The mechanism of target regulating of miR-421 to Menin/Caspase-3 pathway for depression / 实用医学杂志

Objective To explore the mechanism of miR-421 affecting the occurrence and development of depression.Methods A depressive rat model was established by single intraperitoneal injection of lipopolysaccharide(LPS),and depressive behavior was detected by glucose preference test and open-field test.miRNA microarray chips and RT-PCR were used to analyze the expression level of miR-421 in hippocampus of the depressed rats.TargetScan database and mi RDB database were used to predict the target genes of miR-421.Dual luciferase reporter gene assay was used to observe the binding of miR-421 to the target genes.The impact of over-expression and inhibition of miR-421 on target genes was observed,then the influence of over-expression and inhibition of target genes on downstream factors was observed,and the related mechanism of miR-421 on depression was explored.Results miRNA microarray chips and RT-PCR assay showed that miR-421 was highly expressed in the hippocampus of the depressed rats(P<0.001),Inhibition of miR-421 expression could significantly restore the body weight and exercise ability of the depressed rats(P<0.001).Binding targets of Menin and miR-421 were predicted by TargetScan database,and interaction between Menin and miR-421 was demonstrated by dual-luciferase reporter gene assay.Menin expression was down-regulated while miR-421 was overexpressed(P<0.001),whereas it was up-regulated as miR-421 was inhibited(P<0.001).qPCR indicated that expressions of Caspase-3 and NF-κB in the hippocampus of the depressed rats was significantly increased(P<0.001),and IL-1β expression in the hippo-campus was significantly increased(P<0.01).When the expression of Menin was inhibited,the expressions of Caspase-3,NF-κB and IL-1β were increased(P<0.001),while the expressions of Caspase-3,NF-κB and IL-1β were decreased when Menin was overexpressed(P<0.001).Conclusions Inhibition of miR-421 expression can increase Menin expression,decrease Caspase-3 content,and reduce neuroinflammatory response,thereby improving depressive symptoms.

Optimization of Menin inhibitors based on artificial intelligence-driven molecular factory technology / 中国药科大学学报

@#Abstract: The new generation of artificial intelligence technology, represented by deep learning, has emerged as a crucial driving force in the advancement of new drug research and development. This article creatively proposes a workflow named “Molecular Factory” for the design and optimization of drug molecules based on artificial intelligence technology. This workflow integrates intelligent molecular generation models, high-performance molecular docking algorithms, and accurate protein-ligand binding affinity prediction methods. It has been integrated as a core module into DrugFlow, a one-stop drug design software platform, providing a comprehensive set of mature solutions for the discovery and optimization of lead compounds. Utilizing the “Molecular Factory” module, we conducted the research of second-generation inhibitors against Menin that can combat drug resistance. Through the integration of computational and experimental approaches, we rapidly identified multiple promising compounds. Among them, compound RG-10 exhibited the IC50 values of 9.681 nmol/L, 233.2 nmol/L, and 40.09 nmol/L against the wild-type Menin, M327I mutant, and T349M mutant, respectively. Compared to the positive reference molecule SNDX-5613, which has entered Phase II clinical trials, RG-10 demonstrated significantly enhanced inhibitory activity against the M327I and T349M mutants. These findings fully demonstrate the unique advantages of the "Molecular Factory" technology in practical drug design and development scenarios. It can rapidly and efficiently generate high-quality active molecules targeting specific protein structures, holding significant value and profound implications for advancing new drug discovery.

Validación de material educativo del programa "Niñ@s en Movimiento" para el tratamiento de la obesidad infantil / Validation of educational material of the "Niñ@s en Movimiento" program for the treatment of childhood obesity / Avaliação de material educativo do programa "Menin@s em Movimento" para o tratamento do sobrepeso infantil

Resumen Objetivo: Validar, en un contexto colombiano, el contenido de la primera cartilla del programa "Niñ@s en Movimiento" (diseñada en España), dirigida a padres o cuidadores, y a los niños que padecen sobrepeso u obesidad, disponible en internet con acceso libre. Metodología: Investigación cualitativa. Tras el proceso de selección, participaron 14 niños con sobrepeso y sus padres o cuidadores, del Colegio Básico "Camino de Paz" de Medellín. Para la clasificación de los datos antropométricos se utilizó el programa de la Organización Mundial de la Salud. Para la validación de la cartilla se elaboró una guía de preguntas y se realizaron grupos focales; se usaron los criterios de atractividad, entendimiento, identificación, aceptación e inducción a la acción. Los datos se analizaron mediante el software spss® versión 21.0, y un protocolo de análisis de datos. Resultados: En la sección "La importancia del desayuno", del material educativo, algunos padres o cuidadores manifestaron que es necesario indicar la forma adecuada para preparar los alimentos, en qué condiciones y qué cantidad deben servirles a sus hijos, lo cual no es claro en la cartilla. Respecto a los niños, en las secciones "Mis desayunos" y "Clasificación de los alimentos" se encontró que las palabras técnicas dificultan la comprensión; además, al hablar de la clasificación de alimentos, algunos no los han visto ni consumido. En la evaluación de los criterios por parte del padre o cuidador, el entendimiento fue mal calificado, porque no son claros algunos términos; los niños también calificaron negativamente este criterio, por la dificultad para entender vocabulario desconocido debido a su contexto extranjero. Conclusiones: El desayuno, aunque es un hábito establecido, puede mejorar; sin embargo, las orientaciones de la cartilla tendrían que adaptarse al lenguaje y a la cultura alimentaria local, para que las recomendaciones mejoren la aplicabilidad de este recurso educativo.

