGF-ß) tiene un efecto marcado sobre la transición epitelial-mesenquimal y la función de las células inmunes. El factor de crecimiento endotelial vascular (VEGF) es un regulador clave de la vasculogénesis y la angiogénesis. El factor de necrosis tumoral α (TNF-α) media la localización de los linfocitos T y la apoptosis de las células epiteliales. Objetivo: El presente estudio se realizó con el fin de comparar la expresión en suero y saliva de TGF-ß, VEGF, TNF-α entre pacientes con OLP y personas de control para investigar si la saliva se puede utilizar como alternativa al suero para fines de diagnóstico y monitoreo de la enfermedad. Material y Métodos: Se incluyeron 23 pacientes con OLP y 23 individuos control para evaluar los niéveles en suero y en saliva de TGF- ß, VEGF, TNF-α utilizando kits ELISA. Se recogieron cinco mililitros de sangre venosa y se recogió saliva no estimulada por el método de escupir. Resultado: Los niveles séricos y salivales de TGF-ß, VEGF, TNF-α son más altos en pacientes con OLP en comparación con los controles normales. La diferencia media es mayor en saliva que en suero. Además, hubo una diferencia significativa de VEGF y TNF-α en suero y saliva entre los grupos sintomáticos y asintomáticos. Conclusion: La saliva puede usarse como un sustituto del suero para evaluar los niveles de los biomarcadores estudiados

IIncreased serum expression of inflammatory cytokines may serve as potential diagnostic biomarker for bilirubin encephalopathy

OBJECTIVES: The present study was designed to explore the roles of inflammatory cytokines interleukin-1β (IL-1β) and Tumor growth factor-β (TGF-β) in the diagnosis and treatment of neonate bilirubin encephalopathy (BE). METHODS: A total of 128 BE neonates and 128 normal neonates were included. The serum samples of the BE children and controls were collected, and the levels of IL-1β and TGF-β were examined. Moreover, the correlation between the level of bilirubin and serum expression of IL-1β or TGF-β in BE patients was analyzed. Finally, receiver operating characteristic (ROC) curves were generated to determine the diagnostic value of the cytokines. RESULTS: IL-1β and TGF-β levels were higher in the serum of BE patients than those in non-BE patients, and the expression of either IL-1β or TGF-β showed a strong positive correlation with the serum expression of bilirubin in BE patients. Moreover, the results of ROC analysis showed that either IL-1β or TGF-β could distinguish BE patients from healthy controls. CONCLUSION: IL-1β and TGF-β levels were upregulated in BE and might function as potential biomarkers or therapeutic targets for BE patients.

Extract of Ascaris suum induces TGF-ß and early production of IgG1 in experimental autoimmune hepatitis / Extrato de Ascaris suum induz TGF-ß e produção precoce de IgG1 na hepatite autoimune experimental

Abstract In experimental autoimmune hepatitis (EAH) of Th1 profile, an extract of adult Ascaris suum worms (ASC) was previously found to deviate the immune response to a Th2/IL-10 pattern. Here, the effects of treatment with ASC on production of TGF-β and the anti-Ascaris isotypes IgG1 and IgG2a in EAH were evaluated. EAH was induced in BALB/c mice, intravenously with concanavalin A. Two hours later, these animals received ASC (EAH+ASC group) or PBS vehicle (EAH group). IgG1 and IgG2a were evaluated 8 h, 24 h and 7 d after induction. TGF-β was measured in a splenocyte culture at this last time. The isotype levels in the EAH group were low throughout the kinetics. In the EAH+ASC group, there was significant production of IgG1 at 24 h and 7 d, but of IgG2a only at 7 d. There was statistically greater production of TGF-β in the EAH+ASC group. The higher levels of IgG1 and TGF-β in this group suggest that an additional Th1 response control route exists in EAH, which needs to be investigated.

Resumo Na hepatite autoimune experimental (HAE) de perfil Th1, o extrato de vermes adultos Ascaris suum (ASC) desviou a resposta imune para um padrão Th2/IL-10. Neste trabalho, foram avaliados os efeitos do tratamento com ASC na produção TGF-β e dos isótipos de IgG1 e IgG2a anti-Ascaris na HAE. Esta foi induzida em camundongos BALB/c intravenosamente com Concanavalina A. Após duas horas, os animais receberam ASC (grupo HAE+ASC) ou veículo PBS (grupo HAE). IgG1 e IgG2a foram avaliados em 8 horas, 24 horas e 7 dias após indução. TGF-β foi mensurado em cultura de esplenócitos nesse último tempo. Os níveis dos isótipos no grupo HAE foram baixos durante toda a cinética. No grupo HAE+ASC, houve produção significativa de IgG1 em 24 horas e 7 dias, mas somente em 7 dias para IgG2a. A produção de TGF-β foi estatisticamente maior no grupo HAE+ASC. Níveis mais altos de IgG1 e TGF-β nesse grupo sugerem uma via adicional de controle da resposta Th1 na HAE que precisa ser investigada.

