The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology

Abstract Background The WNT pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase enzymes tankyrase1 and 2. LGR5 is a known WNT pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages. Results We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited WNT signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible. Conclusion We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the WNT signalling dependent LGR5+ intestinal epithelial stem cells.

Leisure-time physical activity and cardiometabolic risk among children and adolescents / Atividade física de lazer e risco cardiometabólico em crianças e adolescentes

OBJECTIVE: To assess the effect of Leisure-time physical activity (LTPA) on cardiometabolic risk by nutritional status in Mexican children and adolescents. METHODS: This was a cross-sectional study conducted with 1,309 participants aged between 5 and 17 years. Nutritional status was classified according to the BMI Z-score by age and gender. A previously validated questionnaire was used to evaluate LTPA; a cardiometabolic risk score was calculated. Multiple linear regression analysis was performed to assess the effect of LTPA on cardiometabolic risk. RESULTS: After adjusting for risk factors, mild LTPA were positively associated with cardiometabolic risk score (ßMildvsIntenseLTPA: 0.68; 95% CI: 0.18 to 1.18; pfortrend = 0.007). This association became stronger when estimated for overweight (ß MildvsIntenseLTPA: 1.24; 95% CI: 0.24 to 2.24; pfortrend = 0.015) and obese participants (ß MildvsIntenseLTPA: 1.02; 95% CI: 0.07 to 1.97; pfortrend= 0.045) CONCLUSION: Mild LTPA was positively associated with cardiometabolic risk in overweight and obese children and adolescents. Given the emerging childhood obesity epidemic in Mexico, these results may be useful in the design of strategies and programs to increase physical activity levels in order to achieve better health. .

OBJETIVO: Avaliar o efeito da prática de AFL sobre o risco cardiometabólico em crianças e adolescentes mexicanos de acordo com sua situação nutricional. MÉTODOS: Estudo transversal feito com 1.309 participantes de cinco a 17 anos. A situação nutricional foi classificada de acordo com o escore z de IMC por idade e sexo. Um questionário validado anteriormente foi usado para avaliar a AFL; foi calculado um escore de risco cardiometabólico. A análise de regressão linear múltipla foi feita para avaliar o efeito de AFL sobre o risco cardiometabólico. RESULTADOS: Após o ajuste de acordo com os fatores de risco, a AFL leve foi positivamente associada ao escore de risco cardiometabólico (ßAFLLevexIntensa: 0,68; IC 95%: 0,18 a 1,18; p paratendência = 0,007). Essa associação foi mais intensa quando estimada para participantes acima do peso (ßAFLLevexIntensa: 1,24; IC 95%: 0,24 a 2,24; p paratendência = 0,015) e obesos (ßAFLLevexIntensa: 1,02; IC 95%: 0,07 a 1,97; p paratendência = 0,045). CONCLUSÃO: A AFL leve foi positivamente associada ao escore de risco cardiometabólico em crianças e adolescentes acima do peso e obesos. Considerando a epidemia de obesidade infantil emergente no México, esses resultados poderão ser úteis na elaboração de estratégias e programas para aumentar os níveis de atividade física a fim de obter uma saúde melhor. .