A porcine islet-encapsulation device that enables long-term discordant xenotransplantation in immunocompetent diabetic mice.

Islet transplantation is an effective treatment for type 1 diabetes (T1D). However, a shortage of donors and the need for immunosuppressants are major issues. The ideal solution is to develop a source of insulin-secreting cells and an immunoprotective method.

Functional Analysis of P450 Monooxygenase SrrO in the Biosynthesis of Butenolide-Type Signaling Molecules in .

7434AN4 produces two structurally unrelated polyketide antibiotics lankacidin and lankamycin, and their biosynthesis is tightly controlled by butenolide-type signaling molecules SRB1 and SRB2. SRBs are synthesized by SRB synthase SrrX, and induce lankacidin and lankamycin production at 40 nM concentration. We here investigated the role of a P450 monooxygenase gene (), which is located adjacent to (), in SRB biosynthesis.

Free fatty acid receptor 1 agonist, MR1704, lowers blood glucose levels in rats unresponsive to the sulfonylurea, glibenclamide.

Preclinical Research & Development MR1704 is a selective G protein-coupled receptor 40/free fatty acid receptor 1 agonist, which exhibited favorable pharmacokinetic profiles and glucose-lowering effects in animal models. We studied the effects of MR1704 in a sulfonylurea-desensitized Sprague-Dawley rat model and evaluated the risk of pancreatic β-cell exhaustion compared to that of glibenclamide in Zucker fatty rats. Rats fed ad libitum a diet containing 0.

A novel free fatty acid receptor 1 (GPR40/FFAR1) agonist, MR1704, enhances glucose-dependent insulin secretion and improves glucose homeostasis in rats.

Activation of G protein-coupled receptor 40/Free fatty acid receptor 1 (GPR40/FFAR1), which is highly expressed in pancreatic β cells, is considered an important pharmacologic target for the treatment of type 2 diabetes mellitus. The aim of this study was to determine the effect of MR1704, a novel GPR40/FFAR1 agonist, on glucose homeostasis in rats. MR1704 is a highly potent and selective, orally bioavailable agonist with similar in vitro potencies among humans, mice, and rats.

The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice.

The transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms against oxidative stress. Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is characterized by progressive demyelination and neurodegeneration induced by inflammation and oxidative stress. The induction of Nrf2 signaling has been shown to inhibit disease development and progression in the experimental autoimmune encephalomyelitis (EAE) model of MS in mice.

Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

Objective: Diacylglycerol O-acyltransferase 1 (DGAT1) catalyzes the final committed step in triglyceride biosynthesis. DGAT1 null mice are known to be resistant to diet-induced obesity, and more insulin sensitive relative to the wild-type; however, the mice exhibit abnormalities in the skin. This work determined whether the intestine-targeted DGAT1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice.

The butenolide signaling molecules SRB1 and SRB2 induce lankacidin and lankamycin production in Streptomyces rochei.

New signaling molecules that induce lankacidin and lankamycin production in Streptomyces rochei were extracted from the culture filtrate and purified by Sephadex LH20 and silica gel chromatography with the help of bioassay. Chiral HPLC and ESI-MS analyses indicated the presence of two active components--SRB1 and SRB2--and their molecular formulas were established to be C15H24O5 and C16H26O5, respectively. By extensive NMR analysis, SRB1 and SRB2 were determined to be 2-(1'-hydroxy-6'-oxo-8'-methylnonyl)-3-methyl-4-hydroxybut-2-en-1,4-olide and 2-(1'-hydroxy-6'-oxo-8'-methyldecyl)-3-methyl-4-hydroxybut-2-en-1,4-olide, respectively.

Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans.

Objective: We have provided evidence that saturated fatty acids, which are released from adipocytes via macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for the Toll-like receptor (TLR) 4 complex in macrophages, thereby aggravating obesity-induced adipose tissue inflammation. The aim of this study was to identify the molecule(s) activated in adipose tissue macrophages in obesity.

Research Design And Methods: We performed a cDNA microarray analysis of coculture of 3T3-L1 adipocytes and RAW264 macrophages.

RNA interference with 2',4'-bridged nucleic acid analogues.

In this study, a number of 2',4'-BNA- and 2',4'-BNA(NC)-modified siRNAs were designed and synthesized. Their thermal stability, nuclease resistance and gene silencing properties against cultured mammalian cells were evaluated and compared with those of natural siRNAs. The 2',4'-BNA- and 2',4'-BNA(NC)-modified siRNAs (named siBNA and siBNA(NC), respectively) showed very high T(m) values, were remarkably stable in serum sample and showed promising RNAi properties equal to those exhibited by natural siRNAs.

Antigene-block strategy: effective regulation of gene expression by 2',4'-BNA-modified TFOs with an additional stem-loop structure.

Antigene strategy is promising technology to regulate gene expression. We have previously reported that 2'-O,4'-C-methylene bridged nucleic acid (2',4'-BNA) modification of triplex-forming oligonucleotides (TFOs) significantly enhanced the binding affinity towards the target dsDNA. In spite of its usefulness, the TFO-binding site may not completely overlay the protein-binding site because of the limitation of TFOs targeting sequences.