Impact of history of periodontitis on gene expression of bone-related factors in young patients

Abstract Although dental implants and bone regenerative procedures are important approaches for the reestablishment of esthetics and function in young patients with a history of generalized aggressive periodontitis (GAP), no predictable outcomes have been reported, and the host osteo-immunoinflammatory response may play a relevant role in this context. In view of the lack of molecular investigations into the bone tissue condition of young patients with periodontitis, the aim of this study was to evaluate the gene expression of bone-related factors in this population. Bone biopsies were obtained from the posterior mandible in 16 individuals previously diagnosed with GAP and on periodontal support therapy and from 17 periodontally healthy (PH) patients. The gene expression of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, receptor activator of the NF-κB ligand (RANKL), osteoprotegerin (OPG), osteocalcin (OC), bone sialoprotein (BSP), and type I collagen (COL-I), important biomarkers of bone turnover, was evaluated by qRT-PCR. Lower TGF-β and OPG mRNA levels were observed in GAP patients compared to PH individuals (p ≤ 0.05). There were no between-group differences in levels of TNF-α, BSP, RANKL, OC, or COL-I mRNA (p>0.05). In young adults, a history of periodontal disease can negatively modulate the gene expression of important bone-related factors in alveolar bone tissue. These molecular outcomes may contribute to the future development of therapeutic approaches to benefit bone healing in young patients with history of periodontitis via modulation of osteo-immuno-inflammatory biomarkers.

Definición, patogenia y factores de riesgo de la fibrosis pulmonar idiopática / Definition, pathogenesis and risk factors of idiopathic pulmonary fibrosis

La fibrosis pulmonar idiopática (FPI) es una forma específica de neumonía intersticial idiopática, de tipo fibrosante crónica y progresiva, con patrón radiológico y/o histológico de neumonía intersticial usual (NIU). Su patogenia es compleja, el modelo más aceptado actualmente es basado en las células epiteliales alveolares, aberrantemente activadas que conducen a la proliferación de fibroblastos y su diferenciación a miofibroblastos que depositan matriz extracelular y destruyen irreversiblemente la arquitectura pulmonar. No existe un claro factor inicial que explique la activación y posterior mantención del mecanismo de la fibrosis. El factor de crecimiento transformante beta (TGF-β) liberado por las células epiteliales alveolares se ha implicado como unos de los principales conductores de la inducción y proliferación de fibroblastos alterados que persiste mucho tiempo después de la estimulación inicial, lo que explicaría en gran parte el comportamiento clínico progresivo y crónico.

Idiopathic pulmonary fibrosis (IPF) is a specific form of idiopathic interstitial pneumonia, of chronic and progressive fibrosing type, with radiological and / or histological pattern of usual interstitial pneumonia (UIP). Its pathogenesis is complex, the most accepted model currently is based on the fact that the alveolar epithelial cells, aberrantly activated, lead to the proliferation of fibroblasts and their differentiation to myofibroblasts that deposit extracellular matrix and irreversibly destroy the pulmonary architecture. There is no clear initial trigger that explains the activation and subsequent maintenance of the fibrosis mechanism. The transforming growth factor beta (TGF-β), released by the alveolar epithelial cells, has been implicated as one of the main drivers of the induction and proliferation of altered fibroblasts that persists long after the initial stimulation, which would largely explain progressive and chronic clinical behavior.

Interplay of TGFβ signaling and microRNA in thyroid cell loss of differentiation and cancer progression

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.

Positive outcomes of phosphodiesterase type 5 inhibitor on histopathologic and biochemical changes induced by ureteral obstruction

