Dysregulated NOX1-NOS2 activity as hallmark of ileitis in mice.

Inflammation of the ileum, or ileitis, is commonly caused by Crohn's disease (CD) but can also accompany ulcerative colitis (backwash ileitis), infections or drug-related damage. Oxidative tissue injury triggered by reactive oxygen species (ROS) is considered part of the ileitis etiology. However, not only elevated ROS but also permanently decreased ROS are associated with inflammatory bowel disease (IBD).

Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia.

Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects.

Therapeutic management of a symptomatic Kaposi's sarcoma patient with renal failure undergoing haemodialysis: A case report.

Kaposi's sarcoma (KS) is a rare inflammation- based vascular cancer involving the skin. The viral aetiology of KS is the Human Herpesvirus 8. KS may be frequently diagnosed in immunosuppressed kidneytransplanted patients, while is less common in patients with dialysis.

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood.

Methods: We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4.

Analgesic and Anti-Inflammatory Effects of Perampanel in Acute and Chronic Pain Models in Mice: Interaction With the Cannabinergic System.

Pain conditions, such as neuropathic pain (NP) and persistent inflammatory pain are therapeutically difficult to manage. Previous studies have shown the involvement of glutamate receptor in pain modulation and in particular same of these showed the key role of the AMPA ionotropic glutamate receptor subtype. Antiseizure medications (ASMs) are often used to treat this symptom, however the effect of perampanel (PER), an ASM acting as selective, non-competitive inhibitor of the AMPA receptor on the management of pain has not well been investigated yet.

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation.

Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. HO generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35-40% of patients, who require surgical interventions in the absence of therapeutic options.

Brain control of appetite during sickness.

Given the high-energy requirements to sustain immune responses and healing processes, it is intriguing that lack of appetite (i.e., anorexia) is a cardinal feature of sickness behaviour.

Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects.

Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice.

Imaging Intestinal ROS in Homeostatic Conditions Using L-012.

Reactive oxygen species (ROS) are critical redox regulators of cellular dynamics controlling homeostasis. Although numerous fluorescent probes are currently available to measure ROS in cell-based assays, the short-lived nature of these molecules renders their detection challenging in more complex biological systems, such as the gastrointestinal tract in vivo. However, in the past decade, significant progress has been made in the development of novel imaging technologies and probes, facilitating ROS quantification with high sensitivity, selectivity, and temporal resolution.

Schistosoma mansoni Worm Infection Regulates the Intestinal Microbiota and Susceptibility to Colitis.

Infection with parasite helminths induces potent modulation of the immune system of the host. Epidemiological and animal studies have shown that helminth infections can suppress or exacerbate unrelated autoimmune, allergic, and other inflammatory disorders. There is growing evidence that helminth infection-mediated suppression of bystander inflammatory responses is influenced by alterations in the intestinal microbiome modulating metabolic and immune functions of the infected host.

ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism.

The A20-binding inhibitor of NF-κB 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding-defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2.

Diet induced obesity is independent of metabolic endotoxemia and TLR4 signalling, but markedly increases hypothalamic expression of the acute phase protein, SerpinA3N.

Hypothalamic inflammation is thought to contribute to obesity. One potential mechanism is via gut microbiota derived bacterial lipopolysaccharide (LPS) entering into the circulation and activation of Toll-like receptor-4. This is called metabolic endotoxemia.

NADPH oxidases and ROS signaling in the gastrointestinal tract.

Reactive oxygen species (ROS), initially categorized as toxic by-products of aerobic metabolism, have often been called a double-edged sword. ROS are considered indispensable when host defense and redox signaling is concerned and a threat in inflammatory or degenerative diseases. This generalization does not take in account the diversity of oxygen metabolites being generated, their physicochemical characteristics and their production by distinct enzymes in space and time.

Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis.

Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells. Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells.

Cellular ROS imaging with hydro-Cy3 dye is strongly influenced by mitochondrial membrane potential.

Background: Hydrocyanines are widely used as fluorogenic probes to monitor reactive oxygen species (ROS) generation in cells. Their brightness, stability to autoxidation and photobleaching, large signal change upon oxidation, pH independence and red/near infrared emission are particularly attractive for imaging ROS in live tissue.

Methods: Using confocal fluorescence microscopy we have examined an interference of mitochondrial membrane potential (ΔΨm) with fluorescence intensity and localisation of a commercial hydro-Cy3 probe in respiring and non-respiring colon carcinoma HCT116 cells.

Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection.

NOX/DUOX family of NADPH oxidases are expressed in diverse tissues and are the primary enzymes for the generation of reactive oxygen species (ROS). The intestinal epithelium expresses NOX1, NOX4, and DUOX2, whose functions are not well understood. To address this, we generated mice with complete or epithelium-restricted deficiency in the obligatory NOX dimerization partner Cyba (p22(phox)).

Defects in NADPH Oxidase Genes and in Very Early Onset Inflammatory Bowel Disease.

Background & Aims: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD.

Protective role for caspase-11 during acute experimental murine colitis.

Activation of the noncanonical inflammasome, mediated by caspase-11, serves as an additional pathway for the production of the proinflammatory cytokines IL-1β and IL-18. Noncanonical inflammasome activity occurs during host defense against Gram-negative bacteria and in models of acute septic shock. We propose that the noncanonical inflammasome is activated in mice during acute intestinal inflammation elicited by dextran sodium sulfate (DSS), a model of experimental colitis.

MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice.

Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described.

Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo.

Objective: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases.

Design: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers.

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis.

Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohn's disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis.

The schistosoma granuloma: friend or foe?

Infection of man with Schistosoma species of trematode parasite causes marked chronic morbidity. Individuals that become infected with Schistosomes may develop a spectrum of pathology ranging from mild cercarial dermatitis to severe tissue inflammation, in particular within the liver and intestines, which can lead to life threatening hepatosplenomegaly. It is well established that the etiopathology during schistosomiasis is primarily due to an excessive or unregulated inflammatory response to the parasite, in particular to eggs that become trapped in various tissue.

A mineral extract from red algae ameliorates chronic spontaneous colitis in IL-10 deficient mice in a mouse strain dependent manner.

Inflammatory bowel disease is an urgent public health problem with a high incidence in developed countries. Alterations of lifestyle or dietary interventions may attenuate the disease progression and increase the efficacy of current therapies. Here we tested the effect of chronic supplementation with a mineral extract from red marine algae - rich in calcium (34%), magnesium, phosphorus, selenium and other trace minerals - in a clinically relevant model of spontaneous enterocolitis, interleukin (IL)-10(-/-) mice.