Hasil untuk "Diseases of the digestive system. Gastroenterology"

B. Durie, J. Harousseau, J. Miguel et al.

G. Muscogiuri, Elena Cantone, Sara Cassarano et al.

Shahnaz Sultan, Dennis L. Shung, Jennifer M. Kolb et al.

Waqas Haque, Eman Haque, Iemaan Rana et al.

Shiguan Wang, Pan Han, Ping Mi et al.

Background & Aims: Hepatocellular carcinoma (HCC) frequently involves metabolic reprogramming, which promotes oncogenesis and metastasis. However, the underlying molecular mechanisms remain insufficiently explored. In this study, we aim to investigate the metabolic abnormalities in c-Myc-driven HCC development and their potential therapeutic implications. Methods: RNA sequencing and metabolomics were performed on HCC and adjacent tissues in a murine HCC model established by hydrodynamic tail-vein injection of c-Myc and sgTrp53/Cas9 plasmids. Key catalytic enzyme gene knockout was used to assess tumor formation and murine survival. Gene expression was analyzed using quantitative polymerase chain reaction, immunohistochemistry, and Western blot. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction and luciferase assays verified c-Myc regulation. Results: RNA sequencing data revealed that the hexosamine biosynthetic pathway was significantly activated in c-Myc-driven HCC. The rate-limiting enzyme GFPT1 (rather than GFPT2) was up-regulated in the first step of this pathway. Knocking out GFPT1 reduces tumor growth and prolongs murine survival. Human specimens showed that GFPT1 was overexpressed in HCC tissues and was associated with advanced Edmondson-Steiner grades and short patient survival. Further luciferase reporter assays confirmed that c-Myc binds directly to the promoter region of GFPT1 and activates its transcription. Subsequent examination of the downstream pathways of the hexosamine biosynthetic pathway showed that the sialic acid synthesis (but not O-GlcNac glycosylation) pathway was enhanced, which was mediated by a key enzyme, N-acetylneuraminic acid synthase. Knockout of N-acetylneuraminic acid synthase also inhibits tumor growth and extends murine survival in c-Myc-driven HCC models. Conclusions: These findings indicate that the activation of the hexosamine biosynthetic pathway/sialic acid pathway is an important mechanism underlying the development of c-Myc-driven HCC. Inhibitors of GFPT1, along with anti– N-acetylneuraminic acid synthase may offer a promising therapeutic strategy.

Balasubramaniyan Vairappan, Tanya Mishra, Biju Pottakkat

Aim: Hepatocellular carcinoma (HCC) poses a significant global health threat. The pregnane X receptor (PXR) is a central regulator of xenobiotic metabolism and plays a key role in mediating cellular resistance to anti-tumor drugs in HCC. Indeed, the precise role of PXR in HCC pathogenesis remains unclear. This study aimed to investigate blood and hepatic PXR levels and their association with inflammation in HCC patients. Additionally, we assessed the diagnostic potential of PXR in HCC patients compared to control subjects. Methods: Following approval by the Institute Ethical Committee, 40 HCC patients and 40 healthy volunteers were enrolled in this study. Baseline patient characteristics, serum alpha-fetoprotein (AFP), and biochemical parameters were analyzed. Serum levels of PXR, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-1β were measured using ELISA. The hepatic expression of phosphorylated nuclear factor kappa B (NFκB) and PXR proteins was analyzed by western blotting. Results: When compared to control subjects, serum PXR levels were increased in HCC cases (1.34 ± 0.16 vs. 4.09 ± 0.33; P < 0.0001). Similarly, hepatic PXR expression was increased in HCC tissues. Moreover, HCC patients exhibited elevated inflammatory cytokines and a deranged hepatobiliary profile compared to controls. Conclusions: Elevated serum PXR levels in HCC patients were positively correlated with inflammation. Notably, serum PXR demonstrated greater sensitivity and specificity in diagnosing HCC. These findings suggest that PXR may serve as a plausible biomarker in the diagnosis of HCC.

