The molecular targets and mechanisms of propolis ameliorating metabolic syndrome are not fully understood. Here, we report that Brazilian green propolis reduces fasting blood glucose levels in obese mice by disrupting the formation of CREB/CRTC2 transcriptional complex, a key regulator of hepatic gluconeogenesis. Using a mammalian two-hybrid system based on CREB-CRTC2, we identify artepillin C (APC) from propolis as an inhibitor of CREB-CRTC2 interaction. Without apparent toxicity, APC protects mice from high fat diet-induced obesity, decreases fasting glucose levels, enhances insulin sensitivity and reduces lipid levels in the serum and liver by suppressing CREB/CRTC2-mediated both gluconeogenic and SREBP transcriptions. To develop more potential drugs from APC, we designed and found a novel compound, A57 that exhibits higher inhibitory activity on CREB-CRTC2 association and better capability of improving insulin sensitivity in obese animals, as compared with APC. In this work, our results indicate that CREB/CRTC2 is a suitable target for developing anti-metabolic syndrome drugs.

Artepillin C (APC), a cAMP-response element−binding (CREB)/CREB regulated transcription coactivator 2 (CRTC2) inhibitor isolated from Brazilian green propolis, can ameliorate metabolic syndrome in obese mice. Because the sensitivity and responsiveness of the body to the drug depend on the time of day and the circadian clock alignment, the optimal administration time of APC for desired efficacy in treating metabolic syndrome remains unclear. In this study, APC (20 mg/kg) or the vehicle was intraperitoneally injected into obese mice once daily for one or three weeks. The results of the insulin tolerance test, pyruvate tolerance test, and histological and biochemical assays showed that APC could improve whole−body glucose homeostasis and decrease hepatic lipid synthesis following a circadian rhythm. Further exploration of the underlying mechanism revealed that APC may disturb the diurnal oscillations of the expression of brain and muscle ARNT−like protein (BMAL1) in primary hepatocytes and the livers of the study subjects. Moreover, APC could inhibit hepatic BMAL1 expression by blocking the CREB/CRTC2 transcription complex. BMAL1 overexpression in primary hepatocytes or the livers of db/db mice antagonized the inhibitory effect of APC on hepatic lipid metabolism. In conclusion, the chronotherapy of APC may relieve metabolic syndrome in obese mice, and the mechanism behind APC−mediated time−of−day effects on metabolic syndrome were unveiled, thereby providing a foundation for optimized APC treatment from a mechanistic perspective.

Background: Retinol-binding protein 4 (RBP4) is primarily recognized for its role in retinoid transport, but has recently been implicated in cancer progression and prognosis. However, a comprehensive pan-cancer analysis of RBP4’s expression, prognostic significance, and functional associations across various cancers is lacking. Methods: We conducted a pan-cancer analysis of RBP4 using data from public databases. RBP4 expression levels were examined in 33 tumor types, and correlations with clinical outcomes, immune cell infiltration, DNA methylation, and gene mutations were assessed. Enrichment analyses of RBP4 and its co-expressed genes were performed to explore associated biological pathways. Additionally, in vitro experiments were conducted to assess the effects of RBP4 on cell migration and proliferation. Results: RBP4 showed differential expression between tumor and normal tissues, with downregulation in 21 cancer types and upregulation in 6. High expression levels of RBP4 were associated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in specific cancers, notably in BRCA, HNSC, and STAD, whereas it was a favorable prognostic factor in cancers such as KIRP and MESO. RBP4 expression was also associated with immune cell infiltration, particularly with CD4+ Th2 cells and immune checkpoint genes. DNA methylation analysis suggested that the methylation of RBP4 may play a role in its regulatory mechanisms across cancer types. Enrichment analyses revealed that RBP4 and its co-expressed genes are involved in metabolism-related pathways and immune regulation. Functional assays indicated that RBP4 knockdown promoted tumor cell migration and proliferation. Conclusions: This study provides a comprehensive pan-cancer analysis of RBP4, identifying its prognostic potential and possible involvement in tumor immunity and metabolism. Our findings suggest that RBP4 could serve as a novel biomarker and therapeutic target in cancer, although further experimental studies are required to elucidate its precise mechanisms in specific cancer types.

El principio del interés superior del niño no se materializa en el ámbito de los procesos penales sobre violación sexual en agravio de niños, niñas y adolescente. Una errada práctica judicial, ignora la pericia psicopatológica practicada a la víctima, pese a ser una fuente directa que informa del delito, sus circunstancias, así como la magnitud y gravedad de la lesión causada al ámbito físico, moral y psicológico del menor. La presente investigación analiza estos problemas, como principal causa de impunidad, que revictimiza al menor agraviado y vulnera la garantía especial a su pleno desarrollo bio-psico-social. La metodología empleada es cuantitativa, con una investigación básica de nivel descriptivo y diseño correlacional, contando con una muestra de 95 profesionales pertenecientes al Juzgado Penal de Puente Piedra, Distrito Judicial de Ventanilla. Además, se emplearon encuestas como instrumento de recolección de datos para medir las variables en estudio. Se evidenció que la pericia psicopatológica del menor víctima de violación sexual, es una importante herramienta del campo clínico que amerita ser debidamente analizado por el órgano jurisdiccional, a efectos de establecer objetivamente las consecuencias que generan en los niños y niñas el abuso sexual sufrido, sirviendo de base para la determinación de la responsabilidad penal, la reparación civil y las acciones de asistencia en favor de las víctimas y su familia. Ello amerita capacitar y sensibilizar a los servidores judiciales en el uso e interpretación de estas herramientas orientadoras de su actuación jurisdiccional, bajo el principio rector del interés superior del niño.

El principio del interés superior del niño no se materializa en el ámbito de los procesos penales sobre violación sexual en agravio de niños, niñas y adolescente. Una errada práctica judicial, ignora la pericia psicopatológica practicada a la víctima, pese a ser una fuente directa que informa del delito, sus circunstancias, así como la magnitud y gravedad de la lesión causada al ámbito físico, moral y psicológico del menor. La presente investigación analiza estos problemas, como principal causa de impunidad, que revictimiza al menor agraviado y vulnera la garantía especial a su pleno desarrollo bio-psico-social. La metodología empleada es cuantitativa, con una investigación básica de nivel descriptivo y diseño correlacional, contando con una muestra de 95 profesionales pertenecientes al Juzgado Penal de Puente Piedra, Distrito Judicial de Ventanilla. Además, se emplearon encuestas como instrumento de recolección de datos para medir las variables en estudio. Se evidenció que la pericia psicopatológica del menor víctima de violación sexual, es una importante herramienta del campo clínico que amerita ser debidamente analizado por el órgano jurisdiccional, a efectos de establecer objetivamente las consecuencias que generan en los niños y niñas el abuso sexual sufrido, sirviendo de base para la determinación de la responsabilidad penal, la reparación civil y las acciones de asistencia en favor de las víctimas y su familia. Ello amerita capacitar y sensibilizar a los servidores judiciales en el uso e interpretación de estas herramientas orientadoras de su actuación jurisdiccional, bajo el principio rector del interés superior del niño