The role of adipose tissue-associated macrophages and T lymphocytes in the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract that affect more than 3 million people worldwide, but the pathological etiology is still unknown. The overall purpose of our investigations was to elucidate the possibility of pathological causes of IBD, and therefore, we determined the difference of inflammatory cytokine profiles in adipose tissue macrophages (ATMs) and T lymphocytes (ATTs) obtained near active lesions of IBD; investigated whether the alteration in ATM activation induces genes involved in collagen formation; and evaluated the effects of fatty acid oxidation inhibitors on factors involved in inflammation and collagen production by ATMs in IBD. Adipose tissues (ATs) were collected near active lesions and also at the margin of resected segments of the bowel from IBD patients with ulcerative colitis (UC) and CD (n = 14/group). Normal appearing ATs from control subjects (n = 14) who had colon resection for adenocarcinoma were collected as far away from the cancer lesion as possible to rule out possible changes. Compared with inactive disease lesions, ATMs and ATTs from active lesions released more IL-6, IL-4 and IL-13. Treatments of cytokine IL-4 and/or IL-13 to ATMs reduced iNOS expression but increased Arg-I expression which were exacerbated when treated with T cell- and adipocyte-conditioned medium. However, fatty acid oxidation inhibitors prevented the effects of cytokines IL-4 and/or IL-13 on iNOS and Arg-I expressions. This study was the first to show the effect of IL-4 and IL-13 on collagen formation, through iNOS and Arg-I expressions, that was exacerbated in a condition that mimics in vivo condition of active lesions. Moreover, our study was the first to provide potential benefits of fatty acid oxidation inhibitors to ATMs on preventing collagen formation; thus, providing therapeutic implications for individuals with intestinal fibrosis and stricture lesions, although future study should be guaranteed to elucidate the underlying mechanisms.     

Quercetin supplementation is effective in improving mitochondrial dysfunctions induced by 3-nitropropionic acid: Implications in Huntington's disease

The study was designed to investigate the beneficial effect of quercetin supplementation in 3-nitropropionic acid (3-NP) induced model of Huntington's disease (HD). HD was induced in rats by administering sub-chronic dose of 3-NP, intraperitoneally, twice daily for 17 days. Quercetin was supplemented at a dose of 25 mg/kg body weight by oral gavage for 21 days. At the end of treatment, mitochondrial bioenergetics, mitochondrial swelling, oxidative stress, neurobehavioral deficits and histopathological changes were analyzed. Quercetin supplementation was able to reverse 3-NP induced inhibition of respiratory chain complexes, restore ATP levels, attenuate mitochondrial oxidative stress in terms of lipid peroxidation and prevent mitochondrial swelling. Quercetin administration also restored the activities of superoxide dismutase and catalase along with thiol content in 3-NP treated animals. Beneficial effect of quercetin administration was observed on 3-NP induced motor deficits analyzed by narrow beam walk and footprint analysis. Histopathological analysis of 3-NP treated rats revealed pyknotic nuclei and astrogliosis in striatum, which were reduced or absent in quercetin supplemented animals. Altogether, our results show that quercetin supplementation to 3-NP induced HD animals ameliorated mitochondrial dysfunctions, oxidative stress and neurobehavioral deficits in rats showing potential of this flavonoid in maintaining mitochondrial functions, suggesting a putative role of quercetin in HD management.     

Changing patterns of Helicobacter pylori gastritis in long-standing acid suppression

Background. Helicobacter pylori colonization and associated inflammation are influenced by local acid output. Infected subjects with acid‐related diseases, such as gastroesophageal reflux disease (GERD) are likely to have an antral‐predominant gastritis. We hypothesized that long‐term acid suppression would result in relatively greater bacterial colonization in the corpus leading to diffuse or corpus‐predominant gastritis and that this would be prevented by prior H. pylori eradication. Materials and Methods. To investigate this, we conducted a prospective, double‐blind trial of the effect on gastric histology of 12‐month maintenance treatment with omeprazole in H. pylori–positive GERD patients randomly assigned to either an eradication or omeprazole‐alone regime. A control group of 20 H. pylori–negative GERD patients also received omeprazole throughout the study period. Biopsies taken at baseline and at 12 months were graded “blind” by a single observer according to the updated Sydney System. The 41 H. pylori‐positive subjects with grade B or C esophagitis were randomly assigned (20 to omeprazole alone, 21 to eradication) and 33 subjects completed the 12‐month study. Results. There was a significant decline in antral chronic inflammation in initially positive patients between baseline and end in both the eradication group (p = .035) and the omeprazole‐alone group (p = .008). However, corpus chronic inflammation increased in the omeprazole‐alone group (p = .0156) but decreased in the eradication group. The change toward corpus predominance between baseline and end for the omeprazole‐alone group is highly significant (p = .0078). Furthermore, 5 of 11 in the omeprazole‐alone group developed mild corpus atrophy, compared to 0 of 8 who had undergone H. pylori eradication. The change in frequency of corpus atrophy between the two groups is significant (p = .02). Conclusion. In H. pylori–positive subjects with GERD, long‐term acid suppression leads to a shift from antral‐ to corpus‐predominant gastritis that can be prevented by prior eradication. The shift is accompanied by an increase in corpus atrophy. H. pylori infection should be eradicated prior to long‐term acid suppression with proton pump inhibitors.     

