RESUMO
Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition but the effects and mechanisms that differentiate these two paradigms are unknown. We examined whether IF in the form of every-other-day feeding enhances cognition and adult hippocampal neurogenesis (AHN) when compared to a matched 10% daily CR intake and ad libitum conditions. After 3 months under IF, female C57BL6 mice exhibited improved long-term memory retention. IF increased the number of BrdU-labeled cells and neuroblasts in the hippocampus, and microarray analysis revealed that the longevity gene Klotho (Kl) was upregulated in the hippocampus by IF only. Furthermore, we found that downregulating Kl in human hippocampal progenitor cells led to decreased neurogenesis, whereas Kl overexpression increased neurogenesis. Finally, histological analysis of Kl knockout mice brains revealed that Kl is required for AHN, particularly in the dorsal hippocampus. These data suggest that IF is superior to 10% CR in enhancing memory and identifies Kl as a novel candidate molecule that regulates the effects of IF on cognition likely via AHN enhancement.
Assuntos
Jejum , Consolidação da Memória , Animais , Feminino , Hipocampo/metabolismo , Memória de Longo Prazo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologiaRESUMO
Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain. However, little is known about the molecular mechanisms regulating hippocampal neural progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brain and resulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention directed at endogenous NPCs.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Tiazóis/farmacologia , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Hipocampo/citologia , Masculino , Neurônios/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
PURPOSE: The cancer stem cell hypothesis predicts that standard prostate cancer monotherapy eliminates bulk tumor cells but not a tumor-initiating cell population, eventually leading to relapse. Many studies have sought to determine the underlying differences between bulk tumor and cancer stem cells. EXPERIMENTAL DESIGN: Our previous data suggest that the PTEN/PI3K/AKT pathway is critical for the in vitro maintenance of CD133(+)/CD44(+) prostate cancer progenitors and, consequently, that targeting PI3K signaling may be beneficial in treatment of prostate cancer. RESULTS: Here, we show that inhibition of PI3K activity by the dual PI3K/mTOR inhibitor NVP-BEZ235 leads to a decrease in the population of CD133(+)/CD44(+) prostate cancer progenitor cells in vivo. Moreover, the combination of the PI3K/mTOR modulator NVP-BEZ235, which eliminates prostate cancer progenitor populations, and the chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors in a prostate cancer xenograft model than monotherapy. CONCLUSION: This combination treatment ultimately leads to the expansion of cancer progenitors with a PTEN E91D mutation, suggesting that the analysis of PTEN mutations could predict therapeutic response to the dual therapy.