mocetinostat and Body-Weight

Topics: Adolescent; Adult; Aged; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Atherosclerosis; Body Weight; Cell Adhesion Molecules; Exercise Therapy; Female; Humans; Lipoproteins, LDL; Male; Middle Aged; Obesity; Peroxidase; Resistance Training; Risk Factors; Sex Factors; Walking; Young Adult

To evaluate the effects of canrenone compared to placebo on blood pressure control, some non-conventional biomarkers in cardiovascular stratification, and on metalloproteinases in patients affected by metabolic syndrome.. A total of 156 Caucasian patients were treated with placebo or canrenone, 50 mg once a day, for 3 months and then 50 mg twice a day, till the end of the study. We evaluated: systolic (SBP) and diastolic blood pressure (DBP), body weight, body mass index (BMI), fasting plasma glucose (FPG), lipid profile, plasma aldosterone, creatinine, potassium, brain natriuretic peptide (BNP), metalloproteinases 2 and 9 (MMP-2 and -9), lipoprotein (a) (Lp(a)), and serum myeloperoxidase (MPO).. We observed a significant decrease of SBP and DBP in the canrenone group compared to baseline. Canrenone gave a significant decrease of MMP-2 and -9, Lp(a), and MPO compared to baseline, not observed with placebo. Plasma aldosterone, but not BNP, decreased with canrenone, both compared to baseline and to placebo.. Canrenone seems to be effective in reducing blood pressure in patients with metabolic syndrome. Moreover, canrenone seems also to improve MPO, Lp(a), and metalloproteinases in these patients.

Topics: Aged; Aldosterone; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Canrenone; Creatine; Double-Blind Method; Fasting; Female; Humans; Inflammation; Lipids; Lipoproteins; Male; Metabolic Syndrome; Metalloproteases; Middle Aged; Natriuretic Peptide, Brain; Peroxidase; Potassium; White People

We initiated a pilot study to investigate the effects of 8 wks of aerobic exercise training (ET) on insulin sensitivity and inflammatory markers in obese and insulin-resistant minority adolescents. Eleven morbidly obese (BMI 41.4 ± 1.8 kg/m2) minority adolescents were entered into a supervised ET intervention (~180 min/wk at 40-55%VO2PeakR [(VO2Peak-VO2Rest)/VO2Rest]). The effects of training on insulin sensitivity (SI), inflammation and other metabolic syndrome features were examined.. Insulin action improved in response to training, as indicated by a ~37% increase in SI (p = .018). Plasma levels of several proinflammatory cytokines were reduced in response to ET, as indicated by significant decrements in sTNF-R, CCL2, MPO, IL-6, resistin, and leptin, with no significant changes in hsCRP. ET induced reductions in BMI and percent total body fat.. The present study supports the efficacy of ET interventions on metabolic syndrome features in morbidly obese minority youth.

Topics: Adolescent; Black or African American; Body Composition; Body Weight; Chemokine CCL2; Exercise; Exercise Test; Exercise Therapy; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Insulin Resistance; Leptin; Male; Obesity, Morbid; Oxygen Consumption; Peroxidase; Pilot Projects; Receptors, Tumor Necrosis Factor; Resistin; Statistics, Nonparametric

The complement system is implicated in the pathogenesis of human inflammatory bowel disease, but the specific role of C5a has never been examined. We have compared the efficacy of an orally active human C5a receptor antagonist (AcPhe[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), prednisolone, and infliximab against trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. The drugs were administered either 2 days before or 24 h after TNBS instillation, and rats were then examined after 8 days. Drug-free colitis control rats showed severe disease pathology with significant mortality (39%). Rats pre or posttreated with the C5a antagonist (10 mg/kg/day peroral, 0.3 mg/kg/day s.c.) had reduced mortality and significantly improved macroscopic scores, colon edema, colon myeloperoxidase levels, reduced concentrations of TNF-alpha levels in the colon and serum, and had greater food intake resulting in greater weight gains than colitis-only rats. Rats pretreated with prednisolone (1 mg/kg/day s.c.) displayed significant improvement in parameters measured, but posttreatment was ineffective. Single dose pretreatment with the TNF-alpha inhibitor infliximab (3 mg/kg i.v.) also had significant improvements in the parameters measured. Rats pretreated with a combination of the C5a antagonist and prednisolone showed no greater improvements than either drug alone. These findings suggest a central role for complement, particularly C5a, in the pathology of TNBS-induced colitis in rats, indicating a possible therapeutic role for C5a antagonists in inflammatory bowel disease.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Colon; Disease Models, Animal; Eating; Edema; Humans; Inflammatory Bowel Diseases; Infliximab; Male; Peptides, Cyclic; Peroxidase; Prednisolone; Rats; Rats, Wistar; Receptor, Anaphylatoxin C5a; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The study aimed to assess plasma Myeloperoxidase enzyme (MPO) and Ferric-reducing antioxidant power (FRAP) in obese dogs and compare them with ideal body weight dogs. Thirty-two dogs were distributed into two groups according to a 9-point body condition score (BCS), as follows: Control group (n = 16), dogs with a BCS of 4 or 5; Obese group (n = 16), dogs with a BCS of 8 or 9. Plasma MPO and FRAP assays, neutrophil count, lipid profile (cholesterol and triglycerides), and systolic blood pressure (SBP) were evaluated in both groups. The duration of obesity was defined based on history. The obese group showed higher values for body weight, BCS, SBP, neutrophil count, triglycerides, and MPO than the Control group. A positive correlation was observed between MPO concentrations and BCS and body weight. FRAP concentrations showed a positive correlation with the duration of obesity. The results suggested that an inflammatory state caused by obesity may promote increased neutrophil count and MPO concentrations, besides the positive correlation between MPO with BCS and body weight. The obesity in dogs promoted slight active MPO elevation, influenced by body weight, BCS, and neutrophil count. The FRAP assay did not show the expected reduction and, therefore, needs further investigation.

Topics: Animals; Antioxidants; Body Weight; Dog Diseases; Dogs; Leukocyte Count; Obesity; Peroxidase

Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) are diseases of the gastrointestinal system involving genetic and environmental factors attributed to oxidative stress and inflammation. Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the important therapeutic strategies to keep the disease in remission. As there is no permanent cure for IBD except for chronic long-term treatment or surgery, it is therefore imperative to investigate plant-based agents that are receiving attention for their therapeutic benefits to overcome the debilitating clinical conditions of IBD. Lycopodium (LYCO), a plant of tropical and subtropical origin and known by numerous names such as ground pine, club moss, or devil's claw, has been popularly used for centuries in traditional medicine including Chinese and Indian medicines. In the present study, the effect of LYCO has been investigated in an acetic acid (AA)-induced colitis model in Wistar rats. LYCO was orally administered at the dose of 50 mg/kg/day either 3 days before or 30 min after the induction of IBD and continued for 7 days by intrarectal administration of AA. The changes in body weight and macroscopic and microscopic analysis of the colon of rats of different experimental groups were observed on days 0, 2, 4, and 7. The levels of myeloperoxidase (MPO), reduced glutathione (GSH), and malondialdehyde (MDA) were measured. AA caused a significant reduction in body weight and increased macroscopic and microscopic ulcer scores along with a significant decline in antioxidant enzymes, superoxide dismutase (SOD), and catalase and antioxidant substrate, glutathione (GSH). There was a concomitant increased formation of malondialdehyde (MDA), a marker of lipid peroxidation, and raised myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with LYCO significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. AA also caused the release of proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-23 (IL-23). Furthermore, AA also increased the levels of calprotectin, a protein released by neutrophils under inflammatory conditions of the gastrointestinal tract. LYCO treatment significantly reduced the release of calprotectin and proinflammatory cytokines. The results demonstrate

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis; Colitis, Ulcerative; Cytokines; Glutathione; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Leukocyte L1 Antigen Complex; Lycopodium; Malondialdehyde; Oxidative Stress; Peroxidase; Rats; Rats, Wistar

Heat stress (HS) has detrimental effects on intestinal health by altering digestive and immune responses in animals. Dietary Moringa oleifera leaf powder (MOLP) has been implicated in ameliorating the impact of HS, but its effects in terms of intestinal function improvement under HS remain poorly characterized. Therefore, the current study investigated the impact of HS and MOLP supplementation on tight junction barriers, intestinal microbiota (jejunal digesta), and differentially expressed genes (DEGs) in jejunal mucosa of heat-stressed rabbits by using the next-generation sequencing techniques. A total of 21 male New Zealand White rabbits (32 weeks old mean body weight of 3318 ± 171 g) were divided into three groups (n = 7/group) as control (CON, 25 °C), heat stress (HS, 35 °C for 7 h daily), and HS with MOLP supplementation (HSM, 35 °C for 7 h daily) gavage at 200 mg/kg body weight per day for 4 weeks. The results indicated that MOLP supplementation increased mRNA expression of tight junction proteins and glutathione transferase activity, while the malonaldehyde concentration was decreased in the jejunal mucosa compared to HS group (P < 0.05). Furthermore, MOLP decreased the concentrations of lipopolysaccharide, pro-inflammatory cytokines, and myeloperoxidase compared with HS group (P < 0.05). Intestinal microbiota analysis revealed that at phyla level, the relative abundance of Bacteroidetes was higher in HSM group compared to CON and HS groups. MOLP supplementation also resulted in higher abundance of putatively health-associated genera such as Christensenellaceae R-7 gut group, Ruminococcaceae NK4A214 group, Ruminococcus 2, Lachnospiraceae NK4A136 group, and Lachnospiraceae unclassified along with higher butyrate levels in HSM group as compared to HS group. The analysis of DEGs revealed that MOLP reversed inflammatory response by downregulation of genes, such as TNFRSF13C, LBP, and COX2 in enriched KEGG pathway of NF-kβ pathway. MOLP supplementation also significantly upregulated the expression of genes in protein digestion and absorption pathway, including PRSS2, LOC100349163, CPA1, CPB1, SLC9A3, SLC1A1, and SLC7A9 in HSM group. Three genes of fibrillar collagens, i.e., COL3A1, COL5A3, and COL12A1 in protein digestion were also down-regulated in HSM group. In conclusion, MOLP supplementation could improve jejunal permeability and digestive function, positively modulate microbiota composition and mucosal immunity in heat-stressed rabbits.

Topics: Animals; Body Weight; Butyrates; Chickens; Cyclooxygenase 2; Cytokines; Dietary Supplements; Gastrointestinal Microbiome; Glutathione Transferase; Heat Stress Disorders; Heat-Shock Response; Immunity, Mucosal; Lipopolysaccharides; Male; Malondialdehyde; Moringa oleifera; Permeability; Peroxidase; Plant Leaves; Powders; Rabbits; RNA, Messenger; Tight Junction Proteins

Radiotherapy and chemotherapy can kill tumor cells and improve the survival rate of cancer patients. However, they can also damage normal cells and cause serious intestinal toxicity, leading to gastrointestinal mucositis[1]. Traditional Chinese medicine is effective in improving the side effects of chemotherapy. Wumei pills (WMP) was originally documented in the Treatise on Exogenous Febrile Diseases. It has a significant effect on chronic diarrhea and other gastrointestinal diseases, but it is not clear whether it affects chemotherapy-induced intestinal mucositis (CIM).. To explore the potential mechanism of WMP in the treatment of CIM through experimental research.. We used an intraperitoneal injection of 5-fluorouracil (5-Fu) to establish a CIM mouse model and an oral gavage of WMP decoction (11325 and 22650 mg/kg) to evaluate the efficacy of WMP in CIM. We evaluated the effect of WMP on CIM by observing the general conditions of the mice (body weight, food intake, spleen weight, diarrhea score, and hematoxylin and eosin stained tissues). The expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and myeloperoxidase (MPO), as well as the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway proteins and tight junction proteins (zonula occludens-1, claudin-1, E-cadherin, and mucin-2) was determined. Furthermore, intestinal permeability, intestinal flora, and the levels of short-chain fatty acids (SCFA) were also assessed.. WMP effectively improved the body weight, spleen weight, food intake, diarrhea score, and inflammatory status of the mice with intestinal mucositis, which preliminarily confirmed the efficacy of WMP in CIM. Further experiments showed that in addition to reducing the levels of TNF-α, IL-1β, IL-6, and MPO and inhibiting the expression of the TLR4/MyD88/NF-κB pathway proteins, WMP also repaired the integrity of the mucosal barrier of mice, regulated the intestinal flora, and increased the levels of SCFA (such as butyric acid).. WMP can play a therapeutic role in CIM by alleviating inflammation, restoring the mucosal barrier, and regulating gut microbiota.

Topics: Animals; Antineoplastic Agents; Body Weight; Butyrates; Cadherins; Claudin-1; Diarrhea; Drugs, Chinese Herbal; Eosine Yellowish-(YS); Fluorouracil; Gastrointestinal Microbiome; Hematoxylin; Interleukin-6; Intestinal Mucosa; Mice; Mucin-2; Mucositis; Myeloid Differentiation Factor 88; NF-kappa B; Peroxidase; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Caralluma species are traditional edible herbs used in folkloric medicine as antidiabetic, antioxidant, antipyretic, antirheumatic, anti-inflammatory and anthelmintic agents. C. quadrangula was selected in this study to document the traditional use of the genus as anti-rheumatic treatment and the possible mechanisms of action.. The higher mortality rates and shorter survival among the patients suffering from rheumatoid arthritis (RA) led to the increased interest on searching for new treatments for RA. Russelioside B (RB), a major pregnane glycoside found in C. quadrangula, was evaluated as a new anti-rheumatic agent.. The n-butanol fraction of C. quadrangula was chromatographed on a silica gel column to isolate RB. The adjuvant-induced arthritis (AIA) model was established in rats by intradermal injection of complete Freund's adjuvant (CFA) to evaluate its anti-arthritic effect. Ibuprofen was used as a reference drug. Forty rats were randomly divided into 5 groups (n = 8): normal (NOR); CFA model (CFA); ibuprofen, 5 mg/kg; RB, 25 mg/kg and RB, 50 mg/kg. The treatments were initiated from day 16 when AIA model was established and continued up to day 40. Serum diagnostic rheumatoid markers, inflammatory cytokines, oxidative stress biomarkers, cartilage and bone degeneration enzymes were assessed.. RB at 50 mg/kg b. wt., showed significant decreases in the activities of hyaluronidase and β-glucouronidase enzymes as well significant decreases in the levels of proinflammatory cytokines as nuclear factor-kappa-B (NF-κB), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) compared to the CFA group; 11.04 ± 0.61 pg/mg protein, 4.35 ± 0.25 pg/mg protein, 3.32 ± 0.13 pg/mg protein & 2.75 ± 0.14 pg/mg protein for RB, 50 mg/kg b. wt. group vs. 25.33 ± 2.13 pg/mg protein, 25.65 ± 2.1 pg/mg protein, 22.20 ± 1.34 pg/mg protein & 13.27 ± 1.40 pg/mg protein for the arthritic group, respectively. The total antioxidant capacity (TAC) was significantly restored to normal values in RB, 50 mg/kg treated rats (4.01 ± 0.09 nmol/mL vs. 3.71 ± 0.27 nmol/mL) and the levels of myeloperoxidase (MPO) reduced by 10-folds of the CFA arthritic group. Bone histomorphometry revealed that RB treatment significantly attenuated the CFA-induced bone loss in a dose-dependent manner.. These findings suggested that the anti-arthritic effect of RB was mediated through the reduction of the rheumatoid markers, anti-inflammatory and antioxidant action, inhibition of cartilage and bone degenerative enzymes as well as attenuation of bone loss and osteoclastogenesis.

Topics: 1-Butanol; Animals; Ankle Joint; Anti-Citrullinated Protein Antibodies; Anti-Inflammatory Agents; Antirheumatic Agents; Apocynaceae; Arthritis, Experimental; Blood Cell Count; Body Weight; Cancellous Bone; Carrier Proteins; Cytokines; Edema; Freund's Adjuvant; Glucuronidase; Glycosides; Hyaluronoglucosaminidase; Inflammation; Male; Medicine, Traditional; Oxidative Stress; Peroxidase; Plant Extracts; Pregnanes; Rats, Wistar; Rheumatoid Factor

Brain natriuretic peptide is an established, surrogate follow-up marker, strongly correlated with heart failure severity. Several other biomarkers and tests are useful for assessing the prognosis of patients with HF, such as oxidized low-density lipoprotein antibodies and C-reactive protein. Some inflammatory cells, including monocytes, lymphocytes, and neutrophils, are involved in coronary heart disease and may be useful for prognosis also. This study assessed the potential usefulness of various laboratory biomarkers in predicting long-term outcomes and hospitalization among a cohort of outpatients with chronic, advanced HF.This retrospective, 18-year follow-up study included all patients admitted to the Heart Failure Outpatient Unit in our tertiary care medical center from 2000 through 2001 due to chronic HF. Excluded were patients with malignant disease, severe stroke, active inflammatory disease, or infection. At the first visit, blood was sampled for routine analysis and biomarkers NT-proBNP, C-reactive protein, myeloperoxidase, heat shock protein, and antibodies to oxidized low density lipoprotein. left ventricular ejection fraction and New York Heart Association class class were also established. Patients were followed every 3 months. Study endpoints were mortality or first hospitalization.Among 305 study patients, HF duration ranged from 2 months to 18 years. Mean follow-up was 9.1 ± 6 years. Mean time to first hospitalization was 60 ± 58.1 months, median = 38 (range 0-179). Mortality rate was 41%. Regression analysis showed New York Heart Association class, lymphocyte count and alkaline phosphatase were independent predictors of survival, with hazard ratios of 1.0, 0.973, and 1.006, respectively (P < .05).N-terminal pro-B-type natriuretic peptide, alkaline phosphatase, and lymphocyte count are important prognostic predictors for very long-term follow-up among patients with chronic HF.

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Pressure; Body Weight; C-Reactive Protein; Chronic Disease; Comorbidity; Female; Follow-Up Studies; Heart Failure; Heart Rate; Heat-Shock Proteins; Hematologic Tests; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peroxidase; Retrospective Studies; Sex Factors; Ventricular Function, Left

Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted.. This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury.. GI was induced in rat by oral administration of 5 mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04 g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP.. Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa.. ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Cytokines; Disease Models, Animal; Drugs, Chinese Herbal; Eating; Gastric Mucosa; Indomethacin; Inflammation; Male; MAP Kinase Signaling System; Peroxidase; Protein Interaction Maps; Rats, Sprague-Dawley; Stomach Diseases

Psoriasis is a most common chronic autoimmune-arbitrated cutaneous inflammatory skin disorder by unclear pathogenesis. In this current study we demonstrated the effect of galangin (GAL) on imiquimod (IMQ)-induced psoriasis-like skin inflammation and decipher its possible protective mechanism which has not been investigated. The in vivo results revealed that GAL at 1% w/w and 2% w/w for six consecutive days markedly reduced IMQ-induced PASI scoring, skin, ear thickness, hematological markers, levels of nitrites, TBARS, MPO, histopathological, as well modulated the protein levels of pro-inflammatory mediators of COX-2, iNOS, NF-κB pathway and pro-inflammatory cytokines IL-17, IL-23, IL-1β in the skin and also IL-6, TNF-α in both skin and serum. Besides, GAL restored the levels of antioxidants markers such as SOD, CAT, GST, GSH, GR and Vit-C, anti-inflammatory cytokine of IL-10, and the protein levels of Nrf2/HO-1 in the skin compared to the IMQ group. Finally, our study demonstrates that GAL exerted its protective effect by up-regulating the anti-inflammatory and the antioxidant markers against psoriasis pre-clinical models indicating its potency for treating psoriasis in humans.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Cytokines; Dermatitis; Disease Models, Animal; Down-Regulation; Flavonoids; Heme Oxygenase-1; Imiquimod; Male; Membrane Proteins; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Peroxidase; Psoriasis; Signal Transduction; Spleen

Ulcerative Colitis is a universal autoimmune disease with high incidence rates worldwide. It is characterized by the existence of many other concurrent immune-associated ailments, including diabetes. The used strategies for the management of this highly costing and complicated disease face great challenges. Therefore, the urge for new medication with fewer side effects and high efficacy is growing. The peroxisome proliferator-activated receptor-gamma (PPARγ) and nuclear factor Kappa-B (NF-κB) can be considered as crucial targets for the treatment of ulcerative colitis. Several studies reported the antioxidants, anti-inflammatory, and antiapoptotic actions of gliclazide and evaluated its cardioprotective and renoprotective effects. However, its impact on ulcerative colitis has never been investigated. This study delineated the effect of gliclazide administration on ulcerative colitis induced by acetic acid in rats and the underlying molecular mechanisms. Gliclazide (10 mg/kg; p.o) prominently decreased colon tissue injury as assessed by the histopathological analysis as well as myeloperoxidase, and intercellular adhesion molecule-1 levels. Gliclazide significantly alleviated the proinflammatory mediator, IL-6, promoted the anti-inflammatory cytokine, IL-10 and, withheld oxidative stress in the injured colon tissues. The protective effect of gliclazide was mediated through the upregulation of PPARγ and downregulation of NF-κB expression. The diminution of ulcerative colitis was also accompanied by an inhibition of the elevated activity and expression of mitogen-activated protein kinases and caspase-3 as assessed by Western blot and immunohistochemistry, respectively. Our findings spotlight, for the first time, the potential of the antidiabetic agent, gliclazide, to attenuate the experimentally induced ulcerative colitis. Therefore, gliclazide might be a propitious agent for the management of ulcerative colitis in diabetic patients.

Topics: Acetic Acid; Animals; Apoptosis; Body Weight; Caspase 3; Caspase Inhibitors; Colitis, Ulcerative; Colon; Down-Regulation; Gliclazide; Intercellular Adhesion Molecule-1; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Oxidative Stress; Peroxidase; PPAR gamma; Rats; Rats, Wistar; Signal Transduction

Methotrexate (MTX), widely used as a drug in cancer, has many adverse effects on tissues. Apocynin (APO) is a NADPH oxidase inhibitor and is known with many antioxidant properties. In this study, we aimed to evaluate the adverse effects of MTX on testicular tissue and the protective effects of APO at two different doses (20 mg/kg and 50 mg/kg) on MTX-induced testicular damage.. Fifty adult male Wistar albino rats (8 weeks old and weighing 200–250 g) were divided into five groups of 10 rats each: 1. saline control, 2. dimethyl sulfoxide (DMSO) control, 3. MTX, 4. APO-20 + MTX, and 5. APO-50 + MTX. All injections were performed intraperitoneally. At the end of day 28, all rats were sacrificed under anesthesia. The testes were evaluated histologically and the blood samples were analyzed biochemically.. According to histological and biochemical analyses, there was no significant difference between the DMSO and control groups. In terms of the histological findings, MTX group was significantly the worst affected group compared to the others, and in this group, apoptotic cell number (P = 0.011) was significantly increased in comparison with the control group. Except MTX, there was no significant difference in apoptotic cell number of the other groups compared to the control group. In the MTX group, malondialdehyde (MDA, P = 0.017) and myeloperoxidase (MPO, P < 0.001) levels were significantly increased in tissue and in blood (MDA P < 0.001, MPO P < 0.001), while tissue glutathione (GSH, P < 0.05) and serum testosterone levels (P < 0.01) were decreased compared with the control group. APO + MTX treatment groups exhibited better testis morphology, and apoptotic cells were also significantly decreased compared to MTX group (P < 0.001).. Our results suggest that MTX induced defects on testis via oxidative stress and APO reversed the effects of MTX with its antioxidant properties.

Topics: Acetophenones; Animals; Antioxidants; Apoptosis; Body Weight; Male; Malondialdehyde; Methotrexate; Peroxidase; Rats; Rats, Wistar; Testis

Inflammatory bowel disease (IBD) is characterized by recurring inflammatory disorders in digestive system, and devoid of effective treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9), stimulated via inflammation whose inhibition could decrease secretion of inflammatory factors. We then determined whether inhibition of PCSK9 could improve the inflammation. First, rats model of colitis was first established via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS), and then verified via determination of body weight loss, myeloperoxidase (MPO) activity, and histopathological analysis of colonic damage. Results showed that treatment with TNBS induced a great body weight loss, MPO activity increase, and serious colonic damage, showing an obviously character of IBD. PCSK9 was elevated in TNBS-induced rats, and PCSK9 inhibition delivered by adenovirus vector increased the body weight, decreased MPO activity, and ameliorated histological change of colon. Second, the protective effect of PCSK9 inhibition against TNBS-induced colitis was accompanied by decrease of proinflammatory factors secretion, including tumor necrosis factor-α, interleukin-1β, interleukin-6, intercellular adhesion molecule 1, and monocyte chemoattractant protein-1. TNBS could activate toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway, while PCSK9 inhibition suppressed activation of TLR4/NF-κB in TNBS-induced rats. In conclusion, PCSK9 inhibition attenuated TNBS-induced rat colitis through anti-inflammatory effect under inactivation of TLR4/NF-κB, suggesting potential therapeutic strategy in IBD.

Topics: Adenoviridae; Animals; Body Weight; Chemokine CCL2; Colitis; Colon; Gene Expression Regulation; Genetic Vectors; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Male; NF-kappa B; PCSK9 Inhibitors; Peroxidase; Proprotein Convertase 9; Rats; Rats, Wistar; RNA, Small Interfering; Signal Transduction; Toll-Like Receptor 4; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The objective of the study was to estimate the effects of synbiotics on laboratory, macroscopic, and histopathologic features in dextran sulfate sodium (DSS) experimental colitis.. A total of 40 Wistar rats received 5% of DSS in their drinking water for 8 days to induce ulcerative colitis (UC). Eight rats were sacrificed to confirm the presence of UC. The remaining rats were randomly assigned to two groups: the synbiotics group, which received synbiotics once per day and the control group, which received tap water for another 8 days.. On the 8. Administration of synbiotics in the experimental UC results in an attenuation of mucosal inflammatory neutrophil infiltration and an increase in HT.. Estimar los efectos de los simbióticos en la colitis experimental causada por dextrano sulfato de sodio (DSS).. Cuarenta ratas Wistar recibieron DSS al 5% en su agua de beber por 8 días para inducir colitis ulcerosa (CU). Ocho ratas fueron sacrificadas para confirmar la presencia de CU. Las ratas restantes fueron asignadas aleatoriamente a dos grupos: un grupo que recibió simbióticos una vez al día y un grupo control que recibió agua del grifo por 8 días.. En el octavo día de la administración de DSS los animales desarrollaron CU con diarrea sanguinolenta. En la mayoría de las variables hematológicas estudiadas (hemoglobina, glóbulos rojos, plaquetas, volumen corpuscular medio, hemoglobina corpuscular media), en el peso corporal y en la clasificación histopatológica de la CU no hubo diferencias significativas entre los grupos. Sin embargo, el grupo con simbióticos, en comparación con el grupo control, presentó una longitud del colon más larga en el cuarto día, un hematocrito muy aumentado en el octavo día y un número de células mieloperoxidasa positivas significativamente reducido en el octavo día. Además, hubo una tendencia hacia un mejoramiento histopatológico y clínico.. La administración de simbióticos en la CU experimental tiene como resultado una atenuación de la infiltración inflamatoria de neutrófilos de la mucosa y un aumento del hematocrito.

Topics: Animals; Body Weight; Colitis, Ulcerative; Colon; Dextran Sulfate; Erythrocyte Count; Erythrocyte Indices; Gastrointestinal Microbiome; Hematocrit; Hemoglobin A; Male; Neutrophil Infiltration; Neutrophils; Organ Size; Peroxidase; Platelet Count; Random Allocation; Rats; Rats, Wistar; Synbiotics

Modified Apple Polysaccharide (MAP) has been reported to cure colorectal diseases by up-regulating apoptosis and down regulating metastasis. In the present study, mesalamine (MES) and MAP mini tablets have been prepared and co-administered with probiotics to provide site specific release of drug. Probiotics along with MAP, which acts as a prebiotic would replenish the colonic microflora that have been compromised due to colorectal pathology. MES mini tablets were prepared keeping guar gum in the core and coating them with Eudragit S100 and guar gum. The optimized batch was explored for its curative potential on acetic acid induced ulcerative colitis (UC) in rat model with and without administration of probiotic and MAP. The results revealed that the rats treated with the combination of MAP and MES mini tablets along with probiotics show maximum curative potential. It was also observed that MAP mini tablets show better curative potential as compared to probiotics. The results of disease activity index, macroscopic scoring, antioxidant studies, tumour alpha and histopathological examination suggested that the rats treated with combination of MES-MAP mini tablets and probiotics have maximum therapeutic effect followed by MES mini tablets alone, MAP mini tablets alone and probiotics.

Topics: Animals; Body Weight; Colitis, Ulcerative; Colon; Drug Liberation; Galactans; Malus; Mannans; Mesalamine; Peroxidase; Plant Gums; Polymethacrylic Acids; Polysaccharides; Probiotics; Rats, Sprague-Dawley; Tablets

Atherosclerotic plaque formation is an inflammatory process that involves the recruitment of neutrophil granulocytes and the generation of reactive oxygen species (ROS). ROS formation by myeloperoxidase, a key enzyme in H2O2 degradation, can be modulated by addition of sodium thiocyanate (NaSCN). However, the therapeutic use of NaSCN to counteract atherogenesis has been controversial, because MPO oxidizes NaSCN to hypothiocyanous acid, which is a reactive oxygen species itself. Therefore, this study aimed to investigate the effect of NaSCN treatment on atherogenesis in vivo.. Apolipoprotein E knockout (ApoE-/-) mice on western-diet were treated with NaSCN for 8 weeks. Blood levels of total cholesterol, IL-10, and IL-6 were measured. Aortic roots from these mice were analyzed histologically to quantify plaque formation, monocyte, and neutrophil granulocyte infiltration. Oxidative damage was evaluated via an L-012 chemiluminescence assay and staining for chlorotyrosine in the aortic walls. Endothelial function was assessed by use of endothelium-dependent vasodilation in isolated aortic rings. Neointima formation was evaluated in wild-type mice following wire injury of the carotid artery.. NaSCN treatment of ApoE-/- mice lead to a reduction of atherosclerotic plaque size in the aortic roots but had no effect on monocyte or granulocyte infiltration. Serum levels of the pro-inflammatory cytokine IL-6 decreased whereas anti-inflammatory IL-10 increased upon NaSCN treatment. In our experiments, we found oxidative damage to be reduced and the endothelial function to be improved in the NaSCN-treated group. Additionally, NaSCN inhibited neointima formation.. NaSCN has beneficial effects on various stages of atherosclerotic plaque development in mice.

Topics: Animals; Aorta; Atherosclerosis; Blood Pressure; Body Weight; Carotid Arteries; Endothelium, Vascular; Granulocytes; Heart; Heart Rate; Hydrogen Peroxide; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Neointima; Neutrophils; Oxidative Stress; Peroxidase; Plaque, Atherosclerotic; Reactive Oxygen Species; Regeneration; Thiocyanates; Vasodilation

Preclinical studies have demonstrated that maternal inflammation or neonatal hyperoxia adversely affects kidney maturation. This study explored whether prenatal lipopolysaccharide (LPS) exposure can augment neonatal hyperoxia-induced kidney injury.. Pregnant Sprague-Dawley rats received intraperitoneal injections of LPS (0.5 mg/kg) in normal saline (NS) or NS on 20 and 21 days of gestation. The pups were reared in room air (RA) or 2 weeks of 85% O. The rats exposed to maternal LPS or neonatal hyperoxia exhibited significantly higher kidney injury score, lower glomerular number, higher toll-like receptor 4 (TLR4), myeloperoxidase (MPO), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expressions, and higher MPO activity compared with the rats exposed to maternal NS and neonatal RA. The rats exposed to both maternal LPS and neonatal hyperoxia exhibited significantly lower glomerular number, higher kidney injury score, TLR4, MPO, and 8-OHdG expressions compared with the rats exposed to maternal LPS or neonatal hyperoxia.. Maternal inflammation exacerbates neonatal hyperoxia-induced kidney injury and the underlying mechanism may be related to activation of TLR4 and increased oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Animals, Newborn; Antibodies; Body Weight; Chorioamnionitis; Cytokines; Female; Hyperoxia; Inflammation; Kidney Diseases; Lipopolysaccharides; Maternal Exposure; Organ Size; Oxidative Stress; Oxygen; Peroxidase; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4

Colon-targeted oral nanoparticles (NPs) have emerged as an ideal, safe, and effective therapy for ulcerative colitis (UC) owing to their ability to selectively accumulate in inflamed colonic mucosa. Cyclosporine A (CSA), an immunosuppressive agent, has long been used as rescue therapy in severe steroid-refractory UC. In this study, we developed CSA-loaded dual-functional polymeric NPs composed of Eudragit. CSA-loaded Eudragit FS30D nanoparticles (ENPs), PLGA nanoparticles (PNPs), and Eudragit FS30D/PLGA nanoparticles (E/PNPs) were prepared using the oil-in-water emulsion method. Scanning electron microscope images and zeta size data showed successful preparation of CSA-loaded NPs.. PNPs exhibited a burst drug release of >60% at pH 1.2 (stomach pH) in 0.5 h, which can lead to unwanted systemic absorption and side effects. ENPs effectively inhibited the burst drug release at pH 1.2 and 6.8 (proximal small intestine pH); however, nearly 100% of the CSA in ENPs was released rapidly at pH 7.4 (ileum-colon pH) owing to complete NP dissolution. In contrast to single-functional PNPs and ENPs, the dual-functional E/PNPs minimized burst drug release (only 18%) at pH 1.2 and 6.8, and generated a sustained release at pH 7.4 thereafter. Importantly, in distribution studies in the gastrointestinal tracts of mice, E/PNPs significantly improved CSA distribution to the colon compared with PNPs or ENPs. In a mouse model of colitis, E/PNP treatment improved weight loss and colon length, and decreased rectal bleeding, spleen weight, histological scoring, myeloperoxidase activity, macrophage infiltration, and expression of proinflammatory cytokines compared with PNPs or ENPs.. Overall, this work confirms the benefits of CSA-loaded E/PNPs for efficiently delivering CSA to the colon, suggesting their potential for UC therapy.

Topics: Administration, Oral; Animals; Body Weight; Colitis; Colon; Cyclosporine; Cytokines; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Immunosuppressive Agents; Inflammation Mediators; Lactic Acid; Macrophages; Methylmethacrylates; Mice, Inbred ICR; Nanoparticles; Particle Size; Peroxidase; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Treatment Outcome

Although cisplatin is a potent anticancer drug, it instigates oxidative and pro-inflammatory reactions that pose significant and distressing clinical symptoms. Therefore, this study investigated the effects of vitamin C and (or) l-carnitine on cisplatin-induced gastric mucosa damage in rat. The rats were allocated into 6 groups (n = 5). The control group received distilled water, while the treatment groups received cisplatin alone (CIP), or cisplatin with vitamin C, l-carnitine, or their combination. Cisplatin caused disruption of the gastric mucosa histoarchitecture and altered the mucus barrier function. Moreover, the stomach tissue of the CIP-treated group showed increased levels of oxidative stress markers (malondialdehyde and H

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Body Weight; Carnitine; Cell Count; Cisplatin; Cytokines; Feeding Behavior; Gastric Mucosa; Hydrogen Peroxide; Inflammation; Inflammation Mediators; Male; Malondialdehyde; Mucus; Nitric Oxide Synthase; Oxidants; Peroxidase; Rats, Wistar

Licochalcone A (Lico A) is a characteristic chalcone isolated from licorice root which is widely recognized in traditional Chinese medicine for the ability of anti-inflammatory, antioxidant, anti-parasitic and anti-cancer. The present study was aimed to investigate the effect of Lico A on dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in a mouse model which was induced by administration of 3% DSS in drinking water. Mice were then treated with Lico A (20, 40 and 80 mg/kg, p.o.) or 0.9% saline (20 ml/kg, p.o.) for 17 days. The results showed that treatment with Lico A significantly reduced the colon length, histological damage scores, and colonic myeloperoxidase (MPO) activity in a dose-dependent manner as compared to the UC control group. Besides, Lico A significantly decreased the oxidative stress and pro-inflammatory cytokines, downregulated nuclear transcription factor kappa B (NF-κB) pathway and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Collectively, Lico A is effective in alleviating DSS-induced colitis in mice and the mechanism is associated with its inhibition of NF-κB-regulated pro-inflammatory signaling and activation of Nrf2-regulated cytoprotective protein expression.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Body Weight; Chalcones; Colitis, Ulcerative; Colon; Cyclooxygenase 2; Cytokines; Dextran Sulfate; Male; Mice, Inbred C57BL; Models, Biological; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Peroxidase; Protective Agents; Signal Transduction

Portulacaoleraceal (POL) has been widely used as an edible plant and a folk medicine in many countries, due to its several health benefits. This study examined the effects of POL on trinitrobenzene sulfonic acid (TNBS)-induced colitis via enema administration. Sixty male Sprague-Dawley rats were randomly divided into five groups: untreated, TNBS, TNBS + POL 10 g/kg, TNBS + POL 5 g/kg and TNBS + POL 2.5 g/kg groups. Rats were subjected to enema treatment once a day for 10 consecutive days with POL extract or distilled water after induction of TNBS. The changes of body weight, histological parameters, myeloperoxidase (MPO), superoxide dismutase (SOD), nitric oxide synthase activity (NOS), malondialdehyde (MDA) and nitric oxide (NO) levels in colon tissues were investigated. After POL extract treatment, body weights of rats significantly increased, macroscopic and microscopic damage scores reduced, MPO and NOS activity, as well as MDA and NO level significantly decreased, while SOD activity increased in a dose-dependent manner in the TNBS + POL groups compared with the TNBS group. Our results demonstrated that POL enema treatment attenuated pathologic changes of TNBS-induced colitis in rats through restoring colonic damage and reducing inflammatory response in the intestine. Thus, POL enema might be considered as a potential effective treatment for ulcerative colitis patients.

Topics: Animals; Body Weight; Colitis; Colon; Male; Malondialdehyde; Nitric Oxide; Nitric Oxide Synthase; Peroxidase; Plant Extracts; Portulacaceae; Rats, Sprague-Dawley; Superoxide Dismutase; Trinitrobenzenesulfonic Acid

Beverages containing Trichilia catigua are commonly employed in folk medicine. T. catigua bark extracts possess antioxidant, anti-inflammatory, and bactericidal properties. These properties suggest T. catigua bark extracts as a potential treatment for inflammatory bowel diseases (IBD). Using the 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced model of colitis in rats we evaluated the effect of an ethyl-acetate fraction (EAF) of T. catigua (200 mg/kg) administered by daily oral gavage or intrarectally at different time points after TNBS challenge. TNBS treatment evoked severe colonic inflammation after 24 h that persisted for 7 days, characterized by weight loss, high levels of myeloperoxidase activity, histological and macroscopic damage, and elevated index of oxidative stress in the blood. T. catigua EAF treatment prevented the oxidative stress within 24 h and enhanced tissue recovery observed at day 7, returning histological and macroscopic damage levels to that of the control group. TNBS treatment led to loss of myenteric neurons after 28 days. T. catigua EAF was unable to prevent the neuronal loss. Oral delivery of T. catigua EAF was more effective than intrarectal administration of the extract. In conclusion, T. catigua EAF treatment normalized oxidative stress parameters in blood and reduced the degree of acute inflammation in TNBS colitis.

Topics: Acetates; Administration, Oral; Animals; Biomarkers; Body Weight; Colitis; Colon; Inflammation; Male; Meliaceae; Myenteric Plexus; Neurons; Oxidative Stress; Peroxidase; Plant Extracts; Rats, Wistar; Trinitrobenzenesulfonic Acid; Wound Healing

Cardiovascular morbidity and mortality of premenopausal women are significantly lower compared to men of similar age. However, this protective effect evidently decreases after the onset of menopause. We hypothesized that physical exercise could be a potential therapeutic strategy to improve inflammatory processes and cardiovascular antioxidant homeostasis, which can be affected by the loss of estrogen and the adverse environmental factors, such as overnutrition. Ovariectomized (OVX, n= 40) and sham-operated (SO, n= 40) female Wistar rats were randomized to exercising (R) and non-exercising (NR) groups. Feeding parameters were chosen to make a standard chow (CTRL) or a high triglyceride diet (HT) for 12 weeks. Aortic and cardiac heme oxygenase (HO) activity and HO-1 concentrations significantly decreased in all of the NR OVX and SO HT groups. However, the 12-week physical exercise was found to improve HO-1 values. Plasma IL-6 concentrations were higher in the NR OVX animals and rats fed HT diet compared to SO CTRL rats. TNF-α concentrations were significantly higher in the NR OVX groups. 12 weeks of exercise significantly reduced the concentrations of both TNF-α and IL-6 compared to the NR counterparts. The activity of myeloperoxidase enzyme (MPO) was significantly increased as a result of OVX and HT diet, however voluntary wheel-running exercise restored the elevated values. Our results show that estrogen deficiency and HT diet caused a significant decrease in the activity and concentration of HO enzyme, as well as the concentrations of TNF-α, IL-6, and the activity of MPO. However, 12 weeks of voluntary wheel-running exercise is a potential non-pharmacological therapy to ameliorate these disturbances, which determine the life expectancy of postmenopausal women.

Topics: Animals; Aorta; Body Weight; Cardiovascular Diseases; Diet, High-Fat; Estrogens; Female; Heme Oxygenase (Decyclizing); Inflammation; Interleukin-6; Myocardium; Ovariectomy; Peroxidase; Physical Conditioning, Animal; Random Allocation; Rats, Wistar; Risk Factors; Triglycerides; Tumor Necrosis Factor-alpha

Menthol is an aromatic compound with high antiinflammatory activity. The purpose of the current research is to investigate the effectiveness of menthol on acetic acid induced acute colitis in rats. Animals were injected with menthol (20 and 50 and 80mg/kg, i.p.) 24h prior to induction of colitis for 3 consecutive days. Menthol at medium and higher doses similar to dexamethasone as a reference drug significantly reduced body weight loss, macroscopic damage score, ulcer area, colon weight, colon length and improved hematocrit in rats with colitis. The histopathological examination also confirmed anti-colitic effects of menthol. Menthol also reduced significantly the colonic levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and myeloperoxidase (MPO) activity in inflamed colons. Thus, the findings of the current study provide evidence that menthol may be beneficial in patients suffering from acute ulcerative colitis.

Topics: Acute Disease; Animals; Body Weight; Colitis; Colon; Cytokines; Disease Models, Animal; Hematocrit; Male; Menthol; Peroxidase; Rats; Rats, Wistar

The Na-H exchanger [NHE] performs an electroneutral uptake of NaCl and water from the lumen of the gastrointestinal tract. There are several distinct NHE isoforms, some of which show an altered expression in the inflammatory bowel diseases (IBD). In this study, we examined a role of NHE-2 in experimental colitis.. Colitis was induced in male Sprague-Dawley rats by intra-rectal administration of trinitrobenzenesulphonic acid (TNBS). On day 6 post-TNBS, the animals were sacrificed, colonic and ileal segments were taken out, cleaned with phosphate buffered saline and used in this study.. There was a significant decrease in the level of NHE-2 protein as measured by ECL western blot analysis and confocal immunofluorescence microscopy. The levels of NHE-2 mRNA and heteronuclear RNA measured by an end-point RT-PCR and a real time PCR were also decreased significantly in the inflamed colon. However, there was no change in the level of NHE-2 protein in response to in vitro TNF-α treatment of uninflamed rat colonic segment. These changes were selective and localized to the colon as actin, an internal control, remained unchanged. Confocal immunofluorescence microscopy revealed co-localization of NHE-2 and NHE-3 in the brush borders of colonic epithelial cells. Inflamed colon showed a significant increase in myeloperoxidase activity and colon hypertrophy. In addition, there was a significant decrease in body weight and goblet cells' mucin staining in the TNBS treated colon. These changes were not conspicuous in the non-inflamed ileum.. These findings demonstrate suppression of NHE-2 expression on the brush borders in the colonic epithelial cells which is regulated transcriptionally. However a role of TNF-α in the regulation of NHE-2 is discounted in the present model of colitis. This decrease in the NHE-2 expression will lead to a loss of electrolyte and water uptake thus contributing to the symptoms associated with IBD.

Topics: Animals; Blotting, Western; Body Weight; Colitis; Colon; Down-Regulation; Electrophoresis, Agar Gel; Goblet Cells; Hypertrophy; Ileum; Male; Microscopy, Fluorescence; Peroxidase; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sodium-Hydrogen Exchangers; Staining and Labeling; Tumor Necrosis Factor-alpha

PCOs is a heterogeneous disorder with anovulation/oligo ovulation usually taken as oligo menorrhoea or amenorrhoea, hyperandrogenemia, hirsutism, acne, androgen alopecia and polycystic ovaries as the key diagnostic feathers. The study was undertaken to investigate the possible protective and ameliorating effects of GABA in Letrozole induced PCOS model in rats by targeting insulin resistance.. PCOs in Adult female rat was induced by the daily gastric administration of letrozole (1 mg/kg/day) in CMC (0.5%) for 36 days. Rats were given metformin (2 mg/kg), GABA (100 mg/kg/day) and GABA (500 mg/kg/day) along with letrozole. One group severed as vehicle control. On the 37 day, the animals were euthanized, and anthropometrical, biochemical (glucose, insulin, lipids, testosterone, Estradiol, Progesterone, oral glucose tolerance test, total protein content in ovary, cholesterol level, triglyceride, HDL, LDL), Antioxidants (CAT, POD, GSR, ROS, GSH, TBARS), and histopathological evaluation of ovaries were carried out. Daily colpocytological examination was also carried out until the termination.. Both the doses of GABA significantly reduced body weight, body mass index and testosterone. While the levels of CAT, SOD, POD and Estradiol (E. The results suggest that GABA treatment has shown protective effect in PCOs and provide beneficial effect either by reducing insulin resistance or by inducing antioxidant defence mechanisms.

Topics: Androgen Antagonists; Animals; Blood Glucose; Body Weight; Catalase; Estradiol; Female; gamma-Aminobutyric Acid; Insulin Resistance; Letrozole; Nitriles; Ovary; Peroxidase; Polycystic Ovary Syndrome; Protective Agents; Rats; Reproduction; Superoxide Dismutase; Testosterone; Triazoles

The aim of this study is to examine the anti-inflammatory effect of Euphorbia supina (ES) ethanol extract in dextran sulfate sodium (DSS)-induced experimental colitis model. ES was per orally administered at different doses of 4 or 20 mg/kg body weight with 5% DSS in drinking water for 7 days. Twenty mg/kg of ES administration regulated body weight decrease, recovered colon length shortening, and increased disease activity index score and myeloperoxidase level in DSS-induced colitis. Histological features showed that 20 mg/kg of ES administration suppressed edema, mucosal damage, and the loss of crypts induced by DSS. Furthermore, ES suppressed the expressions of COX-2, iNOS, NF-kB, IkBα, pIkBα in colon tissue. These findings demonstrated a possible effect of amelioration of ulcerative colitis and could be clinically applied.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colitis; Colon; Cyclooxygenase 2; Dextran Sulfate; Ethanol; Euphorbia; Gene Expression Regulation, Enzymologic; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxidase; Plant Extracts; RAW 264.7 Cells; Signal Transduction; Tumor Necrosis Factor-alpha

Dobutamine is the currently recommended β-adrenergic inotropic drug for supporting sepsis-induced myocardial dysfunction when cardiac output index remains low after preload correction. Better and safer therapies are nonetheless mandatory because responsiveness to dobutamine is limited with numerous side effects. Apelin-13 is a powerful inotropic candidate that could be considered as an alternative noncatecholaminergic support in the setting of inflammatory cardiovascular dysfunction.. Interventional controlled experimental animal study.. Tertiary care university-based research institute.. One hundred ninety-eight adult male rats.. Using a rat model of "systemic inflammation-induced cardiac dysfunction" induced by intraperitoneal lipopolysaccharide injection (10 mg/kg), hemodynamic efficacy, cardioprotection, and biomechanics were assessed under IV osmotic pump infusions of apelin-13 (0.25 μg/kg/min) or dobutamine (7.5 μg/kg/min).. In this model and in both in vivo and ex vivo studies, apelin-13 compared with dobutamine provoked distinctive effects on cardiac function: 1) optimized cardiac energy-dependent workload with improved cardiac index and lower vascular resistance, 2) upgraded hearts' apelinergic responsiveness, and 3) consecutive downstream advantages, including increased urine output, enhanced plasma volume, reduced weight loss, and substantially improved overall outcomes. In vitro studies confirmed that these apelin-13-driven processes encompassed a significant and rapid reduction in systemic cytokine release with dampening of myocardial inflammation, injury, and apoptosis and resolution of associated molecular pathways.. In this inflammatory cardiovascular dysfunction, apelin-13 infusion delivers distinct and optimized hemodynamic support (including positive fluid balance), along with cardioprotective effects, modulation of circulatory inflammation and extended survival.

