Anti-diabetic properties of brewer's spent yeast peptides. In vitro, in silico and ex vivo study after simulated gastrointestinal digestion.

Brewer's spent yeast (BSY) hydrolysates are a source of antidiabetic peptides. Nevertheless, the impact of in vitro gastrointestinal digestion of BSY derived peptides on diabetes has not been assessed. In this study, two BSY hydrolysates were obtained (H1 and H2) using ß-glucanase and alkaline protease, with either 1 h or 2 h hydrolysis time for H1 and H2, respectively. These hydrolysates were then subjected to simulated gastrointestinal digestion (SGID), obtaining dialysates D1 and D2, respectively. BSY hydrolysates inhibited the activity of α-glucosidase and dipeptidyl peptidase IV (DPP-IV) enzymes. Moreover, although D2 was inactive against these enzymes, D1 IC50 value was lower than those found for the hydrolysates. Interestingly, after electrophoretic separation, D1 mannose-linked peptides showed the highest α-glucosidase inhibitory activity, while non-glycosylated peptides had the highest DPP-IV inhibitory activity. Kinetic analyses showed a non-competitive mechanism in both cases. After peptide identification, GILFVGSGVSGGEEGAR and IINEPTAAAIAYGLDK showed the highest in silico anti-diabetic activities among mannose-linked and non-glycosylated peptides, respectively (AntiDMPpred score: 0.70 and 0.77). Molecular docking also indicated that these peptides act as non-competitive inhibitors. Finally, an ex vivo model of mouse jejunum organoids was used to study the effect of D1 on the expression of intestinal epithelial genes related to diabetes. The reduction of the expression of genes that codify lactase, sucrase-isomaltase and glucose transporter 2 was observed, as well as an increase in the expression of Gip (glucose-dependent insulinotropic peptide) and Glp1 (glucagon-like peptide 1). This is the first report to evaluate the anti-diabetic effect of BSY peptides in mouse jejunum organoids.

A perspective current and past modes of inhalation therapy.

Inhalation is the preferred route of delivery for anti-asthma and chronic obstructive pulmonary disease (COPD) drugs. The use of this route has demonstrated efficacy in these and other conditions, it offers rapid onset of action, and is associated with minimal systemic exposure, thereby reducing the risk of adverse effects. Therefore, the current brief covers an interesting collection of inhaler action modes, shedding light on their molecular mechanisms and clinical applications for anti-asthma, COPD and antibacterial inhalation therapy. Hence, not only enriches our understanding of inhalation therapy molecular intricacies but also provides a comprehensive overview of the evolving landscape in clinical and antibacterial inhalation therapy. In doing so, it underscores the pivotal role of microbiology and biotechnology in advancing therapeutic approaches that harness the power of inhalation.

Differential Modulation of Mouse Intestinal Organoids with Fecal Luminal Factors from Obese, Allergic, Asthmatic Children.

Asthma is a multifactorial condition that can be associated with obesity. The phenotypes of asthma in lean and obese patients are different, with proinflammatory signatures being further elevated in the latter. Both obesity and asthma are associated with alterations in intestinal barrier function and immunity, and with the composition of the intestinal microbiota and food consumption. In this study, we aimed to establish an organoid model to test the hypothesis that the intestinal content of lean and obese, allergic, asthmatic children differentially regulates epithelial intestinal gene expression. A model of mouse jejunum intestinal organoids was used. A group of healthy, normal-weight children was used as a control. The intestinal content of asthmatic obese children differentially induced the expression of inflammatory and mitochondrial response genes (Tnf-tumor necrosis factor, Cd14, Muc13-mucin 13, Tff2-Trefoil factor 2 and Tff3, Cldn1-claudin 1 and 5, Reg3g-regenerating family member 3 gamma, mt-Nd1-NADH dehydrogenase 1 and 6, and mt-Cyb-mitochondrial cytochrome b) via the RAGE-advanced glycosylation end product-specific receptor, NF-κB-nuclear factor kappa b and AKT kinase signal transduction pathways. Fecal homogenates from asthmatic normal-weight and obese children induce a differential phenotype in intestinal organoids, in which the presence of obesity plays a major role.

Habitual nappers and non-nappers differ in circadian rhythms of LIPE expression in abdominal adipose tissue explants.

Background and purpose: Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or LIPE encodes the protein hormone-sensitive lipase (HSL), an enzyme that plays an important role in lipid mobilization and exhibits a circadian expression rhythm in human adipose tissue. We hypothesized that habitual napping may impact the circadian expression pattern of LIPE, which in turn may attenuate lipid mobilization and induce abdominal fat accumulation. Methods: Abdominal adipose tissue explants from participants with obesity (n = 17) were cultured for a 24-h duration and analyzed every 4 h. Habitual nappers (n = 8) were selected to match non-nappers (n = 9) in age, sex, BMI, adiposity, and metabolic syndrome traits. Circadian LIPE expression rhythmicity was analyzed using the cosinor method. Results: Adipose tissue explants exhibited robust circadian rhythms in LIPE expression in non-nappers. In contrast, nappers had a flattened rhythm. LIPE amplitude was decreased in nappers as compared with non-nappers (71% lower). The decrease in amplitude among nappers was related to the frequency of napping (times per week) where a lower rhythm amplitude was associated with a higher napping frequency (r = -0.80; P = 0.018). Confirmatory analyses in the activity of LIPE's protein (i.e., HSL) also showed a significant rhythm in non-nappers, whereas significance in the activity of HSL was lost among nappers. Conclusion: Our results suggest that nappers display dysregulated circadian LIPE expression as well as dysregulated circadian HSL activity, which may alter lipid mobilization and contribute to increased abdominal obesity in habitual nappers.

Corrigendum: A standardized extract of Lentinula edodes cultured mycelium inhibits Pseudomonas aeruginosa infectivity mechanisms.

[This corrects the article DOI: 10.3389/fmicb.2022.814448.].

A Standardized Extract of Lentinula edodes Cultured Mycelium Inhibits Pseudomonas aeruginosa Infectivity Mechanisms.

The priority pathogen list of the World Health Organization classified Pseudomonas aeruginosa as the second top critical pathogen. Hence, the development of novel antibacterial strategies to tackle this bacterium is highly necessary. Herein we explore the potential antibacterial effect of a standardized extract of cultured mycelium of Lentinula edodes (AHCC®) on P. aeruginosa. AHCC® was found to inhibit the growth rate and biofilm formation of strain PAO1. No change in swarming was observed, but AHCC® hampered swimming and twitching motility. In accordance, a decreased expression of metabolism, growth, and biofilm formation genes was shown. AHCC® also diminished the levels of exotoxin A and bacteria inside IEC18 cells and the secretion of IL-6, IL-10 and TNF by infected macrophages. This effect was related to a reduced phosphorylation of MAPKs and to bacteria internalization. Taken together, our data suggest that AHCC® has a potential role to prevent P. aeruginosa infections and may lead to the development of new therapies.

Modulation of intestinal barrier function by glucocorticoids: Lessons from preclinical models.

Glucocorticoids (GCs) are widely used drugs for their anti-inflammatory and immunosuppressant effects, but they are associated with multiple adverse effects. Despite their frequent oral administration, relatively little attention has been paid to the effects of GCs on intestinal barrier function. In this review, we present a summary of the published studies on this matter carried out in animal models and cultured cells. In cultured intestinal epithelial cells, GCs have variable effects in basal conditions and generally enhance barrier function in the presence of inflammatory cytokines such as tumor necrosis factor (TNF). In turn, in rodents and other animals, GCs have been shown to weaken barrier function, with increased permeability and lower production of IgA, which may account for some features observed in stress models. When given to animals with experimental colitis, barrier function may be debilitated or strengthened, despite a positive anti-inflammatory activity. In sepsis models, GCs have a barrier-enhancing effect. These effects are probably related to the inhibition of epithelial cell proliferation and wound healing, modulation of the microbiota and mucus production, and interference with the mucosal immune system. The available information on underlying mechanisms is described and discussed.

