Abstract BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that has long been considered to be a tumor suppressor in various tumors, including renal cell carcinoma, uveal melanoma, mesothelioma, and cutaneous melanoma. However, the involvement of BAP1 in the progression of prostate cancer has not been studied until recently. Herein, we investigated the tumor promoting function of BAP1 in the context of prostate cancer. Analysis of The Cancer Genome Atlas (TCGA) data set showed that prostate cancer patients express high levels of BAP1 mRNA. High BAP1 expression is inversely correlated with disease-free survival in patients with prostate cancer. Among the prostate cell lines tested, BAP1 expression was high in tumorigenic and metastatic cell lines, but was low in normal prostate cell line. Knockdown of BAP1 in PC3 or DU145 cells induced mesenchymal-to-epithelial transition (MET). Further, BAP1-knockdown resulted in decreased migration and invasion of PC3 and DU145 cells. Conversely, overexpression of BAP1 in RWPE1, a normal prostate cell line, induced the migratory and invasive properties. Collectively, our findings identified that BAP1 has a tumor promoting function in prostate cancer cells, and suggest that BAP1 can serve as a potential therapeutic target for prostate cancer.

Abstract Regulation of target proteins by the ubiquitin-proteasome system (UPS) is common in a wide range of cellular events, including transcriptional regulation, cell cycle progression, differentiation, and tumorigenesis. Ubiquitin-specific protease 7 (USP7) has been implicated in tumor development and metastasis in various malignancies through the regulation of target protein stability. In this study, we found that the enhancer of zeste homolog 2 (EZH2), which catalyzes the methylation at lysine 27 of histone H3, is a target of USP7 and is stabilized by USP7-mediated deubiquitination. In prostate cancer cells, the transcriptional repression function of EZH2 was inhibited by USP7-knockdown. Furthermore, ectopic introduction of EZH2 restored the cell migration, invasion, and sphere-forming potential of prostate cancer cells, which had been decreased by USP7-knockdown. Moreover, combined treatment with the USP7-specific inhibitor P5091 and EZH2 inhibitors, such as GSK126, EPZ6438, and DZNep, induced synergistic inhibitory effects on cell migration, invasion, and sphere-forming potential in prostate cancer cells. Collectively, our findings revealed that the promotion of the malignancy-associated characteristics of prostate cancer cells by USP7 was in part due to EZH2 stabilization. Thus, we suggest that simultaneous treatment with a USP7 inhibitor and an EZH2 inhibitor could be a rational strategy for treating EZH2-dependent cancers.

Resumen Antecedentes: la contaminación de la cebada con micotoxinas de Fusarium causa importantes pérdidas económicas para los productores de carne de cerdo, pero adsorbentes de micotoxinas para prevenir los efectos perjudiciales de las micotoxinas no dieron resultados consistentes. Objetivo: evaluar el producto de la pared celular de la levadura en la prevención de los efectos adversos de las micotoxinas de Fusarium sobre el crecimiento, características de la sangre, y la digestibilidad de nutrientes en cerdas jóvenes alimentadas con dietas que contienen cebada naturalmente contaminada con micotoxinas de Fusarium. Métodos: se prepararon las dietas a base de harina de maíz-soja de control positivo y negativo contienen 20% de control y cebada contaminados con micotoxinas de Fusarium, respectivamente. Adicionalmente se prepararon 2 dietas con productos de la pared celular de levadura de 0,2 o 0,4% a la dieta de control negativo. Fueron alimentados con las dietas experimentales cerdos con un peso corporal inicial de 61,7 Kg durante 2 semanas. Resultados: los cerdos alimentados con la dieta control negativo ganaron menos que aquellos alimentados con la dieta control positivo (p<0,05) a partir del d 0 a 7 y durante el período en general, pero la digestibilidad de los nutrientes y características de la sangre no fueron afectados por la alimentación de la dieta contaminada. La mayoría de las mediciones no fueron afectadas por la suplementación de la pared celular de la levadura con la dieta control negativo. Conclusión: la adición del producto de pared celular de levadura a la dieta control negativo no logró aminorar los efectos adversos de las micotoxinas de Fusarium sobre el crecimiento.