Topics: Animals; Body Weight; Cardiac Output; Cardiomyopathies; Cardiotonic Agents; Cytokines; Disease Models, Animal; Dobutamine; Intercellular Signaling Peptides and Proteins; Lipopolysaccharides; Male; Mitogen-Activated Protein Kinases; Myocardium; Nitric Oxide Synthase Type II; Peroxidase; Phosphorylation; Plasma Volume; Rats; Survival Rate; Vascular Resistance; Water-Electrolyte Balance

Mucositis is the most common side effect due to chemotherapy or radiotherapy. It refers to the inflammation of intestinal mucous membranes, and it is associated with complications such as diarrhea, weight loss, and increased intestinal permeability (IP). This study was designed to evaluate the effect of diet containing conjugated linoleic acid (CLA)-enriched butter on intestinal damage and inflammatory response after 24 h of 5-fluorouracil (5-FU)-induced mucositis. Mice were divided into four groups: CTL; CLA; 5-FU, and CLA 5-FU, and they were fed for 31 days. On the 30th experimental day, mucositis was induced by unique injection of 300 mg/kg of 5-FU. After 24 h (31st experimental day), IP was evaluated; ileum and fecal material were collected to determine cytokine level and myeloperoxidase (MPO) activity and secretory immunoglobulin A (sIgA). The 5-FU group showed an increase in IP and MPO activity (CTL vs. 5-FU: P < 0.05). Additionally, increased levels of IP and MPO were observed in CLA 5-FU group compared to those in the test groups (P < 0.05). Animals in the CLA 5-FU group showed reduced concentrations of sIgA (CTL vs. CLA 5-FU: P < 0.05). CLA-enriched butter exacerbating the 5-FU-induced intestinal damage. Safety concerns regarding the use of CLA require further investigation.

Topics: Animals; Body Weight; Butter; Chemokines; Cytokines; Fluorouracil; Food, Fortified; Immunoglobulin A; Intestinal Mucosa; Intestines; Linoleic Acids, Conjugated; Male; Mice, Inbred BALB C; Mucositis; Permeability; Peroxidase

NOX1/NADPH oxidase, a nonphagocytic isoform of reactive oxygen species-producing enzymes, is highly expressed in the colon, but the physiologic and pathophysiologic roles of this isoform are not fully understood. The present study investigated the role of NOX1 in the development of colonic inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. Intrarectal injection of TNBS caused severe colitis accompanied by body weight loss, diarrhea, and increased myeloperoxidase (MPO) activity in wild-type (WT) mice. In contrast, the severity of colitis was significantly attenuated in NOX1-deficient (NOX1KO) mice (the inhibitions of macroscopic damage score, body weight loss, diarrhea score, and MPO activity were 73.1%, 36.8%, 83.3%, and 98.4%, respectively). TNBS-induced upregulation of inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β), chemokines (CXCL1 and CXLC2), and inducible nitric oxide synthase (iNOS) was also significantly less in NOX1KO than in WT mice (the inhibitions were 100.8%, 89.0%, 63.5%, 96.7%, and 97.1%, respectively). Expression of NOX1 mRNA was detected not only in the lamina propria but also in peritoneal macrophages isolated from WT mice. Increased expression of TNF-α, IL-1β, and iNOS in peritoneal macrophages exposed to lipopolysaccharide was significantly attenuated in macrophages isolated from NOX1KO mice (68.1%, 67.0%, and 79.3% inhibition, respectively). These findings suggest that NOX1/NADPH oxidase plays an important role in the pathogenesis of TNBS-induced colonic inflammation via upregulation of inflammatory cytokines, chemokines, and iNOS. NOX1 in colonic macrophages may become a potential target in pharmacologic intervention for inflammatory bowel disease.

Topics: Animals; Body Weight; Colitis; Colon; Diarrhea; Gene Expression Regulation, Enzymologic; Gene Knockout Techniques; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Peroxidase; RAW 264.7 Cells; Reactive Oxygen Species; RNA, Messenger; Trinitrobenzenesulfonic Acid; Up-Regulation

Inflammation is a common symptom of inflammatory bowel disease (IBD). Actually, many experimental models of colitis exist and try to mimic the human situation in order to understand the pathogenesis of Crohn's disease and ulcerative colitis. These experimental models of inflammation can be characterized by specific parameters, which illustrate the proceeding inflammatory process. By use of these models potentially new reagents for improved therapeutic approaches can be analyzed. Here, we describe the TNBS-mediated colitis model and specify different parameters for the detailed characterization of the inflammatory process in experimental colitis models.

Topics: Animals; Antigens, CD; Antigens, Differentiation; Biomarkers; Body Weight; Colitis; Colonoscopy; Cytokines; Disease Models, Animal; Gene Expression; Humans; Immunity, Mucosal; Immunohistochemistry; Mice; Mucous Membrane; Peroxidase; Severity of Illness Index; Trinitrobenzenesulfonic Acid

To investigate the effects of the coexistence of aflatoxin B1 (AFB1) and protein malnutrition in rat liver, weanling rats were fed either normal protein diet (20% protein), low-protein (PEM) diet (5%), normal protein diet + 40 ppb AFB1, or low-protein diet + 40 ppb AFB1. After 8 weeks, biomarkers of hepatic functions and oxidative stress, caspase-3 activity, and tumor suppressor protein 53 (p53) were determined spectrophotometrically. Randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR) was employed to determine genomic alterations among the groups. Coexistence of aflatoxicosis and PEM significantly decreased glutathione, glutathione-S-transferase, glutathione peroxidase, and superoxide dismutase, while it increased peroxidase and catalase. RAPD-PCR showed genomic alterations that were associated with significant increases in p53 level and caspase-3 activity in rats fed PEM diet + AFB1. In conclusion, the coexistence of aflatoxicosis and protein malnutrition induced oxidative stress with concomitant genomic alterations in the liver of weanling rats.

Topics: Aflatoxin B1; Animals; Body Weight; Caloric Restriction; Caspase 3; Catalase; Chemical and Drug Induced Liver Injury; Diet, Protein-Restricted; Female; Gene Expression Regulation; Glutathione; Glutathione Peroxidase; Glutathione Transferase; Liver; Male; Oxidative Stress; Peroxidase; Rats; Signal Transduction; Superoxide Dismutase; Tumor Suppressor Protein p53

Inflammatory bowel disease (IBD) is an inflammatory condition with mucosal ulceration, edema and hemorrhage of gastrointestinal tract. Curcumin has been shown to mitigate colitis in animal models. However, its usefulness is reduced due to poor pharmacokinetic behavior and low oral bioavailability. To address this, novel pH-sensitive hydrolyzed polyacrylamide-grafted-xanthan gum (PAAm-g-XG) nanoparticles (NPs) loaded with curcumin were prepared for colonic delivery. Optimized nanoparticles (CN20) were spherical, with an average size of 425 nm. A negligible amount of curcumin (≈8%) was released from CN20 NPs in pH 1.2 and 4.5 solutions. When the pH was increased to 7.2, curcumin release was comparatively faster than that observed with pH 1.2 and 4.5 collectively. In pH 6.8 solution, excellent release of curcumin was observed. Highest curcumin release was observed when rat caecal contents were incorporated in pH 6.8 solution, indicating microflora-dependent drug release property of NPs. In acetic acid-induced IBD in rats, curcumin NPs reduced myeloperoxidase and nitrite levels, prevented weight loss and attenuated colonic inflammation. Curcumin was better absorbed systemically in nanoparticulate form with increased Cmax (∼3 fold) and AUC (∼2.5 fold) than when delivered as free curcumin. We demonstrate successful development of grafted co-polymeric NPs containing drug suitable for colon targeting.

Topics: Acrylic Resins; Aluminum Chloride; Aluminum Compounds; Animals; Body Weight; Cell Survival; Chlorides; Chlorocebus aethiops; Colon; Curcumin; Drug Carriers; Drug Compounding; Drug Liberation; HCT116 Cells; Humans; Hydrolysis; Male; Nanoparticles; Nanotechnology; Nitrites; Organ Size; Particle Size; Peroxidase; Polysaccharides, Bacterial; Rats; Rats, Wistar; Solubility; Vero Cells; Water

This study investigates the protective effects of turmeric (Curcuma longa, CL) on acetic acid-induced colitis in rats.. Inflammatory bowel disease (IBD) was induced in male Wistar rats by intra-rectal administration of 1 ml of 4% acetic acid at 8 cm proximal to the anus for 30 s. Curcuma longa (CL) powder, (1, 10, or 100 mg/kg/day) was administered for either 3 days before or after IBD for 7 days. The body weight, macroscopic and microscopic analysis of the colon of CL-treated IBD rats and that of control rats (no IBD, no CL) were performed on 0 day, 2, 4 and 7th day. Myeloperoxidase (MPO), IL-23 and glutathione levels in control, untreated and treated rats were measured by ELISA.. CL significantly (P < 0.05) improved IBD-induced reduction in mean body weight and mean macroscopic ulcer score. Administration of CL also significantly (P < 0.01) reduced the mean microscopic ulcer score when compared to untreated IBD control. Intake of CL by rats resulted in a significant (P < 0.05) increase in the mean serum glutathione level compared to untreated control. CL reduced both MPO and IL-23 levels in the colonic mucosa of the rat.. CL improved body weight gain, mean macroscopic and microscopic ulcer scores in the colon of rats suffering from acetic acid-induced IBD. CL reduced both MPO and IL-23 in the mucosa of the colon. The increase in the mean serum glutathione level may help in the reduction of oxidative stress associated with IBD.

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis, Ulcerative; Colon; Curcuma; Glutathione; Inflammatory Bowel Diseases; Interleukin-23; Intestinal Mucosa; Male; Oxidative Stress; Peroxidase; Phytotherapy; Plant Extracts; Rats, Wistar; Ulcer

Olive flounder (Paralichthys olivaceus), also known as the Japanese flounder in Japan, is one of the most important commercial marine finfish species cultured in Korea and Japan. The purpose of this study was to evaluate how a species of brown algae (Ecklonia cava, E. cava) affects the growth rate of olive flounder and its immune response to pathogenic bacteria. First, the experimental fish were divided into four groups: the control group was fed the diet containing only 1.0% Lactobacillus plantarum (L. plantarum), group I was fed 1.0% L. plantarum and 1.0% E. cava (EC), group II was fed 1.0% L. plantarum and 0.1% ethanol extract of EC (EE), and group III was fed 1.0% L. plantarum and 0.5% EE. The diets fed to the fish twice a day for 16 weeks. The results indicated that supplementation with 1.0% EC and 0.1% EE improved the growth and body weight of olive flounder, and decreased its mortality. This diet, however, did not significantly affect the biochemical profiles of the experimental flounder. The supplementation of 1.0% EC also enhanced the innate immune response of the fish, as evidenced by the high respiratory burst, and increased serum lysozyme and myeloperoxidase activity. The addition of 1.0% EC and either 0.1% or 0.5% EE also decreased the accumulative mortality of olive flounder infected by pathogenic bacteria (Edwardsiella tarda, Streptococcus iniae, and Vibrio harveyi). Overall, these results suggest that E. cava can act as a prebiotic by improving the innate immune response in fish infected with pathogenic bacteria as increased the growth of the probiotic.

Topics: Animals; Body Weight; Edwardsiella tarda; Enterobacteriaceae Infections; Fish Diseases; Flounder; Lactobacillus plantarum; Muramidase; Peroxidase; Phaeophyceae; Prebiotics; Respiratory Burst; Streptococcal Infections; Streptococcus iniae; Vibrio; Vibrio Infections

To explore the effects of methane-rich saline (CH4 saline) on the capability of one-time exhaustive exercise in male SD rats.. Thirty rats were equally divided into to three groups at random: control group (C), placebo group (P) and methane saline group (M). Rats in M group underwent intraperitoneal injection of CH4 saline, and the other two groups simultaneously underwent intraperitoneal injection of normal saline. Then, the exercise capability of rats was tested through one-time exhaustive treadmill exercise except C group. Exercise time and body weight were recorded before and after one-time exhaustive exercise. After exhaustive exercise, the blood and gastrocnemius samples were collected from all rats to detect biochemical parameters in different methods.. It was found that the treadmill running time was significantly longer in rats treated with CH4 saline. At the same time, CH4 saline reduced the elevation of LD and UN in blood caused by one-time exhaustive exercise. The low level of blood glucose induced by exhaustive exercise was also normalized by CH4 saline. Also CH4 saline lowered the level of CK in plasma. Furthermore, this research indicated that CH4 saline markedly increased the volume of T-AOC in plasma and alleviated the peak of TNF-α in both plasma and gastrocnemius. From H&E staining, CH4 saline effectively improved exercise-induced structural damage in gastrocnemius.. CH4 saline could enhance exercise capacity in male SD rats through increase of glucose aerobic oxidation, improvement of metabolic clearance and decrease of exhaustive exercise-induced gastrocnemius injury.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Creatine Kinase; Cytokines; Lactic Acid; Male; Malondialdehyde; Methane; Muscle, Skeletal; Nitrogen; Peroxidase; Physical Conditioning, Animal; Rats, Sprague-Dawley; Sodium Chloride; Superoxide Dismutase; Time Factors; Urea

Ulcerative colitis is a chronic nonspecific inflammatory disease of unknown cause. The aim of this study was to evaluate the anti-inflammatory effect of tauroursodeoxycholate in 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in mice. After the induction of colitis for 24h, the mice were administrated orally with tauroursodeoxycholate (20, 40 and 60mg/kg) and sulfasalazine (500mg/kg) by gavage for 7 consecutive days. The inhibition effects were evaluated by the body of weight change, survival rate, macroscopical and histological evaluations. Besides, myeloperoxidase (MPO) activity, interleukin (IL)-1β, interferon (IFN)-γ and tumour necrosis factor-α (TNF-α) in colon tissue were also determined by enzyme-linked immunosorbent assay. Treatment with different doses of tauroursodeoxycholate (20, 40 and 60mg/kg) significantly improved the body weight change, decreased the macroscopic and histopathological scores. Compared with the model group, the accumulation of MPO activity, the colonic tissue levels of IL-1β, IFN-γ and TNF-α were significantly reduced in the tauroursodeoxycholate treated groups. Moreover, tauroursodeoxycholate assuaged the symptoms of colitis. These results suggested that tauroursodeoxycholate has an anti-inflammatory effect in TNBS-induced ulcerative colitis in mice.

Topics: Acute Disease; Administration, Oral; Animals; Anti-Inflammatory Agents; Body Weight; Colitis, Ulcerative; Colon; Disease Models, Animal; Humans; Interferon-gamma; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Peroxidase; Taurochenodeoxycholic Acid; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Body Weight; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Energy Metabolism; Enzyme Activation; Fatty Acids; Gene Expression; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; Liver; Male; Metabolic Networks and Pathways; Mice; Models, Biological; Oxidation-Reduction; Peroxidase; Phenotype; Piperidines; Quinazolinones; RNA, Messenger; Spleen

Taurocholate is a natural conjugated bile acid. The aim of this study was to evaluate the anti-inflammatory effect of taurocholate in TNBS-induced ulcerative colitis in mice. The colitis were induced by rectal administration of TNBS. After 24h, the experimental animals were treated with sulfasalazine (SASP, 500mg/kg/day) and taurocholate (20, 40 and 60mg/kg) for 7 consecutive days. The anti-inflammatory effects of taurocholate for colitis were assessed by body weight, colonic weight and length, macroscopic scores, and histopathological examinations. In addition, the colonic tissue levels of myeloperoxidase (MPO) activity, interleukin (IL)-1β, interferon (IFN-γ) and tumour necrosis factor-α (TNF-α) were also determined to assess the effect of taurocholate. Compared with the model group, treatment with taurocholate (20, 40 and 60mg/kg) significantly inhibited the body weight loss, improved colonic weight and length, and decreased macroscopic and histopathological scores. Furthermore, the activity accumulation of MPO and the colonic tissue levels of IL-1β, IFN-γ and TNF-α were also decreased by administration of taurocholate. All the findings of this study suggested that taurocholate has the anti-inflammatory effect in ulcerative colitis in mice and indicated it as a good candidate to treat inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colitis, Ulcerative; Colon; Interferon-gamma; Interleukin-1beta; Male; Mice, Inbred BALB C; Peroxidase; Sulfasalazine; Survival Rate; Taurocholic Acid; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Menispermum dauricum DC., commonly known as "Bei Dou Gen" (BDG) in China, has been used extensively in folk medicine to treat inflammatory diseases, especially intestinal inflammations such as enteritis and dysentery, and in pharyngitis, tonsillitis, rheumatism and bronchitis. Although previous studies showed that BDG has anti-inflammatory activities, its effects on ulcerative colitis (UC) have not yet been explored.. To investigate the intestinal anti-inflammatory effect of the rhizome extracts of Menispermum dauricum DC. on UC model induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice.. UC in mice was induced by colonic administration with TNBS. BDG (100, 200 and 400mg/kg/day) and sulfasalazine (500mg/kg/day) were administered orally for 7 consecutive days. The inflammatory degree was assessed by gross appearance, macroscopic and histological analysis, and accumulation of myeloperoxidase (MPO) activity. Pro-inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, were determined by enzyme-linked immunoassay. The expression of cyclooxygenase (COX)-2 was assessed by immunohistochemical analysis.. Treatment with different doses of BDG significantly ameliorated macroscopic damage and histological changes, reduced the accumulation of MPO activity, depressed serum and colonic tissue levels of TNF-α, IL-1β and IL-6 in a dose-dependent manner. In addition, administration of BDG effectively reduced COX-2 overexpression in colon.. We demonstrated for the first time that BDG possessed marked intestinal anti-inflammatory effect in TNBS induced colitis in mice, which might be related to the reduction of up-regulated productions and expressions of pro-inflammatory mediators, suggesting that it may have beneficial use for the treatment of inflammatory bowel disease.

Topics: Animals; Body Weight; Colitis, Ulcerative; Cyclooxygenase 2; Cytokines; Male; Menispermum; Mice; Mice, Inbred ICR; Peroxidase; Plant Extracts; Rhizome; Spleen; Thymus Gland; Trinitrobenzenesulfonic Acid

The objective of this study was to evaluate the effect of supplementation with vitamin C on intestinal anastomosis healing in malnourished rats.. Male Wistar rats were divided into three groups: (1) sham, well-nourished rats that received vehicle; (2) FR+Veh, rats that were subjected to food restriction and received vehicle; and (3) FR+VC, rats that were subjected to food restriction and received vitamin C. Four days before surgery, the animals received vitamin C (100 mg/kg/day) via gavage and underwent colon resection with anastomosis in a single plane. The survival rate of rats was monitored until day 7 after surgery. Regarding anastomosis tissues, we examined intra-abdominal adhesion index, hydroxyproline content, collagen density, inflammatory parameters, and oxidative damage to proteins and lipids.. Malnutrition decreases body weight and increases mortality; the survival rate was 90 % in group 1, 60 % in group 2, and 80 % in group 3. Vitamin C was able to increase hydroxyproline concentration and density of collagen and decrease the intra-abdominal adhesion index, as well as the infiltration of neutrophils and oxidative damage to proteins in malnourished rats compared to group treated with vehicle.. Preoperative vitamin C supplementation can improve the intestinal anastomosis healing, biochemical alterations, and prolong survival in rats subjected to food restriction.

Topics: Anastomosis, Surgical; Animals; Ascorbic Acid; Body Weight; Collagen; Colon; Dietary Supplements; Hydroxyproline; Male; Malnutrition; Nitrates; Nitrites; Oxidative Stress; Peroxidase; Preoperative Care; Rats, Wistar; Rectum; Tissue Adhesions; Tumor Necrosis Factor-alpha; Wound Healing

Leukocyte infiltration, improved levels of intercellular adhesion molecule 1 (ICAM-1), and oxidative stress in the colon are the principal factors in inflammatory bowel disease. The goal of the current study was to explore the effects of adelmidrol, an analog of the anti-inflammatory fatty acid amide signaling molecule palmitoylethanolamide, in mice subjected to experimental colitis. Additionally, to clarify whether the protective action of adelmidrol is dependent on the activation of peroxisome proliferator-activated receptors (PPARs), we investigated the effects of a PPARγ antagonist, GW9662, on adelmidrol action. Adelmidrol (10 mg/kg daily, o.s.) was tested in a murine experimental model of colitis induced by intracolonic administration of dinitrobenzene sulfonic acid. Nuclear factor-κB translocation, cyclooxygenase-2, and phosphoextracellular signal-regulated kinase, as well as tumor necrosis factor-α and interleukin-1β, were significantly increased in colon tissues after dinitrobenzene sulfonic acid administration. Immunohistochemical staining for ICAM-1, P-selectin, nitrotyrosine, and poly(ADP)ribose showed a positive staining in the inflamed colon. Treatment with adelmidrol decreased diarrhea, body weight loss, and myeloperoxidase activity. Adelmidrol treatment, moreover, reduced nuclear factor-κB translocation, cyclooxygenase-2, and phosphoextracellular signal-regulated kinase expression; proinflammatory cytokine release; and the incidence of nitrotyrosine and poly(ADP)ribose in the colon. It also decreased the upregulation of ICAM-1 and P-selectin. Adelmidrol treatment produced a reduction of Bax and an intensification of Bcl-2 expression. This study clearly demonstrates that adelmidrol exerts important anti-inflammatory effects that are partly dependent on PPARγ, suggesting that this molecule may represent a new pharmacologic approach for inflammatory bowel disease treatment.

Topics: Amides; Animals; Anti-Inflammatory Agents; Apoptosis; Body Weight; Colitis; Cyclooxygenase 2; Cytokines; Dicarboxylic Acids; Dinitrofluorobenzene; Ethanolamines; Extracellular Signal-Regulated MAP Kinases; Inflammatory Bowel Diseases; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Mice; NF-kappa B; P-Selectin; Palmitic Acids; Peroxidase; Phosphorylation; PPAR alpha; PPAR gamma; Receptor, Cannabinoid, CB2; Signal Transduction; Tyrosine

Hecogenin is a steroidal sapogenin plays important role in treatment of variety of inflammatory diseases. We have investigated the anti-inflammatory effects of Hecogenin (50 µg/animal) (HG), Fluticasone (50 µg/animal) (FC) and Hecogenin+Fluticasone (HG+FC) combination (25 µg/animal, each) on various inflammatory models. The anti-inflammatory effect of HG, FC and HG+FC combination was studied on % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase assay, serum pro-inflammatory cytokines, colon weight to length ratio, macroscopic lesions, adhesion score, diarrhoea score and histopathological analysis of ear and colon tissue on Cotton pellets induced granuloma in rats, Croton oil induced ear edema in mice and TNBS induced granuloma in rats. Topical administration of HG and its combination with FC showed significant decrease (p<0.001) in the % inhibition of dry weight of granuloma tissue, Δ ear weight, myeloperoxidase level, serum pro-inflammatory cytokines levels, colon weigh to length ratio as compared with Cotton pellets treated with acetone groups and Croton oil treated animals. Further histopathological analysis of ear tissue showed significant decrease in dermal thickness and epidermal hyperplasia and colon tissue showed reduction of edema, infiltration of inflammatory cells and normalization of crypt structure compared to DC animals. Thus, the findings of present study suggest the possible role of HG in the treatment of inflammation by reducing the dose of FC in combination with HG.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colon; Cytokines; Disease Models, Animal; Fluticasone; Inflammation; Mice; Peroxidase; Rats; Rats, Wistar; Sapogenins

Intestinal mucositis is an inflammatory process occurring in the intestinal mucosa and is a common side effect of irinotecan hydrochloride (CPT-11) based anticancer regimens. The transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptor is highly expressed in the intestinal mucosa and has the ability to identify cell damage signaling indicates its possible association with intestinal mucositis. Carvacrol is an agonist of the TRPA1 receptor and has anti-inflammatory properties. Thus, the aim of the present study was to verify the supposed anti-inflammatory and protective action of carvacrol via TRPA1 activation against intestinal mucositis induced by CPT-11 in mice. Briefly, mice were treated with either DMSO 2% or CPT-11 (75 mg/kg, per 4 days, i.p.) or the carvacrol (25, 75 or 150 mg/kg, per 8 days, i.p.) before CPT-11. In other group, the animals were pretreated with HC-030031, a TRPA1 antagonist, 30 min before treatment with carvacrol. On day 7, animal survival and bacteremia were assessed, and following euthanasia, samples of the jejunum were obtained for morphometric analysis and measurement of antioxidant and pro-inflammatory markers. Carvacrol was found to exert an anti-inflammatory action against CPT-11-induced intestinal mucositis through strong interactions with TRPA1 receptors; reduction in the production or release or both of pro-inflammatory cytokines (TNF-α, IL-1β, and KC); and decrease in other indicators of inflammation (MPO, NF-κB, COX-2) and oxidative stress (GSH, MDA, and NOx levels). It also contributed to the restoration of the tissue architecture of the villi and crypts in the small intestine, and improved clinical parameters such as survival, body mass variation, leukogram, and blood bacterial count. Thus, TRPA1 could be a target for future therapeutic approaches in the treatment of intestinal mucositis.

Topics: Animals; Antioxidants; Body Weight; Camptothecin; Cyclooxygenase 2; Cymenes; Female; Immunohistochemistry; Inflammation; Intestines; Irinotecan; Leukocyte Count; Mice; Molecular Docking Simulation; Monoterpenes; Mucositis; NF-kappa B; Oxidative Stress; Peroxidase; Survival Analysis; Transient Receptor Potential Channels; TRPA1 Cation Channel

Previous reports suggest a significant role for N-Methyl-D-aspartate (NMDA) activation in inflammatory processes. So, this study was conducted to investigate the effect of memantine, a commonly used NMDA receptor antagonist, on inflammatory changes in mice model of colitis. Colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS) (40mg/kg). Animals received memantine (12.5, 25 and 50mg/kg, i.p.), glutamate (2g/kg, p.o.) or dexamethasone (1mg/kg, i.p.) 24h before TNBS instillation and daily thereafter for 4 days. The colonic injury was measured by clinical, macroscopic, microscopic and biochemical analysis. Memantine significantly attenuated the body weight loss, colon weight, the plasma levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and colon level of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO); as well as macroscopic and microscopic signs of colitis. Oral administration of glutamate had no significant effect on investigated parameters. Memantine as a NMDA antagonist may provide a novel venue for the development of strategies for the treatment of ulcerative colitis.

Topics: Animals; Body Weight; Colitis, Ulcerative; Colon; Cytokines; Dose-Response Relationship, Drug; Male; Memantine; Mice; Peroxidase; Receptors, N-Methyl-D-Aspartate; Trinitrobenzenesulfonic Acid

Estrogen or combinational hormone therapy can protect to menopausal symptoms but exogenous estrogen therapy has some potential risks which in turns lead to the appearance of various diseases. In recent years plants with high phytoestrogen content are recommended as therapeutic agents for postmenopausal hormonal treatment. In this research, we investigated the effects of Momordica charantia (MC) on the estrogen production and E2 as well as anti-oxidative and anti-apoptotic role on the ovariectomy rat model. The rats were ovariectomized and fed on 2 g/kg of fruit extra of MC for 30 days by gavage. 17-β estradiol (E2) and 8-OHdG levels in serum, markers of oxidative damage of ROS and ESRα, ESRβ and NF-kB gene levels were measured in uterus horn tissue. Caspase-3, caspase-9, TNF-α, IL-6, IL-10, Bcl-2 and Nf-kB proteins expression were assessed by western blotting. Structural changes in tissue were examined with H&E staining. MC administration also stimulated the E2 production and ESRα/ESRβ gene levels and the inhibited oxidative damage. Furthermore, MC treatment enhanced anti-apoptotic and anti-inflammatory process and tissue regeneration. Data herein support that MC directly regulates uterine estrogen response and may serve as a new phytoestrogenic substance for the treatment of post-menopausal symptoms.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoptosis; Body Weight; Deoxyguanosine; DNA Damage; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation; Glutathione; Malondialdehyde; Momordica charantia; NF-kappa B; Organ Size; Ovariectomy; Oxidative Stress; Peroxidase; Plant Extracts; Rats, Wistar; RNA, Messenger; Signal Transduction; Uterus

Human multipotent mesenchymal stromal cells (hMSCs) produce tumor necrosis factor (TNF)-α-stimulated protein 6 (TSG-6). TSG-6 modulates proinflammatory cytokine cascades and enhances tissue repair. This study tests the effects of recombinant human TSG-6 (rhTSG-6) on gingival wound healing within the first 2 days post-surgery.. After gingival resection in 120 Sprague-Dawley rats, 2 µg rhTSG-6 in 5-µL phosphate-buffered saline (PBS) or the same volume of only PBS solution was injected into gingival tissue approximating the surgical wound. Control animals did not receive injections. Tissue biopsies and blood were collected at 1 to 2, 6 to 8, 24, and 48 hours post-surgery (n = 10 per group). Specimens were analyzed via histologic analysis and enzyme-linked immunosorbent assay (ELISA) for quantification and comparison of inflammatory markers interleukin (IL)-1β, IL-6, TNF-α, and myeloperoxidase (MPO). Wound photographs were taken for a double-masked clinical assessment at each time period. Weights were recorded for all animals pre- and post-surgery.. Animals injected with rhTSG-6 had significantly less severe clinical inflammation at 6 to 8 (P = 0.01228), 24 (P = 0.01675), and 48 (P = 0.0186) hours. Sham and control animals had more weight loss at 24 and 48 hours. Sham and control animals had more pronounced cellular infiltrate. rhTSG-6-treated animals had significantly less MPO (P = 0.027) at 24 hours and IL-1β (P = 0.027) at 24 and 48 hours. IL-6 showed a marginal significant difference at 6 to 8 hours, but there was no significant difference for TNF-α.. rhTSG-6 reduced postoperative gingival inflammation by reducing levels of proinflammatory cytokines and cellular infiltrate and may offer significant promise as an anti-inflammatory agent for gingival surgery.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Cell Adhesion Molecules; Erythema; Gingiva; Gingival Diseases; Gingival Hemorrhage; Gingival Hypertrophy; Gingivectomy; Gingivitis; Humans; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Time Factors; Tumor Necrosis Factor-alpha; Wound Healing

The aims of the present study were to compare the toxic effects of benzo[a]pyrene (BaP) and to screen for rapid and sensitive biomarkers that can be used to assess the environmental risks of BaP in earthworms in different natural soil types. The authors exposed Eisenia fetida to 2 types of soil (red soil and fluvo-aquic soil) spiked with different concentrations (0 mg kg(-1), 1 mg kg(-1), 10 mg kg(-1), 100 mg kg(-1), and 500 mg kg(-1)) of BaP for 7 d or 14 d. Benzo[a]pyrene-induced weight variation altered the activities of antioxidant enzymes (superoxide dismutase [SOD]; catalase [CAT]; and guaiacol peroxidase [POD]) and changed the content of malondialdehyde (MDA). In addition, using the comet assay, the authors determined the DNA damage in earthworms. The results revealed that the comet assay was suitable for evaluating the genotoxicity of BaP in the soil, even at the lowest examined concentration. The MDA content was the least sensitive indicator of BaP toxicity. A 3-way analysis of variance (ANOVA) was used to determine whether the soil type, exposure concentration, and duration affected the BaP toxicity. The antioxidant enzyme activities and the MDA content were shown to be significantly correlated with the exposure concentration. The percentage of weight variation (p < 0.001), CAT activity (p < 0.05), and SOD activity (p < 0.01) were significantly affected by the soil type, and the POD activity (p < 0.01), CAT activity (p < 0.001), and SOD activity (p < 0.001) were significantly affected by the exposure duration. Therefore, measuring DNA damage in earthworms is a simple and efficient means of assessing BaP genotoxicity in a terrestrial environment, and the effects of the soil type and exposure time on the other parameters that were investigated in E. fetida, which were used as responsive biomarkers, should be considered.

Topics: Analysis of Variance; Animals; Antioxidants; Benzo(a)pyrene; Body Weight; Catalase; Comet Assay; DNA Damage; Laboratories; Malondialdehyde; Oligochaeta; Peroxidase; Soil; Soil Pollutants; Superoxide Dismutase

Dextran sodium sulphate (DSS)-induced colitis is a widely used model for inflammatory bowel disease. However, various factors including nutrition may affect the development of this colitis. This study aimed to compare and characterize the impact of purified and non-purified basal diets on the development of DSS-induced colitis in the rat.. Wistar rats were fed a non-purified or a semi-synthetic purified diet for 21 days. Colitis was then induced in half of the rats by administration of DSS in drinking water (4% w/v) during the last 7 days of experimentation. At the end of the experimental period, colon sections were taken for histopathological examination, determination of various markers of inflammation (myeloperoxidase: MPO, cytokines) and oxidative stress (superoxide dismutase: SOD, catalase: CAT, glutathione peroxidase: GPx and glutathione reductase: GRed activities), and evaluation of the expression of various genes implicated in this disorder.. DSS ingestion induced a more marked colitis in animals receiving the purified diet, as reflected by higher histological score and increased MPO activity. A significant decrease in SOD and CAT activities was also observed in rats fed the purified diet. Also, in these animals, administration of DSS induced a significant increase in interleukin (IL)-1α, IL-1β and IL-6. In addition, various genes implicated in inflammation were over-expressed after ingestion of DSS by rats fed the purified diet.. These results show that a purified diet promotes the onset of a more severe induced colitis than a non-purified one, highlighting the influence of basal diet in colitis development.

Topics: Animals; Antioxidants; Body Weight; Catalase; Colitis; Colon; Cytokines; Dextran Sulfate; Diet; Disease Models, Animal; Energy Intake; Glutathione Peroxidase; Glutathione Reductase; Inflammation; Interleukin-1alpha; Interleukin-1beta; Interleukin-6; Male; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Superoxide Dismutase; Up-Regulation

What is the central question of this study? It is not known whether treatment with interleukin-10 (IL-10) attenuates hyperoxia-induced acute lung injury in mice. What is the main finding and its importance? Our results showed that exogenous IL-10 treatment alleviated hyperoxia-induced acute lung injury in mice, possibly by regulating neutrophil recruitment and the subsequent generation of cytokines, nitric oxide and matrix metalloproteinases. Lung injury caused by breathing air enriched with oxygen continues to be a major problem in clinical medicine. Here, we investigated the therapeutic role of interleukin-10 (IL-10) in hyperoxia-induced acute lung injury in mice. In the first experiment, mice were exposed to room air or 95% O2 and treated with IL-10 simultaneously. In the second experiment, wild-type mice and IL-10(-/-) mice were exposed to room air or 95% O2 . Exogenous IL-10 treatment attenuated hyperoxia-induced acute lung injury, evidenced by a reduced ratio of lung weight to body weight, ratio of lung wet weight to dry weight, cell numbers and protein content in bronchoalveolar lavage fluid and cell death. Interleukin-10 treatment markedly prolonged the survival of mice during oxygen exposure. Interleukin-10 treatment reduced the activity of myeloperoxidase and mRNA levels of interleukin-6, tumour necrosis factor-α and macrophage inflammatory protein 2, suppressed nuclear factor-κB activation and decreased inducible nitric oxide synthnase expression and nitric oxide formation in lungs of mice exposed to hyperoxia. Interleukin-10 treatment suppressed activities of matrix metalloproteinase 2 and matrix metalloproteinase 9 and reduced lung permeability in mice during oxygen exposure. Furthermore, absence of IL-10 aggravated hyperoxia-induced acute lung injury and reduced the duration of survival of mice during oxygen exposure, which was attenuated by treatment with IL-10. In conclusion, our results show that exogenous IL-10 treatment alleviates hyperoxia-induced acute lung injury in mice, possibly by regulating neutrophil recruitment and the subsequent generation of cytokines, nitric oxide and matrix metalloproteinases. This suggests that IL-10 treatment may be a promising therapeutic strategy to reduce lung injury in patients exposed to hyperoxia.

Topics: Acute Lung Injury; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cell Death; Chemokine CXCL2; Disease Models, Animal; Hyperoxia; Interleukin-10; Interleukin-6; Lung; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Organ Size; Oxygen; Peroxidase; Tumor Necrosis Factor-alpha

Aminotriazole (ATZ) is commonly used as a catalase (CAT) inhibitor. We previously found ATZ attenuated oxidative liver injury, but the underlying mechanisms remain unknown. Acetaminophen (APAP) overdose frequently induces life-threatening oxidative hepatitis. In the present study, the potential hepatoprotective effects of ATZ on oxidative liver injury and the underlying mechanisms were further investigated in a mouse model with APAP poisoning. The experimental data indicated that pretreatment with ATZ dose- and time-dependently suppressed the elevation of plasma aminotransferases in APAP exposed mice, these effects were accompanied with alleviated histological abnormality and improved survival rate of APAP-challenged mice. In mice exposed to APAP, ATZ pretreatment decreased the CAT activities, hydrogen peroxide (H2O2) levels, malondialdehyde (MDA) contents, myeloperoxidase (MPO) levels in liver and reduced TNF-α levels in plasma. Pretreatment with ATZ also downregulated APAP-induced cytochrome P450 2E1 (CYP2E1) expression and JNK phosphorylation. In addition, posttreatment with ATZ after APAP challenge decreased the levels of plasma aminotransferases and increased the survival rate of experimental animals. Posttreatment with ATZ had no effects on CYP2E1 expression or JNK phosphorylation, but it significantly decreased the levels of plasma TNF-α. Our data indicated that the LD50 of ATZ in mice was 5367.4 mg/kg body weight, which is much higher than the therapeutic dose of ATZ in the present study. These data suggested that ATZ might be effective and safe in protect mice against APAP-induced hepatotoxicity, the beneficial effects might resulted from downregulation of CYP2E1 and inhibiton of inflammation.

Topics: Amitrole; Animals; Body Weight; Catalase; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Down-Regulation; Hydrogen Peroxide; Inflammation; Lethal Dose 50; Liver; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Peroxidase; Transaminases; Tumor Necrosis Factor-alpha

Inflammatory bowel diseases (IBD) are complex multi-factorial diseases with increasing incidence worldwide but their treatment is far from satisfactory. Unconventional strategies have consequently been investigated, proposing the use of cells as an effective alternative approach to IBD. In the present study we examined the protective potential of exogenously administered human umbilical cord derived mesenchymal stem cells (UCMSCs) against Dextran Sulfate Sodium (DSS) induced acute colitis in immunodeficient NOD.CB17-Prkdc (scid)/J mice with particular attention to endoplasmic reticulum (ER) stress.. UCMSCs were injected in NOD.CB17-Prkdc (scid)/J via the tail vein at day 1 and 4 after DSS administration. To verify attenuation of DSS induced damage by UCMSCs, Disease Activity Index (DAI) and body weight changes was monitored daily. Moreover, colon length, histological changes, myeloperoxidase and catalase activities, metalloproteinase (MMP) 2 and 9 expression and endoplasmic reticulum (ER) stress related proteins were evaluated on day 7.. UCMSCs administration to immunodeficient NOD.CB17-Prkdc (scid)/J mice after DSS damage significantly reduced DAI (1.45 ± 0.16 vs 2.08 ± 0.18, p < 0.05), attenuating the presence of bloody stools, weight loss, colon shortening (8.95 ± 0.33 cm vs 6.8 ± 0.20 cm, p < 0.01) and histological score (1.97 ± 0.13 vs 3.27 ± 0.13, p < 0.001). Decrease in neutrophil infiltration was evident from lower MPO levels (78.2 ± 9.7 vs 168.9 ± 18.2 U/g, p < 0.01). DSS treatment enhanced MMP2 and MMP9 activities (>3-fold), which were significantly reduced in mice receiving UCMSCs. Moreover, positive modulation in ER stress related proteins was observed after UCMSCs administration.. Our results demonstrated that UCMSCs are able to prevent DSS-induced colitis in immunodeficient mice. Using these mice we demonstrated that our UCMSCs have a direct preventive effect other than the T-cell immunomodulatory properties which are already known. Moreover we demonstrated a key function of MMPs and ER stress in the establishment of colitis suggesting them to be potential therapeutic targets in IBD treatment.

Topics: Acute Disease; Animals; Body Weight; Catalase; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred NOD; Peroxidase; Severity of Illness Index; Transplantation, Heterologous; Umbilical Cord

The seeds of Phaseolus calcaratus Roxburgh (PHCR) are common legumes that comprise part of the daily diet in Chinese and Korean culture. Recent findings highlight anti-inflammatory and anti-septic potentials of catechin-7-O-β-D-glucopyranoside (CGP) isolated from PHCR seeds. We investigated the intestinal anti-inflammatory activity and associated mechanisms of CGP using a rat model of trinitrobenzenesulfonic acid (TNBS)-induced colitis. Oral treatment with CGP (10mg/kg body weight) suppressed body weight loss and intestinal inflammatory damages in TNBS-induced colitic rats. This treatment reduced myeloperoxidase activity and malondialdehyde level, but increased glutathione level in the TNBS colitic rats. CGP treatment also inhibited the TNBS-mediated increases in nitric oxide synthase, cyclooxygenase-2, interleukin-1β, tumor necrosis factor-α, intercellular adhesion molecule-1, and monocyte chemotactic protein-1 proteins or mRNA levels. This inhibition was accompanied by the increased mRNA levels of mucins MUC2 and MUC3. The CGP treatment prevented phosphorylation of p38 mitogen-activated protein kinase, IκB-α, and DNA-nuclear factor-κB binding, all of which were increased in the inflamed colons of TNBS-treated rats. Furthermore, oral administration with a crude PHCR butanol extract (100mg/kg body weight) which contains 1.5% of CGP showed intestinal anti-inflammatory potentials similar to that of CGP. Collectively, our current findings suggest that CGP or CGP-containing PHCR seeds may have favorable effects on intestinal inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Catechin; Crohn Disease; Gene Expression Regulation; Glucosides; Glutathione; Male; Malondialdehyde; Mucins; Peroxidase; Phaseolus; Phosphorylation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seeds; Trinitrobenzenesulfonic Acid

Atorvastatin (ATV) has bone anabolic properties, and alendronate (ALD) is an important antiresorptive drug. This study aimed to evaluate the effects of the combination of ALD and ATV on ligature-induced alveolar bone loss in rats.. Periodontitis was induced by ligature in 78 Wistar rats. Groups of six rats prophylactically received 0.9% saline (SAL), ALD (0.01 or 0.25 mg/kg subcutaneously) or ATV (0.3 or 27 mg/kg by gavage). Then, groups of six rats received the combination of ALD+ATV (0.25 mg/kg + 27 mg/kg, 0.01 mg/kg + 0.3 mg/kg, 0.25 mg/kg + 0.3 mg/kg or 0.01 mg/kg + 27 mg/kg) prophylactically. An extra group of six rats received therapeutic SAL or a lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) therapeutically. Three extra groups of six rats each received SAL or a lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) prophylactically or therapeutically for histometric and immunohistochemical analyses. The rats were killed on day 11 after ligature placement, and the maxillae were removed and processed for macroscopic, histomorphometric and TRAP immunohistochemical analyses. Gingival samples were collected to evaluate myeloperoxidase (MPO) activity. Blood samples were collected to measure serum bone-specific alkaline phosphatase (BALP) and transaminase levels and for hematological studies. Rats were weighed daily.. All combined therapies prevented alveolar bone loss when compared with SAL or low doses of monotherapy (ALD or ATV) (p < 0.05). The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively), administered either prophylactically (39.0%) or therapeutically (53.5%), prevented alveolar bone loss. Decreases in bone and cementum resorption, in leukocyte infiltration and in immunostaining for TRAP and MPO activity corroborated the morphometric findings. The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) prevented BALP reduction (p < 0.05) and did not alter the level of serum transaminases. Moreover, the lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) also reduced neutrophilia and lymphomonocytosis and did not cause weight loss when compared with administration of SAL.. The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) demonstrated a protective effect on alveolar bone loss.

Topics: Acid Phosphatase; Alanine Transaminase; Alendronate; Alkaline Phosphatase; Alveolar Bone Loss; Animals; Aspartate Aminotransferases; Atorvastatin; Body Weight; Bone Density Conservation Agents; Dental Cementum; Gingiva; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Infusions, Parenteral; Injections, Subcutaneous; Isoenzymes; Leukocyte Disorders; Leukocytes; Leukocytosis; Male; Monocytes; Neutrophils; Peroxidase; Pyrroles; Rats, Wistar; Root Resorption; Tartrate-Resistant Acid Phosphatase

We studied a total of eight developmental stages of capped brood and newly emerged workers of Apis mellifera carnica colonies naturally parasitized with Varroa destructor. During winter and early spring four colonies were fed syrup containing 1.8 mg vitamin C kg(-1) (ascorbic acid group; group AA) while four colonies were fed syrup without the vitamin C (control group C). Selected elements of the antioxidative system were analysed including total antioxidant status (TAS), glutathione content and antioxidative enzyme activities (superoxide dismutase, catalase, peroxidase and glutathione S-transferase). Body weight, protein content and indices of infestation were also determined. The prevalence (8.11%) and intensity (1·15 parasite per bee) of the infestation were lower in group AA compared with group C (11.3% and 1.21, respectively). Changes in the indicators of antioxidative stress were evidence for the strengthening of the antioxidative system in the brood by administration of vitamin C. In freshly emerged worker bees of group AA, despite the infestation, protein content, TAS, and the activity of all antioxidative enzymes had significantly higher values in relation to group C.

Topics: Animals; Antioxidants; Ascorbic Acid; Bees; Body Weight; Catalase; Diet; Glutathione; Glutathione Transferase; Host-Parasite Interactions; Mite Infestations; Oxidative Stress; Peroxidase; Proteins; Seasons; Superoxide Dismutase; Varroidae

The non-protein amino acid β-aminobutyric acid (BABA) can induce plant resistance to a broad spectrum of biotic and abiotic stresses. However, BABA-induced plant resistance to insects is less well-studied, especially its underlying mechanism. In this research, we applied BABA to wheat seedlings and tested its effects on Sitobion avenae (F.). When applied as a soil drench, BABA significantly reduced weights of S. avenae, whereas foliar spray and seed treatment had no such effects. BABA-mediated suppression of S. avenae growth was dose dependent and lasted at least for 7 days. The aminobutyric acid concentration in phloem sap of BABA-treated plants was higher and increased with BABA concentrations applied. Moreover, after 10 days of treatment, the aminobutyric acid content in BABA-treated plants was still higher than that in control treatment. Sitobion avenae could not discriminate artificial diet containing BABA from standard diet, indicating that BABA itself is not a deterrent to this aphid. Also S. avenae did not show preference for control plants or BABA-treated plants. Consistent with choice test results, S. avenae had similar feeding activities on control and BABA-treated plants, suggesting that BABA did not induce antifeedants in wheat seedlings. In addition, aminobutyric acid concentration in S. avenae feeding on BABA-treated plants was significantly higher than those feeding on control plants. Sitobion avenae growth rate was reduced on the artificial diet containing BABA, indicating that BABA had direct toxic effects on this aphid species. These results suggest that BABA application reduced S. avenae performance on wheat seedlings and the mechanism is possibly due to direct toxicity of high BABA contents in plant phloem.

