Search

Abstract Despite the massive efforts to develop the treatment of pancreatic cancers, no effective application exhibits satisfactory clinical outcome. Macropinocytosis plays a critical role for continuous proliferation of pancreatic ductal adenocarcinoma (PDAC). In this study, we generated a screening method and identified phellodendrine chloride (PC) as a potential macropinocytosis inhibitor. PC significantly inhibited the viability of KRAS mutant pancreatic cancer cells (PANC-1 and MiaPaCa-2) in a dose-dependent manner; however, it did not affect the wild type KRAS pancreatic cancer cells (BxPC-3). Further experiments indicated that PC reduced the growth of PANC-1 cells through inhibition of macropinocytosis and diminishing the intracellular glutamine level. Disruption of glutamine metabolism led to enhance the reactive oxygen species level and induce mitochondrial membrane potential depolarization in PANC-1 cells. PC treatment caused increased Bax and decreased Bcl-2 expression, along with the activation of cleaved caspase-3, 7, 9 and cleaved-PARP, thus induced mitochondrial apoptosis. Moreover, PC inhibited macropinocytosis in vivo and effectively reduced the growth of PANC-1 xenograft tumors. All together, we demonstrated that inhibition of macropinocytosis might be an effective strategy to treat pancreatic cancers. Thus, PC could be a potential compound with improved therapeutic efficacy in patients with pancreatic cancers. [ABSTRACT FROM AUTHOR]

Childhood under-nutrition and malnutrition are prevalent in low and middle-income countries. Where agriculture is the primary source of food production, consumption, and cash income, it has a close relationship with health and nutrition in these emerging economies. Although Timor-Leste achieved lower middle-income status in 2011, national economic growth has not delivered anticipated nutritional dividends. Seeking to redress a lack of research that clearly demonstrates how agriculture impacts on nutrition in Timor-Leste, we investigated the links between household agricultural activities and children's physical growth in two agro-ecologically varying field sites: lowland Natarbora and mountainous Ossu. Children in both sites were below World Health Organization standards in height, weight, and body mass index. Coastal children recorded better growth than upland children. Livestock production was linked to poorer growth in the upland, but not coastal communities, which may be linked to specific differences in husbandry practices. In both communities, access to a plantation was somewhat associated with children's (0-10 years) increased weight-for-age. As simple agricultural indicators do not fully explain growth outcomes, a livelihood security approach is proposed to better understand how households address food and nutritional needs in relation to broader livelihood concerns. [ABSTRACT FROM AUTHOR]

El artículo discute un caso de organización comunitaria para la cosecha de arroz entre un grupo de desplazados de la República Democrática de Timor Oriental, localizada al sudeste de Asia. El texto ofrece un contexto histórico del caso, así como una descripción de las redes familiares que hicieron posible su consecución.

The article profiles the village of Daisua, a settlement in East Timor. The central focus of the article is the internal displacement and forced migration of the villagers under the Indonesian occupation of the region during the period 1975-79. Among other issues the article examines the importance of kinship ties between the refugees and the population of the region in which they settled.

Nowadays, more and more attention has been paid to osteoporosis caused by diabetes mellitus. Elevated levels of pro-inflammatory cytokines in diabetic patients activate the activity of osteoclasts through the RANKL/OPG pathway. The nuclear transcription factor SREBP2, a master regulator of cholesterol metabolism, has been found involved in osteoclastogenesis. In our previous study, we have identified anhydroicaritin as a potent inhibitor of transcription factor SREBPs, which improves dyslipidemia and insulin resistance. In this study, we demonstrated that anhydroicaritin could also decrease the level of SREBP2 and its target genes in osteoclasts induced by RANKL without significant cytotoxicity. Moreover, anhydroicaritin suppressed RANKL-induced osteoclasts differentiation. In STZ-induced diabetic mice model, we found that the osteoclasts were largely increased accompanied with deterioration of bone structure. Anhydroicaritin decreased the level of blood glucose and alleviated insulin resistance. More importantly, anhydroicaritin inhibited osteoclast differentiation and rescued diabetes-induced bone loss in vivo . In conclusion, anhydroicaritin, a potent SREBP2 inhibitor, inhibits the osteoclasts formation and improves diabetes-induced bone loss. [ABSTRACT FROM AUTHOR]

SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases. Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs. HepG2, HL-7702, and human primary hepatocytes were used to verify the effects of AHI. We explored the mechanism by which AHI blocks the binding of SCAP/SREBPs complex with Sec23α/24D via regulating LKB1/AMPK/mTOR pathway. AHI reduced liver cell lipid level by preventing de novo lipogenesis. In diet induced obese mice, AHI ameliorated obesity, insulin resistance, fatty accumulation in liver and hyperlipemia. In conclusion, AHI improves diet-induced obesity and alleviates insulin resistance by suppressing SREBPs maturation which is dependent on LKB1/AMPK/mTOR pathway. Thus, AHI can serve as a leading compound for pharmacological control of metabolic diseases. [ABSTRACT FROM AUTHOR]