ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer

Background Acquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined. Methods Three separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro. Results The abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU. Conclusions HIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.

Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders

Those with Down syndrome (DS)—trisomy for chromosome 21—are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.

MARCADORES TUMORALES PRONÓSTICOS EN CÁNCER DE MAMA: BAX y Bcl-2

Introducción: El carcinoma de mama representa el 16% de todos los cánceres femeninos, cada año en las Américas, más de 462,000 mujeres son diagnosticadas y casi 100,000 mueren por esta causa, por lo que la detección de nuevos marcadores pronósticos se hace imprescindible para el desarrollo de nuevas terapias oncológicas. Objetivo: Identificar los marcadores tumorales con fines pronósticos en cáncer de mama en células de cultivo de carcinoma de mama MCF7. Método: Se desarrolló un estudio explicativo longitudinal y prospectivo observacional para identificar marcadores tumorales con valor pronóstico en modelos celulares MCF7 de Cáncer de Mama, se utilizarán métodos estadísticos descriptivos e inferenciales. Resultados: Se identificó un predominio de Bcl-2 en las células de cultivo MCF7 de Carcinoma de Mama. Conclusión: La identificación de BAX y Bcl-2 en modelos celulares MCF 7 de Carcinoma de Mama permite evaluar nuevas opciones terapéuticas relacionadas con la inducción de la apoptosis. La predominancia Bcl-2 pudiera constituir un factor de mal pronóstico y menor supervivencia debido a su efecto inhibidor de la apoptosis, donde subyacen alteraciones mitocondriales, que inciden en la regulación del nivel de calcio intracelular, o por su efecto antioxidante. Palabras clave: Neoplasias de la mama, Pronóstico, Apoptosis, Proteína de Susceptibilidad a Apoptosis Celular ABSTRACT Introduction: Breast carcinoma represents 16% of all female cancers, each year in the Americas, more than 462,000 women are diagnosed and almost 100,000 die from this cause, so the detection of new prognostic markers is essential for the development of new oncological therapies. Objective: To identify tumor markers for prognostic purposes in breast cancer in MCF7 breast carcinoma culture cells. Method: A longitudinal and prospective observational explanatory study was developed to identify tumor markers with prognostic value in MCF7 cell models of Breast Cancer, descriptive and inferential statistical methods will be used. Results: A predominance of Bcl-2 was identified in the MCF7 culture cells of Breast Carcinoma. Conclusion: The identification of BAX and Bcl-2 in MCF 7 cell models of Breast Carcinoma allows to evaluate new therapeutic options related to the induction of apoptosis. The Predominance bcl-2 could constitute a factor of poor prognosis and lower survival due to its inhibitory effect of apoptosis, where mitochondrial alterations underlie, which affect the regulation of the level of intracellular calcium, or for its antioxidant effect. Keywords: Breast Neoplasms, Prognosis, Apoptosis, Cellular Apoptosis Susceptibility Protein

Fluorescent probe for the detection of hypochlorous acid in water samples and cell models

A new fluorescence probe was successfully applied to test strips and imaging analysis of exogenous and endogenous hypochlorite in living cells.