Abstract Objective: To validate the content of the first booklet "Niñ@s en Movimiento" (designed in Spain), in the Colombian setting, targeting parents or caretakers, and overweight or obese chil dren, which is available free online. Methodology: Qualitati ve research. After a selection process, 14 overweight children and their parents or caretakers were selected to participate. The children were students at the Colegio Básico "Camino de Paz" School in Medellin. To classify anthropometric data, the study used the World Health Organization program. To validate the booklet, a question guideline was drawn up and focus groups were held. The criteria used included attraction, comprehen sion, identification, acceptance and induction to action. Data were analyzed using the SPSS® software Version 21.0, and a data analysis protocol. Results: In the section "the impor tance of breakfast", in the educational material, some parents or caretakers stated that it is necessary to indicate an adequa te way to prepare food, how to serve it and the amounts that they should their children, which is not clear in the booklet. Regarding the children, in the sections "my breakfasts" and "food classification", there were technical words that compli cated comprehension. Furthermore, when talking about food classification, there are foods they have not seen nor eaten. In the parent or caretaker criteria evaluation, comprehension was poorly scored, as some of the terms were not clear. The children also ranked negatively this criterion. Vocabulary was difficult to understand because it had a foreign context. Con clusions: Breakfast, although an established habit, can impro ve; nevertheless, the guidelines of the booklet would have to be adapted to local language and food culture so that these recommendations may improve the applicability of this edu cational resource.

Resumo Objetivo: Avaliar, num âmbito colombiano, o conteúdo da primeira apostilha do programa "Menin@s em Movimento" (desenhada na Espanha), voltada aos pães ou cuidadores, e aos meninos que padecem sobrepeso ou obesidade, disponível na internet com ingresso libre. Metodologia: Investigação qua litativa. Trás o processo de escolha, participaram 14 meninos com sobrepeso e os seus pães ou cuidadores, da Escola Básica "Caminho de Paz" do Medellín. Para a classificação dos da dos antropométricos se utilizou o programa da Organização Mundial da Saúde. Para a avaliação da apostilha se elaborou uma guia de perguntas e se realizaram grupos focais; se usaram os critérios de atratividade, entendimento, identificação, acei tação e indução pra ação. Os dados se analisaram mediante o software SPSS® versão 21.0, e um protocolo de análises de dados. Resultantes: Na seção "A importância do dejejum", do material educativo, alguns pães ou cuidadores manifestaram que é quesito indicar o jeito mais pertinente na preparação dos alimentos, em que condições e qual quantidade devem servir-lhes aos seus filhos, o qual não apresenta clareza na cartilha. Aludindo aos meninos, nas secções "Meus cafés da manhã" e "Classificação dos alimentos" se encontrou que as expressões técnicas dificultam a compreensão; além disso, ao mencionar a classificação dos alimentos, alguns nem os conhecem nem consumiram jamais. Na avaliação dos critérios por parte do pai ou cuidador, ou entendimento foi mal qualificado, porque não são simples alguns termos; os meninos também qualificaram negativamente este critério, pela dificuldade para compreender glossário desconhecido devido ao seu contexto estrangeiro. Conclusões: O dejejum, ainda que é um hábito estabelecido, pode melhorar; contudo, as dicas do caderno teriam que se customizar com a linguajem e as tradições alimentares locais, para que as recomendações melhorem a aplicabilidade de este recurso educativo.

