Characterizing Autophagy in the Cold Ischemic Injury of Small Bowel Grafts: Evidence from Rat Jejunum.
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SUBMITTER: Caleb I
PROVIDER: S-EPMC8234201 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPancreas transplant volumes are limited because of poor utilization of "extended criteria grafts." Prolonged cold ischemia is a risk factor associated with poor allograft survival. We aimed to establish the feasibility of transplantation using grafts subjected to prolonged cold ischemia and determine whether these grafts could be optimized using normothermic ex vivo perfusion (NEVP) in a porcine model.MethodsThe study population consisted of 35 to 40 kg male Yorkshire pigs in an allotransplantation model with a 3-d survival plan for recipients. Control grafts were subjected to cold storage (CS) in a University of Wisconsin solution for 21 to 24 h (n = 6), whereas the test group received an additional 3 h NEVP after CS of 21 h (n = 5).ResultsThe 3-d survival was 60% in the NEVP arm versus 0% in the control arm (P = 0.008; log rank). Graft parenchyma was 60% to 70% preserved in the NEVP arm at necropsy on gross appearance. In addition, the islet function was well preserved, and both the pancreas (including the islets) and the duodenal morphology were maintained histologically. The intravenous glucose tolerance test on the day of euthanasia was in the normoglycemic range for 80% of cases in the NEVP arm.ConclusionsOptimization of pancreas grafts exposed to extended CS with NEVP seems promising at rescuing and reanimating these grafts for transplantation, resulting in significantly improved survival in a porcine pancreas transplant model.
| S-EPMC11013695 | biostudies-literature
Project description:The global shortage of donor organs has made it crucial to deeply understand and better predict donor liver viability. However, biomarkers that effectively assess viability of marginal grafts for organ transplantation are currently lacking. Here, we showed that hepatocytes, sinusoidal endothelial, stellate, and liver-specific immune cells were released into perfusates from Lewis rat livers as a result of cold ischemia and machine perfusion. Perfusate comparison analysis of fresh livers and cold ischemic livers showed that the released cell profiles were significantly altered by the duration of cold ischemia. Our findings show for the first time that parenchymal cells are released from organs under non-proliferative pathological conditions, correlating with the degree of ischemic injury. Thus, perfusate cell profiles could serve as potential biomarkers of graft viability and indicators of specific injury mechanisms during organ handling and transplantation. Further, parenchymal cell release may have applications in other pathological conditions beyond organ transplantation.
| S-EPMC6981218 | biostudies-literature
Project description:BackgroundIschemic spinal cord injury (SCI) belongs to the heterogeneous group of non-traumatic SCI, while the course of sensorimotor and functional recovery is comparable to traumatic SCI. Recently, we derived from data of patients with traumatic SCI a valid model to predict an independent and reliable bowel management one year after SCI.AimTo evaluate the performance of this model to predict an independent and reliable bowel management one year following ischemic SCI.DesignPrognostic study - observational study.SettingEuropean Multicenter Study about Spinal Cord Injury (EMSCI) ClinicalTrials.gov: NCT01571531.PopulationOne hundred and forty-two patients with ischemic SCI of various level and severity of injury.MethodsThe prediction model relied on a single predictor collected within 40 days from injury, the International Standards for Neurological Classification of Spinal Cord Injury total motor score. Bowel outcome one year after SCI derived from the dichotomization of the Spinal Cord Independence Measure (SCIM) item 7 scores. We defined a positive outcome as independent bowel management with regular movements and appropriate timing with no or rare accidents (score of 10 in SCIM version II and score of 8 or 10 in version III).ResultsThe model showed a fair discrimination with an area under the receiver operating characteristic (ROC) curve of 0.780 (95% confidence interval=0.702-0.860). In addition, the model displayed an acceptable accuracy and calibration.ConclusionsThe study extends the validity of our rule to patients with ischemic SCI, thus providing the first model to predict an independent and reliable bowel management in this population.Clinical rehabilitation impactThe model may be employed in clinical practice to counsel patients, to define the rehabilitation aims and to estimate the need of assistance after discharge, as well as in the research field for the optimization of patients' allocation in the design of future clinical trials.
| S-EPMC10019474 | biostudies-literature
Project description:Objective: the objective of this work was to determine different gene expression patterns in small bowel grafts biopsies with “minimal changes” histology that could identify patients with high rejection risk Methods: 24 samples (17 stable and 7 non stable grafts) from 8 adult patients with small bowel transplantation were included for RNA-Sequencing.Total RNA extracted from intestinal biopsies was used with the TruSeq RNA Sample Preparation v2 Kit to construct index-tagged cDNA libraries. Libraries were sequenced on the Genome Analyzer IIx following the standard RNA sequencing protocol with the TruSeq SBS Kit v5. Fastq files containing reads for each library were extracted and demultiplexed using Casava v1.8.2 pipeline. Sequencing adapter contaminations were removed from reads using Cutadapt software v1.6 and the resulting reads were aligned to the reference human genome (Ensembl gene-build GRCh37.75) using TopHat2 v2.0.13. Gene expression values were calculated as counts using HTSeq v0.6.1. Only genes with at least 1 count per million in all samples were considered for statistical analysis. Data were then normalized and differential expression tested using the R Bioconductor package edgeR. We selected all biopsies from 4 of the patients (18 biopsies, 11 stable and 7 non stable) as the discovery set. The other 6 biopsies from 4 patients (all stable) were used as the test set. Differences in the discovery set were tested by generalized linear model analysis,and results were considered significant when the Benjamini-Hochberg adjusted p-value was < 0,05. Results: We obtained 816 differentially expressed genes (DEGs) between stable and non stable biopsies in the discovery set: 369 upregulated and 447 downregulated in the non stable group. The classification and prediction with the Nearest Shrunken Centroids method identified 5 genes (ADH1C, CYP4F2, PDZK1, SLC39A4 and OPTN) from the 816 DEGs that could classify both groups with an error rate of 11% and classified correctly all samples from the test set. These results were confirmed by Supoprted Vector Machine (SVM), bagSVM and Random Forest methods, showing high accuracy, sensitivity and specificity. Conclusions: We identified 5 genes from the DEGs as possible biomarkers to classify patients with normal histology that could be however in a higher risk of rejection. In this way, gene expression assays are powerful tools with high sensitivity that allow more accurate diagnosis.
2017-11-02 | GSE74118 | GEO
Project description:BACKGROUND AND PURPOSE:Inflammatory cells play a significant role in secondary injury after ischemic stroke. Recent studies have suggested that a lack of autophagy in myeloid cells causes augmented proinflammatory cytokine release and prolonged inflammation after tissue injury. In this study, we investigated the roles of myeloid cell autophagy in ischemic brain injury. METHODS:Focal cerebral ischemia was induced via transient middle cerebral artery occlusion in mice with autophagy-deficient myeloid lineage cells (Atg5flox/flox LysMCre+) and in their littermate controls (Atg5flox/flox). Infarct volume, neurological function, inflammatory cell infiltration, and proinflammatory cytokine expression levels were evaluated. RESULTS:Mice lacking autophagy in myeloid lineage cells had a lower survival rate for 14 days than control mice (20% versus 70%; P<0.05). Although there was no difference in infarct volume at 12 hours between the 2 groups, mice lacking autophagy in myeloid lineage cells had larger infarct volumes at later time points (3 and 7 days after reperfusion) with worse neurological deficit scores and lower grip test scores. There were a higher number of ionized calcium binding adaptor molecule 1-positive cells and cells expressing M1 marker CD16/32 in mice lacking autophagy in myeloid cells at the later time points. Moreover, these mice had higher expression levels of proinflammatory cytokines at later time points; however, there was no difference in ionized calcium binding adaptor molecule 1-positive cells or mRNA levels of proinflammatory cytokines at the earlier time point (12 hours after reperfusion). CONCLUSIONS:These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.
| S-EPMC5970995 | biostudies-literature
Project description:ObjectiveTo examine the effect of autophagy on cerebral damage caused by different models and test the hypothesis that its protection mechanism acts via inhibiting expression of neuroinflammatory mediators.MethodsAutophagy was induced by rapamycin treatment. Cerebral damage was induced using models of IL-6 treatment, oxygen glucose deprivation/reoxygenation (OGD/R) in vitro, and middle cerebral artery occlusion (MCAO) in vivo. The effect and mechanism of autophagy was examined and assessed in terms of cell viability, infarction size in brain tissue, neurological score, production of inflammatory mediators IL-1β and IL-6, transcription and protein expression of autophagy markers beclin-1 and LC-3II in different experimental groups.ResultsAutophagy triggered by rapamycin could protect neurons from IL-6-induced injury and astrocytes from OGD/R-induced injury in vitro and in rat brain tissue from MCAO in vivo. Autophagy significantly increased cell viability, attenuated cerebral infarction and improved neurological scores. It also inhibited production of the IL-1β and IL-6 and elevated the expression of beclin-1 and LC-3II.ConclusionsAutophagy can inhibit the inflammatory response and reduce cerebral I/R injury. There was a relationship between the extent of protection and (i) the level of the autophagic response, (ii) the stage of the cerebral I/R injury, and (iii) the time of intervention.
| S-EPMC8205746 | biostudies-literature
Project description:Transplantation is lifesaving and the most effective treatment for end-stage organ failure. The transplantation success depends on the functional preservation of organs prior to transplantation. Currently, the University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) are the most commonly used preservation solutions. Despite intensive efforts, the functional preservation of solid organs prior to transplantation is limited to hours. In this study, we modified the UW solution containing components from both the UW and HTK solutions and analyzed their tissue-protective effect against ischemic injury. The composition of the UW solution was changed by reducing hydroxyethyl starch concentration and adding Histidine/Histidine-HCl which is the main component of HTK solution. