A Multi-Omics Approach to Disclose Metabolic Pathways Impacting Intestinal Permeability in Obese Patients Undergoing Very Low Calorie Ketogenic Diet.

A very low calorie ketogenic diet (VLCKD) impacts host metabolism in people marked by an excess of visceral adiposity, and it affects the microbiota composition in terms of taxa presence and relative abundances. As a matter of fact, there is little available literature dealing with microbiota differences in obese patients marked by altered intestinal permeability. With the aim of inspecting consortium members and their related metabolic pathways, we inspected the microbial community profile, together with the set of volatile organic compounds (VOCs) from untargeted fecal and urine metabolomics, in a cohort made of obese patients, stratified based on both normal and altered intestinal permeability, before and after VLCKD administration. Based on the taxa relative abundances, we predicted microbiota-derived metabolic pathways whose variations were explained in light of our cohort symptom picture. A totally different number of statistically significant pathways marked samples with altered permeability, reflecting an important shift in microbiota taxa. A combined analysis of taxa, metabolic pathways, and metabolomic compounds delineates a set of markers that is useful in describing obesity dysfunctions and comorbidities.

Effect of a 12-Week Walking Program Monitored by Global Physical Capacity Score (GPCS) on Circulating Cell-Free mtDNA and DNase Activity in Patients with Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) involves low-grade mucosal inflammation. Among the various approaches capable of managing the symptoms, physical activity is still under investigation. Despite its benefits, it promotes oxidative stress and inflammation. Mitochondria impacts gut disorders by releasing damage-associated molecular patterns, such as cell-free mtDNA (cf-mtDNA), which support inflammation. This study evaluated the effects of a 12-week walking program on the cf-mtDNA and DNase in 26 IBS and 17 non-IBS subjects. Pro- and anti-inflammatory cytokines were evaluated by ELISA. Digital droplet PCR was used to quantify cf-mtDNA; DNase activity was assessed using a single radial enzyme diffusion assay. PCR-RFLP was used to genotype DNASE1 rs1053874 SNP. Significantly lower IL-10 levels were found in IBS than in non-IBS individuals. Exercise reduced cf-mtDNA in non-IBS subjects but not in IBS patients. DNase activity did not correlate with the cf-mtDNA levels in IBS patients post-exercise, indicating imbalanced cf-mtDNA clearance. Different rs1053874 SNP frequencies were not found between groups. The study confirms the positive effects of regular moderate-intensity physical activity in healthy subjects and its role in cf-mtDNA release and clearance. Walking alone might not sufficiently reduce subclinical inflammation in IBS, based on imbalanced pro- and anti-inflammatory molecules. Prolonged programs are necessary to investigate their effects on inflammatory markers in IBS.

Metabolomic Profiling of Obese Patients with Altered Intestinal Permeability Undergoing a Very Low-Calorie Ketogenic Diet.

A healthy intestinal permeability facilitates the selective transport of nutrients, metabolites, water, and bacterial products, involving cellular, neural, hormonal, and immune factors. An altered intestinal permeability indicates pathologic phenotypes and is associated with the exacerbation of obesity and related comorbidities. To investigate the impact of altered permeability in obese patients undergoing a calorie-restrictive dietary regimen (VLCKD), we collected urinary and fecal samples from obese patients with both normal and altered permeability (determined based on the lactulose/mannitol ratio) before and after treatment. The analysis of volatile organic compounds (VOCs) aids in understanding the metabolites produced by the intestinal microbiota in this unique ecological niche. Furthermore, we examined clinical and anthropometric variables from the cohort and compared them to significant VOC panels. Consequently, we identified specific markers in the metabolomics data that differentiated between normal and altered profiles before and after the diet. These markers indicated how the variable contribution specifically accounted for interleukins and lipopolysaccharides (LPS). The targeted metabolomics experiment detected no differences in measured short-chain fatty acids (SCFA). In summary, our study evaluated metabolomic markers capable of distinguishing low-grade inflammation conditions, exacerbated in more advanced stages of obesity with altered intestinal permeability.

