Crosstalk between hnRNP K and SET in ATRA-induced differentiation in acute promyelocytic leukemia.

HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all-trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA-induced differentiation in APL. We observed higher (5- to 40-fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short-hairpin RNA led to cell death in ATRA-sensitive NB4 and resistant NB4-R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4-R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis-specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4-R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4-R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.

llex paraguariensis decreases oxidative stress in bone and mitigates the damage in rats during perimenopause.

During perimenopause, oxidative stress increases, which may result in disruption of bone turnover, and consequently in osteoporosis. The use of antioxidants may be an effective nutritional approach to reducing osteoporosis in this period of life. Mate tea (MT) (Ilex paraguariensis), a typical and inexpensive beverage consumed in the Brazilian south-east, Argentina and Uruguay, increases antioxidant defense. Our hypothesis was that MT would decrease oxidative stress and mitigate bone deterioration. To test this, we analyzed oxidative stress markers of bone turnover, and local and systemic markers of bone metabolism of rats during natural perimenopause. Female Wistar rats (aged 16months) in proven perimenopause period received 20mg/kgBW/day of mate tea, by gavage (PM+MT Group, n=10) or water (PM Group, n=10). Female rats aged 4months (AD Group, n=10) received water. The treatment period was four weeks. MT minimized the deterioration of rat microarchitecture, characterized by increase in the bone trabecular area, number of osteocytes and areal bone mineral density. These results were accompanied by a lower level of malondialdehyde, an oxidative stress marker, in femoral tissue homogenate. Plasmatic tartrate-resistant acid phosphatase, a typical osteoclastic function marker, decreases after treatment, indicating a decrease in osteoclastic function. MT also modified the immunostaining pattern of bone metabolism markers, decreasing the receptor activator of nuclear factor kappa-B ligant (RANKL), superoxide dismutase isoform 2 (SOD2) and increasing osteoprotegerin (OPG), a decoy receptor for the RANKL, which positively modulates bone mass. These results suggested MT was capable of decreasing bone resorption by inhibiting the osteoclastogenesis in a RANKL-dependent signaling pathway activated by oxidative stress. Taken together, the results indicated that MT minimized bone loss in perimenopause and this effect is at least partly due to the decrease in oxidative stress, confirming our hypothesis.