Intestinal Ischemia-reperfusion Research Articles

Effects of butyrate on intestinal ischemia-reperfusion injury via the HMGB1-TLR4-MyD88 signaling pathway.

This study combined bioinformatics and experimental verification in a mouse model of intestinal ischemia-reperfusion injury (IRI) to explore the protection mechanism exerted by butyrate against IRI. GeneCards, Bioinformatics Analysis Tool for Molecular Mechanisms of Traditional Chinese Medicine and GSE190581 were used to explore the relationship between butyrate and IRI and aging. Protein-protein interaction networks involving butyrate and IRI were constructed via the STRING database, with hub gene analysis performed through Cytoscape. Functional enrichment analysis was conducted on intersection genes. A mouse model of IRI was established, followed by direct arterial injection of butyrate. The experiment comprised five groups: normal, sham, model, vehicle, low-dose butyrate, and high-dose butyrate. Intestinal tissue observation was done via transmission electron microscopy (TEM), histological examination via hematoxylin and eosin (H&E) staining, tight junction proteins detection via immunohistochemistry, and Western blot analysis of hub genes. Drug-target interactions were evaluated through molecular docking. Butyrate protected against IRI by targeting 458 genes, including HMGB1 and TLR4. Toll-like receptor pathway was implicated. Butyrate improved intestinal IRI by reducing mucosal damage, increasing tight junction proteins, and lowering levels of HMGB1, TLR4, and MyD88. Molecular docking showed strong binding energies between butyrate and HMGB1 (-3.7 kcal/mol) and TLR4 (-3.8 kcal/mol). According to bioinformatics predictions, butyrate mitigates IRI via multiple-target and multiple-channel mechanisms. The extent of IRI can be reduced by butyrate through the inhibition of the HMGB1-TLR4-MyD88 signaling pathway, which is related to senescence.

Oxidative medicine and cellular longevity the role and mechanism of NCOA4 in ferroptosis induced by intestinal ischemia reperfusion

BackgroundFerroptosis is an iron-dependent and cystathione-non-dependent non-apoptotic cell death characterized by elevated intracellular free iron levels and reduced antioxidant capacity, leading to the accumulation of lipid peroxides. Nuclear receptor coactivator 4 (NCOA4) mediates ferritinophagy, increasing labile iron levels, which can result in oxidative damage. However, the specific mechanism of NCOA4-mediated ferritinophagy in intestinal ischemia–reperfusion and the underlying mechanisms have not been reported in detail. Object1. To investigate the role of NCOA4 in ferroptosis of intestinal epithelial cells induced by II/R injury in mouse. 2. To investigate the mechanism of action of NCOA4-induced ferroptosis. Methods1. Construct a mouse II/R injury model and detect ferroptosis related markers such as HE staining, immunohistochemistry, ELISA, and WB methods.2. Detect expression of NCOA4 in the intestine of mouse with II/R injury model and analyze its correlation with intestinal ferroptosis in mouse with II/R injury model.3. Construct an ischemia–reperfusion model at the cellular level through hypoxia and reoxygenation, and overexpress/knockdown NCOA4 to detect markers related to ferroptosis. Based on animal experimental results, analyze the correlation and mechanism of action between NCOA4 and intestinal epithelial ferroptosis induced by II/R injury in mouse. Results1. Ferroptosis occurred in the intestinal epithelial cells of II/R-injured mouse, and the expression of critical factors of ferroptosis, ACSL4, MDA and 15-LOX, was significantly increased, while the levels of GPX4 and GSH were significantly decreased. 2. The expression of NCOA4 in the intestinal epithelium of mouse with II/R injure was significantly increased, the expression of ferritin was significantly decreased, and the level of free ferrous ions was significantly increased; the expression of autophagy-related proteins LC3 and Beclin-1 protein was increased, and the expression of P62 was decreased, and these changes were reversed by autophagy inhibitors. 3. Knockdown of NCOA4 at the cellular level resulted in increased ferritin expression and decreased ferroptosis, and CO-IP experiments suggested that NCOA4 can bind to ferritin, which suggests that NCOA4 most likely mediates ferritinophagy to induce ferroptosis. ConclusionThis thesis explored the role of NCOA4 in II/R injury in mice and the mechanism of action. The research results suggest that NCOA4 can mediate ferritinophagy to induce ferroptosis during II/R injury. This experiment reveals the pathological mechanism of II/R injury and provides some scientific basis for the development of drugs for the treatment of II/R injury based on the purpose of alleviating ferroptosis.

