Induction of perineural invasion in salivary adenoid cystic carcinoma by circular RNA RNF111

Objective Local recurrence, distant metastasis, and perineural invasion (PNI) viciously occur in salivary adenoid cystic carcinoma (SACC), resulting in a poor prognosis. This study aimed to explore the mechanism by which circular RNA RNF111 (circ-RNF111) regulates PNI in SACC by targeting the miR-361-5p/high mobility group box 2 (HMGB2) axis. Method Circ-RNF111 and HMGB2 were highly expressed in SACC specimens, while miR-361-5p was underexpressed. Functional experiments showed that ablating circ-RNF111 or promoting miR-361-5p hindered the biological functions and PNI of SACC-LM cells. Results HMGB2 overexpression induced the reversal of SACC-LM cell biological functions and PNI caused by circ-RNF111 knockout. Furthermore, reduction of circ-RNF111 suppressed PNI in a SACC xenograft model. Circ-RNF111 regulated HMGB2 expression through targeted modulation of miR-361-5p. Conclusion Taken together, circ-RNF111 stimulates PNI in SACC by miR-361-5p/HMGB2 axis and may serve as a potential therapeutic target for SACC (AU)

LncRNA OTUD6B-AS1 overexpression promoted GPX4-mediated ferroptosis to suppress radioresistance in colorectal cancer

Background Radiotherapy is widely employed in colorectal cancer (CRC) treatment but is often compromised by developed radioresistance. This study explored the mechanism of long non-coding RNA ovarian tumor domain containing 6B-antisense RNA1 (lncRNA OTUD6B-AS1) in CRC radioresistance through tripartite motif 16 (TRIM16). Methods CRC and non-cancerous tissues were collected and radioresistant CRC cells were established, with real-time quantitative polymerase chain reaction to determine gene expression in tissues and cells. Radioresistance was evaluated by cell counting kit-8 assay and immunofluorescence (γ-H2AX) and ferroptosis was tested by Western blot assay (ACSL4/GPX4) and assay kits (Fe2+/ROS/MDA/GSH). The association between ferroptosis and lncRNA OTUD6B-AS1-inhibited radioresistance was testified using ferroptosis inhibitor. The subcellular localization of lncRNA OTUD6B-AS1 was tested by the nuclear/cytoplasmic fractionation assay, with RNA immunoprecipitation assay to validate gene interactions. Rescue experiments were conducted to analyze the role of TRIM16 in CRC radioresistance. Results LncRNA OTUD6B-AS1 and TRIM16 were poorly expressed (P < 0.01) in CRC tissues and cells and further decreased (P < 0.01) in radioresistant CRC cells. OTUD6B-AS1 overexpression decreased cell survival (P < 0.01), increased γ-H2AX levels (P < 0.01), and elevated ferroptosis and oxidative stress (P < 0.01) after X-ray radiation. Ferroptosis inhibitor attenuated radioresistance (P < 0.01) caused by lncRNA OTUD6B-AS1 overexpression. LncRNA OTUD6B-AS1 stabilized TRIM16 mRNA via binding to HuR. TRIM16 knockdown reduced ferroptosis and increased radioresistance (P < 0.05). Conclusion OTUD6B-AS1 overexpression stabilized TRIM16 via binding to HuR and increased GPX4-mediated ferroptosis, thus attenuating CRC radioresistance. Our study provided a new rationale for the treatment of CRC (AU)

RNF20/RNF40 ameliorates streptozotocin-induced type 1 diabetes by activating vitamin D receptors in vivo