Topics: Amino Acids; Aminobutyrates; Animals; Aphids; Body Weight; Feeding Behavior; Peroxidase; Phloem; Seedlings; Triticum

There are opposite views in the available literature: Whether physical exercise has a protective effect or not on the onset of inflammatory bowel disease (IBD). Therefore, we investigated the effects of recreational physical exercise before the induction of colitis. After 6 weeks of voluntary physical activity (running wheel), male Wistar rats were treated with TNBS (10 mg). 72 hrs after trinitrobenzene sulphonic acid (TNBS) challenge we measured colonic gene (TNF-α, IL-1β, CXCL1 and IL-10) and protein (TNF-α) expressions of various inflammatory mediators and enzyme activities of heme oxygenase (HO), nitric oxide synthase (NOS), and myeloperoxidase (MPO) enzymes. Wheel running significantly increased the activities of HO, constitutive NOS (cNOS) isoform. Furthermore, 6 weeks of running significantly decreased TNBS-induced inflammatory markers, including extent of lesions, severity of mucosal damage, and gene expression of IL-1β, CXCL1, and MPO activity, while IL-10 gene expression and cNOS activity were increased. iNOS activity decreased and the activity of HO enzyme increased, but not significantly, compared to the sedentary TNBS-treated group. In conclusion, recreational physical exercise can play an anti-inflammatory role by downregulating the gene expression of proinflammatory mediators, inducing anti-inflammatory mediators, and modulating the activities of HO and NOS enzymes in a rat model of colitis.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colitis; Colon; Gene Expression Profiling; Heme Oxygenase (Decyclizing); Inflammation Mediators; Intestinal Mucosa; Male; Nitric Oxide Synthase; Peroxidase; Physical Conditioning, Animal; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Inflammatory bowel disease (IBD) is a chronic, relapsing and remitting condition of inflammation involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies for the treatment of IBD are desperately needed. In the present study, we aimed to examine the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Andrographolide sulfonate was administrated through intraperitoneal injection to mice with TNBS-induced colitis. TNBS-induced body weight loss, myeloperoxidase activity, shortening of the colon and colonic inflammation were significantly ameliorated by andrographolide sulfonate. Both the mRNA and protein levels of pro-inflammatory cytokines were reduced by andrographolide sulfonate administration. Moreover, andrographolide sulfonate markedly suppressed the activation of p38 mitogen-activated protein kinase as well as p65 subunit of nuclear factor-κB (NF-κB). Furthermore, CD4(+) T cell infiltration as well as the differentiation of Th1 (CD4(+)IFN-γ(+)) and Th17 (CD4(+)IL17A(+)) subset were inhibited by andrographolide sulfonate. In summary, these results suggest that andrographolide sulfonate ameliorated TNBS-induced colitis in mice through inhibiting Th1/Th17 response. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating gastrointestinal inflammatory disorders.

Topics: Alkanesulfonates; Animals; Body Weight; Colitis; Colon; Cytokines; Diterpenes; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Models, Animal; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Peroxidase; Signal Transduction; Th1 Cells; Th17 Cells; Trinitrobenzenesulfonic Acid

In the present study, we investigated the ameliorative potential of aliskiren in dextran sulfate sodium (DSS) induced colitis in mice. Aliskiren (3 and 10mg/kg, i.p.) was administered for 10 days from the day of DSS administration. The severity of colitis in mice was assessed using body weight loss, colon and spleen weight, hematological parameters, food intake, stool consistency, rectal bleeding and colon shortening. Colonic malondialdehyde (MDA), myeloperoxidase (MPO) and renin mRNA levels were also estimated. Furthermore, TNF-α and IL-6 in plasma and colon were analyzed. The results showed that aliskiren (10mg/kg, i.p.) significantly improved the severity of colitis by, decrease in weight loss, improvement in food intake and stool consistency, decrease in rectal bleeding, decrease in relative colon and spleen weight and improvement in colonic shortening. Aliskiren (10mg/kg, i.p.) improved blood hemoglobin, red blood cells (RBC) and hematocrit. Colonic malondialdehyde (MDA), MPO and histolopathological score were significantly diminished by aliskiren (10mg/kg, i.p.). Furthermore, aliskiren (10mg/kg, i.p.) significantly diminished the elevated levels of TNF-α, IL-6 and renin mRNA in inflammed colon. These results indicate involvement of renin in colitis and inhibition of renin by aliskiren ameliorates colitis.

Topics: Amides; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis; Colon; Cytokines; Dextran Sulfate; Eating; Erythrocytes; Female; Fumarates; Gene Expression Regulation; Hematocrit; Hemoglobins; Malondialdehyde; Mice; Organ Size; Peroxidase; Renin; RNA, Messenger; Spleen

A huge body evidences suggest that obesity is the single great risk factor for the development of dementia. Recently, silymarin, a flavonoid, clinically in use as a hepatoprotectant, has been reported to prevent amyloid beta-induced memory impairment by reducing oxidative stress and inflammation in mice brain. However, its potential in high-fat-diet (HFD)-induced dementia has not yet been investigated. Therefore, the present study is designed to explore the role of silymarin in HFD-induced experimental dementia in mice. Morris water maze test was employed to assess learning and memory. Various biochemical estimations including brain acetylcholinerstarse activity (AchE), thiobarbituric acid-reactive species (TBARS) level, reduced glutathione level (GSH), nirate/nitrite, and myeloperoxidase (MPO) activity were measured. Serum cholesterol level was also determined. HFD significantly impaired the cognitive abilities, along with increasing brain AchE, TBARS, MPO, nitrate/nitrite, and serum cholesterol levels. Marked reduction of brain GSH levels was observed. On the contrary, silymarin significantly reversed HFD-induced cognitive deficits and the biochemical changes. The present study indicates strong potential of silymarin in HFD-induced experimental dementia.

Topics: Acetylcholinesterase; Animals; Body Weight; Brain; Cholesterol; Dementia; Diet, High-Fat; Disease Models, Animal; Female; Glutathione; Male; Maze Learning; Memory Disorders; Mice; Neuroprotective Agents; Nitrates; Nitrites; Peroxidase; Silymarin; Thiobarbituric Acid Reactive Substances

Idiopathic pulmonary fibrosis is a progressive fatal lung disease characterized by excessive collagen deposition, with no effective treatments. We investigated the efficacy of natural products with high anti-inflammatory activity, such as passion fruit peel extract (PFPE), in a mouse model of bleomycin-induced pulmonary fibrosis (PF). C57BL/6J mice were subjected to a single intratracheal instillation of bleomycin to induce PF. Daily PFPE treatment significantly reduced loss of body mass and mortality rate in mice compared with those treated with bleomycin. While bleomycin-induced PF resulted in elevated total numbers of inflammatory cells, macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid on both days 7 and 21, PFPE administration significantly attenuated these phenomena compared with bleomycin group. On day 7, the decreased superoxide dismutase and myeloperoxidase activities observed in the bleomycin group were significantly restored with PFPE treatment. On day 21, enhanced hydroxyproline deposition in the bleomycin group was also suppressed by PFPE administration. PFPE treatment significantly attenuated extensive inflammatory cell infiltration and accumulation of collagen in lung tissue sections of bleomycin-induced mice on days 7 and 21, respectively. Our results indicate that administration of PFPE decreased bleomycin-induced PF because of anti-inflammatory and antioxidant activities.

Topics: Animals; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antioxidants; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Female; Flavonoids; Hydroxyproline; Inflammation; Mice, Inbred C57BL; Oxidative Stress; Passiflora; Peroxidase; Phytotherapy; Plant Extracts; Pulmonary Fibrosis; Superoxide Dismutase

The effects of methotrexate on 5-hydroxytryptamine (5-HT) metabolism in the intestinal tissue of rats were investigated during the delayed phase after a single administration. Rats were i.p. injected with methotrexate or with saline as a control, and kaolin and food intakes were measured by an automatic monitoring apparatus. At 96 h after administration, dissected-out ileal tissue was frozen rapidly in liquid nitrogen for further analysis or fixed for immunohistochemical staining. Methotrexate at a dose of 50 mg/kg caused a time-dependent increase in kaolin intake lasting up to 72 h after administration, which returned to the control level at 96 h after administration. This dose of methotrexate caused a gradual decrease in body weight, food intake, and water intake lasting up to 72 h, which approached the control level at 96 h. Methotrexate caused pathologic changes, including a moderate inflammatory response in the ileal tissue and an increase in the number of L-tryptophan hydroxylase (TPH)-expressing cells in the ileal mucosa. Methotrexate also caused a significant increase in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content and in TPH1 mRNA expression in the ileal tissues. It had no significant effects on mRNA expression of serotonin transporter, COX-1, or COX-2 or on myeloperoxidase activity. This study demonstrated, for the first time, that methotrexate caused a change in the ileal 5-HT metabolism associated with hyperplasia of mucosal enterochromaffin cells.

Topics: Animals; Body Weight; Cyclooxygenase 1; Cyclooxygenase 2; Eating; Hydroxyindoleacetic Acid; Ileum; Kaolin; Male; Membrane Proteins; Methotrexate; Peroxidase; Rats, Wistar; RNA-Binding Proteins; RNA, Messenger; Serotonin; Tryptophan Hydroxylase

In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF), a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied.. Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD). Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test). Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically.. The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes.. This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and immune-related gastrointestinal disorders among shift workers.

Topics: Adaptation, Physiological; Animals; ARNTL Transcription Factors; Body Weight; Circadian Rhythm; Cytokines; Diet, High-Fat; Feeding Behavior; Gastric Emptying; Gene Expression Regulation; Gene Knockout Techniques; Ghrelin; Immunity; Mice; Neutrophil Infiltration; Peroxidase

Opposing emotional events (negative/trauma or positive/maternal care) during the postnatal period may differentially influence vulnerability to the effects of stress later in life. The development and course of intestinal disorders such as inflammatory bowel disease are negatively affected by persistent stress, but to date the role of positive life events on these pathologies has been entirely unknown. In the present study, the effect of early life beneficial experiences in the development of intestinal dysfunctions, where inflammation and stress stimuli play a primary role, was investigated. As a "positive" experimental model we used adult male rat progeny nursed by mothers whose drinking water was supplemented with moderate doses of corticosterone (CORT) (0.2 mg/ml) during the lactation period. Such animals have been generally shown to cope better with different environmental situations during life. The susceptibility to inflammatory experimental colitis induced by intracolonic infusion of TNBS (2,4,6-trinitrobenzenesulphonic acid) was investigated in CORT-nursed rats in comparison with control rats. This mild increase in maternal corticosterone during lactation induced, in CORT-nursed rats, a long lasting protective effect on TNBS-colitis, characterized by improvements in some indices of the disease (increased colonic myeloperoxidase activity, loss of body weight and food intake) and by the involvement of endogenous peripheral pathways known to participate in intestinal disorder development (lower plasma corticosterone levels and colonic mast cell degranulation, alterations in the colonic expression of both corticotrophin releasing factor/CRF and its receptor/CRH-1R). All these findings contribute to suggesting that the reduced vulnerability to TNBS-colitis in CORT-nursed rats is due to recovery from the colonic mucosal barrier dysfunction. Such long lasting changes induced by mild hormonal manipulation during lactation, making the adult also better adapted to colonic inflammatory stress, constitute a useful experimental model to investigate the etiopathogenetic mechanisms and therapeutic treatments of some gastrointestinal diseases.

Topics: Animals; Animals, Newborn; Blotting, Western; Body Weight; Chymases; Colitis; Colon; Corticosterone; Corticotropin-Releasing Hormone; Eating; Female; Immunohistochemistry; Lactation; Male; Peroxidase; Protective Agents; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Trinitrobenzenesulfonic Acid

The pentacyclic triterpene α,β-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that α,β-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the α,β-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with α,β-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, α,β-amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin (IL)-1β and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the α,β-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1), β(2)-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB(1)), but not CB(2), pharmacological blockade significantly reversed the beneficial effects of α,β-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of α,β-amyrin-treated mice. Altogether, these results suggest that the α,β-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms.

Topics: Administration, Oral; Amidohydrolases; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Asialoglycoproteins; Body Weight; Cannabinoids; CD18 Antigens; Cell Adhesion Molecules; Chemokines; Colitis; Colon; Dextran Sulfate; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-4; Ki-67 Antigen; Lectins, C-Type; Male; Membrane Proteins; Mice; Oleanolic Acid; P-Selectin; Peroxidase; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation; Vascular Cell Adhesion Molecule-1

This study investigated the expression pattern of PTEN and its effect on carcinogenesis of ulcerative colitis-associated colorectal cancer, leading to insights into the underlying molecular mechanism.. We established a mouse model of ulcerative colitis-associated colorectal cancer by treating the animals with azoxymethane (AOM) and dextran sulphate sodium (DSS), and investigated the inflammation-dysplasia-carcinoma sequence. Expression patterns of PTEN, p-Akt and Ki-67 were shown by immunohistochemistry; western blotting techniques were used to detect protein expression of PTEN, p-Akt and caspase 3; TUNEL assay was used to measure apoptosis in colon epithelial cells; and colorimetric analysis was able to determine MPO activity in colon tissues.. During the inflammation-dysplasia-carcinoma sequence, PTEN expression gradually decreased, while p-Akt expression increased; PTEN and p-Akt levels were negatively correlated. Compared to the AOM-DSS and Ad-0 groups, Ad-PTEN mice had longer colons, fewer tumours (P < 0.01) and smaller tumour sizes (P < 0.05). After injecting Ad-PTEN, expression of p-Akt, Ki-67 and MPO activity decreased dramatically, whereas PTEN increased. The TUNEL assay showed increased apoptotic cells and caspase 3 expression in the Ad-PTEN group.. PTEN plays an important role in the inflammation-dysplasia-carcinoma sequence and may be a new molecular target in preventing and treating ulcerative colitis-associated colorectal cancer.

Topics: Adenoviridae; Animals; Apoptosis; Body Weight; Cell Proliferation; Colitis, Ulcerative; Colon; Colorectal Neoplasms; Disease Models, Animal; Down-Regulation; Female; Genetic Therapy; Mice; Mice, Inbred BALB C; Peroxidase; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Up-Regulation

To examine the excessive reactive oxygen species (ROS) mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the combined effect of glutamine supplementation and diphenyleneiodonium (DPI) on the function of neutrophils induced by overtraining.. Fifty male Wistar rats were randomly divided into 5 groups: control group (C), overtraining group (E), DPI-administration group (D), glutamine-supplementation group (G), and combined DPI and glutamine group (DG). Blood was sampled from the orbital vein after rats were trained on treadmill for 11 wk. Cytokine and lipid peroxidation in blood plasma were measured by enzyme-linked immunosorbent assay. The colocalization between gp91phox and p47phox of the NADPH oxidase was detected using immunocytochemistry and confocal microscopy. The activity of NADPH oxidase was assessed by chemiluminescence. Neutrophils' respiratory burst and phagocytosis function were measured by flow cytometry.. NADPH oxidase was activated by overtraining. Cytokine and lipid peroxidation in blood plasma and the activity of NADPH oxidase were markedly increased in Group E compared with group C. Neutrophil function was lower in group E than group C. Both lower neutrophils function and higher ROS production were reversed in Group DG. The glutamine and DPI interference alone in group D and group G was less effective than DPI and glutamine combined in group DG.. Activation of NADPH oxidase is responsible for the production of superoxide anions, which leads to excessive ROS and is related to the decrease in neutrophil function induced by overtraining. The combined DPI administration and glutamine supplementation reversed the decreased neutrophil function after overtraining.

Topics: Animals; Body Weight; Cortisone; Dietary Supplements; Enzyme-Linked Immunosorbent Assay; Glutamine; Granulocytes; Hemoglobins; Immunohistochemistry; Interleukin-1beta; Interleukin-6; Lipid Peroxidation; Male; Malondialdehyde; Microscopy, Confocal; NADPH Oxidases; Neutrophils; Onium Compounds; Peroxidase; Phagocytosis; Physical Conditioning, Animal; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxides; Testosterone; Tumor Necrosis Factor-alpha

Acetaminophen (APAP) is an antipyretic analgesic drug that when taken in overdose causes depletion of glutathione (GSH) and hepatotoxicity. N-acetylcysteine (NAC) is the antidote of choice for the treatment of APAP toxicity; however, due to its short-half-life repeated dosing of NAC is required.. To determine whether a NAC-loaded liposomal formulation (Lipo-NAC) is more effective than the conventional NAC in protecting against acute APAP-induced hepatotoxicity.. Male Sprague-Dawley rats were challenged with an intragastric dose of APAP (850 mg/kg b.wt.); 4 h later, animals were administered saline, NAC, Lipo-NAC or empty liposomes and sacrificed 24 h post-APAP treatment.. APAP administration resulted in hepatic injury as evidenced by increases in plasma bilirubin, alanine (AST) and aspartate (ALT) aminotransferase levels and tissue levels of lipid peroxidation and myeloperoxidase as well as decreases in hepatic levels of reduced GSH, GSH peroxidase and GSH reductase. Treatment of animals with Lipo-NAC was significantly more effective than free NAC in reducing APAP-induced hepatotoxicity. Histological evaluation showed that APAP caused periacinar hepatocellular apoptosis and/or necrosis of hepatocytes around the terminal hepatic venules which was reduced by NAC treatment, the degree of reduction being greater for Lipo-NAC.. These data suggest that administration of Lipo-NAC ameliorated the APAP-induced hepatotoxicity.

Topics: Acetaminophen; Acetylcysteine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Bilirubin; Body Weight; Chemical and Drug Induced Liver Injury; Chemistry, Pharmaceutical; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Lipid Peroxidation; Liposomes; Liver; Male; Peroxidase; Rats; Rats, Sprague-Dawley

Elemental mercury (Hg(0)) is a hazardous metal with significant human exposure through diverse sources. In this study, the role of salicylic acid (SA) was assessed against Hg(0)-induced injury in mice, with the aim of screening alternative clinical drugs to prevent or treat Hg(0) poisoning. An exposure to Hg(0) (1.0 mg/m(3) in a glass box) for 2 h per day for successive 15 d significantly increased Hg accumulation in mouse brain and lung, inhibited the animal growth and altered the neurobehavior such as impairing the spatial learning and memory in the Barnes maze test. However, although oral SA (5.5 mg/kg body weight) during the Hg(0) exposure did not reduce the Hg levels in these organs, it effectively counteracted the Hg(0)-induced growth inhibition, and improved the behavioral performance, accompanied by a series of ameliorations in the antioxidative defense and anti-inflammatory response. For instance, when compared with control, Hg(0)-inhaled animals had significant decreases in the activities of superoxide dismutase and peroxidase, and in the levels of reduced form of glutathione and the ratio to its oxidized form, concomitantly with a high accumulation of hydrogen peroxide and malondialdehyde in the brain and lung. However, these values in Hg(0) + SA-exposed animals were comparable with the basal levels in control. Likewise, interleukin-6 in the brain and lung of Hg(0)-exposed animals were dramatically elevated, whereas it was maintained to the basal level in Hg(0) + SA-exposed animals. These data suggested that application of SA could protect mice against Hg(0)-induced injury.

Topics: Animals; Body Weight; Brain; Bronchoalveolar Lavage Fluid; Environmental Pollutants; Female; Glutathione; Glutathione Disulfide; Interleukin-6; Lipid Peroxidation; Lung; Malondialdehyde; Maze Learning; Memory; Memory Disorders; Mercury; Mice; Peroxidase; Protective Agents; Salicylic Acid; Superoxide Dismutase

The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.

Topics: Acetylcholinesterase; Alzheimer Disease; Analysis of Variance; Animals; Body Weight; Brain; Cholesterol; Cholesterol, Dietary; Diet, High-Fat; Female; Glutathione; Injections, Intraventricular; Lansoprazole; Male; Maze Learning; Memory; Mice; Peroxidase; Proton Pump Inhibitors; Streptozocin; Thiobarbituric Acid Reactive Substances

A significant increase in serum lipase, amylase, capase-1 and myeloperoxidase activities, oxidative stress index (OSI), IL-1beta and IL-18 was observed in rats receiving ethanol (EtOH) and high fat diet (HFD). Thymoquinone (TQ) supplementation along with EtOH and HFD significantly decreased the levels of serum lipase, amylase, capase-1, myeloperoxidase, OSI and maintained the antioxidant status when compared to untreated EtOH and HFD fed rats. Among the 4 doses, 100 mg of TQ/kg body weight was found to provide optimum protective effect on pancreas against EtOH and HFD induced abnormal changes. Histological observations added more evidence for the anti-inflammatory effect of TQ.

Topics: Animals; Antioxidants; Benzoquinones; Body Weight; Diet, High-Fat; Dose-Response Relationship, Drug; Ethanol; Glutathione; Inflammation; Interleukin-18; Interleukin-1beta; Lipase; Lipid Peroxides; Male; Oxidative Stress; Pancreatitis, Chronic; Peroxidase; Rats; Rats, Wistar

Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells expressing CD11b and Gr-1 marker in mice and comprise at least two subsets: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). This study aimed to evaluate the therapeutic efficacy of transplantation of G-MDSC subsets from normal mice to colitis mice.. Murine colitis model was induced by the intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The mice were divided into four groups: control group, TNBS-induced colitis, TNBS-induced colitis plus normal saline injection and TNBS-induced colitis plus bone marrow-derived G-MDSCs injection (transplantation group). G-MDSCs were sorted and enriched via magnetic-activated cell sorting (MACS) program, the purity of the sorted cells was then identified using flow cytometry analysis. Sex cross-transplantation of dominant G-MDSCs was applied from normal mice to colitis models using i.v. injection. Changes of body weight, survival rate, myeloperoxidase (MPO) activity were monitored and macroscopic and microscopic injury scores are calculated. Donor cell Y chromosomes were assessed by in situ hybridization to assess reconstitutions.. After the transplantation of bone marrow-derived G-MDSCs from normal mice to colitis models, recipient mice showed increased survival rate, decreased macroscopic and microscopic injury scores and MPO activity, as well as lowered concentration of serum interleukin-6. Y chromosomes staining displayed colonization of donor cells of liver, spleen and colon tissues.. Bone marrow-derived G-MDSCs are effective in the improvement of murine colitis, but its effect in human needs further investigation.

Topics: Animals; Body Weight; Colitis; Cytokines; Disease Models, Animal; Female; Graft Survival; Granulocytes; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Myeloid Cells; Peroxidase; Trinitrobenzenesulfonic Acid

Conventional medical therapies for ulcerative colitis (UC) are still limited due to the adverse side effects like dose-dependent diarrhoea and insufficient potency to keep in remission for long-term periods. So, new alternatives that provide more effective and safe therapies for ulcerative colitis are constantly being sought. In the present study, probiotic LaBb Dahi was selected for investigation of its therapeutic effect on DSS-induced colitis model in mice. LaBb Dahi was prepared by co-culturing Dahi culture of Lactococci along with selected strain of Lactobacillus acidophilus LaVK2 and Bifidobacterium bifidum BbVK3 in buffalo milk. Four groups of mice (12 each) were fed for 17 d with buffalo milk (normal control), buffalo milk plus DSS (Colitis control), Dahi plus DSS, and LaBb Dahi plus DSS, respectively, with basal diet. The disease activity scores, weight loss, organ weight, colon length, myeloperoxidase (MPO) and β-glucoronidase activity was assessed, and the histopathological picture of the colon of mice was studied. All colitis control mice evidenced significant increase in MPO, β-glucoronidase activity and showed high disease activity scores along with histological damage to colonic tissue. Feeding with LaBb Dahi offered significant reduction in MPO activity, β-glucoronidase activity and improved disease activity scores. We found significant decline in length of colon, organ weight and body weight in colitis induced controls which were improved significantly by feeding LaBb Dahi. The present study suggests that LaBb Dahi can be used as a potential nutraceutical intervention to combat UC related changes and may offer effective adjunctive treatment for management of UC.

Topics: Animals; Bifidobacterium; Body Weight; Buffaloes; Colitis, Ulcerative; Colon; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Glucuronidase; Lactobacillus acidophilus; Male; Mice; Milk; Peroxidase; Probiotics

Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this study was to optimize the timing of MSCs transplantation. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (90% for 2 weeks and 60% for 1 week) or normoxia after birth for 21 days. Human UCB-derived MSCs (5×10(5) cells) were delivered intratracheally early at postnatal day (P) 3 (HT3), late at P10 (HT10) or combined early+late at P3+10 (HT3+10). Hyperoxia-induced increase in mortality, TUNEL positive cells, ED1 positive alveolar macrophages, myeloperoxidase activity and collagen levels, retarded growth and reduced alveolarization as evidenced by increased mean linear intercept and mean alveolar volume were significantly better attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced up-regulation of both cytosolic and membrane p47(phox) indicative of oxidative stress, and increased inflammatory markers such as tumor necrosis factor-α, interleukin (IL) -1α, IL-1β, IL-6, and transforming growth factor-β measured by ELISA, and tissue inhibitor of metalloproteinase-1, CXCL7, RANTES, L-selectin and soluble intercellular adhesion molecule-1 measured by protein array were consistently more attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced decrease in hepatocyte growth factor and vascular endothelial growth factor was significantly up-regulated in both HT3 and HT3+10, but not in HT10. In summary, intratracheal transplantation of human UCB derived MSCs time-dependently attenuated hyperoxia-induced lung injury in neonatal rats, showing significant protection only in the early but not in the late phase of inflammation. There were no synergies with combined early+late MSCs transplantation.

Topics: Animals; Animals, Newborn; Body Weight; Cell Membrane; Collagen; Cytokines; Cytosol; Female; Fetal Blood; Gene Expression Regulation; Hepatocyte Growth Factor; Humans; Hyperoxia; Lung Injury; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; NADPH Oxidases; Peroxidase; Pregnancy; Rats; Rats, Sprague-Dawley; Survival Rate; Time Factors; Vascular Endothelial Growth Factor A

Polymorphonuclear granulocytes (PMNs) have been attributed a primarily deleterious role in the pathogenesis of acute lung injury (ALI). However, evidence exists that PMNs might also act beneficially in certain types of ALI. In this regard, we investigated the role of activated neutrophils in the pathophysiology of lung contusion-induced ALI. We used the model of blunt chest trauma accompanied by PMN-depletion in male C3H/HeN mice. Animals received 25 μg/g body weight PMN-depleting antibody Gr-1 intravenously 48 h before trauma. Bronchoalveolar lavage (BAL) and lung tissue interleukin 6 (IL-6) were similarly elevated in PMN-depleted and control animals after trauma, whereas macrophage inflammatory protein 2 and monocyte chemoattractant protein 1 in BAL and lungs, IL-10 in BAL, and lung keratinocyte chemoattractant (KC) were even further increased in the absence of PMNs. Plasma IL-6 and KC were also increased in response to the insult and even further in the absence of PMNs. Chest trauma induced an enhanced release of IL-6, tumor necrosis factor α, macrophage inflammatory protein 2, monocyte chemoattractant protein 1, and IL-10 from isolated KU, which was blunted in the absence of PMNs. In the presence of PMNs, BAL protein was further increased at 30 h when compared with the 3-h time point, which was not the case in the absence of PMNs. Taken together, in response to lung trauma, activated neutrophils control inflammation including mediator release from distant immune cells but simultaneously mediate pulmonary tissue damage. Thus, keeping in mind potential inflammatory adverse effects, modulation of neutrophil activation or trafficking might be a reasonable therapeutic approach in chest trauma-induced lung injury.

Topics: Animals; Body Weight; Bronchoalveolar Lavage; Granulocytes; Keratinocytes; Kupffer Cells; Lung Injury; Male; Mice; Mice, Inbred C3H; Neutrophils; Peroxidase; Spleen; Time Factors; Wounds, Nonpenetrating

In this study, we investigated the effects and the protective mechanism of ginsenoside Rd (GRd) which has been identified as one of the effective compounds from ginseng on relapsing colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. After inducing relapsing colitis in experimental rats on two occasions by intracolonic injection of TNBS, GRd (10, 20 and 40 mg/kg) was administered to experimental colitis rats for 7 days. The inflammatory degree was assessed by macroscopic score, histology and myeloperoxidase (MPO) activity. The levels of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6 were determined by ELISA. Mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by western blotting method. The results showed that GRd markedly attenuates the inflammatory response to TNBS-induced relapsing colitis, as evidenced by improved signs, increased body weight, decreased colonic weight/length ratio, reduced colonic macroscopic and microscopic damage scores, inhibited the activity of MPO, lowered proinflammatory cytokine levels and suppressed phosphorylation of p38 and JNK. The possible mechanism of protection on experimental colitis after GRd administration was that it could reduce the accumulation of leukocytes and down-regulate multiple proinflammatory cytokines through modulation of JNK and p38 activation.

Topics: Animals; Body Weight; Colitis; Colon; Down-Regulation; Ginsenosides; Interleukin-1beta; Interleukin-6; Leukocytes; Male; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Peroxidase; Phosphorylation; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Polycan is a promising candidate for the treatment of periodontal disease. This study was undertaken to examine whether Polycan, a type of β-glucan, has a protective effect on ligature-induced experimental periodontitis and related alveolar bone loss in Sprague-Dawley rats..  Polycan was orally administered, daily, for 10 d, at 21.25, 42.5 or 85 mg/kg, beginning 1 d after ligation. Changes in body weight and alveolar bone loss were monitored, and the anti-inflammatory effects of Polycan were determined by measuring the levels of myeloperoxidase (MPO), interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in gingival tissue. We also evaluated inducible nitric oxide synthase (iNOS) activity and malondialdehyde (MDA) concentrations as a measure of the antioxidant effect.. Ligature placement led to a marked decrease in body weight, increased alveolar bone loss and increased concentrations of MPO, IL-1β, TNF-α and MDA, as well as increased iNOS activity and inflammatory cell infiltration and decreased collagen-fiber content. Histological examination revealed increases in the number and activity of osteoclast cells, decreases in alveolar bone volume and elevated percentages of osteclasts on the alveolar bone surface. Daily oral treatment with 42.5 or 85 mg/kg of Polycan for 10 d led to significant, dose-dependent inhibition of the effect of ligature placement.. Taken together, these results suggest that 10 d of oral treatment with Polycan effectively inhibits ligature placement-induced periodontitis and related alveolar bone loss via an antioxidant effect.

Topics: Alveolar Bone Loss; Animals; Antioxidants; beta-Glucans; Body Weight; Gingiva; Interleukin-1beta; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Oxidative Stress; Periodontitis; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Conventional dendritic cells (cDCs) have been reported to participate in the pathophysiology of acute lung injury (ALI). Fms-like tyrosine kinase 3 (FLT3) signaling represents a highly specific pathway for the manipulation of cDCs in vivo. The purpose of this study was to clarify the effect of FLT3 signaling on the accumulation and maturation of pulmonary cDCs, and whether inhibition of FLT3 signaling may attenuate acute lung inflammation and lung injury. C57BL/6 mice were pretreated with FLT3-ligand (FLT3L) and lestaurtinib separately for five consecutive days. A murine model of ALI was subsequently generated by intra-tracheal instillation of lipopolysaccharide (LPS) and lung specimens were harvested 24 h later. Flow cytometry was conducted to measure the accumulation and maturation of pulmonary cDCs. IL-6, IFN-γ, IL-4, MPO activity and transcription factor T-bet/GATA-3 mRNA ratio were quantified to evaluate lung inflammation. Lung injury was estimated by lung wet weight/body weight ratio (LWW/BW) and histopathological analysis. LPS challenge resulted in rapid accumulation and maturation of pulmonary cDCs. FLT3L pretreatment further stimulated the accumulation and maturation of pulmonary cDCs, leading to a markedly increased LWW/BW and aggravated lung histopathology. Meanwhile, lung MPO activity, T-bet/GATA-3 mRNA ratio and concentrations of IL-6 and IFN-γ were elevated by FLT3L administration. In contrast, lestaurtinib pretreatment inhibited the accumulation and maturation of pulmonary cDCs, leading to a significantly decreased LWW/BW and improved lung histopathology. Lestaurtinib administration also suppressed lung MPO activity, T-bet/GATA-3 mRNA ratio and production of IL-6 and IFN-γ. Our findings show that FLT3 signaling ameliorates ALI by regulating the accumulation and maturation of pulmonary cDCs, suggesting an innovative pharmacotherapy for ALI.

Topics: Acute Lung Injury; Animals; Body Weight; Carbazoles; Cytokines; Dendritic Cells; fms-Like Tyrosine Kinase 3; Furans; GATA3 Transcription Factor; Gene Expression; Lipopolysaccharides; Lung; Lymphocyte Count; Male; Mice; Mice, Inbred C57BL; Organ Size; Peroxidase; Protein Kinase Inhibitors; RNA, Messenger; Signal Transduction; T-Box Domain Proteins

Acute pancreatitis (AP) is a complicated inflammatory disease that has an unknown underlying pathogenesis. Because alpha-pinene can modulate inflammation, we examined whether alpha-pinene plays a role in AP.. Alpha-pinene was administered intraperitoneally 1h prior to the first injection of cerulein. Once AP developed, cerulein, a stable cholecystokinin analog, was injected hourly over a 6-h period. Blood samples were taken 6h later to determine serum amylase and lipase levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. We also isolated the pancreatic acinar cells using a collagenase solution. Cell viability, and cytokine productions were measured in pancreatic acini.. Intraperitoneal administration of alpha-pinene reduced the pancreatic weight (PW) to body weight (BW) ratio and the serum levels of amylase and lipase. Alpha-pinene treatment also reduced histological damage and myeloperoxidase activity in the pancreas and lungs. Furthermore, alpha-pinene pretreatment reduced the production of pancreatic tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 during cerulein-induced AP. In vitro, alpha-pinene inhibited cerulein-induced cell death and cytokine production in isolated cerulein-treated pancreatic acinar cells.. These findings suggest that alpha-pinene has an anti-inflammatory effect during cerulein-induced AP.

Topics: Acute Disease; Amylases; Animals; Bicyclic Monoterpenes; Body Weight; Cells, Cultured; Ceruletide; Female; Immunologic Factors; Injections, Intraperitoneal; Lipase; Lung; Mice; Mice, Inbred C57BL; Monoterpenes; Pancreas; Pancreatitis; Peroxidase

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potential therapeutic peptide with anti-inflammatory and anti-oxidative effects. In order to increase the efficiency of traversing biological barriers, a novel fusion peptide PACAP-TAT was produced by tagging PACAP at its C-terminus with 11-amino acid TAT protein transduction domain. The results of characteristic assays showed that PACAP-TAT activated PACAP specific receptor PAC1 with the same potency as PACAP and PACAP-TAT crossed blood-brain barrier (BBB), blood-air barrier (BAB) and blood-testis barrier (BTB) with the efficiency about 2.5-fold higher than that of PACAP. Both PACAP-TAT and PACAP were used treat the mice with lung injury induced by repeated smoke inhalation. It was shown that both PACAP-TAT and PACAP decreased the mortality, increased the body weight and inhibited the edema and vascular permeability in the lungs of the mice received repeated smoke inhalation, while PACAP-TAT displayed more marked effects than PACAP. PACAP-TAT decreased myeloperoxidase (MPO) activity, increased catalase (CAT) activity and down-regulated interleukin 6 (IL-6) and malondialdehyde (MDA) levels in the lungs with a significantly higher efficiency than PACAP. The histopathological analysis also showed that PACAP-TAT attenuated the cell filtration and bronchi epithelial hyperplasia more significantly than PACAP. Moreover the leukocyte count in blood and the serum superoxide dismutase (SOD) activity in the mice treated with PACAP-TAT were significantly different from that in mice treated with PACAP (p<0.05). All these data indicated that PACAP-TAT with increased traversing ability was more effective than PACAP in protecting the mice from the lung injury induced by repeated smoke inhalation.

Topics: Animals; Blood-Air Barrier; Blood-Brain Barrier; Blood-Testis Barrier; Body Weight; Catalase; CHO Cells; Cricetinae; Cricetulus; Gene Products, tat; Lung Injury; Male; Mice; Oxidative Stress; Peroxidase; Pituitary Adenylate Cyclase-Activating Polypeptide; Pulmonary Edema; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Recombinant Fusion Proteins; Smoke Inhalation Injury

Dextran sulfate sodium (DSS)-induced colitis is an experimental model of ulcerative colitis, although the precise mechanism has not yet been elucidated. We investigate whether Zn deficiency affects the pathogenesis of colitis induced by DSS with a focus on immune responses. Male WKAH/Hkm Slc rats were fed either a Zn-adequate (ZA, 30 mg Zn/kg diet) as a control or Zndeficient (ZD, 5 mg Zn/kg diet) diet for 21 days and then treated with 2% DSS via deionized drinking water for 7 days. The disease activity index (DAI) was recorded daily throughout DSS treatment. Serum Zn concentrations were significantly lowered in rats fed the ZD diet than those fed the ZA diet at day 7 and 14. Surprisingly, DSS treatment considerably reduced the serum Zn in both groups. The rats fed the ZD diet showed exacerbated colitis based on clinical outcomes, including weight loss, increased DAI, and shortened colon length. An in vitro study corroborated these results, showing that a large amount of TNFα was induced by rat mesenteric leukocytes in response to lipopolysaccharide in ZD medium, but not in ZA medium. These results indicate that a modulation of TNFα production due to Zn deficiency influences disease activity in DSS-induced colitis. In addition, more attention should be given to Zn for prevention of colitis.

Topics: Animals; Body Weight; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Diet; Disease Models, Animal; Femur; Liver; Male; Organ Size; Peroxidase; Rats; Severity of Illness Index; Zinc

In human pathology, the "creeping fat" (CF) of the mesentery is unique to Crohn's disease (CD). CF is usually referred to as an ectopic extension of mesenteric adipose tissue (MAT). However, since no animal model developing CF has ever been established, very little is known about this type of fat-depot expansion and its role in the development of the disease.. We developed and standardized an experimental protocol in mice that reproducibly induces CF development when a severe colonic inflammation is obtained by intracolonic instillation of DNBS.. Macro-microscopic observations revealed a fatty appearance of CF. Yet when compared to MAT from the same animals, CF contains very little triglycerides, few adipocytes, and we observed a very low expression and protein levels of both adipose markers (hormone-sensitive lipase, perilipin) and adipocytokines (leptin, adiponectin). The decreased expression of perilipin in CF was also observed by immunohistochemistry. Conversely, the expression of proinflammatory and fibrous markers (Pref-1) was much higher in CF than in MAT. These observations were fully consistent with those made on CF recovered from five CD patients and compared with subcutaneous and mesenteric fat from the same patients.. Altogether, this work reports an original experimental mice model of CF. In this model we establish for the first time that CF only occurs in severe colonic inflammation and shows an inflammatory, fibrous but not an adipose pattern.

Topics: Adipose Tissue; Animals; Blotting, Western; Body Weight; Colitis; Crohn Disease; Dinitrofluorobenzene; Enzyme-Linked Immunosorbent Assay; Humans; Immunoenzyme Techniques; Lipids; Male; Mesentery; Mice; Mice, Inbred BALB C; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Dietary supplementation of n-3 PUFAs, containing docosahexaenoic acid (DHA), modulates the symptoms of colitis. Hence, we investigated the effects of oral administration of pure DHA and the therapeutic agent sulfasalazine (SAL) on chemically induced colitis in mice, and analyzed the expression levels of DHA-responsive genes in colonic tissue using cDNA arrays.. Colitis in BALB/c mice was induced by feeding 5% dextran sulfate sodium (DSS) in drinking water for 7 days. DHA (30 mg/kg/day, DHA) or SAL (100 mg/kg/day, SAL) was administered orally throughout the treatment along with DSS. The DHA-treated group showed significant reduction of the weight loss and colon shortening compared to the DSS-treated colitis group. In contrast, SAL treatment was effective in reducing colon shortening, stool consistency and bleeding scores. DHA and SAL treatments also significantly reduced the changes in inflammation of the colon, and reversed the increase in myeloperoxidase activity induced by DSS. Among DSS-responsive genes, those for inflammatory cytokines (IL-1β, CD14 antigen and tumor necrosis factor receptor superfamily, member 1b), membrane remodeling genes (matrix metalloproteinase-3, -10 and -13) and acute phase proteins (S100 calcium-binding protein A8), which were increased by DSS, were downregulated by DHA or SAL treatment.. DHA was effective in alleviating DSS-induced colitis in mice, partly by modulating the expression levels of genes involved in colitis.

Topics: Acute-Phase Proteins; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Colitis; Colon; Dextran Sulfate; Docosahexaenoic Acids; Gene Expression Regulation; Inflammation Mediators; Intestinal Mucosa; Irritants; Male; Mice; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Peroxidase; Random Allocation; RNA, Messenger; Severity of Illness Index; Sulfasalazine

We examined the effects of calcium gluconate, an anti-inflammatory calcium salt, on ligature-induced experimental periodontitis and related alveolar bone loss. Calcium gluconate was orally administered daily for 10 days at 250, 125 or 62.5 mg/kg, beginning 1 day after ligation. We recorded changes in body-weight and alveolar bone loss and quantified the anti-inflammatory effects of calcium gluconate by measuring levels of myeloperoxidase (MPO), IL-1β and TNF-α. We also evaluated inducible nitric oxide synthase (iNOS) activity and malondialdehyde (MDA) concentration as a measure of antioxidant effects. Ligature placement produced a marked decrease in body-weight, increased alveolar bone loss, and led to increased MPO, IL-1β, TNF-α and MDA concentrations, as well as elevated iNOS activity, increased inflammatory cell infiltration and decreased collagen fibre content in gingival tissue. Histopathology revealed decreased alveolar bone volume, increased osteoclast cell numbers and activity, and an elevated percentage of osteclasts on the alveolar bone surface. The effects of ligature placement were significantly and dose-dependently inhibited by 10 days of daily oral treatment with 250 and 125 mg/kg of calcium gluconate. The results suggest that 10 days daily oral treatment with calcium gluconate effectively inhibits ligature placement-induced periodontitis and related alveolar bone loss via antioxidant effects.

Topics: Alveolar Bone Loss; Analysis of Variance; Animals; Anti-Inflammatory Agents; Body Weight; Calcium Gluconate; Gingiva; Indomethacin; Interleukin-1beta; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Osteoclasts; Periodontitis; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Distinct roles of the two T cell G protein-coupled receptors for vasoactive intestinal peptide (VIP), termed VPAC1 and VPAC2, in VIP regulation of autoimmune diseases were investigated in the dextran sodium sulfate (DSS)-induced murine acute colitis model for human inflammatory bowel diseases. In mice lacking VPAC2 (VPAC2-KO), DSS-induced colitis appeared more rapidly with greater weight loss and severe histopathology than in wild-type mice. In contrast, DSS-induced colitis in VPAC1-KO mice was milder than in wild-type mice and VPAC2-KO mice. Tissues affected by colitis showed significantly higher levels of myeloperoxidase, IL-6, IL-1β and MMP-9 in VPAC2-KO mice than wild-type mice, but there were no differences for IL-17, IFN-γ, IL-4, or CCR6. Suppression of VPAC1 signals in VPAC2-KO mice by PKA inhibitors reduced the clinical and histological severity of DSS-induced colitis, as well as tissue levels of IL-6, IL-1β and MMP-9. Thus VIP enhancement of the severity of DSS-induced colitis is mediated solely by VPAC1 receptors.

Topics: Animals; Body Weight; Colitis; Colon; Cyclic AMP-Dependent Protein Kinases; Dextran Sulfate; Disease Models, Animal; Female; Forkhead Transcription Factors; Gene Expression; Interleukin-17; Interleukin-1beta; Interleukin-6; Intestinal Mucosa; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Peroxidase; Protein Kinase Inhibitors; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Signal Transduction; T-Lymphocytes, Regulatory; Vasoactive Intestinal Peptide

This study sought to define the mechanism by which PPAR-γ ligands affect the course of experimentally induced colitis in rats.. Inflammation was induced in Wistar rats by a single rectal administration of 2,4,6,-trinitrobenzene sulfonic acid (TNBS). The antagonist of PPARγ antagonist, bisphenol A diglycidyl ether (BADGE), was administrated intraperitoneally 120 mg/kg 4 times every other day. Rosiglitazone 8 mg/kg was administrated by gastric tube 4 times. Body weight was measured daily. After killing, the large intestinal tissue was weighed and collected for histopathologic and immunoenzymatic tests. Levels of IL-6, IL-10, and myeloperoxidase (MPO) were determined in serum and in intestinal homogenates.. Rats receiving rosiglitazone had higher body weight, whereas large intestine weight/length ratio was lower; histology showed fewer inflammatory markers. Rats receiving TNBS and TNBS along with BADGE had more intensive inflammatory changes. Rosiglitazone alone decreased expression of IL-6; used with TNBS it decreased expression of MPO in intestinal tissue, yet did not increase the expression of IL-10. Decreased levels of MPO indicate reduced neutrophil-dependent immune response. The antagonist of PPAR-γ increased IL-6 in serum and decreased IL-10 in intestinal homogenates. Bisphenol A diglycidyl ether administrated to healthy animals increases serum IL-6 levels.. Rosiglitazone inhibits experimental inflammation; administration of its selective antagonist abolishes this protective influence. Rosiglitazone inhibits expression of proinflammatory IL-6 and does not affect IL-10. Agonists of PPARs-γ are possibilities for inflammatory bowel disease prevention. Exogenous substances blocking PPARs-γ may contribute to development or relapse of nonspecific inflammatory bowel diseases.

Topics: Animals; Body Weight; Colitis; Colon; Interleukin-10; Interleukin-6; Organ Size; Peroxidase; PPAR gamma; Rats; Rats, Wistar; Tissue Extracts

To evaluate potential effect modifications on the association between BMI and thyrotropin (TSH) by smoking, race, and menopausal status among euthyroid women.. A cross-sectional population-based study was carried out in the city of Rio de Janeiro, Brazil, in 2004-2005. Households (1,500) were selected using three-stage probability sampling. A sample of 1,084 women aged 35 years or older and with TSH values within the reference range (0.3-4.0 mIU/l) was investigated. Weight and height were measured at household and blood collected for serum TSH and anti-thyroperoxidase (anti-TPO) antibody analysis.. Overall, BMI was positively and significantly associated with serum TSH (β = 0.87; p = 0.001). This association was modified by smoking, race, and menopausal status (p < 0.05). Adjusted regression coefficients were 1.78 versus 0.58 comparing smokers with non-smokers, 1.39 for Blacks compared to 0.79 for Non-Blacks, and 0.70 for women in menopause compared to 1.04 for premenopausal women. The percentage of high anti-TPO (greater than 35 UI/ml) was 8.8%, and the association between TSH and BMI was no longer significant in this group.. BMI was positively associated with serum TSH specifically in its normal range, but only for those women who tested negative for anti-TPO. Smoking and race are negatively associated with anti-TPO, possibly explaining the effect modification observed.

Topics: Adult; Aged; Autoantibodies; Black People; Body Mass Index; Body Weight; Brazil; Cross-Sectional Studies; Female; Humans; Menopause; Middle Aged; Peroxidase; Racial Groups; Reference Values; Smoking; Thyrotropin; White People

Vitamin deficiencies are common in patients with inflammatory bowel disease (IBD). Homocysteine (Hcys) is a thrombogenic amino acid produced from methionine (Met), and its increase in patients with IBD indicates a disruption of Met metabolism; however, the role of Hcys and Met metabolism in IBD is not well understood. We hypothesized that disrupted Met metabolism from a B-vitamin-deficient diet would exacerbate experimental colitis. Mice were fed a B(6)-B(12)-deficient or control diet for 2 wk and then treated with dextran sodium sulfate (DSS) to induce colitis. We monitored disease activity during DSS treatment and collected plasma and tissue for analysis of inflammatory tissue injury and Met metabolites. We also quantified Met cycle activity by measurements of in vivo Met kinetics using [1-(13)C-methyl-(2)H(3)]methionine infusion in similarly treated mice. Unexpectedly, we found that mice given the B-vitamin-deficient diet had improved clinical outcomes, including increased survival, weight maintenance, and reduced disease scores. We also found lower histological disease activity and proinflammatory gene expression (TNF-α and inducible nitric oxide synthase) in the colon in deficient-diet mice. Metabolomic analysis showed evidence that these effects were associated with deficient B(6), as markers of B(12) function were only mildly altered. In vivo methionine kinetics corroborated these results, showing that the deficient diet suppressed transsulfuration but increased remethylation. Our findings suggest that disrupted Met metabolism attributable to B(6) deficiency reduces the inflammatory response and disease activity in DSS-challenged mice. These results warrant further human clinical studies to determine whether B(6) deficiency and elevated Hcys in patients with IBD contribute to disease pathobiology.

