Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-␣ 1 and -2 (Col1a1 and -2). Transforming growth factor ␤1 (TGF-␤), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-␤ increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, ␦EF1. TGF-␤ treatment or short hairpin RNAs targeting ␦EF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-␤ also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to ␦EF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), a key miR highly expressed in the kidney. miR-192 levels also were increased by TGF-␤ in MMC. TGF-␤ treatment or transfection with miR-192 decreased endogenous SIP1 expression as well as reporter activity of a SIP1 3 UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitor enhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192 synergized with ␦EF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the in vivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative to corresponding nondiabetic controls, in parallel with increased TGF-␤ and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-␤-induced Col1a2 expression by down-regulating E-box repressors.diabetic nephropathy ͉ mesangial cells ͉ small noncoding RNA ͉ transforming growth factor ␤1 D iabetic nephropathy (DN) is the most common cause of kidney failure in patients with diabetes mellitus. The major characteristics of DN include glomerular basement-membrane thickening, mesangial expansion and hypertrophy, and an accumulation of extracellular matrix (ECM) proteins (1). Evidence shows that transforming growth factor ␤1 (TGF-␤) levels are increased under diabetic conditions in renal cells, including mesangial cells (MC), can up-regulate ECM proteins such as collagens (2, 3), and also can promote MC survival and oxidant stress (4).To date, Smad transcription factors have been shown to be the major effectors of TGF-␤ signaling (5, 6). Collagen 1-␣ 1 and -2 (Col1a1 and -2) and other ECM genes are regulated in MC by TGF-␤ via Smads (7,8). The regulation of collagen by TGF-␤ in MC also is mediated by mitogen-activated protein kinases (MAPKs) such as p38 and ERKs (9-11). However, the molecular mechanisms by which TGF-␤ regulates ECM genes still are not understood fully. The collagen gene has E-box elements in the far upstream enhancer region (12, 13). An E-box repressor, ␦EF1, is a key inhibitor of E-cadherin (14) and E2-box transcription factors such as Nkx2.5 (12). Moreover, it is a known repressor of collagen type 1 and type 2 genes in other cells (12, 13), but its role in MC is ...

SYNOPSISObjectives. We explored living and working conditions, health status, and health-care access in Chinese rural-to-urban migrants and compared them with permanent rural and urban residents. Methods.A questionnaire was administered to 1,958 urban workers, 1,909 rural workers, and 4,452 migrant workers in Zhejiang Province, Eastern China, in 2004. Blood samples for human immunodeficiency virus (HIV) and syphilis were taken from the migrant and urban workers.Results. Migrants were young, worked very long hours, and their living conditions were very basic. Nineteen percent had some form of health insurance and 26% were entitled to limited sick pay compared with 68% and 66%, respectively, for urban workers. Migrants had the best self-rated health and reported the least acute illness, chronic disease, and disability, after controlling for age and education. There were no HIV infections detected in either the migrant or urban workers. However, 15 urban workers (0.68%, 95% confidence interval [CI] 0.35, 1.02) and 20 migrants (0.48%, 95% CI 0.26, 0.66, p 0.06) tested positive for syphilis. The high cost of health care in the city was a barrier to health-care access in the last year for 15% of the migrants and 8% of the urban workers. Forty-seven percent of the migrants were unwilling to make contributions to health insurance.Conclusions. These migrants demonstrated the "healthy migrant effect." However, poor living conditions and inattention to health may make migrants vulnerable to poor long-term health. Because health insurance schemes will remain limited for the forseeable future, attention should focus on providing affordable health care to both uninsured migrants and the urban poor.

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is the leading cause of end-stage liver diseases worldwide. Understanding NAFLD prevalence and trends over time at the global, regional and national levels is critical to understanding the NAFLD disease burden and creating more tailored prevention strategies.DesignPopulation-based observational study.SettingThe study was global, including 21 regions and 195 countries or territories.Main outcomes measureThe estimated annual percentage change for NAFLD prevalence.ResultsWorldwide, cases of NAFLD have increased from 391.2 million in 1990 to 882.1 million in 2017, with the prevalence rate increasing from 8.2% to 10.9% during the same period. The increasing trends were consistent across sexes. Case numbers were highest in East Asia, followed by South Asia, then North Africa and the Middle East. The highest prevalence of NAFLD was observed in North Africa and the Middle East, while the greatest increase was detected in Western Europe, followed by Tropical Latin America, then high-income North America.ConclusionNearly all countries or territories worldwide have experienced a significant increase in NAFLD prevalence. The greatest increase was observed in Oman. Almost all countries showed a significant increasing trend in NAFLD prevalence over the past three decades. This drastic increase is alarming and suggests that NAFLD has emerged as a new public health concern worldwide. As such, more efficient prevention strategies are urgently needed.

Caspases play a very important role in initiating and executing apoptotic processes in animal cells. In this study we show that plant mitochondria were able to initiate the activation of caspase 3 in a Xenopus cell free system. Caspase 3-like activity was found to be present in plant cells and could only be inhibited by the specific caspase 3 inhibitor N-acetyl-Asp-GluVal-Asp-fluoromethylketone (Ac-DEVD-fmk) and not by cysteine protease inhibitors. By micro-injection of the caspase 3 substrate in living Chara cells we showed that caspase 3-like activity was mainly present in the cytosol rather than in the vacuole. This is the first time that in vivo caspase 3-like activity has been demonstrated in plants. ß

These results suggested that quercetin could improve therapeutic index of DOX by its opposing effects on HIF-1α in tumor and normal cells, and was a promising candidate as anticancer agents.