oxyntomodulin and Inflammation

Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antioxidant defense systems might be more promising. Since basic research demonstrated the contribution of different inflammatory cells to vascular oxidative stress and clinical trials identified chronic inflammatory disorders as risk factors for cardiovascular events, atherosclerosis and cardiovascular disease are closely associated with inflammation. Therefore, modulation of the inflammatory response is a new and promising approach in the therapy of cardiovascular disease. Classical anti-inflammatory therapeutic compounds, but also established drugs with pleiotropic immunomodulatory abilities, demonstrated protective effects in various models of cardiovascular disease. However, results from ongoing clinical trials are needed to further evaluate the value of immunomodulation for the treatment of cardiovascular disease.

Topics: Animals; Antioxidants; Cardiovascular Diseases; Endothelium, Vascular; Glucagon-Like Peptides; Humans; Immunologic Factors; Inflammation; Oxidative Stress

The objective of this study was to investigate the effects of semaglutide, a long acting glucagon-like peptide-1 receptor agonist, on atherosclerotic inflammation and calcification using a multimodality positron emission tomography and computed tomography (PET/CT) approach.. Atherosclerotic New Zealand White rabbits were randomized to an intervention- (n = 12) or placebo group (n = 11) receiving either semaglutide or saline-placebo. PET/CT imaging was done before and after 16-weeks of intervention. Three different radiotracers were used: [. Semaglutide decreased vascular uptake of tracers imaging activated macrophages and cellular metabolism but not micro-calcifications compared to a saline placebo. This supports the hypothesis that semaglutide reduces atherosclerotic inflammation by means of decreased activated macrophage activity.

Topics: Animals; Atherosclerosis; Calcinosis; Fluorodeoxyglucose F18; Glucagon-Like Peptides; Inflammation; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Rabbits; Radionuclide Imaging; Radiopharmaceuticals

Topics: Animals; Apoptosis; Cell Line; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Epilepsy; Glucagon-Like Peptides; Hippocampus; Inflammasomes; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Pentylenetetrazole; Seizures

To investigate the protective efficacies and potent mechanisms of combination therapy with semaglutide and rosiglitazone (RSG) on the high-glucose incubated human ARPE-19 cells and diabetic retinopathy (DR) model rats.. The CCK-8 methods were used to evaluate the protective effects of semaglutide and RSG alone or combination on the cell viability of high-glucose treated ARPE-19 cells. After the DR rat model was established, the effects of combined treatment on general indexes, retinal morphological changes, retinal Müller cells as well as PI3K/Akt/MTOR related factors of DR model rats were investigated.. The CCK-8 assay showed obviously enhanced protective efficacies of combination therapy with semaglutide and RSG on the ARPE-19 with oxidative stress induced by high-glucose with combination index all below 1.5 demonstrating obvious synergistic effects. Combined incubation could also effectively decrease the expression of inflammatory factors, including TNF-α, IL-1β, IL-6, and the increase of ROS content in ARPE cell culture supernatant induced by high-glucose. Combined use of the antioxidant, PI3K/Akt and mTOR inhibitors, we further demonstrated that combined incubation of semaglutide and RSG could effectively by reduce high glucose-induced inflammatory injury inhibiting ROS/PI3K/Akt/mTOR signaling. Furthermore, chronic combination treatment effectively improved the histopathological characteristics and down-regulated the GFAP expression in Müller cells as well as PI3K/Akt/MTOR signaling pathway-related factors in retina which was better than any monomer treatment group.. Combined semaglutide with RSG exhibited synergistically protective efficacies on retinal cells by decreasing the GFAP expression, inhibiting oxidative stress and PI3K/Akt/MTOR signaling-transduction in DR model rats.

Topics: Animals; Antioxidants; Cell Line; Cell Survival; Diabetic Retinopathy; Disease Models, Animal; Drug Therapy, Combination; Ependymoglial Cells; Glial Fibrillary Acidic Protein; Glucagon-Like Peptides; Humans; Inflammation; Male; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Rosiglitazone; Signal Transduction; TOR Serine-Threonine Kinases

To investigate the protective effects and mechanism of semaglutide on exercise-induced myocardial injury.. Effects of semaglutide on lipopolysaccharide (LPS)-induced oxidative stress injuries and inflammatory response were assessed in H9c2 cell via MTT assay and Western blot. Quiet control group, over training group and three doses of semaglutide treated overtraining groups were subjected to the swimming training with increasing load for consecutive 10 weeks. Immediately after the last training, the body weight, myocardial morphological changes, injury markers and inflammatory response related proteins of the model rats were analyzed.. Semaglutide at three concentrations in LPS treated H9c2 cells significantly increased the survival rate and inhibited the apoptosis of cardiomyocytes. Moreover, semaglutide activated AMPK pathway, improve autophagy and inhibited reactive oxygen species production in LPS treated H9C2 cells. In vivo results further revealed that chronic treatment of semaglutide induced significant increase in myocardial injury markers. The pathological histology analysis results showed that semaglutide ameliorated myocardial morphological changes, reduced area of lipid accumulation and significantly decreased the expression levels of NF-κB, TNF-α and IL-1β.. Semaglutide exert the protective effects on exercise-induced cardiomyopathy by activating AMPK pathway, increasing autophagy, reducing the production of ROS and inflammation-related proteins.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Cell Line; Cell Survival; Cytokines; Glucagon-Like Peptides; Heart Injuries; Inflammation; Interleukin-1beta; Lipids; Lipopolysaccharides; Male; Myocardium; NF-kappa B; Oxidative Stress; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Stroke is a condition with few medical treatments available. Semaglutide, a novel Glucagon-like peptide-1 (GLP-1) analogue, has been brought to the market as a treatment for diabetes. We tested the protective effects of semaglutide against middle cerebral artery occlusion injury in rats. Animals were treated with 10 nmol/kg bw ip. starting 2 h after surgery and every second day for either 1, 7, 14 or 21 days. Semaglutide-treated animals showed significantly reduced scores of neurological impairments in several motor and grip strength tasks. The cerebral infarction size was also reduced, and the loss of neurons in the hippocampal areas CA1, CA3 and the dentate gyrus was much reduced. Chronic inflammation as seen in levels of activated microglia and in the activity of the p38 MAPK - MKK - c-Jun- NF-κB p65 inflammation signaling pathway was reduced. In addition, improved growth factor signaling as shown in levels of activated ERK1 and IRS-1, and a reduction in the apoptosis signaling pathway C-raf, ERK2, Bcl-2/BAX and Caspase-3 was observed. Neurogenesis had also been normalized by the drug treatment as seen in increased neurogenesis (DCX-positive cells) in the dentate gyrus and a normalization of biomarkers for neurogenesis. In conclusion, semaglutide is a promising candidate for re-purposing as a stroke treatment.

Topics: Animals; Apoptosis; Brain; Disease Models, Animal; Doublecortin Protein; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hippocampus; Hypoglycemic Agents; Infarction, Middle Cerebral Artery; Inflammation; Insulin Receptor Substrate Proteins; Microglia; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Motor Activity; Neurogenesis; Neurons; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-jun; Rats; Stroke; Transcription Factor RelA

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognition; Cognitive Dysfunction; Gene Expression Regulation; Glucagon-Like Peptides; Hippocampus; Histone-Lysine N-Methyltransferase; Histones; Inflammation; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Quinazolines

Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment.. To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD.. Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight.. Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change.. Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Biomarkers; Body Weight; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Inflammation; Liver; Male; Middle Aged; Multicenter Studies as Topic; Non-alcoholic Fatty Liver Disease; Obesity; Randomized Controlled Trials as Topic; Retrospective Studies; Weight Reduction Programs; Young Adult

Protein level in the maternal diet plays a crucial role in fetal programming during pregnancy. Low or high protein level increases the risk of intrauterine growth retardation (IUGR). The aim of this study was to investigate the structural and functional development of the small intestine in piglets from sows fed a control (C, 12.1% protein), a high protein (HP, 30% protein), or a low protein (LP, 6.5% protein) diet during pregnancy. Newborns were classified as IUGR (birth weight ≤1.18 kg) and non-IUGR (birth weight >1.18 kg). The piglets were euthanized on postnatal day (PD)1, PD28 and PD188. The LP diet in non-IUGR neonates resulted in decreased body weight on PD1. The LP and HP diets resulted in both decreased body weight and delayed catch-up growth in the IUGR piglets. The HP and LP-diets increased the length of villi on PD1 in non-IUGRs but not in IUGRs. At birth, the expressions of Ki67 and active caspase 3 in mid-jejunum epithelium of HP and LP non-IUGR neonates were significantly lower as compared to C non-IUGRs whilst in IUGRs the respective expressions were as high as in C non-IUGRs. The postnatal dynamics of brush border enzyme activities and vacuolated enterocytes disappearance showed significant drop in enterocyte maturation in IUGR as compared to non-IUGR neonates. In conclusion, both HP and LP diets led to retarded development of non-IUGR piglets. In IUGR piglets both HP and LP diets resulted in delayed catch-up growth, without adaptive changes in brush border digestive enzymes.

Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Apoptosis; Birth Weight; Body Weight; Caspase 3; Cholecystokinin; Cytokines; Diet; Dietary Proteins; Female; Fetal Development; Fetal Growth Retardation; Glucagon-Like Peptides; Inflammation; Intestinal Mucosa; Jejunum; Ki-67 Antigen; Male; Mitosis; Pregnancy; Pregnancy Complications; Random Allocation; RNA, Messenger; Sus scrofa

Stress-induced intestinal barrier dysfunction may be involved in chronic intestinal disorders. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic growth hormone that can rapidly improve intestinal epithelial barrier function. Here, we investigated whether mouse intestine is responsive to chronic psychological stress and whether pretreatment with GLP-2 can ameliorate stress-induced changes. Mice were subjected to water avoidance stress (WAS; 1 h/day for 10 days) with GLP-2 or saline administered 4 h before each WAS session. After the final stress period, the intestine was removed for assessment of physiological/morphological changes. Compared with controls (sham-stressed mice), stressed mice demonstrated enhanced ion secretion and permeability in the jejunum, ileum, and colon. In addition, increased numbers of bacteria were observed adhering to and/or penetrating the epithelium, associated with infiltration of mononuclear cells into the mucosa. GLP-2 treatment improved intestinal barrier function in stressed mice and ameliorated other aspects of impaired host defense. Our study extends previous findings in rats of stress-induced intestinal dysfunction and provides insights into potential novel therapeutics.

Topics: Animals; Bacterial Infections; Body Weight; Colon; Diffusion Chambers, Culture; Epithelium; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Horseradish Peroxidase; Inflammation; Intestines; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron; Peptides; Stress, Psychological

A number of human diseases with intestinal adaptation have been investigated, including acute infective diarrhoea, intestinal resection, jejuno-ileal bypass, coeliac disease, tropical sprue, chronic pancreatitis and cystic fibrosis. In all, the newly isolated hormone enteroglucagon appeared to be elevated in proportion to the degree of adaptation. In rats after gut resection and cold adaptation, enteroglucagon was also elevated and the degree of elevation correlated closely with the crypt cell production rate (CCPR). Chronic administration of somatostatin suppressed both enteroglucagon and CCPR, while bombesin stimulated both. A crude preparation of enteroglucagon was found to directly stimulate DNA synthesis in enterocyte cultures. It is thus concluded that, at present, the most likely candidate for the humoral component of intestinal adaptation is the hormonal peptide enteroglucagon.

Topics: Adaptation, Physiological; Adult; Animals; Cattle; Diarrhea; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Hypertrophy; Infant; Inflammation; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Intestines; Mice; Motilin; Obesity; Rats