Adiponectin deficiency: role in chronic inflammation induced colon cancer

Adiponectin (APN), an adipokine, exerts an anti-inflammatory and anti-cancerous activity with its role in glucose and lipid metabolism and its absence related to several obesity related malignancies including colorectal cancer. The aim of this study is to determine the effect of APN deficiency on the chronic inflammation-induced colon cancer. This was achieved by inducing inflammation and colon cancer in both APN knockout (KO) and C57B1/6 wild type (WT) mice. They were divided into four treatment groups (n=6): 1) control (no treatment); 2) treatment with three cycles of dextran sodium sulfate (DSS); 3) weekly doses of 1,2-dimethylhydrazine (DMH) (20mg/kg of mouse body weight) for twelve weeks; 4) a single dose of DMH followed by 3 cycles of DSS (DMH+DSS). Mice were observed for diarrhea, stool hemoccult, and weight loss and were sacrificed on day 153. Tumor area and number were counted. Colonic tissues were collected for Western blot and immunohistochemistry analyses. APNKO mice were more protected than WT mice from DSS induced colitis during first DSS cycle, but lost this protection during the second and the third DSS cycles. APNKO mice had significantly severe symptoms and showed greater number and larger area of tumors with higher immune cell infiltration and inflammation than WT mice. This result was further confirmed by proteomic study including pSTAT3, pAMPK and Cox-2 by western blot and Immunohistochemistry. Conclusively, APN deficiency contributes to inflammation-induced colon cancer. Hence, APN may play an important role in colorectal cancer prevention by modulating genes involved in chronic inflammation and tumorigenesis.     

Synthesis of graft copolymer (CgOH-g-AGA): Physicochemical properties, characterization and application

A graft copolymer of κ-carrageenan and 2-acrylamidoglycolic acid (CgOH-g-AGA) was synthesized via free radical polymerization initiated by potassium peroxymonosulphate/malonic acid redox pair. For affording maximum percentage of grafting, optimum conditions were determined by varying the concentrations of κ-carrageenan, 2-acrylamidoglycolic acid, potassium peroxymonosulphate, malonic acid, hydrogen ion, time and temperature. The swelling, metal ion uptake and flocculation studies were investigated with water, three metals (Ni(2+), Pb(2+) and Zn(2+)) solutions, coal (coking and non-coking) suspensions, respectively. Both, polymer backbone and its corresponding graft copolymer samples were characterized by Fourier transform infrared spectroscopy and thermogravimetric analysis.     

Synthesis and properties of a water soluble graft (chitosan-g-2-acrylamidoglycolic acid) copolymer

The present paper reports the graft copolymerization of 2-acrylamidoglycolic acid onto chitosan by using potassium bromate/silver nitrate as an efficient redox initiator in an inert atmosphere. The effect of reaction conditions on grafting parameters i.e. grafting ratio, efficiency, conversion, add on, homopolymer and rate of grafting has been studied. Experimental results show that maximum grafting has been obtained at 0.4 g dm(-3) concentration of chitosan, 8.0×10(-2) mol dm(-3) concentration of 2-acrylamidoglycolic acid and 1.0×10(-3) mol dm(-3) concentration of hydrogen ion. It has also been observed that grafting ratio, add on, conversion, efficiency and rate of grafting increase up to 3.2×10(-3) mol dm(-3) of silver nitrate and 1.7×10(-2) mol dm(-3) of potassium bromate. Time (120 min) and temperature (40°C) were kept constant during reaction. The physicochemical properties of graft copolymer synthesized have been performed in terms of water swelling, metal ion sorption, flocculation and resistance to biodegradability with respect to the chitosan as a parent polymer. The graft copolymer has been characterized by Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis.     

Characterisation of the first enzymes committed to lysine biosynthesis in Arabidopsis thaliana

In plants, the lysine biosynthetic pathway is an attractive target for both the development of herbicides and increasing the nutritional value of crops given that lysine is a limiting amino acid in cereals. Dihydrodipicolinate synthase (DHDPS) and dihydrodipicolinate reductase (DHDPR) catalyse the first two committed steps of lysine biosynthesis. Here, we carry out for the first time a comprehensive characterisation of the structure and activity of both DHDPS and DHDPR from Arabidopsis thaliana. The A. thaliana DHDPS enzyme (At-DHDPS2) has similar activity to the bacterial form of the enzyme, but is more strongly allosterically inhibited by (S)-lysine. Structural studies of At-DHDPS2 show (S)-lysine bound at a cleft between two monomers, highlighting the allosteric site; however, unlike previous studies, binding is not accompanied by conformational changes, suggesting that binding may cause changes in protein dynamics rather than large conformation changes. DHDPR from A. thaliana (At-DHDPR2) has similar specificity for both NADH and NADPH during catalysis, and has tighter binding of substrate than has previously been reported. While all known bacterial DHDPR enzymes have a tetrameric structure, analytical ultracentrifugation, and scattering data unequivocally show that At-DHDPR2 exists as a dimer in solution. The exact arrangement of the dimeric protein is as yet unknown, but ab initio modelling of x-ray scattering data is consistent with an elongated structure in solution, which does not correspond to any of the possible dimeric pairings observed in the X-ray crystal structure of DHDPR from other organisms. This increased knowledge of the structure and function of plant lysine biosynthetic enzymes will aid future work aimed at improving primary production.