Adiponectin, also known as Acrp30, is an adipose tissue-derived hormone with anti-atherogenic, anti-diabetic and insulin sensitizing properties. Two seven-transmembrane domain-containing proteins, AdipoR1 and AdipoR2, have recently been identified as adiponectin receptors, yet signalling events downstream of these receptors remain poorly defined. By using the cytoplasmic domain of AdipoR1 as bait, we screened a yeast two-hybrid cDNA library derived from human fetal brain. This screening led to the identification of a phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, APPL1 (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding (PTB) domain and leucine zipper motif). APPL1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. Overexpression of APPL1 increases, and suppression of APPL1 level reduces, adiponectin signalling and adiponectin-mediated downstream events (such as lipid oxidation, glucose uptake and the membrane translocation of glucose transport 4 (GLUT4)). Adiponectin stimulates the interaction between APPL1 and Rab5 (a small GTPase) interaction, leading to increased GLUT4 membrane translocation. APPL1 also acts as a critical regulator of the crosstalk between adiponectin signalling and insulin signalling pathways. These results demonstrate a key function for APPL1 in adiponectin signalling and provide a molecular mechanism for the insulin sensitizing function of adiponectin.

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In this study, we characterized a specific population of nanoparticles derived from edible ginger (GDNPs 2) and demonstrated their efficient colon targeting following oral administration. GDNPs 2 had an average size of ~230 nm and exhibited a negative zeta potential. These nanoparticles contained high levels of lipids, a few proteins, ~125 microRNAs (miRNAs), and large amounts of ginger bioactive constituents (6-gingerol and 6-shogaol). We also demonstrated that GDNPs 2 were mainly taken up by intestinal epithelial cells (IECs) and macrophages, and were nontoxic. Using different mouse colitis models, we showed that GDNPs 2 reduced acute colitis, enhanced intestinal repair, and prevented chronic colitis and colitis-associated cancer (CAC). 2D-DIGE/MS analyses further identified molecular target candidates of GDNPs 2 involved in these mouse models. Oral administration of GDNPs 2 increased the survival and proliferation of IECs and reduced the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), and increased the anti-inflammatory cytokines (IL-10 and IL-22) in colitis models, suggesting that GDNPs 2 has the potential to attenuate damaging factors while promoting the healing effect. In conclusion, GDNPs 2, nanoparticles derived from edible ginger, represent a novel, natural delivery mechanism for improving IBD prevention and treatment with an added benefit of overcoming limitations such as potential toxicity and limited production scale that are common with synthetic nanoparticles.

Gene silencing via orally delivered small interfering RNAs (siRNAs) represents a promising treatment strategy for numerous gastrointestinal (GI) diseases associated with chronic intestinal inflammation; however, the oral delivery of siRNA to inflamed isntestinal tissues remains a major challenge. Here, we present a delivery vehicle for siRNA, termed thioketal nanoparticles (TKNs), that can localize orally deliver siRNA to sites of intestinal inflammation, and thus inhibit gene expression in diseased intestinal tissue. TKNs are formulated from a new polymer, poly-(1,4-phenyleneacetone dimethylene thioketal) (PPADT), that degrades selectively in response to reactive oxygen species (ROS). Therefore, when delivered orally, TKNs release siRNA in response to the abnormally high levels of ROS specific to sites of intestinal inflammation1–3. Using a murine model of ulcerative colitis (UC), we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine tumor necrosis factor-alpha (TNFα) diminish TNFα messenger RNA (mRNA) levels in the colon and protect mice from UC.

Even though knowing the contributions of transpiration (T), soil and open water evaporation (E), and interception (I) to terrestrial evapotranspiration (ET = T + E + I) is crucial for understanding the hydrological cycle and its connection to ecological processes, the fraction of T is unattainable by traditional measurement techniques over large scales. Previously reported global mean T/(E + T + I) from multiple independent sources, including satellite‐based estimations, reanalysis, land surface models, and isotopic measurements, varies substantially from 24% to 90%. Here we develop a new ET partitioning algorithm, which combines global evapotranspiration estimates and relationships between leaf area index (LAI) and T/(E + T) for different vegetation types, to upscale a wide range of published site‐scale measurements. We show that transpiration accounts for about 57.2% (with standard deviation ± 6.8%) of global terrestrial ET. Our approach bridges the scale gap between site measurements and global model simulations,and can be simply implemented into current global climate models to improve biological CO2 flux simulations.