Development of an XBP1 agonist, HLJ2, as a potential therapeutic agent for ulcerative colitis / 中国药理学与毒理学杂志

OBJECTIVE To identify the valid targets and new drugs of ulcerative colitis (UC), a recurrent and intractable inflammatory bowel disease. METHODS and RESULTS In an in vivo mouse model of DSS-induced colitis, HLJ2 decreased weight loss, colon contracture, disease activity index (DAI), colon mucosa damage index (CMDI) and histopathological index (HI). HLJ2 also decreased myelo?peroxidase(MPO) activity and reduced production of the inflammatory cytokines TNF- α, IL- 1β, andIL- 6. HLJ2 improved intestinal mucosa damage induced by dextran sodium sulfate (DSS) and increased the expression of ZO-1 and claudin-1. Fecal 16s rRNA high-throughput sequencing demon?strated a significant improvement in UC intestinal dysbacteriosis in mice treated with HLJ2, including increased abundance of probiotics such as Lachnospiraceae, Prevotellaceae, and Lactobacillaceae. At the same time there was a reduction in the abundance of pathogenic or conditional pathogenic microor?ganisms such as Bacteroidaceae, Porphyromonadaceae, Deferribacteraceae, and Pseudomonadaceae in HLJ2- treated mice compared with untreated mice. CONCLUSION Our results demonstrated that the XBP1 agonist HLJ2 inhibits inflammation, regulates the intestinal flora, and protects the intestinal mucosa. It is thus a potential therapeutic agent for ulcerative colitis.

Relative Orientation and Position Detections Based on an RGB-D Sensor and Dynamic Cooperation Strategies for Jumping Sensor Nodes Recycling.

This paper presents relative orientation and position detection methods for jumping sensor nodes (JSNs) recycling. The methods are based on motion captures of the JSNs by an RGB-D sensor mounted on a carrier robot and the dynamic cooperation between the carrier and the JSNs. A disc-like label with two different colored sides is mounted on the top of the JSNs. The RGB-D sensor can detect the motion of the label to calculate the orientations and positions of the JSNs and the carrier relative to each other. After the orientations and positions have been detected, the JSNs jump into a cabin mounted on the carrier in dynamic cooperation with the carrier for recycling. The performances of the proposed methods are tested with a prototype system. The results show that the carrier can detect a JSN from up to 2 m away and sense its relative orientation and position successfully. The errors of the JSN's orientation and position detections relative to the carrier could be reduced to the values smaller than 1° and 1 cm, respectively, by using the dynamic cooperation strategies. The proposed methods in this paper could also be used for other kinds of mobile sensor nodes and multi-robot systems.

Biological activity of EXf, a peptide analogue of exendin-4.

Exendin-4 is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. EXf is an available carboxy-terminal truncated fragment of exendin-4 with two amino acid substitutions. The purpose of these studies was to evaluate the biological activity of EXf. After a single subcutaneous injection, EXf significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge both in non-diabetic (ICR), monosodium l-glutamate induced insulin resistance (MSG-IR) and diabetic KK-ay mice. Meanwhile, EXf resulted in an increase of first-phase insulin secretion in normal mice and KK-ay mice following the glucose challenge. EXf was also shown to inhibit small intestinal transit in rodent models. EXf activated the cAMP response element (CRE) of the rat insulin I gene promoter (RIP1) GFP-construct in a dose-dependent manner in the cultured mouse insulinoma cell line, termed NIT-1, and this agonist activity was blocked by the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). In summary, EXf, an analogue of exendin-4, has agonist activity to GLP-1 receptor in vitro and glucoregulatory activities in vivo, thus it can be considered as a new candidate for the treatment of type 2 diabetes.

Atorvastatin improves insulin sensitivity in mice with obesity induced by monosodium glutamate.

AIM: To examine the mechanisms underlying the effects of atorvastatin on glucose and lipid metabolism. METHODS: Mice with insulin resistance and obesity induced by monosodium glutamate (MSG) were used. Atorvastatin (80 mg.kg(-1).d(-1)) or vehicle control treatment was given orally once a day for 30 days. Plasma levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and free fatty acids were monitored. Serum insulin and glucose concentrations were used to calculate the insulin resistance index and insulin sensitivity index using a homeostasis model. Body length, waistline circumference, intraperitoneal adipose tissue mass, and total body mass were measured. Semi-quantitative RT-PCR and Western analysis were used to determine the expression of inflammatory factors and proteins involved in inflammation signaling pathways. RESULTS: Atorvastatin improved insulin sensitivity, ameliorated glucose tolerance, and decreased plasma levels of total cholesterol, triglycerides, LDL-C, HDL-C and free fatty acids. Semi-quantitative RT-PCR and Western analysis revealed increased expression of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in serum and adipose tissue in MSG obese mice. Atorvastatin treatment decreased expression of IL-6, TNF-alpha, nuclear factor kappaB (NF-kappaB) and I-kappa-B (IkappaB) kinase-beta, but increased the expression of IkappaB, in adipose tissue. CONCLUSION: Atorvastatin is a potential candidate for the prevention and therapy of diseases associated with insulin resistance such as type 2 diabetes mellitus and cardiovascular disease. One possible mechanism underlying the effects of atorvastatin on glucose and lipid metabolism may be to ameliorate a state of chronic inflammation.

[Analysis on the genetic structure of 8 Asia buffalo populations].

One hundred and forty seven alleles were detected when thirteen microsatellite loci were analyzed applying fluorescence-multiplex PCR technology in eight buffalo populations were analyzed, including six indigenous Chinese native breeds (DechangXinglongFuzhongWenzhouDongliuFu'an), and two introduced breeds (MurrahNili-Ravi). Seven populations have their own unique alleles, total number is twenty-three. As to all the eight populations, effective number of alleles (Ne) was between 2.2908 and 4.2308, heterozygosity (H) between 0.4951 and 0.7194, and polymorphism information content (PIC) between 0.4495 and 0.6776. Eleven of the thirteen microsatellite loci were of high polymorphism and were then the appropriate, polymorphism marker could be used to analyze properly genetic diversity of the involved buffalo populations. Cluster analysis indicated that Fuzhong and Dongliu were clustered together, then with an independent cluster of Xinglong. Wenzhou and Fu'an were clustered together, Dechang was an independent cluster. Murrah and Nili-Ravi were clustered together.