Intestinal Mucosa Research Articles

A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD.

Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo nicotinamide adenine dinucleotide (NAD + ) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail, we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a decrease of NAD + . We further demonstrate that Trp degradation along the KP occurs locally in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT in-vitro induces NAD + depletion and a pro-inflammatory state, which can largely be rescued by bypassing QPRT via other NAD + precursors. We hence propose a model of impaired de-novo NAD + synthesis from Trp in IBD. These findings point towards the replenishment of NAD + precursors as a novel therapeutic pathway in IBD.

Iron regulatory protein 1 is required for the propagation of inflammation in inflammatory bowel disease

Inflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. This study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

Features of the parietal and cavity intestinal microbiota in infants born to mothers with bronchial asthma, depending on the mode of delivery

Introduction. Intestinal microbiota is a complex and unique system in its composition, performing a huge number of diverse functions in the body. Its formation begins in utero.Aim. To study the features of the parietal and cavity intestinal microbiota in children born to mothers suffering from moderate bronchial asthma, depending on the mode of delivery.Material and methods. A prospective longitudinal study was carried out, which included children from the first day of life to 12 months. A total of 68 children at high risk of atopy (HRA) from mothers with asthma were included, of whom 22 were born by cesarean section and 46 were born through the vaginal birth canal. Qualitative and quantitative analysis of GM was carried out by real-time PCR with group- and species-specific primers: in the examined children, the dynamics of 4 phylums including 31 microorganisms was assessed. The child’s feces and brush-biopsy were taken from the rectum at 7 control points of measurement.Results and discussion. The data obtained showed that the method of delivery has an impact on the formation of the intestinal microbiota: in children born by cesarean section, in the parietal microbiota, starting from the age of 1–2 months, and in the cavity microbiota – 3–4 months, representatives of phylum Firmicutes (Clostridium leptum gr m.). In children born through the vaginal birth canal, all the first 8 months of life in the cavity and parietal microbiota were dominated by representatives of phylum Bacteroidetes (Bacteroides spp., Prevotella spp.). Clostridium leptum can be a marker of an inflammatory process in the intestinal mucosa in children at high risk of atopy. The research conducted over the past few years has found that Clostridium leptum promotes the secretion of anti-inflammatory (IL-10 and IL-12) and inhibition of the production of pro-inflammatory (IL-8) cytokines, and also boosts the number of Treg cells.Conclusion. The mode of delivery in children with a high risk of atopy is an additional epigenetic factor that influences the nature of both the parietal and cerebrospinal microbiota.

Difficulties in diagnosing non-IgE-dependent gastrointestinal forms of food allergy: How informative is fecal calprotectin?

The prevalence of allergic diseases is increasing at rates corresponding to epidemic’s spread rates. Cow’s milk protein allergy (CMPA) is one of the most common food allergies in infancy. Its clinical variants remain hard-to-diagnose diseases due to their multiple clinical faces. Food allergy can develop along the pathway associated with both IgE and non-IgE, or mixed one. Non-IgEassociated variants of food allergies, due to the lack of accurate and specific laboratory markers, can cause significant difficulties in making a diagnosis. The search for new diagnostic markers continues. Faecal calprotectin, a calcium-binding leukocyte protein consisting of a complex of two monomers S100A8 and S100A9, may be one of them. Faecal calprotectin concentration is directly proportional to the number of leukocytes migrating into the intestinal wall, due to which faecal calprotectin becomes an accurate, non-invasive and sensitive indicator reflecting the level of inflammation in the intestines. Today, serum and faecal calprotectin are used as laboratory markers, and the latter, being more accessible and not critical for collection material is widely known as a diagnostic marker of inflammatory bowel diseases. Some studies suggest that faecal calprotectin may be used to diagnose cow’s milk protein allergy in young infants when other diagnostic tests are not available. Data from various studies remain contradictory. Further studies to investigate the possibilities of using faecal calprotectin as a marker of the gastrointestinal food allergy in young children is needed.

