dehydroxymethylepoxyquinomicin and Body-Weight

Interactions between intestinal neuroendocrine peptides/amines and the immune system appear to have an important role in the pathophysiology of inflammatory bowel disease (IBD). The present study investigated the effects of activator protein (AP)‑1 and nuclear factor (NF)‑κB inhibitors on inflammation‑induced alterations in enteroendocrine cells. A total of 48 male Wistar rats were divided into the following four groups (n=12 rats/group): Control, trinitrobenzene sulfonic acid (TNBS)‑induced colitis only (TNBS group), TNBS‑induced colitis with 3‑[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM‑G) treatment (DTCM‑G group), and TNBS‑induced colitis with dehydroxymethylepoxyquinomicin (DHMEQ) treatment (DHMEQ group). A total of 3 days following administration of TNBS, the rats were treated as follows: The control and TNBS groups received 0.5 ml vehicle (0.5% carboxymethyl cellulose; CMC), respectively; the DTCM‑G group received DTCM‑G (20 mg/kg body weight) in 0.5% CMC; and the DHMEQ group received DHMEQ (15 mg/kg body weight) in 0.5% CMC. All injections were performed intraperitoneally twice daily for 5 days. The rats were sacrificed, and tissue samples obtained from the colon were examined histopathologically and immunohistochemically. Inflammation was evaluated using a scoring system. In addition, the sections were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), oxyntomodulin, pancreatic polypeptide (PP) and somatostatin, and immunostaining was quantified using image‑analysis software. The density of cells expressing CgA, PYY and PP was significantly lower in the TNBS group compared with in the control group, whereas the density of cells expressing serotonin, oxyntomodulin and somatostatin was significantly higher in the TNBS group compared with in the control group. None of the endocrine cell types differed significantly between the control group and either the DTCM‑G or DHMEQ groups. All of the colonic endocrine cell types were affected in rats with TNBS‑induced colitis. The expression density of these endocrine cell types was restored to control levels following treatment with AP‑1 or NF‑κB inhibitors. These results indicated that the immune system and enteroendocrine cells interact in IBD.

Topics: Animals; Benzamides; Biomarkers; Body Weight; Chromogranin A; Colitis; Cyclohexanones; Disease Models, Animal; Endocrine Cells; Gene Expression; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; NF-kappa B; Piperidones; Rats; Serotonin; Transcription Factor AP-1; Trinitrobenzenesulfonic Acid

Atherosclerosis is a chronic inflammatory process, and anti-inflammatory agents potentially inhibit the development of atherosclerosis. We tested whether a novel NFkappaB inhibitor reduces atherosclerosis.. Dehydroxymethylepoxyquinomicin (10 mg/kg) or vehicle (chloromethyl cellulose) was injected intraperitoneally into apoE-deficient mice three times a week for 16 weeks. The entire aorta was excised and atherosclerotic area was determined at 4 and 16 weeks. Serum levels of cholesterol, triglyceride, TNF-alpha and adiponectin were also measured.. The atherosclerotic area was significantly smaller in mice treated with dehydroxymethyl-epoxyquinomicin both at 4 and 16 weeks. There was no significant difference in body weight or serum levels of cholesterol, triglyceride, and adiponectin.. A new NFkappaB inhibitor, dehydroxymethylepoxyquinomicin, reduced atherosclerosis without affecting plasma lipid levels in apoE-deficient mice.

Topics: Adiponectin; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Benzamides; Body Weight; Cholesterol; Cyclohexanones; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Triglycerides; Tumor Necrosis Factor-alpha

To investigate the association between serum interleukin-6 (IL-6) and cachexia in patients with prostate cancer and the inhibitory effect of a new nuclear factor kappaB (NF-kappaB) inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on IL-6 production and cachexia in an animal model of hormone-refractory prostate cancer.. The association between serum IL-6 levels and variables of cachexia was evaluated in 98 patients with prostate cancer. The inhibitory effects of DHMEQ on IL-6 secretion and cachexia were investigated in in vitro and in vivo studies using JCA-1 cells derived from human prostate cancer.. Serum IL-6 levels were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. IL-6 secretion was significantly inhibited in JCA-1 cells exposed to DHMEQ. Intraperitoneal administration of DHMEQ (8 mg/kg) to tumor-bearing mice produced a significant amelioration of the reduction in body weight, epididymal fat weight, gastrocnemius muscle weight, hematocrit, and serum levels of triglyceride and albumin when compared with administration of DMSO or no treatment. DHMEQ caused a significant decrease of serum IL-6 level in JCA-1 tumor-bearing mice (all P < 0.05).. These results suggested an association between serum IL-6 and cachexia in patients with prostate cancer and in JCA-1 tumor-bearing mice and that a new NF-kappaB inhibitor, DHMEQ, could prevent the development of cachexia in JCA-1 tumor-bearing mice presumably through the inhibition of IL-6 secretion. DHMEQ seems to show promise as a novel and unique anticachectic agent in hormone-refractory prostate cancer.

Topics: Albumins; Animals; Antineoplastic Agents; Benzamides; Body Mass Index; Body Weight; Cachexia; Cell Line, Tumor; Cyclohexanones; Disease Models, Animal; Dose-Response Relationship, Drug; Hematocrit; Humans; Interleukin-6; Male; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Neoplasm Transplantation; NF-kappa B; Prostatic Neoplasms; Time Factors; Triglycerides; Weight Loss