Topics: Analysis of Variance; Animals; Body Weight; Colitis; Dextran Sulfate; Gene Expression; Glutathione; Homocysteine; Inflammation; Interleukin-10; Kaplan-Meier Estimate; Male; Metabolomics; Methionine; Methylmalonic Acid; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Peroxidase; Pyridoxal Phosphate; S-Adenosylhomocysteine; Severity of Illness Index; Tumor Necrosis Factor-alpha; Vitamin B 12 Deficiency; Vitamin B 6 Deficiency

In this study, we report that α,β-amyrin, a plant-derived pentacyclic triterpene, reduced persistent inflammatory and neuropathic hyperalgesia in mice by a direct activation of the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R). The oral treatment with α,β-amyrin (30 mg/kg) significantly reduced mechanical and thermal hyperalgesia and inflammation induced by complete Freund's adjuvant (CFA) and by partial sciatic nerve ligation (PSNL). The pretreatment with either CB(1)R or CB(2)R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of α,β-amyrin. Of note, binding studies showed that α,β-amyrin directly bound with very high affinity to CB(1)R (K(i)=0.133 nM) and with a lower affinity to CB(2)R (K(i)=1989 nM). Interestingly, α,β-amyrin, ACEA (CB(1)R agonist), or JWH-133 (CB(2)R agonist), at doses that caused antinociception, failed to provoke any behavioral disturbance, as measured in the tetrad assay. In addition, α,β-amyrin largely decreased interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), keratinocyte-derived chemokine (KC) and interleukin 6 (IL-6) levels, and myeloperoxidase activity. Likewise, α,β-amyrin prevented the activation of the transcriptional factors: nuclear factor κB (NF-κB) and cyclic adenosine monophosphate response element binding (CREB) and the expression of cyclooxygenase 2 in mice footpads and spinal cords. The present results demonstrated that α,β-amyrin exhibits long-lasting antinociceptive and anti-inflammatory properties in 2 models of persistent nociception via activation of cannabinoid receptors and by inhibiting the production of cytokines and expression of NF-κB, CREB and cyclooxygenase 2.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Area Under Curve; Body Weight; Cyclohexanols; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Edema; Enzyme-Linked Immunosorbent Assay; Freezing Reaction, Cataleptic; Hyperalgesia; Inflammation; Locomotion; Male; Mice; Neuralgia; Oleanolic Acid; Oligodeoxyribonucleotides, Antisense; Pain Threshold; Pentacyclic Triterpenes; Peroxidase; Protein Binding; Rats; Rats, Wistar; Receptors, Cannabinoid; Tritium

Agent solubility is a problem for aspiration of agents into lungs for chemopreventive efficacy evaluation, since many agents have to be dissolved in solvents. These solvents may be toxic to the lung epithelium. A study was conducted in female A/J mice to determine toxicity of different solvent concentrations by using saline, dimethyl sulfoxide (DMSO), ethanol, polyethylene glycol 400 (PEG-400), and labrasol for 1, 5, and 28 days via aspiration route. Toxicity was determined by measuring changes in body weight and bronchoalveolar lavage fluid (BALF). No significant difference was observed in body weight, differential cell counts, lactate dehydrogenase (LDH) and total protein in all solvent groups compared to saline by 28 days except 50% ethanol. However, myeloperoxidase (MPO) and macrophage inflammatory protein-2 (MIP-2) showed significant increase in 2% and 10% DMSO, 10% ethanol, 0.1% and 2% PEG-400, and 1% labrasol by longer dosing. All solvents except for 10% ethanol and 2% PEG-400 are suitable for agent aspiration.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Chemokine CXCL2; Epithelium; Female; Inhalation Exposure; L-Lactate Dehydrogenase; Lung; Mice; Peroxidase; Solvents

Tumour necrosis factor (TNF)-α plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wild-type counterparts. TNF-R1(-/-) mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2(-/-) and TNF-R1(-/-) TNF-R2(-/-) (TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1(-/-) mice after TNBS, instead of TNF-R2(-/-) and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1(-/-) or TNF-R2(-/-) mice correlated with lower amounts of interleukin (IL)-6, IL-1β, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-γ production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-κB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Body Weight; Chemokines; Colitis, Ulcerative; Colon; Cytokines; Edema; Gene Expression; Granulocytes; I-kappa B Proteins; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Monocytes; Neutrophils; NF-KappaB Inhibitor alpha; Organ Size; Peroxidase; Proto-Oncogene Proteins c-bcl-2; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Spleen; Survival Analysis; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Although adrenomedullin (AM) is known to ameliorate inflammatory processes, few data exist regarding the effect of AM on inflammatory colitis. Therefore, we examined the effect of AM on inflammatory response in vitro and in vivo colitis model.. In mice experimental colitis induced by 3% dextran sulfate sodium (DSS) in drinking water for 7 days, AM with 225-900 μg/kg in 0.5 ml of saline or saline alone were given intraperitoneally once a day. In the in vitro experiment, we determined the cytokine response in THP-1 cell activated by lipopolysaccharide with or without AM of 10 nM. Additionally, we performed wound healing assay in Caco-2 cell interfered by DSS with or without AM of 100 nM.. In the colitis model, AM significantly reduced the disease activity index, histological score, and local production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in accordance with reduction of serum amyloid A levels. Secretion of TNF-α in lipopolysaccharide-stimulated THP-1 cells was significantly reduced in the presence of AM. The distance of wound healing interfered by 0.25% DSS was significantly improved in the presence of AM of 100 nM.. These results demonstrate that AM could ameliorate DSS-induced experimental colitis possibly through suppression of systemic and local production of cytokines such as TNF-α, associated with acceleration of ulcer reepithelialization and colon tissue regeneration.

Topics: Adrenomedullin; Animals; Body Weight; Cell Line; Cell Movement; Colitis; Colon; Cytokines; Dextran Sulfate; Epithelium; Humans; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Peroxidase; Serum Amyloid A Protein; Ulcer; Up-Regulation

Ulcerative colitis is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration and up-regulation of pro-inflammatory cytokines. The aim of this study is to evaluate the effect of taurohyodeoxycholic acid (THDCA) isolated from Pulvis Fellis Suis on acute ulcerative colitis model induced by trinitrobenzene sulfonic acid (TNBS) in mice. The efficacy of THDCA was studied by macroscopical and histological scoring systems as well as myeloperoxidase (MPO) activity. Serum levels, including tumor necrosis factor (TNF)-α and interleukin (IL)-6 were assayed by enzyme-linked immunoassay. The expression of cyclooxygenase (COX)-2 in the colons was assessed by immunohistochemical analysis. Treatment with THDCA in doses of 25, 50 and 100mg/kg/day and sulfasalazine in a dose of 500 mg/kg/day used as reference for 7 consecutive days after the induction of colitis, significantly decreased colonic MPO activity, TNF-α, IL-6 serum levels and the expression of COX-2 in colon compared with TNBS induced ulcerative colitis model group. Moreover, THDCA attenuated the macroscopic colonic damage and the histopathological changes induced by TNBS. All the effects of these parameters were comparable to that of the standard sulfasalazine, especially at the highest dose level. The results suggested that THDCA from Pulvis Fellis Suis has a protective effect in TNBS-induced ulcerative colitis which might be due to its anti-inflammatory activities, and that it may have therapeutic value in the setting of inflammatory bowel disease.

Topics: Animals; Body Weight; Colitis, Ulcerative; Colon; Drugs, Chinese Herbal; Gene Expression Regulation; Male; Mice; Peroxidase; Taurodeoxycholic Acid; Trinitrobenzenesulfonic Acid

Resveratrol, a polyphenol compound with anti-inflammatory properties, has been previously evaluated for its beneficial effects in several ulcerative colitis models. However, the current study elucidates the effect of resveratrol on adhesion molecules, as well as its antioxidant efficacy in a trinitrobenzene sulfonic acid (TNBS)-induced ulcerative-colitis model. Colitis was induced by rectal instillation of TNBS, followed by daily per os administration of either sulphasalazine (300 mg/kg) or resveratrol (2 and 10 mg/kg) for 7 days. Administration of resveratrol decreased the ulcerative area and colon mass index; these effects were further supported by the reduction in colon inflammation grades, as well as histolopathological changes, and reflected by the stalling of body mass loss. The anti-inflammatory effects of resveratrol were indicated by lowered myeloperoxidase activity, and by suppressing ICAM-1 and VCAM-1 levels in the colon and serum. In addition, it restored a reduced colonic nitric oxide level and reinstated its redox balance, as evidenced by the suppression of lipid peroxides and prevention of glutathione depletion. The anti-ulcerative effect of the higher dose of resveratrol was comparable with those of sulphasalazine. The study confirms the anti-ulcerative effect of resveratrol in TNBS-induced experimental colitis via reduction of neutrophil infiltration, inhibition of adhesive molecules, and restoration of the nitric oxide level, as well as the redox status.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cell Adhesion Molecules; Colitis, Ulcerative; Colon; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glutathione; Inflammation; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Peroxidase; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfasalazine; Trinitrobenzenesulfonic Acid; Vascular Cell Adhesion Molecule-1

omega 3 polyunsaturated fatty acids have anti-inflammatory properties and can be beneficial in the treatment of inflammatory diseases, such as ulcerative colitis. Dextran sodium sulphate (DSS) colitis in rats appears to mimic nearly all of the morphological characteristics and lesion distributions of ulcerative colitis. The purpose of the current study was to investigate the efficacy of omega 3 fatty acids in the treatment of experimental ulcerative colitis.. thirty-six Wistar rats were randomly assigned to group A or group B receiving 5% dextran sulfate sodium (DSS) in their drinking water for eight days. For the next eight days post-DSS, group A animals received tap-water, and group B animals were fed a nutritional solution containing high levels of omega 3 polyunsaturated fatty acids (ProSure®, Abbott Laboratories, Zwolle, Netherlands) once per day, administrated with a orogastric feeding tube.. animals fed an omega 3 rich diet exhibited a statistically significant increase in hematocrit and hemoglobin levels, compared to animals drinking tap water, and a trend towards histopathological and clinical improvement, with the administration of omega 3 fatty acids ameliorating epithelial erosion by day 8 post-DSS, but no statistically significant difference was observed between group A and group B animals at 4 or 8 days post-DSS. Also, a statistically significant increase in neutrophil infiltration was observed, as depicted by myelohyperoxidase activity.. our findings support a positive role of omega 3 polyunsaturated fatty acids supplementation in an experimental model of ulcerative colitis despite the increased colonic neutrophil infiltration. Further studies are needed in order to investigate the role of increased neutrophils in colonic mucosa.

Topics: Animals; Blood Cell Count; Body Weight; Colitis, Ulcerative; Colon; Dextran Sulfate; Fatty Acids, Omega-3; Immunohistochemistry; Intestinal Mucosa; Male; Neutrophil Infiltration; Peroxidase; Rats; Rats, Wistar; Tissue Fixation

A feeding trial was conducted for 40 days to delineate the effect of treatment with probiotics as water additives on tilapia (Oreochromis niloticus) growth performance and immune response. About 360 juveniles were randomly distributed into four treatment groups, each with three replicates. Different probiotics (T-1, Bacillus subtilis B10; T-2, Bacillus coagulans B16; T-3, Rhodopseudomonas palustris G06) were added to the water of tanks at final concentration of 1 x 10(7) cfu ml(-1) every 2 days, with no probiotic added to control tanks. At the end of the feeding trial, fish treated with B. coagulans B16 (T-2) and R. palustris G06 (T-3) had significantly (P < 0.05) higher final weight, daily weight gain, and specific growth rate compared with those treated with B. subtilis B10 (T-1) and those without probiotics (control). The highest (P < 0.05) content of total serum protein was found in T-2 compared with that in T-1, T-3, and the control. However, albumin concentration and albumin/globulin ratio were not affected by the probiotics treatments. Compared with the control, probiotic supplementation remarkably improved activities of superoxide dismutase and catalase (P < 0.05). T-2 fish exhibited higher average myeloperoxidase activity than the control, T-1, and T-3 groups. Regarding serum lysozyme content in tilapia, assays showed no difference (P > 0.05) among the treatment groups. Furthermore, probiotics treatments remarkably increased respiratory burst activity compared with control, with T-2 showing higher values than T-1 and T-3. This indicated that treatment with probiotics, B. coagulans B16 and R. palustris G06, as water additives could be used to enhance immune and health status, thereby improving growth performance of O. niloticus.

Topics: Analysis of Variance; Animals; Aquaculture; Blood Proteins; Body Weight; Case-Control Studies; Catalase; Cichlids; Peroxidase; Probiotics; Serum Albumin; Species Specificity; Superoxide Dismutase; Water Microbiology

Recent studies have demonstrated an essential role of alveolar macrophages during influenza virus infection. Enhanced mortalities were observed in macrophage-depleted mice and pigs after influenza virus infection, but the basis for the enhanced pathogenesis is unclear. This study revealed that blocking macrophage recruitment into the lungs in a mouse model of influenza pneumonitis resulted in enhanced alveolar epithelial damage and apoptosis, as evaluated by histopathology, immunohistochemistry, Western blot, RT-PCR, and TUNEL assays. Abrogation of macrophage recruitment was achieved by treatment with monoclonal antibody against monocyte chemoattractant protein-1 (MCP-1) after sub-lethal challenge with mouse-adapted human influenza A/Aichi/2/68 virus. Interestingly, elevated levels of hepatocyte growth factor (HGF), a mitogen for alveolar epithelium, were detected in bronchoalveolar lavage samples and in lung homogenates of control untreated and nonimmune immunoglobulin (Ig)G-treated mice after infection compared with anti-MCP-1-treated infected mice. The lungs of control animals also displayed strongly positive HGF staining in alveolar macrophages as well as alveolar epithelial cell hyperplasia. Co-culture of influenza virus-infected alveolar epithelial cells with freshly isolated alveolar macrophages induced HGF production and phagocytic activity of macrophages. Recombinant HGF added to mouse lung explants after influenza virus infection resulted in enhanced BrdU labeling of alveolar type II epithelial cells, indicating their proliferation, in contrast with anti-HGF treatment showing significantly reduced epithelial regeneration. Our data indicate that inhibition of macrophage recruitment augmented alveolar epithelial damage and apoptosis during influenza pneumonitis, and that HGF produced by macrophages in response to influenza participates in the resolution of alveolar epithelium.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; Blotting, Western; Body Weight; Bronchoalveolar Lavage Fluid; Cell Proliferation; Cells, Cultured; Chemokine CCL2; Chemokine CXCL1; Chemotaxis, Leukocyte; Coculture Techniques; Disease Models, Animal; Female; Hepatocyte Growth Factor; Humans; Hyperplasia; Immunohistochemistry; In Situ Nick-End Labeling; Influenza A virus; Injections, Intraperitoneal; Macrophages, Alveolar; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Peroxidase; Pneumonia, Viral; Pulmonary Alveoli; Recombinant Proteins; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Viral Load

Nardostachys jatamansi belonging to the family Valerianaceae has been used as a remedy for stomach and skin ailments in Korea. The effect of N. jatamansi on acute pancreatitis (AP) has not been defined. Therefore, we investigated the effect of N. jatamansi on cerulein-induced AP.. In the pretreatment group, N. jatamansi was administered orally to mice at 10 and 20 mg/kg for 5 days, and the mice were intraperitoneally injected with the stable cholecystokinin analogue cerulein hourly for 6 hours. In the posttreatment group, cerulein was injected hourly for 6 hours, and N. jatamansi was administered at the indicated time (1, 3, and 5 hours after the first cerulein injection) and dose (10 and 20 mg/kg) during the cerulein injection. Blood samples were taken 6 hours later to determine the serum amylase, the lipase, and the cytokine levels. The pancreas and the lung were rapidly removed for morphologic examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction.. Nardostachys jatamansi treatment attenuated the AP, as shown by the histological examination results of the pancreas and the lung, reductions in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and messenger RNA expressions of inflammatory mediators.. These results suggest that N. jatamansi attenuates the severity of AP and pancreatitis-associated lung injury.

Topics: Acute Disease; Amylases; Animals; Body Weight; Cell Survival; Cells, Cultured; Ceruletide; Cytokines; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Female; Lipase; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Nardostachys; Organ Size; Pancreas; Pancreatitis; Peroxidase; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction

The present study investigated the preventive effect of eugenol, a naturally occurring food flavouring agent on thioacetamide (TA)-induced hepatic injury in rats. Adult male Wistar rats of body weight 150-180 g were used for the study. Eugenol (10.7 mg/kg b.w./day) was administered to rats by oral intubation for 15 days. TA was administered (300 mg/kg b.w., i.p.) for the last 2 days at 24h interval and the rats were sacrificed on the 16th day. Markers of liver injury (aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyl transferase and bilirubin), inflammation (myeloperoxidase, tumor necrosis factor-alpha and interleukin-6), oxidative stress (lipid peroxidation indices, protein carbonyl and antioxidant status) and cytochrome P4502E1 activity were assessed. Expression of cyclooxygenase-2 (COX-2) and the extent of DNA damage were analyzed using immunoblotting and comet assay, respectively. Liver injury and collagen accumulation were assessed using histological studies by hematoxylin and eosin and Masson trichrome staining. Rats exposed to TA alone showed increased activities of hepatocellular enzymes in plasma, lipid peroxidation indices, inflammatory markers and pro-inflammatory cytokines and decreased antioxidant status in circulation and liver. Hepatic injury and necrosis were also evidenced by histology. Eugenol pretreatment prevented liver injury by decreasing CYP2E1 activity, lipid peroxidation indices, protein oxidation and inflammatory markers and by improving the antioxidant status. Single-cell gel electrophoresis revealed that eugenol pretreatment prevented DNA strand break induced by TA. Increased expression of COX-2 gene induced by TA was also abolished by eugenol. These findings suggest that eugenol curtails the toxic effects of TA in liver.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blotting, Western; Body Weight; Chemical and Drug Induced Liver Injury; Comet Assay; Cyclooxygenase 2; Cytochrome P-450 CYP2E1; Cytokines; DNA Damage; Enzymes; Eugenol; Lipid Peroxidation; Liver; Male; Organ Size; Peroxidase; Protective Agents; Rats; Rats, Wistar; Thioacetamide

Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn's disease.. Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored.. For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients.. Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn's disease.

Topics: Adamantane; Aminosalicylic Acids; Animals; Body Weight; Colon; Crohn Disease; Disease Models, Animal; Drug Therapy, Combination; Enzyme Inhibitors; Epithelial Cells; Female; Gastrointestinal Agents; Humans; Interleukin-1beta; Leukocytes; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Phosphotransferases (Alcohol Group Acceptor); Prednisolone; Pyridines; Rats; Rats, Sprague-Dawley; Treatment Outcome; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Copper is known as Gunma Kaalan in Siddha literature, which means that the drug is effective for healing ulcers. The herbomineral drug "Thamira parpam" is prepared by calcining the purified copper foils with rock salt, lime juice, bracteated birth wort juice, and Alangium root decoction according to Siddha medicine. Our study investigated the possible role of Thamira parpam (TP) in the management of cysteamine-induced duodenal ulcers. Cysteamine (400 mg kg(-1) body weight(-1), two doses at 4 h interval) orally given to rats resulted in high ulcer index, increased TBARS with concomitant depletion of antioxidants such as superoxide dismutase, glutathione, glutathione peroxidase, and inflammatory markers cathepsin D, and myeloperoxidase (p < 0.01). Herbomineral drug TP (0.5, 1, and 2 mg/kg, p.o.) challenged with cysteamine attenuated the elevation of TBARS and imbalance of antioxidants. In the increases in liver inflammatory markers, tissue histopathology changes were not severe in TP treatment. Positive control omeprazole (25 mg/kg, body weight, orally) showed considerable protection against anomaly in biochemical parameters and tissue histology. Hence, our results indicate that the attenuation of oxidative stress by the herbomineral drug in experimentally induced damage to liver and duodenum of rats could be mediated by free radical quenching property.

Topics: Animals; Body Weight; Cathepsin D; Cysteamine; Duodenal Ulcer; Duodenum; Glutathione; Lipid Peroxidation; Liver; Oxidative Stress; Peroxidase; Plant Extracts; Radiation-Protective Agents; Rats; Superoxide Dismutase

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum. We examined the effect of AA in dextran sulfate sodium (DSS)-induced colitis. AA (100 mg/kg or 300 mg/kg) was administered p.o. daily for 7 days. AA significantly inhibited Disease Activity Index, histological score, and myeloperoxidase activity. Furthermore, AA markedly suppressed the protein expression of TNF-alpha, COX-2, NF-kappaB and chymase as well as the mRNA expression of TNF-alpha and COX-2. These results suggest that AA exerts beneficial effects in experimental colitis, and therefore we propose that this compound may have therapeutic implications for ulcerative colitis.

Topics: Animals; Blotting, Western; Body Weight; Chymases; Colitis, Ulcerative; Colon; Cyclooxygenase 2; Diarrhea; Diterpenes; Eleutherococcus; Female; Hemorrhage; Mice; Mice, Inbred BALB C; NF-kappa B; Peroxidase; Plant Roots; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha

HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is an orally bio-available synthetic derivative of naturally occurring androstene-3beta, 7beta, 17beta-triol. Our present data show that oral treatment with HE3286, favourably influenced the course of arthritis in the rat model of adjuvant-induced arthritis (reduced cumulative disease scores and paw edema), and in the mouse model of collagen antibody-induced arthritis (reduced clinical paw scores). Importantly, HE3286 was not immune suppressive in human mixed lymphocyte reaction or in animals challenged with Coxsackie B3 virus. HE3286 is currently in phase I/II clinical trials in rheumatoid arthritis and ulcerative colitis and these findings further strengthen the possibility that HE3286 may represent an effective anti-inflammatory agent useful for treating chronic inflammation with a more attractive safety profile than glucocorticoids or cyclooxygenase inhibitors.

Topics: Administration, Oral; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Body Weight; Dehydroepiandrosterone; Disease Models, Animal; Disease Progression; Enterovirus B, Human; Humans; Immunization; Interleukin-6; Lymphocyte Culture Test, Mixed; Male; Mice; Myocarditis; Organ Size; Peroxidase; Rats; Time Factors; Tumor Necrosis Factor-alpha

Consumption of diets high in fat and calories leads to hyperphagia and obesity, which is associated with chronic "low-grade" systemic inflammation. Ingestion of a high-fat diet alters the gut microbiota, pointing to a possible role in the development of obesity. The present study used Sprague-Dawley rats that, when fed a high-fat diet, exhibit either an obesity-prone (DIO-P) or obesity-resistant (DIO-R) phenotype, to determine whether changes in gut epithelial function and microbiota are diet or obese associated. Food intake and body weight were monitored daily in rats maintained on either low- or high-fat diets. After 8 or 12 wk, tissue was removed to determine adiposity and gut epithelial function and to analyze the gut microbiota using PCR. DIO-P but not DIO-R rats exhibit an increase in toll-like receptor (TLR4) activation associated with ileal inflammation and a decrease in intestinal alkaline phosphatase, a luminal enzyme that detoxifies lipopolysaccharide (LPS). Intestinal permeability and plasma LPS were increased together with phosphorylation of myosin light chain and localization of occludin in the cytoplasm of epithelial cells. Measurement of bacterial 16S rRNA showed a decrease in total bacterial density and an increase in the relative proportion of Bacteroidales and Clostridiales orders in high-fat-fed rats regardless of phenotype; an increase in Enterobacteriales was seen in the microbiota of DIO-P rats only. Consumption of a high-fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype.

Topics: Adiposity; Alkaline Phosphatase; Animals; Body Weight; Dietary Fats; Disease Susceptibility; Eating; Enteritis; Hyperphagia; Intestinal Mucosa; Intestines; Lipopolysaccharides; Male; Membrane Proteins; Metagenome; Obesity; Permeability; Peroxidase; Rats; Rats, Sprague-Dawley; Tight Junctions; Toll-Like Receptor 4

The specific purpose of this study was to evaluate the significant effects of medium-chain triglycerides (MCTs) and N-3 fatty acids on chemically induced experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. Male Wistar rats were fed liquid diets enriched with N-6 fatty acid (control diets), N-3 fatty acid (MCT- diets), and N-3 fatty acid and MCT (MCT+ diets) for 2 weeks and then were given an intracolonic injection of TNBS. Serum and tissue samples were collected 5 days after ethanol or TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase activity was measured in colonic tissues. Furthermore, protein levels for inflammatory cytokines and a chemokine were assessed by an enzyme-linked immunosorbent assay in colonic tissues. Induction of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the colon by TNBS enema was markedly attenuated by the MCT+ diet among the 3 diets studied. Furthermore, the induction of chemokines macrophage inflammatory protein-2 and monocyte chemotactic protein-1 also was blunted significantly in animals fed the MCT+ diets. As a result, MPO activities in the colonic tissue also were blunted significantly in animals fed the MCT+ diets compared with those fed the control diets or the MCT- diets. Furthermore, the MCT+ diet improved chemically induced colitis significantly among the 3 diets studied. Diets enriched with both MCTs and N-3 fatty acids may be effective for the therapy of inflammatory bowel disease as antiinflammatory immunomodulating nutrients.

Topics: Animal Feed; Animals; Body Weight; Chemokines; Colitis; Colon; Disease Models, Animal; Endotoxemia; Endotoxins; Enema; Enteral Nutrition; Fatty Acids, Omega-3; Male; Peroxidase; Rats; Rats, Wistar; Triglycerides; Trinitrobenzenesulfonic Acid

In this study, we evaluated the protective effect and therapeutic potential of the prostaglandin E(2) (PGE(2)) synthetic analog 16,16-dimethyl-PGE(2) (dmPGE(2)) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intratracheal administration of bleomycin (1 mg/kg) received a dmPGE(2) dose of 30 microg/kg/day by continuous subcutaneous infusion. Bronchoalveolar lavage (BAL); immunohistochemical analysis for IL-1, TNF-alpha, and nitrotyrosine; measurement of fluid content in lung; myeloperoxidase activity assay; and lung histology were performed 1 week later. Lung histology and Sircol assay for collagen deposition were performed 3 weeks after treatments. Changes of body weight and survival rate were also evaluated at 1 and 3 weeks. Compared with bleomycin-treated mice, dmPGE(2) co-treated mice exhibited a reduced degree of body weight loss and mortality rate as well as of lung damage and inflammation, as shown by the significant reduction of: (1) lung infiltration by leukocytes; (2) myeloperoxidase activity; (3) IL-1, TNF-alpha, and nitrotyrosine immunostaining; (4) lung edema; and (5) histologic evidence of lung injury and collagen deposition. In a separate set of experiments, dmPGE(2) treatment was started 3 days after bleomycin administration, and the evaluation of lung damage and inflammation was assessed 4 days later. Importantly, delayed administration of dmPGE(2) also was able to protect from inflammation and lung injury induced by bleomycin. These results, indicating that dmPGE(2) is able to prevent and to reduce bleomycin-induced lung injury through its regulatory and anti-inflammatory properties, encourage further research to find new options for the treatment of pulmonary fibrosis.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Collagen; Disease Models, Animal; Infusions, Subcutaneous; Interleukin-1beta; Lung; Lung Injury; Male; Mice; Peroxidase; Pneumonia; Protective Agents; Pulmonary Edema; Pulmonary Fibrosis; Time Factors; Tumor Necrosis Factor-alpha; Tyrosine

Morbid obesity (body mass index (BMI)> or =40 kg/m(2)) is associated with thyroid function disturbances, with a high rate of subclinical hypothyroidism (SH) being the most consistently reported. We evaluated the circulating thyroid function parameters in morbid obese patients and related the results to the presence of circulating thyroid antibodies (Thyr-Ab).. Morbid obese patients were consecutively enrolled (n=350). Two control groups were used: control group (CG)1, healthy normo-weight subjects (n=50); CG2, normo-weight patients with SH (n=56) matched for TSH with the obese patients with SH. Serum levels of free triiodothyronine (FT(3)), free thyroxine (FT(4)), TSH, antithyroglobulin antibodies, and antithyroperoxidase antibodies were measured in all patients.. i) Compared with CG1, obese patients having thyroid function parameters in the normal range and negative Thyr-Ab showed significantly higher serum TSH and lower free thyroid hormones levels, but a similar FT(4)/FT(3) ratio; ii) SH was recorded in 13.7% obese patients; iii) compared with CG2, obese patients with untreated SH had a significantly lower rate of positive Thyr-Ab (32.1 vs 66.1%; P<0.005); iv) no gender prevalence was observed in SH obese patients with negative Thyr-Ab; and v) the comparison of the untreated SH patients (obese and normo-weight) with CG1 demonstrated that in SH obese subjects, unlike normo-weight SH patients, the FT(3) levels were significantly lower. This resulted in a normal FT(4)/FT(3) ratio in SH obese patients.. Thyroid autoimmunity is not a major cause sustaining the high rate of SH in morbid obese patients. In these patients, the diagnosis of SH itself, as assessed by a raised TSH alone, appears questionable.

Topics: Adult; Autoantibodies; Biomarkers; Body Weight; Female; Humans; Hypothyroidism; Male; Middle Aged; Obesity, Morbid; Peroxidase; Predictive Value of Tests; Prevalence; Thyroiditis, Autoimmune; Thyrotropin; Thyroxine; Triiodothyronine

Contradicting reports exist about the pathogenicity of Chlamydia pneumoniae and the severity of the respiratory disease they cause. This study aimed to clarify, in mice, our hypothesis that marked differences in virulence of well-defined C. pneumoniae strains might exist for lung infections. C57BL/6J mice were intranasally infected with equal amounts of five different, identically prepared laboratory strains of C. pneumoniae. Based on the clinical score, weight, histopathological score, the granulocyte marker-enzyme myeloperoxidase, and the amount of Chlamydiae in the lung tissue, the C. pneumoniae isolates exhibited clear differences in overall growth characteristics or clearance, and pathological potential. Thus, we could identify chlamydial strains (Kajaani-K6 and CWL-029), where mice became seriously ill, as well as a relatively low-virulent isolate (TWAR-183). Cytokine profiles also varied drastically between the five strains in extent and kinetic. Our results indicate that C. pneumoniae isolates differ markedly with regard to their interaction with the host and their pathological potential. This might also be true for the infection in humans. Because the genomic diversity of C. pneumoniae is rather small, more subtle genomic deviations account most likely for the apparent functional differences. Our results will be useful to identify additional virulence factors in the future.

Topics: Animals; Body Weight; Chlamydophila pneumoniae; Colony Count, Microbial; Cytokines; Lung; Mice; Mice, Inbred C57BL; Peroxidase; Pneumonia, Bacterial; Severity of Illness Index; Virulence

To investigate the therapeutic effects of four strains of probiotics (E. feacalis, L. acidophilus, C. butyricum and B. adolescentis) on dextran sulphate sodium (DSS)-induced experimental colitis in Balb/c mice.. Eighty Balb/c mice were randomly divided into 8 groups. Weight-loss, fecal character, fecal occult blood and hematochezia were recorded daily. Disease activity index (DAI) scores were also evaluated everyday. Length of colon was measured and histological scores were evaluated on the 13th day. Myeloperoxidase (MPO) activity was detected. Interleukin-1 (IL-1) and IL-4 expression was detected by ELISA and RT-PCR.. The four strains of probiotics relieved the inflammatory condition of DSS-induced experimental colitis in mice. Weight loss was slowed down in all probiotics-treated mice. Even weight gain was observed by the end of probiotics treatment. The DAI and histological scores of probiotics-treated mice were lower than those of mice in the control group (1.9 +/- 0.2 vs 8.6 +/- 0.4, P < 0.05 for E. faecalis). The length of colon of probiotics-treated mice was longer than that of mice in the control group (10.3 +/- 0.34 vs 8.65 +/- 0.77, P < 0.05 for E. faecalis). The four strains of probiotics decreased the MP activity and the IL-1 expression, but increased the IL-4 expression. E. faecalis had a better effect on DSS-induced experimental colitis in mice than the other three strains.. The four strains of probiotics have beneficial effects on experimental colitis in mice. E. faecalis has a better effect on DSS-induced experimental colitis in mice than the other three strains. Supplement of probiotics provides a new therapy for UC.

Topics: Animals; Body Weight; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Disease Progression; Female; Interleukin-1beta; Interleukin-4; Male; Mice; Mice, Inbred BALB C; Peroxidase; Probiotics; Random Allocation

Ingestion by mice of dextran sodium sulfate (DSS) induces colonic vasoconstriction and inflammation, with some of the effects potentially mediated by the vasoconstrictor endothelin-1 (ET-1).. In this study, mice given 5% 40 kD DSS for 5-6 days had elevated colonic immunostaining for ET-1 and platelet endothelial cell adhesion molecule-1 (PECAM-1). Increased ET-1 can induce microvascular constriction; however, the increase in PECAM-1 is consistent with angiogenesis that could decrease flow resistance.. Our measurements of intestinal blood flow, via infused microspheres, suggests that these 2 factors may offset each other, with only a nonsignificant tendency for a DSS-induced decrease in flow. Daily administration of the endothelin converting enzyme inhibitor SM-19712 (15 mg/kg) attenuated DSS-induced increases in colonic immunostaining of ET-1 and PECAM-1.. SM-19712 attenuated histologic signs of tissue injury and inflammation induced by DSS, and decreased the extent of loose stools and fecal blood. However, the inhibitor did not significantly decrease DSS-induced colon shortening or tissue levels of myeloperoxidase (an indicator of neutrophil infiltration).

Topics: Animals; Aspartic Acid Endopeptidases; Blood Pressure; Body Weight; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Ileum; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Organ Size; Peroxidase; Platelet Endothelial Cell Adhesion Molecule-1; Sulfonamides; Sulfonylurea Compounds; Vasoconstriction

The aim of the present study was to examine the effects of verbascoside (VB) in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of 2,4 dinitrobenzene sulfonic acid (DNBS; 25 mg/rat). VB was administered daily per os (0.2 and 2 mg/kg) 4 days after DNBS administration in the colon. Treatment with VB significantly (P < 0.01) reduced macroscopic damage score, loss of body weight, myeloperoxidase activity and thiobarbituric acid-reactant substances. Moreover, the intensity of the positive staining for tumor necrosis factor-alpha, interleukin-1beta, intercellular adhesion molecule-1, P-selectin, inducible nitric oxide synthase, and poly(ADP ribose) was also significantly (P < 0.01) reduced by VB treatment. Therefore, VB treatment significantly (P < 0.01) reduced the degree of NF-kappaB p65 and activation of the pro-active form metalloproteinase (MMP)-2 and pro-MMP-9 activity. The results of this study suggested that VB functions as an intracellular radical scavenger and so reduces the microscopic and macroscopic signs of colitis in the rat. Therefore, administration of VB may be beneficial for the treatment of inflammatory bowel disease.

Topics: Animals; Antioxidants; Body Weight; Cells, Cultured; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Precursors; Gelatinases; Glucosides; Male; Matrix Metalloproteinase 9; Peroxidase; Phenols; Rats; Rats, Sprague-Dawley; Syringa; Thiobarbituric Acid Reactive Substances; Transcription Factor RelA

Beneficial bacteria (probiotics) and probiotic-derived factors have the potential to ameliorate disorders of the intestine. The aim of this study was to compare live Streptococcus thermophilus TH-4 (TH-4), dead TH-4 and TH-4 supernatant in rats treated with 5-Fluorouracil. Rats were randomly allocated to five treatment groups (n=8-10): Saline+Water; 5-FU+Skim Milk; 5-FU+Live TH-4; 5-FU+Supernatant TH-4; and 5-FU+Dead TH-4. 5-FU (150mg.kg(-1)) was administered by a single intraperitoneal injection on day 0; animals were killed on day 4. Treatments were administered daily from days -2 to 3 via oro-gastric gavage. Metabolic parameters were measured daily. Blood was obtained by cardiac puncture, and intestinal tissues removed for quantitative and qualitative histological assessment, including: villous height and area; crypt depth and area, mitotic count and crypt fission; biochemical determination of sucrase and myeloperoxidase (MPO) activity; and disease severity scoring. One-way ANOVA statistical analyses were conducted for the majority of outcome measures. Live TH-4 significantly reduced disease severity score by 13% (p< 0.05), and partially normalised mitotic counts compared with 5-FU+Skim milk controls. Live and supernatant TH-4 reduced crypt fission by 69% and 48% (p< 0.05), respectively, compared to 5-FU+Skim Milk controls. No significant differences (p> 0.05) in the occurrence of bacteraemia were evident across all groups. Live TH-4 partially normalised mitotic count and histological severity score in 5-FU treated rats. The inhibitory effect of live TH-4 and TH-4 supernatant on crypt fission suggests therapeutic utility in the prevention of disorders characterised by increased crypt fission, such as colorectal carcinoma.

Topics: Animals; Body Weight; Female; Fluorouracil; Injections, Intraperitoneal; Intestinal Mucosa; Jejunum; Mucositis; Peroxidase; Probiotics; Rats; Rats, Inbred Strains; Streptococcus thermophilus; Sucrase

Susceptibility to inflammatory bowel diseases depends upon interactions between the genetics of the individual and induction of chronic mucosal inflammation. We hypothesized that administration of dietary phenolics, caffeic acid and rutin, would suppress upregulation of inflammatory markers and intestinal damage in a mouse model of colitis. Colitis was induced in C3H/ HeOuJ mice (8 weeks old, 6 male/6 female per treatment) with 1.25% dextran sulfate sodium (DSS) for 6 d in their drinking water. Rutin (1.0 mmol (524 mg)/kg in diet), caffeic acid (1.0 mmol (179 mg)/kg in diet), and hypoxoside extract (15 mg/d, an anticolitic phenolic control) were fed to the mice for 7 d before and during DSS treatment, as well as without DSS treatment. Body weight loss was prevented by rutin and caffeic acid during DSS treatment. Colon lengths in mice fed caffeic acid and hypoxoside during DSS treatment were similar to DSS-negative control. Food intake was improved and myeloperoxidase (MPO) was decreased with each phenolic treatment in DSS-treated mice compared with DSS treatment alone. Colonic mRNA expression of IL-17 and iNOS were inhibited when IL-4 was increased by each phenolic treatment combined with DSS, whereas CYP4B1 mRNA was increased only by caffeic acid in DSS-treated mice, compared with DSS treatment alone. Colonic and cecal histopathology scores of DSS-treated mice were significantly more severe (P < 0.01) than in mice fed caffeic acid before and during DSS treatment, based on mucosal height, necrosis, edema, erosion, and inflammatory cell infiltration. Although both rutin and caffeic acid suppressed the expression of selected inflammatory markers, only caffeic acid protected against DSS-induced colitis, in association with normalization of CYP4B1 expression. The inhibition of DSS-induced colitic pathology by caffeic acid was mediated by mechanisms in addition to anti-inflammatory effects that deserve further study.

Topics: Alkynes; Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Body Weight; Caffeic Acids; Colitis; Colon; Dextran Sulfate; Eating; Female; Gene Expression Regulation, Enzymologic; Glucosides; Humans; Inflammatory Bowel Diseases; Interleukin-17; Interleukin-4; Male; Mice; Nitric Oxide Synthase Type II; Organ Size; Peroxidase; RNA, Messenger; Rutin; Time Factors

3,3-Diindolylmethane (DIM) is a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C) derived from Brassica food plants. Although DIM is known as a chemopreventive and chemotherapeutic phytochemical, the effects of DIM on inflammation in vivo are still unknown. In the present study we investigated the antiinflammatory effects of DIM on experimental colitis and colitis-associated colorectal carcinogenesis.. To determine if DIM has an antiinflammatory effect in vivo, we examined the therapeutic effects of DIM in dextran sodium sulfate (DSS)-induced experimental colitis and colitis-associated colon carcinogenesis induced by azoxymethane (AOM)/DSS in BALB/c mice.. Treatment with DIM significantly attenuated loss of body weight, shortening of the colon, and severe clinical signs in a colitis model. This was associated with a remarkable amelioration of the disruption of the colonic architecture and a significant reduction in colonic myeloperoxidase activity and production of prostaglandin E(2), nitric oxide, and proinflammatory cytokines. Further, DIM administration dramatically decreased the number of colon tumors in AOM/DSS mice.. These results suggest that DIM-mediated antiinflammatory action at colorectal sites may be therapeutic in the setting of inflammatory bowel disease and colitis-associated colon cancer.

Topics: Animals; Anticarcinogenic Agents; Azoxymethane; Body Weight; Carcinogens; Cell Transformation, Neoplastic; Colitis; Colonic Neoplasms; Dextran Sulfate; Dinoprostone; Disease Models, Animal; Indoles; Mice; Mice, Inbred BALB C; NF-kappa B; Nitric Oxide; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Weight Loss

We recently showed that patients with inflammatory bowel disease (IBD) report significantly more sleep disturbances. To determine whether disrupted sleep can affect the severity of inflammation and the course of IBD, we used an animal model of colonic inflammation to determine the effects of acute and chronic intermittent sleep deprivation on the severity of colonic inflammation and tissue damage in colitis and recovery from this damage.. Acute sleep deprivation (ASD) consisted of 24h of forced locomotor activity in a mechanical wheel rotating at a constant speed. Chronic intermittent sleep deprivation (CISD) consisted of an acute sleep deprivation episode, followed by additional sleep deprivation periods in the wheel for 6h every other day throughout the 10day study period. To induce colitis, mice were given 2% dextran sodium sulfate (DSS) in their daily drinking water for 7days. The development and severity of colitis were monitored by measuring weight loss and tissue myeloperoxidase (MPO) activity daily and colon histology scores 10days after initiation of colitis.. ASD or CISD did not cause colonic inflammation in vehicle-treated mice. Changes in daily body weight, tissue MPO levels and colon histopathology score were similar between mice that were sleep deprived and controls. Daily DSS ingestion caused colitis in mice. ASD worsened colonic inflammation: tissue MPO levels in ASD/DSS-treated mice were significantly higher than in DSS-treated mice that were not sleep deprived. However, the worsening of colonic inflammation by ASD was not enough to exacerbate clinical manifestations of colitis such as weight loss. In contrast, the deleterious effects of CISD were severe enough to cause worsening of histological and clinical manifestations of colitis. The deleterious effects of sleep deprivation on severity of colitis appeared to be due to both increased colonic inflammation and a decrease in the ability of mice to recover from DSS-induced colonic injury.. Both acute and chronic intermittent sleep deprivation exacerbate colonic inflammation. Thus, sleep deprivation could be an environmental trigger that predisposes IBD patients to develop flare ups and a more severe disease course. These results provide a scientific rationale to conduct an interventional trial to determine whether improvement in sleep patterns will prevent IBD flare ups, modify the disease course, and improve quality of life.

Topics: Acute Disease; Animals; Body Weight; Chronic Disease; Colitis; Colon; Dextran Sulfate; Diarrhea; Disease Models, Animal; Gastrointestinal Hemorrhage; Male; Mice; Mice, Inbred C57BL; Organ Size; Peroxidase; Rectal Diseases; Sleep Deprivation

Cinnamophilin (CINN, (8R, 8'S)-4, 4'-dihydroxy-3, 3'-dimethoxy-7-oxo-8, 8'-neolignan) protects against ischemic stroke in mice. While some anti-oxidative effects of CINN have been characterized, its therapeutic window and molecular basis for neuroprotection remain unclear. We evaluated antioxidant and anti-inflammatory properties and therapeutic window of CINN against brain ischemia using a panel of in vitro and in vivo assays. Data from lipid peroxidation and radical scavenging assays showed that CINN was a robust antioxidant and radical scavenger. CINN effectively inhibited the production of tumor necrosis factor alpha (TNF-alpha), nitrite/nitrate, interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells (P<0.05, respectively). Relative to controls, CINN, administrated at 80 mg/kg, 2, 4, or 6 h postinsult, but not 12 h, significantly reduced brain infarction by 34-43% (P<0.05) and improved neurobehavioral outcome (P<0.05) following transient focal cerebral ischemia in rats. CINN (10-30 microM) also significantly reduced oxygen-glucose deprivation-induced neuronal damage (P<0.05) in rat organotypic hippocampal slices, even when it was administrated 2, 4, or 6 h postinsult. Together, CINN protects against ischemic brain damage with a therapeutic window up to 6 h in vivo and in vitro, which may, at least in part, be attributed by its direct antioxidant and anti-inflammatory effects.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Benzothiazoles; Body Weight; Cell Line, Transformed; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose; Guaiacol; Hippocampus; Hypoxia; Interleukin-6; Ischemic Attack, Transient; Lignans; Lipid Peroxidation; Microglia; Nitrates; Nitrites; Organ Culture Techniques; Peroxidase; Phenethylamines; Polysaccharides; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonic Acids; Time Factors; Tumor Necrosis Factor-alpha

Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease.. Female mice were used for study.. Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle.. Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed.. High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48-96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment.. The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.

Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Female; Humans; Imidazoles; Inflammatory Bowel Diseases; Leucine; Mice; Mice, Inbred BALB C; Peptidyl-Dipeptidase A; Peroxidase; Random Allocation

Inflammatory bowel diseases (IBD), including mainly ulcerative colitis (UC) and Crohn's disease (CD), are inflammatory disorders of the gastrointestinal tract caused by an interplay of genetic and environmental factors. Murine colitis model induced by Dextran Sulfate Sodium (DSS) is an animal model of IBD that is commonly used to address the pathogenesis of IBD as well as to test efficacy of therapies. In this study we systematically analyzed clinical parameters, histological changes, intestinal barrier properties and cytokine profile during the colitic and recovery phase.. C57BL/6 mice were administered with 3.5% of DSS in drinking water for various times. Clinical and histological features were determined using standard criteria. Myeloperoxidase (MPO) activity, transepithelial permeability and proinflammatory mediators were determined in whole colon or proximal and distal parts of colon.. As expected after administration of DSS, mice manifest loss of body weight, shortening of colon length and bloody feces. Histological manifestations included shortening and loss of crypts, infiltration of lymphocytes and neutrophil, symptoms attenuated after DSS withdrawal. The MPO value, as inflammation indicator, also increases significantly at all periods of DSS treatment, and even after DSS withdrawal, it still held at very high levels. Trans-mucosal permeability increased during DSS treatment, but recovered to almost control level after DSS withdrawal. The production of proinflammatory mediators by colonic mucosa were enhanced during DSS treatment, and then recovered to pre-treated level after DSS withdrawal. Finally, enhanced expression of proinflammatory mediators also revealed a different profile feature in proximal and distal parts of the colon.. Experimental colitis induced by DSS is a good animal model to study the mechanisms underlying the pathogenesis and intervention against IBD, especially UC.

Topics: Animals; Body Weight; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Models, Biological; Permeability; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

Fructus Mume pill (FMP) has been used as a folk remedy for gastrointestinal diseases in China over thousands of years. FMP was approved for the treatment of gastrointestinal diseases in 2001 by the State Food and Drug Administration (SFDA) of China. Although FMP had significant efficacy for treatment of the patients with inflammatory bowel disease (IBD) in the clinic, the mechanism of action is still unclear.. In the present study, the effects and possible mechanism of FMP on colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) were investigated.. Fifty-four SD rats were divided into six groups. Nine rats for each group from three independent experiments were investigated for the effects of FMP.. FMP protected against diarrhea, colon weight increase, colonic accretion, ulceration and myeloperoxidase (MPO) activity elevation. The effects of FMP on recovery of colonic damage and restoration of the normal structures of colorectums were superior to dexamethasone (DEX). FMP promoted the restoration of abnormal cytokine secretion after TNBS treatment. FMP was effective in restoring the balance of intestinal bacteria population from the imbalance of G(+)/G(-) in rats with colitis.. The results indicated that FMP is effective in treatment of colitis in an experimental rat model. The possible mechanisms may be through down-regulation of Th1-polarized immune response and opsonic effect of intestinal commensal bacteria in this model system.

Topics: Animals; Body Weight; Colitis; Cytokines; Dexamethasone; Diarrhea; Herbal Medicine; Intestines; Male; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

Si-Ni-San, a traditional Chinese medicinal formula, exerts an important function in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice, but the underlying mechanism is still unclear. In this study, we investigated the therapeutic potential of Si-Ni-San and its ingredient glycyrrhizin in trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis in mice, a well-characterized murine model for Crohn's disease. Si-Ni-San and glycyrrhizin significantly ameliorated TNBS-induced colitis with reduced mortality and recovery of body weights. In addition, Si-Ni-San and glycyrrhizin dose-dependently decreased macroscopic inflammation scores, microscopic histological scores, and myeloperoxidase activity. Furthermore, Si-Ni-San and glycyrrhizin caused a decrease in pro-inflammatory cytokines including IFN-gamma, IL-12, TNF-alpha and IL-17 and an increase in regulatory cytokine IL-10 in colon of the mice. It should be noticed the therapeutic effect of Si-Ni-San at 450 mg/kg was much better than that of its contained content of glycyrrhizin at 10 mg/kg. In conclusion, Si-Ni-San and glycyrrhizin significantly ameliorated TNBS-induced colitis in mice through regulating pro- and anti-inflammatory cytokine production.

Topics: Animals; Body Weight; Colitis; Colon; Crohn Disease; Cytokines; Diarrhea; Disease Models, Animal; Drugs, Chinese Herbal; Female; Glycyrrhizic Acid; Humans; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Peroxidase; Trinitrobenzenesulfonic Acid

This study investigated the effect of diabetes mellitus on lacrimal gland morphology and function.. The lacrimal glands of rats (n = 6) were removed 8 weeks after the onset of diabetes and processed for electron microscopy. The lacrimal gland of control rats (n = 6) were processed similarly. Lacrimal tissue samples of diabetic rats (n = 12) were also incubated with different concentrations (10(-6)-10(-3) M) of acetylcholine and noradrenaline to investigate secretagogue-induced peroxidase release. The lacrimal glands of control rats (n = 12) were treated in a similar manner.. Diabetic rats and their lacrimal glands gained significantly (p < 0.05) less weight compared to age-matched controls. Lacrimal acinar cells of diabetic rat have significantly (p < 0.001) smaller and more homogenous secretory granules compared to age-matched control. Lacrimal glands of diabetic rats contained significantly (p < 0.05) less peroxidase and secrete significantly less quantity (p < 0.05) of the enzyme in response to either acetylcholine or noradrenaline challenge compared to control glands.. The results indicate that diabetes is associated with lacrimal gland insufficiency as a result of abnormal acinar morphology and reduced peroxidase content and secretion.

Topics: Animals; Body Weight; Diabetes Complications; Humans; Lacrimal Apparatus; Lacrimal Apparatus Diseases; Microscopy, Electron, Transmission; Oxidative Stress; Peroxidase; Rats; Secretory Vesicles

The relationship between a predisposition to obesity and the development of colitis is not well understood. Our aim was to characterize the adipokine response and the extent of colitis in diet-induced obese (DIO) rats. DIO and control, diet-resistant (DR) animals were administered either saline or trinitrobenzene sulfonic acid (TNBS) to induce colitis. Macroscopic damage scores and myeloperoxidase (MPO) activity were measured to determine the extent of inflammation. Trunk blood was collected for the analysis of plasminogen activator inhibitor-1 (PAI-1) as well as leptin, ghrelin, and adiponectin. Colonic epithelial physiology was assessed using Ussing chambers. DIO rats had a modestly increased circulating PAI-1 before TNBS treatment; however, during colitis, DR animals had more than a fourfold increase in circulating PAI-1 compared with DIO rats. Circulating leptin was higher in DIO rats compared with DR animals, in the inflamed and noninflamed states. These changes in TNBS-induced adipokine profile were accompanied by decreased macroscopic tissue damage score in DIO animals compared with DR tissues. Furthermore, TNBS-treated DR animals lost significantly more weight than DIO rats during active inflammation. Colonic epithelial physiology was comparable between groups, as was MPO activity. The factors contributing to the decreased colonic damage are almost certainly multifold, driven by both genetic and environmental factors, of which adipokines are likely to play a part given the increasing body of evidence for their role in modulating intestinal inflammation.

Topics: Adipokines; Adiponectin; Animals; Body Weight; Colitis, Ulcerative; Colon; Eating; Electric Impedance; Electrophysiological Phenomena; Genetic Predisposition to Disease; Ghrelin; Inflammation; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Peroxidase; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred Strains; Serpin E2; Serpins; Thinness; Trinitrobenzenesulfonic Acid

Metabolic syndrome (MetS) is a group of cardiovascular risk factors, including visceral obesity, glucose intolerance, hypertension, and dyslipidemia. Increased oxidative and nitrative stress and inflammation and decreased endothelial function occur in an animal model of metabolic syndrome, SHR/NDmcr-cp (SHR/cp) rats. The present study investigated the effects of coenzyme Q10 (CoQ10), one of the important antioxidants, on the abnormal oxidative condition and characteristic components of metabolic syndrome in SHR/cp rats by maintaining them on a diet supplemented with 0.07% - 0.7% CoQ10 for 26 weeks. We determined serum levels of oxidatively modified low-density lipoprotein (Ox-LDL) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as oxidative stress markers, 3-nitrotyrosine as a nitrative stress marker, 3-chlorotyrosine as a marker of myeloperoxidase (MPO)-catalyzed oxidation and high-sensitivity C-reactive protein (hsCRP) as an inflammatory marker. The administration of CoQ10 significantly attenuated the increase of oxidative and nitrative stress markers and inflammatory markers in a dose-dependent manner. CoQ10 prevented the elevated serum insulin levels, although it did not affect the elevated glucose level and dyslipidemia. CoQ10 also reduced elevated blood pressure, but did not affect body weight gain. In addition, CoQ10 improved endothelial dysfunction in the mesenteric arteries. These findings suggest that the antioxidant properties of CoQ10 can be effective for ameliorating cardiovascular risk in MetS.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Blood Glucose; Body Weight; Deoxyguanosine; Disease Models, Animal; Inflammation; Insulin; Lipids; Lipoproteins, LDL; Metabolic Syndrome; Oxidative Stress; Peroxidase; Rats; Rats, Inbred SHR; Tyrosine; Ubiquinone

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

Topics: Acute Disease; Adipokines; Adiponectin; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Chemokines; Cytokines; Disease Models, Animal; Female; Insulin; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index

The therapeutic efficacy of immunosuppressants for treating rapidly progressive glomerulonephritis (RPGN) with crescent formation remains controversial. SCG/Kj mice spontaneously develop RPGN-like symptoms, characteristic of crescentic glomerulonephritis and systemic small vessel vasculitis, associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). We evaluated the "ameliorative", not prophylactic, effects of immunosuppressive agents, deoxyspergualin (DSG), cyclophosphamide (CYC) and prednisolone (PDN), on RPGN in these mice. DSG at intraperitoneal doses of 3 and 6 mg/kg, CYC at an oral dose of 12 mg/kg, or PDN at an intraperitoneal dose of 120 mg/kg was administered once a day for 21 days to female mice "at the onset of hematuria". A set of control SCG/Kj mice received only saline injections. DSG and CYC significantly prolonged survival, improved the proteinuria, hematuria and hyperuremia, and decreased the serum level of myeloperoxidase-ANCA. Moreover, DSG significantly suppressed the formation of crescents in glomeruli. PDN failed to affect any of the parameters. DSG might be useful for inducing remission in crescentic glomerulonephritis involved in RPGN.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Blood Cell Count; Blood Urea Nitrogen; Body Weight; Churg-Strauss Syndrome; Female; Glomerulonephritis; Guanidines; Hematuria; Immunosuppressive Agents; Kidney; Mice; Mice, Inbred Strains; Peroxidase; Survival Analysis; Urinalysis

The antioxidant effects of exogenous salicylic acid (SA) and vitamin C (Vit C) on the oxidative stress induced by 56 mg/m(3) of sulfur dioxide (SO2) in mouse livers and brains were investigated. The exposure of SO2 caused significant elevation of thiobarbituric acid-reactive substance (TBARS) levels and reduction of enzyme activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in brain and liver, accompanied by a decrease in relative growth rate, when compared with controls. Application of moderate concentrations of SA and Vit C markedly reduced the SO2-induced elevation of TBARS levels, with 5.5 mg/kg SA or 200 mg/kg Vit C being most effective. In contrast to the decrease of TBARS levels, the levels of SOD, POD, and CAT in liver and brain were significantly increased in comparison with controls. The polyacrylamide gel electrophoresis (PAGE) of total liver proteins showed that the SO2 inhalation caused a 30-kD protein band disappearance compared with the control. However, the band remained unchanged in the samples treated with 5.5 and 8.25 mg/kg SA or 100, 200, and 400 mg/kg Vit C. Therefore, this protein band may serve as a marker for the damage induced by SO2 and an additional basis for drug screening and selection.

Topics: Administration, Inhalation; Air Pollutants; Animals; Antioxidants; Ascorbic Acid; Body Weight; Brain; Catalase; Disease Models, Animal; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Oxidative Stress; Peroxidase; Salicylic Acid; Sulfur Dioxide; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The effect of dietary sphingomyelin (SM) on inflammatory bowel disease (IBD) induced with dextran sodium sulfate (DSS) was examined in mice. Although the severity of IBD as expressed by the disease activity index (DAI) markedly increased with DSS administration, feeding a diet containing SM lowered the DAI value significantly. Myeloperoxidase (MPO) activity in colonic tissue also increased with DSS administration, suggesting the development of inflammation. Because simultaneous administration of SM with DSS prevented the MPO activity increase, we concluded that SM could suppress the development of inflammation. These results provide novel evidence that dietary supplementation with SM can alleviate the symptoms of IBD in mice. Dietary SM also increased the amount of IgA in the large intestine, suggesting that SM promotes IgA secretion into the large intestine. These results suggest that the mechanism of IBD mitigation by SM is complex and involves the immune system.

Topics: Animals; Body Weight; Dextran Sulfate; Diet; Disease Models, Animal; Immunoglobulin A; Inflammatory Bowel Diseases; Intestine, Large; Male; Mice; Mice, Inbred ICR; Peroxidase; Severity of Illness Index; Sphingomyelins; Spleen; Time Factors; Treatment Outcome

The vagus nerve is an important pathway signaling immune activation of the gastrointestinal tract to the brain. Probiotics are live organisms that may engage signaling pathways of the brain-gut axis to modulate inflammation. The protective effects of Lactobacillus rhamnosus [corrected] (LR) and Bifidobacterium infantis (BI) during intestinal inflammation were studied after subdiaphragmatic vagotomy in acute dextran sulfate sodium (DSS) colitis in BALB/c mice and chronic colitis induced by transfer of CD4(+) CD62L(+) T lymphocytes from BALB/c into SCID mice. LR and BI (1 x 10(9)) were given daily. Clinical score, myeloperoxidase (MPO) levels, and in vivo and in vitro secreted inflammatory cytokine levels were found to be more severe in mice that were vagotomized compared with sham-operated animals. LR in the acute DSS model was effective in decreasing the MPO and cytokine levels in the tissue in sham and vagotomized mice. BI had a strong downregulatory effect on secreted in vitro cytokine levels and had a greater anti-inflammatory effect in vagotomized- compared with sham-operated mice. Both LR and BI retained anti-inflammatory effects in vagotomized mice. In SCID mice, vagotomy did not enhance inflammation, but BI was more effective in vagotomized mice than shams. Taken together, the intact vagus has a protective role in acute DSS-induced colitis in mice but not in the chronic T cell transfer model of colitis. Furthermore, LR and BI do not seem to engage their protective effects via this cholinergic anti-inflammatory pathway, but the results interestingly show that, in the T cell, transfer model vagotomy had a biological effect, since it increased the effectiveness of the BI in downregulation of colonic inflammation.

Topics: Acute Disease; Administration, Oral; Animals; Bifidobacterium; Body Weight; CD4-Positive T-Lymphocytes; Chronic Disease; Colitis; Colon; Dextran Sulfate; Interleukin-6; Limosilactobacillus reuteri; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Peroxidase; Probiotics; Spleen; T-Lymphocytes; Tumor Necrosis Factor-alpha; Vagotomy; Vagus Nerve

Continuous disruption of circadian rhythms, as seen in human shift workers, has been associated with the development of a number of adverse mental and physiological conditions. However, scientific evidence linking circadian disruption to overall health, particularly in animal models, is not well documented. In this study, we have demonstrated that exposing C57BL/6J mice to 12-h phase shifts every 5 days for 3 mo had no effect on body weight or intestinal physiology. However, when animals were further challenged with dextran sodium sulfate to induce colitis, chronic shifting of the light-dark cycle led to a dramatic increase in the progression of the colitis as indicated by reduced body weight, abnormal intestinal histopathology, and an exacerbated inflammatory response. These data indicate that circadian disruption is an important predisposing factor that may provoke the onset or worsening of various disease states such as inflammatory disorders. This study provides further evidence for continued investigations using animal models of circadian disruption to examine the consequences of circadian disruption on health when organisms are faced with a "challenging" environment.

Topics: Adaptation, Physiological; Animals; Body Weight; Chronic Disease; Chronobiology Disorders; Circadian Rhythm; Colitis; Colon; Dextran Sulfate; Environment; Male; Mice; Mice, Inbred C57BL; Peroxidase; Photoperiod; Risk Factors

To investigate the effect of Gardenia jasminoides (GJ) on cerulein-induced acute pancreatitis (AP) in mice.. C57BL/6 mice weighing 18-20 g were divided into three groups. (1) Normal saline-treated group, (2) treatment with GJ at a dose of 0.1 g/kg, (3) treatment with GJ at a dose of 1 g/kg. GJ was administered orally (n = 6 per group) for 1 wk. Three hours later, the mice were given an intraperitoneal injection of cerulein (50 microg/kg), a stable cholecystokinin (CCK) analogue, every hour for a total of 6 h as described previously. The mice were sacrificed at 6 h after completion of cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphologic examination and scoring. A portion of pancreas was stored at -70 degree and prepared for the measurement of tissue myeloperoxidase (MPO) activity, an indicator of neutrophil sequestration, and for reverse-transcriptase PCR (RT-PCR) and real-time PCR measurements.. Treatment with GJ decreased significantly the severity of pancreatitis and pancreatitis-associated lung injury. Treatment with GJ attenuated the severity of AP compared with saline-treated mice, as shown by reduction in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and mRNA expression of multiple inflammatory mediators.. These results suggest that GJ attenuated the severity of AP as well as pancreatitis-associated lung injury.

Topics: Acute Disease; Administration, Oral; Amylases; Animals; Anti-Inflammatory Agents; Body Weight; Ceruletide; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gardenia; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Lipase; Lung; Lung Injury; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Organ Size; Pancreas; Pancreatitis; Peroxidase; Plant Extracts; RNA, Messenger; Tumor Necrosis Factor-alpha

Although probiotics are beginning to enter mainstream medicine for disorders of the colon, their effects on the small bowel remain largely unexplored. We investigated the recently identified probiotic, Lactobacillus fermentum (L. fermentum) BR11 (BR11) and the prebiotic, fructo-oligosaccharide (FOS), both individually and in synbiotic combination, for their potential to alleviate intestinal mucositis. From Days 0-9, rats consumed skim milk (SM; saline + SM), low dose (LD-BR11; 1 x 10(6)cfu/ml), high dose (HD-BR11; 1 x 10(9)cfu/ml), LD-FOS (3%), HD-FOS (6%), or synbiotic (HD-BR11/FOS). On Day 7, rats were injected with 5-fluorouracil (5-FU; 150 mg/kg). All rats were sacrificed on Day 10. Intestinal tissues were collected for quantitative histology, sucrase, and myeloperoxidase (MPO) determinations. 5-FU decreased sucrase activity, villus height, crypt depth, and crypt cell proliferation compared to controls. Compared to 5-FU + SM, histological damage severity scores were increased for all treatments, although all were effective at reducing jejunal inflammation, indicated by reduced MPO activity (P < 0.05). The combination of BR11 and FOS did not provide additional protection. Moreover, HD-FOS and the synbiotic actually increased clinical mucositis severity (P < 0.05). We conclude that L. fermentum BR11 has the potential to reduce inflammation of the upper small intestine. However, its combination with FOS does not appear to confer any further therapeutic benefit for the alleviation of mucositis.

Topics: Animals; Body Weight; Female; Fluorouracil; Jejunum; Limosilactobacillus fermentum; Mucositis; Oligosaccharides; Organ Size; Peroxidase; Probiotics; Rats; Sucrase

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of acute respiratory failure associated with high morbidity and mortality. Although ALI/ARDS pathogenesis is only partly understood, pulmonary endothelium plays a major role by regulating lung fluid balance and pulmonary edema formation. Consequently, endothelium-targeted therapies may have beneficial effects in ALI/ARDS. Recently, attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface P2Y receptors. We previously described ATP-induced endothelial cell (EC) barrier enhancement via a complex cell signaling and hypothesized endothelial purinoreceptors activation to exert anti-inflammatory barrier-protective effects. To test this hypothesis, we used a murine model of ALI induced by intratracheal administration of endotoxin/lipopolysaccharide (LPS) and cultured pulmonary EC. The nonhydrolyzed ATP analog ATPgammaS (50-100 muM final blood concentration) attenuated inflammatory response with decreased accumulation of cells (48%, P < 0.01) and proteins (57%, P < 0.01) in bronchoalveolar lavage and reduced neutrophil infiltration and extravasation of Evans blue albumin dye into lung tissue. In cell culture model, ATPgammaS inhibited junctional permeability induced by LPS. These findings suggest that purinergic receptor stimulation exerts a protective role against ALI by preserving integrity of endothelial cell-cell junctions.

Topics: Adenosine Triphosphate; Animals; Blood-Air Barrier; Body Weight; Endothelial Cells; Humans; Leukocytes; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Peroxidase; Pneumonia; Purines; Respiratory Distress Syndrome; Weight Loss

The purpose of this study was to determine the effect of exercise on wound healing and inflammation in young (3 mo) and old (18 mo) female BALB/cByJ mice. Mice were assigned to either exercise or sedentary control (control) groups. The exercise group mice were run on a motorized treadmill at a moderate intensity 30 min/day for 8 days. All mice were given four full-thickness dermal wounds, and the rate of wound closure was assessed daily for 10 days. Four months later, the aged mice were rerandomized to treatment, wounded again in different locations, and wounds were harvested at 1, 3, or 5 days postwounding. Wound tissue was analyzed for IL-1beta, IL-6, keratinocyte chemoattractant (KC), monocyte chemoattractant protein-1 (MCP-1), and TNF-alpha protein. Myeloperoxidase (MPO) activity and F4/80 mRNA were assessed as an indirect measure of neutrophil and macrophage content, respectively. There was a trend (P = 0.10) for exercise to reduce wound size in young mice, and exercise significantly (P < 0.05) decreased wound size in old mice. TNF-alpha, KC, and MCP-1 were significantly (P < 0.05) lower in wounds from exercised old mice compared with control. No group differences were found for wound IL-1beta or IL-6, MPO activity, or F4/80 mRNA. Our data suggest that exercise accelerates the wound healing process in old mice. This improved healing response in the old mice may be the result of an exercise-induced anti-inflammatory response in the wound.

Topics: Aging; Animals; Antigens, Differentiation; Body Weight; Chemokines; Eating; Female; Inflammation; Mice; Mice, Inbred BALB C; Peroxidase; Physical Conditioning, Animal; Random Allocation; Skin; Tumor Necrosis Factor-alpha; Wound Healing

Fish oils (FO) - rich in EPA and DHA - may protect against colitis development. Moreover, inflammatory bowel disease patients have elevated colonic arachidonic acid (AA) proportions. So far, effects of dietary AA v. FO on colitis have never been examined. We therefore designed three isoenergetic diets, which were fed to mice for 6 weeks preceding and during 7 d dextran sodium sulfate colitis induction. The control diet was rich in oleic acid (OA). For the other two diets, 1.0 % (w/w) OA was exchanged for EPA+DHA (FO group) or AA. At 7 d after colitis induction, the AA group had gained weight (0.46 (sem 0.54) g), whereas the FO and OA groups had lost weight (- 0.98 (SEM 0.81) g and - 0.79 (SEM 1.05) g, respectively; P < 0.01 v. AA). The AA group had less diarrhoea than the FO and OA groups (P < 0.05). Weight and length of the colon, histological scores and cytokine concentrations in colon homogenates showed no differences. Myeloperoxidase concentrations in plasma and polymorphonuclear cell infiltration in colon were decreased in the FO group as compared with the OA group. We conclude that in this mice model an AA-enriched diet increased colonic AA content, but did not result in more colonic inflammation as compared with FO- and OA-enriched diets. As we only examined effects after 7 d and because the time point for evaluating effects seems to be important, the present results should be regarded as preliminary. Future studies should further elucidate differential effects of fatty acids on colitis development in time.

Topics: Animals; Arachidonic Acid; Body Weight; Colitis; Colon; Cytokines; Dextran Sulfate; Diet; Disease Models, Animal; Fatty Acids; Female; Fish Oils; Food Analysis; Mice; Mice, Inbred C57BL; Oleic Acid; Organ Size; Peroxidase; Serum Amyloid P-Component

Methotrexate (MTX), a structural analogue of folic acid, is widely used as a chemotherapeutic agent for leukemia and other malignancies. One of the major toxic effects of MTX is intestinal injury and enterocolitis .The mechanism of gastrointestinal toxicity of methotrexate has not been investigated completely. Therefore cancer chemotherapy has to be accompanied by symptomatic therapy such as antibiotics and anti-diarrheal drugs. It is important to investigate the mechanism by which methotrexate induces intestinal damage in order to perform cancer chemotherapy effectively by preventing the side effects. This study aimed at investigating whether nitrosative stress plays a role in methotrexate induced small intestinal damage using a rat model. Adult male rats were administered methotrexate at the dose of 7 mg/kg body weight intraperitoneally for 3 consecutive days and sacrificed 12 or 24 h after the final dose of methotrexate. Vehicle treated rats served as control. The intestinal tissue was used for light microscopic studies and markers of nitrosative stress including tissue nitrite level and nitrotyrosine. Myeloperoxidase (MPO) activity, a marker of neutrophil infiltration was also measured in intestinal homogenates. The villi were damaged at 12 h and the damage progressed and became severe at 24 h after the final dose of MTX. Biochemically, tissue nitrate was elevated fivefold at 12 h and fourfold at 24 h after the final dose of MTX as compared with control. Nitrotyrosine, measured immunohistochemically was detected in all the parts of the small intestine. Duodenum stained the most for nitrotyrosine, followed by ileum and then jejunum. The staining for nitrotyrosine was more intense at 24 h as compared with 12 h after the final dose of methotrexate. There was marked neutrophil infiltration as evidenced by increase in MPO activity in the small intestines. In conclusion, the results of the present study reveal that nitrosative stress may play a critical role in methotrexate induced small intestinal damage. Intervention studies using nitric oxide synthase inhibitors is being carried out in order to confirm the role of nitrosative stress in methotrexate induced small intestinal damage.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Duodenum; Ileum; Immunohistochemistry; Injections, Intraperitoneal; Intestine, Small; Jejunum; Male; Methotrexate; Neutrophil Infiltration; Neutrophils; Nitrites; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Reactive Nitrogen Species; Time Factors; Tyrosine

Angiotensin II (Ang II) receptor blockers have been reported to contribute to cytoprotective effects in various organs. However, the role of renin-angiotensin system (RAS) in modulation of the inflammatory bowel disease (IBD) remains unclear. In this study we assessed the role of angiotensin II type 1a (AT1a) receptor on the outcome of dextran sulfate sodium (DSS)-induced acute colitis by employing AT1a receptor deficient mice.. The acute colitis was induced in wild type (WT) and AT1a receptor deficient mice by giving orally 3% DSS in drinking water for 7 days.. Induction of DSS colitis resulted in up-regulation of Ang II and AT1a receptor in the colonic mucosa of WT mice. In parallel, loss of body weight, an increase in disease activity index (DAI), and the shortening of colon were found in DSS-challenged WT mice. In addition, an increase in thiobarbituric acid (TBA)-reactive substances and myeloperoxidase (MPO) activity, along with the up-regulation of tumor necrosis factor (TNF)-alpha were detected in the colonic mucosa of DSS-challenged WT mice. The endpoints mentioned above were significantly ameliorated in DSS-challenged AT1a receptor deficient mice.. RAS is involved in the pathophysiology of DSS-induced colitis and AT1a receptor may be a novel therapeutic target for the treatment of IBD.

Topics: Angiotensin II; Animals; Body Weight; Colitis; Colon; Dextran Sulfate; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peroxidase; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Tumor Necrosis Factor-alpha

VGX-1027 is an isozaxoline compound that has recently been found to primarily target the function of murine macrophages but not of T cells, inhibiting secretion of tumor necrosis factor (TNF)-alpha in response to different Toll-like receptor agonists in vitro and in vivo. The well-defined role of innate immunity in inflammatory bowel diseases prompted us to consider the use of VGX-1027 in these diseases leading us to in vitro and in vivo test the drug in related experimental conditions. These consist, respectively, of the proliferation assay of CD4+CD25- T cells to enterobacteria, and the acute inflammatory colitis induced in mice by intracolonic challenge with dinitrobenzene sulfonic acid. The data from the two sets of experiments revealed that VGX-1027 inhibited both proliferation of enterobacterial antigen-reactive CD4+CD25- T cells in vitro and the development of clinical and histological signs of colitis in vivo. The beneficial effect in this model was associated with reduced colonic production of proinflammatory cytokines such as interleukin (IL)-1beta, TNF-alpha, IL-12p70 and interferon (IFN)-gamma and lower content of nuclear factor (NF)-kappaB (p65). These findings seem to warrant investigations of VGX-1027 for use in human.

Topics: Acetates; Animals; Antigen-Presenting Cells; Body Weight; CD4-Positive T-Lymphocytes; Cell Proliferation; Cell Separation; Colitis; Cytokines; Diarrhea; Enterobacteriaceae; Female; Gastrointestinal Hemorrhage; Immunologic Factors; Interleukin-2 Receptor alpha Subunit; Intestinal Mucosa; Mice; Mice, Inbred BALB C; Oxazoles; Peroxidase; Transcription Factor RelA

Cachexia, a debilitating syndrome characterized by skeletal muscle wasting, is associated to many chronic diseases and diminishes the quality of life and survival of patients. Tumor-derived factors and proinflammatory cytokines, including TNF-alpha, IL-6 and IL-1 beta, mediate cachexia. In response to elevated cytokine levels, increased proteasome-mediated proteolysis and auto-phagocytosis result in muscle wasting. The histologic features of muscle cachexia are not fully elucidated. Therefore, we analysed alterations of different cell populations in cachectic muscle.. By immunohistochemical and cytological approaches, we characterized changes in the abundance of cellular populations in the musculature of a murine model of cancer cachexia (C26-bearing mice).. Cachectic muscle displayed a decreased DNA content proportional to muscle mass wastage. A decrease in the number of nuclei occurred in the muscular but not in the stromal compartment. Cachectic muscle showed: mild modulation of myeloperoxidase activity, a neutrophil marker; reduction of macrophages in the endomysium; decrease in CD3(+) lymphocyte number. Conversely, a statistically significant enrichment in Sca-1(+) CD45(+) hematopoietic stem cells (HSCs) occurred in cachectic muscle.. The elevated levels of cytokines which characterize cachexia may represent a trigger for inflammatory cell activation. However, we find that in cachexia, inflammatory cells in muscle are not increased while muscle tissue nuclei decline. Our data suggest that the inflammatory cell-mediated stress is not an etiologic component of muscle wasting in cachexia. The relative increase in HSCs in cachectic skeletal muscle suggests an attempt to maintain muscle homeostasis by recruitment and/or activation of stem cells.

Topics: Animals; Antigens, Ly; Body Weight; Cachexia; Disease Models, Animal; DNA; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Hematopoietic Stem Cells; Leukocyte Common Antigens; Lymphocytes; Macrophages; Membrane Proteins; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Muscular Atrophy; NADP Transhydrogenases; Neoplasms; Peroxidase; Time Factors

Functional changes induced by inflammation persist following recovery from the inflammatory response, but the mechanisms underlying these changes are not well understood. Our aim was to investigate whether the excitability and synaptic properties of submucosal neurons remained altered 8 wk post-trinitrobenzene sulfonic acid (TNBS) treatment and to determine whether these changes were accompanied by alterations in secretory function in submucosal preparations voltage clamped in Ussing chambers. Mucosal serotonin (5-HT) release measurements and 5-HT reuptake transporter (SERT) immunohistochemistry were also performed. Eight weeks after TNBS treatment, colonic inflammation resolved, as assessed macroscopically and by myeloperoxidase assay. However, fast excitatory postsynaptic potential (fEPSP) amplitude was significantly increased in submucosal S neurons from previously inflamed colons relative to those in control tissue. In addition, fEPSPs from previously inflamed colons had a hexamethonium-insensitive component that was not evident in age-matched controls. AH neurons were hyperexcitable, had shorter action potential durations, and decreased afterhyperpolarization 8 wk following TNBS adminstration. Neuronally mediated colonic secretory function was significantly reduced after TNBS treatment, although epithelial cell signaling, as measured by responsiveness to both forskolin and bethanecol in the presence of tetrodotoxin, was comparable with control tissue. 5-HT levels and SERT immunoreactivity were comparable to controls 8 wk after the induction of inflammation, but there was an increase in glucagon-like peptide 2-immunoreactive L cells. In conclusion, sustained alterations in enteric neural signaling occur following the resolution of colitis, which are accompanied by functional changes in the absence of active inflammation.

Topics: Action Potentials; Animals; Bethanechol; Body Weight; Cell Count; Colforsin; Colitis; Colon; Enteric Nervous System; Enteroendocrine Cells; Excitatory Postsynaptic Potentials; Glucagon-Like Peptide 2; Guinea Pigs; Male; Membrane Potentials; Neurons; Peptide YY; Peroxidase; Serotonin; Serotonin Plasma Membrane Transport Proteins; Submucous Plexus; Tetrodotoxin; Trinitrobenzenesulfonic Acid; Veratridine

Connexin43 (Cx43) gap-junction channels are highly abundant in intestinal smooth muscle but their functional impact has not been studied so far. Here, we have aimed to elucidate the functional role of Cx43 in the tunica muscularis of the mouse intestine in vivo. Transgenic mice with conditional deletion of Cx43 in smooth muscle cells (SMC) were generated. Histological investigations by immunofluorescence analyses and organ-bath recordings to assess the contractility of intestinal tissue strips were carried out. Measurements of gastrointestinal transit and of the visceromotor response by utilizing a standardized colorectal distension model to quantify alterations of visceral sensory function were also performed in SMC-specific Cx43 null mice and control littermates. Histologically, we found thickening of the tunica muscularis and a 13-fold increase of neutrophil infiltration of the gastrointestinal wall of SMC-specific Cx43 null mice. These animals also exhibited a decrease of 29% in gastrointestinal transit time. In contrast, the visceromotor response to a standardized colorectal distension was elevated, as was the contractility in SMC-specific Cx43 null mice, compared with controls. Thus, SMC-specific ablation of Cx43 in mice leads to morphological and functional alterations of the intestinal tunica muscularis, to gastrointestinal motor dysfunction and to altered visceral sensory function.

Topics: Animals; beta-Galactosidase; Body Weight; Carbachol; Cell Nucleus; Connexin 43; Gene Deletion; Gene Expression; Inflammation; Integrases; Intestinal Mucosa; Intestines; Lac Operon; Mice; Mice, Inbred Strains; Mice, Transgenic; Microfilament Proteins; Muscle Contraction; Muscle Proteins; Muscle, Smooth; Neutrophils; Pain Measurement; Peroxidase; Potassium Chloride; Tamoxifen

Hepatic warm ischemia during surgery remains a significant problem, particularly in organs with possible baseline dysfunction. The objective of this study was to investigate whether age influences the degree of warm ischemia-reperfusion injury in rat livers.. The left and median lobes of young (3 months) and adult (9 months) male rats were exposed to 75 min of ischemia followed by reperfusion. Each age group was divided into two sub-groups. One sub-group was observed for 8 h, whereas the other was allowed to survive. Animals in the 8-h groups (young and adult) were sacrificed, and blood and tissue were taken to determine liver enzymes, neutrophil accumulation, and blood metabolic profiles and to examine the histology.. Hepatocellular injury was significantly greater in adult rats after 8 h of reperfusion, as determined by hepatic enzyme levels and histology. Liver enzyme levels were massively elevated in adult rats and were significantly higher compared with those of young rats. The degree of necrosis and neutrophil accumulation was significantly higher in adult rats. After 8 h of reperfusion, the metabolic profiling of the blood revealed elevated levels of creatine, creatinine, allantoin, and amino acids (tyrosine, methionine) in the adult rats. At 24 h of reperfusion, all adult rats died, in contrast to young rats, which all survived.. Aging in rats is associated with greater hepatocellular injury and poor survival rate after 75 min of warm hepatic ischemia.

Topics: Aging; Animals; Body Weight; Liver; Magnetic Resonance Spectroscopy; Male; Neutrophils; Organ Size; Peroxidase; Rats; Rats, Inbred Lew; Reperfusion Injury; Severity of Illness Index; Survival Rate; Temperature

beta-Caryophyllene (BCP), a naturally occurring plant sesquiterpene, was examined for anti-inflammatory activity in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by exposing male BALB/c mice to 5% DSS in drinking water for 7 days. BCP in doses of 30 and 300 mg/kg was administered orally once a day, beginning concurrently with exposure to DSS. The body weight and colon length were measured, and histological damage and myeloperoxidase (MPO) activity as well as inflammatory cytokines were assessed in both serum and colonic tissue after 7 days of treatment with DSS. The DSS treatment damaged the colonic tissue, increased MPO activity and inflammatory cytokines, lowered the body weight, and shortened the length of the colon. Oral administration of BCP at 300 mg/kg significantly suppressed the shortening of colon length and slightly offset the loss of body weight. BCP treatment (300 mg/kg) also significantly reduced the inflammation of colon and reversed the increase in MPO activity that had been induced by exposure to DSS. Further, BCP significantly suppressed the serum level of IL-6 protein (a 55% reduction) as well as the level of IL-6 mRNA in the tissue. These results demonstrate that BCP ameliorates DSS-induced experimental colitis, and may be useful in the prevention and treatment of colitis.

Topics: Animals; Body Weight; Colitis; Cytokines; Dextran Sulfate; Enzyme-Linked Immunosorbent Assay; Indicators and Reagents; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; Organ Size; Peroxidase; Polycyclic Sesquiterpenes; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes

Single injection of streptozotocin (STZ) resulted diabetes mellitus which was reflected here by the levels of fasting blood glucose and serum insulin. Moreover, this experimental diabetes also resulted testicular dysfunctions evaluated by count, viability and motility of sperm as well as by the activities of key enzymes for androgen synthesis. Diabetes induced testicular oxidative stress has been indicated here by the monitoring of testicular peroxidase and catalase activities as well as by quantification of TBARS and CD of testis. Testicular glucose was increased and leydig cell nuclear area was decreased in STZ induced diabetes. Treatment of herbal formulated drug named as MTEC consist of aqueous-methanol extract of Musa paradisiaca, Tamarindus indica, Eugenia jambolana and Coccinia indica to streptozotocin induced diabetic rat at the ratio of 2:2:1:1 at the dose of 60 mg/d for two times a day for 14 d resulted a significant protection in fasting blood glucose and serum insulin levels (p<0.05) along with correction of testicular above parameters towards the control level (p<0.05). This herbal formulated drug has no general toxic effects on the body weight, as well as on the activities of serum glutamate and pyruvate transaminases in serum. The results support the validity of this herbal drug for the management of testicular disorders noted in diabetic state.

Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Animals; Blood Glucose; Body Weight; Catalase; Cell Survival; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; Glucose; Hypoglycemic Agents; Insulin; Lipid Peroxidation; Male; Peroxidase; Rats; Rats, Wistar; Sperm Count; Sperm Motility; Spermatozoa; Testicular Diseases; Testis; Testosterone; Time Factors

Studies showed that early postnatal exposure to the herbicide atrazine (ATR) delayed preputial separation (PPS) and increased incidence of prostate inflammation in adult Wistar rats. A cross-fostering paradigm was used in this study to determine if gestational exposure to ATR would also result in altered puberty and reproductive tissue effects in the male rat. Timed-pregnant Long-Evans (LE) rats were dosed by gavage on gestational days (GD) 15-19 with 100 mg ATR/kg body weight (BW) or 1% methylcellulose (controls, C). On postnatal day (PND)1, half litters were cross-fostered, creating 4 treatment groups; C-C, ATR-C, C-ATR, and ATR-ATR (transplacental-milk as source, respectively). On PND4, male offspring in the ATR-ATR group weighed significantly less than the C-C males. ATR-ATR male pups had significantly delayed preputial separation (PPS). BWs at PPS for C-ATR and ATR-ATR males were reduced by 6% and 9%, respectively, from that of C-C. On PND120, lateral prostate weights of males in the ATR-ATR group were significantly increased over C-C. Histological examination of lateral and ventral prostates identified an increased distribution of inflammation in the lateral prostates of C-ATR males. By PND220, lateral prostate weights were significantly increased for ATR-C and ATR-ATR, but there were no significant changes in inflammation in either the lateral or ventral prostate. These results suggest that in LE rats, gestational ATR exposure delays PPS when male offspring suckle an ATR dam, but leads to increased lateral prostate weight via transplacental exposure alone. Inflammation present at PND120 does not increase in severity with time.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Animals, Newborn; Animals, Suckling; Atrazine; Body Weight; Female; Genitalia, Male; Gonadal Steroid Hormones; Herbicides; Lactation; Male; Maternal-Fetal Exchange; Organ Size; Peroxidase; Pituitary Gland; Pregnancy; Rats; Rats, Long-Evans

This study investigated the effect of n-3 fatty acids on adhesion molecules and tissue myeloperoxidase (MPO) activity in diabetic mice with sepsis. Diabetes was induced by a streptozotocin injection. Mice with blood glucose levels exceeding 2000 mg/l were considered diabetic. Diabetic mice were assigned to two groups with a medium-fat (10 %, w/w) diet either provided by soyabean oil (SO, n 30) or fish oil (FO, n 30). n-3 fatty acids provided 4.3 % of the total energy and the n-3/n-6 fatty acid ratio was 1:2 in the FO diet. After feeding the respective diet for 3 weeks, all mice had sepsis induced by caecal ligation and puncture (CLP) and were killed at 0, 6 or 24 h after CLP, with ten mice at each time-point. The result showed that compared with the SO group, FO group had lower PGE2 and TNF-alpha levels in peritoneal lavage fluid after CLP. Lymphocyte CD11a/CD18 expressions were higher at 6 h, whereas the percentage was lower at 24 h in the SO group than in the FO group. Neutrophil CD11b/CD18 expressions were significantly higher in the SO group than in the FO group at 0 h. The FO group had lower organ MPO activities at various time-points after CLP when compared with those of the SO group. The present findings suggest that compared with the diabetic mice fed SO, a low-dose n-3 fatty acid supplementation may attenuate leucocyte adhesion and infiltration into tissues in diabetic mice complicated with sepsis.

Topics: Animals; Ascitic Fluid; Blood Glucose; Body Weight; CD11a Antigen; CD11b Antigen; CD18 Antigens; Cell Adhesion; Cell Adhesion Molecules; Diabetes Mellitus, Experimental; Dietary Supplements; Dinoprostone; Fatty Acids, Omega-3; Fish Oils; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred ICR; Peroxidase; Sepsis; Tumor Necrosis Factor-alpha

Sinomenine is a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum. It was demonstrated that sinomenine had anti-inflammatory and immunosuppressive effects in the previous studies. The aim of the present study was to evaluate therapeutic effects of sinomenine on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) induced colitis in mice. Two hours following colonic instillation of TNBS, sinomenine with several doses (30, 100, 200 mg/kg) was given by gastric gavage once daily for 7 days. Comparing with the saline-treated mice with TNBS-induced colitis, sinomenine (100 mg/kg and 200 mg/kg)-treated mice with TNBS-induced colitis were shown improvements of weight loss, macroscopic score, histological score, and myeloperoxidase activity. Moreover, treatments with sinomenine (100 mg/kg and 200 mg/kg) decreased the up-regulated mRNA and protein levels of tumour necrosis factor-alpha(TNF-alpha) and interferon-gamma (IFN-gamma) caused by TNBS. Our findings suggest that sinomenine attenuates TNBS-induced colitis in mice and the therapeutic mechanism might be related to the reduction of up-regulated colonic TNF-alpha and IFN-gamma production caused by TNBS.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Colitis; Colon; Enzyme-Linked Immunosorbent Assay; Female; Interferon-gamma; Mice; Mice, Inbred BALB C; Morphinans; Peroxidase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

Adenosine modulates the immune system and inhibits inflammation via reduction of cytokine biosynthesis and neutrophil functions. Drugs able to prevent adenosine catabolism could represent an innovative strategy to treat inflammatory bowel disorders. In this study, the effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP; novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; standard adenosine deaminase inhibitor), and dexamethasone were tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid (DNBS). DNBS-treated animals received APP (5, 15, or 45 micromol/kg), EHNA (10, 30, or 90 micromol/kg), or dexamethasone (0.25 micromol/kg) i.p. for 7 days starting 1 day before colitis induction. DNBS caused bowel inflammation associated with decrease in food intake and body weight. Animals treated with APP or EHNA, but not dexamethasone, displayed greater food intake and weight gain than inflamed rats. Colitis induced increment in spleen weight, which was counteracted by all test drugs. DNBS administration was followed by macroscopic and microscopic inflammatory colonic alterations, which were ameliorated by APP, EHNA, or dexamethasone. In DNBS-treated rats, colonic myeloperoxidase, malondialdehyde, and tumor necrosis factor (TNF)-alpha levels as well as plasma TNF-alpha and interleukin-6 were increased. All test drugs lowered these phlogistic indexes. Inflamed colonic tissues displayed an increment of inducible nitric-oxide synthase mRNA, which was unaffected by APP or EHNA, but reduced by dexamethasone. Cyclooxygenase-2 expression was unaffected by DNBS or test drugs. These findings indicate that 1) inhibition of adenosine deaminase results in a significant attenuation of intestinal inflammation and 2) the novel compound APP is more effective than EHNA in reducing systemic and intestinal inflammatory alterations.

Topics: Adenine; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Benzenesulfonates; Body Weight; Colitis; Colon; Cyclooxygenase 2; Dexamethasone; Eating; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Interleukin-6; Intestinal Mucosa; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Organ Size; Peroxidase; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; Spleen; Tumor Necrosis Factor-alpha

Chitosan-Ca-alginate microparticles for colon-specific delivery and controlled release of 5-aminosalicylic acid after peroral administration were prepared using spray drying method followed by ionotropic gelation/polyelectrolyte complexation. Physicochemical characterization pointed to the negatively charged particles with spherical morphology having a mean diameter less than 9 microm. Chitosan was localized dominantly in the particle wall, while for alginate, a homogeneous distribution throughout the particles was observed. (1)H NMR, FTIR, X-ray and DSC studies indicated molecularly dispersed drug within the particles with preserved stability during microencapsulation and in simulated in vivo drug release conditions. In vitro drug release studies carried out in simulated in vivo conditions in respect to pH, enzymatic and salt content confirmed the potential of the particles to release the drug in a controlled manner. The diffusional exponents according to the general exponential release equation indicated anomalous (non-Fickian) transport in 5-ASA release controlled by a polymer relaxation, erosion and degradation. Biodistribution studies of [(131)I]-5-ASA loaded chitosan-Ca-alginate microparticles, carried out within 2 days after peroral administration to Wistar male rats in which TNBS colitis was induced, confirmed the dominant localization of 5-ASA in the colon with low systemic bioavailability.

Topics: Alginates; Animals; Anti-Inflammatory Agents, Non-Steroidal; B-Lymphocytes; Body Weight; Calcium; Calorimetry, Differential Scanning; Chemical Phenomena; Chemistry, Physical; Chitosan; Colitis; Colon; Crystallography, X-Ray; Delayed-Action Preparations; Drug Compounding; Drug Delivery Systems; Electrochemistry; Excipients; Gels; Magnetic Resonance Spectroscopy; Male; Mesalamine; Microspheres; Organ Size; Particle Size; Peroxidase; Rats; Rats, Wistar; Solubility; Spectroscopy, Fourier Transform Infrared; Tissue Distribution

To establish the therapeutic potential of proteasome inhibition, we examined the therapeutic effects of MG132 (Z-Leu-Leu-Leu-aldehyde) in an experimental model of acute pancreatitis.. Pancreatitis was induced in rats by two hourly intraperitoneal (ip) injections of cholecystokinin octapeptide (CCK; 2 x 100 microg/kg) and the proteasome inhibitor MG132 (10 mg/kg ip) was administered 30 min after the second CCK injection. Animals were sacrificed 4 h after the first injection of CCK.. Administering the proteasome inhibitor MG132 (at a dose of 10 mg/kg, ip) 90 min after the onset of pancreatic inflammation induced the expression of cell-protective 72 kDa heat shock protein (HSP72) and decreased DNA-binding of nuclear factor-kappaB (NF-kappaB). Furthermore MG132 treatment resulted in milder inflammatory response and cellular damage, as revealed by improved laboratory and histological parameters of pancreatitis and associated oxidative stress.. Our findings suggest that proteasome inhibition might be beneficial not only for the prevention, but also for the therapy of acute pancreatitis.

Topics: Acute Disease; Animals; Body Weight; Cholecystokinin; Cysteine Proteinase Inhibitors; Cytokines; HSP72 Heat-Shock Proteins; Leupeptins; Male; NF-kappa B; Organ Size; Oxidative Stress; Pancreas; Pancreatitis; Peroxidase; Proteasome Inhibitors; Rats; Rats, Wistar

There is a gender-related comorbidity of pain-related and inflammatory bowel diseases with psychiatric diseases. Since the impact of experimental gastrointestinal inflammation on the emotional-affective behavior is little known, we examined whether experimental gastritis modifies anxiety, stress coping and circulating corticosterone in male and female Him:OF1 mice. Gastritis was induced by adding iodoacetamide (0.1%) to the drinking water for at least 7 days. Inflammation was assessed by gastric histology and myeloperoxidase activity, circulating corticosterone determined by enzyme immunoassay, anxiety-related behavior evaluated with the elevated plus maze and stress-induced hyperthermia tests, and depression-like behavior estimated with the tail suspension test. Iodoacetamide-induced gastritis was associated with gastric mucosal surface damage and an increase in gastric myeloperoxidase activity, this increase being significantly larger in female mice than in male mice. The rectal temperature of male mice treated with iodoacetamide was enhanced, whereas that of female mice was diminished. The circulating levels of corticosterone were reduced by 65% in female mice treated with iodoacetamide but did not significantly change in male mice. On the behavioral level, iodoacetamide treatment caused a decrease in nocturnal home-cage activity, drinking and feeding. While depression-related behavior remained unaltered following induction of gastritis, behavioral indices of anxiety were significantly enhanced in female but not male mice. There was no correlation between the estrous cycle and anxiety as well as circulating corticosterone. Radiotracer experiments revealed that iodoacetamide did not readily enter the brain, the blood-brain ratio being 20:1. Collectively, these data show that iodoacetamide treatment causes gastritis in a gender-related manner, its severity being significantly greater in female than in male mice. The induction of gastritis in female mice is associated with a reduction of circulating corticosterone and an enforcement of behavioral indices of anxiety. Gastric inflammation thus has a distinct gender-dependent influence on emotional-affective behavior and its neuroendocrine control.

Topics: Alkylating Agents; Animals; Animals, Outbred Strains; Anxiety; Body Weight; Brain; Circadian Rhythm; Corticosterone; Drinking Behavior; Estrous Cycle; Feeding Behavior; Female; Gastric Mucosa; Gastritis; Iodine Radioisotopes; Iodoacetamide; Male; Maze Learning; Mice; Peroxidase; Sex Characteristics; Stress, Psychological; Tomography, Emission-Computed, Single-Photon

The aim of this study was to evaluate and compare the effectiveness of N-acetylcysteine (NAC) and liposomally-encapsulated NAC (L-NAC) in ameliorating the hepatotoxic effects of lipopolysaccharide (LPS). LPS, a major cell wall molecule of Gram-negative bacteria and the principal initiator of septic shock, causes liver injury in vivo that is dependent on neutrophils, platelets, and several inflammatory mediators, including tumour necrosis factor-alpha (TNF-alpha). Male Sprague-Dawley rats were pretreated intravenously with saline, plain liposomes (dipalmitoylphosphatidylcholine [DPPC]), NAC (25 mg/kg body weight), or L-NAC (25 mg/kg NAC body weight) and 4 h later were challenged intravenously with LPS (Escherichia coli O111:B4, 1.0 mg/kg body weight); animals were killed 20 h post-LPS challenge. Hepatic cell injury was evaluated by measuring the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in plasma. LPS-induced activation of the inflammatory response was evaluated by measuring the levels of myeloperoxidase activity and chloramine concentration in liver homogenates as well as TNF-alpha levels in plasma. The hepatic levels of lipid peroxidation products and non-protein thiols (NPSH) were used to assess the extent of involvement of oxidative stress mechanisms. In general, challenge of animals with LPS resulted in hepatic injuries, activation of the inflammatory response, decreases in NPSH levels and increases in the levels of lipid peroxidation products (malondialdehyde and 4-hydroxyalkenals). Pretreatment of animals with NAC or empty liposomes did not have any significant protective effect against LPS-induced hepatotoxicity. On the other hand, pretreatment of animals with an equivalent dose of L-NAC conferred protection against the liver injuries induced following LPS challenge. These data suggest that NAC when delivered as a liposomal formulation is a potentially more effective prophylactic pharmacological agent in alleviating LPS-induced liver injuries.

Topics: Acetylcysteine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Chloramines; Disease Models, Animal; Lipid Peroxidation; Lipopolysaccharides; Liver; Lysine; Male; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds; Tumor Necrosis Factor-alpha

The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days) caused a dose-dependent reduction in the colonic inflammation induced by intracolonic TNBS assessed after 3 days, both as the area of macroscopic involvement and as a score using 0-10 scale. Likewise, following administration of the GSK-3beta inhibitor SB 415286 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days), the extent and degree of the TNBS-provoked colonic inflammation was reduced. Administration of either TDZD-8 or SB 415286 reduced the fall in body weight following challenge with TNBS at each dose level studied. The increase in myeloperoxidase activity, an index of neutrophil infiltration into the TNBS-induced inflamed colon, was significantly inhibited by both TDZD-8 and SB 415286 at each dose level. The increase in the levels of the proinflammatory cytokine, TNF-alpha, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. The elevated levels of the transcription factor NF-kappaB subunit p65, as determined by Western blot in the nuclear extracts from the TNBS-provoked inflamed colonic tissue, were dose-dependently reduced by TDZD-8 or SB 415286 treatment. These findings demonstrate that two chemically distinct selective inhibitors of the activity of GSK-3beta reduce the inflammation and tissue injury in a rat model of acute colitis. The mechanisms underlying this anti-inflammatory action may be related to downregulation of NF-kappaB activity, involved in the generation of proinflammatory mediators.

Topics: Aminophenols; Animals; Body Weight; Colitis; Colon; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Maleimides; Organ Size; Peroxidase; Rats; Rats, Wistar; Thiadiazoles; Transcription Factor RelA; Tumor Necrosis Factor-alpha

In cerebral stroke, the overall mortality rate of older individuals is higher than that of younger individuals. We therefore investigated aging-related changes in brain tissue damage and immune response in response to intracerebral hemorrhage (ICH) in mice.. ICH was induced by microinjecting autologous whole blood (5 microL) into the striatum of 4- or 14-month-old senescence-accelerated prone (SAMP8) mice or senescence-accelerated resistant (SAMR1) mice.. In all groups, neurological deficits occurred within 6 hours and gradually improved after the first day, but improvement was most delayed in 14-month-old SAMP8 mice. Isolectin B4-positive and amoeboid microglia/macrophages were abundantly distributed around and inside the hemorrhagic lesions in 14-month-old SAMP8 mice. In contrast, myeloperoxidase-immunoreactive neutrophils and reactive astrocytes with intensified glial fibrillary acidic protein-stained processes and swollen cytoplasm did not differ in number or distribution between SAMP8 and SAMR1 mice. Regardless of their age, the immunoreactivity of Mn-SOD, a major antioxidant enzyme in mitochondria, was much weaker in SAMP8 than in SAMR1 mice. The expression of inducible nitric oxide, however, was higher in old SAMP8 mice than in the other experimental groups.. These results suggest that activated microglia/monocytes may aggravate intracerebral hemorrhagic damage in old SAMP8 mice. Further studies on the exact role of activated microglia/monocytes and the altered activities of antioxidant enzymes in old SAMP8 mice may provide useful information for ICH-induced brain injury in relation with aging.

Topics: Aging; Animals; Antioxidants; Astrocytes; Body Weight; Brain; Brain Injuries; Cellular Senescence; Cerebral Hemorrhage; Immunohistochemistry; Macrophages; Male; Mice; Microglia; Neurons; Neutrophils; Oxidative Stress; Oxygen; Peroxidase; Superoxide Dismutase; Time Factors

Matrine is an alkaloid found in kinds of Sophora plants mainly including Sophora flavescens, Sophora alopecuroides and Sophora subprotrata. The aim of the present study was to evaluate therapeutic effects of matrine on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. Two hours following colonic instillation of TNBS, matrine with several doses was given by gastric gavage once daily for 7 days. Comparing with the 0.9% NaCl-treated mice with TNBS-induced colitis, matrine (10 and 20 mg kg(-1))-treated mice with TNBS-induced colitis were shown improvements of weight loss, macroscopic score, histological score, and myeloperoxidase (MPO) activity. Moreover, treatments with matrine (10 and 20 mg kg(-1)) decreased the up-regulated mRNA and protein levels of tumour necrosis factor-alpha (TNF-alpha) caused by TNBS. Our findings suggest that matrine improves TNBS-induced colitis in mice and the therapeutic mechanism might be related to the reduction of up-regulated colonic TNF-alpha production caused by TNBS.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Body Weight; Colitis; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Matrines; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Quinolizines; RNA, Messenger; Time Factors; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

There is increased interest in the study of manipulation of the flora with pro- and prebiotics regarding inflammatory bowel disease. The aim of this work was to evaluate the effect of oligosaccharides from goat milk in a rat model of dextran sodium sulfate- (DSS-) induced colitis.. Twenty rats were fed the same diet but with different sources of fiber (5% of the diet): cellulose or a mixture of goat's milk oligosaccharides (GMO) and cellulose. DSS treatment was used to induce a colonic inflammation. Several clinical and inflammatory parameters, as well as intestinal micorbiota and gene expression by DNA microarray technology, were evaluated.. DSS induced a decrease in body weight which was not observed in rats fed the GMO (decrease of 21+/-11% in control rats vs increase of 5.2+/-8.6 in GMO rats, P<0.05). DSS also caused an acute colonic inflammatory process which was weaker in rats fed the GMO, as shown by colon myeloperoxidase activity (0.53+/-0.16 vs 0.14+/-0.07U/mg of protein, P<0.05), as well as clinical symptoms measured by a scoring system (1.25+/-1.14 vs 0.4+/-0.07, P<0.05). GMO rats also showed less severe colonic lesions and a more favorable intestinal microbiota. The expression of genes involved in intestinal function, such as mucine-3, was down-regulated in DSS-control rats but returned to normal values in GMO rats.. GMO reduce intestinal inflammation and contribute to the recovery of damaged colonic mucosa.

Topics: Animals; Body Weight; Colitis; Colon; Dextran Sulfate; Diet; Fatty Acids, Volatile; Feces; Female; Gene Expression Profiling; Glutathione; Goats; Inflammation; Liver; Male; Milk; Oligonucleotide Array Sequence Analysis; Oligosaccharides; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley

Geranylgeranylacetone (GGA) has recently been reported to have a protective effect against ischemic, injurious and apoptotic stress in several tissues. The aim of this study was to determine the effect of GGA on colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. Colitis was induced by intrarectal instillation of TNBS in 50% ethanol in BALB/c mice. Survival, change in body weight and change in wet colon weight were assessed. Histological score in the colon was evaluated 5 days after TNBS treatment. The level of myeloperoxidase (MPO) activity in the colon was also determined. Immunohistochemistry for CD4 in the colon was performed. In addition, the level of heat shock protein (HSP) 70 in the colon was determined by Western blot analysis. Mice were orally treated with GGA (300 mg/kg) 2 h before and every other day after starting TNBS administration. Treatment with GGA markedly improved the survival rate, and reduced the loss of body weight and loss of wet colon weight in mice with TNBS-induced colitis. GGA also suppressed the increase in MPO activity and the number of CD4-positive cells infiltrating the colons of mice with TNBS-induced colitis. Furthermore, treatment with GGA remarkably up-regulated the expression of HSP70 in the colons of mice with TNBS-induced colitis. Our results provide further evidence that GGA has therapeutic potential for intestinal inflammation.

Topics: Animals; Body Weight; CD4-Positive T-Lymphocytes; Colitis; Diterpenes; HSP70 Heat-Shock Proteins; Male; Mice; Mice, Inbred BALB C; Organ Size; Peroxidase; Survival Rate; Trinitrobenzenesulfonic Acid

The present study was to investigate the effects of l-arginine (l-Arg) supplementation on cardiac oxidative stress and the inflammatory response in rats following acute exhaustive exercise on a treadmill. Rats were randomly divided into four groups: sedentary control (SC); SC with l-Arg treatment (SC+Arg); exhaustive exercise (E); exhaustive exercise with l-Arg treatment (E+Arg). Rats in groups SC+Arg and E+Arg received a 2 % l-Arg diet. Rats in groups E and E+Arg performed an exhaustive running test on a treadmill at a final speed of 30 m/min, 10 % grade, at approximately 70-75 % VO2max. The results showed a significant increase in cardiac xanthine oxidase (XO) and myeloperoxidase activities and membrane lipid peroxidation endproduct (malondialdehyde; MDA) levels of exercised rats compared with SC rats. The increased cardiac XO activity and MDA levels in exercised rats were significantly decreased in exercised rats supplemented with l-Arg. Myocardial GSSG content increased whereas the GSH:GSSG ratio was depressed in exercised rats compared with SC rats. Cardiac GSSG levels significantly decreased, whereas total glutathione, GSH and the GSH:GSSG ratio increased in exercised rats supplemented with l-Arg compared with exercised rats. The activities of creatinine kinase (CK) and lactate dehydrogenase (LDH), and lactate, uric acid, and nitrite and nitrate levels in the plasma significantly increased in exercised rats compared with SC rats. The activities of plasma CK and LDH were significantly decreased in l-Arg-supplemented plus exercised rats compared with exercised rats. These findings suggest that l-Arg supplementation reduces the oxidative damage and inflammatory response on the myocardium caused by exhaustive exercise in rats.

Topics: Animals; Antioxidants; Arginine; Blood Chemical Analysis; Body Weight; Dietary Supplements; Glutathione; Lipid Peroxidation; Male; Myocardium; Oxidation-Reduction; Oxidative Stress; Peroxidase; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Sprague-Dawley; Xanthine Oxidase

Lipid peroxidation mediated by oxygen free radicals plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Vitamin E is a lipid-soluble antioxidant and is generally considered to protect against lipid peroxidation of the cell membrane and to scavenge singlet oxygen and superoxide anion radical. Therefore, vitamin E or its derivatives are expected to have particular application for patients suffering from IBD. The aim of this study was to investigate the antioxidative effects of the water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetra-methylchroman-6-ol(TMG), on the therapy of experimental colitis in rats. Colitis was induced in male Wistar rats weighing 200 g using an enema of trinitrobenzene sulfonic acid (TNBS) dissolved in 50% ethanol; TMG dissolved in physiological saline was injected intra-peritoneally every day from 24 h after the enema of TNBS. The damage score, wet weight of the colon, and increase in body weight were estimated 1 week after the enema of TNBS. Thiobarbituric acid-reactive substances (TBA-RS), an index of lipid peroxidation, and tissue-associated myeloperoxidase (MPO) activity in the colonic mucosa were measured 1 week after the induction of colitis. As a result, increase in body weight was inhibited by the induction of colitis, although the inhibition was reduced in the group treated with TMG. The damage score, wet weight, TBA-RS and MPO activity were increased significantly in the colitis group; however, they were inhibited by the administration of TMG. These results suggest that TMG is effective for the treatment of colitis in rats induced by TNBS. In the future, TMG could be a new therapeutic agent for IBD.

Topics: Animals; Body Weight; Chromans; Colitis; Colon; Cytokines; Glycosides; Inflammation; Intestinal Mucosa; Male; Peroxidase; Rats; Rats, Wistar; Solubility; Thiobarbituric Acid Reactive Substances; Trinitrobenzenesulfonic Acid; Vitamin E

Nitric oxide (NO) plays a role in regulating the mucosal integrity of the stomach. However, its part in the mucosal defense of the inflamed stomach remains unclear. In the present study, we examined the effects of various NO synthase (NOS) inhibitors on gastric ulcerogenic and acid secretory responses following daily exposure of the stomach to iodoacetamide and investigated the role of each NOS isozyme in gastric protection from subchronic mucosal irritation. Gastric mucosal irritation was induced in rats by addition of 0.1% iodoacetamide to drinking water, and the gastric mucosa was examined on the 6th day. L-NAME (a nonselective NOS inhibitor: 20 mg/kg) or aminoguanidine (a selective iNOS inhibitor: 20 mg/kg) was given s.c. twice 24 h and 3 h before the termination of iodoacetamide treatment. Giving iodoacetamide in drinking water for 5 days produced minimal damage in the stomach with an increase in myeloperoxidase (MPO) activity and lipid peroxidation. Iodoacetamide treatment up-regulated the expression of iNOS mRNA and NO production in the stomach, without affecting nNOS expression. Both L-NAME and aminoguanidine markedly aggravated gastric lesions induced by iodoacetamide treatment, with a further enhancement in MPO activity and lipid peroxidation. Basal acid secretion as determined in pylorous-ligated stomachs was decreased following iodoacetamide treatment, but the response was significantly restored by both L-NAME and aminoguanidine. These results suggest that endogenous NO derived from both cNOS and iNOS is involved in mucosal defense of the inflamed stomach, partly by decreasing acid secretion, and contributes to maintaining mucosal integrity under such conditions.

Topics: Animals; Body Weight; Enzyme Inhibitors; Gastric Acid; Gastric Mucosa; Gastritis; Guanidines; Iodoacetamide; Lipid Peroxidation; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Sprague-Dawley

Gliotoxin, a fungal metabolite, has been known to show strong immunosuppressive properties, although its mechanisms are not completely understood. In this report, the authors investigated the mechanism whereby gliotoxin has anti-inflammatory properties in vitro and in trinitrobenzene sulfonic acid-induced colitis.. Body weight, histological scores, and myeloperoxidase activity were evaluated in trinitrobenzene sulfonic acid colitis. Nuclear factor-kappaB (NF-kappaB) p65, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-12, and intercellular adhesion molecule-1 were detected by immunohistochemical staining. IL-8 secretion was measured by an enzyme-linked immunosorbent assay. Heme oxygenase-1 (HO-1) expression and I-kappaB degradation were analyzed by Western blot.. Pretreatment of human epithelial HT-29 cells with gliotoxin significantly blocked the I-kappaB degradation and NF-kappaB p65 nuclear translocation induced by tumor necrosis factor-alpha or IL-1beta; these were parallel with the inhibition of IL-8 secretion and intercellular adhesion molecule-1 expression in the same cells. Interestingly, gliotoxin induced HO-1 in HT-29 cells and, in turn, inhibition of HO-1 activity by a zinc protoporphyrin IX reversed the effects of gliotoxin in terms of I-kappaB degradation, intercellular adhesion molecule-1 expression, and IL-8 production. In trinitrobenzene sulfonic acid colitis, gliotoxin administration significantly improved the clinical and histopathological symptoms. Notably, gliotoxin also induced HO-1 in the colonic mucosa and zinc protoporphyrin IX reversed the protective effects of gliotoxin in trinitrobenzene sulfonic acid colitis.. These results demonstrate for the first time that the anti-inflammatory actions mediated by gliotoxin include HO-1 induction and the subsequent blockade of NF-kappaB-dependent signaling pathways in vitro and in vivo. The current results also demonstrate that gliotoxin may be an effective agent for the treatment of diseases characterized by mucosal inflammation.

Topics: Animals; Anti-Inflammatory Agents; Body Weight; Caco-2 Cells; Colitis; Gliotoxin; Heme Oxygenase-1; Humans; Immunosuppressive Agents; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; Mice; NF-kappa B; Peroxidase; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

We recently demonstrated that both lisinopril and candesartan, an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, respectively, attenuate pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori (WBN/Kob) rats. The purpose of the present study was to assess whether combination therapy with low doses of both, ineffective when given alone, might synergistically exert protective effects. Lisinopril, candesartan, or a combination of both in drinking water was administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for alpha-smooth muscle actin, and gene expression of cytokine and growth factors were assessed, as well as circulating renin-angiotensin system components. Dose-dependent effects of combination therapy were also investigated. Only combination therapy attenuated gross alterations in the pancreas, as quantitatively confirmed by increases in pancreatic weights and decreases in myeloperoxidase activity, hydroxyproline content, histologic scores, relative fibrosis area, and relative area of alpha-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA in the pancreas. Dose dependence of combination therapy was recognized with reference to improvement in these parameters. The conclusions are that combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA. Compared with the either therapy alone, combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker may be more beneficial for treating chronic pancreatitis.

Topics: Actins; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Body Weight; Chronic Disease; Cytokines; Dose-Response Relationship, Drug; Drug Synergism; Fibrosis; Genes, ras; Hydroxyproline; Immunohistochemistry; Lisinopril; Male; Organ Size; Pancreatitis; Peptidyl-Dipeptidase A; Peroxidase; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; RNA, Messenger; Tetrazoles

To examine the effect of eradication of Helicobacter pylori prior to usage of NSAIDs, by investigating gastric inflammatory activity, myeloperoxidase (MPO) activity, prostaglandin (PG) E2 synthesis in H pylori-infected, and H pylori-eradicated gerbils followed by administration of indomethacin and rofecoxib.. Six-week-old male gerbils were orally inoculated with H pylori. Seven weeks later, anti-H pylori triple therapy and vehicle were given to gerbils respectively and followed by oral indomethacin (2 mg/kg.d) or rofecoxib (10 mg/kg.d) for 2 wk. We examined the area of lesions, gastric inflammatory activity, PGE2 synthesis and MPO activity in the stomach.. In indomethacin and rofecoxib-treated gerbils, the following results were obtained in H pylori-infected group vs H pylori-eradicated group respectively: hyperplasia area of the stomach (mm2): 82.4+/-9.2 vs 13.9+/-3.5 (P<0.05), 30.5+/-5.1 vs 1.3+/-0.6 (P<0.05); erosion and ulcer area (mm2): 14.4+/-4.9 vs 0.86+/-0.5 (P<0.05), 1.3+/-0.6 vs 0.4+/-0.3 (P<0.05); score of gastritis: 7.0+/-0.0 vs 3.6+/-0.5 (P<0.05), 7.0+/-0.0 vs 2.7+/-0.5 (P<0.05); MPO activity (micromol H2O2/min/g tissue): 104.7+/-9.2 vs 9.0+/-2.3 (P<0.05), 133.5+/-15.0 vs 2.9+/-0.7 (P<0.05); PGE2 synthesis (pg/mg wet weight/min): 299.2+/-81.5 vs 102.8+/-26.2 (P<0.05), 321.4+/-30.3 vs 11.9+/-4.8 (P<0.05).. Eradication of H pylori reduced gastric damage of NSAID-treated Mongolian gerbils. Rofecoxib caused less severe gastric damage than indomethacin in H pylori-eradicated gerbils.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Chronic Disease; Dinoprostone; Gastritis; Gerbillinae; Helicobacter Infections; Helicobacter pylori; Indomethacin; Lactones; Male; Organ Size; Peroxidase; Stomach; Stomach Ulcer; Sulfones

To assess the effect of our novel cell-permeable nuclear factor-kappaB (NF-kappaB) inhibitor peptide PN50 in an experimental model of acute pancreatitis. PN50 was produced by conjugating the cell-penetrating penetratin peptide with the nuclear localization signal of the NF-kappaB p50 subunit.. Pancreatitis was induced in male Wistar rats by administering 2X100 mug/kg body weight of cholecystokinin-octapeptide (CCK) intraperitoneally (IP) at an interval of 1 h. PN50-treated animals received 1 mg/kg of PN50 IP 30 min before or after the CCK injections. The animals were sacrificed 4 h after the first injection of CCK.. All the examined laboratory (the pancreatic weight/body weight ratio, serum amylase activity, pancreatic levels of TNF-alpha and IL-6, degree of lipid peroxidation, reduced glutathione levels, NF-kappaB binding activity, pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease were improved before and after treatment with the PN50 peptide. According to the histological findings, PN50 protected the animals against acute pancreatitis by favoring the induction of apoptotic, as opposed to necrotic acinar cell death associated with severe acute pancreatitis.. Our study implies that reversible inhibitors of stress-responsive transcription factors like NF-kappaB might be clinically useful for the suppression of the severity of acute pancreatitis.

Topics: Active Transport, Cell Nucleus; Acute Disease; Amino Acid Sequence; Amylases; Animals; Body Weight; Cell Line, Transformed; Electrophoretic Mobility Shift Assay; Glutathione; Interleukin-6; Lipid Peroxidation; Lung; Male; Mice; Molecular Sequence Data; NF-kappa B; Organ Size; Pancreas; Pancreatitis; Peptides; Peroxidase; Rats; Rats, Wistar; Sincalide; Transcription, Genetic; Tumor Necrosis Factor-alpha

The in vivo contribution of neutrophil elastase (NE) in phorbol myristate acetate (PMA)-induced acute lung injury has so far been unclear. This study examined the role of NE in PMA-induced acute lung injury in conscious rabbits, using a specific NE inhibitor, sivelestat sodium hydrate (Sivelestat). A single bolus injection of PMA (40 microg/kg) caused acute lung injury as indicated by an increase in protein concentration and hemorrhage in bronchoalveolar lavage fluid (BALF) 4h after PMA injection. These changes were associated with mild decrease in arterial oxygen pressure and peripheral white blood cell and platelet. When continuously infused starting 1h before and ending 4h post-PMA injection, Sivelestat at 3-30 mg/kg/h that are able to inhibit rabbit NE activity by 60-90%, dose-dependently attenuated both PMA-induced hemorrhagic pneumonitis and the increase in protein concentration in BALF without affecting myeloperoxidase activity in the lung. Histopathological study indicated that sivelestat (30 mg/kg/h) markedly attenuated lung histopathological changes, alveolar hemorrhage and white blood cells migration with evidence of inhibition of NE activity in BALF. These results suggest that NE plays a significant role in PMA-induced acute lung injury and further supports the importance of this enzyme in acute lung injury.

Topics: Acute Disease; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Glycine; Hemorrhage; Injections, Intravenous; Leukocyte Elastase; Lung; Male; Organ Size; Peroxidase; Proteinase Inhibitory Proteins, Secretory; Proteins; Pulmonary Alveoli; Pulmonary Edema; Rabbits; Respiratory Insufficiency; Sulfonamides; Tetradecanoylphorbol Acetate

Secretory phospholipase A(2) (sPLA(2)) enzymes have been implicated in the pathogenesis of human inflammatory bowel disease (IBD). In this study we compared the efficacy of a potent, new and highly selective inhibitor of group IIa human sPLA(2) enzyme (5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)-pentanoic acid; sPLA(2)I), with that of sulfasalazine, in a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Following a single oral dose of sPLA(2)I (5 mg/kg), pharmacoactive levels of drug were detected in the serum within 15 min and for up to 24 h by liquid chromatography mass spectrometry analysis. Rats treated with sPLA(2)I (5 mg/kg/day) prior to induction of colitis were significantly healthier than TNBS-alone rats, as shown by reduced mortality, improved food intake and increased body weight, and significantly reduced colon myeloperoxidase levels, edema, tumour necrosis factor-alpha levels, and colon macroscopic pathology scores after 8 days. Rats pretreated with sulfasalazine (100 mg/kg/day) also had reduced disease expression markers similar to the sPLA(2)I, but exhibited no improvement in colon edema. This study supports a role for the group IIa sPLA(2) enzyme in pathology associated with the TNBS rat model of IBD, and suggests a possible therapeutic application for selective inhibitors of group IIa sPLA(2) inhibitors in the treatment of IBD.

Topics: Animals; Body Weight; Colitis; Disease Models, Animal; Eating; Edema; Enzyme Inhibitors; Female; Group II Phospholipases A2; Humans; Hypertension; Inflammatory Bowel Diseases; Lipopolysaccharides; Neutropenia; Pentanoic Acids; Peroxidase; Phospholipases A; Phospholipases A2; Rats; Rats, Wistar; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

FTY720, a novel synthetic immunosuppressant, decreases peripheral blood lymphocytes by accelerating their homing to the peripheral and mesenteric lymph nodes and Peyer's patches. We previously reported that tacrolimus, another immunosuppressant, attenuates chronic pancreatitis by suppressing T-cell infiltration in male Wistar Bonn/Kobori rats but also may cause toxicity. To assess the effects of FTY720 on the development of pancreatic inflammation and fibrosis in the same model, the agent dissolved in physiologic saline was subcutaneously injected to 10-week-old male WBN/Kob rats for 10 weeks.. Parameters for inflammation and fibrosis were assessed and interferon-gamma and transforming growth factor-beta1 mRNA in the pancreas were determined by RT-PCR.. Treatment with FTY720 attenuated gross alterations in the pancreas, including pigmentation and atrophy. This protective effect was quantitatively confirmed by significant increase in pancreatic weights and decreases in pancreatic myeloperoxidase activity (an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), ratio of fibrous tissue, and histologic scores. The obvious infiltration of CD4- and CD8-positive T cells into the pancreas in the saline group was almost completely prevented by administration of FTY720, which also suppressed overexpression of interferon and transforming growth factor-beta1 mRNA in the pancreas.. We conclude that FTY720 prevents pancreatic inflammation and fibrosis by suppressing infiltration of CD4- and CD8-positive T cells and by downregulating induction of interferon and transforming growth factor-beta1 mRNA in the pancreas.

Topics: Animals; Body Weight; Fingolimod Hydrochloride; Hydroxyproline; Immunosuppressive Agents; Interferon-gamma; Male; Organ Size; Pancreas; Pancreatitis, Chronic; Peroxidase; Propylene Glycols; Rats; Rats, Wistar; RNA, Messenger; Sphingosine; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1

Lyprinol (Pharmalink International), the stabilised lipid extract of the New Zealand green-lipped mussel, is currently used to relieve symptoms of arthritis. We investigated the effect of pretreatment with Lyprinol (LYP) on experimentally induced inflammatory bowel disease (IBD) in mice.. Male C57BL/6 mice (aged 6 weeks) were gavaged daily for 13 days with (150 microl) olive oil (OO; n = 7), fish oil (FO; n = 8), or LYP (n = 8). Mice consumed 2% dextran sulfate sodium (DSS) for 6 days, starting on day 7. Body weight and disease activity index (DAI) scores were recorded daily. Colonic damage was determined by histopathology. Colonic inflammation was quantified by myeloperoxidase (MPO) activity.. LYP treatment significantly (P < 0.05) reduced body weight loss, DAI scores, crypt area losses, and cecum and colon weights, compared with FO treatment. MPO activity was not significantly affected by any treatment.. These findings provide preliminary evidence that Lyprinol may be potentially useful in ameliorating symptoms of IBD. The benefit, however, is unlikely to be due to the omega-3 fatty acid content. Dose-response evaluation of Lyprinol in experimental IBD is warranted.

Topics: Administration, Oral; Animals; Body Weight; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Fish Oils; Follow-Up Studies; Lipids; Male; Mice; Mice, Inbred C57BL; Olive Oil; Organ Size; Peroxidase; Plant Oils; Plasma Substitutes; Treatment Outcome

It has been reported that the progestin medroxyprogesterone acetate (MPA), but not norethindrone acetate (NETA), inhibits the beneficial vascular effects of post-menopausal estrogen therapy, but their effects on the myocardium are unclear. The goal of this study is to compare the effects of these two progestins on post-ischemic myocardial damage.. Ovariectomized monkeys were fed an atherogenic diet for 18 months while receiving, or not receiving (control, n=15), the monkey equivalent to a woman's dose of 5 mug ethinyl estradiol with either 1 mg NETA daily (n=15) or 2.5 mg MPA daily (n=15). The left anterior descending coronary artery was occluded for 1 h and then released to allow myocardial reperfusion for 4 h. Infarct size was quantified using the histochemical stain triphenyl-tetrazolium chloride. Regional myocardial blood flow was measured by 15 mum neutron-activated microspheres, blood pressure and heart rates with a pneumatic cuff, stroke volume by echocardiography, coronary output by thermodilution and neutrophil accumulation in the myocardium using myeloperoxidase (MPO) activity.. The infarct size (area of necrosis/area at risk) was similar between the control group (21+/-3%) and the MPA group (29+/-3%) (P<0.05) but significantly less in the NETA group (3+/-2%) than other groups (P<0.05). The hemodynamic myocardial function and regional myocardial blood values were similar among groups before, during and 4 h after reperfusion (all P-values >0.05). Similarly, there were no treatment effects on MPO activity (P>0.05).. NETA, but not MPA, diminished ischemia-reperfusion injury in estrogen-treated post-menopausal females. The mechanism(s) of this difference remains unclear.

Topics: Animals; Biomarkers; Blood Flow Velocity; Blood Pressure; Body Weight; Contraceptive Agents, Female; Coronary Circulation; Disease Models, Animal; Drug Interactions; Estrogens; Estrogens, Conjugated (USP); Ethinyl Estradiol; Female; Haplorhini; Heart Rate; Lipids; Medroxyprogesterone Acetate; Myocardial Reperfusion Injury; Neovascularization, Physiologic; Norethindrone; Norethindrone Acetate; Ovariectomy; Peroxidase; Progestins; Research Design; Stroke Volume; Vascular Resistance

To investigate the effect of 17beta-estradiol (E2) on ischemia-reperfusion (I/R) injury in diabetic ovariectomized female rats. Streptozotocin(STZ)-induced diabetic female rats received E2 treatment for 2 weeks after ovariectomy (OVX). A period of 90 min of temporary middle cerebral artery occlusion (tMCAO) was used for the study. Rats were evaluated for physiological data including plasma glucose, E2, MAP, PaCO2 and PaO2 before and after tMCAO. P-selectin expression, myeloperoxidase (MPO) enzyme activity and the cerebral infarct volume were analyzed.. The infarct volume in the E2-treated OVX rats is bigger than that in intact and OVX groups. However, there is not a significant different area of cerebral infarct between diabetic OVX and intact rats. Significant upregulation of P-selectin expression and MPO activity of the ischemia-reperfusion hemisphere were observed in E2 + OVX, intact and OVX groups at 8, 24, 72 h in time manner after tMCAO compared with that of the contralateral hemisphere of cerebral ischemia-reperfusion. Both P-selectin expression and MPO activity in the E2 + OVX and intact rats are significantly higher than that in the untreated OVX rats. Chronic estrogen replacement therapy (ERT) potentiates the I/R injury in diabetes female rats. This may be related to the increased expression of P-selectin and MPO activity.

Topics: Analysis of Variance; Animals; Blood Glucose; Blotting, Western; Body Weight; Brain Infarction; Diabetes Mellitus, Experimental; Estradiol; Female; Gene Expression Regulation; Ovariectomy; P-Selectin; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors

The complement system is a potent effector of innate immunity. To elucidate the pathophysiological role of the complement system in inflammatory bowel disease (IBD), we evaluated the development of dextran sulfate sodium (DSS)-induced colitis in genetically complement C5-deficient mice. We used DBA2/J mice, which are genetically deficient in complement C5. DBA1/J mice have a normal complement system, and were used as controls. Experimental colitis was induced by the oral administration of 3.5% (w/v) DSS in their drinking water for 10 days. On day 10, all mice were sacrificed and their colons were collected. The development of colitis was assessed by the histological score, disease activity index, myeloperoxidase (MPO) activity, and macroscopic changes of the colon. Body weight loss was more apparent in the DBA2/J mice than in control DBA1/J mice. The colon length was shorter in the DBA2/J mice than in DBA1/J mice. The disease activity index, histological colitis score, and MPO activity were all significantly higher in the DBA2/J mice than in DBA1/J mice. Microscopically, mucosal edema, cellular infiltration and disruption of the epithelium were much more severe in the DBA2/J mice than in DBA1/J mice. The development of DSS colitis was aggravated in genetically C5-deficient DBA2/J mice. These findings suggest that the complement system might play a protective role in the development of DSS-induced experimental colitis.

Topics: Animals; Body Weight; Colitis; Complement C5; Dextran Sulfate; Intestinal Mucosa; Mice; Mice, Inbred DBA; Mice, Knockout; Peroxidase; Time Factors

The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.o., b.i.d.) caused a dose-dependent reduction in macroscopic damage, inhibition of the TNBS-provoked elevation of both colonic myeloperoxidase and tumour necrosis factor-alpha (TNF-alpha), and a reduction in the histologically assessed increase in mucosal and submucosal thickness and neutrophil infiltration. JNJ 7777120 (100 mg/kg p.o., b.i.d.) likewise reduced the macroscopic injury and the increases in colonic myeloperoxidase and TNF-alpha levels. These findings indicate a pro-inflammatory role for the histamine H(4) receptor in this model and suggest a novel pharmacological approach to the treatment of colitis.

Topics: Acute Disease; Animals; Benzimidazoles; Body Weight; Colitis; Colon; Dose-Response Relationship, Drug; Indoles; Male; Organ Size; Peroxidase; Piperazines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The toxic effects of Cr(VI) on antioxidant enzymes of Oxya chinensis (Orthoptera: Acridoidae) were determined. Changes in the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and guaiacol peroxidase (GPx) were measured in O. chinensis insects injected with Cr(VI). Fifth-nymphs of O. chinensis insects were injected with Cr(VI) with different concentrations (0, 75, 150, 225, 300, 375, 450 mg/kg of body weight). The results showed that Cr(VI) led to the change of SOD, CAT, and GPx activities at different concentrations, which revealed that: (1) The oxidative stress of SOD increased with the increase of Cr(VI) concentration. (2) With the increase of Cr(VI) concentrations, CAT activities for females increased at lower concentrations, but decreased at higher concentration range, which indicated that antioxidant system of O. chinensis was not influenced by the presence of Cr(VI). A very similar response to Cr(VI) effect for males indicated that Cr(VI) concentrations were not high enough to damage O. chinensis in terms of CAT. (3) The GPx activity for females increased in all treatments, which revealed that the damage power of Cr(VI) was increased with the increase of Cr(VI) concentrations in terms of GPx, but the effect was not so remarkable. There was not a consistent trend of GPx activities for males in all treatments of Cr(VI). Cr (VI)-induced changes in antioxidant enzymes were different for SOD, CAT and GPx, of which the tendency was that activities generally changed with increase of concentrations of Cr(VI) suggesting SOD, CAT, and GPx could serve as indices of oxidative stress to some extent.

Topics: Analysis of Variance; Animals; Body Weight; Catalase; China; Chromium; Dose-Response Relationship, Drug; Enzyme Activation; Female; Grasshoppers; Male; Nymph; Oxidative Stress; Peroxidase; Sex Factors; Superoxide Dismutase; Toxicity Tests, Acute

Using a gastrostomy-fed (GF) rat infant "pup-in-a-cup" model, the effects of protein deprivation and supplemental glutamine (Gln) and glutamate (Glu) were examined to test the hypothesis that Gln decreases the proinflammatory response induced by LPS in the developing infant rat small intestine. Four groups of 6- to 7-day-old pups were fed a rat milk substitute (RMS), one providing 100% and three providing 25% of normal protein intake for another 6 days. Two of the 25% protein-fed groups received supplemental Gln or Glu. GF and LPS treatment blunted body growth and intestinal villus height and increased intestinal cytokine-induced neutrophil chemoattractant (CINC) mRNA in the protein-deprived, non-Gln-treated group compared with mother-fed pups (P < 0.05). Gln blunted intestinal CINC mRNA (P < 0.05), but Glu did not. Intestinal CINC peptide in the LPS-treated pups provided 100 and 25% protein was elevated approximately 13-fold compared with the mother-reared pups (P < 0.001). Gln and Glu decreased intestinal CINC peptide by 73 and 80%, respectively. GF, LPS-treated pups also had a higher level of plasma CINC peptide (P < 0.05). Gln but not Glu decreased plasma CINC peptide (P < 0.05). An approximate sixfold elevation of intestinal MPO activity in the GF, LPS-treated rats was decreased by Gln and Glu by 92% (P < 0.001) and 54% (P < 0.05), respectively. Intestinal and plasma TNF-alpha were increased in GF, LPS-treated pups (P < 0.01), and Gln and Glu both blunted this increase (P < 0.05) in the intestine but not in the plasma. The results indicate that Gln decreases the LPS-induced inflammatory response in infant rat intestine under different conditions of protein intake.

Topics: Animals; Animals, Newborn; Body Weight; Chemokines, CXC; Dietary Proteins; Enteritis; Glutamine; Intercellular Signaling Peptides and Proteins; Intestines; Lipopolysaccharides; Peptide Fragments; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

In this study we examined the effects of hydroxyethyl starch (HES 200/0.5) on lung capillary permeability in endotoxic rats and explored the possible mechanisms. Male Wistar rats were randomly divided into seven groups treated with saline, lipopolysaccharide (LPS; 6 mg/kg), LPS plus HES (3.75, 7.5, 15, or 30 mL/kg), or HES (30 mL/kg) alone for 4 or 2 h. Lung capillary permeability, lung neutrophil accumulation, expression of CD11b on the blood neutrophil cell surface, lung cytokine-induced neutrophil chemoattractant protein level, and nuclear factor kappa B (NF-kappaB) activation in blood neutrophils and lungs were measured. HES at doses of 3.75 and 7.5 mL/kg significantly reduced LPS-induced increases of lung capillary permeability. HES was found to inhibit lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and NF-kappaB activation in parallel and to inhibit CD11b expression in a dose-dependent manner. These findings demonstrate that HES has beneficial effects on capillary leak in acute lung injury and that the mechanisms underlying this action involve an antiinflammatory effect of HES, including inhibition of NF-kappaB activation.. A randomized, controlled laboratory experiment indicated that hydroxyethyl starch (HES) could reduce increased lung capillary permeability in endotoxemia. This effect may be due to an antiinflammatory effect of HES.

Topics: Animals; Body Weight; Capillary Permeability; Cell Adhesion Molecules; Chemokines, CXC; Coloring Agents; Electrophoretic Mobility Shift Assay; Endotoxemia; Evans Blue; Hydroxyethyl Starch Derivatives; Intercellular Signaling Peptides and Proteins; Lung; Male; Molecular Weight; Neutrophil Infiltration; Organ Size; Peroxidase; Plasma Substitutes; Pulmonary Circulation; Rats; Rats, Wistar

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.

Topics: Animals; Benzenesulfonates; Body Weight; Chemokine CXCL2; Chromonar; Colitis; Colon; Injections, Subcutaneous; Intestinal Mucosa; Male; Monokines; Organ Size; Peroxidase; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Treatment Outcome; Tumor Necrosis Factor-alpha

Previous studies found that repeated application of smoke condensate from tobacco-burning reference cigarettes to chemically initiated SENCAR mouse skin promoted the development of tumors in a statistically significant and dose-dependent manner, while condensate from prototype cigarettes that primarily heat tobacco promoted statistically fewer tumors. Based on the recognized correlation between sustained, potentiated epidermal hyperplasia and tumor promotion, we conducted tests to examine the utility of selected short-term analyses for discriminating between condensates exhibiting significantly different promotion activities. In vitro analyses assessing the potential for inducing cytotoxicity (ATP bioluminescence) or free radical production (cytochrome c reduction, salicylate trapping) demonstrated significant reductions when comparing condensate collected from prototype cigarettes to reference condensate. Short-term in vivo analyses conducted within the context of a mouse skin, tumor-promotion protocol (i.e., comparative measures of epidermal thickness, proliferative index, myeloperoxidase activity, leukocyte invasion, mutation of Ha-ras, and formation of modified DNA bases) provided similar results. Reference condensate induced statistically significant and dose-dependent increases (relative to vehicle control) for nearly all indices examined, while prototype condensate possessed a significantly reduced potential for inducing changes that we regarded as consistent with sustained epidermal hyperplasia and/or inflammation. Collectively, these data support the contention that selected short-term analyses associated with sustained hyperplasia and/or inflammation are capable of discriminating between smoke condensates with dissimilar tumor-promotion potentials. Moreover, our results suggest that comparative measures of proliferative index and myeloperoxidase activity, both possessing favorable correlation coefficients relative to tumor formation (i.e., > or = 0.95 after 8 or 12 weeks of promotion), may constitute reasonable end points for further investigation.

Topics: Adenosine Triphosphate; Animals; Body Weight; Carcinogenicity Tests; Carcinogens; Cell Proliferation; Cytochromes c; DNA Adducts; Genes, ras; Hydroxyl Radical; Hyperplasia; Inflammation; Leukocytes; Luminescent Measurements; Mice; Mice, Inbred SENCAR; Oxidation-Reduction; Oxidative Stress; Peroxidase; Salicylates; Skin; Skin Neoplasms; Smoke; Superoxides

Since glycolipid biosynthesis is potentially involved in immunological and inflammatory responses, we tested the effect of a novel inhibitor of intracellular glycolipid biosynthesis N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) in two hapten-induced colitis models: trinitrobenzene sulphonic acid (TNBS)- and oxazolone (4-ethoxymethylene-2phenyl-2oxazoline-5-one; Oxa)-induced colitis. AMP-DNM was given either by intraperitoneal injection or orally via the diet. Mice treated with AMP-DNM had less severe colitis and a more rapid weight recovery, less edema and less wall thickness. Cellular infiltration, goblet cell loss and myeloperoxidase (MPO) activity were reduced in colons of AMP-DNM-treated animals. Intralesional IFN-gamma and IL-18 production were lower in mice of the AMP-DNM-treated groups. Furthermore, AMP-DNM treatment reduced the serum anti-TNBS and anti-Oxa antibody levels. Our findings show that the glycolipid biosynthesis inhibitor AMP-DNM has a strong anti-inflammatory and immune suppressive activity on both TNBS- and Oxa-induced colitis. The data also provide evidence that glycolipid biosynthesis is involved in the inflammatory cascade in these inflammatory bowel disease (IBD) models.

Topics: 1-Deoxynojirimycin; Adamantane; Animals; Anti-Inflammatory Agents; Antibodies; Body Weight; Colitis; Colon; Disease Models, Animal; Enzyme Inhibitors; Glycolipids; Haptens; Immunoglobulin G; Immunosuppressive Agents; Interferon-gamma; Interleukin-18; Male; Mice; Mice, Inbred C57BL; Oxazolone; Peroxidase; Trinitrobenzenesulfonic Acid

Oxidant stress has been implicated in the pathogenesis of inflammatory bowel disease. Antioxidant enzymes, such as superoxide dismutase (SOD), are candidate drugs for modulating this pathogenic factor. This study was designed to determine the therapeutic value of SOD in an experimental model of colitis and to study the mechanisms underlying its effects on intestinal inflammation. For that purpose, colitic (trinitrobenzene sulfonic acid-induced) and control rats were studied. Groups of colitic animals were treated with different doses of SOD (1, 4, or 13 mg/kg/day) or vehicle, starting after induction of colitis and during 7 days. Clinical and pathological markers of colitis severity and lipid peroxidation in colonic tissue were measured. Leukocyte-endothelial cell interactions in colonic venules and expression of vascular cell adhesion molecule 1 (VCAM-1) were determined. Development of colitis was associated with a significant loss in body weight, an increase in macroscopic and microscopic damage scores, and colonic myeloperoxidase activity. Administration of SOD significantly attenuated these changes in a dose-dependent manner and reduced lipid peroxidation in colonic tissue. The increase in leukocyte rolling and adhesion in colonic venules of colitic rats were significantly reduced by administration of SOD, 13 mg/kg/day. Development of colitis was associated with a marked increase in endothelial VCAM-1 expression, which was significantly reduced by treatment with SOD. In conclusion, treatment with SOD significantly reduces peroxidation reactions in the inflamed colon and affords significant amelioration of colonic inflammatory changes in experimental colitis. This effect is related to a reduction in VCAM-1 expression and leukocyte recruitment into the inflamed intestine.

Topics: Animals; Body Weight; Cell Adhesion; Cell Adhesion Molecules; Chemotaxis, Leukocyte; Colitis; Colon; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Intestinal Mucosa; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Trinitrobenzenesulfonic Acid; Vascular Cell Adhesion Molecule-1; Venules

The therapeutic efficacy of the immunomodulator 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) in colonic inflammation was assessed in rats. One hour following colonic instillation of ethanolic 2,4,6-trinitrobenzene sulphonic acid (TNBS), intracolonic administration of 0.4 mg/kg ST1959 was started and continued once daily for 1 or 2 weeks. Daily administration of ST1959 for 1 week significantly reduced macroscopic and histological damage, myeloperoxidase activity, and colonic tissue levels of tumour necrosis factor-alpha and interferon-gamma. ST1959 did not affect interleukin-12 levels but significantly enhanced the production of interleukin-10 (sixfold increase). Two weeks of ST1959 treatment reduced the thickness of the colonic wall and myeloperoxidase activity to the same extent, and the histologic appearance of the mucosa was largely restored. The ameliorating effects seem to be ascribable to an impairment of both neutrophil infiltration/activation and tumour necrosis factor-alpha and interferon-gamma production, possibly consequent to the observed increase in the colonic tissue levels of the potent anti-inflammatory cytokine interleukin-10. Similar results were observed with the reference drug 5-aminosalycilic acid.

Topics: Animals; Body Weight; Colitis; Colon; Cytokines; Diarrhea; Immunohistochemistry; Immunosuppressive Agents; Male; Neutrophil Infiltration; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Triazoles; Trinitrobenzenesulfonic Acid

To examine the effects of tegaserod, a serotonin (5-HT) 4 receptor partial agonist, on abdominal withdrawal reflex (AWR) to rectal distention (RD) and c-Fos expression in limbic system.. Neonatal Sprague-Dawley rats randomly received colonic irritation by acetic acid from postnatal day 8 to d 21 as a visceral hypersensitive model (group H) or by intrarectal saline as a control group (group C). When they became adults, rectal distention (RD) was performed by a balloon (6F; Fogarty arterial embolectomy catheter; length, 20 mm; diameter, 2 mm) which was rapidly inflated with increasing volumes of saline (0.4, 0.8 and 1.2 mL) for 20 s at five-minute intervals. Five subgroups of group H (H-saline, H-vehicle, H-Teg0.1, H-Teg0.3 and H-Teg1.0) were injected randomly with saline, vehicle (1-methyl-2-thpyrrolidone) or tegaserod at doses of 0.1, 0.3 and 1.0 mg/kg ip, respectively. Two subgroups of group C (C-Saline and C-Teg1.0) were injected with saline or tegaserod (1.0 mg/kg) ip. RD was performed 10 min after injection, AWR was recorded and c-Fos expression in limbic system was analyzed quantitatively by immunohistochemistry.. Compared to saline, tegaserod significantly inhibited AWR in group H (0.4 mL: from 2.0 to 0.5; 0.8 mL: from 3.5 to 1.5; 1.2 mL: from 4.0 to 3.0, P<0.01), but had no significant effect on group C. Tegaserod dose-dependently attenuated the number of c-Fos positive neurons in limbic structures, anterior cingulate cortex (ACC) showed the greatest attenuation. In group H, tegaserod (1.0 mg/kg) resulted in a significant overall decrease to 57% of H-saline (283+/-41 vs 162+/-16, P<0.01), in ACC to 42% of H-saline (72+/-10 vs 31+/-8, P<0.01). In group C, tegaserod (1.0 mg/kg) resulted in an overall decrease to 77% of C-saline (214+/-13 vs 164+/-22, P<0.01), in ACC to 65% of C-saline (48+/-8 vs 31+/-7, P<0.01).. Tegaserod inhibits the response to rectal distention in rats with visceral hypersensitivity and dose-dependently attenuates c-Fos expression in limbic system, especially in anterior cingulate cortex.

Topics: Animals; Animals, Newborn; Body Weight; Colon; Gastrointestinal Agents; Indoles; Limbic System; Peroxidase; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Rectum

Glucocorticoids are potent anti-inflammatory drugs. The molecular mechanisms underlying these effects have not yet been fully revealed. The aim of the present study was to establish whether methylprednisolone pretreatment is beneficial and if it can block the pancreatic DNA binding of the transcription factor nuclear factor-kappaB (NF-kappaB) and proinflammatory cytokine synthesis during cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats. Additionally, we set out to investigate the potential effects of methylprednisolone and CCK on pancreatic heat shock protein (HSP) synthesis. The dose-response (5-40 mg/kg) and time-course (6-72 h) curves of methylprednisolone on pancreatic HSP60 and HSP72 synthesis were evaluated following methylprednisolone treatment. We demonstrated that methylprednisolone specifically and dose-dependently induced HSP72 in the pancreas of rats, while it did not have a significant effect on HSP60 expression. The pancreatitis was induced near the peak level of HSP72 synthesis (2 x 30 mg/kg body weight [b.w.] methylprednisolone i.m. at an interval of 12 h, followed by a 12-h recovery period after the second injection of methylprednisolone) by administering 2 x 100 microg/kg CCK subcutaneously at an interval of 1 h. The injections of CCK in the vehicle-pretreated group significantly elevated the levels of pancreatic HSP60 and HSP72 2-4 h after the second CCK injection. Methylprednisolone pretreatment ameliorated many of the examined laboratory (the pancreatic weight/body weight [p.w./b.w.] ratio, the serum amylase activity, the plasma trypsinogen activation peptide concentration, the pancreatic levels of tumor necrosis factor-alpha and interleukin-6, the degree of lipid peroxidation, protein oxidation, nonprotein sulfhydryl group content and the pancreatic myeloperoxidase activity) and morphological parameters of the disease. Methylprednisolone pretreatment did not influence pancreatic NF-kappaB DNA binding, but decreased proinflammatory cytokine synthesis in this acute pancreatitis model. The findings suggest that the anti-inflammatory effect of large doses of methylprednisolone in secretagogue-induced pancreatitis occurs downstream of NF-kappaB DNA binding, and that increased pancreatic HSP72 synthesis may play a role in the protective effect of the drug.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents; Body Weight; Chaperonin 60; DNA; Dose-Response Relationship, Drug; Enzyme Activation; HSP70 Heat-Shock Proteins; I-kappa B Proteins; Interleukin-6; Lipid Peroxides; Male; Methylprednisolone; NF-kappa B; NF-KappaB Inhibitor alpha; Oligopeptides; Organ Size; Oxidation-Reduction; Pancreas; Pancreatitis; Peroxidase; Protein Binding; Proteins; Rats; Rats, Wistar; Sincalide; Sulfhydryl Compounds; Time Factors; Tumor Necrosis Factor-alpha

Pancreatic stellate cells have some similarities to hepatic stellate cells and an intrinsic renin-angiotensin system is present in the pancreas and is enhanced in acute pancreatitis and chronic pancreatic hypoxia. We assessed the effects of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, on spontaneously occurring chronic pancreatitis.. Lisinopril in drinking water (20, 50, or 200 mg/L) was administered to 10-week-old male Wistar Bonn/Kobori (WBN/Kob) rats for 10 weeks and then the inflammatory parameters, fibrosis, serum and pancreatic ACE activity, and expression of transforming growth factor-beta1 (TGF-beta1) messenger RNA (mRNA) as well as positive immunostaining for alpha-smooth muscle actin (alpha-SMA) were assessed.. Lisinopril attenuated gross alterations in the pancreas. This protective effect was confirmed quantitatively by significant increases in pancreatic weights and decreases in pancreatic myeloperoxidase (MPO) activity (an index of granulocyte infiltration), pancreatic hydroxyproline content (an index of collagen deposition), ratio of fibrous tissue, and histologic scores. Lisinopril significantly reduced serum ACE activity but it did not affect pancreatic activity. High doses of lisinopril suppressed the overexpression of TGF-beta1 mRNA measured by reverse-transcription polymerase chain reaction (RT-PCR) and decreased the number of alpha-SMA-positive cells (activated pancreatic stellate cells) in the pancreas.. Lisinopril alleviated chronic pancreatitis and fibrosis in male WBN/Kob rats. It suppressed the expression of TGF-beta1 mRNA, resulting in the prevention of pancreatic stellate cell activation, which may be involved in the observed protection. We propose that an ACE inhibitor may be useful for treating chronic pancreatitis.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Fibrosis; Gene Expression; Hydroxyproline; Immunohistochemistry; Lisinopril; Male; Organ Size; Pancreas; Pancreatitis; Peptidyl-Dipeptidase A; Peroxidase; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1

To evaluate the antioxidant activity of the glycosaminoglycans hyaluronic acid (HYA) and chondroitin-4-sulphate (C4S), we used a rat model of collagen-induced arthritis (CIA). Arthritis was induced in Lewis rats by multiple intradermal injections of 250 microl of emulsion containing bovine type II collagen in complete Freund's adjuvant at the base of the tail and into three to five other sites on the back. Rats were challenged again with the same antigen preparation 7 days later. Disease developed about 11 days after the second immunization. The effects of treatment in the rats were monitored by biochemical parameters and by macroscopic and histological evaluations in blood, synovial tissue and articular cartilage. Arthritis produced the following symptoms: severe periarticular erythema, edema and inflammation in the hindpaws; membrane peroxidation in the cartilage of the joints; endogenous antioxidant wasting; high tumour necrosis factor-alpha (TNF-alpha) plasma levels; and synovial neutrophil accumulation. Treatment with HYA and C4S, starting at the onset of arthritis for 10 days, limited the erosive action of the disease in the articular joints of knee and paw, reduced lipid peroxidation, restored the endogenous antioxidants reduced glutathione (GSH) and superoxide dismutase, decreased plasma TNF-alpha levels, and limited synovial neutrophil infiltration. These data confirm that erosive destruction of the joint cartilage in CIA is due at least in part to free radicals released by activated neutrophils and produced by other biochemical pathways. The beneficial effects obtained with the treatment suggest that HYA and C4S could be considered natural endogenous macromolecules to limit erosive damage in CIA or as a useful tool with which to study the involvement of free radicals in rheumatoid arthritis.

Topics: Animals; Arthritis, Experimental; Body Weight; Chondroitin Sulfates; Collagen; Drug Evaluation, Preclinical; Glutathione; Glycosaminoglycans; Hyaluronic Acid; Male; Malondialdehyde; Neutrophils; Peroxidase; Rats; Rats, Inbred Lew; Superoxide Dismutase; Treatment Outcome; Tumor Necrosis Factor-alpha

We evaluated the neuroprotective effect of UK-279,276 (also referred to as recombinant neutrophil inhibitory factor), a selective CD11b/CD18 antagonist, in combination with thrombolytic therapy on focal cerebral ischemia.. Male Wistar rats (n=88) were subjected to embolic middle cerebral artery occlusion. Animals were randomly assigned to the following groups (n=11 in each group): vehicle treatment alone at 2 or 4 hours, UK-279,276 treatment alone at 2 or 4 hours, recombinant human tissue plasminogen activator (rhtPA) treatment alone at 2 or 4 hours, or the combination of UK-279,276 and rhtPA at 2 or 4 hours. Infarct volume, neurological function, hemorrhagic transformation, neutrophil accumulation, and parenchymal fibrin deposition were measured 7 days after middle cerebral artery occlusion.. Treatment with UK-279,276 significantly (P<0.05) improved neurological severity scores, an index of neurological functional deficit, but had no effect on infarct volume compared with vehicle-treated animals. Treatment with rhtPA alone at 2 but not 4 hours significantly (P<0.05) reduced infarct volume and improved neurological function compared with vehicle-treated animals. Combination treatment with UK-279,276 and rhtPA at 2 or 4 hours significantly (P<0.01) reduced infarct volume and enhanced recovery of neurological function compared with control. Neutrophil accumulation and fibrin deposition in the brain parenchyma of combination-treated rats at 2 and 4 hours after stroke were significantly reduced (P<0.05) compared with corresponding vehicle-treated control groups. The neuroprotective effect of the combined treatments was superior to the additive effects from each treatment of rhtPA or UK-279,276 alone.. These data suggest that the combination treatment with UK-279,276 and rhtPA may extend the window of thrombolytic therapy for the acute treatment of stroke.

Topics: Animals; Body Weight; Brain; CD11b Antigen; Cerebral Hemorrhage; Disease Models, Animal; Fibrin; Glycoproteins; Helminth Proteins; Humans; Infarction, Middle Cerebral Artery; Intracranial Embolism; Male; Membrane Proteins; Neurologic Examination; Neuroprotective Agents; Peroxidase; Rats; Rats, Wistar; Recombinant Proteins; Severity of Illness Index; Stroke; Tissue Plasminogen Activator

The clinical use of doxorubicin (Dxr) is limited by its cardiotoxic effects which are mediated by oxygen radicals. The purpose of this study was to investigate in vivo protective effects of erdosteine, an antioxidant agent because of its secondary active metabolites in vivo, against the cardiotoxicity induced by Dxr in rats. Three groups of male Sprague-Dawley rats (60 days old) were used. Group 1 was untreated group used as control; the other groups were treated with Dxr (single i.p. dosage of 20 mg kg(-1) b.wt.) or Dxr plus erdosteine (10 mg kg(-1) day(-1), orally), respectively. Erdosteine or oral saline treatment was done starting 2 days before Dxr for 12 days. The analyses were done at the 10th day of Dxr treatment. The protein carbonyl content, the activities of myeloperoxidase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) as well as heart rate and blood pressures were significantly increased in Dxr group in comparison with the other groups. However, pulse pressure was decreased in Dxr group. The body and heart weights were decreased in both Dxr administered groups in comparison with control group. Disorganization of myocardial histology, picnotic nuclei, edema, and increase in collagen content around vessels were seen in the slides of Dxr group, whereas normal myocardial microscopy was preserved in Dxr plus erdosteine group. Collectively, these in vivo hemodynamic, enzymatic and morphologic studies provide an evidence for a possible prevention of cardiac toxicity in Dxr-treated patients.

Topics: Administration, Oral; Animals; Aspartate Aminotransferases; Blood Pressure; Body Weight; Creatine Kinase; Doxorubicin; Drug Administration Schedule; Heart Diseases; Heart Rate; Humans; Injections, Intraperitoneal; L-Lactate Dehydrogenase; Male; Myocardium; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Thioglycolates; Thiophenes; Turkey

Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate fibrosis in the kidney, heart, and liver by suppressing transforming growth factor-beta1 mRNA and decreasing production of extracellular matrix proteins. We recently demonstrated that lisinopril, an angiotensin-converting enzyme inhibitor, alleviates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats. The involvement of angiotensin II receptor and its receptor interaction in the pathogenesis of spontaneous chronic pancreatitis was assessed in this model. Candesartan, an angiotensin II receptor antagonist, was administered in drinking water (10.5, 42, or 125 mg/l) to 10-week-old male WBN/Kob rats for 10 weeks and inflammatory parameters, fibrosis, and gene expression of renin-angiotensin system components and transforming growth factor-beta1 were assessed in the pancreas. Immunostaining for alpha-smooth muscle actin was also performed. Candesartan significantly suppressed decrease in pancreatic weight and increases in pancreatic myeloperoxidase activity, hydroxyproline content, ratio of fibrous tissue, histologic scores, and ratio of alpha-smooth muscle actin-positive cells (activated pancreatic stellate cells) at 20 weeks. The high dose enhanced the expression of angiotensinogen and angiotensin II receptor type 2 mRNA and suppressed the overexpression of transforming growth factor-beta1 mRNA. The conclusion is that candesartan alleviates chronic pancreatitis and fibrosis by suppressing the overexpression of transforming growth factor-beta1, resulting in prevention of activation of pancreatic stellate cells in male WBN/Kob rats. We propose that angiotensin II receptor type 1 antagonists may be useful for the treatment of chronic pancreatitis involving angiotensin II interaction with its receptor.

Topics: Actins; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Body Weight; Fibrosis; Hydroxyproline; Immunohistochemistry; Inflammation; Male; Muscle, Smooth; Organ Size; Pancreatitis; Peroxidase; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

To investigate subacute and chronic functional consequences of localized irradiation of rat small intestine on exposed and shielded segments (proximal and distal).. The surgical model of a scrotal hernia was used. The ileal loop was exposed to single doses of 18, 21 or 29.6 Gy X-irradiation. Epithelial structure and transport capacity were followed 2 and 26 weeks post-exposure.. Irradiated segments showed mucosal ulceration followed by transmural fibrosis. Transport capacity was impaired from 2 to 26 weeks. Subacute functional impairment was noticed in the proximal segment, without either morphological alteration or neutrophil influx. At 26 weeks, both proximal and distal segments showed impaired epithelial transport capacity, with neutrophil influx in the submucosa in cases of 21-Gy exposure and in the submucosa and muscularis propria after 29.6 Gy.. Radiation enteritis was characterized by functional impairment, within as well as outside, the irradiation field. During the subacute phase, the irradiated segment may be a source of mediators which might influence intestinal function outside the site of injury via the blood stream and/or enteric nervous system. The development of an intestinal occlusion syndrome during the chronic phase might be responsible for intestinal dysfunction but it does not rule out a possible inflammatory process developing in the shielded parts of the small intestine.

Topics: Animals; Body Weight; Carbachol; Dose-Response Relationship, Radiation; Enteritis; Intestine, Small; Male; Neutrophils; Peroxidase; Radiation Injuries, Experimental; Rats; Rats, Wistar; Time Factors; X-Rays

To study the effects of Rheum tanguticum polysaccharide(-1) (RTP(-1)) on ulcerative colitis in rats induced by 2, 4, 6-trinitrophene sulphonic acid (TNBS) and their possible mechanism.. RTP1 (200 mg.kg(-1), i.g.) extracted from Rheum tanguticum Maxim. ex Regel was administrated to rats with colitis induced by TNBS for 5 d, 7 d, 10 d and 14 d, respectively. The effects of RTP1 and dexamethasone (DX, 0.2 mg.kg(-1), i.g.) were contrastively investigated. The MPO level and SOD activity were determined by chromatometry. The expansion and protein expression of CD4+T lymphocytes isolated from colon mucosae and mesenteric lymph nodes of colitis rats were performed by immunohistochemical analysis and Western-blot methods.. Treatments of RTP1 (200 mg.kg(-1), i.g.) significantly reduced diarrhea, mortality, colon mass, ulcer areas and MPO level in colon mucosae on days 5, 7, 10 and 14 (5.2+/-1.4, 5.4+/-0.7, 5.2+/-1.8, P<0.05. 3.4+/-0.8, P<0.01. 16.1+/-12.1, P<0.01. 31.8+/-8.6, 17.7+/-5.3, 12.7+/-4.1, P<0.05). The effects of RTP1 were similar to those noted above in DX group, but there were no immunosuppressive effects of DX in RTP(-1) group, such as body mass loss, thymus and spleen atrophy. The decreased number and down-regulated protein levels of CD4+T cells isolated from the colon of colitis rats treated with RTP1 were found.. RTP1 shows significantly protective effects but lower side effects on rats with colitis induced by TNBS. The mechanism may be due to the resistance to over expansion of CD4.

Topics: Animals; Body Weight; CD4-Positive T-Lymphocytes; Colitis; Drugs, Chinese Herbal; Intestinal Mucosa; Male; Organ Size; Peroxidase; Phytotherapy; Polysaccharides; Rats; Rats, Sprague-Dawley; Rheum; Spleen; Superoxide Dismutase; Thymus Gland; Trinitrobenzenesulfonic Acid

The effects of glucocorticoids on acute pancreatitis (AP) have remained contradictory. To investigate the time courses of the effects of the exogenous glucocorticoid agonists dexamethasone (DEX) and hydrocortisone (HYD) and a glucocorticoid antagonist (RU-38486), and to characterize the local and systemic responses in experimental AP.. The glucocorticoid agonists and antagonist were administered just before AP induction. Serum amylase activity determinations, IL-6 bioassays, pancreatic weight/body weight ratio measurements and survival analysis were performed. Liver and lung injuries were assessed via neutrophil leukocyte infiltration in myeloperoxidase (MPO) assays, tissue adenosine triphosphate (ATP) level determinations and histology.. In the glucocorticoid agonist groups, the survival rate increased, while the serum amylase level, the IL-6 activity and the pancreatic weight/body weight ratio decreased significantly as compared with the control and RU-treated groups. AP resulted in significant decreases in tissue ATP levels in both the liver and the lung. In the DEX- or HYD-treated groups, the liver ATP levels were significantly elevated, while both the liver and the lung MPO levels were attenuated as compared with the AP and RU-treated groups.. These results suggest that glucocorticoids may play important roles in mitigating the progression of the inflammatory reaction during the early phases of AP.

Topics: Acute Disease; Adenosine Triphosphate; Amylases; Animals; Body Weight; Clinical Enzyme Tests; Glucocorticoids; Interleukin-6; Liver; Lung; Multiple Organ Failure; Neutrophils; Organ Size; Pancreatitis; Peroxidase; Rats; Rats, Wistar

Poly (ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, has been shown to play an important role in the pathogenesis of inflammatory bowel disease. Here we investigate the effects of 1,11b-dihydro-[2H]benzopyrano [4,3,2-de]isoquinolin-3-one (GPI 6150), a new poly (ADP-ribose) polymerase inhibitor, in animal models of experimental colitis. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulfonic acid. Rats experienced hemorrhagic diarrhea and weight loss. At 4 days after administration of dinitrobenzensulfonic acid, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology and an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for poly (ADP-ribose) showed an intense staining in the inflamed colon. GPI 6150 (20 or 40 mg/kg daily, i.p.) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of dinitrobenzensulfonic acid. GPI 6150 also caused a substantial reduction of (i) the degree of colon injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for poly (ADP-ribose), as well as (v) the upregulation of ICAM-1 and P-selectin caused by dinitrobenzensulfonic acid in the colon. Thus, GPI 6150 reduces the degree of colitis caused by dinitrobenzensulfonic acid. We propose that GPI 6150 may be useful in the treatment of inflammatory bowel disease.

Topics: Animals; Benzenesulfonates; Benzopyrans; Body Weight; Colitis; Colon; Cytokines; Drug Interactions; Isoquinolines; Male; Neutrophil Infiltration; Peroxidase; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley

To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid.. The testicular D5, 3b-hydroxysteroid dehydrogenase (HSD), 17b-HSD, peroxidase and catalase activities along with the levels of malondialdehyde (MDA) and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress. The plasma testosterone (T) level was measured by immunoassay. Various germ cells at stage VII of spermatogenic cycle were quantified from testicular stained sections.. Cyclophosphamide treatment results in a significant inhibition in the testicular D5, 3b-HSD and 17b-HSD activities, a decrease in plasma T level and a diminution in the counts of various germ cells. Moreover, this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis. All these changes were reversed by ascorbic acid co-administration.. Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.

Topics: Animals; Antioxidants; Ascorbic Acid; Body Weight; Catalase; Cyclophosphamide; Hydroxysteroid Dehydrogenases; Infertility, Male; Lipid Peroxidation; Male; Mutagens; Peroxidase; Rats; Rats, Wistar; Spermatogenesis; Testosterone

Oxidative stress, inducible nitric oxide synthase (iNOS) and neutrophils all contribute to post-ischemic brain damage. This study has determined the time courses of these three phenomena after ischemia in parallel with histological and functional outcomes. Ischemia was produced in rats by occluding the left middle cerebral artery and both common carotid arteries for 20 min. Regional cerebral blood flow (rCBF) rapidly decreased to 20% of its preischemic value during occlusion and stabilized at 60% following reperfusion. The striatal infarction was maximal 15 h after reperfusion (50+/-3 mm(3)), whereas the cortical infarction reached its maximum at 48 h (183+/-10 mm(3)). This drastic decrease in rCBF followed by incomplete reperfusion and massive infarction is, thus, extremely severe. The cortical infarction was strongly correlated with the neurologic deficit and loss of body weight. Oxidative stress, evaluated by the decrease in glutathione concentrations, appeared in the striatum at 6 h after reperfusion and in the cortex at 15 h. Calcium-independent NOS activity, considered as inducible NOS activity, was significantly enhanced at 24 h in the striatum and at 48 h in the cortex. Myeloperoxidase activity, a marker of neutrophil infiltration, was significantly increased at 48 h in both the striatum and cortex. These time courses show that the delayed iNOS activity and neutrophil infiltration that occur after the maturation of infarction in severe ischemia may not contribute to ischemic brain damage. By contrast, early oxidative stress may well be implicated in cerebral injury.

Topics: Animals; Body Weight; Calcium; Calcium Signaling; Cerebral Infarction; Cerebrovascular Circulation; Chemotaxis, Leukocyte; Disease Models, Animal; Free Radicals; Glutathione; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley

Nitric oxide (NO) synthesis is up-regulated in inflammatory bowel disease. However, its role in the pathophysiology of this condition is controversial. The aims of this study were to assess whether nitric oxide administration ameliorates experimental colitis and to determine the possible mechanisms underlying its effects on intestinal inflammation. For this purpose, the NO donor diethylamine NONOate (DETA/NO; 0.01, 0.1, 1, 5, or 10 mg/kg/day), or the DETA moiety, was administered daily to mice with dextran sulfate sodium-induced colitis. Daily body weight and colonic pathologic alterations at Day 10 were determined. Leukocyte endothelial cell interactions in colonic venules were assessed with intravital microscopy, and expression of endothelial cell adhesion molecules was determined using radiolabeled antibodies. IL-12 and IFN-gamma production were measured in intestinal tissue. Colitis induced a significant loss of body weight, reduction of colon length, and increase in colon weight and myeloperoxidase activity. Administration of 1 mg/kg/day DETA/NO significantly attenuated these pathologic changes. The marked increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of 1 mg/kg/day DETA/NO. Development of colitis was associated with a marked increase in endothelial expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Supplementation with NO significantly attenuated the up-regulation of endothelial intercellular adhesion molecule-1 and P-selectin, but not vascular cell adhesion molecule-1, in colonic tissue. NO abrogated the increase in IL-12 and IFN-gamma mRNA expression in the colon of colitic mice. The DETA moiety alone did not have any effect on any of the parameters studied. In conclusion, exogenous NO supplementation significantly ameliorates dextran sulfate sodium-induced colitis. This effect is related to a reduction in leukocyte recruitment and proinflammatory cytokine production.

Topics: Animals; Body Weight; Cell Adhesion; Cell Adhesion Molecules; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Epithelium; Hydrazines; Interferon-gamma; Interleukin-12; Leukocytes; Male; Mice; Mice, Inbred Strains; Nitric Oxide Donors; Nitrogen Oxides; Peroxidase; RNA, Messenger; Venules

Experimental colitis induces the expression of Na+-H+ exchanger (NHE) isoforms 1 and 3 in the rat colon, however, their status in rat kidney is not established.. The renal cortical NHE-1 and -3 expression was examined in the colitic rats. Since cyclooxygenase-2 (cox-2) plays an important role in inflammation, its regulatory role on these isoforms was also investigated by using a cox-2-selective phosphorothioated antisense oligonucleotide (S-oligo).. Male Sprague-Dawley rats having colitis induced by acetic acid or trinitrobenzenesulfonic acid (TNBS) were given injection of S-oligo (3 mg/kg, i.p.) and a mismatched control oligonucleotide (C-oligo) daily 2 h before inducing colitis. Colonic myeloperoxidase activity (MPO) was used to indicate colitis. The renal cortical levels of NHE-1, NHE-3 and alpha-actin, an internal control, were estimated by the Western blot analysis.. Colonic MPO activity was increased and urine output was decreased in both models of colitis. Serum, but not the renal cortical level of TNF-alpha, was increased in both cases. Only TNBS condition showed an increased PGE2 level and a decreased body weight. Water intake and renal histology remained unchanged in either case. The NHE-3 protein, localized on the proximal tubules, was increased significantly without any change in NHE-1 and alpha-actin in both cases. These changes, except the body weight, were significantly reversed by the S-oligo.. Selective induction of NHE-3 and TNF-alpha, and their reversal by cox-2 inhibition, suggest a cox-2-dependent regulation of NHE-3, which possibly involves TNF-alpha released from the site of inflammation and not from the kidney in colitis. The induction of NHE-3 is independent of the nature of colitides, and might be important to compensate for the loss of electrolyte and water in experimental colitis.

Topics: Acetic Acid; Animals; Antibody Specificity; Blotting, Western; Body Weight; Colitis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Isoenzymes; Male; Microsomes; Oligonucleotides, Antisense; Peroxidase; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Tumor Necrosis Factor-alpha; Urodynamics

Recent studies have suggested that inducible nitric oxide synthase (iNOS) plays a role in the development of asbestos-related pulmonary disorders. The pulmonary reactions of rats and hamsters upon exposure to asbestos fibers are well known to be disparate. In addition, in vitro experiments have indicated that mononuclear phagocytes from hamsters, in contrast to those from rats, lack the iNOS pathway. Therefore, the purpose of this study was to investigate whether rats and hamsters differ in lung iNOS expression in vivo upon exposure to asbestos fibers and whether differences in iNOS induction are associated with differences in the acute pulmonary inflammatory reaction. Body weight, alveolar-arterial oxygen difference, differential cell count in bronchoalveolar lavage fluid, total protein leakage, lung myeloperoxidase activity and lipidperoxidation, wet/dry ratio, iNOS mRNA and protein expression, and nitrotyrosine staining of lung tissue were determined 1 and 7 days after intratracheal instillation of asbestos fibers in CD rats and Syrian golden hamsters. Exposure of rats to asbestos fibers resulted in enhanced pulmonary iNOS expression and nitrotyrosine staining together with an acute inflammation that was characterized by an influx of neutrophils, enhanced myeloperoxidase activity and lipid peroxidation, damage of the alveolar-capillary membrane, edema formation, and impairment of gas exchange. In comparison, instillation of asbestos fibers in hamsters resulted in a significantly milder inflammatory reaction of the lung with no induction of iNOS in pulmonary cells. The data obtained provide important information to understand the underlying mechanisms of species differences in the pulmonary response upon exposure to asbestos fibers.

Topics: Animals; Asbestos, Crocidolite; Asbestosis; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Cricetinae; Disease Models, Animal; Inhalation Exposure; Intubation, Intratracheal; Lung; Mesocricetus; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxygen; Peroxidase; Rats; RNA, Messenger; Species Specificity; Thiobarbituric Acid Reactive Substances; Tyrosine

The association between oral contraceptives or pregnancy and inflammatory bowel disease is unclear. We investigated whether 17beta-estradiol modulates intestinal inflammation in two models of colitis. Female mice were treated with 17beta-estradiol alone or with tamoxifen, tamoxifen alone, 17 alpha-estradiol, or placebo. Dinitrobenzene sulfonic acid (DNB)- or dextran sodium sulfate (DSS)-induced colitis were assessed macroscopically, histologically, and by myeloperoxidase (MPO) activity. Malondialdehyde and mRNA levels of intercellular adhesion molecule-1 (ICAM-1), interferon-gamma (IFN-gamma), and interleukin-13 (IL-13) were determined. In DNB colitis, 17beta-estradiol alone, but not 17beta-estradiol plus tamoxifen, or 17 alpha-estradiol reduced macroscopic and histological scores, MPO activity and malondialdehyde levels. 17beta-Estradiol also decreased the expression of ICAM-1, IFN-gamma, and IL-13 mRNA levels compared with placebo. In contrast, 17beta-Estradiol increased the macroscopic and histological scores compared with placebo in mice with DSS colitis. These results demonstrate anti-inflammatory and proinflammatory effects of 17beta-estradiol in two different models of experimental colitis. The net modulatory effect most likely reflects a combination of estrogen receptor-mediated effects and antioxidant activity and may explain, in part, conflicting results from clinical trials.

Topics: Animals; Benzenesulfonates; Body Weight; Colitis; Dextran Sulfate; Drug Administration Schedule; Estradiol; Female; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-13; Macrophage Colony-Stimulating Factor; Mice; Mice, Inbred C57BL; Peroxidase; RNA, Messenger; Tamoxifen; Tumor Necrosis Factor-alpha

The present study was performed to determine the role of alpha4 (CD49d), a member of the integrin family of adhesion molecules, in ischemic brain pathology.. Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-rat alpha4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG(1), 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of fresh tissue with tetrazolium chloride and myeloperoxidase activity measured in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blood pressure was recorded before and after MCAO in animals treated with TA-2 and 1E6. Fluorescence-activated cell sorting analysis was performed on peripheral blood leukocytes before and after MCAO.. TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2+/-11.5 mm(3), n=17; TA-2, 35.7+/-5.9 mm(3), n=16) and 35.5% in hypertensive rats (1E6, 146.6+/-15.5 mm(3), n=15; TA-2, 94.4+/-25.8 mm(3), n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2-treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO.. These data demonstrate that inhibition of alpha4 integrin can protect the brain against ischemic brain injury and implicate endogenous alpha4 integrin in the pathogenesis of acute brain injury. The mechanism by which alpha4 integrin inhibition offers cerebroprotection is independent of blood pressure modulation and is likely due to inhibition of leukocyte function.

Topics: Animals; Antibodies; Antigens, CD; Blood Pressure; Body Temperature; Body Weight; Brain; Cell Adhesion Molecules; Cerebral Infarction; Disease Models, Animal; Flow Cytometry; Infarction, Middle Cerebral Artery; Integrin alpha4; Ischemic Attack, Transient; Leukocyte Count; Leukocytes; Male; Peroxidase; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Reproducibility of Results

The stilbene derivative resveratrol (RES) is a phytoalexin of grapes, peanuts and other fruits. It is structurally related to stilbene estrogens and an estrogenic potential of RES has recently been demonstrated in a number of in vitro studies. In this investigation, the uterotrophic responses of immature Wistar rats to subcutaneous administration of RES (18, 58, and 575 mg/ kg) and the reference estrogen ethinylestradiol (EE2; 0.3, 1, 3, 30 microg/kg) on three consecutive days were determined. Uterine weight, histopathological changes, immunohistochemical expression of nuclear estrogen receptor-alpha (ERalpha) and progesterone receptor (PR) protein, gene expression of ERalpha and PR at the messenger ribonucleic acid (mRNA) level and peroxidase induction were examined. EE2 dose dependently increased uterine weight, enlarged the uterine lumen and induced hypertrophy of epithelial, stromal and myometrial cells. Expression of ERalpha protein in epithelial, stromal and myometrial nuclei and of PR protein in epithelial nuclei was reduced in EE2-treated rats, while PR protein in stromal and myometrial nuclei was increased in a dose-dependent manner. EE2 increased messenger ribonucleic acid (mRNA) levels of uterine PR and induced peroxidase activity. In contrast, RES rather mildly decreased uterine weight, while histology did not reveal differences between controls and RES-treated rats. Expression of nuclear ERalpha protein was dose dependently decreased in epithelial, stromal and myometrial cells of RES-treated rats, while nuclear PR protein content was similar in controls and RES-treated rats. Following administration of RES, a trend toward reduced levels of ERalpha and PR mRNA was found, while no peroxidase induction occurred. Plasma levels of RES, 45 min after the administration of a single subcutaneous dose of 500 mg/kg, were in the range 1-2 microM. In summary, an estrogenic potential of RES could not be substantiated in this in vivo study, although the most effective route of administration and extremely high doses were used and plasma levels were in the range reported to be effective in vitro. Whether other pharmacological properties of RES could mediate the observed changes in RES-treated animals is discussed.

Topics: Animals; Body Weight; Estradiol Congeners; Estrogen Receptor alpha; Estrogens, Non-Steroidal; Ethinyl Estradiol; Female; Gene Expression; Immunohistochemistry; Organ Size; Peroxidase; Rats; Rats, Wistar; Receptors, Estrogen; Receptors, Progesterone; Resveratrol; RNA, Messenger; Sexual Maturation; Stilbenes; Uterus

To assess the early effects of primary afferent nerve suppression by systemic treatment with the neurotoxin capsaicin in an acute model of abdominal irradiation in rats (10Gy, gamma).. Changes in myeloperoxidase (MPO) activity, calcitonin gene-related peptide (CGRP) tissue content, number of mast cells and apoptotic cells were determined in jejunum and ileum in four groups of rat male Wistar (vehicle sham-irradiated, vehicle irradiated, capsaicin sham-irradiated and capsaicin irradiated) at 1 and 3 days post-irradiation.. In vehicle irradiated rats, CGRP was significantly increased from the first day after irradiation in jejunal mucosa; MPO activity increased in both segments at day 3 but not at day 1 after irradiation; the number of detectable mucosal mast cells dropped to nearly zero on days 1 and 3, while the apoptotic cells in the intestinal mucosa were significantly increased at day 1. Similar results were obtained for mast cells and apoptosis in capsaicin irradiated rats as compared to capsaicin sham-irradiated rats, while MPO activity was significantly increased and CGRP concentration in jejunal mucosa significantly decreased from the first day in these rats in comparison with capsaicin sham-irradiated rats.. Intestinal sensory innervation seems not to have a major protective role against a radiation-induced intestinal inflammatory reaction.

Topics: Animals; Body Weight; Calcitonin Gene-Related Peptide; Capsaicin; Cell Count; Denervation; Eating; Ileum; Intestinal Mucosa; Jejunum; Male; Mast Cells; Neurons, Afferent; Peroxidase; Radiation Injuries, Experimental; Rats; Rats, Wistar; Visceral Afferents

The two aims of this study were (i) to compare the effects of prolonged exercise on circulating neutrophil number and muscle myeloperoxidase (MPO) activity between RAG2/gamma c null and immune-competent mice, and (ii) to evaluate the general suitability of the lymphocyte-deficient RAG2/gamma c null strain for use in exercise models of immune regulation. RAG2/gamma c null (male and female) and C57BL/6 (congenic immune-competent, male) mice were assigned to either control (C) or treadmill exercise (EX, 22 m/min, 90 min, 6% grade) groups. EX mice were killed immediately (EX0) or 24 h (EX24) after exercise. RAG2/gamma c null males had significantly (P < 0.05) fewer circulating CD45+ cells and higher %CD45+ neutrophils than did C57BL/6 males, independent of exercise. A significant interaction was observed for the effects of exercise and gender on %CD45+ neutrophils in the blood. At EX24, gastrocnemius (Gastroc) MPO significantly increased in EX mice. Gastroc MPO activity was 44% and 35% higher in RAG2/gamma c null vs. C57BL/6 males, and in female vs. male RAG2/gamma c null mice, respectively. Heart MPO activity did not differ between strains or among treatments. We concluded that the Rag2/gamma c null strain is a suitable model for future investigations on immune regulation following acute exercise stress.

Topics: Animals; Body Weight; DNA-Binding Proteins; Immunity; Leukocyte Common Antigens; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peroxidase; Physical Exertion

The use of nanoparticles for targeted oral drug delivery to the inflamed gut tissue in inflammatory bowel disease was examined. Such a strategy of local drug delivery would be a distinct improvement compared with existing colon delivery devices for this disease. An experimental colitis was induced by trinitrobenzenesulfonic acid to male Wistar rats. Rolipram, an anti-inflammatory model drug, was incorporated within poly(lactic-coglycolic acid) nanoparticles, which were administered once a day orally for five consecutive days. A clinical activity score and myeloperoxidase activity were determined to assess the inflammation, whereas an adverse effect index reflected the remaining neurotropic effect of rolipram resulting from its systemic absorption. All nanoparticle formulations proved to be as efficient as the drug in solution in mitigating the experimental colitis. The clinical activity score and myeloperoxidase activity decreased significantly after the oral administration of rolipram nanoparticles or solution. During the next 5 days when animals were kept without drug treatment the drug solution group displayed a strong relapse, whereas the nanoparticle groups continued to show reduced inflammation levels. The rolipram solution group had a high adverse effect index, whereas the rolipram nanoparticle groups proved their potential to retain the drug from systemic absorption as evidenced by a significantly reduced index. This new delivery system enabled the drug to accumulate in the inflamed tissue with higher efficiency than when given as solution. The nanoparticle deposition in the inflamed tissue should be given particular consideration in the design of new carrier systems for the treatment of inflammatory bowel disease.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Colon; Drug Carriers; Drug Delivery Systems; Inflammatory Bowel Diseases; Lactic Acid; Male; Microspheres; Organ Size; Particle Size; Peroxidase; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rats; Rats, Wistar; Rolipram

Enlimomab, a murine monoclonal anti-human intercellular adhesion molecule (ICAM)-1 antibody, had a negative outcome in a multicenter acute-stroke trial. We did a bedside-to-bench study in standardized rat stroke models to explore mechanisms for these untoward results.. After focal brain ischemia in Wistar rats and spontaneously hypertensive rats (SHR), we administered murine anti-rat ICAM-1 antibody (1A29), subclass-matched murine immunoglobulin (IgG1), or vehicle intravenously. To examine whether rat anti-mouse antibodies were generated against the mouse protein and whether these were deleterious, we sensitized Wistar rats with 1A29 or vehicle 7 days before surgery. Infarct volume, tissue myeloperoxidase activity, neutrophil CD11b expression, and microvascular E-selectin, P-selectin, and ICAM-1 expression were examined 48 hours after surgery. Complement activation was serially assessed for 2 hours after a single injection of either 1A29 or vehicle.. 1A29 treatment did not significantly reduce infarct size in either strain. 1A29 sensitization augmented infarct size and generated rat anti-mouse antibodies. Although 1A29 inhibited neutrophil trafficking shown by reduction in brain myeloperoxidase activity, circulating neutrophils were activated and displayed CD11b upregulation. Complement was activated in 1A29-sensitized Wistar rats and 1A29-treated SHR. E-selectin (SHR), endothelial P-selectin (Wistar and SHR), and ICAM-1 (SHR) were upregulated in animals treated with 1A29.. Administration to rats of a murine antibody preparation against ICAM-1, 1A29, elicits the production of host antibodies against the protein, activation of circulating neutrophils, complement activation, and sustained microvascular activation. These observations provide several possible mechanisms for central nervous system-related clinical deterioration that occurred when Enlimomab was given in acute ischemic stroke.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Brain; Brain Infarction; Brain Ischemia; Cerebrovascular Circulation; Clinical Trials as Topic; Complement C3a; Flow Cytometry; Humans; Immunohistochemistry; Intercellular Adhesion Molecule-1; Isoantibodies; Laser-Doppler Flowmetry; Leukocyte Count; Mice; Peroxidase; Rats; Rats, Inbred SHR; Rats, Wistar; Selectins; Stroke

Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, upregulation of the expression of intercellular adhesion molecule 1 (ICAM-1) and upregulation of P-selectin in the colon. Here, we investigate the effects of the selective cyclo-oxygenase-2 inhibitor, celecoxib, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhoea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology, as well as an increase in myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed intense staining in the inflamed colon. Celecoxib (5 mg/kg twice a day orally) significantly reduced the degree of hemorrhagic diarrhoea and the weight loss caused by administration of DNBS. Celecoxib also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that a selective cyclo-oxygenase-2 inhibitor celecoxib reduces the degree of colitis caused by DNBS.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzenesulfonates; Body Weight; Celecoxib; Colitis; Colon; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytokines; Immunohistochemistry; Intercellular Adhesion Molecule-1; Isoenzymes; Lipid Peroxidation; Male; Neutrophils; P-Selectin; Peroxidase; Peroxynitrous Acid; Poly(ADP-ribose) Polymerases; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides

Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of the present study was to examine the effects of M40403, a superoxide dismutase mimetic, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS). Rats experienced bloody diarrhoea and significant loss of body weight. At 4 days after TNBS administration, the colon damage was characterised by areas of mucosal necrosis. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and expression of P-selectin and high levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase showed an intense staining in the inflamed colon. Treatment with M40403 (5 mg/kg daily i.p.) significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture as well as a significant reduction of colonic myeloperoxidase activity and malondialdehyde levels. M40403 also reduced the appearance of nitrotyrosine and poly (ADP-ribose) synthetase immunoreactivity in the colon as well as reduced the up-regulation of ICAM-1 and the expression of P-selectin. The results of this study suggested that administration of a superoxide dismutase mimetic may be beneficial for treatment of inflammatory bowel disease.

Topics: Animals; Body Weight; Colitis; Colon; Cytokines; Enzyme Activation; Free Radical Scavengers; Immunohistochemistry; Intercellular Adhesion Molecule-1; Lipid Peroxidation; Male; Manganese; Organometallic Compounds; P-Selectin; Peroxidase; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Survival Analysis; Time Factors; Tyrosine

The proteasome inhibitor PS-519 blocks activation of nuclear factor-kappaB, a major mediator of inflammation. We tested the hypothesis that combination treatment of recombinant human tissue plasminogen activator (rhtPA) and PS-519 extends the therapeutic window for treatment of stroke with rhtPA without increasing incidence of hemorrhagic transformation.. The middle cerebral artery (MCA) of male Wistar rats (n=56) was occluded by an embolus. After embolization, animals were randomly divided into the following groups: PS-519 treatment groups: PS-519 was given at 2, 4, or 6 hours after MCA occlusion; rhtPA treatment groups: rhtPA was given at 2 or 4 hours after MCA occlusion; combination treatment groups: PS-519 and rhtPA were given at 2, 4, or 6 hours after MCA occlusion; control group: the same volume of saline was given at 2 hours after MCA occlusion.. Administration of PS-519 alone at 2 or 4 hours, but not 6 hours, significantly (P<0.05) reduced infarct volume and improved neurological recovery compared with the control group. Administration of rhtPA alone at 2 hours, but not 4 hours, significantly (P<0.05) reduced infarct volume and improved neurological recovery compared with the control group. Furthermore, combination treatment with rhtPA and PS-519 even at 6 hours significantly (P<0.05) reduced infarct volume, improved neurological recovery, and did not increase the incidence of hemorrhagic transformation compared with the control group or the group treated with PS-519 alone.. Our data suggest that combination treatment with PS-519 and rhtPA extends the neuroprotective effect to at least 6 hours after embolization.

Topics: Acetylcysteine; Animals; Behavior, Animal; Blood Pressure; Body Weight; Brain Ischemia; Cell Count; Cerebral Hemorrhage; Cerebral Infarction; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Intracranial Embolism; Male; Multienzyme Complexes; Neurologic Examination; Peroxidase; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Recombinant Proteins; Time Factors; Tissue Plasminogen Activator

Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-alpha convertase (TACE; ADAM17). TNF-alpha plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-alpha levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-alpha and NOx- levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-alpha. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-alpha release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-alpha release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Blotting, Western; Body Weight; Colitis; Enzyme-Linked Immunosorbent Assay; Female; Inflammation; Metalloendopeptidases; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Wistar

The effect of orally or intraperitoneally administered particulate 1,3-beta-D-glucan (PBG), carboxymethylglucan (CMG) or sulfoethylglucan (SEG), obtained from the culture filtrate of Saccharomyces cerevisiae, on the functions of murine peritoneal adherent cells (PC) (peroxidase activity, nitric oxide synthesis), on relative organ mass and on proliferation of splenocytes was determined. The modulating activities after parenteral and non-parenteral administration of these polysaccharides were compared. Significant enhancement of NO production was observed only after in vitro cultivation of PC in the presence of lipopolysaccharide (LPS) in groups of mice treated repeatedly orally with CMG, PBG and SEG at a dose of 50 mg/kg body mass. Peroxidase activity increased significantly after repeated oral administration of CMG and PBG at doses 150 and 50 mg/kg, SEG 150 mg/kg body mass. The peroxidase activity and NO synthesis in mice given a single intraperitoneal injection of glucans (15 mg/kg body mass) were slightly higher than those after oral administration. Neither a significant enhancement of relative organ mass nor enhancement of the proliferative response of splenocytes to in vitro added stimuli (LPS, phytohemagglutinin) after repeated oral or single intraperitoneal administration of beta-glucans was observed.

Topics: Administration, Oral; Animals; beta-Glucans; Body Weight; Cell Division; Cells, Cultured; Enzyme Activation; Glucans; Injections, Intraperitoneal; Lipopolysaccharides; Macrophages, Peritoneal; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Organ Size; Peroxidase; Saccharomyces cerevisiae; Spleen

Several studies have indicated the involvement of macrophages and dendritic cells in active inflammatory bowel disease (IBD). Manipulation of these cells is considered a very important therapeutic strategy for patients with IBD. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with poly(DL-lactic acid) microspheres containing dexamethasone (Dx). Colitis was induced in BALB/c mice by 5% dextran sodium sulfate. Dx microspheres (n = 10) and only Dx (n = 10) were orally administered to dextran sodium sulfate-treated mice. Thereafter, serum levels and tissue distributions of Dx were investigated. To estimate the efficacy of this drug delivery system, we measured the histological score, myeloperoxidase activity and nitric oxide production, and gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma in the colonic tissue. Serum Dx levels were not increased after oral administration of Dx microspheres. The tissue distribution of microspheres containing (125)I-labeled Dx in inflamed colon was significantly higher than in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of the group treated with Dx microspheres were significantly lower than of those treated with Dx alone. Gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma were down-regulated in mice treated with Dx microspheres. Microspheres containing glucocorticoids such as Dx, which target microfold cells and macrophages, can facilitate mucosal repair in experimental colitis and could be an ideal agent for treatment of human IBD.

Topics: Administration, Oral; Animals; Body Weight; Colitis; Colon; Dexamethasone; Dextrans; Drug Delivery Systems; Female; Gene Expression; Interferon-gamma; Interleukin-1; Lactic Acid; Macrophages; Mice; Mice, Inbred BALB C; Microspheres; Nitric Oxide; Peroxidase; Polyesters; Polymers; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha

Chronic airway inflammation induced by Pseudomonas aeruginosa is the eventual cause of respiratory failure in most people affected by cystic fibrosis. Recent evidence implicates the involvement of free radical and oxidant stress in the pathogenesis of the inflammatory injury. Here we report the efficacy of a novel experimental therapeutic, mercaptoethylguanidine (MEG), which has combined actions as a selective inhibitor of the inducible nitric oxide synthase and as a scavenger of peroxynitrite, a potent oxidant formed in the reaction of nitric oxide and superoxide radical. Chronic pulmonary infection was established in FVB/N mice by intratracheal administration of 10(5) colony-forming units of P. aeruginosa in agar beads. Treatment with MEG (10 mg/kg/dose every 8 h i.p.) inhibited weight loss in the first 3 days and reduced histologic injury at 8 days postinfection. MEG also reduced myeloperoxidase activity, a marker of neutrophil infiltration, at 8 days and concentrations of the proinflammatory cytokines interleukin-1beta, tumor necrosis factor-alpha, and macrophage inflammatory protein 2 in whole lung homogenates. MEG-treated animals and controls had similar perioperative mortality and comparable colony counts of P. aeruginosa at 8 days, indicating that MEG did not exacerbate infection. Our data suggest that MEG may be an effective immunomodulatory therapy of pulmonary inflammation induced by chronic infection.

Topics: Anesthesia; Animals; Biomarkers; Body Weight; Cytokines; Enzyme Inhibitors; Female; Guanidines; Inflammation; Intubation, Intratracheal; Mice; Neutrophil Infiltration; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidants; Peroxidase; Pneumonia, Bacterial; Pseudomonas Infections; Time Factors

Our aim was to investigate the cause-effect relationship between intestinal inflammation induced by infection with enteric stages of Trichinella spiralis and decreased host food intake. A suppression of food intake in T. spiralis-infected rats occurred within the first 24 h postinfection (PI) and was maximized by day 6 PI. Food intake, cumulated over an 8-day PI period, decreased by 59% compared with uninfected animals. The anti-inflammatory glucocorticoid betamethasone 21-phosphate was orally administered to rats in their drinking water to suppress T. spiralis-induced jejunal inflammation. When treated with a low dose of glucocorticoid (5.2 microg/ml), food intake in infected rats was still significantly reduced, but only by 21% compared with glucocorticoid-treated, uninfected rats. At the highest glucocorticoid dose (10.4 microg/ml) administered, infection-induced reduction in food intake was not different from that of glucocorticoid-treated, uninfected counterparts. The elevation in jejunal myeloperoxidase activity caused by infection was also significantly blunted by oral glucocorticoid treatment. Our results suggest that suppressed host food intake during enteric T. spiralis infection is directly linked to intestinal inflammation.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Betamethasone; Body Weight; Drinking; Eating; Enteritis; Mice; Nematode Infections; Peroxidase; Rats; Rats, Sprague-Dawley; Reference Values; Trichinellosis

Thiamine deficiency (TD) models the cellular and molecular mechanisms by which chronic oxidative deficits lead to death of select neurons in brain. Region- and cell-specific oxidative stress and vascular changes accompany the TD-induced neurodegeneration. The current studies analyzed the role of oxidative stress in initiating these events by testing the role of intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS) in the selective neuronal loss that begins in the submedial thalamic nucleus of mice. Oxidative stress to microvessels is known to induce eNOS and ICAM-1. TD increased ICAM-1 immunoreactivity in microvessels within the submedial nucleus and adjacent regions 1 day prior to the onset of neuronal loss. On subsequent days, the pattern of ICAM-1 induction overlapped that of neuronal loss, and of induction of the oxidative stress marker heme oxygenase-1 (HO-1). The intensity and extent of ICAM-1 and HO-1 induction progressively spread in parallel with the neuronal death in the thalamus. Targeted disruption of ICAM-1 or eNOS gene, but not the neuronal NOS gene, attenuated the TD-induced neurodegeneration and HO-1 induction. TD induced ICAM-1 in eNOS knockout mice, but did not induce eNOS in mice lacking ICAM-1. These results demonstrate that in TD, an ICAM-1-dependent pathway of eNOS induction leads to oxidative stress-mediated death of metabolically compromised neurons. Thus, TD provides a useful model to help elucidate the role of ICAM-1 and eNOS in the selective neuronal death in diseases in which oxidative stress is implicated.

Topics: Animals; Antibodies, Monoclonal; Behavior, Animal; Biomarkers; Blood-Brain Barrier; Body Weight; Gene Deletion; Genotype; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Immunoglobulin G; Intercellular Adhesion Molecule-1; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peroxidase; Thalamus; Thiamine Deficiency

There is increasing evidence that the intestinal microflora plays an important role in the pathogenesis of inflammatory bowel disease. In the present study, we examined the role of the resident intestinal flora in our model of dextran sulfate sodium (DSS)-induced acute and chronic colitis in mice.. Acute colitis was induced in BALB/c mice with 5% DSS in their drinking water for 7 days. Chronic colitis was established after four cycles of feeding 5% DSS for 7 days and water for 10 days. For eliminating intestinal bacteria, mice were injected intraperitoneally with metronidazole and ciprofloxacin. We analysed four parameters: (1) body weight, (2) length of the colon, (3) histological score, and (4) myeloperoxidase activity.. In acute DSS colitis treatment with antibiotics led to an improvement of the histological parameters (epithelial damage, P< 0.05; inflammatory infiltrate, P< 0.05) and colon length (P < 0.0028). A significant reduction in granulocyte infiltration was indicated by a 52.6% reduced myeloperoxidase activity in colonic biopsies. By contrast, in chronic colitis, treatment of mice with antibiotics failed to show significant effects.. In acute DSS-induced colitis bacteria and/or bacterial products play a major role in initiation of inflammation but not in chronic DSS colitis.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Biopsy; Body Weight; Chronic Disease; Ciprofloxacin; Colon; Dextran Sulfate; Disease Models, Animal; Female; Inflammatory Bowel Diseases; Interleukins; Metronidazole; Mice; Peroxidase

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1), and up-regulation of P-selectin in the colon. Here we investigate the effects of the tyrosine kinase inhibitor, Tyrphostin AG 126, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhea and weight loss. Four days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed an intense staining in the inflamed colon. Staining with an anti-COX-2 antibody of sections of colon obtained from DNBS-treated rats showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase was found mainly in macrophages located within the inflamed colon of DNBS-treated rats. Tyrphostin AG 126 (5 mg/kg daily ip) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of DNBS. Tyrphostin AG 126 also caused a substantial reduction of (1) the phosphorylation of tyrosine residues of proteins (immunoblots of inflamed colon), (2) the degree of colonic injury, (3) the rise in myeloperoxidase activity (mucosa), (4) the increase in the tissue levels of malondialdehyde, (5) the increase in staining (immunohistochemistry) for nitrotyrosine and poly(ADP-ribose) polymerase, as well as (6) the up-regulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that the tyrosine kinase inhibitor Tyrphostin AG126 reduces the degree of colitis caused by DNBS.

Topics: Animals; Body Weight; Colitis; Cyclooxygenase 2; Cytokines; Enzyme Inhibitors; Isoenzymes; Lipid Peroxidation; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Prostaglandin-Endoperoxide Synthases; Protein-Tyrosine Kinases; Rats; Rats, Sprague-Dawley; Tyrosine; Tyrphostins

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of the present study was to examine the effects of tempol, a membrane-permeable radical scavenger, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid. Rats experienced bloody diarrhea and significant loss of body weight. At 4 days after the administration of dinitrobenzene sulfonic acid, the colon injury comprised of large areas of mucosal necrosis. Neutrophil infiltration (measured as increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and expression of P-selectin and high levels of malondialdehyde (an indicator of lipid peroxidation). Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase showed an intense staining in the inflamed colon. Treatment of rats with tempol (15 mg/kg daily i.p.) significantly reduced the appearance of diarrhea and the loss in body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture as well as a significant reduction in the degree of both neutrophil infiltration and lipid peroxidation in the inflamed colon. Tempol also reduced the appearance of nitrotyrosine and poly (ADP-ribose) synthetase immunoreactivity in the colon as well as the up-regulation of ICAM-1 and P-selectin. The results of this study suggest that membrane-permeable radical scavengers, such as tempol, exert beneficial effects in experimental colitis and may, hence, be useful in the treatment of inflammatory bowel disease.

Topics: Animals; Benzenesulfonates; Body Weight; Cell Membrane Permeability; Colitis; Colon; Cyclic N-Oxides; Free Radical Scavengers; Immunohistochemistry; Intestinal Mucosa; Lipid Peroxidation; Male; Neutrophil Infiltration; Organ Size; Peroxidase; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Spin Labels; Spleen; Survival Rate; Tyrosine

The involvement of pancreatic acinar cell apoptosis and its relation to glucocorticoid exposure were investigated in spontaneously occurring chronic pancreatitis in male Wistar Bonn/Kobori (WBN/Kob) rats. Although most lobules were not inflamed in 10-week-old WBN/Kob, increased apoptosis of pancreatic acinar cells, confirmed by TUNEL staining was focally observed (0.10 +/- 0.10 vs. 0.05 +/- 0.10/field in 10-week Wistar rats). Localized hemorrhagic lesions and brown foci in the splenic lobes were apparent, with significant decrease in pancreas weight in 20-week WBN/Kob rats along with marked apoptosis (1.95 +/- 0.31 vs. 0.07 +/- 0.04/field in 20-week Wistar rats). Electron microscopy revealed apoptotic bodies to be present in acinar cells. Pancreatic myeloperoxidase activities, indirect indices of granulocyte infiltration, as well as histologic scores were significantly increased at 15 and 20 weeks, and endogenous corticosterone levels were significantly decreased at 10, 15, and 20 weeks as compared with values for age-matched Wistar rats. Prednisolone in the drinking water (0.01 mg/mL; calculated dose, 1.03 0.03 mg/kg/d) for 10 weeks significantly attenuated increases in numbers of apoptotic acinar cells and pancreatic myeloperoxidase activities and tended to reduce the histologic scores in 20-week WBN/Kob rats as compared with the vehicle group. In summary, (a) apoptosis of pancreatic acinar cells is involved in chronic pancreatitis, (b) endogenous corticosterone is decreased, and (c) prednisolone treatment attenuates both apoptosis of pancreatic acinar cells and chronic pancreatitis in male WBN/Kob rats. We conclude that apoptosis of acinar cells related to decreased corticosterone may be a trigger of chronic pancreatitis in this model.

Topics: Adrenocorticotropic Hormone; Animals; Apoptosis; Blood Glucose; Body Weight; Cell Nucleus; Chronic Disease; Coloring Agents; Corticosterone; Glucocorticoids; In Situ Nick-End Labeling; Insulin; Male; Microscopy, Electron; Organ Size; Pancreas; Pancreatitis; Peroxidase; Prednisolone; Rats; Rats, Wistar

Stachybotrys chartarum is a fungal species that can produce mycotoxins, specifically trichothecenes. Exposures in the indoor environment have reportedly induced neurogenic symptoms in adults and hemosiderosis in infants. However, little evidence has linked measured exposures to any fungal agent with any health outcome. We present here a study that focuses on quantitatively assessing the health risks from fungal toxin exposure. Male, 10 week old Charles River-Dawley rats were intratracheally instilled with approximately 9.6 million Stachybotrys chartarum spores in a saline suspension. The lungs were lavaged 0 h (i.e., immediately post-instillation), 6, 24 or 72 h after instillation. Biochemical indicators (albumin, myeloperoxidase, lactic dehydrogenase, hemoglobin) and leukocyte differentials in the bronchoalveolar lavage fluid and weight change were measured. We have demonstrated that a single, acute pulmonary exposure to a large quantity of Stachybotrys chartarum spores by intratracheal instillation causes severe injury detectable by bronchoalveolar lavage. The primary effect appears to be cytotoxicity and inflammation with hemorrhage. There is a measurable effect as early as 6 h after instillation, which may be attributable to mycotoxins in the fungal spores. The time course of responses supports early release of some toxins, with the most severe effects occurring between 6 and 24 h following exposure. By 72 h, recovery has begun, although macrophage concentrations remained elevated.

Topics: Albumins; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Hemoglobins; L-Lactate Dehydrogenase; Leukocyte Count; Lung; Macrophages, Alveolar; Male; Mycotoxins; Peroxidase; Rats; Spores, Fungal; Stachybotrys; Time Factors; Trachea

To examine the efficacy of an antileukocyte adhesion antibody (anti-CD18) as an adjuvant for delayed (2 hours and 4 hours) thrombolytic therapy (recombinant human tissue plasminogen activator [rt-PA]) in middle cerebral artery occlusion (MCAO) in rats.. Thrombolytic therapy with rt-PA is limited in its application by a short therapeutic window.. Male Wistar rats were subjected to MCAO by a single fibrin-rich clot. The rats were assigned to the following experimental groups: Experiment 1 (treatment 2 hours after embolization), 1) rt-PA, 2) anti-CD18 antibody, 3) rt-PA and anti-CD18 antibody, 4) immunoglobulin (Ig) G, and 5) vehicle; Experiment 2 (treatment 4 hours after occlusion), 1) rt-PA alone, 2) rt-PA and anti-CD18 antibody, and 3) nontreated control group. Neurologic deficits, infarction volume, hemorrhage, and brain myeloperoxidase (MPO) immunoreactivity were measured.. Administration of rt-PA and anti-CD18 antibody 2 hours later reduced significantly (p < 0.05) the infarct volume and improved neurologic deficits compared with the vehicle-treated group. Treatment with rt-PA alone improved neurologic deficits significantly and reduced mean infarct volume compared with the vehicle-treated group. However, treatment with anti-CD18 antibody neither reduced infarct volume nor improved neurologic deficits compared with the IgG-treated group. The combination of rt-PA and anti-CD18 antibody treatment at 4 hours reduced significantly the infarct volume and MPO immunoreactive cells compared with rt-PA treatment alone at 4 hours, and reduced neurologic deficits compared with rt-PA treatment alone and compared with the nontreated animals.. The combination of antileukocyte adhesion antibody and thrombolytic therapy may increase the therapeutic window for the treatment of stroke.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Monoclonal; Arterial Occlusive Diseases; Body Weight; CD18 Antigens; Cerebral Arteries; Cerebral Infarction; Fibrinolytic Agents; Humans; Intracranial Embolism and Thrombosis; Male; Peroxidase; Rats; Rats, Wistar; Recombinant Proteins; Tissue Plasminogen Activator; Treatment Outcome

An association between lipid peroxidation and alpha-naphthylisothiocyanate (ANIT)-induced liver injury was examined in rats injected once with the toxicant (75 mg/kg body weight). The severity of liver injury was estimated 12, 24, 48, and 72 h after ANIT injection. Liver injury appeared 24 h after ANIT injection, progressed at 48 h, and recovered at 72 h, judging from the serum levels of marker enzymes and components. Serum lipid peroxide (LPO) concentration increased 24 h after ANIT injection and further increased at 48 h, but this increase was attenuated at 72 h. In contrast, liver LPO content increased 12 h after ANIT injection and further increased 24 and 48 h, but this increase was attenuated at 72 h. Similarly, myeloperoxidase (MPO) activity, an index of neutrophil infiltration, in the liver tissue increased 12 h after ANIT injection and further increased at 24 and 48 h, but this increase was attenuated at 72 h. Either serum LPO concentration or liver LPO content was significantly correlated with liver MPO activity (r = 0.661 for serum LPO concentration; r = 0.585 for liver LPO content). These results suggest that lipid peroxidation might be associated with ANIT-induced liver injury in rats and that this lipid peroxidation might occur via oxygen radicals derived from neutrophils infiltrated into the liver tissue of ANIT-intoxicated rats.

Topics: 1-Naphthylisothiocyanate; Alanine Transaminase; Animals; Bile Acids and Salts; Bilirubin; Body Weight; Cholestasis; gamma-Glutamyltransferase; Injections, Intraperitoneal; Lipid Peroxidation; Lipid Peroxides; Liver; Male; Organ Size; Peroxidase; Rats; Rats, Wistar; Statistics as Topic

The purpose of this study was to determine the efficacy of a novel human protein, keratinocyte growth factor-2 (KGF-2), in a model of murine colitis induced by ad libitum exposure to a 4% solution of dextran sulfate sodium (DSS) in the drinking water. Initial evaluation of KGF-2 was based on its ability to reduce weight loss, stool score, and histological score in mice exposed to DSS for 7 days. When KGF-2 (0.1-10.0 mg/kg i.p. or s.c.) was injected daily into DSS-treated mice from day 0 to 7, it significantly reduced all three parameters in a dose-response fashion, with a minimum effective dose of between 1 and 3 mg/kg. When KGF-2 was given therapeutically, starting 4 days after initiation of the 7-day DSS treatment, the 3- but not the 0.5-mg/kg dose significantly enhanced weight recovery after discontinuation of DSS treatment. When DSS treatment was prolonged beyond the normal 7 days, therapeutic intervention on day 2 or 4 also significantly reduced mortality, weight loss, and stool score at the 1- and 3-mg/kg dose. Therapeutic treatment also resulted in reduction of colon myloperoxidase levels by more than 50%. These experiments suggest that KGF-2 may be clinically useful in the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.

Topics: Animals; Body Weight; Colitis; Colon; Dextran Sulfate; Feces; Female; Fibroblast Growth Factor 10; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Growth Substances; Humans; Keratinocytes; Mice; Organ Size; Peroxidase

In Japan and China, Oren-gedoku-to (a complex mixture of ingredients derived from plants) has been used as a herbal medicine in the treatment of inflammatory and ulcerative diseases. In other countries salicylazosulfapyridine has been used to treat inflammatory bowel disease. In this study, we have compared the effect of Oren-gedoku-to with salicylazosulfapyridine on trinitrobenzene-sulphonic acid-induced colonic damage in rats, a model representative of ulcerative colitis and Crohn's disease in man. Oren-gedoku-to was administered orally for one or two weeks over a range of doses. Tissue damage scores, body weight, spleen weight, colon wet weight and colon wall thickness were measured, and colonic tissue levels of interleukin-8 (IL-8), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and myeloperoxidase activity were examined. The results indicated that Oren-gedoku-to was effective in the treatment of inflammatory bowel disease in the rat model. Histological observation showed a quicker healing process of the lesions, and a reduction of inflammatory cell infiltration following administration of Oren-gedoku-to. The precise mechanism of action for Oren-gedoku-to is still unclear; however, the reduction of IL-8, LTB4, and PGE2 observed suggests that the mechanism may be different from salicylazosulfapyridine (which has no effect on IL-8). There may be a potential benefit in offering combination therapy for the treatment of inflammatory bowel disease.

Topics: Animals; Anti-Ulcer Agents; Body Weight; Colitis; Drugs, Chinese Herbal; Gastrointestinal Agents; Male; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Sulfasalazine; Trinitrobenzenesulfonic Acid

The objective of this study was to determine the effects that certain nitric oxide synthase inhibitors have on the spontaneous intestinal and colonic inflammation that develops in HLA-B27 transgenic rats and compare these data to those obtained using sulfasalazine (SZ). In an attempt to more closely mimic the clinical situation, drug treatment was begun after the onset of colitis. HLA-B27 male rats that developed clinical signs of colitis (diarrhea/loose stools) at 17 wk of age were randomized into fours groups consisting of one untreated colitic group and three treatment groups that received either aminoguanidine (AG; 52 micromol/kg/day), NG-nitro-L-arginine methyl ester (L-NAME; 45 micromol/kg/day) or SZ (130 mg/kg/day) in their drinking water for 14 days. Aged-matched Fisher 344 male rats were used as healthy controls. After 3 wk of treatment, ileal and colonic mucosal permeabilities, granulocyte infiltration and nitric oxide were quantified using blood-to-lumen clearance of 51Cr-EDTA, tissue myeloperoxidase activity, and plasma levels of nitrate and nitrite, respectively. We found that both AG and L-NAME but not SZ significantly attenuated the increases in plasma nitrate and nitrite levels. Interestingly, all three drugs were effective at significantly attenuating the increases in myeloperoxidase activity in the distal colon. Treatment with AG and SZ but not L-NAME were effective at significantly attenuating the increase in ileal and colonic permeabilities. Quantitative histological analysis revealed that AG and L-NAME but not SZ significantly attenuated the increase in the mucosal thickness and crypt depth in the distal colon compared to untreated colitis. Taken together, these data demonstrate that oral administration of certain nitric oxide synthase inhibitors or SZ to animals with active colitis attenuates the colonic inflammation by at least two different mechanisms. One mechanism appears to be dependent on inhibition of NO production whereas the other mechanism does not.

Topics: Animals; Animals, Genetically Modified; Body Weight; Colitis; Colon; Enzyme Inhibitors; HLA-B27 Antigen; Ileum; Male; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide Synthase; Nitrites; Permeability; Peroxidase; Rats; Rats, Inbred F344; Sulfasalazine

The aim of the current study was to elucidate the synergism of dietary calcium restriction and exhaustive exercise in the antioxidant enzyme system of rat soleus muscle, and to investigate the involvement of neutrophils in exercise-induced muscle damage. Forty-eight male Wistar rats were assigned to the following groups: control (C) or calcium-restricted [1 month (1 M) or 3 months (3 M)]. Each group was subdivided into acutely exercised or non-exercised groups. Soleus muscle from each rat was analysed to determine the levels of antioxidant enzymes [Mn-superoxide dismutase (SOD), Cu, Zn-SOD, glutathione peroxidase (GPX), and catalase (CAT)]. Dietary calcium restriction resulted in calcium deficiency and upregulated the antioxidant enzymes examined except GPX. Conversely, exhaustive exercise significantly decreased GPX and CAT, but not SODs activities in the calcium-restricted (1 M and/or 3 M) rats. Contents of immunoreactive Mn-SOD and Cu,Zn-SOD were only increased in the 3 M rats. During calcium restriction, the mRNA expression of both forms of SOD showed initial upregulation, followed by downregulation. Exhaustive exercise significantly increased the mRNA expressions only in the 3 M rats. Moreover, exhaustive exercise markedly increased myeloperoxidase activity in soleus muscles from the 1 M and 3 M rats compared with the C rats, and significantly enhanced the ability of neutrophils to generate superoxide in the 3 M rats. The results demonstrate that dietary calcium restriction upregulates certain antioxidant enzyme activities in rat soleus muscle, indicating an enhanced resistance to potential increases in intracellular reactive oxygen species. The results also suggest that exhaustive exercise may cause oxidative damage in soleus muscle of calcium-deficient rats through the activation of neutrophils.

Topics: Animals; Antioxidants; Body Weight; Calcium; Calcium, Dietary; Catalase; Glutathione Peroxidase; Male; Muscle, Skeletal; Neutrophils; Organ Size; Peroxidase; Phosphorus; Physical Endurance; Physical Exertion; Rats; Rats, Wistar; RNA, Messenger; Superoxide Dismutase; Superoxides

The present investigation was designed to characterize the biochemical and connective tissue components and to correlate the significance of morphological and biochemical perturbations in cyclophosphamide (CP)-induced lung fibrosis in rats. Lung fibrosis was induced in male Wistar rats by intraperitoneal injection of 20 mg/100 g body weight of CP, and their pneumotoxic derangements were characterized during an early destructive phase followed by a proliferative and synthetic phase. Serum angiotensin-converting enzyme (ACE) activity was higher in CP-treated rats at days 2, 3, 5, 7, and 11, but there was a significant decrease in lung ACE activity during the same time period. Elevated levels of beta-glucuronidase activity were observed in the lung lavage fluid of CP-administered rats days 2, 3, 5, and 7. Lung myeloperoxidase activity was higher in CP rats. Of significance was the presence of collagenase and collagenolytic cathepsin in the lavage fluid of CP rats, when compared with the barely detectable levels in controls. A similar increase in these enzyme activities was also noticed in the lung tissue of CP rats during the same experimental period. Lavage fluid hydroxyproline content was higher in CP rats when compared with controls. Similarly, lung protein and DNA levels were elevated significantly after treatment with CP. The pulmonary histamine and serotonin contents were significantly higher in CP rats. The incorporation of [3H]thymidine into lung total DNA, [3H]proline into lung hydroxyproline, and [35S]sulphate into lung glycosaminoglycan, measured as indicators of lung DNA, collagen, and glycosaminoglycan synthesis, respectively, was also higher in CP groups. Increased levels of hydroxyproline, elastin, hexosamine, total hexose, fucose, sialic acid, and uronic acid in the lungs of rats 14, 28, and 42 days after CP insult were characterized as biomarkers of CP-induced interstitial changes. These findings indicate that CP-induced lung fibrosis results in alterations not only in collagen synthesis and accumulation, but also in glycosaminoglycan and glycoprotein content.

Topics: Animals; Body Weight; Bronchoalveolar Lavage Fluid; Collagen; Connective Tissue; Cyclophosphamide; DNA; Enzyme Activation; Extracellular Matrix; Glycosaminoglycans; Glycoside Hydrolases; Hydroxyproline; Injections, Intraperitoneal; Lung; Male; Organ Size; Peptide Hydrolases; Peptidyl-Dipeptidase A; Peroxidase; Pulmonary Fibrosis; Rats; Rats, Wistar

The preventive effects of the dietary germinated barley foodstuff (GBF), which increases the contents of protein, RNA and DNA in the intestinal mucosa of rats on the mucosal damage and diarrhea were examined in a methotrexate (MTX)-induced enteritis model in rats. Sprague-Dawley rats intraperitoneally injected with MTX (10 mg/kg body weight) were used as an enteritis model. After consumption of diets containing GBF, glutamine or a glutamine-rich stuff (gluten), mucosal damage, contents of mucosal protein, RNA and DNA, myeloperoxidase (MPO) activity, bacterial translocation and DNA synthetic activity in the small intestine were assessed. GBF more effectively prevented diarrhea and mucosal damages, and increased mucosal protein, DNA and RNA contents than glutamine or gluten. The bacterial trans-location and elevation of MPO activity induced by MTX were depressed only by the consumption of GBF. GBF has a potential as therapeutic diet to decrease the adverse effects of anti-cancer chemotherapy.

Topics: Animals; Body Weight; Diarrhea; Dietary Fiber; DNA; Eating; Enteritis; Germination; Hordeum; Intestinal Mucosa; Male; Methotrexate; Peroxidase; Proteins; Rats; Rats, Sprague-Dawley; RNA; Sucrase

The clinical use of bleomycin in the treatment of squamous cell carcinomas, lymphomas and testicular tumours has been limited by its toxic effects, the most serious being pulmonary injury. The present study was undertaken to investigate whether alpha-tocopherol, incorporated in liposomes and delivered directly to the lung, could offer protection against bleomycin-induced lung damage and fibrosis in the rat. Animals were administered, intratracheally, plain liposomes (composed of dipalmitoylphosphatidylcholine, DPPC) or alpha-tocopherol-containing liposomes (8 mg alpha-tocopherol/kg body weight) and 30 min later, were exposed to bleomycin sulphate (4 units/kg body weight) by intratracheal instillation; treated animals were killed 21 days later. Results of this study showed that lungs of animals treated with bleomycin were seriously damaged, as evidenced by significant histological changes and increases in lung weight, lipid peroxidation, myeloperoxidase activity and hydroxyproline content as well as decreases in lung angiotensin converting enzyme (ACE) and alkaline phosphatase (AKP) activities. Pretreatment of rats with plain liposomes alone did not alter significantly the bleomycin-induced changes of all parameters examined. In contrast, pretreatment of rats with alpha-tocopherol liposomes 30 min prior to bleomycin administration resulted in little or no histological changes and conferred a significant protection against bleomycin-induced changes in edema, lipid peroxidation, hydroxyproline content, and ACE, AKP and myeloperoxidase activities. Results of this study suggested that pretreatment of rats with alpha-tocopherol liposomes can provide a significant protection against bleomycin-induced lung injury.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Alkaline Phosphatase; Analysis of Variance; Animals; Antibiotics, Antineoplastic; Bleomycin; Body Weight; Drug Carriers; Drug Interactions; Hydroxyproline; Instillation, Drug; Lipid Peroxidation; Liposomes; Lung; Male; Organ Size; Peptidyl-Dipeptidase A; Peroxidase; Pulmonary Edema; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Vitamin E

Intraluminal bacteria, food intake, and bile play important roles in indomethacin-induced small intestinal inflammation in rats. Tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) inhibit hydrophobic bile acid-induced damage in various types of cells. We investigated the effects of these bile acids along with the possible influence of other bile acids on this model of inflammation. Clinical and intestinal inflammatory parameters and bile secretion were assessed after 7-day dietary bile acid pretreatments and subsequent indomethacin injections. UDCA significantly enhanced indomethacin-associated reductions in food intake and body weight, increases in gross inflammatory scores and myeloperoxidase activity, and the shortening of small intestinal length. Taurochenodeoxycholic acid (TCDCA) significantly normalized the clinical inflammatory parameters, prevented indomethacin-induced increases in the biliary contents of secondary bile acids and hydrophobicity index, and tended to attenuate the intestinal inflammation. Although elevated biliary levels of muricholic acids and a decreased hydrophobicity index were evident before indomethacin injection in the TCDCA case, these alterations could not explain the TCDCA-mediated protection. Dietary TCDCA attenuates whereas UDCA exacerbates intestinal inflammation in this model. Alterations in the bile composition (increases in UDCA and chenodeoxycholic acid) may explain the observed modification effects.

Topics: Animals; Bile; Blood; Body Weight; Diet; Dose-Response Relationship, Drug; Eating; Enteritis; Indomethacin; Intestine, Small; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Taurochenodeoxycholic Acid; Ursodeoxycholic Acid

Controlled feeding of linoleic acid (LA) or arachidonic acid (AA) to essential fatty acid-deficient (EFAD) rats was used to define the relationship between dietary AA and the inflammatory response evoked during adjuvant-induced arthritis. Based on energy percentage, EFAD rats were fed AA at the human daily equivalent (1x; 5.5 mg/day) or 10 times that amount (10x; 55 mg/day) or, alternatively 0.5x of LA (273 mg/day). Feeding of 0.5x LA restored the plasma level of AA to that in chow-fed controls. In contrast, feeding of 1x AA only partially restored the plasma level of AA; 10x AA was required to fully replete AA. In parallel to the degree of repletion of AA in plasma, there were accompanying decreases in the levels of palmitoleic acid, oleic acid, and Mead acid. Compared to rats fed the standard laboratory chow diet (Control), edema in the primary hind footpads was decreased by 87% in EFAD, 71% in EFAD + 1x AA, 45% in EFAD + 10x AA, and 30% in EFAD + 0.5x LA. The decrease in edema in the footpads of EFAD rats was nearly identical to the decrease in edema in the footpads of Control rats dosed with indomethacin. Hind footpad edema correlated with the final AA plasma level and eicosanoid levels extracted from hind footpad tissue, but not with neutrophil infiltration. The data showed that 0.5x LA and 10x AA, but not 1x AA, could quickly replete AA, accompanied by the synthesis of AA-derived eicosanoids and restoration of edema. These results suggest that in humans consumption of the average daily amount of AA without concurrent ingestion of LA would not alleviate an EFAD state.

Topics: Animals; Arachidonic Acid; Arthritis, Experimental; Body Weight; Dietary Fats; Disease Models, Animal; Eicosanoids; Energy Intake; Fatty Acids; Fatty Acids, Essential; Humans; Indomethacin; Linoleic Acid; Male; Neutrophils; Peroxidase; Rats; Rats, Inbred Lew; Time Factors

Recently we observed that ursodeoxycholic acid (UDCA) ameliorates an experimental small intestinal inflammation induced by indomethacin in the rat. In this study, we have tested whether ursodeoxycholic acid also reduces mucosal damage in the bile-independent trinitrobenzene sulphonic acid (TNB) model of experimental colitis.. Intestinal inflammation (colitis) was induced in male Sprague-Dawley rats (250-300 g) by intracolonic administration of TNB (30 mg in 50% ethanol). Rats were treated with UDCA (10 mg/kg) either for 3 days starting with the administration of TNB for an acute inflammation (n = 11) or for 8 days starting one day after induction of colitis related to a more acute/chronic inflammation (n = 11). Rats were sacrificed at day 3 or day 9, respectively. Healing of induced colitis was assessed by macroscopic and blinded microscopic analysis as well as by measurement of bowel wet weight, daily body weight, and myeloperoxidase activity. All examinations were separately performed in three colon segments (S1 3-5 cm, S2 5.5-8 cm and S3 8.5-11 cm from anus).. UDCA treatment significantly reduced macroscopically and microscopically detectable injury in acute inflammation in segments 1 and 2. The colitis-rats with acute/chronic inflammation had less marked mucosal damage. Nevertheless, UDCA treatment led to a significant decrease of visible injury parameters which was seen exclusively at the area of maximal ulceration (S2). Furthermore, a significant increase in body weight of UDCA-treated TNB rats compared to controls from day 5 on was found.. Ursodeoxycholic acid attenuates the severity of acute inflammation and inhibits the development of acute/chronic inflammation predominantly around the area of maximal ulceration in TNB-induced colitis. In addition to our previous studies and results in indomethacin induced enteritis, these data may provide a rationale for studying how UDCA modulates functions of immune cells in the colonic mucosa.

Topics: Animals; Body Weight; Colitis; Intestinal Mucosa; Male; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Time Factors; Trinitrobenzenesulfonic Acid; Ursodeoxycholic Acid

The 21-aminosteroid tirilazad mesylate (U74006F) is a lipophilic antioxidant and free radical scavenger that has been reported to attenuate brain or spinal cord injury caused by trauma, stroke, ischemia and reperfusion injury. In this study, we have examined the effect of U74006F in reducing the inflammatory parameters of trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) in rats. To induce IBD, rats were given ethanolic TNBS intracolonically. Rats received either 1) TNBS and U74006F 2) TNBS and vehicle or 3) saline and vehicle. Rats were sacrificed 1, 2 and 3 weeks after IBD induction. Colon to body weight ratio (an index of tissue edema) was markedly increased in the vehicle-treated IBD rats after 1 week of administration of TNBS. The ratio was significantly lower after U74006F treatment and the trend remained even after 3 weeks of chronic inflammation. Myeloperoxidase (MPO) activity in vehicle-treated IBD rats was substantially increased compared with controls during the entire 3 weeks of the experiment. U74006F-treated animals had significantly reduced MPO activity (60% lower) when compared with vehicle-treated animals at the end of the second and third weeks. These observations were confirmed by histopathology studies showing reduced granulocyte infiltration after drug treatment. U74006F treatment decreased basal (by 70%) and fMLP stimulated (by 75%) superoxide generation from colonic tissue from IBD rats compared with vehicle treatment after 2 weeks, but there was no apparent difference in superoxide generation among all three groups after 3 weeks. The results of this study suggested that administration of U74006F effectively reduces the inflammatory parameters in this chronic rat model of IBD. As such, U74006F may be therapeutically beneficial for the treatment of IBD in humans.

Topics: Animals; Antioxidants; Body Weight; Colitis; Colon; Free Radical Scavengers; Inflammatory Bowel Diseases; Lipid Peroxides; Luminescent Measurements; Male; Organ Size; Peroxidase; Pregnatrienes; Rats; Rats, Sprague-Dawley; Superoxides; Trinitrobenzenesulfonic Acid

The acute phase of inflammation induces both anorexia and fever. Because several analyses suggest a linkage between the meal size and body temperature, we assessed whether temperature changes were causal to anorexia in situations involving acute inflammation. Specifically, we evaluated whether elevations of body temperature could account for the reduced food intake after induction of experimental colitis [via intrarectal infusions of trinitrobenzene sulfonic acid (TNB)] or injection of 100 micrograms/kg lipopolysaccharide (LPS). Temperature was monitored telemetrically in rats via implanted temperature transmitters. TNB-treated rats demonstrated a 5-day anorexia that resulted specifically from a decrease in meal size. Although TNB-treated rats were hypothermic on the day of treatment, no other body temperature changes were noted. LPS reduced food intake and elevated temperature, but these two effects were uncorrelated temporally. Although these results do not identify the mechanisms of anorexia, the findings indicate clearly that the anorexia associated with the acute inflammatory response is not secondary to fever.

Topics: Animals; Anorexia; Body Temperature; Body Weight; Colitis; Eating; Feeding Behavior; Lipopolysaccharides; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

We investigated the involvement of nitric oxide in trinitrobenzene-sulfonic acid (TNB) colitis. Every 24 h after TNB, rats were orally dosed with NG-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg), NG-nitro-D-arginine methyl ester (D-NAME), or water, and food intake, body weight, and plasma nitrite levels were measured. On day 6, colonic nitric oxide synthase and myeloperoxidase (MPO) activity, histology, intestinal muscle growth, NADPH-diaphorase, and myenteric nerve function were assessed. Food intake and body weight were reduced during the first 72 h of colitis. On day 6 post-TNB, a fourfold increase in mucosal nitric oxide synthase, a 30-fold increase in MPO, and a fivefold elevation in plasma nitrite were measured. Smooth muscle hyperplasia and hypertrophy in both colonic muscle layers, numerous diaphorase-positive macrophages in the myenteric plexus, and a suppression of myenteric nerve function were also observed. Unlike D-NAME, oral L-NAME reduced MPO and intestinal muscle hyperplasia by > 90%. Likewise, plasma nitrite and colonic nitric oxide synthase were reduced by > 70%. L-NAME completely prevented macrophage infiltration into the muscle. Conversely, it had no effect on anorexia or intestinal smooth muscle hypertrophy, nor did it affect suppressed myenteric nerve neurotransmitter release. These results demonstrate the selective transmural protective effects of L-NAME in the inflamed colon, implicating nitric oxide as a mediator.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Body Weight; Colitis; Colon; Eating; Hyperplasia; Hypertrophy; Intestines; Male; Muscle, Smooth; Myenteric Plexus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Peroxidase; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

There are no clinically efficacious drugs available for preventing the development of pulmonary fibrosis (PF). In the present study, we tested the antifibrotic potential of pirfenidone (PD) in the bleomycin (BL) hamster model of PF. Hamsters were intratracheally instilled with isotonic saline solution or BL (7.5 U/kg/5 ml). The animals were fed control diet containing 0.5% PD or the same diet without the drug 2 days before and throughout the study. The four groups were as follows: saline-instilled and fed the control diet (SCD); saline-instilled and fed the same diet containing PD (SPD); BL-instilled and fed the control diet (BCD); and BL-instilled and fed the same diet containing PD (BPD). The animals were killed at 21 days after intratracheal instillation and their lungs processed for various assays. The lung hydroxyproline levels, an index of PF, in SCD, SPD, BCD, and BPD groups were 949, 970, 1759, and 990 micrograms/lung, respectively. The SOD activity and malondialdehyde equivalent levels in the corresponding groups were 443, 524, 612, and 499 units/lung and 56, 49, 108, and 63 nmol/lung, respectively. The lung prolyl hydroxylase activities in the SPD, BCD, and BPD groups were 87%, 147%, and 93% of the control (SCD) group (4.2 x 10(4) dpm/lung/30 minutes), respectively. The lung myeloperoxidase activities were 97%, 236%, and 159% of the control group (0.73 units/lung), respectively. BL alone caused significant increases in all the biochemical markers of lung toxicity, and dietary intake of PD minimized the BL toxicity as reflected by significant decreases in all the above markers.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Bleomycin; Body Weight; Cricetinae; Diet; Hydroxyproline; Lipid Peroxidation; Lung; Male; Mesocricetus; Peroxidase; Procollagen-Proline Dioxygenase; Pulmonary Fibrosis; Pyridones; Superoxide Dismutase

Nitric oxide (NO) synthesis is increased in ulcerative colitis, but the role of NO in colitis is poorly understood. The present study employed Nw-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats to evaluate the effect of NO on 2,4,6-trinitrobenzenesulphonic acid (TNB)-induced colitis. L-NAME solutions were placed in subcutaneous, osmotic mini-pumps which continuously released L-NAME at 0.042, 0.208, 0.417, or 1.667 mg kg-1 h-1. L-NAME dose-dependently enhanced lesions in TNB-induced colitis. The two higher doses of L-NAME significantly increased colonic mucosal damage, although there was slight, nonsignificant reduced lesion formation with the lowest dose of L-NAME. 0.042 mg kg-1 h-1. A single dose of L-NAME at 100 mg kg-1 subcutaneously injected daily in TNB-treated rats also increased lesions, and these ulcerogenic actions of L-NAME were reversed by L-arginine but not by D-arginine (both at 500 mg kg-1, s.c.). Only the highest dose of L-NAME (mini-pump) significantly depressed myeloperoxidase (MPO) activity. Faecal occult bleeding showed a close relationship with severity of colitis. These findings suggest that there may exist a balance between NO protective and aggressive effects. In TNB-induced colitis, antagonism of endogenous NO generation was intensified, whereas slight inhibition of NO synthesis reduced lesions. Variations in responses, related to timing or dose changes in L-NAME, may reflect the differences in inducible vs constitutive NO synthase isoforms.

Topics: Animals; Arginine; Body Weight; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Infusion Pumps, Implantable; Injections, Subcutaneous; Intestinal Mucosa; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Peroxidase; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

The mechanisms of the increased tolerance to hyperoxia of neonatal animals of many species is incompletely understood. To investigate the etiology of this difference we compared neutrophil entry into the lungs of neonatal and adult rats after hyperoxic exposure. Adult rats were studied after exposure to > or = 98% O2 for 60 h and neonatal rats after 3 and 7 d. Neonatal survival was prolonged compared with that reported for adult rats (77% after 7 d of exposure). In adult rats, there were significant increases in pulmonary neutrophils after 60 h of O2 exposure. In neonatal rats, these changes were not evident after 72 h of exposure, but pulmonary neutrophils increased after 7 d of hyperoxia. Before mortality, pulmonary neutrophils were distributed differently in the age groups. After 7 d of O2 exposure in the neonates, total neutrophil counts in lung tissue (21.92 +/- 7.29 per cm2 grid) and lung myeloperoxidase (0.085 +/- 0.02 U/mg protein) remained significantly lower than in adults after 60 h of O2 exposure (41.44 +/- 9.08 per cm2 grid and 0.411 +/- 0.085 U/mg protein, respectively). However, in histologic specimens, O2-exposed neonates had higher percentages of neutrophils free in the alveolar air space than did adults, corresponding to a trend toward higher neutrophil counts in bronchoalveolar lavage fluid in the neonates. It appears that, in addition to delay in neutrophil influx into the lung, neonatal rats have lowered retention of neutrophils to the alveolar tissue.

Topics: Aging; Animals; Animals, Newborn; Body Weight; Bronchoalveolar Lavage Fluid; Cell Movement; Hyperoxia; Leukocyte Count; Lung; Male; Neutrophils; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley

To study the effect of local or parenteral administration of the glucocorticoid budesonide in the acetic acid-induced colitis model in the rat.. Colitis was induced in an exteriorized colonic segment by administration of 4% acetic acid for 15 s. Four days later, this colonic segment with colitis was examined using a morphological scoring system, and measurements of myeloperoxidase activity and of plasma exudation into the colonic segment. The experimental colitis showed morphological similarities to human ulcerative colitis, with 3-fold increase in myeloperoxidase activity and 6-fold increase in the plasma exudation. Budesonide in different doses administered for 3 days, starting one day after acetic acid instillation, prevented the development of colitis in a dose-dependent manner. The best effect of budesonide on the morphological score was achieved after local treatment at a dose of 10(-5) M twice daily (76% reduction compared with a control colitis group) and parenteral treatment with 0.75 mg/kg (80% reduction). These doses also normalized myeloperoxidase activity and significantly reduced the plasma exudation. The systemic effects of the drug were most pronounced in the group treated with parenteral budesonide. This group showed the greatest reduction in body weight and a significant reduction of the weight of adrenal glands and spleen (as compared to controls). Thymus weight in animals treated systemically was significantly lower than in locally treated animals. In the group treated with local budesonide the weight of adrenals was reduced. However, the weights of spleen and thymus were not reduced and the reduction of the body weight was even less than in the control group.. Local treatment with budesonide at a dose of 10(-5) M (0.17 mg/kg if completely absorbed, but only 0.03 mg/kg with 15% bioavailability on colonic application) was as effective as parenteral treatment at a dose of 0.75 mg/kg in the attenuation of acetic acid-induced colitis in the rat, but resulted in minor systemic side-effects.

Topics: Acetates; Acetic Acid; Administration, Topical; Animals; Anti-Inflammatory Agents; Body Weight; Budesonide; Colitis; Dose-Response Relationship, Drug; Female; Glucocorticoids; Injections, Subcutaneous; Organ Size; Peroxidase; Pregnenediones; Rats; Rats, Sprague-Dawley

Experimental colitis, induced in rats by intrarectal administration of trinitrobenzenesulfonic acid (TNB), results in a suppression of eating for 3 days. Because interleukin-1 (IL-1) is elevated within 24 h after TNB treatment, and because chronic administration of IL-1 leads to a pattern of anorexia similar to that seen after TNB, we evaluated the role of endogenous IL-1 in the anorexia observed in the TNB model. Human recombinant IL-1 receptor antagonist (rhIL-1ra) was administered chronically via osmotic minipump either peripherally or centrally after TNB treatment. Peripheral delivery of 40 micrograms/h rhIL-1ra significantly attenuated TNB-induced anorexia. However, 24 micrograms/h rhIL-1ra attenuated TNB-induced anorexia only when delivered centrally, not peripherally. These findings implicate central IL-1 receptors in the suppression of eating during acute experimental colitis but leave open a possible involvement of peripheral IL-1 receptors.

Topics: Animals; Body Weight; Colitis; Ethanol; Feeding Behavior; Humans; Inflammation; Interleukin-1; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-1; Recombinant Proteins; Time Factors; Trinitrobenzenesulfonic Acid

It has been shown that lung nicotinamide adenine dinucleotide (NAD) depletion accompanies bleomycin (BL)-induced lung fibrosis in the hamster and that treatment with niacin (NA), a precursor of NAD, was found to attenuate lung fibrosis caused by this agent. Niacin was used in the present study to investigate changes in some biochemical parameters and enzymes involved in the development of BL-induced lung fibrosis in the hamster. Niacin (500 mg/kg, IP), or an equivalent volume of saline (SA, IP), was given daily 2 days prior to intratracheal instillation of BL (7.5 U/5 mL/kg) or SA and everyday thereafter throughout the study. Hamsters were killed at 1, 4, 7, 10, and 14 days after the BL or SA instillation and their lungs processed for various biochemical assays. Hydroxyproline content and superoxide dismutase (SOD) activity in SABL treated animals were significantly (P < or = 0.05) elevated at 7 and 10 days, peaking at 14 days to 161 +/- 11% and 159 +/- 11% of the SASA treated animals, respectively. Although the hydroxyproline level of NABL treated animals was significantly elevated at 7 and 10 days and peaked at 14 days to 123 +/- 8% of the NASA control, these values were significantly lower than the SABL treated animals at the corresponding times. The lung SOD activity of NABL groups was significantly higher at 4 days but significantly lower at 10 and 14 days than the SABL groups at the corresponding times. Prolyl hydroxylase (PH) activity and total lung calcium in SABL treated groups were significantly elevated compared to SASA treated groups starting at 4 days, with PH peaking at 10 days to 163 +/- 13% and calcium peaking at 7 days to 148 +/- 8% of SASA treated groups. The NABL treated animals displayed a significant elevation in PH activity at 4 days only (132 +/- 15%), while the calcium content in this group was significantly increased at 4 and 14 days compared to NASA treated animals. However, the activity of PH in the NABL treated animals was significantly lower than the SABL treated animals at 7, 10, and 14 days. The calcium content of the NABL group was significantly lower than the SABL group at 7 and 10 days. The thiobarbituric acid reactive substance equivalents (TBARS) content and myeloperoxidase (MPO) activity were significantly elevated at all time points in SABL groups as compared to SASA groups, with peak elevation of TBARS to 160 +/- 9% at 4 days and MPO to 268 +/- 40% at 1 day.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Bleomycin; Body Weight; Calcium; Collagen; Cricetinae; Hydroxyproline; Lung; Male; Mesocricetus; Niacin; Peroxidase; Procollagen-Proline Dioxygenase; Pulmonary Fibrosis; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Delayed onset of puberty and mammary development is assumed to reduce the risk of mammary cancer. An animal experiment was performed to investigate the influence of dietary fiber, which is known to affect hormonal balance, on these characteristics. Forty-five immature female rats were randomized into three groups, which were fed ad libitum a low-fiber diet (less than 0.5% dietary fiber based on white wheat flour), a high-fiber diet (9.2% dietary fiber based on wheat bran), or an energy-restricted low-fiber diet providing 90% of the energy of the ad libitum low-fiber diet. Energy intake in the second and third groups was similar. Wheat bran slightly delayed onset of puberty, whereas restricted energy intake delayed onset of puberty by about six days. At 48-58 days of age, 14 rats of the low-fiber group, 10 of the high-fiber group and 7 of the restricted group were in cycle. Development of mammary tissue was rudimentary in rats of the energy-restricted low-fiber group, stronger in the high-fiber group and strongest in the ad libitum low-fiber group. Cell proliferation in mammary tissue was similar for both groups fed ad libitum, but significantly lower in the restricted group. Peroxidase activity, a biomarker for estrogenicity, was lower in the high-fiber group than in the two low-fiber groups. It is concluded that wheat bran and, even more effectively, an imposed restricted energy intake delays onset of puberty and mammary development. This shortens the time for mammary cells to be initiated to tumor cells and hence reduces the risk of mammary cancer development.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Body Weight; Cell Division; Dietary Fats; Dietary Fiber; Endometrium; Energy Intake; Female; Mammary Glands, Animal; Peroxidase; Rats; Rats, Inbred F344; Sexual Maturation; Triticum

Male Wistar rats were subjected to colonic resection and randomized to one of four groups: control group (intraperitoneal NaCl, intravenous NaCl); 5-fluorouracil (5-FU) group (intraperitoneal 5-FU, intravenous NaCl); folinic acid group (intraperitoneal NaCl, intravenous folinic acid); and 5-FU-folinic acid group (intraperitoneal 5-FU, intravenous folinic acid). Treatment was started immediately after surgery and continued until the animals were killed at 3 or 7 days. Anastomotic complications (abscesses or dehiscence) occurred in four of 33 animals in the control group, 12 of 36 in the 5-FU group, one of 32 in the folinic acid group and nine of 36 in the 5-FU-folinic acid group. Anastomotic and skin breaking strength did not differ between groups on day 3 but by day 7 were significantly reduced in the 5-FU group. In rats given 5-FU-folinic acid, breaking strength was also reduced, but less so than in the 5-FU group. Breaking strength in animals receiving folinic acid was similar to that in the control group. In this model colonic healing was impaired after intraperitoneal 5-FU administration, but when folinic acid was added no further deterioration occurred.

Topics: Anastomosis, Surgical; Animals; Body Weight; Colon; Fluorouracil; Hydroxyproline; Leucovorin; Leukocyte Count; Male; Peroxidase; Rats; Rats, Inbred Strains; Skin; Time Factors; Wound Healing

The polymorphonuclear granulocyte (PMN) kills ingested bacteria by mechanisms that include myeloperoxidase (MPO) and a sudden increase in oxygen consumption (the oxidative burst), both of which are iron dependent. The magnitude of the oxidative burst and activity of MPO were determined in PMNs during the progression of iron deficiency (ID) and following its treatment in rats. As ID developed, the oxidative burst after zymosan activation was less depressed than the activity of MPO. There was no change in the oxidative burst after activation with phorbol myristate acetate (PMA) or in the generation of superoxide (O2-) by NADPH oxidase-containing particles from PMNs. Following iron treatment, impairment of the oxidative burst after zymosan activation was corrected after 1 day. In contrast, the deficit in MPO activity was not corrected until 7 days after initiation of iron treatment. The pattern of recovery in MPO activity after iron treatment corresponded to the prolonged period of maturation of the PMN primary granule since the formation of primary granules, which contain MPO, takes place only in the early, mitotic stages of maturation. The tendency of the PMN to maintain the oxidative burst allows the cell to preserve its capacity for bacterial killing during the progression of iron deficiency.

Topics: Animals; Body Weight; Hemoglobins; Iron; Iron Deficiencies; Male; Neutrophils; Oxygen; Peroxidase; Phagocytosis; Rats; Rats, Inbred Strains; Superoxides; Tetradecanoylphorbol Acetate; Zymosan

Topics: Aging; Animals; Body Size; Body Weight; Cataract; Growth Hormone; Human Growth Hormone; Liver; Oxidoreductases; Peroxidase; Peroxidases; Rats; Tryptophan