Background: Type 1 diabetes is one of the chronic autoimmune diseases. Its features include the immune-triggered pancreatic beta-cells destruction. Ubiquitin ligases RNF20 and RNF40 have been discovered to participate into beta cells gene expression, insulin secretion, and expression of vitamin D receptors (VDRs). However, no reports about the role of RNF20/RNF40 in type 1 diabetes are known till now. The aim of this study was to clarify the role of RNF20/RNF40 in type 1 diabetes and explore the mechanism. Methods: In this study, streptozotocin (STZ)-induced mice type 1 diabetes model was used. The protein expressions of genes were examined through Western blot analysis. Fasting blood glucose was detected through glucose meter. The plasma insulin was tested through the commercial kit. Hematoxylin and eosin staining was utilized to observe pathological changes of pancreatic tissues. Immunofluorescence assay was performed to evaluate the level of insulin. The levels of pro-inflammatory cytokines in serum were assessed by enzyme-linked-immunosorbent serologic assay. The cell apoptosis was measured through terminal deoxynucleotidyl transferase dUTP nick end labelling assay. Results: STZ was used to stimulate mice model for type 1 diabetes. At first, both RNF20 and RNF40 expressions were down-regulated in STZ-mediated type 1 diabetes. Additionally, RNF20/RNF40 improved hyperglycemia in STZ-stimulated mice. Moreover, RNF20/RNF40 relieved pancreatic tissue injury in STZ-induced mice. Further experiments found that RNF20/RNF40 rescued the strengthened inflammation mediated by STZ treatment. The cell apoptosis was enhanced in the pancreatic tissues of STZ-triggered mice, but this effect was weakened by overexpression of RNF20/RNF40 (AU)

Gamma-Tocotrienol prevents cell cycle arrest in aged human fibroblast cells through p16INK4a pathway

Human diploid fibroblasts (HDFs) proliferation in culture has been used as a model of aging at the cellular level. Growth arrest is one of the most important mechanisms responsible for replicative senescence. Recent researches have been focusing on the function of vitamin E in modulating cellular signaling and gene expression. Therefore, the aim of this study was to elucidate the effect of palm γ-tocotrienol (vitamin E) in modulating cellular aging through p16INK4a pathway in HDF cells. Primary culture of senescent HDFs was incubated with 70 μM of palm γ-tocotrienol for 24 hours. Silencing of p16INK4a was carried out by siRNA transfection. RNA was extracted from the different treatment groups and gene expression analysis was carried out by real-time reverse transcription polymerase chain reaction. Proteins that were regulated by p16INK4a were determined by western blot technique. The finding of this study showed that p16INK4a mRNA was overexpressed in senescent HDFs, and hypophosphorylated-pRb and cyclin D1 protein expressions were increased (p < 0.05). However, downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (p < 0.05) by γ-tocotrienol led to modulation of the cell cycle regulation during cellular aging. In conclusion, senescent HDFs showed change in biological process specifically in cell cycle regulation with elevated expression of genes and proteins which may contribute to cell cycle arrest. Palm γ-tocotrienol may delay cellular senescence of HDFs by regulating cell cycle through downregulation of p16INK4a and hypophosphorylated-pRb and cyclin D1 protein expressions (AU)

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La expresión inmunohistoquímica de ciclina B1 conlleva mayores valores de SUV en la 18F-FDG-PET de pacientes con carcinomas no microcíticos de pulmón. Primeros resultados / The immunohistochemical expression of cyclin B1 is associated with higher SUV in 18F-FDG-PET in non-sma ll cell lung cancer patients. Initial results

Objetivo: estudiar la posible correlación entre la expresión de ciclina B1, proliferación celular y la SUV máxima-18F-FDG-PET en pacientes con carcinomas no microcíticos pulmonares. Material y metodo: se incluyó a 49 pacientes (15 adenocarcinomas, 27 carcinomas escamosos y 7 carcinomas broncoalveolares) y se realizó la expresión inmunohistoquímica de ciclina B1 mediante tissue-arrays. Asimismo, analizamos la proliferación celular (MIB-1). El PET se realizó 60 min después de la administración intravenosa (i.v.) de 350-518 MBq de 18F-FDG en un PET (Advance, GE) y adquisión en 2D. Resultados: la expresión inmunohistoquímica de ciclina B1 se detectó en 40 (81,6%) casos y no se relacionó con el estadio clínico (I-II: 17/21 frente a III-IV: 23/28). Los valores de SUV fueron mayores (p = 0,04) en los casos positivos (16,4 ± 8,1) que en los negativos (10,9 ± 6,2) y no difirieron en función del estadio clínico. La expresión de ciclina B1 se correlacionó (p < 0,0001) con la de MIB1. Tras análisis univariable, la ciclina B1 y los valores SUV no fueron factores pronósticos, pero sí la proliferación celular (p = 0,037). Conclusiones: nuestros resultados muestran una relación directa entre la expresión de ciclina B1 y los valores max SUV en el PET de pacientes afectos de carcinomas no microcíticos de pulmón, lo cual, unido a la asociación de aquella con la positividad del MIB1, apoya el papel de la proliferación celular en la captación del radiofármaco por el tumor(AU)