Enhanced Physical Capacity and Gastrointestinal Symptom Improvement in Southern Italian IBS Patients following Three Months of Moderate Aerobic Exercise.

Moderate-intensity aerobic exercise improves gastrointestinal (GI) health and alleviates irritable bowel syndrome (IBS) symptoms. This study explored its effects on physical capacity (PC) and IBS symptoms in 40 patients from Southern Italy (11 males, 29 females; 52.10 ± 7.72 years). The exercise program involved moderate-intensity aerobic exercise (60/75% of HRmax) for at least 180 min per week. Before and after the intervention, participants completed the IBS-SSS questionnaire to assess IBS symptoms, reported their physical activity levels, and underwent field tests to evaluate PC. PC was quantified as the Global Physical Capacity Score (GPCS). A total of 38 subjects (21 males, 17 females; 53.71 ± 7.27 years) without lower GI symptoms served as a No IBS group. No significant differences were found between IBS patients and No IBS subjects, except for the symptom score, as expected. After the exercise, all participants experienced significant improvements in both IBS symptoms and PC. Higher PC levels correlated with greater benefits in IBS symptomatology, especially with GPCS reaching above-average values. Engaging in moderate-intensity aerobic exercise for at least 180 min per week positively impacts IBS symptoms and PC. Monitoring GPCS in IBS patients provides insights into the connection between physical activity and symptom severity, aiding healthcare professionals in tailoring effective treatment plans.

The Role of Intestinal Barrier Function in Overweight Patients with IBS with Diarrhea Undergoing a Long-Term Low Fermentable Oligo-, Di-, and Monosaccharide and Polyol Diet.

Overweight and obesity have been suggested as significant factors in irritable bowel syndrome (IBS) development. However, the relationship between overweight/obesity and IBS is unclear. It is known that a modified intestinal barrier, especially the permeability of the small intestine (s-IP), can play a significant role in the pathogenesis of both obesity and IBS. Moreover, dietary interventions are essential for treating both pathologies. We evaluated the gastrointestinal (GI) symptoms and the urinary and circulating markers of GI barrier function and integrity, the markers of intestinal dysbiosis and bacterial translocation, in 40 IBS patients with predominant diarrhea (IBS-D) (32 females and 8 males; mean age = 43.5 ± 1.4 years), categorized using their Body Mass Index levels as normal (NW) and overweight (OW). Evaluations were performed before and after 12 weeks of a Low FODMAP Diet (LFD). At the baseline, OW patients showed a significantly higher s-IP than NW. After an LFD, a significant improvement of s-IP in OW patients occurred, along with a significant decrease in markers of epithelial integrity and bacterial translocation. Our findings highlight the close relationship between overweight and the intestinal barrier and support their involvement in IBS-D pathophysiology. Furthermore, the positive role of an LFD in managing overweight IBS-D was highlighted.

Effects of a Very-Low-Calorie Ketogenic Diet on the Fecal and Urinary Volatilome in an Obese Patient Cohort: A Preliminary Investigation.

Several recent studies deepened the strong connection between gut microbiota and obesity. The effectiveness of the very-low-calorie ketogenic diet (VLCKD) has been measured in terms of positive impact on the host homeostasis, but little is known of the modification exerted on the intestinal metabolome. To inspect this complex relationship, we analyzed both fecal and urinary metabolome in terms of volatile organic compounds (VOCs) by the GC-MS method in 25 obese patients that were under VLCKD for eight weeks. Partial least square discriminant analysis evidenced specific urinary and fecal metabolites whose profile can be considered a signature of a partial restore toward the host eubiosis. Specifically, among various keystone VOCs, the decreased concentration of four statistically significant fecal esters (i.e., propanoic acid pentyl ester, butanoic acid hexyl ester, butanoic acid pentyl ester, and pentanoic acid butyl ester) supports the positive effect of VLCKD treatment. Our pilot study results suggest a potential positive effect of VLCKD intervention affecting fecal and urinary volatilome profiles from obese patients. Meta-omics techniques including the study of genes and transcripts will help in developing new interventions useful in preventing or treating obesity and its associated health problems.