p27 Loss Is Associated with Poor Prognosis in Gastroenteropancreatic Neuroendocrine Tumors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogeneous disease group originating from the neuroendocrine cells. Identification of prognostic markers, related to neuroendocrine tissue-selective tumorigenesis, is necessary to find therapeutic targets. MATERIALS AND METHODS: A total of 327 patients with GEP-NETs were included in this study; there were 49 gastric, 29 duodenal, 49 pancreatic, 12 hepatobiliary, 33 appendiceal, 5 proximal colon, and 150 distal colon cases. We performed immunostaining with the tissue microarray method for menin, p27, and p18. RESULTS: We observed negative staining for menin, p27, and p18 in 34%, 21%, and 56% of GEP-NETs, respectively. The loss of p27, but not menin, was positively correlated with the grade of Ki-67. Menin-/p27-, menin-/p27+, menin+/p27-, and menin+/p27+ phenotype groups included 13%, 22%, 8%, and 57% of patients, respectively. A dichotomized comparison showed that menin- or p27- tumors were significantly associated with foregut and midgut localizations, high World Health Organization (WHO) grade, lymph node metastasis, and more advanced stage as compared to menin+/p27+ patients. Kaplan-Meier analysis for the overall survival showed that p27 loss was significantly associated with decreased survival. Multivariate analysis showed that p27 loss is an independent factor for poor overall survival. CONCLUSION: Our results revealed that the loss of p27 is associated with poor prognosis and the menin-p27 pathway is important in the tumorigenesis of GEP-NETs.

Mutation analysis in two Chinese families with multiple endocrine neoplasia type 1 / Análise de mutações em duas famílias chinesas com neoplasia endócrina múltipla tipo 1

OBJECTIVE: This study aimed at identifing mutations in two Chinese genealogies with MEN1. SUBJECTS AND METHODS: Three members of two Chinese families with MEN1 were enrolled in this study, and all of the coding regions and adjacent sequences of the MEN1 gene were amplified and sequenced. RESULTS: A recurrent mutation of heterozygous change T>A at IVS 4+1 was found in family I, and a novel insGAGGTGG mutation (c.703-709dup7bp) resulted in a frameshift (p.A237Gfsx13) in family II. CONCLUSION: We are able to add a new mutation of MEN1 gene in Chinese patients with MEN1 that will be useful for the diagnosis and treatment of the disease.

OBJETIVO: O objetivo deste estudo foi identificar as mutações em duas famílias chinesas com NEM1. SUJEITOS E MÉTODOS: Três membros das duas famílias chinesas foram estudados. Em todos eles, as regiões codificadoras e sequências adjacentes do gene MEN1 foram amplificadas e sequenciadas. RESULTADOS: Uma alteração heterozigota recorrente de T>A em IVS 4+1 foi encontrada na família I, e uma nova mutação insGAGGTGG (c.703-709dup7bp) levou a um frameshift (p.A237Gfsx13) na família II. CONCLUSÃO: Adicionou-se uma nova mutação ao gene MEN1 em pacientes chineses com diagnóstico de NEM1 que vai ser útil no diagnóstico e tratamento da doença.

Intron 9 of MEN1 gene mutation-induced multiple endocrine neoplasia type 1 : one case and analysis of his pedigree / 中华内分泌代谢杂志

To study the MEN1 gene mutations in a multiple endocrine neoplasia type 1 ( MEN 1 ) family,and determine the possible mechanism of disease induced by the mutations.Genomic DNA was isolated from peripheral blood leukocytes and the MEN1-related tumor tissues of the patient and the family members,then the coding exons and exon/intron boundaries of the MEN1 gene were amplified by polymerase chain reaction (PCR) and sequenced.Subclone sequencing was performed to identify the heterozygosity.Further immunohistochemistry was performed to observe menin protein expression in the tumor tissues.We identified a heterozygous deletion mutation of intron 9 ( IVS9+ 1_11 delGTGAGGGACAG) in the proband and two family menbers.We also demonstrated for the first time that the expression of menin protein is absent in the parathyroid adenoma tissue.The heterozygous mutation in the initial of intron 9,IVS9+ 1_11 delGTGAGGGACAG is a new type of MEN1 gene mutations in China.This mutation may produce an aberrant splicing of MEN1 mRNA,generating easily degradation and loss of expression of menin protein and resulting eventually in the disease.

Multiple endocrine neoplasia: the Chilean experience

Multiple endocrine neoplasia (MEN) types 1 and 2 are genetic diseases that are inherited as autosomal traits. The major clinical manifestations of multiple endocrine neoplasia type 1 include the so-called "3 P's": parathyroid, pituitary, and pancreatic tumors, including gastroenteroneuroendocrine tumors. Genetic testing can be performed on patients and the potential carriers of the menin gene mutation, but the genotype-phenotype correlation in multiple endocrine neoplasia type 1 is less straightforward than multiple endocrine neoplasia type 2. Most likely, the main advantage of genetic testing in MEN1 is to exclude from further studies those who are negative for the genetic mutation if they belong to a family with a known history of MEN1. In Chile, we started with rearranged during transfection proto-oncogene genetic testing (MEN2) 15 years ago. We carried out a prophylactic total thyroidectomy to prevent medullary thyroid carcinoma in a three-year-old girl who presented with microscopic medullary thyroid carcinoma. More than 90% of the individuals who tested positive using a genetic test achieved a biochemical cure compared with only 27% of patients who receive a clinical diagnosis. Mutations are mainly located in exon 11; the most common is C634W, rather than C634R. Hypertensive crisis was the cause of death in three patients, and extensive distant metastases occurred in nine (including two patients with multiple endocrine neoplasia type 2B) of 14 patients. Earlier recognition of medullary thyroid carcinoma and the other features of the disease, especially pheochromocytoma, will improve the survival rate of patients with multiple endocrine neoplasia.

Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation

Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype-phenotype correlation has been established. In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype-phenotype correlation.

Mutación del gen de la menina: desde el hiperparatiroidismo familiar aislado a la neoplasia endocrina múltiple de tipo 1: [revisión] / Mutation of the menin gen: from isolated familial hyperparathyroidism to the multiple endocrine neoplasia syndrome type 1: [review]

La menina es una proteína supresora de tumor codificada por el gen MEN1, cuya mutación produce procesos neoplásicos en múltiples tejidos del organismo que pueden manifestarse por generaciones como síndromes familiares. La mutación genera un espectro de enfermedad que va desde el hiperparatiroidismo familiar aislado hasta la neoplasia endocrina múltiple de tipo 1, caracterizada por neoplasias de paratiroides, hipófisis anterior, páncreas endocrino y duodeno, entre otras. Como ejemplo, se presentan dos casos de pacientes con neoplasias endocrinas secundarias a la mutación del gen MEN1. Se revisa la información actual sobre la etiopatogenia y carcinogénesis entendidos apenas recientemente, al igual que otras mutaciones involucradas en los síndromes neoplásicos expuestos y se dan unas recomendaciones finales.

Menin is a tumor suppressor protein, encoded by the MEN1 gene, whose mutation can generate neoplastic disease in multiple tissues of the human body, which for generations can manifest as familial syndromes. The mutation generates a spectrum of diseases ranging from familial isolated hyperparathyroidism to multiple endocrine neoplasia type 1, characterized by neoplasm of parathyroid glands, anterior pituitary, endocrine pancreas and duodenum, among others. We present two cases of patients with endocrine neoplastic disease secondary to menin’s mutation. We review current information regarding its ethiopathogeny and its mechanism of carcinogenesis just recently understood. Additionally we review other mutations involved in the neoplastic syndromes exposed and present some final recommendations.

Role of menin in regulation of SOX4 gene expression / 上海第二医科大学学报

Objective To explore the role of menin in regulation of SOX4 gene expression. Methods Reporter gene vectors with SOX4 promoter were constructed,and the influence of menin on SOX4 gene promoter activity was analyzed by dual-luciferase reporter gene assay system.Real-time PCR was employed to detect the expression of SOX4 gene in mef cells of MEN1-/-mice and wild-type mef cells. Results Compared with wild-type mef cells,the SOX4 gene promoter activity was significantly higher in mef cells of MEN1-/-mice.After MEN1 gene was transfected into mef cells of MEN1-/-mice,the SOX4 gene promoter activity significantly descreased.The expression of SOX4 gene in mef cells of MEN1-/-mice was 2.5 time higher than that in wild-type mef cells. Conclusion Menin can inhibit the expression of SOX4 gene.

A Case of Multiple Endocrine Neoplasia Type 1 with Mutation in MENIN Gene / 대한내분비학회지

Multiple endocrine neoplasia type 1(MEN 1) is an autosomal dominantly inherited syndrome, characterized by the combined occurrence of tumors of the parathyroid glands, endocrine pancreas, and anterior pituitary gland. The MENIN gene, which is a kind of tumor suppressor gene, is located at the chromosomal locus 11q13. It consists of one untranslated exon and nine exons encoding the menin protein. We report a case of a 22-yearss-old woman with MEN type 1, who was proven to have a mutation in the MENIN gene. The patient was admitted because of repeated hypoglycemia. The fasting plasma glucose level was 32mg/dL. Seventy two hours fasting test showed an the insulin/glucose ratio as 0.33. Endoscopic ultrasonography detected multiple masses on the pancreas. The arterial -stimulated venous sampling(ASVS) with calcium showed sudden step up of insulin at the head and tail portions of the pancreas. The sellar MRI showed a pituitary mass that produced prolactin. Instead of a pathologic diagnosis from operational specimen, the genetic analysis revealed a mutation in the MENIN 1 gene(exon 2, 200~201insAGCCC).