Aim: to study the expression of cyclin B1 and its possible relationship with the maximum SUV in FDG-PET and MIB1 expression in patients with NSCLC. Materials and methods: 49 patients (15 adenocarcinomas, 27 squamous cell carcinomas and 7 bronchoalveolar carcinomas) were included in this study; the immunohistochemical expression of cyclin B1 was determined using the tissue-array technique. Each PET was performed 60 minutes after the i.v. administration of 350-518 MBq of FDG on an Advance system (GE) in 2D acquisition mode. Results: cyclin B1 expression was detected in 40 out of 45 cases. The SUV values were higher (p = 0.04) in the cyclin B1+ cases than in the negative cases (16.4 ± 8.1 vs 10.9 ± 6.2). Cyclin B1 expression and SUV values were not correlated with the clinical stage. The expression of cyclin B1+ correlated positively (p < 0.0001) with that of MIB1. After univariate analysis, only the cellular proliferation was a prognostic factor (p = 0.037). Conclusions: our results suggest that there is a direct correlation between cyclin B1 expression and max-SUV values in the PET of NSCLC patients. When the association of cyclin B1 with positive MIB1 is also considered(AU)

Vía de la ubiquitina-proteosoma / Ubiquitin-proteasome pathway

Los sistemas intracelulares proteolíticos reconocen y degradan proteínas lesionadas o mal plegadas. La vía de la ubiquitina proteosoma se encuentra implicada en el recambio intracelular de las proteínas y juega un papel importante en la degradación de proteínas reguladoras de vida corta, implicadas en una serie amplia de procesos celulares tales como: regulación del ciclo celular, modulación de los receptores de superficie y canales iónicos, procesamiento y presentación de antígenos y activacion de factores de transcripción. Esta vía utiliza una cascada enzimática, mediante la cual moléculas de ubiquitina se insertan covalentemente a la proteína sustrato. Un paso importante en la cascada proteolítica es el reconocimiento del sustrato por una de las muchas ubiquitina ligasas, E3, lo cual conduce a la poliubiquitinación o señal de degradación. La modificación por poliubiquitinación marca a la proteína para su destrucción y la conduce al complejo proteosoma 26S para su degradación proteolítica

Intracellular proteolytic systems recognize and destroy misfolded or damaged proteins. The ubiquitin-proteasome pathway is widely involved in intracellular protein turnover. It plays a central role in degradation of short-lived and regulatory proteins important in a broad array of cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, antigen processing and presentation and activation of transcription factors. The pathway employs an enzymatic cascade by which multiple ubiquitin molecules are covalently attached to the protein substrate. An important step in the proteolytic cascade is the specific recognition of the substrate by one of many ubiquitin ligases, E3s, which is followed by generation of the polyubiquitin degradation signal.The polyubiquitin modification marks the protein for destruction and directs it to the 26S proteasome complex for proteolytic degradation

Análisis mutacional del gen vhl en el carcinoma de células renales de aparición esporádica / Mutational anaylysis of the vhl gene in the sporadic renal cell carcinoma

