RESUMO
Nonnutritive sweetener use is a common practice worldwide. Although considered safe for human consumption, accumulating evidence suggests these compounds may affect metabolic homeostasis; however, there is no consensus on the role of frequent sweetener intake in appetite and weight loss. We sought to determine whether frequent intake of commercial sweeteners induces changes in the JAK2/STAT3 signaling pathway in the brain of mice, as it is involved in the regulation of appetite and body composition. We supplemented adult BALB/c mice with sucrose, steviol glycosides (SG), or sucralose, daily, for 6 weeks. After supplementation, we evaluated body composition and expression of total and phosphorylated JAK2, STAT3, and Akt, as well as SOCS3 and ObRb, in brain tissue. Our results show that frequent intake of commercial SG decreases energy intake, adiposity, and weight gain in male animals, while increasing the expression of pJAK2 and pSTAT3 in the brain, whereas sucralose increases weight gain and pJAK2 expression in females. Our results suggest that chronic intake of commercial sweeteners elicits changes in signaling pathways that have been related to the control of appetite and energy balance in vivo, which may have relevant consequences for the nutritional state and long term health of the organism.
Assuntos
Encéfalo/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Edulcorantes/farmacologia , Animais , Feminino , Janus Quinase 2/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-akt/biossíntese , Receptores para Leptina/biossíntese , Fator de Transcrição STAT3/biossíntese , Proteína 3 Supressora da Sinalização de Citocinas/biossínteseRESUMO
Cysteine peptidases play a central role in the biology of Leishmania. In this work, we sought to further elucidate the mechanism(s) by which the cysteine peptidase CPB contributes to L. mexicana virulence and whether CPB participates in the formation of large communal parasitophorous vacuoles induced by these parasites. We initially examined the impact of L. mexicana infection on the trafficking of VAMP3 and VAMP8, two endocytic SNARE proteins associated with phagolysosome biogenesis and function. Using a CPB-deficient mutant, we found that both VAMP3 and VAMP8 were down-modulated in a CPB-dependent manner. We also discovered that expression of the virulence-associated GPI-anchored metalloprotease GP63 was inhibited in the absence of CPB. Expression of GP63 in the CPB-deficient mutant was sufficient to down-modulate VAMP3 and VAMP8. Similarly, episomal expression of GP63 enabled the CPB-deficient mutant to establish infection in macrophages, induce the formation of large communal parasitophorous vacuoles, and cause lesions in mice. These findings implicate CPB in the regulation of GP63 expression and provide evidence that both GP63 and CPB are key virulence factors in L. mexicana.
Assuntos
Regulação da Expressão Gênica/fisiologia , Leishmania mexicana/patogenicidade , Leishmaniose Cutânea/metabolismo , Metaloendopeptidases/biossíntese , Proteínas de Protozoários/metabolismo , Animais , Western Blotting , Cisteína/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Peptídeo Hidrolases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Virulência , Fatores de Virulência/metabolismoRESUMO
Leishmania parasites have the ability to modify macrophage signaling pathways in order to survive and multiply within its mammalian host. They are also known to invade other cells including neutrophils, fibroblasts and dendritic cells (DCs). DCs have an important role in immunity as the link between innate and adaptive immunity, necessary for the development of an effective response; however, the impact of Leishmania mexicana infection on DCs has been poorly studied. Herein, we report that Leishmania infection rapidly induced DC protein tyrosine phosphatases activity, leading to MAP kinases inactivation. In line with this, L. mexicana was found to decrease the nuclear translocation of transcription factors such as AP-1 and NF-κB. Concomitantly, L. mexicana-infected DCs showed reduced expression of several surface antigen-presenting and co-stimulatory molecules upon LPS stimulation. Leishmania-induced interference on DC maturation was further reflected by their reduced capacity to present OVA antigen to OVA-specific T cells, as shown by abrogation of IL-2 production by the T cells. Collectively, our data revealed that DC infection by L. mexicana appears to affect the cellular and immunological mechanisms necessary for the development of an effective and protective immune response, therefore favouring the survival and propagation of the parasite within its host.