A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations

Perturbations in cellular chloride concentrations can affect cellular pH, autophagy and lead to the onset of apoptosis. With this in mind synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in the lysosomal pH which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis

Long-Term Growth Model in Myanmar Based on the Growth Trajectory of Vietnam

The purpose of this study is to identify major drivers of Myanmar’s long-term economic growth and draw implications to implement development policies. This study investigated Myanmar, as the country is the most recently opened economy in Southeast Asia. This study conducted simulation analysis based on scenarios by applying World Bank’s Long-Term Growth Model, Penn World Table 9.1, and World Development Indicator data. This study makes extensive use of LTGM and the LTGM-TFP extension to improve the validity of models for data calibration. This study confirms the validity of the model with data calibration and specifies scenarios for simulation analyses by setting the growth trajectory of Vietnam due to common geographical, political, and economic conditions. Main findings include that Myanmar’s economic growth rate will continue to fall below 3% in 2040 without proper improvement of growth drivers. The results of this study also provide that total factor productivity growth and female labor participation are key factors for Myanmar’s long-term economic growth. This study advises policymakers in Myanmar to strengthen human capital, which is crucial for total factor productivity growth in Myanmar’s context and directly affects economic growth. Further, labor market policies to promote female labor participation is important to sustain economic growth.1

Regulatory Roles of Invariant Natural Killer T Cells in Adipose Tissue Inflammation: Defenders Against Obesity-Induced Metabolic Complications

Adipose tissue is a metabolic organ that plays a central role in controlling systemic energy homeostasis. Compelling evidence indicates that immune system is closely linked to healthy physiologic functions and pathologic dysfunction of adipose tissue. In obesity, the accumulation of pro-inflammatory responses in adipose tissue subsequently leads to dysfunction of adipose tissue as well as whole body energy homeostasis. Simultaneously, adipose tissue also activates anti-inflammatory responses in an effort to reduce the unfavorable effects of pro-inflammation. Notably, the interplay between adipocytes and resident invariant natural killer T (iNKT) cells is a major component of defensive mechanisms of adipose tissue. iNKT cells are leukocytes that recognize lipids loaded on CD1d as antigens, whereas most other immune cells are activated by peptide antigens. In adipose tissue, adipocytes directly interact with iNKT cells by presenting lipid antigens and stimulate iNKT cell activation to alleviate pro-inflammation. In this review, we provide an overview of the molecular and cellular determinants of obesity-induced adipose tissue inflammation. Specifically, we focus on the roles of iNKT cell-adipocyte interaction in maintaining adipose tissue homeostasis as well as the consequent modulation in systemic energy metabolism. We also briefly discuss future research directions regarding the interplay between adipocytes and adipose iNKT cells in adipose tissue inflammation

High-Throughput Profiling of Peptide–RNA Interactions Using Peptide Microarrays

A rapid and quantitative method to evaluate binding properties of hairpin RNAs to peptides using peptide microarrays has been developed. The microarray technology was shown to be a powerful tool for high-throughput analysis of RNA–peptide interactions by its application to profiling interactions between 111 peptides and six hairpin RNAs. The peptide microarrays were also employed to measure hundreds of dissociation constants (<i>K</i>_d) of RNA–peptide complexes. Our results reveal that both hydrophobic and hydrophilic faces of amphiphilic peptides are likely involved in interactions with RNAs. Furthermore, these results also show that most of the tested peptides bind hairpin RNAs with submicromolar <i>K</i>_d values. One of the peptides identified by using this method was found to have good inhibitory activity against TAR–Tat interactions in cells. Because of their great applicability to evaluation of nearly all types of RNA–peptide interactions, peptide microarrays are expected to serve as robust tools for rapid assessment of peptide–RNA interactions and development of peptide ligands against RNA targets

Synthetic Aminopyrrolic Receptors have Apoptosis Inducing Activity

We report two synthetic aminopyrrolic compounds that induce apoptotic cell death. These compounds have been previously shown to act as receptors for mannosides. The extent of receptor-induced cell death is greater in cells expressing a high level of high-mannose oligosaccharides than in cells producing lower levels of high-mannose glycans. The ability of synthetic receptors to induce cell death is attenuated in the presence of external mannosides. The present results provide support for the suggestion that the observed cell death reflects an ability of the receptors to bind mannose displayed on the cell surface. Signaling pathway studies indicate that the synthetic receptors of the present study promote JNK activation, induce Bax translocation to the mitochondria, and cause cytochrome c release from the mitochondria into the cytosol, thus promoting caspase-dependent apoptosis. Such effects are also observed in cells treated with mannose-binding ConA. The present results thus serve to highlight what may be an attractive new approach to triggering apoptosis via modes of action that differ from those normally used to promote apoptosis.National Creative Research Initiative program in Korea 2010-0018272U.S. Department of Energy Office of Basic Energy Sciences DOE: DE-FG02-01ER15186Chemistr

Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity

Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity.—Hwang, I., Park, Y. J., Kim, Y. -R., Kim, Y.N.,Ka, S., Lee,H.Y., Seong, J.K., Seok,Y. -J., andKim, J.B. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity.OAIID:oai:osos.snu.ac.kr:snu2015-01/102/0000005231/3ADJUST_YN:YEMP_ID:A072580DEPT_CD:3344CITE_RATE:5.043FILENAME:cv no.111.pdfDEPT_NM:생명과학부SCOPUS_YN:YCONFIRM:

Additional file 2: of O-linked N-acetylglucosamine glycosylation of p65 aggravated the inflammation in both fibroblast-like synoviocytes stimulated by tumor necrosis factor-α and mice with collagen induced arthritis

MTT assay. TNF-α (10 μg/mL) significantly increased proliferation of fibroblast-like synoviocytes (FLS), compared to controls and proliferation was further enhanced following treatment with by NButGT (50 μM, for 24 h). (JPEG 79 kb