Sebastián Martínez-López, Oriol Juanola, Isabel Gómez-Hurtado et al.

Background &amp; Aims: LSECtin downregulation during cirrhosis progression is associated with adaptive T-cell expansion. We analyzed the molecular mechanism for LSECtin modulation of Th17 proliferation in an experimental cirrhosis model. Methods: A transgenic mouse model of Clec4g/LSECtin overexpression (Clec4g KI) was subjected to CCl4-induced cirrhosis. Cell death, liver function, and inflammation markers (n = 6/group) were evaluated. LSECtin-LAG3 signaling in Th17-differentiated spleen cells (n = 5) and LAG3 expression in livers of human individuals with cirrhosis (n = 6) were also characterized. Results: Densitometred LSECtin expression was significantly downregulated during cirrhosis in wild-type but not Clec4g-KI mice (0.6 ± 0.2 vs. 2.3 ± 0.6 AU, p = 0.001). LSECtin overexpression in cirrhotic mice resulted in less histological damage and improved liver enzyme levels (alanine aminotransferase: 152.7 ± 66.3 vs. 76.33 ± 13.33 U/L, p = 0.004). Cell-death pathway analysis revealed no differences in apoptosis markers Casp3 and Casp8 but reduced levels of necroptotic intermediates Mlkl and Ripk3. LSECtin overexpression reduced hepatic leukocyte infiltration and enriched the differentiation from inflammatory Rorgt+/IL-17+ (2.4 ± 0.8 vs. 7.7 ± 3.5% CD4+, p = 0.043) to regulatory Foxp3+/IL-10+ cells (3.6 ± 0.9 vs. 1.2 ± 0.7% CD4+, p = 0.047) in cirrhotic animals. LSECtin interacted with LAG-3 on polarized spleen-derived CD4+ T cells, inhibiting Th17 differentiation (10.5 ± 2.7 vs. 6.6 ± 2.1% CD4+, p = 0.037) by suppressing Stat3 and Zap70 pathways. LSECtin did not restrain the Th17 subset expansion during LAG3 blockade (6.6 ± 2.1 vs. 14.2 ± 4.0% CD4+, p = 0.005). Livers of human individuals with cirrhosis showed increased LAG-3-expressing Th17 cells compared with controls (3.2 ± 1.4 vs. 0.1 ± 0.1 cells/mm2, p = 0.001). Conclusions: We have established a valuable murine model of LSECtin overexpression to assess its impact on hepatic inflammation during cirrhosis. LAG-3 was identified as the molecular mechanism by which LSECtin attenuates Th17 differentiation. Given LSECtin capacity to modulate the Th profile and decrease proinflammatory cell death, liver-directed molecular approaches to restore its expression may be of therapeutic interest during cirrhosis. Impact and implications: LSECtin downregulation is associated with the expansion of Th17 cell subpopulation during cirrhosis. Findings highlight the crucial role of LSECtin in regulating immune responses and mitigating liver damage in cirrhosis. Restoring LSECtin expression through targeted liver-directed molecular interventions may be of therapeutic relevance in cirrhosis.

Gi Eun Kim, Mariam Imran, Sherif Mostafa et al.

Primary biliary cholangitis is a progressive disease with complications such as liver cirrhosis and hepatocellular carcinoma, and the treatment goal is to delay its progression. One of the markers for treatment response is alkaline phosphatase levels. Baricitinib has been used in one randomized controlled trial involving two patients to improve outcomes in unresponsive primary biliary cholangitis. We present a case of primary biliary cholangitis who had incomplete response to ursodeoxycholic acid, obeticholic acid, and fenofibrate but showed complete response to baricitinib in terms of sustained normalized alkaline phosphatase levels.

David Leonardo Flores-Marin, Justin Linden, Emma Frank et al.

Rena Yadlapati

S. Houterman, A. Dullemen, M. Versteegh et al.

Aim The aim of this article is to present the method and results of the data quality control system and audit within the Netherlands Heart Registration (NHR) using data of patients treated with percutaneous coronary intervention (PCI) in the Netherlands as an example. Methods The NHR is a Dutch nationwide registry of all cardiac interventions, comprising data from all 71 hospitals, of which 30 are cardiac intervention or heart centres. Each year, within the NHR, data validation and verification is performed by standard quality controls and monitoring visits (audits). For the audit in 2019, a sample of 50–100 medical records of patients treated with PCI in 2016 and 2017 were reviewed in each hospital by an independent auditor. The data received by the NHR were compared with the information in the hospitals’ medical records. In total 12 patient characteristics, 5 intervention variables and 3 outcome variables were screened. The value of a variable was considered discrepant if more than 10% of the medical records reviewed regarding this variable were not consistent with the reported data received by the NHR. Results For all variables together, the consistency was high, 97.6%. All variables, except multivessel disease (9.3% discrepancy in the 2622 medical records reviewed), had an accuracy above 95%. Conclusion The results of the audit of the PCI medical records show that the overall quality of the data is high. For variables such as multivessel disease it is important to improve knowledge of the definitions and to train all those involved in the registration process.

C. Loras, X. Andújar, J. Gornals et al.

BACKGROUND Endoscopic balloon dilation (EBD) is the established endoscopic treatment for short strictures in Crohn's disease. Fully covered self-expandable metal stents (FCSEMS) have been used for endoscopic treatment of patients for whom EBD was unsuccessful. We aimed to determine the efficacy and safety of the two endoscopic treatments in patients with Crohn's disease with stenosis and compare the mean cost of both treatments. METHODS This multicentre, open-label, randomised trial was done in 19 tertiary and secondary hospitals in Spain. Patients with Crohn's disease with obstructive symptoms and predominantly fibrotic strictures of less than 10 cm in length were eligible for inclusion. We excluded patients with stenosis treated with SEMS or EBD in the previous year and stenosis not accessible to a colonoscope. Patients were randomly assigned (1:1) to receive either EBD (EBD group) or FCSEMS (FCSEMS group) using a digital en-block randomisation system (block size of four). In the EBD group, dilation was done with a CRE Boston Scientific (Marlborough, MA, USA) pneumatic balloon with the diameter set at the discretion of the endoscopist; a maximum of two sessions of dilation were allowed with a minimum interval of 15-30 days between them. In the FCSEMS group, a 20 mm diameter Taewoong (Gimpo-si, South Korea) fully covered metal stent was placed; stent length was set at the discretion of the endoscopist. The primary outcome was to assess the efficacy of the endoscopic treatment, defined by the proportion of patients free of a new therapeutic intervention (EBD, FCSEMS, or surgery) due to symptomatic recurrence at 1 year of follow-up. Patients were analysed according to the intention-to-treat principle. Adverse events were recorded for all the patients; events were considered associated to be with the procedure when a causal association was possible, probable, or definite. This trial is registered with ClinicalTrials.gov, NCT02395354. FINDINGS From Aug 28, 2013, to Oct 9, 2017, we assessed the eligibility of 99 patients, of whom 19 (19%) patients were excluded. Thus, 80 (81%) patients were randomly assigned to treatment: 39 (49%) patients to the FCSEMS group and 41 (51%) patients to the EBD group. 33 (80%) of 41 patients in the EBD group and 20 (51%) of 39 patients in the FCSEMS group were free of a new therapeutic intervention at 1 year (odds ratio [OR] 3·9 [95% CI 1·4-10·6]; p=0·0061). Two (3%) of 80 patients had severe adverse events (one [2%] patient in the EBD group and one [3%] patient in the FCSEMS group); both patients had perforations. INTERPRETATION EBD is more effective than FCSEMS for Crohn's disease strictures, with a good safety profile for both treatments. FUNDING Spanish National Institute of Health, Foundation of Spanish Society of Digestive Endoscopy, Catalan Society of Gastroenterology, and Taweoong.

David E Kleiner, Mauricio Lisker‐Melman, Abdus S Wahed et al.

AbstractBackground and AimStaining for hepatitis B viral antigens is often done in liver biopsies from patients with chronic hepatitis B, but its correlates with clinical phenotypes are not well described.MethodsBiopsies were collected from a large cohort of adults and children with chronic hepatitis B viral infection through the Hepatitis B Research Network. Immunohistochemical staining of sections was done for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) and then centrally read by the pathology committee. The degree of liver injury and pattern of staining were then correlated with clinical characteristics, including the clinical phenotype of hepatitis B.ResultsBiopsies from 467 subjects were studied, including 46 from children. Immunostaining for HBsAg was positive in 417 (90%) with scattered hepatocyte staining being the most common pattern. HBsAg staining correlated best with serum levels of HBsAg and hepatitis B viral DNA; the absence of HBsAg staining was often a prelude to loss of HBsAg from serum. HBcAg staining was positive in 225 (49%), and, while cytoplasmic staining was more frequent than nuclear staining, both nuclear and cytoplasmic positivity were often seen in the same specimen. Staining for HBcAg correlated with both level of viremia and liver injury. No biopsies from inactive carriers had stainable HBcAg, while 91% of the biopsies from those with hepatitis B e antigen‐positive chronic hepatitis B stained positively for HBcAg.ConclusionImmunostaining for hepatitis B viral antigens may yield helpful insights into liver disease pathogenesis but appears to add little to commonly used serological and biochemical blood tests.

O.S. Khukhlina, I.V. Dudka, T.V. Dudka

Background. The frequency of chronic pancreatitis (CP) comorbidity with chronic obstructive pulmonary disease (COPD) has significantly increased recently. It may be accompanied by changes in oxidant-antioxidant homeostasis and activates a cascade of reactions of mutual burdening of these pathologies. The purpose of the current research was to evaluate the intensity of lipid peroxidation, oxidative modification of proteins and the state of individual factors of the antioxidant defense system in the development and course of CP, depending on the comorbid COPD. Materials and methods. Three hundred and seventeen patients were examined, including 62 patients with CP alone (group 1), 132 CP patients with comorbid COPD (group 2), 123 patients with COPD alone (group 3). The content in blood of isolated double bonds in compounds, conjugated dienes, ketodienes and conjugated trienes, malonic aldehyde, nitrites/nitrates, reduced glutathione, the activity of catalase, glutathione-S-transferase, glutathione peroxidase were evaluated in all patients. Results. In CP patients with comorbid COPD, the maximum oxidative stress intensity among the compared groups was registered. There was a reliable increase in the content of malonic aldehyde — by 2.0 times (p < 0.05), isolated double bonds — by 2.2 times (p < 0.05), conjugated dienes — by 1.9 times (p < 0.05), ketodienes and conjugated trienes — by 1.9 times (p < 0.05), nitrites/nitrates — by 2.6 times (p < 0.05). A reliable decrease in reduced glutathione content of erythrocytes was detec­ted: in group 1 — by 1.5 times, in group 2 — by 1.9 times (p < 0.05), in group 3 — by 1.2 times (p < 0.05). The compensatory increase in the activity of glutathione-S-transferase, glutathione peroxidase and blood catalase was revealed: in group 1 — by 1.3, 1.2 and 1.5 times (p < 0.05); in group 2 — by 1.5, 1.3 and 1.8 times (p < 0.05), in group 3 — by 1.2, 1.2 and 1.4 times, respectively (p < 0.05). Conclusions. The comorbid course of CP and COPD is accompanied by the maximum intensity of oxidative and nitrosative stress compared to the isolated course of the disease. An increase was detected in intermediate and final metabolites of peroxide oxidation in the blood, oxidative modification of proteins, nitrites/nitrates in the blood against the background of a deep imbalance of antioxidant defense factors, an increase in ceruloplasmin content in the blood, which requires the administration of antioxidant agents to correct detected disorders and prevent the progression of both comorbid diseases.

