Inducible generalized activation of hSTING-N154S expression in mice leads to lethal hypercytokinemia: a model for "cytokine storm".

Excessive levels of circulating proinflammatory mediators, known as "hypercytokinemia," that are generated by overwhelming immune system activation can lead to death due to critical organ failure and thrombotic events. Hypercytokinemia has been frequently associated with a variety of infectious and autoimmune diseases, with severe acute respiratory syndrome coronavirus 2 infection currently being the commonest cause, of what has been termed the cytokine storm. Among its various functions within the host, STING (stimulator of interferon genes) is critical in the defense against certain viruses and other pathogens.

Nano-Delivery of a Novel Inhibitor of Polynucleotide Kinase/Phosphatase (PNKP) for Targeted Sensitization of Colorectal Cancer to Radiation-Induced DNA Damage.

Inhibition of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) increases the sensitivity of cancer cells to DNA damage by ionizing radiation (IR). We have developed a novel inhibitor of PNKP, i.e.

PNKP is required for maintaining the integrity of progenitor cell populations in adult mice.

DNA repair proteins are critical to the maintenance of genomic integrity. Specific types of genotoxic factors, including reactive oxygen species generated during normal cellular metabolism or as a result of exposure to exogenous oxidative agents, frequently leads to "ragged" single-strand DNA breaks. The latter exhibits abnormal free DNA ends containing either a 5'-hydroxyl or 3'-phosphate requiring correction by the dual function enzyme, polynucleotide kinase phosphatase (PNKP), before DNA polymerase and ligation reactions can occur to seal the break.

A synthetically lethal nanomedicine delivering novel inhibitors of polynucleotide kinase 3'-phosphatase (PNKP) for targeted therapy of PTEN-deficient colorectal cancer.

Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a major tumor-suppressor protein that is lost in up to 75% of aggressive colorectal cancers (CRC). The co-depletion of PTEN and a DNA repair protein, polynucleotide kinase 3'-phosphatase (PNKP), has been shown to lead to synthetic lethality in several cancer types including CRC. This finding inspired the development of novel PNKP inhibitors as potential new drugs against PTEN-deficient CRC.

Stimulator of interferon genes (STING) activation exacerbates experimental colitis in mice.

Detection of cytoplasmic DNA by the host's innate immune system is essential for microbial and endogenous pathogen recognition. In mammalian cells, an important sensor is the stimulator of interferon genes (STING) protein, which upon activation by bacterially-derived cyclic dinucleotides (cDNs) or cytosolic dsDNA (dsDNA), triggers type I interferons and pro-inflammatory cytokine production. Given the abundance of bacterially-derived cDNs in the gut, we determined whether STING deletion, or stimulation, acts to modulate the severity of intestinal inflammation in the dextran sodium sulphate (DSS) model of colitis.

Expression of a constitutively active human mutant in hematopoietic cells produces an -dependent vasculopathy in mice.

STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disorder characterized by blood vessel occlusions, acral necrosis, myositis, rashes, and pulmonary inflammation that are the result of activating mutations in the STimulator of Interferon Genes (STING). We generated a transgenic line that recapitulates many of the phenotypic aspects of SAVI by targeting the expression of the human STING-N154S-mutant protein to the murine hematopoietic compartment. mice demonstrated failure to gain weight, lymphopenia, progressive paw swelling accompanied by inflammatory infiltrates, severe myositis, and ear and tail necrosis.

Orally administered indomethacin acutely reduces cellular prion protein in the small intestine and modestly increases survival of mice exposed to infectious prions.

Objective: The oral uptake of infectious prions represents a common way to acquire a prion disease; thus, host factors, such as gut inflammation and intestinal "leakiness", have the potential to influence infectivity. For example, the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to induce intestinal inflammation and increase intestinal permeability. Previously, we reported that normal cellular prion protein (PrP(C)) expression was increased in experimental colitis, and since the level of PrP(C) expressed is a determinant of prion disease propagation, we hypothesized that NSAID administration prior to the oral inoculation of mice with infectious prions would increase intestinal PrP(C) expression and accelerate the onset of neurological disease.

Endogenous prion protein attenuates experimentally induced colitis.

Although the cellular prion protein (PrP(C)) is expressed in the enteric nervous system and lamina propria, its function(s) in the gut is unknown. Because PrP(C) may exert a cytoprotective effect in response to various physiologic stressors, we hypothesized that PrP(C) expression levels might modulate the severity of experimental colitis. We evaluated the course of dextran sodium sulfate (DSS)-induced colitis in hemizygous Tga20 transgenic mice (approximately sevenfold overexpression of PrP(C)), Prnp(-/-) mice, and wild-type mice.

Prion protein expression level alters regional copper, iron and zinc content in the mouse brain.

The central role of the prion protein (PrP) in a family of fatal neurodegenerate diseases has garnered considerable research interest over the past two decades. Moreover, the role of PrP in neuronal development, as well as its apparent role in metal homeostasis, is increasingly of interest. The host-encoded form of the prion protein (PrP(C)) binds multiple copper atoms via its N-terminal domain and can influence brain copper and iron levels.

Hydrogen sulphide synthesis in the rat and mouse gastrointestinal tract.

Aims: Hydrogen sulphide (H2S) exerts several anti-inflammatory effects, accelerates the healing of experimental gastric ulcers, and can stimulate intestinal secretion. Little is known about H2S synthesis in the gastrointestinal tract. The aim of this study was to characterize H2S synthesis throughout the gastrointestinal tract.

Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats.

Background & Aims: Hydrogen sulfide (H(2)S) is an endogenous gaseous mediator of mucosal defense with antiinflammatory effects that promote ulcer healing. The effects of H(2)S during the pathogenesis of colitis have not been established. We analyzed the contribution of H(2)S to inflammation and ulceration of the colon in a rat model of colitis.

Annexin-1 modulates repair of gastric mucosal injury.

Annexin-1 is a glucocorticoid-inducible protein that plays an important effector role in the resolution of inflammation and has recently been shown to contribute to the resistance of the stomach to injury. Using an integrated genetic and pharmacological approach, we have tested the hypothesis that annexin-1 contributes to the healing of mucosal injury, given that such injury is accompanied by an inflammatory response, which is often associated with an overexpression of annexin-1 expression. Gastric ulcers were induced in mice through serosal application of acetic acid.

Hydrogen sulfide enhances ulcer healing in rats.

Hydrogen sulfide is an endogenous mediator that relaxes vascular smooth muscle, exhibits several antiinflammatory activities, and contributes to gastric mucosal defense. This study was performed to examine the role of hydrogen sulfide in the resolution of injury; specifically, the healing of gastric ulcers. Ulcers were induced in rats by serosal application of acetic acid.

Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2.

Glucagon-like peptide-2 (GLP-2) is an important regulator of nutritional absorptive capacity with anti-inflammatory actions. We hypothesized that GLP-2 reduces intestinal mucosal inflammation by activation of vasoactive intestinal polypeptide (VIP) neurons of the submucosal plexus. Ileitis or colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water.

Gastrointestinal inflammation: a central component of mucosal defense and repair.

The mucosal layer of the gastrointestinal (GI) tract is able to resist digestion by the endogenous substances that we secrete to digest foodstuffs. So-called "mucosal defense" is multi-factorial and can be modulated by a wide range of substances, many of which are classically regarded as inflammatory mediators. Damage to the GI mucosa, and its subsequent repair, are also modulated by various inflammatory mediators.

Acute denervation alters the epithelial response to adrenoceptor activation through an increase in alpha1-adrenoceptor expression on villus enterocytes.

Loss of sympathetic input due to intestinal denervation results in hypersensitivity and increased intestinal secretion. It is unknown whether denervation-induced alterations in intestinal epithelial physiology are the result of changes in adrenoceptors on enterocytes (ENTs). The purpose of this study was to examine adrenoceptor distribution and pharmacology on small intestinal ENTs following acute intestinal denervation.

A pilot study of the use of epidermal growth factor in pediatric short bowel syndrome.

Background: This study examined the effects of enterally administered epidermal growth factor (EGF) on nutrient absorption and tolerance of enteral feeds in pediatric patients with short bowel syndrome (SBS).

Methods: Patients identified with severe SBS (<25% bowel length predicted for age) were prospectively enrolled in treatment using human recombinant EGF (1-53); 100 microg/kg per day given mixed with enteral feeds and patients were treated for 6 weeks. End points followed were patient weight, tolerance of enteral feeds, nutrient absorption, and intestinal permeability as determined using carbohydrate probes and hematologic values for liver function parameters.

The effects of systemic hypoxia on colon anastomotic healing: an animal model.

Purpose: Acute postoperative systemic hypoxia occurs frequently in the clinical setting following intestinal resection, as a result of complications such as pneumonia, pulmonary edema, or the acute respiratory distress syndrome. Although it is well established that oxygen is essential for metabolism in general and intestinal anastomotic healing, the mechanisms by which systemic hypoxia affect this process are not clear. The purpose of this study was to establish an animal model to simulate acute systemic hypoxia and to examine the effects on anastomotic healing.

Effect of the anticoagulant, pindone, on the breeding performance and survival of merino sheep, Ovis aries.

The effect of the anticoagulant, pindone, on the breeding performance and survival of relatively free-ranging merino sheep was assessed. Pindone (2-pivalyl-1, 3-indandione) was administered orally as a single (10, 3, or 2 mg pindone kg(-1) over three consecutive days) or multiple exposure (dosing regime repeated after a further 8 days). Prothrombin times (PT) increased up to 4-fold in treated sheep, and haemorrhage occurred in some instances, particularly with the double dose treatment.

3-0 methylglucose uptake as a marker of nutrient absorption and bowel length in pediatric patients.

Background: Inert carbohydrate probes are commonly used to assess intestinal permeability; we have previously shown that the actively transported moiety 3-0 methylglucose (3-0 MG) is a useful marker of intestinal surface area and nutrient absorption in animal models of short bowel syndrome (SBS). This study examines the correlation of 3-0 MG absorption with nutrient absorption, bowel length, and the tolerance of enteral feeds in pediatric patients.

Methods: Fifteen children (1 month to 15 years in age) were studied after intestinal surgery.

Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome.

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion.

3-0 methylglucose absorption in vivo correlates with nutrient absorption and intestinal surface area in experimental short bowel syndrome.

Background: Inert carbohydrate probes are widely used to study intestinal permeability and examine the passive uptake of markers. This study examined the use of quantifying 3-0 methylglucose (3-0 MG) absorption as a marker of intestinal surface area and active nutrient transport capability.

Methods: Using a rat model, varying degrees of short bowel syndrome (SBS) were induced: sham operation (intestinal transection only), 50% resection (R50), 75% resection (R75), and 90% resection (R90; n = 6 to 8 in each group).