INFLUENCE OF PIGEON PARAMYXOVIRUS TYPE-1 ON CLINCOPATHOLOGICAL PROFILES IN RACING PIGEONS ASSOCIATED WITH RECENT OUTBREAKS IN IRAQ

The number of racing pigeons recently increased in Iraq accompanied by significant increases in the number of events similar to the neurotrophic velogenic group of ND viruses in different regions. Thus, this research was designed to study the influence of natural infection with PPMV-1 on clincopathological profiles in four PPMV-1-associated mortality events in racing pigeons in the southern part of Iraq. The result revealed that HI antibody titers above the positivity threshold of four events were seen in (9 out of 24) of tested pigeons in all events, and the predominant signs included polyuria followed by neural symptoms which appear in most of the affected pigeons in the flock. All events showed a high mortality rate (60% - 70%) and absence of gross abnormalities in necropsied pigeons. kidney showed widespread interstitial hemorrhage and intensive epithelial sloughing of renal tubular epithelium, marked white pulp hyperplasia and marked peri-arteriolar fibrosis with onion skin appearance in the spleen, and marked destruction of the superficial intestinal mucosa and intensive inflammation in the site of tissue destruction. This study demonstrates the role of PPMV-1 on clincopathological profiles in racing pigeons associated with recent outbreaks in Iraq, polyuria followed by neural symptoms represent the predominant symptoms in the affected pigeons.

The emerging role of neutrophil extracellular traps in ulcerative colitis.

Ulcerative colitis (UC) is characterized by chronic non-recessive inflammation of the intestinal mucosa involving both innate and adaptive immune responses. Currently, new targeted therapies are urgently needed for UC, and neutrophil extracellular traps (NETs) are new therapeutic options. NETs are DNA-based networks released from neutrophils into the extracellular space after stimulation, in which a variety of granule proteins, proteolytic enzymes, antibacterial peptides, histones, and other network structures are embedded. With the deepening of the studies on NETs, their regulatory role in the development of autoimmune and autoinflammatory diseases has received extensive attention in recent years. Increasing evidence indicates that excess NETs exacerbate the inflammatory response in UC, disrupting the structure and function of the intestinal mucosal barrier and increasing the risk of thrombosis. Although NETs are usually assigned a deleterious role in promoting the pathological process of UC, they also appear to have a protective role in some models. Despite such progress, comprehensive reviews describing the therapeutic promise of NETs in UC remain limited. In this review, we discuss the latest evidence for the formation and degradation of NETs, focusing on their double-edged role in UC. Finally, the potential implications of NETs as therapeutic targets for UC will be discussed. This review aims to provide novel insights into the pathogenesis and therapeutic options for UC.

Short-peptide-based enteral nutrition affects rats MDP translocation and protects against gut-lung injury via the PepT1-NOD2-beclin-1 pathway in vivo.

Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.

Formation mechanism, prevention of malignant ascites effusion and reduction of intestinal mucosal irritation of natural microemulsion from Euphorbia lathyris Pulveratum

Malignant ascites effusion (MAE) is a common complication of advanced malignant tumors with limited treatments. Euphorbia lathyris (EL) has a long history of application in patients with edema and ascites. Herein, we reported for the first time a mode in which EL and EL Pulveratum (PEL) spontaneously formed natural microemulsions (ELM and PELM) without the addition of any carriers and excipients, and found that the protein and phospholipid contained in them encapsulated fatty oil and diterpenoid esters through non-covalent interactions. The denaturation and degradation of protein in PELM resulted in stronger binding of diterpenoid esters to the hydrophobic region of protein, which facilitated the sustained and slow release of diterpenoid esters and improved their bioavailability in vivo, thereby retaining the efficacy of preventing MAE while alleviating the irritation of intestinal mucosa. The mechanism by which PELM retained efficacy might be related to increased feces moisture and urine volume, and decreased expression of AVPR2, cAMP, PKA and AQP3 in MAE mice. And its mechanism of reducing intestinal mucosal irritation was related to decreased cell apoptosis, amelioration of oxidative stress, elevation of mitochondrial membrane potential, and up-regulation of Occludin and Claudin-1 expression in IEC-6 cells. This nano-adjuvant-free natural microemulsions may be a promising therapeutic strategy in the field of phytochemistry for promoting the application of natural and efficient nano-aggregates spontaneously formed by medicinal plants in MAE, and provide a new perspective for advancing the development of the fusion of Chinese herbal medicine and nanomedicine and its clinical translation.

Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.

Diet and epigenetics of colon carcinogenesis: A review article

The following article includes a chart illustrating the dietary components of various food classes that are involved in the pathogenesis of colorectal cancer (CRC), as well as information on the key players in the digestive tract microbiota and the many dysfunctions involved in the onset or progression of CRC. With its complex course throughout history, colorectal cancer has advanced the understanding of its initiation and improvement. The understanding of how colorectal cancer starts and improves through eating less has advanced over time. By and enormous, the utilization of ruddy and organized meats has been related to an expanded chance of start. These meats contain compounds such as nitrates and nitrites that can serve as diagram carcinogens inside the colon. Understanding how diets affect epigenetic modifications inside the intestinal mucosa is particularly important since abnormally methylated genes may serve as early detection and prognostic markers for colon cancer. Epigenetic changes, such as changes in methylation, are potentially reversible and, therefore, offer interesting targets for supportive and preventative therapy, unlike intrinsic changes in cancer. The growing role of microbial metabolites and a few clearly beneficial dietary additions in the management of CRC are outlined in this article.