D. Trukhan, E. N. Degovtsov, Alexander Yu. Novikov

Syndrome of increased epithelial permeability is one of the most studied pathogenic syndromes in the 21st century. In the English literature, the term “the leaky gut syndrome” is widely used to refer to Syndrome of increased epithelial permeability. The participation of Syndrome of increased epithelial permeability in the development of diseases and pathological conditions of the gastrointestinal tract, as well as the pathology of other organs and systems, is widely discussed. In early 2021, the first multidisciplinary national consensus “Syndrome of increased epithelial permeability in clinical practice” was published, and in 2022, practical recommendations for physicians were published on one of the topical aspects of Syndrome of increased epithelial permeability – epithelial protective therapy. Of the epithelial protectors used in gastroenterology, only rebamipide has a universal positive effect on the barrier function of the gastrointestinal tract throughout its entire length and at three structural levels (preepithelial, epithelial, and subepithelial). As part of the review, experimental and clinical studies, systematic reviews on Syndrome of increased epithelial permeability and the use of rebamipide, published in domestic and foreign literature in 2022, were considered. Separately, the issues of the use of rebamipide in diseases of the cardiovascular system, its protective effect and the ability to level possible problems associated with drug therapy in terms of increasing its safety in the practice of internists (cardiologist and therapist) and surgeons (cardiac surgeon and vascular surgeon) are considered. The data presented in the review demonstrate the comorbidity of the Syndrome of increased epithelial permeability, which takes a certain part in the development of diseases not only of the digestive system, but also of non-gastroenterological diseases, in particular, the pathology of the cardiovascular system, which suggests the formation of new therapeutic strategies, the use of which will improve the clinical prognosis.

Ijarotimi O, Osasona Eo, Betiku Oa et al.

Primary Biliary Cholangitis (PBC) is a chronic cholestatic disease of the liver. Due to the permanent cholestasis, fibrosis and cirrhosis eventually occur. It is said to be a rare disease in black Africans. We reported a case of Anti-Mitochondrial Antibody (AMA) negative PBC in a forty-one-yearold woman who fulfilled two out of the three diagnostic criteria. This case was reported because a diagnosis of PBC is very rare in our environment especially, AMA negative PBC which is indeed the first to be reported in our environment. Although, access to newer methods of AMA assay were not possible in the light of the resource-limited environment we practice in.

Ying Zhang, Lu Zhang, Sheng Zheng et al.

Metastasis is the leading cause of death for colorectal cancer (CRC) patients, and the spreading tumor cells adhesion to endothelial cells is a critical step for extravasation and further distant metastasis. Previous studies have documented the important roles of gut microbiota-host interactions in the CRC malignancy, and Fusobacterium nucleatum (F. nucleatum) was reported to increase proliferation and invasive activities of CRC cells. However, the potential functions and underlying mechanisms of F. nucleatum in the interactions between CRC cells and endothelial cells and subsequent extravasation remain unclear. Here, we uncovered that F. nucleatum enhanced the adhesion of CRC cells to endothelial cells, promoted extravasation and metastasis by inducing ICAM1 expression. Mechanistically, we identified that F. nucleatum induced a new pattern recognition receptor ALPK1 to activate NF-κB pathway, resulting in the upregulation of ICAM1. Interestingly, the abundance of F. nucleatum in tumor tissues of CRC patients was positively associated with the expression levels of ALPK1 and ICAM1. Moreover, high expression of ALPK1 or ICAM1 was significantly associated with a shorter overall survival time of CRC patients. This study provides a new insight into the role of gut microbiota in engaging into the distant metastasis of CRC cells.

J. BouSaba, Y. Magnus, W. Sannaa et al.

Qais Dawod, MD, Sanad Dawod, MD, David Carr-Locke, MD et al.

Toshifumi Hibi, Gerhard Rogler

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