The Impact of a Twelve-Week Moderate Aerobic Exercise Program on Gastrointestinal Symptom Profile and Psychological Well-Being of Irritable Bowel Syndrome Patients: Preliminary Data from a Southern Italy Cohort.

Walking is popular moderate-intensity aerobic exercise that improves mental and gastrointestinal (GI) health. It can relieve symptoms associated with irritable bowel syndrome (IBS), e.g., intestinal gas, abdominal distension, and bowel disturbances. This study examined the impact of a moderate-intensity aerobic exercise program on the clinical and psychological parameters of IBS patients. In total, 40 IBS patients (11 males and 29 females; mean age 51.9 ± 7.8 years) participated in a 12-week aerobic exercise program. Participants completed questionnaires assessing GI symptoms, psychological profiles, and quality of life (QoL) before and after the intervention. Field tests, anthropometric measurements, and bioimpedance assessments were also conducted. The present findings confirmed a significant improvement in IBS symptoms after the aerobic exercise program. Bloating was the most common symptom and, together with abdominal pain, was significantly reduced after treatment. Psychological and QoL questionnaires indicated decreased anxiety, depression, somatization, and stress levels. Correlations were found between anxiety/depression and the severity of abdominal pain as well as between stress and the severity of abdominal distension. Moderate-intensity aerobic exercise positively impacted GI symptoms and psychological well-being, complementing dietary and psychological support as a non-pharmacological therapy for the management of IBS. These findings emphasize the importance of alternative approaches for IBS treatment.

The Effects of a Very-Low-Calorie Ketogenic Diet on the Intestinal Barrier Integrity and Function in Patients with Obesity: A Pilot Study.

The very-low-calorie ketogenic diet (VLCKD) is effective and safe for obese individuals, but limited information exists on its impact on the intestinal barrier. This study analyzed the effects of 8 weeks of VLCKD on 24 obese patients (11M/13F). Carbohydrate intake was fixed at 20-50 g/day, while protein and lipid intake varied from 1-1.4 g/kg of ideal body weight and 15-30 g per day, respectively. Daily calorie intake was below 800 kcal. The lactulose-mannitol absorption test assessed small intestinal permeability. Multiple markers, such as serum and fecal zonulin, fatty acid-binding protein, diamine oxidase concentrations, urinary dysbiosis markers (indican and skatole), and circulating lipopolysaccharide levels, were analyzed. Inflammation markers (serum interleukin 6, 8, 10, and tumor necrosis factor-α concentrations) were also evaluated. The results showed significant reductions in weight, BMI, and waist circumference post-diet. However, the lactulose-mannitol ratio increased by 76.5%, and a significant increase in dysbiosis markers at the end of the diet occurred. This trend was particularly evident in a subgroup of patients. Despite initial benefits, the VLCKD might negatively affect the intestinal barrier function in obese patients, potentially worsening their compromised intestinal balance.

A Tritordeum-Based Diet for Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome: Effects on Abdominal Bloating and Psychological Symptoms.

Most female patients with irritable bowel syndrome (IBS) complain of abdominal bloating rather than abdominal pain and diarrhea. The higher incidence in women could be due to the so-called dysfunctional gas handling. Since diet seems the most effective and durable strategy for managing IBS symptoms, we aimed to evaluate the effects of a 12 week diet based on a relatively new cereal, Tritordeum (TBD), on gastrointestinal (GI) symptoms, anthropometric and bioelectrical impedance parameters, and psychological profiles in 18 diarrhea-predominant IBS (IBS-D) female patients with abdominal bloating as the dominant symptom. The IBS Severity Scoring System (IBS-SSS), the Symptom Checklist-90 Revised, the Italian version of the 36-Item Short-Form Health Survey, and the IBS-Quality of Life questionnaire were administered. The TBD reduces the IBS-SSS "Intensity of abdominal bloating" with a concomitant improvement in the anthropometric profile. No correlation was found between "Intensity of abdominal bloating" and "Abdominal circumference". Anxiety, depression, somatization, interpersonal sensitivity, and phobic and avoidance manifestations were significantly reduced after TBD. Lastly, anxiety was correlated with "Intensity of abdominal bloating". Overall, these results suggest the possibility of lowering abdominal bloating and improving the psychological profile of female IBS-D patients using a diet based on an alternative grain such as Tritordeum.

