Schlafen 11 (SLFN11), a regulator of cell fate following DNA injury, sensitizes tumor cells to DNA-damaging agents. Patients with SLFN11-positive tumors may benefit from DNA-damaging chemotherapies. SLFN11 has been studied in different types of cancer including colorectal carcinomas. However, colorectal carcinomas with diffuse positivity (expression in ≥80% of tumor cells) have not been meticulously characterized. SLFN11 immunostaining of tumor microarrays (TMAs) with 3,300 primary CRCs identified 65 (~2.0%) tumors with focal staining (<10% of tumor nuclei positive), 83 (~2.5%) with patchy (≥10% and <80%) and 51 (~1.5%) with diffuse (≥80%) SLFN11 positivity. The latter was confirmed on full sections from donor blocks in 31 (~1%) cases, which were further studied including evaluation of additional immunohistochemical markers, genotyping with targeted DNA sequencing, and assessment of microsatellite instability. SLFN11-positive carcinomas were mostly (21/31, 68%) right-sided tumors with a female predominance (21/31, 68%) and median age of 67 years. Eighteen of 31 (58%) contained areas of mucinous differentiation. Deficiency of mismatch repair proteins was detected in 65% (20/31) of SLFN11-positive carcinomas. Moreover, MLH1 (n = 2), MSH2, MSH6, and PMS2 germline mutations were identified in 25% (5/20) of patients with mismatch repair deficient tumors. BRAF p.V600E mutation was found in 45% (9/20) of mismatch repair deficient, but only 1 of 11 proficient tumors. Colorectal carcinomas with diffuse SLFN11 positivity were often mismatch repair deficient tumors with their typical clinical, morphological, and molecular characteristics.

• MeSH
• dospělí MeSH
• jaderné proteiny * metabolismus   MeSH
• karcinom * metabolismus   patologie   MeSH
• kolon * metabolismus   patologie   MeSH
• kolorektální nádory * metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrosatelitní nestabilita * MeSH
• nádorové biomarkery metabolismus   MeSH
• oprava chybného párování bází DNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.

• MeSH
• antiflogistika farmakologie   chemie   MeSH
• furany farmakologie   MeSH
• kolitida farmakoterapie   chemicky indukované   metabolismus   patologie   MeSH
• kolon účinky léků   patologie   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pregnanový X receptor * metabolismus   genetika   MeSH
• zánět farmakoterapie   metabolismus   MeSH
• zázvor lékařský * chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: This research aims to design and evaluate an enteric-coated hard capsule dosage form for targeted delivery of biological materials, such as FMT (fecal microbiota transplant) or live microbes, to the distal parts of the GIT. The capsules are designed to be internally protected against destruction by hydrophilic filling during passage through the digestive tract. METHODS: Hard gelatin capsules and DRcapsTMcapsules based on HPMC and gellan were used to encapsulate a hydrophilic body temperature-liquefying gelatin hydrogel with caffeine or insoluble iron oxide mixture. Different combinations of polymers were tested for the internal (ethylcellulose, Eudragit® E, and polyvinyl acetate) and external (Eudragit® S, Acryl-EZE®, and cellacefate) coating. The external protects against the acidic gastric environment, while the internal protects against the liquid hydrophilic filling during passage. Coated capsules were evaluated using standard disintegration and modified dissolution methods for delayed-release dosage forms. RESULTS: Combining suitable internal (ethylcellulose 1.0 %) and external (Eudragit® S 20.0 %) coating of DRcapsTM capsules with the wiping and immersion method achieved colonic release times. While most coated capsules met the pharmaceutical requirements for delayed release, one combination stood out. Colonic times were indicated by the dissolution of soluble caffeine (during 120-720 min) measured by the dissolution method, and capsule rupture was indicated by the release of insoluble iron oxide (after 480 min) measured by the disintegration method. This promising result demonstrates the composition's suitability and potential to protect the content until it's released, inspiring hope for the future of colon-targeted delivery systems and its potential for the pharmaceutical and biomedical fields. CONCLUSION: Innovative and easy capsule coatings offer significant potential for targeted drugs, especially FMT water suspension, to the GIT, preferably the colon. The administration method is robust and not considerably affected by the quantity of internal or external coatings. It can be performed in regular laboratories without specialized individual and personalized treatment equipment, making it a practical and feasible method for drug delivery.