Mice carrying an epithelial deletion of the glucocorticoid receptor NR3C1 develop a higher tumor load in experimental colitis-associated cancer.

The glucocorticoid receptor NR3C1 is expressed in multiple cell types in the gut and elsewhere. Intestinal epithelial cells both produce and respond to glucocorticoids in different physiological and pathological contexts. In experimental colitis, glucocorticoids have been shown to exert a dual role, dampening inflammation while producing a deterioration in animal status, including death. Mice with tamoxifen-inducible, intestinal epithelial-specific deletion of NR3C1 (NR3C1ΔIEC mice) are protected against experimental colitis, suggesting glucocorticoid epithelial actions are deleterious. Since glucocorticoids modulate epithelial proliferation, it follows that they may affect the development of colon cancer. In this study, we set out to test this hypothesis using the dextran sulfate sodium-azoxymethane model of colitis-associated cancer. Knockout (KO) mice were found to exhibit a twofold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend close to the submucosal layer (36% vs. 0%) in NR3C1ΔIEC mice, and overexpressed Lgr5, Egfr, and Myc, consistent with distinct expression of proliferative/stemness markers. Snai1 and Snai2 were upregulated specifically in tumors of NR3C1ΔIEC mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial glucocorticoid (GC) receptor. We conclude that endogenous GC epithelial signaling is involved in colitis-associated cancer.NEW & NOTEWORTHY Mice carrying a tamoxifen-inducible deletion of the glucocorticoid receptor in intestinal epithelial cells (NR3C1ΔIEC mice) and their corresponding controls were subjected to the azoxymethane-dextran sulfate sodium model of colitis-associated cancer. KO mice exhibit a twofold higher tumor load, with a higher trend to extend close to the submucosal layer (36% vs. 0%), but with similar incidence and tumor size. Colonic tumors in NR3C1ΔIEC mice showed signs of increased neoplastic transformation and tumor-associated inflammation.

Impact of alternative splicing on mechanisms of resistance to anticancer drugs.

A shared characteristic of many tumors is the lack of response to anticancer drugs. Multiple mechanisms of pharmacoresistance (MPRs) are involved in permitting cancer cells to overcome the effect of these agents. Pharmacoresistance can be primary (intrinsic) or secondary (acquired), i.e., triggered or enhanced in response to the treatment. Moreover, MPRs usually result in the lack of sensitivity to several agents, which accounts for diverse multidrug-resistant (MDR) phenotypes. MPRs are based on the dynamic expression of more than one hundred genes, constituting the so-called resistome. Alternative splicing (AS) during pre-mRNA maturation results in changes affecting proteins involved in the resistome. The resulting splicing variants (SVs) reduce the efficacy of anticancer drugs by lowering the intracellular levels of active agents, altering molecular targets, enhancing both DNA repair ability and defensive mechanism of tumors, inducing changes in the balance between pro-survival and pro-apoptosis signals, modifying interactions with the tumor microenvironment, and favoring malignant phenotypic transitions. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the impact of AS on MPR in cancer cells.

Leptin-resistant Zucker rats with trinitrobenzene sulfonic acid colitis present a reduced inflammatory response but enhanced epithelial damage.

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n = 10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4-kDa FITC-dextran. Obese Zucker rats showed a lower intestinal myeloperoxidase and alkaline phosphatase activity, reduced alkaline phosphatase sensitivity to levamisole, and diminished colonic expression of Nos2, Tnf, and Il6, indicating attenuated intestinal inflammation, associated with attenuated STAT3, AKT, and ERK signaling in the colonic tissue. S100a8 and Cxcl1 mRNA levels were maintained, suggesting that in the absence of leptin signaling neutrophil activation rather than infiltration is hampered. Despite the lower inflammatory response, leptin resistance enhanced intestinal permeability, reflecting an increased epithelial damage. This was shown by augmented LPS presence in the portal vein of colitic obese Zucker rats, associated with induction of tissue nonspecific alkaline phosphatase, LPS-binding protein, and CD14 hepatic expression (involved in LPS handling). This was linked to decreased ZO-1 immunoreactivity in tight junctions and lower occludin expression. Our results indicate that obese Zucker rats present an attenuated inflammatory response to TNBS, but increased intestinal epithelial damage allowing the passage of bacterial antigens.NEW & NOTEWORTHY Obese Zucker rats, which are resistant to leptin, exhibit a diminished inflammatory response in the trinitrobenzenesulfonic acid (TNBS) model of colitis, suggesting leptin role is proinflammatory. At the same time, obese Zucker rats present a debilitated intestinal barrier function, with increased translocation of LPS. Zucker rats present a dual response in the TNBS model of rat colitis.

