Thermo‐ and pH‐responsive microgels for controlled release of insulin

Microgel particles were prepared, made of hydroxypropylcellulose‐graft‐(acrylic acid) (HPC‐g‐AA) and acrylic acid(AA). The particles undergo reversible volume phase transitions in response to both pH and temperature changes while keeping the inherent properties of PAA and HPC‐g‐AA. Dynamic light scattering measurements reveal that the average hydrodynamic radius and hydrodynamic radius distributions of the microgel particles depend on temperature and pH. The microgels exhibit excellent pH sensitivity and a higher swelling ratio at higher pH in aqueous solution. In vitro release study shows that the amount of insulin released from the microgels is less at pH = 1.2 than at pH = 6.8. The results indicate that the resultant microgels seem to be of great potential for intelligent oral drug delivery. Copyright © 2012 Society of Chemical Industry     

低温干燥过程中LEA-motif对热敏性药物胰岛素的活性保护研究

用LEA蛋白特征重复片段作为干燥活性保护剂,研究其对热敏性胰岛素的干燥保护效果和作用机理。结果表明,LEA-motif保护的胰岛素的三维活性结构保持良好,并且氨基酸残基振动明显减弱,LEA-motif保护的胰岛素六聚体冻干后的效价稳定,说明LEA蛋白特征重复片段对热敏性蛋白药物有良好的干燥活性保护效果。     

Fucosylated Chondroitin Sulfate from Sea Cucumber Improves Insulin Sensitivity via Activation of PI3K/PKB Pathway

This study was to investigate the effects of fucosylated chondroitin sulfate (CHS) from sea cucumber on insulin sensitivity in skeletal muscle of type 2 diabetic mice induced by a high‐fat high‐sucrose diet (HFSD). CHS supplementation for 19 wk significantly improved insulin sensitivity by 20%, and reduced blood glucose and insulin levels. Western blotting assay showed that CHS significantly increased insulin‐stimulated glucose transporter 4 (GLUT4) translocation to 1.7‐fold, phosphorylation of phosphoinositide 3‐kinase (PI3K) at p85 to 5.0‐fold, protein kinase B (PKB) at Ser473 to 1.5‐fold, and Thr308 to 1.6‐fold in skeletal muscle. However, PI3K, PKB, and GLUT4 total proteins expression were unchangeable. In addition, qRT‐PCR analysis proved that the insulin signaling was activated by CHS treatment, showing the increased mRNA expressions of glucose uptake‐related key genes. It indicated that CHS improved insulin sensitivity by activation of PI3K/PKB signaling in skeletal muscle of type 2 diabetic mice. Identification of potential mechanism by which CHS increased insulin sensitivity might provide a new functional food or pharmaceutical application of sea cucumber.     

Crossing Paths in Human Renal Cell Carcinoma (hRCC)

Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.     

One‐Step Formulation of Protein Microparticles with Tailored Properties: Hard Templating at Soft Conditions

Formulation of therapeutic proteins into particulate forms is a main strategy for site‐specific and prolonged protein delivery as well as for protection against degradation. Precise control over protein particle size, dispersity, purity, as well as mild preparation conditions and minimal processing steps are highly desirable. It is, however, hard to fit all these criteria with conventional preparation techniques. Here a one‐step hard‐templating synthesis of microparticles composed of functional, non‐denatured protein is reported. The method is based on filling porous CaCO₃ microtemplates with the protein near to its isoelectric point (pI) followed by pH‐ or EDTA‐mediated dissolution of the tempplates. In principle, a wide variety of proteins can be converted into microparticles using this approach. The main requirement is an overlap of the protein insolubility and a template solubility for a certain parameter (here pH or EDTA). Here the formulation of insulin particles is studied in detail and it is shown that particles consisting of high molecular weight protein (catalase) can also be prepared. In this context, the synthesis of CaCO₃ templates with controlled size, the mechanism of the protein microparticle formation and mechanical properties of the microparticles are discussed. For the first time, the fabrication of mesoporous monodispersed CaCO₃ microtemplates with identical porocity but tuned diameter from 3 to 20 μm is demonstrated. The protein particle diameter can be adjusted by choosing the appropriate template size that is critical for successful pulmonary delivery of insulin. As a first step towards insulin delivery, the in vitro release of insulin at physiological conditions is studied.     

Examining the Signaling Effect of E-tailers’ Return Policies

E-tailers normally have more accurate information regarding their products and services than consumers due to the nature of online transactions. To reduce consumers’ concerns of hidden information, e-tailers can use lenient return policies to attempt to signal high product and service quality. This research proposes a model to investigate the signaling effect of two components of return policy, return window—short return window vs. long return window and return depth—full refund vs. partial refund, on product quality and service quality. Data was collected using an online survey and analyzed using structural equation modeling. The results show that both a long return window and a full refund signal high service quality, which then positively affects purchase intention. When it comes to product quality, return window does not have a signaling effect, while the signaling effect of return depth is moderated by service quality.     

3-<i>epi</i>-bufotalin suppresses the proliferation in colorectal cancer cells through the inhibition of the JAK1/STAT3 signaling pathway

Traditional Chinese medicine (TCM) has been increasingly employed in the last decades in China for both preventing and treating a variety of cancers. 3-epi-bufotalin is an active ingredient of TCM “Chanpi” with anti-tumor potential. However, the effect and mechanism of 3-epi-bufotalin on colorectal cancers were not well disclosed. The present study demonstrated that 3-epi-bufotalin could reduce viability, trigger apoptosis, and block the cell cycle at the G₂/M stage in colorectal cancer cell lines HT29, RKO, and COLO205 in vitro. Moreover, 3-epi-bufotalin inhibited the JAK1/STAT3 signaling pathway. These results indicated the anti-proliferation ability of 3-epi-bufotalin in colorectal cancer cells.     

Interaction of IL-22/IL-22R1 promotes cell proliferation and suppresses apoptosis of colorectal cancer via phosphorylation of STAT3

Interleukin-22 (IL-22) is a member of IL-10 cytokine family which is expressed in activated T cells predominantly and in activated natural killer cells at lower levels. Previous studies have demonstrated the link between elevated levels of IL-22 and disease severity of psoriasis, Crohn’s disease, rheumatoid arthritis and interstitial lung diseases. However, the function of IL-22 in the development and progression of colorectal cancer (CRC) remains elusive. In this study, we first evaluated the IL-22/IL-22R1 level in CRC patients, and found that tumor tissues have more active expression of IL-22 and IL-22R1 than normal tissues, presenting correlation with the degree of differentiation of tumor tissues. Subsequently, Caspase and cell viability assays were performed on SW-480 cell line which expresses high level of IL-22R1 to examine if the supplementation of IL-22 has an impact on apoptosis and proliferation. In comparison with treatment of 5-FU, supplementation of IL-22 promoted cell proliferation and ameliorated apoptosis. To unveil signal transduction upon activation of IL-22R, we examined the phosphorylation of STAT3 in SW-480 cell line following supplementation of IL-22. The treatment of IL-22 also increased the level of p-Akt, an essential component in PI3K/Akt pathway. Although the link between STAT3 phosphorylation and PI3K/ Akt activation remains to be explored, our study revealed the mechanism underlying the effects of IL-22R activation on apoptosis as well as tumor differentiation, indicating the prognostic value of IL-22/IL-22R.