Probiotics may alleviate intestinal damage induced by cardiopulmonary bypass in children.

Intestinal ischemia-reperfusion injury induced by cardiopulmonary bypass causes intestinal epithelial barrier dysfunction, leading to dysbiosis and bacterial translocation. We conducted a randomized prospective study with two objectives: (1) to investigate epithelial barrier dysfunction and bacterial translocation induced by cardiopulmonary bypass and changes in the gut microbiota and (2) to verify whether probiotics can improve these conditions. Between 2019 and 2020, patients 0-15 years old scheduled to undergo cardiac surgery using cardiopulmonary bypass were enrolled and randomly allocated to 2 groups: the intervention group received probiotics, and the control group did not receive probiotics. We analyzed the microbiota in feces and blood, organic acid concentrations in feces, plasma intestinal fatty-acid binding protein, and immunological responses. Eighty-two patients were enrolled in this study. The characteristics of the patients were similar in both groups. The total number of obligate anaerobes was higher in the intervention group than in the control group after postoperative day 7. We identified four clusters within the perioperative gut microbiota, and cluster changes showed a corrective effect of probiotics on dysbiosis after postoperative day 7. Organic acid concentrations in feces, incidence of bacterial translocation, Intestinal fatty-acid binding protein levels, and immunological responses, except for Interleukin -17A, were not markedly different between the two groups. Administration of probiotics was able to correct dysbiosis but did not sufficiently alleviate the intestinal damage induced by cardiopulmonary bypass. More effective methods should be examined to prevent disturbances induced by cardiac surgery using cardiopulmonary bypass.

Effect of the semisynthetic form of glucagon-like peptide-2 analog in an experimental model of intestinal ischemia-reperfusion injury

Effect of the semisynthetic form of glucagon-like peptide-2 analog in an experimental model of intestinal ischemia-reperfusion injury

Sacubitril/valsartan protective effect on induced intestinal ischemia/reperfusion injury via immune modulation of IL6/STAT1 pathway.

Intestinal ischemia reperfusion (IIR) is a critical emergency situation that needs immediate intervention. Small intestine is one of the most sensitive tissues to IR injury and it remains a highly morbid condition, with reported mortality rates ranging from 30% to 90%. Thus, we aimed to evaluate the suspected protective role of sacubitril/valsartan (SAC/VAL) on IIR injury. Thirty-two adult male Wistar rats were used in our model and divided into four groups: sham group, SAC/VAL treated group without IIR, IIR group, and SAC/VAL treated group with IIR. SAC/VAL in a dose of 30mg/kg was administered orally just before induction of IIR. SAC/VAL significantly ameliorated IIR-induced changes as it decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), angiotensin II (ANG II), interleukin 6 (IL 6), active caspase 3, and signal transducer- and activator-of transcription (STAT1). However, SAC/VAL administration significantly increased antioxidant parameters such as total antioxidant capacity (TAC), superoxide dismutase (SOD), and reduced glutathione (GSH). Moreover, alteration of the histological structure was observed in IIR group that was improved by SAC/VAL. SAC/VAL prevents IIR-induced damage via modulation of renin angiotensin aldosterone system, antioxidant, anti-apoptotic, anti-inflammatory properties, and regulation of IL6/STAT1 pathway.

Unveiling the molecular complexity of intestinal ischemia-reperfusion injury through omics technologies.

Intestinal ischemia-reperfusion injury (IR) is implicated in various clinical conditions and causes damage to the intestinal epithelium resulting in intestinal barrier loss. This presents a substantial clinical challenge, emphasizing the importance of gaining a comprehensive understanding of molecular events to aid in the identification of novel therapeutic targets. This review systematically explores the extent to which omics technologies-transcriptomics, proteomics, metabolomics, and metagenomics-have already contributed to deciphering the molecular mechanisms contributing to intestinal IR injury, in in vivo and in vitro animal and human models, and in clinical samples. Recent breakthroughs involve applying omics methodologies on exosomes, organoids, and single cells, shedding light on promising avenues and valuable targets to reduce intestinal IR injury. Future directions aimed at expediting clinical translation are discussed as well and include multi-omics data integration to facilitate the identification of key regulatory nodes driving intestinal IR injury and advancing human organoid models based on the novel insights by single-cell omics technologies, offering hope for clinical application of therapeutic strategies in the years to come.

Attenuation of intestinal ischemia-reperfusion-injury by anesthetics: a potentially protective effect of anesthetic management in experimental studies.

Intestinal ischemia-reperfusion injury (IRI) is a potentially severe clinical syndrome after major surgical procedures. In addition to causing intestinal mucosa injury, intestinal IRI further damages distant organs, causing the severity of the condition in patients. So far, effective therapy for intestinal IRI is still absent, and the survival rate of the patients is low. Previous experimental studies have shown that some anesthetics can alleviate intestinal IRI and protect organs while exerting their pharmacological effects, indicating that reasonable perioperative anesthesia management may provide potential benefits for patients to avoid intestinal IRI. These meaningful findings drive scholars to investigate the mechanism of anesthetics in treating intestinal IRI in-depth to discuss the possible new clinical uses. In the present mini-review, we will introduce the protective effects of different anesthetics in intestinal IRI to help us enrich our knowledge in this area.

Si-based agent alleviated small bowel ischemia–reperfusion injury through antioxidant effects

The progression of small bowel ischemia–reperfusion (IR) injury causes cells in the intestinal tract to undergo necrosis, necessitating surgical resection, which may result in loss of intestinal function. Therefore, developing therapeutic agents that can prevent IR injury at early stages and suppress its progression is imperative. As IR injury may be closely related to oxidative stress, antioxidants can be effective therapeutic agents. Our silicon (Si)-based agent, an antioxidant, generated a large amount of hydrogen in the intestinal tract for a prolonged period after oral administration. As it has been effective for ulcerative colitis, renal failure, and IR injury during skin flap transplantation, it could be effective for small intestinal IR injury. Herein, we investigated the efficacy of an Si-based agent in a mouse model of small intestinal IR injury. The Si-based agent suppressed the apoptosis of small intestinal epithelial cells by reducing the oxidative stress induced by IR injury. In addition, the thickness of the mucosal layer in the small intestine of the Si-based agent-administered group was significantly higher than that in the untreated group, revealing that Si-based agent is effective against small intestinal IR injuries. In the future, Si-based agents may improve the success rate of small intestine transplantation.

PRMT6-FOXO3A ATTENUATES APOPTOSIS BY UPREGULATING PARKIN EXPRESSION IN INTESTINAL ISCHEMIA-REPERFUSION INJURY.

Intestinal ischemia-reperfusion injury (IIRI) is a serious disease with high morbidity and mortality. This study aims to investigate the potential regulatory mechanisms involving protein arginine methyltransferase 6 (PRMT6), Forkhead box O3a (FoxO3a), and Parkin in IIRI and elucidate their roles in mediating cell apoptosis. The IIRI animal model was established and confirmed using hematoxylin and eosin staining. Oxygen-glucose deprivation and reperfusion (OGD/R) cell model was established to mimic ischemic injury in vitro . Transient transfection was used to overexpress or knock down genes. Cell death or apoptosis was assessed by propidium iodide staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and flow cytometry. The expression of proteins was detected by western blot. The histopathology observed by hematoxylin and eosin staining suggested that the IIRI animal model was successfully established. Our findings revealed that IIRI resulted in increased Bax and decreased Bcl-2 levels. In vitro experiments showed that overexpression of Parkin decreased OGD/R injury and suppressed elevation of Bax/Bcl-2. PRMT6 regulated the methylation level of FoxO3a. Moreover, FoxO3a directly binds to Parkin, and FoxO3a overexpression reduced OGD/R-induced cell death and regulation of Parkin. Overexpression of PRMT6 can attenuate the downregulation of Parkin and elevation of Bax/Bcl-2 caused by OGD/R. Knockdown of PRMT6 promoted apoptosis in intestinal epithelial cells of OGD/R group, while PRMT6 overexpression exhibited the opposite effect. Notably, the levels of PRMT6, FoxO3a, and Parkin were decreased in IIRI mouse intestinal tissue. Knocking out PRMT6 causes a significant decrease in the lifespan of mice. Altogether, our results demonstrated that PRMT6 upregulated the expression of Parkin by regulating FoxO3a methylation level, attenuating the apoptosis induced by IIRI.

PROSTAGLANDIN E-MAJOR URINARY METABOLITES AS A NEW BIOMARKER FOR ACUTE MESENTERIC ISCHEMIA.

Acute mesenteric ischemia (AMI) is an emergent vascular disease caused by cessation of the blood supply to the small intestine. Despite advances in the diagnosis, intervention, and surgical procedures, AMI remains a life-threatening condition. Prostaglandin E2 Major Urinary Metabolite (PGE-MUM), the urinary metabolite of Prostaglandin E2, is known to be stable in urine and has been suggested to be a valuable biomarker for intestinal mucosal inflammation, such as ulcerative colitis. We therefore investigated whether or not PGE-MUM levels reflect the degree of ischemia in an intestinal ischemia-reperfusion (IR) model. Male rats were used to establish a superior mesenteric artery occlusion (SMAO) group, in which the superior mesenteric artery was clamped, and a sham group. The clamping times in the SMAO group were either 30 or 60 min, and reperfusion times were either 3 or 6 h, after which PGE-MUM values were measured. The histological injury score of the SMAO (30-min ischemia and 6-h reperfusion group: 1.8 ± 0.4 and 60-min ischemia and 6-h reperfusion group: 4.7 ± 0.5) and were significantly greater than that of the sham group (0.4 ± 0.7, p < 0.05). The PGE-MUM levels in the SMAO group (30-min ischemia and 6-h reperfusion group:483 ± 256 and 60-min ischemia and 6-h reperfusion group:889 ± 402 ng/mL) were significantly higher than in the sham group (30-min and 6-h observation group:51 ± 20, and 60-min and 6-h observation group:73 ± 32 ng/mL p < 0.05). Furthermore, the PGE-MUM value was corrected by the concentration of urinary creatinine (Cr). The PGE-MUM/urinary Cr levels in the SMAO group were also significantly higher than in the sham group (p < 0.05). We found that intestinal IR increased urinary PGE-MUM levels depending on the ischemic time. This suggests the potential utility of PGE-MUM as a noninvasive marker of intestinal ischemia.

Gut lymph purification alleviates acute lung injury induced by intestinal ischemia-reperfusion in rats by removing danger-associated molecular patterns from gut lymph

BackgroundThe potential effect of removing danger-associated molecular patterns (DAMPs) from gut lymph on reducing acute lung injury (ALI) induced by gut ischemia-reperfusion injury (GIRI) is uncertain. This study aimed to investigate whether gut lymph purification (GLP) could improve GIRI-induced acute lung injury in rats by clearing danger-associated molecular patterns. Materials and methodsRats were divided into four groups: Sham, GIRI, GIRI + gut lymph drainage (GLD), and GIRI + GLP. After successful modeling, lung tissue samples were collected from rats for hematoxylin-eosin (HE) staining and detection of apoptotic indexes. We detected the DAMPs levels in blood and lymph samples. We observed the microstructure of AEC Ⅱ and measured the expression levels of apoptosis indexes. ResultsThe GIRI group showed destruction of alveolar structure, thickened alveolar walls, and inflammatory cell infiltration. This was accompanied by significantly increased levels of high mobility group protein-1 (HMGB-1) and Interleukin-6 (IL-6), while reduced levels of heat shock protein 70 (HSP 70) and Interleukin-10 (IL-10) in both lymph and serum. In contrast, the lung tissue damage in the GIRI + GLP group was significantly improved compared to the GIRI group. This was evidenced by a reduction in the expression levels of HMGB-1 and IL-6 in both lymph and serum and an increase in HSP 70 and IL-10 levels. Additionally, organelle structure of AEC II was significantly improved in the GIRI + GLP group compared to the GIRI group. ConclusionsGLP inhibits inflammation and cell apoptosis in GIRI-induced ALI by blocking the link between DAMPs and mononuclear phagocytes, reducing the severity of ALI.

Polysaccharide Isolated from Agaricus blazei Murill Alleviates Intestinal Ischemia/Reperfusion Injury through Regulating Gut Microbiota and Mitigating Inflammation in Mice.

Intestinal ischemia-reperfusion (I/R) injury is a serious disease in medical settings, and gut dysbiosis is a major contributor to its development. Polysaccharides from Agaricus blazei Murill (ABM) showed a range of pharmacological activities, yet no studies assessed the potential of ABM polysaccharides for alleviating intestinal I/R injury. Here, we purified a major polysaccharide (ABP1) from an ABM fruit body and subsequently tested its potential to mitigate intestinal I/R injury in a mouse model of temporary superior mesenteric artery occlusion. The results reveal that ABP1 pretreatment enhances gut barrier function via upregulation of the expression of tight junction proteins such as ZO-1 and occludin. Additionally, ABP1 intervention reduces the recruitment of neutrophils and the polarization of M1 macrophages and limits inflammation by blocking the assembly of the NLRP3 inflammasome. Moreover, the role of ABP1 in regulating the gut microbiota was confirmed via antibiotic treatment. The omics data reveals that ABP1 reprograms gut microbiota compositions, characterized by a decrease of Proteobacteria and an increase of Lachnospiraceae and Lactobacillaceae, especially the SCFA-producing genera such as Ligilactobacillus and Blautia. Overall, this work highlights the therapeutic potential of ABP1 against intestinal I/R injury, which mainly exhibits its effects via regulating the gut microbiota and suppressing the overactivated inflammation response.

The crucial role of SETDB1 in structural and functional transformation of epithelial cells during regeneration after intestinal ischemia reperfusion injury.

Su (var) 3-9, enhancer of seste, trithorax (SET)-domain bifurcated histone lysine methyltransferase (SETDB1) plays a crucial role in maintaining intestinal stem cell homeostasis; however, its physiological function in epithelial injury is largely unknown. In this study, we investigated the role of SETDB1 in epithelial regeneration using an intestinal ischemia/reperfusion injury (IRI) mouse model. Jejunum tissues were sampled after 75min of ischemia followed by 3, 24, and 48h of reperfusion. Morphological evaluations were performed using light microscopy and electron microscopy, and the involvement of SETDB1 in epithelial remodeling was investigated by immunohistochemistry. Expression of SETDB1 was increased following 24h of reperfusion and localized in not only the crypt bottom but also in the transit amplifying zone and part of the villi. Changes in cell lineage, repression of cell adhesion molecule expression, and decreased histone H3 methylation status were detected in the crypts at the same time. Electron microscopy also revealed aberrant alignment of crypt nuclei and fusion of adjacent villi. Furthermore, increased SETDB1 expression and epithelial remodeling were confirmed with loss of stem cells, suggesting SETDB1 affects epithelial cell plasticity. In addition, crypt elongation and increased numbers of Ki-67 positive cells indicated active cell proliferation after IRI; however, the expression of PCNA was decreased compared to sham mouse jejunum. These morphological changes and the aberrant expression of proliferation markers were prevented by sinefungin, a histone methyltransferase inhibitor. In summary, SETDB1 plays a crucial role in changes in the epithelial structure after IRI-induced stem cell loss.

E3 ligase TRIM65 alleviates intestinal ischemia/reperfusion injury through inhibition of TOX4-mediated apoptosis

Intestinal ischemia-reperfusion (II/R) injury is an urgent clinical disease with high incidence and mortality, and impaired intestinal barrier function caused by excessive apoptosis of intestinal cells is an important cause of its serious consequences. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase that is recently reported to suppress the inflammatory response and apoptosis. However, the biological function and regulation of TRIM65 in II/R injury are totally unknown. We found that TRIM65 was significantly decreased in hypoxia-reoxygenation (H/R) induced intestinal epithelial cells and II/R-induced intestine tissue. TRIM65 knockout mice markedly aggravated intestinal apoptosis and II/R injury. To explore the molecular mechanism of TRIM65 in exacerbating II/R-induced intestinal apoptosis and damage, thymocyte selection-associated high mobility group box factor 4 (TOX4) was screened out as a novel substrate of TRIM65 using the yeast two-hybrid system. TRIM65 binds directly to the N-terminal of TOX4 through its coiled-coil and SPRY structural domains. Immunofluorescence confocal microscopy showed that they can co-localize both in the cytoplasm and nucleus. Furthermore, TRIM65 mediated the K48 ubiquitination and degradation of TOX4 depending on its E3 ubiquitin ligase activity. In addition, TRIM65 inhibits H/R-induced intestinal epithelial apoptosis via TOX4. In summary, our results indicated that TRIM65 promotes ubiquitination and degradation of TOX4 to inhibit apoptosis in II/R. These findings provide a promising target for the clinical treatment of II/R injury.

Apigenin-7-glucoside-loaded nanoparticle alleviates intestinal ischemia-reperfusion by ATF3/SLC7A11-mediated ferroptosis

Intestinal ischemia reperfusion injury (II/R injury) is a common and intractable pathophysiological process in critical patients, for which exploring new treatments and mechanisms is of great importance to improve treatment outcomes. Apigenin-7-O-Glucoside (AGL) is a sugar derivative of apigenin natural product with various pharmacological activities to protect against intestinal diseases. In this study, we synthesized two amphiphilic molecules, namely DTPA-N10–10 and mPEG-TK-DA, which can scavenge free radicals and reactive oxygen species (ROS). They were successfully encapsulated AGL through self-assembly, resulting in the formation of multi-site ROS scavenging nanoparticles called PDN@AGL. In vitro and in vivo experiments demonstrated that PDN@AGL could protect intestinal tissues by reducing lipid peroxidation, lowering ROS levels and inhibiting ferroptosis during II/R injury. Furthermore, our study revealed, for the first time, that the regulation of the ATF3/SLC7A11 pathway by PDN@AGL may play a crucial role in mitigating II/R injury. In conclusion, our study confirmed the beneficial effects of PDN@AGL in combating II/R injury through the ATF3/SLC7A11-mediated regulation of ferroptosis and oxidative stress. These findings lay the groundwork for the potential application of PDN@AGL in the treatment of II/R injury.

Bifidobacterium longum GL001 alleviates rat intestinal ischemia-reperfusion injury by modulating gut microbiota composition and intestinal tissue metabolism.

Intestinal ischemia-reperfusion (IIR) injury leads to inflammation and oxidative stress, resulting in intestinal barrier damage. Probiotics, due to their anti-inflammatory and antioxidant properties, are considered for potential intervention to protect the intestinal barrier during IIR injury. Bifidobacterium longum, a recognized probiotic, has targeted effects on IIR injury, but its mechanisms of action are not yet understood. To investigate the mechanism of Bifidobacterium longum intervention in IIR injury, we conducted a study using a rat IIR injury model. The results showed that Bifidobacterium longum could alleviate inflammation and oxidative stress induced by IIR injury by suppressing the NF-κB inflammatory pathway and activating the Keap1/Nrf2 signaling pathway. Bifidobacterium longum GL001 also increased the abundance of the gut microbiota such as Oscillospira, Ouminococcus, Corynebacterium, Lactobacillus, and Akkermansia, while decreasing the abundance of Allobaculum, [Prevotella], Bacteroidaceae, Bacteroides, Shigella, and Helicobacter. In addition, Bifidobacterium longum GL001 reversed the changes in amino acids and bile acids induced by IIR injury and reduced the levels of DL-cysteine, an oxidative stress marker, in intestinal tissue. Spearman correlation analysis showed that L-cystine was positively correlated with Lactobacillus and negatively correlated with Shigella, while DL-proline was positively correlated with Akkermansia. Moreover, bile acids, cholic acid and lithocholic acid, were negatively correlated with Lactobacillus and positively correlated with Shigella. Therefore, Bifidobacterium longum GL001 may alleviate IIR injury by regulating the gut microbiota to modulate intestinal lipid peroxidation and bile acid metabolism.

EFFECT OF RESVERATROL AND QUERCETİN ON INTESTİNAL ISCHEMİA REPERFUSİON INJURY İN RATS

Aim: Intestinal ischemia reperfusion (I/R) injury is an emergency condition with a high mortality rate and early diagnosis is very difficult. In this study, we aimed to examine the biochemical and histopathological effects of resveratrol and quercetin on intestinal I/R injury model.&#x0D; Material and Method: In our study, 56 male Sprague-Dawley rats weighing 250-300 g were randomly divided into 7 groups consisting of 8 rats. Groups were control group (group 1), saline group (group 2), ethanol group (group 3), resveratrol group (group 4) (30mg/kg), quercetin group (group 5) (30mg/kg), resveratrol+quercetin group A (group 6) (15 mg/kg+15 mg/kg), resveratrol+quercetin group B (group 7) (30 mg/kg+30 mg/kg). At the end of the experiment rats intestinal tissues were divided into 2 parts for biochemical and histopathological examination. Total oxidant level (TOS), total antioxidant level (TAS), total thiol [(-SH)+(-S-S-)] (TT), native thiol [-SH] (NT), and protein content levels were measured spectrophotometrically, oxidative stress index (OSI) and disulfide [-S-S-] levels were calculated.&#x0D; Results: A statistically significant difference was found between the groups in terms of TOS, OSI, TT, NT and disulfide levels (p

EFFECTS OF HYPERBARIC OXYGEN THERAPY ON INTESTINAL ISCHEMIA-REPERFUSION AND ITS MECHANISM.

Ischemia can cause reversible or irreversible cell or tissue damage, and reperfusion after ischemia not only has no therapeutic effect but also aggravates cell damage. Notably, gut tissue is highly susceptible to ischemia-reperfusion (IR) injury under many adverse health conditions. Intestinal IR (IIR) is an important pathophysiological process in critical clinical diseases. Therefore, it is necessary to identify better therapeutic methods for relieving intestinal ischemia and hypoxia. Hyperbaric oxygenation refers to the intermittent inhalation of 100% oxygen in an environment greater than 1 atm pressure, which can better increase the oxygen level in the tissue and change the inflammatory pathway. Currently, it can have a positive effect on hypoxia and ischemic diseases. Related studies have suggested that hyperbaric oxygen can significantly reduce ischemia-hypoxic injury to the brain, spinal cord, kidney, and myocardium. This article reviews the pathogenesis of IR and the current treatment measures, and further points out that hyperbaric oxygen has a better effect in IR. We found that not only improved hypoxia but also regulated IR induced injury in a certain way. From the perspective of clinical application, these changes and the application of hyperbaric oxygen therapy have important implications for treatment, especially IIR.

Analysis of lipid metabolites derived from gut microbiota in ischemia-reperfusion model.

Disruption of intestinal barrier caused by intestinal ischemia due to hemorrhagic shock is associated with the pathogenesis of multiple organ dysfunction (MOD) after severe trauma. Mesenteric lymph (ML) plays an important role as a route for transporting inflammatory mediators, including lipids. Postbiotics, such as 10-hydroxy-cis-12-octadecenoic acid (HYA), have received much attention as a treatment option. However, the relationship between postbiotics and MOD has yet to be clarified. The aim of the present study was to analyze lipid metabolites derived from gut microbiota in the intestinal ischemia-reperfusion (IR) rat model. Male Sprague-Dawley rats underwent laparotomy, and their ML duct and superior mesenteric artery were exposed. The superior mesenteric artery was clamped for 60 minutes, followed by 120 minutes of reperfusion. The ML and the plasma were collected before and after intestinal IR. Lipids were extracted from plasma and ML, and liquid chromatography-tandem mass spectrometry was performed. The concentration of linoleic acid in plasma samples was not different before and after IR; however, the linoleic acid concentration in the ML samples increased after intestinal IR. Eicosapentaenoic acids and docosahexaenoic related to linoleic acids showed similar changes with IR-induced increase in the ML. The concentration of HYA, a linoleic acid-derived bioactive metabolite produced by gut bacteria, was high in ML samples, while that in plasma samples was low. The relative increase rate of HYA in ML samples after IR was higher than that of the plasma samples (the ML samples: relative increase, 3.23 ± 1.36; the plasma samples: relative increase, 0.95 ± 0.35; n = 3, p = 0.048). The present study demonstrated increased linoleic acids and high concentrations of HYA, lipid metabolites derived from gut bacteria in the ML after intestinal IR. These findings may contribute to clarifying the relation between gut microbiota and MOD after severe trauma.

Microfluidic intestinal organoid-on-a-chip uncovers therapeutic targets by recapitulating oxygen dynamics of intestinal IR injury.

Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury.