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.
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
Anastomotický leak je v kolorektální chirurgii závažnou komplikací. Problematikou poruch hojení střevní anastomózy se zabývá řada experimentálních prací zejména ve smyslu aplikovaného výzkumu. Design zvířecích modelů je přitom různorodý a výsledky jednotlivých prací jsou těžko porovnatelné. Tato práce pojednává souhrnně o hlavních bodech problematiky plánování zvířecích modelů střevních anastomóz, které jsou jednotlivě rozebrány. Hlavní částí textu je popis modelu defektní střevní anastomózy prasete. Anastomóza je v modelu konstruována s lokalizovanou protruzí sliznice. Zvířata jsou pooperačně sledována 3 týdny, monitorovány jsou jak klinický stav, tak změny vitálních hodnot, laboratorních parametrů, je prováděno v definovaných bodech CT vyšetření. Na konci observačního období jsou odebrány vzorky, hodnocen makroskopický nález v dutině břišní, skórování adhezí, známky leaku či poruch pasáže. Histologicky jsou preparáty hodnoceny jak standardními metodami analyzujícími vaskularitu, zánětlivou infiltraci a podíl kolagenu, tak metodami vyvinutými de novo pro potřeby experimentu, jako je analýza integrity střevní stěny v místě slizniční protruze. Experimentálního modelu si ceníme pro možnost systematické a podrobné analýzy stavu zhojení anastomózy v kombinaci s podrobným observačním protokolem, jež vytvářejí klinicky relevantní výsledky.
Anastomotic leak is a serious complication in colorectal surgery. The problem of intestinal anastomosis healing disorders is dealt with by a number of experimental studies, especially in applied research. The design of animal models is diverse and the results of individual studies are difficult to compare. This paper summarizes the main issues of planning animal models of intestinal anastomoses, which are discussed individually. The main part of the text is a description of the defective intestinal anastomosis model of the pig. The anastomosis is constructed in the model with a localized mucosal protrusion. The animals are monitored for 3 weeks postoperatively, the clinical condition and changes in vital values and laboratory parameters are monitored, and CT examinations are performed at defined points. At the end of the observation period, samples are taken, macroscopic findings in the abdominal cavity are evaluated, adhesions are scored, and signs of leakage or passage disorders are assessed. The preparations are evaluated histologically both by standard methods analyzing vascularity, inflammatory infiltration and the proportion of collagen, and by methods developed de novo for the needs of the experiment, such as the analysis of the integrity of the intestinal wall at the site of the mucosal protrusion. We value the experimental model for the possibility of a systematic and detailed analysis of the healing state of the anastomosis in combination with a detailed observation protocol, which produces clinically relevant results.