Extrahepatic Portal Venous Gas Is the Strongest Predictor of Mortality in Patients with Portal Venous Gas and Pneumatosis Intestinalis.

Very few studies have examined the association between contrast-enhanced computed tomography (CT) findings observed in portal venous gas (PVG) and pneumatosis intestinalis (PI) and the underlying diseases in these conditions. In this study, we analyzed this association and report the findings for predicting mortality. Overall, 50 patients diagnosed with PVG or PI, observed on contrast-enhanced CT, underwent treatment at our hospital. Based on the underlying disease, we divided the patients into three groups, those with ischemic disease, infectious disease, or gastrointestinal dilatation. Furthermore, cases that underwent surgical treatment or needed surgery but were inoperable were assigned to the high risk group (n=16) and patients who received conservative treatment were assigned to the low risk group (n=34). We reviewed the patients' medical charts, laboratory data, and CT images retrospectively, and analyzed the relationship between CT findings, underlying disease, and association with the high risk or low risk group in each case. Poor enhancement of the intestinal wall, mesenteric fat stranding, extrahepatic PVG, advanced age, and renal disease were significantly associated with ischemic disease (p=0.02, p=0.02, p=0.005, p=0.008 and p=0.049, respectively). PI alone was strongly associated with gastrointestinal dilatation (p=0.009). Patients in the low risk group had more favorable outcomes with conservative treatment. In multivariate analysis, extrahepatic PVG was the only factor associated with the high risk group (p=0.002). Extrahepatic PVG associated with ischemic disease was the strongest predictive factor of mortality. Other CT findings, though useful in diagnosing the underlying disease, were not significant predictive factors.

Metabolism of baicalin by different microbiota determined by MimiCol.

Substances metabolised by the intestinal microbiota can be used as colon markers and are gaining importance. The flavonoid glycoside baicalin has been described in the literature to be metabolised by the intestinal microbiota. The aim of this work was to investigate how the biotransformation of baicalin to baicalein is related to the intestinal microbiota. For this purpose, stool samples from healthy volunteers with different dietary habits were used. From the pre-cultured stool samples, different standard microbiota were obtained which were used for the subsequent metabolism studies in the in vitro model MimiCol. MimiCol represents the ascending section of the colon, the colon ascendens, in terms of available volume, pH-value, redox potential and bacterial abundance. While during the experiments with added standard microbiota a metabolism of baicalin to baicalein could be detected, this was not the case in a series of experiments without added microbiota. This confirmed the hypothesis that the metabolism of baicalin relies on the bacterial species that are present in the colon. The data collected in the MimiCol therefore support the use of baicalin as a potential marker for the determination of the colon arrival. This can be explained by the fact that baicalin in its native form is poorly absorbed from the gastrointestinal tract. Enzymes of the colonic microbiota, namely β-glucuronidases, hydrolyze baicalin to the aglycone baicalein. The resulting aglycone can be absorbed through the intestinal mucosa and detected in blood plasma. This potentially enables the use of baicalin as a marker to determine the time of arrival in the colon.

Acute toxicity of deoxynivalenol and bioremediation of a highly effective deoxynivalenol degrading Achromobacter spanius P-9 on zebrafish embryos and adults