Summary Background: contamination of barley with Fusarium mycotoxins causes significant economic losses for pork producers, and alleviation with mycotoxin sequestering agents has proven inconsistent. Objective: to evaluate a yeast cell wall product in preventing adverse effects of Fusarium mycotoxins on growth performance, blood characteristic, and nutrient digestibility in gilts fed diets containing barley naturally contaminated with Fusarium mycotoxins. Methods: positive and negative controls of corn-soybean meal diets containing 20% control and contaminated barley with Fusarium mycotoxins, respectively, were prepared. Two additional diets were prepared by adding 0.2 or 0.4% of a yeast cell wall product to the negative control diet. The experimental diets were fed to pigs with 61.7 Kg initial body weight for 2 weeks. Results: pigs fed the negative control diet gained less than those fed the positive control diet (p<0.05) from d 0 to 7 and during the overall period, but nutrient digestibility and blood characteristics were not affected by feeding the contaminated diet. Most measurements were not affected by supplementing the yeast cell wall to the negative control diet. Conclusion: addition of the yeast cell wall product to negative control diets failed to ameliorate the adverse effects of dietary Fusarium mycotoxin on growth performance.

Resumo Antecedentes: a contaminação da cevada com a micotoxinas Fusarium causa perdas econômicas significativas para os produtores de suínos, porèm os adsorventes de micotoxinas que evitam efeitos prejudiciais de micotoxinas não deram resultados consistentes. Objetivo: avaliar o produto da parede celular das leveduras para prevenir efeitos adversos da micotoxinas Fusarium no desempenho do crescimento, inchaço da vulva, característica do sangue, digestibilidade dos nutrientes em porcas jòvens que são alimentadas com dietas contendo a cevada naturalmente contaminada com micotoxinas do Fusarium. Métodos: foram preparadas dietas de controle positivo e negativo à base de milho e soja, contendo 20% do controle e cevada contaminada com micotoxinas Fusarium, respectivamente. Duas dietas adicionais foram preparadas complementando com 0,2 ou 0,4% o produto da parede celular das leveduras à dieta do controle negativo. As dietas experimentais foram fornecidas aos suínos com peso corporal inicial de 61,7 Kg por 2 semanas. Resultados: os suínos alimentados com a dieta do controle negativo ganharam menos peso do que aqueles alimentados com a dieta do controle positivo (p<0,05) a partir do dia 0 até 7 durante todo o período, a digestibilidade dos nutrientes e as características do sangue não foram afetadas pela alimentação da dieta contaminada. A maioria das medidas não foram afetadas pela complementação da parede celular das leveduras à dieta do controle negativo. Conclusão: a complementação do produto da parede celular das leveduras nas dietas de controle negativo não conseguiu melhorar o efeito adverso das micotoxinas Fusariume no desempenho de crescimento.

Antecedentes: la estimación precisa de las pérdidas endógenas basales (BEL) de aminoácidos (AA) es importante para calcular los valores de la digestibilidad ileal estandarizada. Objetivos: establecer la influencia del peso corporal y el consumo de alimento sobre las BEL de proteína cruda (CP) y AA, y desarrollar ecuaciones de predicción para las BEL de CP y AA en cerdos alimentados con dietas libres de nitrógeno. Métodos: basados en información proveniente de 34 artículos científicos, fueron generadas ecuaciones de predicción para las BEL de CP y AA usando el peso corporal (BW) y el consumo de alimento por consumo de mantenimiento (FI:MFI) con base en la concentración de energía como variables independientes. Resultados: BW y FI:MFI variaron de 13,8 a 109,8 kg y de 1 a 5, respectivamente. Los valores de la media para BEL de CP, Lys, Met, Thr, y Trp fueron 17,2 (CV = 50,9%), 0,42 (CV = 56,0%), 0,14 (CV = 80,8%), 0,55 (CV = 41,3%), y 0,14 (CV = 57,5%) g/kg de consumo de materia seca (DMI), respectivamente. El FI:MFI se correlacionó negativamente con las BEL de CP y AA excepto con la Met (r < -0,39; p<0,05). Las ecuaciones de predicción para estimar las BEL de la CP y AA (g/kg DMI) desarrolladas fueron: BEL de CP = 47,5 - (8,09 × 10-2 × IBW) - (8,83 × FI:MFI) con un R² = 0,32 y un p = 0,011; BEL de Lys = 0,979 - (1,00 × 10-3 × IBW) - (0,174 × FI:MFI) con un R² = 0,24 y un p = 0,014; BEL de Thr = 1,09 - (1,82 × 10-3 × IBW) - (0,153 × FI:MFI) con un R² = 0,28 y un p = 0,007; y las BEL de Trp = 0,552 - (1,11 × 10-3 × IBW) - (0,120 × FI:MFI) con un R² = 0,47 y un p = 0,002. Conclusión: con base en las anteriores ecuaciones, el IBW y el FI:MFI claramente redujeron las BEL de CP y AA. Las ecuaciones suministradas en este artículo pueden ser utilizadas para estimar las BEL de CP y AA.

Background: accurate estimations of basal endogenous losses (BEL) of amino acids (AA) are important for the calculation of standardized ileal digestibility values. Objectives: to address the influence of body weight (BW) and feed intake on BEL of crude protein (CP) and AA and to develop prediction equations for BEL of CP and AA in pigs fed nitrogen-free diets. Methods: based on data derived from 34 research papers, prediction equations for BEL of CP and AA were generated using BW and feed intake per maintenance feed intake (FI:MFI) based on energy concentration as independent variables. Results: initial BW (IBW) and FI:MFI ranged from 13.8 to 109.8 kg and from 1 to 5, respectively. Mean values for BEL of CP, Lys, Met, Thr, and Trp were 17.2 (CV = 50.9%), 0.42 (CV = 56.0%), 0.14 (CV = 80.8%), 0.55 (CV = 41.3%), and 0.14 (CV = 57.5%) g/kg dry matter intake (DMI), respectively. The FI:MFI was negatively correlated with BEL of CP and AA except Met (r < -0.39; p<0.05). Prediction equations for estimating the BEL of CP and AA (g/kg DMI) developed were: BEL of CP = 47.5 - (8.09 × 10-2 × IBW) - (8.83 × FI:MFI) with R² = 0.32 and p = 0.011; BEL of Lys = 0.979 - (1.00 × 10-3 × IBW) - (0.174 × FI:MFI) with R2 = 0.24 and p = 0.014; BEL of Thr = 1.09 - (1.82 × 10-3 × IBW) - (0.153 × FI:MFI) with R² = 0.28 and p = 0.007; and BEL of Trp = 0.552 - (1.11 × 10-3 × IBW) - (0.120 × FI:MFI) with R² = 0.47 and p = 0.002. Conclusion: based on the equations above, IBW and FI:MFI clearly decrease BEL of CP and AA. The equations provided in this paper may be used for estimating BEL of CP and AA.

Antecedentes: a estimação precisa das perdas endógenas basais (BEL) de aminoácidos (AA) é importante para calcular os valores da digestibilidade ileal padronizada. Objetivos: estabelecer a influencia do peso corporal e do consumo de alimento sobre as BEL da proteína bruta (CP) e AA, e desenvolver equações de predição para as BEL da CP e AA em porcos alimentados com dietas livres de nitrogênio. Métodos: baseados em informação proveniente de 34 artigos científicos, foram geradas equações de predição para as BEL da CP e AA usando o peso corporal (BW) e o consumo de alimento por consumo de manutenção (FI:MFI) com base na concentração de energia como variáveis independentes. Resultados: BW e FI:MFI variaram de 13,8 a 109,8 kg e de 1 a 5, respectivamente. Os valores da média para BEL da CP, Lys, Met, Thr, e Trp foram 17,2 (CV = 50,9%), 0,42 (CV = 56,0%), 0,14 (CV = 80,8%), 0,55 (CV = 41,3%), e 0,14 (CV = 57,5%) g/kg de consumo de matéria seca (DMI), respectivamente. O FI:MFI teve correlação negativa com as BEL da CP e AA exceto com a Met (r < -0,39; p<0,05). As equações de predição para estimar as BEL da CP e AA (g/kg DMI) desenvolvidas foram: BEL da CP = 47,5 - (8,09 × 10-2 × IBW) - (8,83 × FI:MFI) com um R² = 0,32 e um p = 0,011; BEL de Lys = 0,979 - (1,00 × 10-3 × IBW) - (0,174 × FI:MFI) com um R² = 0,24 e um p = 0,014; BEL de Thr = 1,09 - (1,82 × 10-3 × IBW) - (0,153 × FI:MFI) com um R² = 0,28 e um p = 0,007; e as BEL de Trp = 0,552 - (1,11 × 10-3 × IBW) - (0,120 × FI:MFI) com um R² = 0,47 e um p = 0,002. Conclusão: Com base nas anteriores equações, o IBW e o FI:MFI claramente diminuíram as BEL da CP e AA. As equações fornecidas neste artigo podem ser utilizadas para estimar as BEL do CP e AA.

The effect of hypoxia on the release of tumor necrosis factor-alpha (TNF-alpha) in transformed rat retinal ganglion cells (RGCs) and the effect of agmatine on the hypoxia-induced production of TNF-alpha in RGCs were evaluated. RGCs were cultured under hypoxic conditions with 5% oxygen, with or without 100μM agmatine. The expression levels of TNF-alpha and its receptor-1 (TNF-R1) were investigated by Western blot analysis. After 6 hours of hypoxia, we noted an increase in TNF-alpha production in RGCs. Agmatine significantly reduced TNF-alpha level after 12 hours of hypoxic treatment. The expression of TNF-R1 was not affected by the hypoxia or agmatine treatment. Our results show that agmatine inhibits the TNF-alpha production of RGCs in hypoxic condition. These results demonstrate a possible neuroprotective mechanism for agmatine against hypoxic damage in RGCs.