OBJETIVO: Determinar mutaciones en el gen vhl y caracterizar las mismas en muestras de tejido tumoral de 30 pacientes intervenidos por carcinoma renal de células claras en nuestro servicio.MÉTODO: Estudio descriptivo observacional y analítico sobre 30 pacientes intervenidos por CCR, que analiza la secuencia del gen vhl del tejido tumoral y se usa como control tejido renal sano de los mismos pacientes. Los tejidos fueron sometidos a procesos de extracción de ADN, amplificación de los 3 exones que conforman el gen mediante PCR y posterior secuenciación automática de los exones amplificados entre cebadores intrónicos diseñados previamente. La secuencia se compara con la de los correspondientes exones incluidos en GenBank. Las alteraciones fueron corroboradas mediante secuenciación en dirección opuesta. RESULTADOS: Se han encontrado un total de 9 mutaciones (30 por ciento) en las distintas muestras tumorales analizadas. 7 de ellas fueron puntuales, siendo una de ellas intrónica; las otras dos mutaciones halladas consistieron en deleciones. Las mutaciones se repartieron entre los tres exones de la siguiente manera: 3 en exón 1, 4 en exón 2, 1 en exón 3 y 1 intrónica. En una misma muestra se hallaron 2 mutaciones. El tejido control está libre de alteraciones.CONCLUSIÓN: El CCR esporádico presenta mutaciones en el gen vhl, que aparecen fundamentalmente en el subtipo de células claras. Dichas alteraciones dan lugar a graves perturbaciones en la proteína, alterando su función supresora tumoral (AU)

Diagnóstico de la enfermedad de Parkinson / Diagnosis of parkinson's disease

Introducción. En el presente artículo se realiza una revisión actualizada de la literatura sobre el diagnóstico de la enfermedad de Parkinson, y se consideran los aspectos clínicos, la neuroimagen y el diagnóstico genético. Desarrollo. La enfermedad de Parkinson es la segunda enfermedad neurodegenerativa más común y, a pesar del importante desarrollo que se ha producido en los últimos años, tanto en genética molecular como en neurorradiología, el diagnóstico de esta enfermedad es todavía eminentemente clínico; el conocimiento adecuado de los llamados 'signos cardinales' y su aplicación en el diagnóstico aumentan la posibilidad que éste acierte; lamentablemente, el criterio definitivo sólo se obtiene en la autopsia. Los estudios genéticos y de neurorradiología, sobre todo, se presentan como herramientas para un diagnóstico diferencial más fiable con respecto a otras formas de parkinsonismo, y el conocimiento de estas técnicas puede resultar útil en la toma de decisiones terapéuticas o en el tratamiento integral del paciente afectado. Además, se han encontrado formas monogénicas diferentes en origen a la forma esporádica de la enfermedad. Conclusión. El conocimiento y búsqueda de los signos clínicos preponderantes aumenta la capacidad de diagnóstico de la enfermedad, e, igualmente, el uso adecuado de métodos adicionales de investigación, sobre todo en el diagnóstico diferencial (AU)

Introduction. Presently article carried out an up-to-date revision of the literature on the diagnosis of the Parkinson’s disease, considering the clinical aspects, those of neuroradiology and the genetic diagnosis. Development. The Parkinson’s disease is the second most common neurodegenerative disorder and despite of the important development that has taken place in the last years as much in molecular genetics and neuroradiology, the diagnosis of this disease continuous being eminently clinical, the appropriate knowledge of the calls ‘cardinal signs’ and its application in the diagnosis increases the possibility that this it is guessed right, regrettably the definitive approach is only obtained in the autopsy. The genetic studies and of neuroradiology mainly are presented as tools for a more reliable differential diagnosis with other parkinsonism forms and the knowledge of these techniques can be useful in the taking of therapeutic decisions or of the affected patient’s integral treatment. They have also been different monogenics forms in origin to the sporadic form of the illness. Conclusion. The knowledge and search of the preponderant clinical signs increases the capacity of diagnostic of the illness, in the same way the appropriate use of additional methods of investigation, mainly in the differential diagnosis (AU)

Genética de la enfermedad de Parkinson / Genetics and Parkinson disease

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