Deoxynivalenol (DON) is one of the mostly concerned mycotoxins and several microbes showed bioremediation effects on DON toxic effects. In this study, the acute toxicity of a new DON degrading strain Achromobacter spanius P-9 with DON on zebrafish embryos and adults were firstly performed. For zebrafish embryos, bacterial concentrations of 2.5 × 107 CFU/mL and 5.0 × 107 CFU/mL had no significant effects on growth and development. However, at 7.5 × 107 CFU/mL, some effects were observed, and at 10.0 × 107 CFU/mL, the embryo survival rate decreased to 70%, with 3.3% teratogenicity. Higher bacterial concentrations correlated with faster heart rates. DON (100 μg/mL) significantly reduced embryo survival to 36.7% in 96 h. Bacterial solutions at 7.5 × 107 CFU/mL and 10.0 × 107 CFU/mL expanded the zebrafish intestinal tissue wall, while DON at 100 μg/mL negatively impacted intestinal morphology. Liver tissue in zebrafish exposed to Achromobacter spanius P-9 showed no significant differences from the control group. However, exposure to DON solution increased liver fluorescence intensity and caused liver cell changes, including edema, vacuolization, and blurred boundaries. For adult zebrafish, the ROS and 8-OHdG contents in the exposure group increased with the increase of bacterial solution concentration, the SOD enzyme activity, CAT enzyme activity, GST enzyme activity and MDA was not significantly different with the control group. Compared with the control group, the content of ROS, GST enzyme activity, MDA and 8-OHdG after DON treatment showed an upward trend, SOD and CAT enzyme activities showed a decreasing trend. Achromobacter spanius P-9 has no obvious inhibitory effect on the growth and development of zebrafish embryos and has no obvious death and toxicity during the growth of adult fish, providing data support for the future application of this strain in the biodegradation of DON.

Pichia pastoris composition expressed aerolysin mutant of Aeromonas veronii as an oral vaccine evaluated in zebrafish (Danio rerio)

Vaccines are one of the most practical means to stop the spreading of Aeromonas veronii in aquaculture. In this study, virulence factor aerolysin mutant NTaer which has lost its hemolytic activity was used as a target antigen. Pichia pastoris constitutive secretory expression NTaer (GS115-NTaer) was used as a potential safe oral vaccine to evaluate its effectiveness on zebrafish immunity. The result shows that vaccination of GS115- NTaer for four weeks did not affect the growth performance of the host, while eliciting an effective immune protective response. Compared with the control group, the GS115-NTaer could significantly up-regulate the relative expression level of the intestinal tight junction protein 1α (TJP1α) gene, and significantly increased the contents of lysozyme (LYZ), complement C3 and C4 in the gut, indicating that the innate immune response of the fish was activated. The relative gene expression levels of macrophage-expressed gene 1 (MPEG1) and T cell receptor (TCR-α) in the gut, and MPEG1, CD4, CD8, TCR-α, GATA3, and T-bet in the spleen were all increased significantly, indicating that the cellular immune response of the fish was activated. Furthermore, the contents of serum IgM and intestinal mucosa IgZ antibodies were significantly increased, which showed that humoral immunity was also activated. Moreover, inoculation with GS115-NTaer significantly changed the structure of gut microbiota. In particular, the relative ratio of (Firmicutes + Fusobacteriota + Bacteroidota)/Proteobacteria was significantly higher than that of the control and GS115 groups. Lastly, the vaccinated fish were challenged with A. veronii, and the relative percent survival of GS115 and the GS115-NTear groups was 14.28% and 33.43%. This improvement of immunity was not only due to the specific immune response but also attributed to the improvement of innate immunity and the gut microbiota which was demonstrated by the germ-free zebrafish model. Collectively, this study provides information on the effectiveness of GS115-NTear as an oral vaccine for the green prevention and control of A. veronii infection in fish aquaculture.

Immunomodulatory properties of chicken cathelicidin-2 investigated on an ileal explant culture.

As the threat posed by antimicrobial resistance grows more crucial, the development of compounds that can replace antibiotics becomes increasingly vital. Chicken cathelicidin-2 (Cath-2) belongs to the group of Host Defense Peptides (HDPs), which could provide a feasible solution for the treatment of gastrointestinal infections in poultry. It is a small peptide produced by the heterophil granulocytes of chickens as part of the innate immune response, and its immunomodulatory activity has already been demonstrated in several cell types. In this study, the effects of Cath-2 on the intestinal immune response were examined using ileal explant cultures isolated from chicken. Regarding our results, Cath-2 displayed a potent anti-inflammatory effect as it alleviated the LTA-caused elevation of interleukin (IL)-6 and IL-2 concentrations, and that of the IFN-γ/IL-10 ratio, furthermore, it increased the concentration of IL-10, alleviating the LTA-evoked decreased level of the anti-inflammatory cytokine. Moreover, when applied alone, it elevated the concentrations of IL-6, CXCLi2, and IL-2, providing evidence of its complex immunomodulatory mechanisms. In summary, Cath-2 was able to modulate the immune response of the intestinal wall not only by reducing pro-inflammatory cytokine release, but also through immune stimulation, demonstrating that it has the ability to improve innate immunity via a complex mechanism that may make it a suitable candidate for the control of intestinal infections.

The effects of using hydrolyzed feather meal, amino acids, and probiotics in the diet of juvenile rainbow trout on growth, digestibility, and expression of growth-related genes

The study investigated the effect of replacing fishmeal by varying levels of hydrolyzed feather meal (HFM) as well as dietary probiotic supplementation on growth performance, digestibility, histology, and gene expression of juvenile rainbow trout (Oncorhynchus mykiss). Five iso-nitrogenous (average of 50.60% crude protein), iso-energetic (average of 21.79 kJ/g), and iso-lipidic (average of 21.86% crude lipid) diets were formulated and fed to triplicate groups of juvenile rainbow trout weighing 29.65 ± 0.39 g (mean ± SD) for 75 days. Dietary treatments included one control (50% fishmeal) and four experimental diets, each containing 2 g/kg probiotics (Lactobacillus plantarum and Bacillus subtilis). The experimental diets included HFM30 (150 g/kg HFM, 9 g/kg lysine, and 4 g/kg methionine), HFM35 (175 g/kg HFM, 11 g/kg lysine, and 5 g/kg methionine), HFM40 (200 g/kg HFM, 13 g/kg lysine, and 6 g/kg methionine), and HFM45 (225 g/kg HFM, 15 g/kg lysine, and 7 g/kg methionine). Up to 40% replacement of fishmeal with HFM showed no significant difference compared to control group in growth performance (P > 0.05). Feed utilization of HFM45 was slightly lower than control and all the other experimental groups. There was no statistically significant difference in FCR value between HFM40 and control groups (P > 0.05). The apparent digestibility coefficients (ADCs) for protein and amino acids were very high in all groups (P < 0.05). Intestinal mucosa and sub‐mucosa layers of experimental fish showed general tissue integrity with no signs of tissue necrosis. For intestinal morphology, where 45% HFM replacement was applied, villus length to crypt depth (VL to CD) and villus surface area (SA) decreased by 46.01% and 44.44%, respectively, compared to the control group (P < 0.05). This situation shows that intestinal morphology can be damaged when the highest level (HFM45) of feather meal is used. Dietary HFM upregulated growth-related genes such as IGF-II, IGFBP-1b, IGFr1a, GDF9, and FGF2 and downregulated GHR-I and IGF-I. Overall, inclusion of HFM at 40% showed similar results to control group in juvenile rainbow trout feeding.

Understanding the Impacts of Presystemic Metabolism on the Human Oral Bioavailability of Chemicals.

Animal-free new approach methods promote chemical assessments based on the comparison between in vitro bioactivity and human internal concentrations, which necessitates a dependable knowledge of human oral bioavailability, i.e., the fraction of an orally ingested chemical that escapes from presystemic ("first-pass") metabolic processes and eventually enters systemic circulation. Using a physiologically based toxicokinetic model, we show how human oral bioavailability is impacted by presystemic metabolism within the gut lumen, gut wall, and liver and how this impact differs among chemicals with various permeability and stability properties. Our results highlight the gut lumen as a primary site of presystemic metabolism of certain chemicals, such as di-2-ethylhexyl phthalate (DEHP), for which the gut lumen may even exceed the liver in importance of presystemic metabolism due to these metabolic processes occurring in sequence. For chemicals with low transmembrane permeability and low stability, metabolism within the gut lumen is the most remarkable of the three presystemic metabolic processes. Notably, for chemicals that undergo substantial metabolism within the gut lumen, where the metabolites have high permeability, there is a notable discrepancy between the "theoretical bioavailability" (bioavailability of the unchanged parent compound) and the "apparent bioavailability" in measurement practices (bioavailability inferred from measured metabolites). Our work highlights the importance of considering presystemic metabolism, notably within the gut lumen, in human exposure and toxicokinetic modeling.

Antioxidant Activities and Laxative Effect of Bioactive Compounds from Cynara cardunculus var. sylvestris

