Gastrointestinal Injury Research Articles

Potential role of carvedilol in intestinal toxicity through NF-κB/iNOS/COX-2/TNF-α inflammatory signaling pathway in rats

Background The increased use of indomethacin (IND) is associated with gastrointestinal injury. This research aims to investigate the effects of a beta-blocker, carvedilol (CAR) on a rat model of IND-induced acute intestinal damage and clarify the probable underlying protective mechanisms. Materials and methods Twenty-four male Wistar rats were divided into four groups. Control group: given vehicles; CAR-treated group: given 10 mg/kg/day CAR PO daily by gastric gavage for 10 consecutive days; IND-treated group: given a single Sc dose of 10 mg/kg IND at the end of the ninth day of the experiment; combined CAR/IND-treated group: given both IND and CAR. Results In the rats that received IND, severe intestinal histopathological changes together with oxidative and nitrosative intestinal stress were present biochemically and immunohistochemically. Obvious inflammatory and tissue damage were represented by the significant intestinal increases in TNF-α, COX-2, and caspase-3 together with the elevated expression of VCAM-1 adhesion molecules. Intestinal gene expression of NF-kB and COX-2 was also increased. Pretreatment with CAR significantly reversed the IND-induced intestinal toxic manifestations. Conclusion CAR has beneficial intestinal protective effects. Its ameliorative action is conferred through its antioxidant, antinitrosative, anti-inflammatory, and antiapoptotic properties.

Calprotectin: The Link Between Acute Lung Injury and Gastrointestinal Injury in Covid-19: Ban or Boon.

The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and associated hyper-inflammation due to exaggerated immune response. Different experimental and clinical studies revealed that many biomarkers could be used to determine the Covid-19 severity, such as Ddimer, procalcitonin, C-reaction protein (CRP), IL-6, and ferritin. Calprotectin (CP) is associated with intestinal inflammation, intestinal injury, and different respiratory diseases such as cystic fibrosis. Thus, CP might be a possible biomarker linking intestinal injury and acute lung injury (ALI) in Covid-19. Therefore, this study aimed to find a potential role of CP regarding GITI and ALI in Covid-19. CP is a complex protein consisting of S100A8 and S100A9, belonging to the Ca+2-binding proteins S100 family abundant in the cytosol of neutrophils and expressed on the monocyte membranes, macrophages, and intestinal epithelial cells. CP is a proinflammatory protein that acts through activation of the receptor for the advanced glycation end product (RAGE) and toll-like receptor 4 (TLR4). CP is a biomarker of neutrophil activation and is released following the turnover of neutrophils. CP could be controversial; it increases airway inflammation or protects lung and airway epithelium from an exaggerated immune response. Therefore, a high level of CP in different respiratory disorders might be protective and compensate against abnormal immune responses. CP level is high in Covid-19 and correlated with Covid-19 severity and oxygen demand due to activation of proinflammatory cytokines and inflammatory signaling pathways. Therefore, CP level is elevated in both ALI and intestinal inflammation so that it could be a potential biomarker that links the respiratory and intestinal injury in Covid-19.

Pharmacological Preconditioning by Corticotropin Releasing Factor (CRF) or ACTH Protects the Gastric Mucosa against Ulcerogenic Action of Indomethacin through Involvement of Glucocorticoids

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are widely used as analgesic and anti‐inflammatory drugs. However, adverse effects, including gastrointestinal, renal, cardiovascular side effects, seriously complicate NSAIDs use. Their gastrointestinal side effects are the most known serious complications in patients taking these drugs. Previously we have shown that preconditioning stress attenuates the ulcerogenic action of indomethacin (IM) on the gastric mucosa. According our findings glucocorticoids, released in response to stressor, are gastroprotective hormones and involved in stress preconditioning protective effects. Corticotropin releasing factor (CRF), a major mediator of stress response, stimulates ACTH release through CRF receptors of subtype 1 and ACTH, in turn, stimulates glucocorticoid production. Here we verify the hypothesis that pharmacological preconditioning by CRF or ACTH can protect the gastric mucosa against ulcerogenic action of IM in rats through mechanism associated with glucocorticoids. For this, preliminary fasted (24 h) rats were administered by CRF (2.5 or 5 µg/ kg, ip) or ACTH (1U/kg, ip) 30 min before IM injection (35 mg/kg, sc). Gastric lesions were examined 4 h after IM administration. Plasma corticosterone levels were measured before and 4 h after IM injection. Since the gastrointestinal injury is accompanied by changes in somatic pain sensitivity, we also measured tail flick latencies (tail flick test) before and 4 h after IM. Both CRF and ACTH by itself caused an elevation of plasma corticosterone levels, which was accompanied by an increase of tail flick latencies (analgesic effect). IM administration resulted in the gastric erosion 4 h later. Pretreatment with CRF or ACTH reduced an area of gastric lesions caused by IM (gastroprotective effect). IM‐induced gastric injury was accompanied by an increase of tail flick latencies, which was prevented by CRF (normalization of somatic pain sensitivity). To estimate the role of glucocorticoids in CRF‐induced gastroprotection an inhibitor of corticosterone synthesis metyrapone (30 mg/kg) or CRF receptor type 1 antagonist NBI 27914 (10 mg/kg) or glucocorticoid receptor antagonist RU‐38486 (20 mg/kg) was administered before CRF. Both metyrapone and NBI 27914 injected before CRF administration caused an inhibition of CRF‐induced corticosterone response and prevented protective effect of CRF on the gastric mucosa against the IM‐induced injury. The gastroprotective effect of CRF was also eliminated by the pretreatment with RU‐38486. Thus, CRF as well as ACTH can protect the gastric mucosa against ulcerogenic action of IM. Gastroprotective action of CRF accompanied by normalization of somatic pain sensitivity is provided by mechanism associated with glucocorticoids.

MP23-11 PERIOPERATIVE COMPLICATIONS AFTER RADICAL CYSTECTOMY FOR BLADDER CANCER: AN INTERNATIONAL MULTICENTER COLLABORATION

MP23-11 PERIOPERATIVE COMPLICATIONS AFTER RADICAL CYSTECTOMY FOR BLADDER CANCER: AN INTERNATIONAL MULTICENTER COLLABORATION

Comparisons between short-peptide formula and intact-protein formula for early enteral nutrition initiation in patients with acute gastrointestinal injury: a single-center retrospective cohort study.

BackgroundEarly enteral nutrition (EN) in critically ill patients is important and most of them have suffered acute gastrointestinal injury (AGI). In this study, we investigated the influence of short-peptide EN formula and intact-protein EN formula on the prognosis of patients with AGI grades I–II to provide some guidance.MethodsA retrospective cohort study was performed. The primary outcomes were the percentage of EN calories (25 kcal/kg/d) and protein (1.2 g/kg/d) on the 3rd and 7th days of intensive care unit (ICU) admission, EN percent elevation in calories and protein on days 3–7, and the incidence of gastric retention and diarrhea after EN administration. Secondary outcomes included ICU and 28-day mortality, length of ICU stay, total hospitalization cost, and ventilator-free days. Univariate and multivariate Cox regression analysis was used to identify factors associated with gastric retention and diarrhea. And we used Kaplan-Meier survival curves to compare 28-day mortality rates between the two groups.ResultsThere were no statistically significant differences in ICU and 28-day mortality, ICU length of stay, total hospitalization cost, or ventilator-free days in the short-peptide formula group compared with the intact-protein formula group. Kaplan-Meier survival curves of 28-day mortality also showed no statistically significant difference. The EN percent elevation in calories and protein on days 3–7 in the short-peptide formula group was significantly higher than the intact-protein formula group (48% vs. 38%, P=0.03 and 37% vs. 38%, P=0.04, respectively). For gastrointestinal (GI) adverse events, the incidence of gastric retention (15.5% vs. 29.8%, P=0.03) and diarrhea (8.5% vs. 19.8%, P=0.04) were lower in the short-peptide group. In the multivariate-adjusted model, the use of short-peptide formula was the only independent variable of reduction in gastric retention and diarrhea [HR =0.469 (95% CI: 0.239–0.922), P=0.028; and HR =0.394 (95% CI: 0.161–0.965), P=0.041, respectively].ConclusionsShort-peptide formula is more easily tolerated by patients in the acute phase of AGI and can quickly achieve nutritional goals by EN provision, making it the preferred formula for the initiation of EN in the acute phase of AGI.

Effects of Gamma-Tocotrienol on Intestinal Injury in a GI-Specific Acute Radiation Syndrome Model in Nonhuman Primate.

The gastrointestinal (GI) system is highly susceptible to irradiation. Currently, there is no Food and Drug Administration (FDA)-approved medical countermeasures for GI radiation injury. The vitamin E analog gamma-tocotrienol (GT3) is a promising radioprotector in mice and nonhuman primates (NHP). We evaluated GT3-mediated GI recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques were divided into two groups; eight received vehicle and eight GT3 24 h prior to 12 Gy TBI. Proximal jejunum was assessed for structural injuries and crypt survival on day 4 and 7. Apoptotic cell death and crypt cell proliferation were assessed with TUNEL and Ki-67 immunostaining. Irradiation induced significant shortening of the villi and reduced mucosal surface area. GT3 induced an increase in crypt depth at day 7, suggesting that more stem cells survived and proliferated after irradiation. GT3 did not influence crypt survival after irradiation. GT3 treatment caused a significant decline in TUNEL-positive cells at both day 4 (p < 0.03) and 7 (p < 0.0003). Importantly, GT3 induced a significant increase in Ki-67-positive cells at day 7 (p < 0.05). These data suggest that GT3 has radioprotective function in intestinal epithelial and crypt cells. GT3 should be further explored as a prophylactic medical countermeasure for radiation-induced GI injury.

RETRACTED: Arabinogalactan derived from Larix gmelinii (Rupr.) Kuzen. Alleviates cisplatin-induced acute intestinal injury in vitro and in vivo through IRE1α/ JNK axis mediated apoptotic signaling pathways

Many dietary polysaccharides have been shown to protect against various harmful external stimuli by protecting the integrity of the intestinal barrier. Arabinogalactan (AG) is a high molecular weight polysaccharide composed of arabinose and galactose, which has good immunomodulatory, antioxidant and intestinal conditioning activities. Gastrointestinal injury caused by cisplatin (CP) is an inevitable damage during CP chemotherapy. This research explored the ameliorative effect of AG on cisplatin-induced intestinal toxicity and its possible molecular targets and mechanisms. The results showed that AG (200, 400mg/kg) could significantly reverse the intestinal histopathological changes and oxidative stress injury caused by CP. Meantime, AG could target the IRE1α/JNK axis to inhibit the expression of apoptosis-related proteins and block the apoptotic cascade, thus reducing intestinal damage. In vitro, AG (10, 20, and 40μg/mL) could regulate the IRE1α/JNK axis, inhibit apoptosis, and restore the antioxidant defense system damaged by CP to play a protective role in the intestine. In addition, 4-phenylbutyrate (4-PBA), a specific inhibitor of endoplasmic reticulum stress, was used to verify that AG also affected protein expression levels by regulating the IRE1α/JNK pathway-mediated endoplasmic reticulum stress signaling pathway, thereby alleviating CP-induced gastrointestinal dysfunction. Therefore, AG may be a potential drug to prevent CP-induced intestinal damage.

Gastrointestinal Tract Injury by Yttrium-90 Appears Largely Restricted to Resin Microspheres But Can Occur Years After Embolization.

Radioembolization therapy utilizes yttrium-90 (Y90) impregnated resin (SIR-Spheres) or glass (TheraSpheres) microspheres to selectively target hepatic lesions via transarterial radioembolization. Occasional cases of gastrointestinal tract injury, secondary to nontargeted delivery of microspheres, have been reported, but large descriptive pathology series are lacking. We identified 20 cases of histologically confirmed mucosal injury associated with Y90 from 17 patients and assessed the corresponding clinical and pathologic sequelae. The mucosal biopsies were obtained from 1 to 88 months following Y90 therapy (median: 5 mo). Most cases were gastric (17, 85%), while the remaining were duodenal. Endoscopic ulceration was seen in the majority of cases (16, 80%), and mucosal erythema in the remaining 4. Histologically, a majority (19, 95%) of cases showed rounded, dark blue to purple microspheres measuring 4 to 30 µm, consistent with resin microspheres. A single case with glass microspheres demonstrated 26 µm translucent beads. Histologic evidence of ulceration was appreciated in 14 (70%) cases, and the microspheres were clearly intravascular in 6 (30%). A foreign body giant cell reaction to the microspheres was uncommon (3 cases, 15%). We additionally performed a retrospective review of all gastrointestinal tissue obtained postprocedure from 784 sequential patients treated with Y90 microspheres. Three patients (0.4%) demonstrated the presence of resin microspheres upon histologic examination. No cases involving glass-based Y90 were identified ( P =0.0078), despite the majority of patients having received glass radioembolization (630, 80%). This increased risk of secondary sphere dissemination is likely related to the increased number of particles required per activity for resin versus glass microspheres. We conclude that Y90 microspheres may be encountered in the gastrointestinal tract years after initial liver-targeted therapy and, when present, are often associated with mucosal ulceration. This finding is less likely to be encountered in patients who received Y90 radioembolization utilizing glass microspheres.

Nutritional intake and gastro-intestinal symptoms in critically ill COVID-19 patients

Background & aimsCritically ill COVID-19 patients seem hypermetabolic and difficult to feed enterally, due to gastro-intestinal (GI) symptoms such as high gastric residual volumes (GRV) and diarrhea. Our aim was to describe the association of nutritional intake and GI symptoms during first 14 days of ICU admission.MethodsObservational study including critically ill adult COVID-19 patients. Data on nutritional intake [enteral nutrition (EN) or parenteral nutrition] and GI symptoms were collected during 14 days after ICU admission. Target energy and protein feeding goals were calculated conform ESPEN guidelines. GI symptoms included GRV (ml/d), vomiting, abdominal distension, and faeces (ml/d). High GRV's were classified as ≥2 times ≥150 ml/d and diarrhea as Bristol stool chart ≥6. GI symptoms were defined as mild if at least one symptom occurred and as moderate when ≥2 symptoms occurred. Acute gastrointestinal injury (AGI) grades of III were classified as GI dysfunction and grades of IV were considered as GI failure with severe impact on distant organs. Linear mixed model analysis was performed to explore the development of nutritional intake and GI symptoms over time at day (D) 0, 4, 10, and 14.ResultsOne hundred and fifty patients were included [75% male; median age 64 years (IQR 54–70)]. BMI upon admission was 28 kg/m2 (IQR 25–33), of which 43% obese (BMI > 30 kg/m2). Most patients received EN during admission (98% D4; 96% D10-14). Mean energy goals increased from 87% at D4 to 93% D10-14 and protein goals (g/kg) were increasingly achieved during admission (84% D4; 93% D10-14). Presence of moderate GI symptoms decreased (10% D0; 6% D4-10; 5% D14), reversely mild GI symptoms increased. Occurrence of GI dysfunction fluctuated (1% D0; 18% D4; 12% D10; 8% D14) and none of patients developed grade IV GI failure. Development of high GRV fluctuated (5% D0; 23% D4; 14% D10; 8% D14) and occurrence of diarrhea slightly increased during admission (5% D0; 22% D4; 25% D10; 27% D14). Linear mixed models showed only an association between AGI grades III and lower protein intake at day 10 (p = 0.020).ConclusionOccurrence of GI symptoms was limited and seems no major barrier for EN in our group of critically COVID-19 patients. Nutritional intake was just below requirements during the first 14 days of ICU admission. The effect on nutritional status remains to be studied.

Screening of radiation gastrointestinal injury biomarkers in rat plasma by high-coverage targeted lipidomics

Introduction In the event of radiological accidents and cancer radiotherapies in the clinic, the gastrointestinal (GI) system is vulnerable to ionizing radiation and shows GI injury. Accessible biomarkers may provide means to predict, evaluate, and treat GI tissue damage. The current study investigated radiation GI injury biomarkers in rat plasma. Material and methods High-coverage targeted lipidomics was employed to profile lipidome perturbations at 72 h after 0, 1, 2, 3, 5, and 8 Gy (60Co γ-rays at 1 Gy/min) total-body irradiation in male rat jejunum. The results were correlated with previous plasma screening outcomes. Results In total, 93 differential metabolites and 28 linear dose-responsive metabolites were screened in the jejunum. Moreover, 52 lipid species with significant differences both in jejunum and plasma were obtained. Three lipid species with linear dose-response relationship both in jejunum and plasma were put forth, which exhibited good to excellent sensitivity and specificity in triaging different exposure levels. Discussion The linear dose-effect relationship of lipid metabolites in the jejunum and the triage performance of radiation GI injury biomarkers in plasma were studied for the first time. Conclusion The present study can provide insights into expanded biomarkers of IR-mediated GI injury and minimally invasive assays for evaluation.

Topical application of sustained released-carbon monoxide promotes cutaneous wound healing in diabetic mice

Clinical incidences of pressure ulcers in the elderly and intractable skin ulcers in diabetic patients are increasing because of the aging population and an increase in the number of diabetic patients worldwide. Although various agents are used to treat pressure and skin ulcers, these ulcers are often refractory and deteriorate the patients’ quality of life. Therefore, a novel therapeutic agent with a novel mechanism of action is required. Carbon monoxide (CO) contributes to many physiological and pathophysiological processes, including anti-inflammatory activity; therefore, it can be a therapeutic gaseous molecule. Recent studies have revealed that CO accelerates wound healing in gastrointestinal tract injuries. However, it remains unclear whether CO promotes cutaneous wound healing. Therefore, we aimed to evaluate the therapeutic effects of topical application of a CO-containing solution and elucidate the underlying mechanism. A full-thickness skin wound generated on the back of diabetic mice was treated topically with CO or vehicle. Sustained release of CO was achieved using polyacrylic acid (PAA) as a thickener. The administration of CO-containing PAA aqueous solution resulted in a significant acceleration in wound recovery without elevating serum CO levels in association with increased angiogenesis and supported by elevated expression of vascular endothelial growth factor mRNA in the wound granulomatous tissues. These data suggest that CO might represent a novel therapeutic agent for the treatment of cutaneous wounds.

The Protective Effects of Sour Orange (Citrus aurantium L.) Polymethoxyflavones on Mice Irradiation-Induced Intestinal Injury.

Sour orange (Citrus aurantium L.) is one of the biological sources of polymethoxyflavones (PMFs), which are often used to deal with gastrointestinal diseases. The intestine is highly sensitive to irradiation damage. However, limited certain cures have been released for irradiation-induced gastrointestinal injury, and the potentials of sour orange PMFs as radio-resistance agents have not been fully discussed yet. The present study aims to (1) investigate the PMF components in 12 sour orange cultivars, (2) determine the protective effects of PMFs on irradiation-induced intestinal injury by treating mice that received 12 Gy abdominal irradiation with different doses of PMFs and observing the changes in organ indexes and pathological sections and (3) test cytotoxicity of PMFs by CCK-8 method. The results showed that sour orange PMFs appeared to have high intraspecies similarity. Besides, PMFs protected mice from irradiation-induced injury by alleviating body weight loss, reliving organ index changing and maintaining the intestinal structure. Finally, IC50 concentrations to cell line CCD 841 CoN of PMFs and nobiletin were calculated as 42.23 μg/mL and 51.58 μg/mL, respectively. Our study uncovered PMF contents in 12 sour orange materials and determined the protective effects on irradiation-induced intestinal injuries, providing guidance for the utilization of sour orange resources.

Ischemic injury of the upper gastrointestinal tract after out-of-hospital cardiac arrest: a prospective, multicenter study

BackgroundThe consequences of cardiac arrest (CA) on the gastro-intestinal tract are poorly understood. We measured the incidence of ischemic injury in the upper gastro-intestinal tract after Out-of-hospital CA (OHCA) and determined the risk factors for and consequences of gastrointestinal ischemic injury according to its severity.MethodsProspective, non-controlled, multicenter study in nine ICUs in France and Belgium conducted from November 1, 2014 to November 30, 2018. Included patients underwent an esophago-gastro-duodenoscopy 2 to 4 d after OHCA if still intubated and the presence of ischemic lesions of the upper gastro-intestinal tract was determined by a gastroenterologist. Lesions were a priori defined as severe if there was ulceration or necrosis and moderate if there was mucosal edema or erythema. We compared clinical and cardiac arrest characteristics of three groups of patients (no, moderate, and severe lesions) and identified variables associated with gastrointestinal ischemic injury using multivariate regression analysis. We also compared the outcomes (organ failure during ICU stay and neurological status at hospital discharge) of the three groups of patients.ResultsAmong the 214 patients included in the analysis, 121 (57%, 95% CI 50–63%) had an upper gastrointestinal ischemic lesion, most frequently on the fundus. Ischemic lesions were severe in 55/121 (45%) patients. In multivariate regression, higher adrenaline dose during cardiopulmonary resuscitation (OR 1.25 per mg (1.08–1.46)) was independently associated with increased odds of severe upper gastrointestinal ischemic lesions; previous proton pump inhibitor use (OR 0.40 (0.14–1.00)) and serum bicarbonate on day 1 (OR 0.89 (0.81–0.97)) were associated with lower odds of ischemic lesions. Patients with severe lesions had a higher SOFA score during the ICU stay and worse neurological outcome at hospital discharge.ConclusionsMore than half of the patients successfully resuscitated from OHCA had upper gastrointestinal tract ischemic injury. Presence of ischemic lesions was independently associated with the amount of adrenaline used during resuscitation. Patients with severe lesions had higher organ failure scores during the ICU stay and a worse prognosis.Clinical Trial RegistrationNCT02349074.

Methionine Sulfoxide Reductase A in Human and Mouse Tissues is Responsible for Sulindac Activation, Making a Larger Contribution than the Gut Microbiota.

Sulindac is a nonsteroidal anti-inflammatory prodrug that is converted to its pharmacologically active metabolite, sulindac sulfide, via a reduction reaction. It is widely accepted that the gut microbiota is responsible for sulindac activation; however, sulindac-induced gastrointestinal injury, which is caused by irritation of the gastrointestinal tract by its active metabolite, is uncommon. Therefore, it is surmised that sulindac is converted to its active metabolite in tissues after absorption. In this study, we sought to identify the enzyme(s) responsible for sulindac activation in tissues and to compare its/their contribution to the gut microbiota. Sulindac is enzymatically reduced in human intestinal, liver, and renal cytosols. Since sulindac is known to be reduced by methionine sulfoxide reductase (Msr) in Escherichia coli, we investigated whether the human ortholog MSRA catalyzes the sulindac reduction reaction. We found that recombinant human MSRA shows sulindac reductase activity with a similar Michaelis constant value as tissue cytosols. In addition, it was revealed that cytosolic factor(s) efficiently enhanced MSRA activity. By using the relative expression factor, the contribution of MSRA to the sulindac reductase activities in each tissue cytosol was calculated to be almost 100%. In mice, depletion of the gut microbiota by administration of antibiotics resulted in a 31% decrease in the area under the curve ratio of sulindac sulfide to sulindac, indicating that the contribution of tissue MsrA to sulindac activation is expected to be 69% in the body. In conclusion, we demonstrated that MSRA expressed in tissues is involved in sulindac activation, making a larger contribution than the gut microbiota. SIGNIFICANCE STATEMENT: Methionine sulfoxide reductase A is responsible for the activation of sulindac, a nonsteroidal anti-inflammatory prodrug, to sulindac sulfide, an active form, in human tissues. Methionine sulfoxide reductase A expressed in tissues activates sulindac with a higher contribution than gut microbiota in body.

Gamma-tocotrienol, a radiation countermeasure, reverses proteomic changes in serum following total-body gamma irradiation in mice

Radiological incidents or terrorist attacks would likely expose civilians and military personnel to high doses of ionizing radiation, leading to the development of acute radiation syndrome. We examined the effectiveness of prophylactic administration of a developmental radiation countermeasure, γ-tocotrienol (GT3), in a total-body irradiation (TBI) mouse model. CD2F1 mice received GT3 24 h prior to 11 Gy cobalt-60 gamma-irradiation. This dose of radiation induces severe hematopoietic acute radiation syndrome and moderate gastrointestinal injury. GT3 provided 100% protection, while the vehicle control group had 100% mortality. Two-dimensional differential in-gel electrophoresis was followed by mass spectrometry and Ingenuity Pathway Analysis (IPA). Analysis revealed a change in expression of 18 proteins in response to TBI, and these changes were reversed with prophylactic treatment of GT3. IPA revealed a network of associated proteins involved in cellular movement, immune cell trafficking, and inflammatory response. Of particular interest, significant expression changes in beta-2-glycoprotein 1, alpha-1-acid glycoprotein 1, alpha-2-macroglobulin, complement C3, mannose-binding protein C, and major urinary protein 6 were noted after TBI and reversed with GT3 treatment. This study reports the untargeted approach, the network, and specific serum proteins which could be translated as biomarkers of both radiation injury and protection by countermeasures.

The role of Astragalus polysaccharides in promoting IEC-6 cell migration from polyamine-mediated Ca2+ regulation

Astragalus polysaccharide (APS) has a protective effect on injured intestinal mucosa by promoting intestinal cell migration, but the specific mechanism is unclear. The polyamine-mediated calcium signaling pathway is an important mechanism of cell migration, generally, and we tested the hypothesis that APS can protect damaged intestinal mucosa through the polyamine-mediated calcium signaling pathway. High-performance liquid chromatography (HPLC), infrared chromatography, cell scratch test, Western blot, co-immunoprecipitation, polyamine inhibitor (DFMO), si-Cav1, RhoA inhibitor (Rhosin) and Rac1 inhibitor (NSC23766) were used to detect the pharmacodynamic of APS. The results show that APS can promote cell migration. In addition, APS increased the formations of RhoA/TRPC1, Cav1/TRPC1, and Rac1/PLCγ-1 complexes as well as the expressions of TRPC1, PLCγ-1, RhoA, Cav1, and Rac1, and it reversed the inhibitory effect of DFMO on the above factors. APS also reversed the inhibitory effect of si-Cav1 on Cav1 expression, cytoplasmic Ca2+ concentrations ([Ca2+]cyt), and cell migration. Moreover, APS removed the inhibition of NSC23766 and Rhosin on [Ca2+]cyt and cell migration. In vivo study, the water extract of Astragalus membranaceus (WEA) (15 g/kg) reduced the indomethacin-induced injury of intestinal mucosa as well. These observations suggest that APS can treat gastrointestinal mucosal injury through the polyamine calcium signaling pathway.

CLINICAL AND DIAGNOSTIC ASPECTS OF FIRE I NFLAMMATION INJURIES OF HOLLOW ABDOMINAL ORGANS (ATO / OOS EXPERIENCE)

Among the features of radiological diagnosis for the wounded with injuries of the gastrointestinal tract, we can point to a set of radiological methods of research, among which the leading place is occupied by X-ray contrast studies of the abdomen — vulnerography, fistulography, enterography, irigoscopy. The most important task of special methods of X-ray examination of gastrointestinal injuries, accompanied by the introduction of X-ray contrast agents, is the control of the postoperative period, radiological support during surgery and diagnosis of failure of sutures, anastomoses, intraperitoneal walls fistula, phlegmon of retroperitoneal tissue. Materials and methods. The results of retrospective analysis of radiological diagnostics of 76 (7.5 ± 1.6) % of wounded in the abdomen, waist, retroperitoneal space from the total mass of subjects (n = 1013 people), due to the mechanical and multifactorial nature of the lesion. Of these, 42 subjects with a predominant abdominal component of gastric injury injuries were in 6 cases out of 42 (14.3 %), 3 (7.1 %) cases of esophageal and duodenal injuries, small bowel injuries were observed in 12 cases (28, 6 %), colon damage in 14 cases (33.4 %) and rectal damage in 4 cases (9.5 %). All X-ray contrast studies of different parts of the digestive tract were performed with one-time double contrast and other methods in the X-ray diagnostic department of the clinic (radiation diagnostics and therapy) of the National Military Medical Clinical Center «GVKG» on modern X-ray machine expert class OPERA SWING. Discussion of results. There are no fundamental differences in the tactics of radiation control of injuries (TCU) of the gastrointestinal tract in abdominal injuries. However, in the preoperative period of urgent radiological diagnosis of damage to the esophagus, stomach, small, colon, and other parts of the colon, preference is given to non-contrast radiological examination of the abdomen (review radiography in direct projection standing / lying, lateroposition and lateral projection). In the future, the postoperative period of the wounded is accompanied by the widespread use of X-ray contrast studies of internal organs with gastrointestinal damage for radiation support during surgery and diagnosis of complications in the early and late postoperative periods. Conclusions. Given the multiple and combined nature of gunshot and non-gunshot injuries to the abdomen, lower back, retroperitoneal space in the wounded with injuries of the esophagus, stomach, small, colon and other parts of the colon, immediate radiological diagnosis should be provided to all wounded. preoperative period to address the clinical and diagnostic problem of emergencies. Since the natural X-ray contrast of the abdominal cavity and retroperitoneal space is very low, and damaged hollow organs increase pneumatization of the gastrointestinal tract, the use of artificial contrast (barium mixture, iodine-containing water-soluble X-ray contrast agents) significantly increases the diagnostic value. The use of special methods of X-ray examination with artificial contrast in the postoperative period is determined by the condition of the wounded and the specific clinical situation.

Preventive effect of rebamipide on NSAID-induced lower gastrointestinal tract injury using FAERS and JADER

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for their antipyretic, analgesic, and anti-inflammatory properties. However, various aspects of NSAID-induced lower gastrointestinal tract injury remain unclear, and effective prophylaxis has not been established. Based on its pharmacological effect and clinical trials, rebamipide may prevent lower gastrointestinal tract injury, although this evidence is limited by the small scale of trials. The present study used the FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Event Reporting Database (JADER) to assess the efficacy of rebamipide in combination with loxoprofen and diclofenac in preventing NSAID-induced lower gastrointestinal tract injury. The calculated reporting odds ratio and 95% confidence interval (CI) for rebamipide in combination with loxoprofen and diclofenac were 1.15 (95% CI 0.88–1.51) and 1.28 (95% CI 0.82–2.01) for FAERS, and 0.50 (95% CI 0.35–0.71) and 0.43 (95% CI 0.27–0.67) for JADER, respectively. No signal was detected when combining drugs. These results suggest a prophylactic effect of rebamipide on NSAID-induced lower gastrointestinal tract injury.

Effects of Nalbuphine on Gastrointestinal Function in Post-Operative Critical Ill Patients Admitted to the ICU: A Multicenter Randomized Controlled Trial.

BackgroundGastrointestinal (GI) function can be a significant problem in critically ill patients and is associated with detrimental outcomes. The administration of opioids for pain reduction is thought to contribute to GI dysfunction. We tested whether nalbuphine, a mixed agonist/antagonist opioid modulator, can promote GI recovery in postoperative critical patients admitted to the intensive care unit (ICU) and compared it with fentanyl, a selective mu opioid receptor (MOR) agonist.MethodsThis is a multicenter, single-blind, randomized controlled trial to investigate whether nalbuphine improves the GI recovery in ICU patients after surgery, and compared it with fentanyl. The primary outcome was the time to first defecation. Secondary outcomes included the use of sedatives, enemas or laxatives, the acute gastrointestinal injury (AGI) grade, the incidence of vomiting, and the lengths of ICU and hospital stays.ResultsWe randomized 436 patients, and a total of 369 patients were included in the modified intention-to-treat population (mITT) (185 to the nalbuphine group and 184 to the fentanyl group). The baseline demographic characteristics of the two groups were comparable after randomization. There was no significant difference in the time to defecation between the two groups [hazard ratio (HR) 0.94, 95% CI 0.74–1.19, p = 0.62]. There was no significant difference in the secondary outcomes between the two groups.ConclusionWe found no evidence that nalbuphine administration can improve the GI function in postoperative critical patients admitted to the ICU compared with fentanyl. However, the CI was wide and we could not exclude the clinically important difference.

The association between gastrointestinal injury, complaints, and food intake in 60-km ultramarathon runners.

We aimed to assess the association between gastrointestinal (GI) injury, complaints, and food intake in 60-km ultramarathon runners. Thirty-three ultramarathon runners provided pre- and post-race blood samples for assessment of GI injury by intestinal fatty-acid binding protein (I-FABP), and inflammatory response by interleukin (IL)-6, IL-8, tumour necrosis factor alpha (TNF-α), and C-reactive protein (CRP). GI complaints and nutritional intake were reported by a post-race questionnaire. GI complaints were reported by 73% of the runners, of which 20% reported 1 or 2 severe complaints. IL-6, IL8, TNF-α, and CRP increased significantly from pre- to post-race (P < 0.001 for all biomarkers), while I-FABP did not (1375 [IQR: 1264-2073] to 1726 [IQR: 985-3287] pg/mL; P = 0.330). The 'GI complaints score', as the integral of the number and severity of GI complaints, did not correlate with ΔI-FABP (rs: -0.050, P = 0.790) or energy intake (rs: 0.211, P = 0.260). However, there was a significant negative correlation between energy intake and ΔI-FABP (rs: -0.388, P = 0.031). In conclusion, GI complaints were neither associated with food intake nor GI injury as assessed by plasma I-FABP response. Energy intake, however, was inversely related to the I-FABP response to exercise. This finding suggests that substantial energy intakes during exercise may prevent exercise-induced GI injury as assessed by the I-FABP response. Novelty: No association between gastrointestinal complaints and gastrointestinal injury (I-FABP response) or food intake was present. There was an inverse correlation between energy intake and plasma I-FABP response, suggesting that higher energy intakes may prevent gastrointestinal injury as assessed by the I-FABP response.