Immunoregulatory Effects of Porcine Plasma Protein Concentrates on Rat Intestinal Epithelial Cells and Splenocytes.

Serum protein concentrates have been shown to exert in vivo anti-inflammatory effects. Specific effects on different cell types and their mechanism of action remain unraveled. We aimed to characterize the immunomodulatory effect of two porcine plasma protein concentrates, spray dried serum (SDS) and an immunoglobulin concentrate (IC), currently used as animal nutritional supplements with established in vivo immunomodulatory properties. Cytokine production by the intestinal epithelial cell line IEC18 and by primary cultures of rat splenocytes was studied. The molecular pathways involved were explored with specific inhibitors and gene knockdown. Our results indicate that both products induced GROα and MCP-1 production in IEC18 cells by a MyD88/NF-κB-dependent mechanism. Inhibition of TNF production was observed in rat primary splenocyte cultures. The immunoglobulin concentrate induced IL-10 expression in primary splenocytes and lymphocytes. The effect on TNF was independent of IL-10 production or the stimulation of NF-kB, MAPKs, AKT, or RAGE. In conclusion, SDS and IC directly regulate intestinal and systemic immune response in murine intestinal epithelial cells and in T lymphocytes and monocytes.

Epithelial deletion of the glucocorticoid receptor (Nr3c1) protects the mouse intestine against experimental inflammation.

BACKGROUND AND PURPOSE: Glucocorticoids are the first line treatment for the flare-ups of inflammatory bowel disease, but they have significant limitations. The objective of this study is to investigate whether glucocorticoid epithelial actions contribute to such limitations. EXPERIMENTAL APPROACH: Intestinal epithelium glucocorticoid receptor knockout mice (Nr3c1ΔIEC ) received dextran sulfate sodium (DSS) to induce colitis. Inflammatory status was assessed by morphological and biochemical methods, and corticoid production was measured in colonic explants. Some mice were administered budesonide. KEY RESULTS: After 7 days of DSS Nr3c1ΔIEC , mice exhibited 23.1% lower disease activity index (DAI) and 37% lower diarrheal score than WT mice, with decreased weight loss in days 5-7 of colitis, attenuated tissue damage, reduced colonic expression of S100A9 and STAT3 phosphorylation, and a better overall state. Ki67 immunoreactivity was increased at the crypt base, indicating enhanced epithelial proliferation. Mice administered budesonide (6 µg·day-1 PO) showed modest antiinflammatory effects but increased weight loss, which was prevented in knockout mice. Epithelial deletion of the glucocorticoid receptor also protected mice in a protracted colitis protocol. Conversely, knockout mice presented a worse status compared to the control group at 1 day post DSS. In a separate experiment, colonic corticosterone production was shown to be significantly increased in knockout mice at 7 days of colitis but not at earlier stages. CONCLUSIONS AND IMPLICATIONS: The intestinal epithelial glucocorticoid receptor has deleterious effects in experimental colitis induced by DSS, probably related to inhibition of epithelial proliferative responses leading to impaired wound healing and reduced endogenous corticosterone production.

Insulin Crystals Grown in Short-Peptide Supramolecular Hydrogels Show Enhanced Thermal Stability and Slower Release Profile.

Protein therapeutics have a major role in medicine in that they are used to treat diverse pathologies. Their three-dimensional structures not only offer higher specificity and lower toxicity than small organic compounds but also make them less stable, limiting their in vivo half-life. Protein analogues obtained by recombinant DNA technology or by chemical modification and/or the use of drug delivery vehicles has been adopted to improve or modulate the in vivo pharmacological activity of proteins. Nevertheless, strategies to improve the shelf-life of protein pharmaceuticals have been less explored, which has challenged the preservation of their activity. Herein, we present a methodology that simultaneously increases the stability of proteins and modulates the release profile, and implement it with human insulin as a proof of concept. Two novel thermally stable insulin composite crystal formulations intended for the therapeutic treatment of diabetes are reported. These composite crystals have been obtained by crystallizing insulin in agarose and fluorenylmethoxycarbonyl-dialanine (Fmoc-AA) hydrogels. This process affords composite crystals, in which hydrogel fibers are occluded. The insulin in both crystalline formulations remains unaltered at 50 °C for 7 days. Differential scanning calorimetry, high-performance liquid chromatography, mass spectrometry, and in vivo studies have shown that insulin does not degrade after the heat treatment. The nature of the hydrogel modifies the physicochemical properties of the crystals. Crystals grown in Fmoc-AA hydrogel are more stable and have a slower dissolution rate than crystals grown in agarose. This methodology paves the way for the development of more stable protein pharmaceuticals overcoming some of the existing limitations.

Deficiency in Tissue Non-Specific Alkaline Phosphatase Leads to Steatohepatitis in Mice Fed a High Fat Diet Similar to That Produced by a Methionine and Choline Deficient Diet.

The liver expresses tissue-nonspecific alkaline phosphatase (TNAP), which may participate in the defense against bacterial components, in cell regulation as part of the purinome or in bile secretion, among other roles. We aimed to study the role of TNAP in the development of hepatosteatosis. TNAP+/- haplodeficient and wild type (WT) mice were fed a control diet (containing 10% fat w/w) or the same diet deficient in methionine and choline (MCD diet). The MCD diet induced substantial weight loss together with hepatic steatosis and increased alanine aminotransferase (ALT) plasma levels, but no differences in IL-6, TNF, insulin or resistin. There were no substantial differences between TNAP+/- and WT mice fed the MCD diet. In turn, TNAP+/- mice receiving the control diet presented hepatic steatosis with alterations in metabolic parameters very similar to those induced by the MCD diet. Nevertheless, no weight loss, increased ALT plasma levels or hypoglycemia were observed. These mice also presented increased levels of liver TNF and systemic resistin and glucagon compared to WT mice. The phenotype of TNAP+/- mice fed a standard diet was normal. In conclusion, TNAP haplodeficiency induces steatosis comparable to that produced by a MCD diet when fed a control diet.

Circadian Rhythms in Hormone-sensitive Lipase in Human Adipose Tissue: Relationship to Meal Timing and Fasting Duration.

BACKGROUND: Fat mobilization in adipose tissue (AT) has a specific timing. However, circadian rhythms in the activity of the major enzyme responsible for fat mobilization, hormone-sensitive lipase (HSL), have not been demonstrated in humans. OBJECTIVE: To analyze in a cross-sectional study whether there is an endogenous circadian rhythm in HSL activity in human AT ex vivo and whether rhythm characteristics are related to food timing or fasting duration. METHODS: Abdominal AT biopsies were obtained from 18 severely obese participants (age: 46 ± 11 years; body mass index 42 ± 6 kg/m2) who underwent laparoscopic gastric bypass. Twenty-four-hour rhythms of HSL activity and LIPE (HSL transcript in humans) expression in subcutaneous AT were analyzed together with habitual food timing and night fasting duration. RESULTS: HSL activity exhibited a circadian rhythm (P = .023) and reached the maximum value at circadian time 16 (CT) that corresponded to around midnight (relative local clock time. Similarly, LIPE displayed a circadian rhythm with acrophase also at night (P = .0002). Participants with longer night fasting duration >11.20 hours displayed almost double the amplitude (1.91 times) in HSL activity rhythm than those with short duration (P = .013); while habitual early diners (before 21:52 hours) had 1.60 times higher amplitude than late diners (P = .035). CONCLUSIONS: Our results demonstrate circadian rhythms in HSL activity and may lead to a better understanding of the intricate relationships between food timing, fasting duration and body fat regulation.

Efficacy and Safety of a Novel Submucosal Injection Solution for Resection of Gastrointestinal Lesions.

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are minimally invasive and efficient techniques for the removal of gastrointestinal (GI) mucosal polyps. In both techniques, submucosal injection solutions are necessary for complete effectiveness and safety during the intervention to be obtained. The main objective of this study was to evaluate the efficacy and safety of a new sterile submucosal injection solution for EMR/ESD used within a clinical protocol in patients with intestinal polyps. We carried out a prospective study between 2016 and 2017 with patients who attended the Endoscopy Consultation-Digestive Department of Primary Hospital. Patients were selected for EMR/ESD after the application of clinical protocols. Thirty-six patients were selected (≥ 66 years with comorbidities and risk factors). Lesions were located mainly in the colon. Our solution presented an intestinal lift ≥ 60 min in EMR/ESD and a high expansion of tissue, optimum viscosity, and subsequent complete resorption. The genes S100A9 and TP53 presented an expression increase in the distal regions. TP53 and PCNA were the only genes whose expression was increased in polyp specimens vs. the surrounding tissue at the mRNA level. In EMR/ESD, our solution presented a prolonged effect at the intestinal level during all times of the intervention. Thus, our solution seems be an effective and safe alternative in cases of flat lesions in both techniques.

Molecular action mechanism of anti-inflammatory hydrolysates obtained from brewers' spent grain.

BACKGROUND: Brewers' spent grain (BSG) is a relevant, protein-rich by-product of the brewing process. Protein hydrolysates from different sources exert immune-regulatory actions activating toll-like receptors (TLRs), nuclear factor kappa B (NFκB), and mitogen-activated protein kinases (MAPKs). Effects of gastrointestinal digestion have been poorly studied. Here, we studied the immune-regulatory effect of BSG hydrolysates, and their in-vitro-digested products, on rat splenocytes, macrophages, and T lymphocytes RESULTS: In primary cultures of rat spleen cells, BSG hydrolysates induced interleukin 10 and tumor necrosis factor production in basal conditions. Under stimulation with lipopolysaccharide or concanavalin A, hydrolysates further induced interleukin 10 production. Tumor necrosis factor and interferon-γ were inhibited in lipopolysaccharide- and concanavalin-A-stimulated cells respectively. In vitro gastrointestinal digestion attenuated the observed effects. Splenic macrophages and T lymphocytes behaved in a similar fashion. In spleen cells from TLR2-/- and TLR4-/- mice, immune-regulatory effects were greatly reduced or abrogated. The study of signal transduction pathways indicated a major involvement of NFκB, and the contribution of MAPKs p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinases 1 and 2. CONCLUSION: BSG hydrolysates, like those obtained from other food sources, regulate the immune response, involving TLR2 and TLR4 and the activation of NFκB and MAPKs, an effect partly maintained after in vitro gastrointestinal digestion. Our data support the hypothesis of a shared, rather unspecific, mechanism of action of protein hydrolysates. © 2020 Society of Chemical Industry.

Premature Birth Infants Present Elevated Inflammatory Markers in the Meconium.

Introduction: Prematurity, a well-established risk factor for various intestinal diseases in newborns, results in increased morbidity and mortality. However, the intestinal inflammatory status of preterm (PT) infants has been poorly characterized. Here we have broadly described the intestinal and systemic inflammatory status of PT children. Materials and Methods: Meconium and plasma from 39 PT and 32 full term (T) newborns were studied. Fecal calprotectin, polymorphonuclear leukocyte elastase (PMN-E), TNF, IL-17A, IL-8, IP-10, MCP-1, MIP-1, IL-1ß, IL-1α, and E-selectin and the enzymatic activities of myeloperoxidase (MPO) and alkaline phosphatase (AP) in meconium were measured. Plasma levels of AP, hepatocyte growth factor, nerve growth factor (NGF), proinflammatory cytokines, leptin, adiponectin, PAI-1, and resistin were also determined. Correlations with gestational age (GA) and birth weight (BW) were studied. Results: Neutrophil derived PMN-E, MPO and calprotectin were increased in the meconium of PT compared to T newborns, while AP was decreased. No significant differences were found in other inflammatory parameters. Considering data from all children, GA and BW showed inverse correlation with neutrophil markers, while AP directly correlated with BW. Plasma levels of IL-1ß and NGF were enhanced in PT infants, and were also negatively correlated with BW. PT children additionally showed neutropenia and decreased adiponectin, leptin, haematocrit, and haemoglobin. These parameters (neutrophils, adiponectin, and so forth) were positively correlated with GA and BW, while IL-8, MCP-1, PAI-1, and plasma AP were negatively correlated. PT children showing postnatal morbidity exhibited increased meconium MPO and MIP-1α. Conclusion: PT neonates present a significant elevation of intestinal inflammatory parameters, characterized by the presence of neutrophil markers, associated with mild systemic inflammation.

Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function.

Glucocorticoids (GCs) are important hormones involved in the regulation of multiple physiologic functions. GCs are also widely used in anti-inflammatory/immunosuppressant drugs. GCs are synthesized by the adrenal cortex as part of the hypothalamus-pituitary-adrenal axis and also by intestinal epithelial cells, among other peripheral sites. GCs are one of the main therapy choices for the exacerbations of inflammatory bowel disease, but they are not useful to prolong remission, and development of tolerance with secondary treatment failure is frequent. Thus, GC actions at the intestinal epithelial level are of great importance, both physiologically and pharmacologically. We generated a tamoxifen-inducible nuclear receptor subfamily 3 group C member 1 (NR3C1)ΔIEC mouse model to study the effects of GCs on epithelial cells in vivo. Nr3c1 deletion in epithelial cells of the small intestine and colon was associated with limited colonic inflammation at 1 wk postdeletion, involving augmented epithelial proliferation and mucus production, plus local and systemic immune/inflammatory changes. This phenotype regressed substantially, but not completely, after 2 wk. The mechanism may involve augmented inflammatory signaling by epithelial cells or defective barrier function. We conclude that the epithelial GC receptor plays a significant role in colonic homeostasis in basal conditions, but its deficiency can be compensated in the short term. Future studies are required to assess the impact of Nr3c1 deletion in other conditions such as experimental colitis.-Aranda, C. J., Arredondo-Amador, M., Ocón, B., Lavín, J. L., Aransay, A. M., Martínez-Augustin, O., Sánchez de Medina, F. Intestinal epithelial deletion of the glucocorticoid receptor NR3C1 alters expression of inflammatory mediators and barrier function.

Exogenous leptin reinforces intestinal barrier function and protects from colitis.

Besides its function controlling energy expenditure and food intake, leptin is an important modulator of inflammatory responses. The role of leptin in intestinal inflammation remains controversial, since both pro-inflammatory and anti-inflammatory effects have been reported. This study was carried out to further understand leptin contribution in the inflamed intestinal mucosa. Exogenous PEG-leptin or saline solution was given to C57BL/6 mice for two weeks. After 1 week, acute colitis was induced to C57BL/6 mice using dextran sulfate sodium (DSS) in drinking water. The severity of colitis, inflammatory parameters and mucosal barrier function were evaluated. Overall our results indicate that colitis was less severe in mice receiving leptin, as shown by a decrease in rectal bleeding, epithelial damage and colon inflammatory markers, and improved diarrhea. Leptin-treated mice displayed an increase in the expression of tight junction proteins and proliferative expression markers in colon, indicating a reinforcement in the mucosal barrier function induced by leptin administration. PEG-leptin treatment conferred protection to mice in the DSS model of colitis by reinforcing mucosal barrier function.