Somatization is associated with altered serum levels of vitamin D, serotonin, and brain-derived neurotrophic factor in patients with predominant diarrhea irritable bowel syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) often show psychological disorders, including somatization, usually driven by an altered gut-brain axis. These changes are also accompanied by modifications in the circulating levels of vitamin D (VD) and neurotransmitters such as serotonin (5-HT) and brain-derived neurotrophic factor (BDNF). The present study aimed to evaluate the relationship between gastrointestinal (GI) symptoms and circulating levels of VD, 5-HT, and BDNF in IBS patients with diarrhea (IBS-D) categorized according to somatization. METHODS: Fifty-three IBS-D patients were recruited and profiled for GI symptoms by validated questionnaires. The fasting serum concentrations of VD, 5-HT, and BDNF were assessed. The health of the intestinal barrier, minimal inflammation, and dysbiosis was also evaluated. KEY RESULTS: Thirty patients showed high somatization scores, IBS-D(S+), and 23 low somatization scores, IBS-D(S-). IBS-D(S+) patients reported higher "Abdominal pain" and the "Abdominal pain duration in days" scores, lower serum VD levels and increased 5-HT and BDNF concentrations than IBS-D(S-). Besides, in IBS-D(S+) patients, the GI symptoms correlated with 5HT, BDNF, and VD concentrations. These parameters were associated with impaired small intestinal permeability and increased inflammation markers. CONCLUSIONS AND INFERENCES: These data support the multifactorial IBS pathogenesis in which organic and psychological factors interact. An active role by VD, 5-HT, and BDNF in affecting the clinical and biochemical profiles in IBS-D(S+) patients may be conceivable. Therefore, the routine VD estimation and the assay of circulating levels of 5-HT and BDNF could be considered a new approach for managing these patients.

Evaluation of the Effects of the Tritordeum-Based Diet Compared to the Low-FODMAPs Diet on the Fecal Metabolome of IBS-D Patients: A Preliminary Investigation.

Since irritable bowel syndrome (IBS)-a common gastrointestinal (GI) disorder-still lacks effective therapy, a nutritional approach may represent a practical alternative. Different reports demonstrated that a low-fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) diet (LFD) reduces symptoms in IBS with diarrhea (IBS-D) patients, also inducing beneficial pathophysiological and biochemical modifications. More recently, diets with alternative cereals having a different gluten composition, such as tritordeum, have also been considered (TBD). We investigated the impact of TBD and LFD on the fecal metabolome composition in 38 IBS-D patients randomly allocated to the two diets for 12 weeks. Summarily, at baseline, the profile of fecal volatile organic compounds (VOCs) of IBS-D patients was not significantly different in the two groups. After treatment, significant changes were observed in the two groups regarding the VOCs content since some of them increased in the TBD group (namely, decanoic acid), whereas others (i.e., nonanal and ethanol) increased in the LFD one. Further, at baseline, short-chain fatty acids were positively related to inflammation and showed a significant decreasing trend after both diets compared to baseline values (namely, acetic and propanoic acid). Preliminary results from this pilot study suggest a potential positive intervention of TBD and LFD affecting the fecal metabolome composition in IBS-D patients.

A Comparison of the Low-FODMAPs Diet and a Tritordeum-Based Diet on the Gastrointestinal Symptom Profile of Patients Suffering from Irritable Bowel Syndrome-Diarrhea Variant (IBS-D): A Randomized Controlled Trial.