• MeSH
• bakteriální polysacharidy chemie   MeSH
• biokompatibilní materiály chemie   MeSH
• celulosa * chemie   analogy a deriváty   MeSH
• deriváty hypromelózy chemie   MeSH
• hydrofobní a hydrofilní interakce * MeSH
• hydrogely chemie   MeSH
• kofein chemie   aplikace a dávkování   MeSH
• kolon * metabolismus   MeSH
• kyseliny polymethakrylové chemie   MeSH
• lékové transportní systémy * metody   MeSH
• léky s prodlouženým účinkem chemie   MeSH
• polymery chemie   MeSH
• polyvinyly chemie   MeSH
• tobolky * MeSH
• uvolňování léčiv * MeSH
• želatina * chemie   MeSH
• železité sloučeniny chemie   aplikace a dávkování   MeSH
• Publikační typ
• časopisecké články MeSH

SCOPE: This multi-omic study investigates the bidirectional interactions between gut microbiota and silymarin metabolism, highlighting the differential effects across various age groups. Silymarin, the extract from Silybum marianum (milk thistle), is commonly used for its hepatoprotective effects. METHODS AND RESULTS: An in vitro fermentation colon model was used with microbiota from 20 stool samples obtained from healthy donors divided into two age groups. A combination of three analytical advanced techniques, namely proton nuclear magnetic resonance (1H NMR), next-generation sequencing (NGS), and liquid chromatography-mass spectrometry (LC-MS) was used to determine silymarin microbial metabolites over 24 h, overall metabolome, and microbiota composition. Silymarin at a low diet-relevant dose of 50 μg mL-1 significantly altered gut microbiota metabolism, reducing short-chain fatty acid (acetate, butyrate, propionate) production, glucose utilization, and increasing alpha-diversity. Notably, the study reveals age-related differences in silymarin catabolism. Healthy elderly donors (70-80 years) exhibited a significant increase in a specific catabolite associated with Oscillibacter sp., whereas healthy young donors (12-45 years) showed a faster breakdown of silymarin components, particularly isosilybin B, which is associated with higher abundance of Faecalibacterium and Erysipelotrichaceae UCG-003. CONCLUSION: This study provides insights into microbiome functionality in metabolizing dietary flavonolignans, highlighting implications for age-specific nutritional strategies, and advancing our understanding of dietary (poly)phenol metabolism.

• MeSH
• dítě MeSH
• dospělí MeSH
• feces mikrobiologie   MeSH
• fermentace MeSH
• kolon * mikrobiologie   metabolismus   účinky léků   MeSH
• kyseliny mastné těkavé metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• silymarin * farmakologie   MeSH
• střevní mikroflóra * účinky léků   fyziologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The middle colic artery usually arises from the superior mesenteric artery, but in rare cases it may arise from the coeliac trunk or its branches. The aim of this study was to investigate variant origins of the middle colic artery on computed tomography and anatomical dissection. Variant middle colic arteries were identified on computed tomography as part of an ongoing study investigating anatomical variations of vessels of the upper abdomen. Three-dimensional reconstructions were made to demonstrate the variant findings. Cadaveric dissections were performed as part of a routine dissection course. We report five cases of rare variant origins of the middle colic artery arising from the coeliac axis. Among these sites of origin were the coeliac trunk, the gastrosplenic trunk, the splenic artery, and the common hepatic artery. Four cases were identified on multi-detector computed tomography and one in a cadaver. In all cases, the vessels passed posterior to the body of the pancreas before entering the transverse mesocolon. Knowledge of middle colic artery variations is important to prevent inadvertent injury in digestive surgery, especially in the hepatopancreatic area. Variant origins of the middle colic artery are rare, and their knowledge is crucial to prevent unnecessary iatrogenic injury during abdominal surgery.

