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Current Research in Pharmacology and... 2023Non-steroidal anti-inflammatory drugs (NSAIDs) injure the proximal and distal gut by different mechanisms. While many drugs reduce gastrointestinal injury, no drug...
Non-steroidal anti-inflammatory drugs (NSAIDs) injure the proximal and distal gut by different mechanisms. While many drugs reduce gastrointestinal injury, no drug directly stimulates mucosal wound healing. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, induces epithelial sheet migration. We synthesized and evaluated a water-soluble FAK-activating small molecule, M64HCl, with drug-like properties. Monolayer wound closure and Western blots measured migration and FAK phosphorylation in Caco-2 cells, in vitro kinase assays established FAK activation, and pharmacologic tests assessed drug-like properties. 30 mg/kg/day M64HCl was administered in two murine small intestine injury models for 4 days. M64HCl (0.1-1000 nM) dose-dependently increased Caco-2 FAK-Tyr 397 phosphorylation, without activating Pyk2 and accelerated Caco-2 monolayer wound closure. M64HCl dose-responsively activates the FAK kinase domain vs. the non-salt M64, increasing the V of ATP-binding. Pharmacologic tests suggested M64HCl has drug-like properties and is enterally absorbed. M64HCl 25 mg/kg/day continuous infusion promoted healing of ischemic jejunal ulcers and indomethacin-induced small intestinal injury in C57Bl/6 mice. M64HCl-treated mice exhibited smaller ulcers 4 days after ischemic ulcer induction or indomethacin injury. Renal histology and plasma creatinine were normal. Mild hepatic inflammatory changes and ALT elevation were similar among M64HCl-treated mice and controls. M64HCl was concentrated in kidney and gastrointestinal mucosa and functional nephrectomy studies suggested predominantly urinary excretion. Little toxicity was observed in vitro or in single-dose mouse toxicity studies until >1000x higher than effective concentrations. M64HCl, a water-soluble FAK activator, promotes epithelial restitution and intestinal mucosal healing and may be useful to treat gut mucosal injury.
PubMed: 36632414
DOI: 10.1016/j.crphar.2022.100147 -
The Journal of Pharmacy and Pharmacology Mar 2023The study compared the protective effects against indomethacin-induced GI ulceration of chlorogenic acid with quercetin in rats.
OBJECTIVES
The study compared the protective effects against indomethacin-induced GI ulceration of chlorogenic acid with quercetin in rats.
METHODS
Rats were orally given chlorogenic acid or quercetin (100 mg/kg; 5 days), followed by indomethacin (40 mg/kg; single dose). After 24 h, GI tissues were assessed for histopathological damages, then analysed by ELISA and western blot methods. Cell viability was measured in vitro by MTT assay.
KEY FINDINGS
Unlike quercetin, chlorogenic acid could not prevent gastric ulcers in indomethacin-treated rats. The levels of gastric prostaglandin E2 (PGE2) and Bax/Bcl-2 ratio in the chlorogenic acid-treated group were not different from those receiving indomethacin alone. Nevertheless, both compounds alleviated jejunum ulcers through suppression of PERK/eIF-2/ATF-4/CHOP-related endoplasmic reticulum (ER) stress and decrease Bax/Bcl-2 ratio. Moreover, at 100 µM, they abolished the cytotoxicity of tunicamycin (an ER stress inducer) in gastric (AGS) and intestinal (Caco-2) cells. In silico docking studies suggested that both compounds could interact with key amino acid residues in the -catalytic domain of PERK.
CONCLUSION
Chlorogenic acid and quercetin exerted comparable protective effects against indomethacin-induced intestinal ulcer through suppression of ER stress-mediated apoptosis but, unlike quercetin, chlorogenic acid offered no protection against gastric ulceration due to its -inability to increase PGE2 production.
Topics: Humans; Rats; Animals; Ulcer; Indomethacin; Quercetin; bcl-2-Associated X Protein; Caco-2 Cells; Dinoprostone; Chlorogenic Acid; Stomach Ulcer; Proto-Oncogene Proteins c-bcl-2
PubMed: 36617303
DOI: 10.1093/jpp/rgac098 -
Diagnostics (Basel, Switzerland) Dec 2022Eosinophilic gastroenteritis (EoGE) is a rare digestive disorder characterized by eosinophilic infiltration of the stomach and intestines. In the diagnosis of EoE, it is... (Review)
Review
Eosinophilic gastroenteritis (EoGE) is a rare digestive disorder characterized by eosinophilic infiltration of the stomach and intestines. In the diagnosis of EoE, it is extremely important to recognize distinctive endoscopic findings and accurately detect increased eosinophilia in gastrointestinal tissues. However, endoscopic findings of EoGE in the small intestine remain poorly understood. Therefore, we conducted a literature review of 16 eligible papers. Redness or erythema was the most common endoscopic finding in the small bowel, followed by villous atrophy, erosion, ulceration, and edema. In some cases, stenosis due to circumferential ulceration was observed, which led to retention of the capsule during small bowel capsule endoscopy. Although many aspects of small bowel endoscopic findings in EoGE remain elusive, the findings presented in this review are expected to contribute to the further development of EoGE practice.
PubMed: 36611405
DOI: 10.3390/diagnostics13010113 -
Clinical Immunology (Orlando, Fla.) Feb 2023Glycoprotein 2 (GP2) is an autoantigen in Crohn's (CD) and coeliac disease (CeD). We assessed GP2-isoform (GP2)-expression in intestinal biopsies of paediatric patients...
Glycoprotein 2 (GP2) is an autoantigen in Crohn's (CD) and coeliac disease (CeD). We assessed GP2-isoform (GP2)-expression in intestinal biopsies of paediatric patients with CD, CeD, ulcerative colitis (UC), and healthy children (HC). Transcription of GP2 was elevated in proximal small intestine in CeD and CD patients (only GP2) compared to jejunum (CeD/CD) and large bowel (CD). CeD patients demonstrated higher duodenal GP2-mRNA levels compared to HC/UC patients whereas CD patients showed higher GP2-mRNA levels compared to UC patients. Duodenal synthesis of only small GP2 isoforms (GP2) was demonstrated in epithelial cells in patients/HC and in Brunner glands (also large isoforms) with a more frequent apical location in CD/CeD patients. All four GP2 isoforms interacted with gliadin and phosphopeptidomannan. Gliadin digestion improved binding to GP2 isoforms. GP2 binding to CeD/CD-related antigens, elevated duodenal GP2-mRNA transcription, and GP2-protein secretion in Brunner glands of CeD/CD patients suggest an autoimmune CeD/CD link.
Topics: Humans; Child; Celiac Disease; Brunner Glands; Gliadin; GPI-Linked Proteins; Autoantibodies; Crohn Disease; Colitis, Ulcerative; Protein Isoforms; RNA, Messenger
PubMed: 36608744
DOI: 10.1016/j.clim.2022.109214 -
Revista Espanola de Enfermedades... Oct 2023A 27-year-old Nepalese male presented with recurrent abdominal pain accompanied by a lower stool consistency over the past 2 years. These episodes occurred several times...
A 27-year-old Nepalese male presented with recurrent abdominal pain accompanied by a lower stool consistency over the past 2 years. These episodes occurred several times a year, lasting 1 to 2 weeks, and resolved spontaneously, after adjustment of diet and/or medication for symptomatic control (e.g., antispasmodics, probiotics). Over the last year, the patient had undergone an extensive diagnostic investigation, which revealed no alterations in the laboratory workup, abdominal scan, esophagogastroduodenoscopy, and colonoscopy, including biopsies of the duodenum, and colon, so the symptoms have been attributed to irritable bowel syndrome. However, the symptoms had become more frequent, so the patient was referred to our gastroenterology department. We repeated and extended the work-up. Laboratory investigations showed an elevated erythrocyte sedimentation rate and faecal calprotectin. The remaining laboratory as well an extensive stool workup for infection were unremarkable. Esophagogastroduodenoscopy and ileocolonoscopy were normal. Small bowel capsule endoscopy revealed jejunal mucosa with lymphangiectasias, pseudopolypoids formations and superficial longitudinal ulcers, these findings were corroborated by the double-balloon enteroscopy, and biopsies showed marked architectural distortion, chronic inflammatory infiltrate, and an epithelioid granuloma. The clinical, endoscopic, biochemical, and histological findings were consistent with isolated jejunal Crohn's disease. The patient started adalimumab with complete remission after one year. We present this case given its exuberant endoscopic findings and due to the difficulty in making the diagnosis due to its rarity, location, and unspecific presentation.
PubMed: 36562531
DOI: 10.17235/reed.2022.9423/2022 -
Frontiers in Pharmacology 2022This study aimed to establish a pharmacological basis for evaluating the effects of bergapten (5-methoxypsoralen) in gastrointestinal diseases and assessment of its...
Pharmacological basis of bergapten in gastrointestinal diseases focusing on H/K ATPase and voltage-gated calcium channel inhibition: A toxicological evaluation on vital organs.
This study aimed to establish a pharmacological basis for evaluating the effects of bergapten (5-methoxypsoralen) in gastrointestinal diseases and assessment of its toxicological profile. The pharmacokinetic profile was evaluated using the SwissADME tool. AUTODOCK and PyRx were used for evaluating the binding affinities. The obtained results were further investigated for a post-dock analysis using Discovery Studio Visualizer 2016. The Desmond software package was used to conduct molecular dynamic simulations of best bound poses. Bergapten was further investigated for antidiarrheal, anti-secretory, charcoal meal transit time, anti-ulcer, anti- activity. Bergapten at a dose of 50, 100, and 200 mg/kg was proved effective in reducing diarrheal secretions, intestinal secretions, and distance moved by charcoal meal. Bergapten at the aforementioned doses acts as a gastroprotective agent in the ethanol-induced ulcer model that can be attributed to its effectiveness against Bergapten shows concentration-dependent relaxation of both spontaneous and K (80 mM)-induced contractions in the isolated rabbit jejunum model; the Ca concentration-response curves (CRCs) were shifted to the right showing potentiating effect similar to papaverine. For molecular investigation, the H/K ATPase inhibitory assay indicated inhibition of the pump comparable to omeprazole. Oxidative stress markers GST, GSH, and catalase showed increased expression, whereas the expression of LPO (lipid peroxidation) was reduced. Histopathological examination indicated marked improvement in cellular morphology. ELISA and western blot confirmed the reduction in inflammatory mediator expression. RT-PCR reduced the mRNA expression level of H/K ATPase, confirming inhibition of the pump. The toxicological profile of bergapten was evaluated by an acute toxicity assay and evaluated for behavioral analysis, and the vital organs were used to analyze biochemical, hematological, and histopathological examination. Bergapten at the tested doses proved to be an antioxidant, anti-inflammatory, anti-ulcer, and antidiarrheal agent and relatively safe in acute toxicity assay.
PubMed: 36467058
DOI: 10.3389/fphar.2022.1005154 -
Clinical Journal of Gastroenterology Feb 2023Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation as the result of immunosuppressant medications. Epstein-Barr...
Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation as the result of immunosuppressant medications. Epstein-Barr virus (EBV) has been implicated in most of these cases, specifically with B-cell predominant lymphoma. This case report describes a 24-year-old female who presented with recurrent GI bleed within 6 months post-orthostatic heart transplant. Endoscopic evaluations including video capsule study, push enteroscopy, and colonoscopy revealed multiple ulcerated lesions in duodenum, jejunum, and colon secondary to Epstein-Barr Virus-associated monomorphic PTLD. Despite continuation of rituximab after discharge, she returned to the hospital for recurrent GI bleed requiring additional endoscopic intervention. PTLD is a devastating disease of the post-transplant population. Due to a high risk of recurrent GI bleeding, patients with PTLD may benefit from careful monitoring by gastroenterology as an outpatient with a low threshold for repeat endoscopic evaluation despite being on immunotherapy or chemotherapy.
Topics: Female; Humans; Young Adult; Adult; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Ulcer; Duodenum; Lymphoproliferative Disorders
PubMed: 36251246
DOI: 10.1007/s12328-022-01718-1 -
Zhonghua Wei Chang Wai Ke Za Zhi =... Oct 2022At present, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) have become the major bariatric and metabolic surgical procedures, but neither of them is...
At present, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) have become the major bariatric and metabolic surgical procedures, but neither of them is perfect. Adding jejunojejunal bypass (JJB) to SG can enhance weight loss and hypoglycemic effect. Present clinical results show that the short-term weight loss effect of SG-JJB is better than SG, and the weight loss and hypoglycemic effect is similar to RYGB. However, SG-JJB does not have various complications like traditional jejunal ileal bypass (JIB). The existing evidence shows that SG-JJB is a safe and effective bariatric and metabolic surgery, with relatively simple technical requirement. Meanwhile, SG-JJB has almost no dumping syndrome or ulcers, and facilitates endoscopic examination of the biliary tract, and has no blind gastric pouch. Thus, SG-JJB has some clinical application prospects, but further high-quality research with long-term follow-up is needed.
Topics: Gastrectomy; Gastric Bypass; Humans; Hypoglycemic Agents; Obesity, Morbid; Retrospective Studies; Treatment Outcome; Weight Loss
PubMed: 36245113
DOI: 10.3760/cma.j.cn441530-20220712-00301 -
Clinical Journal of Gastroenterology Feb 2023A 46-year-old man, receiving continuous steroid therapy for refractory ulcerative colitis with an insufficient response to anti-tumor necrosis factor-α therapy,...
A 46-year-old man, receiving continuous steroid therapy for refractory ulcerative colitis with an insufficient response to anti-tumor necrosis factor-α therapy, presented with left buttock pain. He was diagnosed with steroidal left femoral head necrosis, and total proctocolectomy with permanent ileostomy was performed. At 6 months postoperatively, the patient developed general fatigue, abdominal pain, and severe ileostomy diarrhea. Computed tomography revealed continuous intestinal edema from the descending duodenal leg to the upper jejunum. Gastrointestinal endoscopy revealed deep ulcers, coarse mucosa, and duodenal erosion. Based on clinical progress, findings, and pathology, the patient was diagnosed with ulcerative colitis-related postoperative enteritis. Although 5-aminosalicylic acid treatment was initiated, his symptoms persisted, bloody diarrhea from colostomy was observed. Subsequently, granulocyte and monocyte apheresis treatment was added. Symptoms and endoscopic findings improved with granulocyte and monocyte apheresis. Azathioprine was introduced as maintenance therapy, and no sign of recurrence was observed. Although ulcerative colitis-related postoperative enteritis has no definitive treatment, granulocyte and monocyte apheresis may be considered for initial treatment.
Topics: Male; Humans; Middle Aged; Colitis, Ulcerative; Monocytes; Leukapheresis; Treatment Outcome; Blood Component Removal; Enteritis; Steroids; Granulocytes
PubMed: 36214972
DOI: 10.1007/s12328-022-01716-3