The dietary approach low in oligosaccharides, disaccharides, monosaccharides, and fermentable polyols (FODMAPs-LFD) is a good strategy for treating irritable bowel syndrome (IBS). Beyond the LFD, other dietary approaches with beneficial effects may be hypothesized. Among them, consumption of Tritordeum-based foods (TBD, bread, bakery products, and pasta) in substitution of other cereals seem to achieve promising results. In a randomized controlled trial, we compared the effects of 12 weeks of LFD to TBD in improving the symptom profile of IBS-diarrhea (IBS-D) patients. The two diets equally improved gastrointestinal symptoms and QoL, measured by the IBS Severity Scoring System (IBS-SSS) questionnaire, reducing the total score after four weeks and maintaining this range until the end of treatment (IBS-SSS total score change: −132.1; 95% CI: −74.9 to −189.4 and −130.5; 95% CI: −73.2 to −187.7; p < 0.0001 after LFD and TBD, respectively). The two diets did not modify the micronutrients content when extended for 12 weeks. LFD could be regarded as a first-line dietary approach for IBS-D patients. However, TBD may represent a valid alternative, with high palatability, especially among Italian patients, for whom pasta is considered one of the main assets of dietetic culture, and would be easier to manage in their daily habits.

Oxidative imbalance and muscular alterations in diverticular disease.

BACKGROUND: It is still a matter of debate if neuromuscular alterations reflect a primary event in diverticular disease (DD). AIMS: This study aimed to assess colonic wall layers from both stenotic and non-stenotic complicated DD, bio-phenotypic alterations, inflammatory and oxidative status. METHODS: A systematic analysis of colonic specimens obtained from stenotic and non-stenotic DD specimens was conducted and compared with controls. Biological activity and qPCR analysis were performed on longitudinal and circular muscles. Western blot analysis was performed throughout colonic wall layers to quantify oxidative and inflammatory markers. RESULTS: A homogenous increase in oxidative stress was observed through all the layers, which were more sharpened in the longitudinal muscle for a loss in antioxidant defenses. In both stenotic and non-stenotic colon, the longitudinal muscle presented an impaired relaxation and a cellular phenotypic switch driven by transforming growth factor-ß with an increase in mRNA expression of collagen Iα and a decrease in myosin heavy chain. The circular muscle, as the mucosa, was less affected by molecular alterations. No peculiar increase in inflammatory markers was observed. CONCLUSION: A longitudinal colonic myopathy is present in DD, independently from the disease stage associated with an oxidative imbalance that could suggest new therapeutic strategies.

PDGFRα expression as a novel therapeutic marker in well-differentiated neuroendocrine tumors.

AIMS: To evaluate the biological significance of dense vascular networks associated with low-grade NENs, we assessed the impact of PDGFRα tissue expression in 77 GEP/NEN patients, associating PDGFRα expression with the morphological characterization in low-grade tumors. METHODS AND RESULTS: Paraffin-embedded specimens of 77 GEP- NEN tissues, collected from January 2006 to March 2018, were evaluated for PDGFRα tissue expression and correlations with clinicopathological characteristics. PDGFRα tissue expression was significantly correlated with grade and the NEN growth pattern (p < 0.001) but not with gender, primary site or lymph nodes metastatic status. PDGFRα staining was mainly localized in the vascular pole of the neuroendocrine cells and in Enterochromaffin (EC) cells. In particular PDGFRα tissue expression was significantly more expressed in G2 (p < 0.001) than G1 and G3 cases (p 0.004; p < 0.0002;) and correlated with an insular growth pattern. PDGFRα tissue expression was associated with the Ki67 index and we found a significant negative trend of association with the Ki67 proliferation index (P < 0.001): thus PDGFRα expression is referred to morphological and not to proliferative data. CONCLUSIONS: PDGFRα represents an effective target for new anti-angiogenic treatment in WD- GEP-NENs, in particular in G2 cases, and in G3 cases only when there is a mixed insular-acinar pattern. In this context, it is important to carefully delineate those tumors that might better respond to this type of treatment alone or in combination. Further investigation of the relationship between PD-L1 and PDGFRa is warranted, and may contribute to optimize the therapeutic approach in patients with GEP-NENs.

Increased nerve twigs in small intestinal mucosa with programmed cell death-ligand 1 and somatostatin receptor type 2A expression in recurrent Crohn disease: A case report.