The present study aims to investigate the antioxidant and anti-constipation activities of the derived phenolic extracts in ribs wild cardoon (Cynara sylvestris). Analysed extracts (acetone, methanol and aqueous) exhibited high level of phenolic compounds and excellent antioxidant activities with significant IC50 values (p ≤0.05), as assessed by the DPPH radical-scavenging activity (0.84±0.08 - 2.44±0.007 μg/mL), ABTS cationic radical test (0.96 ±0.01- 136.67±6.75 μg/mL) and β-carotene bleaching assay (2.09±0.02-51.12±1.32 μg/mL). Also, higher levels of insoluble dietary fibers were found (56.18 ± 0.91% DW of neutral detergent fiber). The in vivo investigation was performed on Wistar rats to explore the ability of C. sylvestris aqueous extract (CSAE) in the enhancement of the gastrointestinal transit and the treatment of induced constipation by Loperamide (commercialized as Idium). A significant increase of 15, 24.5 and 32.4% in gastrointestinal motility was recordedwhen doses of CSAE increased (75, 150 and 300 mg/kg b.w, respectively). Food intake, water consumption, number and weight of stools were also increased in a dose-dependent manner, compared to the positive control (untreated). Moreover, CSAE provided significantly (p ≤0.05) and dose-dependently protection against oxidative stress by preserving normal antioxidant enzymes activities (SOD and GPx) in intestinal and colonic mucosa, and resorted hepatic enzymes (AST and ALT) and renal (urea and creatinine) levels to normal values. These results can be explained by the abundance of phenolic compounds and insoluble fibers in this plant. Therefore, its use can be encouraged in alimentary and pharmaceutical applications as antioxidant and laxative food supplements.

Circulating MicroRNAs and Cytokines Associated with Celiac Disease.

The current research examines the molecular terrain of celiac disease (CD) through microRNA (miRNA) and cytokines as potential new diagnostic and therapeutic markers. Gluten-appropriate immune response is a key feature of an autoimmune clinical entity known as CD that leads to inflammation and degeneration of small intestine mucosa. However, the mechanisms responsible for this remain unclear. Quantitative reverse transcription polymerase chain reaction (RT-qPCR ) was carried out on serum samples obtained from patients with CD and control groups to unravel their pathogenesis. Assessing miR-155, miR-15b, interleukin (IL)-2, IL-7, IL-35and IL-37 levels in expression might be useful in diagnosing or treating the disorder. A significant dysregulation of these molecular players in patients with CD compared with healthy controls has been evidenced by results from this study. For instance, miR-155 was up-regulated, whereas miR-15b was significantly down-regulated in CD, illustrating their roles in immune responses and inflammation-mediated processes. Besides, there was an over-expression of IL-2 and an under-expression of IL-37 in patients with CD, indicating these biomolecules' role in immuno-dysregulation and inflammatory process underlying CD. In addition, a positive correlation between IL-2 and miRNA 155 expression levels was observed in patients with CD, suggesting that they could be involved together with other cytokines, showing the interplay between immune response pathways and inflammatory cascades during CD pathogenesis. These molecular signature discoveries might result in new and revolutionary diagnostic modalities and molecular-targeted therapies for CD pathogenesis. When used with the scientific understanding of miRNAs and cytokines associated with CD pathophysiology, it creates a basis for personalized medicine based on the individualized molecular profile of all patients. This will undoubtedly increase the efficacy of CD treatment strategies. In brief, more research on molecular pathways' workings should be done to harness their potential in CD diagnosis and treatment.

Treatment of anastomotic leak in colorectal surgery by endoluminal vacuum therapy with the VACStent avoiding a stoma - a pilot study

PurposeAnastomotic leak (AL) represents the most relevant and devastating complication in colorectal surgery. Endoscopic vacuum therapy (EVT) using the VACStent is regarded as a significant improvement in the treatment of upper gastrointestinal wall defects. The innovative concept of the VACStent was transferred to the lower GI tract, gaining initial experience by investigating safety and efficacy in 12 patients undergoing colorectal resections.MethodsThe pilot study, as part of a German registry, began with 2 patients suffering from AL, who were treated with the VACStent after stoma placement. Subsequently, 6 patients with AL were treated with the VACStent omitting a stoma placement, with a focus on fecal passage and wound healing. Finally, the preemptive anastomotic coverage was investigated in 4 patients with high-risk anastomoses to avoid prophylactic stoma placement.ResultsIn total 26 VACStents were placed without problems. The conditioning and drainage function were maintained, and no clogging problems of the sponge cylinder were observed. No relevant clinical VACStent-associated complications were observed; however, in 2 patients, a dislodgement of a VACStent occurred. The 6 patients with AL but without stoma had a median treatment with 3 VACStents per case with a laytime of 17 days, leading to complete wound healing in all cases. The 4 prophylactic VACStent applications were without complications.ConclusionThe clinical application of the VACStent in the lower GI tract shows that successful treatment of anastomotic colonic leaks and avoidance of creation of an anus praeter is possible.Trial registration numberClinicaltrials.gov NCT04884334, date of registration 2021-05-04, retrospectively registered.