A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD

Correlação entre fotoproteção e concentrações de 25 hidroxi-vitamina D e paratormônio Correlation between photoprotection and 25 hydroxyvitamin D and parathyroid hormone levels

FUNDAMENTOS- A preocupação com o risco de câncer da pele levou à difusão da fotoproteção em larga escala, e atualmente se discute se haveria, associado a essa recomendação, risco para o desenvolvimento de hipovitaminose D. OBJETIVOS - Avaliar em pacientes orientados para proteção solar, o estado atual de seu estoque de vitamina D. MÉTODOS - Avaliaram-se as concentrações de 25 hidroxivitamina D (25OHD e do hormônio da paratireóide (PTH) em grupos de indivíduos com e sem orientação para fotoproteção, moradores da cidade de São Paulo. RESULTADOS - Encontrou-se diferença significativa entre os níveis de 25OHD, maiores no grupo fotoexposto, 35,4ng/mL [21,86- 72,20], em relação ao fotoprotegido, 29,2ng/mL [23,10-45,80]. Também houve diferença com relação ao PTH, maior no grupo fotoexposto, 29,8pg/mL [18,98-73,94], do que no fotoprotegido, 19,24pg/mL [8,06-66,18]. CONCLUSÕES - Apesar dessas diferenças, não havia indivíduos deficientes de vitamina D nessa amostra, e os níveis de PTH mantiveram- se dentro dos valores de normalidade. A radiação ultravioleta solar do cotidiano foi suficiente para promover uma síntese adequada de 25OHD.<br>BACKGROUND - The great concern about skin cancer risk led to the dissemination of photoprotection in high scale. Nowadays the association of this recommendation and the risk of develop hypovitaminosis D is discussed. OBJECTIVE - To evaluate vitamin D storage in patients submitted to sun protection. METHODS - The levels of 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were evaluated in groups of individuals living in the city of São Paulo who received or not orientation about photoprotection. RESULTS - Significant differences in 25OHD levels were found between the groups, being higher in the photoexposed group (35.40 ng/mL [21.86-72.20]) as compared to the photoprotected group (29.20 ng/mL [23.10-45.80]). There was also difference in PTH levels, being higher in the photoexposed group (29.80 pg/mL [18.98-73.94]) in comparison to the photoprotected group (19.24 pg/mL [8.06-66.18]). CONCLUSIONS - Despite these differences, there were no individuals presenting vitamin D deficiency in this sample and PTH levels were within normal range. The routine solar ultraviolet radiation was enough to promote appropriate synthesis of 25OHD