• MeSH
• arteria coeliaca MeSH
• arteria hepatica MeSH
• arteria mesenterica inferior MeSH
• arteria mesenterica superior * diagnostické zobrazování   MeSH
• colon transversum * MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

V článku jsou prezentovány kazuistiky dvou pacientů, kteří byli přijati do Fakultní nemocnice v Plzni s náhlou příhodou břišní na podkladě rozvinuté poruchy pasáže gastrointestinálním traktem (GIT). Oba nemocní byli indikováni k operačnímu výkonu, při němž u nich byl peroperačně diagnostikován raritně se vyskytující volvulus céka (CV). Nálezy vyžadovaly provedení ileocékání resekce, ale díky časně poskytnuté chirurgické intervenci došlo i přes nutnost provedení resekčního výkonu u obou jedinců k plnému zotavení.

In this article, we present case reports of two patients admitted to the University Hospital in Pilsen for acute abdomen due to a disorder of the passage through the gastrointestinal tract (GIT). Both were indicated for surgery. The patients were diagnosed intraoperatively with rarely occurring cecal volvulus (CV). The findings required an ileocecal resection; nevertheless, both patients fully recovered despite the need the resection.

• MeSH
• akutní bolest břicha * chirurgie   diagnostické zobrazování   etiologie   MeSH
• břicho chirurgie   diagnostické zobrazování   patologie   MeSH
• břišní dutina chirurgie   diagnostické zobrazování   patologie   MeSH
• cékum chirurgie   patologie   MeSH
• chirurgie trávicího traktu metody   MeSH
• dospělí MeSH
• gastrointestinální trakt chirurgie   diagnostické zobrazování   patologie   MeSH
• ileus chirurgie   diagnostické zobrazování   etiologie   MeSH
• kolon chirurgie   patologie   MeSH
• laparotomie MeSH
• lidé MeSH
• senioři MeSH
• volvulus intestini * chirurgie   diagnóza   etiologie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

Ulceration colitis (UC) is a chronic and recurrent inflammatory disorder in the gastro-intestinal tract. The purpose of our study is to explore the potential mechanisms of ginsenoside Rg1 (GS Rg1) on dextran sulfate sodium (DSS)-induced colitis in mice and lipopolysaccharide (LPS)-induced RAW 264.7 cells. Acute colitis was induced in male C57BL/6 mice. In vitro model of LPS-induced RAW 264.7 cells to simulate enteritis model. The disease activity index (DAI), colon length, body weight and histopathological analysis were performed in vivo. Pro-inflammatory cytokines and markers for oxidative and anti-oxidative stress, MPO level were measured in vivo and in vitro. Nuclear erythroid 2-related factor 2 (Nrf2) and NF-?B p65 protein levels were analyzed using western blotting. Our results indicated that the UC models were established successfully by drinking DSS water. GS Rg1 significantly attenuated UC-related symptoms, including preventing weight loss, decreasing DAI scores, and increasing colon length. GS Rg1 ameliorated the DSS-induced oxidative stress. IL-1beta, IL-6, and TNF-alpha levels were significantly increased in serum and cell supernatant effectively, while treatment with the GS Rg1 significantly reduced these factors. GS Rg1 reduced MPO content in the colon. GS Rg1 treatment increased SOD and decreased MDA levels in the serum, colon, and cell supernatant. GS Rg1 restored the Nrf-2/HO-1/NF-?B pathway in RAW 264.7 cells and UC mice, and these changes were blocked by Nrf-2 siRNA. Overall, GS Rg1 ameliorated inflammation and oxidative stress in colitis via Nrf-2/HO-1/NF-kappaB pathway. Thus, GS Rg1 could serve as a potential therapeutic agent for the treatment of UC.