SUMMARY OBJECTIVES: We examined the effects of tadalafil, one of the phosphodiesterase type 5 (PDE5) inhibitors, in a rat model of with partial and complete unilateral ureteral obstruction (UUO). METHODS: The rats were divided into 5 groups: sham (n=6), partial unilateral ureteral obstruction (PUUO, n=6), PUUO with tadalafil treatment (PUUO+T; Cialis, 10 mg/72 h, intragastric; Lilly, Indianapolis, Indiana, USA), complete unilateral ureteral obstruction (CUUO, n=6), and CUUO with tadalafil treatment (CUUO+T). RESULTS: Fifteen days after the UUO, the ureter presented changes in the layers of urothelium and significant infiltration of inflammatory cells in the PUUO and CUUO groups. Compared with the sham, PUUO and CUUO groups had severe increased inflammatory cell infiltration. The urothelial epithelium exhibited cell degeneration and loss because of the swollen, atrophic, and denuded epithelial cells in the PUUO and CUUO groups. In the PUUO+T and CUUO+T groups, the urothelium revealed less epithelial cell degeneration and loss. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β) exhibited up-regulation in the PUUO and CUUO groups. The expression of TGF-β decreased positively correlated with that of α-SMA in the tadalafil therapy groups, PUUO+T and CUUO+T. CONCLUSION: The phosphodiesterase type 5 inhibitor's tadalafil reduced expressions of α-SMA and TGF-β in the obstructed ureters, measured by biochemical examinations. In addition, tadalafil decreased urothelium degeneration due to the decreased epithelial cell loss and inflammatory cell infiltration. Our results show that tadalafil prevents or slows down the onset of ureter inflammation and urothelial degeneration in rats with UUO.

RESUMO OBJETIVOS: Examinamos os efeitos do tadalafil em um dos inibidores da fosfodiesterase tipo 5 (PDE5) em um modelo de rato com obstrução ureteral unilateral parcial e completa (UUO). MÉTODOS: Os ratos foram divididos em cinco grupos: sham (n = 6), obstrução ureteral unilateral parcial (PUUO, n = 6), PUUO com tadalafil (PUUO T; Cialis, 10 mg/72 h, intragástrica; Lilly, Indianapolis, Indiana, EUA), completa obstrução ureteral unilateral (CUUO, n = 6) e CUUO com tratamento com tadalafil (CUUO T). RESULTADOS: Quinze dias após a UUO, o ureter apresentou alterações nas camadas de urotélio e infiltração significativa de células inflamatórias nos grupos PUUO e CUUO. Em comparação com os grupos sham, PUUO e CUUO, houve um aumento grave da infiltração de células inflamatórias. O epitélio urotelial exibiu degeneração e perda celular devido às células epiteliais inchadas, atróficas e desnudas nos grupos PUUO e CUUO. Nos grupos PUUO T e CUUO T, o urotélio revelou menor degeneração e perda de células epiteliais. Nós mostramos que a expressão da actina do músculo liso-α (α-SMA) e do fator de crescimento transformador-β (TGF-β) foram exibidas como sub-regulação nos grupos PUUO e CUUO. A expressão do TGF-β foi diminuída positivamente correlacionada com a da α-SMA nos grupos de terapia com tadalafil, PUUO T e CUUO T. CONCLUSÃO: O tadalafil do inibidor da fosfodiesterase tipo 5 reduziu as expressões α-SMA e TGF-β nos ureteres obstruídos, medidos por exames bioquímicos. Além disso, o tadalafil diminuiu a degeneração do urotélio devido à diminuição da perda de células epiteliais e da infiltração de células inflamatórias. Nossos resultados mostram que o tadalafil previne ou retarda o início da inflamação do ureter e degeneração urotelial em ratos com UUO.

Cytokines and chemokines associated with Treg/Th17 response in chronic inflammatory periapical disease

Abstract Cytokines and chemokines have a fundamental role in the maintenance of inflammation and bone response, which culminate in the development of chronic periapical lesions. Regulatory (Treg) and Th17 cytokines play a key role in regulating the immune response involved in this process. The aim of this study was to investigate the role of Treg and Th17 cells in chronic inflammatory periapical disease, by comparing the expression of the immunoregulatory mediators TGF-β, IL-10, CCL4, and the proinflammatory IL-17 and CCL20 in the periapical tissue of teeth with pulp necrosis, with and without associated chronic lesions. Eighty-six periapical tissue samples were obtained from human teeth. The samples were divided into three groups: pulp necrosis with a periapical lesion (n=26); pulp necrosis without a periapical lesion (n=30), and control (n=30). All samples were submitted to histopathological analysis and cytokine and chemokine measurement through ELISA. Statistical analyses were done with Kruskal-Wallis and Mann-Whitney tests and Spearman correlation. The group with pulp necrosis and a periapical lesion showed a higher expression of CCL4 and TGF-β in comparison with pulp necrosis without a lesion. CCL20 was higher in the group with a periapical lesion when compared to the control. In all groups there was a weak positive correlation between IL-17/CCL20, IL-10/CCL4, and IL-17/TGF-β. Both types of cytokines, pro-inflammatory and immunoregulatory, occur simultaneously in periapical tissue. However, a rise in immunosuppressive cytokines and chemokines (CCL4 and TGF-β) in periapical lesions suggests a role of these cytokines in stable periapical disease.