RATIONALE: Inflammatory bowel disease (IBD) patients manifest symptoms of disturbed gut function, such as neural sensory-motor changes. Programmed cell death-ligand 1 (PD-L1), normally present in neural tissue, exists in close apposition to the mucosal immune system and intestinal epithelium, and a bi-directional communication is known to occur at these interfaces. Somatostatin has been shown to suppress the inflammatory reaction, and has been used in several clinical trials to treat inflammatory disorders, such rheumatoid arthritis. Recently, somatostatin receptor type 2A, that regulates neurotransmission, proliferation, and apoptosis, has been recognized in IBD. Although prominent abnormalities in the morphology of the enteric nervous system have been observed in idiopathic IBD, they are more marked in Crohn disease. PATIENT CONCERNS: A 55-year-old woman with recurrent Crohn disease, just surgically treated for ileal resection, have a stenotic complication. INTERVENTIONS: At surgery 5 cm of preterminal ileum with stenosis and anastomotic ileocolic block was removed. DIAGNOSES: The histopathology showed a recurrent Crohn in fistulo-stenotic phase; the stenosis was mainly sustained by mass-forming, ganglioneuromatous hyperplasia. Normally very rare, fine nerve twigs extend up into mucosa but we found a new-formed fibrillary network, extending into the inflammation area at the subepithelial luminal site of the mucosa, that was positive to PD-L1 and somatostatin receptor type 2A (SSTR2A) immunostaining but not visualized in routinary stained slides. OUTCOMES: After surgery the patient was semestrally followed with clinical endoscopic evaluation that results uneventfully. LESSONS: Our case shows that before surgery neuromatous abnormalities can be predicted by immunostained new-formed twigs in the mucosa.

Gender-differences of in vitro colonic motility after chemo- and radiotherapy in humans.

BACKGROUND: The aim of the present in vitro study was to investigate, in different genders, motor responses in surgical colonic specimens from patients with rectal cancer undergoing and not undergoing chemotherapy with capecitabine and radiotherapy. METHODS: This in vitro study was conducted from October 2015 to August 2017 at the Experimental Pharmacology Laboratory at the National Institute "S. de Bellis" after collecting samples at the Department of Surgery. Segments of sigmoid colon were obtained from 15 patients (Male (M)/Female (F) = 8/7; control group, CG) operated on for elective colorectal resection for rectal cancer without obstruction and 14 patients (M/F = 7/7; study group, SG) operated on for elective colorectal resection for rectal cancer who also received chemotherapy, based on capecitabine twice daily, and radiotherapy. Isometric tension was measured on colonic circular muscle strips exposed to increasing carbachol or histamine concentrations to obtain concentration-response curves. The motor responses to electrically evoked stimulation were also investigated. RESULTS: In males, carbachol and histamine caused concentration-dependent contractions in the CG and SG. An increased sensitivity and a higher response to carbachol and histamine were observed in SG than CG (P < 0.01). On the contrary, in females, the response to carbachol was not significantly different in CG from the SG and the maximal responses to carbachol were greater in CG than in SG (P < 0.001). The same applied to histamine for half-maximal effective concentrations and maximal response in that they were not significantly different in CG from the SG. Electrically evoked contractions were significantly more pronounced in males, especially in the SG (P < 0.05). CONCLUSIONS: This preliminary in vitro study has shown gender differences in motor responses of colonic circular muscle strips in patients who had received chemotherapy with capecitabine and radiotherapy.

Galunisertib modifies the liver fibrotic composition in the Abcb4Ko mouse model.

Transforming growth factor (TGF)-ß stimulates extracellular matrix (ECM) deposition during development of liver fibrosis and cirrhosis, the most important risk factor for the onset of hepatocellular carcinoma. In liver cancer, TGF-ß is responsible for a more aggressive and invasive phenotype, orchestrating remodeling of the tumor microenvironment and triggering epithelial-mesenchymal transition of cancer cells. This is the scientific rationale for targeting the TGF-ß pathway via a small molecule, galunisertib (intracellular inhibitor of ALK5) in clinical trials to treat liver cancer patients at an advanced disease stage. In this study, the hypothesis that galunisertib modifies the tissue microenvironment via inhibition of the TGF-ß pathway is tested in an experimental preclinical model. At the age of 6 months, Abcb4ko mice-a well-established model for chronic liver disease development and progression-are treated twice daily with galunisertib (150 mg/kg) via oral gavage for 14 consecutive days. Two days after the last treatment, blood plasma and livers are harvested for further assessment, including fibrosis scoring and ECM components. The reduction of Smad2 phosphorylation in both parenchymal and non-parenchymal liver cells following galunisertib administration confirms the treatment effectiveness. Damage-related galunisertib does not change cell proliferation, macrophage numbers and leucocyte recruitment. Furthermore, no clear impact on the amount of fibrosis is evident, as documented by PicroSirius red and Gomori-trichome scoring. On the other hand, several fibrogenic genes, e.g., collagens (Col1α1 and Col1α2), Tgf-ß1 and Timp1, mRNA levels are significantly downregulated by galunisertib administration when compared to controls. Most interestingly, ECM/stromal components, fibronectin and laminin-332, as well as the carcinogenic ß-catenin pathway, are remarkably reduced by galunisertib-treated Abcb5ko mice. In conclusion, TGF-ß inhibition by galunisertib interferes, to some extent, with chronic liver progression, not by reducing the stage of liver fibrosis as measured by different scoring systems, but rather by modulating the biochemical composition of the deposited ECM, likely affecting the fate of non-parenchymal cells.

Myogenic oxidative imbalance interferes with antral motility in obese subjects.

BACKGROUND: Obesity is characterized by a systemic low-grade chronic inflammatory oxidative condition that affects vascular and cardiac smooth muscle relaxation. In human antrum, relaxation is mediated by vasoactive intestinal peptide (VIP) through cAMP and cGMP signaling pathways. A genome-wide association study has demonstrated an association between VIP and obesity. AIM: To evaluate smooth muscle activity in human obese antrum, both in in vitro preparations as well as in vivo. METHODS: Antral muscle strips and cells were isolated from surgical gastric samples from obese and normal weight subjects. Muscle contraction and relaxation, myogenic oxidative stress and inflammatory status were analyzed in vitro. Distal antral motility was evaluated in vivo by magnetic resonance imaging. RESULTS: Obese antral muscle cells showed an oxidative-inflammatory imbalance with overexpression of NLRP3 inflammasome, increased IL-1ß secretion and caspase1-activation, and reduced antioxidant capacity associated with a myogenic motor impairment of VIP-induced relaxation. The intracellular alterations were characterized by a decreased activation of the cAMP-signaling pathway and a decreased expression of eNOS. These in vitro alterations coincided with the hindering of antral motor activity observed in vivo. Apocynin treatment, counteracting oxidative stress, reverted alterations observed in obese antral muscle. CONCLUSION: Antral myogenic activity of obese subjects can be impaired by alterations of signaling pathways induced by oxidative stress.

Small bowel capsule endoscopy revealing neuromuscular and vascular hamartoma of the jejunum: A case report.

RATIONALE: Digestive hemorrhage is a life-threatening and represents for both clinicians and patient a challenger problematic condition with the urgencies to discover the origin for correct the cause and safe the life of patient. PATIENT CONCERNS: We report the case of a 58 -year-old man with extremely rare hamartomatous neurovascular lesion. Following recurrent episode of intestinal hemorrhage the patient underwent small bowel capsule endoscopy. DIAGNOSES: Diagnosed with small intestine neoplasia. INTERVENTIONS: The patient underwent curative small bowel resection. Histologic diagnosis was neuromuscular and vascular hamartoma (NMVH). In the small intestine, neoplastic lesions are very rare (2%) and mostly malformative while the more frequent cause of cryptic digestive hemorrhage remains angiodysplasia (50%) . The preexisting NMVH was exacerbated by the use of non-steroidal anti-inflammatory drugs, causing hemorrhage due to diffuse ulceration. OUTCOMES: The patient stay healthy after treatment. LESSONS: This is an hemorrhagic lesion with macroscopic "neoplastic" patterns due to abnormal mixing of normal indigenous tissue components. It poses a diagnostic challenge for clinicians and pathologists, but diagnosis is facilitated by capsule endoscopy and surgical treatment should provide definitive resolution.