• MeSH
• dextrany metabolismus   farmakologie   terapeutické užití   MeSH
• ginsenosidy * MeSH
• kolitida * chemicky indukované   MeSH
• kolon metabolismus   MeSH
• lipopolysacharidy metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• síran dextranu toxicita   metabolismus   MeSH
• sírany * MeSH
• ulcerózní kolitida * chemicky indukované   farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet. Current evidence suggests that specific ligands of both AhR and PXR can protect intestinal epithelium against inflammation and assist in the maintenance of epithelial barrier integrity. AhR, and to a lesser extent also PXR, have been shown to play a protective role against inflammation-induced colon cancer, or, in mouse models employing overactivation of Wnt/β-catenin signaling. In contrast, other evidence suggests that both receptors may contribute to modulation of transformed colon cell behavior, with a potential to promote cancer progression and/or chemoresistance. The review focuses on both overlapping and separate roles of the two receptors in these processes, and on possible implications of their activity within the context of intestinal tissue.

• MeSH
• karcinogeneze genetika   metabolismus   MeSH
• kolon metabolismus   MeSH
• myši MeSH
• pregnanový X receptor metabolismus   MeSH
• receptory aromatických uhlovodíků * genetika   metabolismus   MeSH
• steroidní receptory * metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.

• MeSH
• cytokiny metabolismus   MeSH
• glutamátkarboxypeptidasa II * antagonisté a inhibitory   MeSH
• idiopatické střevní záněty * farmakoterapie   patologie   MeSH
• kolitida * farmakoterapie   metabolismus   MeSH
• kolon patologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• zánět patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND & AIMS: In this STARDUST substudy, the effect of ustekinumab on transmural bowel inflammation was assessed in adults with moderate-to-severe Crohn's disease (CD) by using intestinal ultrasound (IUS), a noninvasive imaging procedure. METHODS: STARDUST was an international, multicenter, phase 3b, interventional, randomized controlled trial specifically designed to compare treat-to-target and standard-of-care treatment strategies in ustekinumab-treated CD patients. In this substudy, the most affected bowel segment at baseline by IUS was used for all analyses. Key IUS endpoints (centrally read, parameter-blinded) were IUS response, transmural remission, bowel wall thickness (BWT), blood flow, bowel wall stratification, and inflammatory fat. RESULTS: Seventy-seven patients were evaluated. IUS response could be determined 4 weeks after treatment initiation, with progressive improvement through week 48. IUS response and transmural remission rates at week 48 were 46.3% and 24.1%, respectively. IUS response, transmural remission, BWT, and blood flow normalization rates were more pronounced in the colon and biologic-naive patients. Fair/moderate reliability (κ = 0.21-0.51) was observed between week 4 IUS response and week 48 overall endoscopic response and fecal calprotectin/complete biomarker outcomes. Endoscopy and IUS baseline agreement was >90% in determining the terminal ileum as the most affected bowel segment. IUS response absence at week 4 was associated with no endoscopic response (based on the simplified endoscopic score for Crohn's disease terminal ileum subscore) at week 48 (negative predictive value = 73%). CONCLUSIONS: In this first international, multicenter, interventional study, IUS showed that ustekinumab-treated CD patients achieved progressive IUS response (46.3%) and transmural remission (24.1%) through week 48, with a more robust response in the colon and biologic-naive patients. CLINICALTRIALS: gov number: NCT03107793.

• MeSH
• biologické přípravky * MeSH
• Crohnova nemoc * diagnostické zobrazování   farmakoterapie   MeSH
• dospělí MeSH
• indukce remise MeSH
• kolon MeSH
• lidé MeSH
• reprodukovatelnost výsledků MeSH
• ustekinumab terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH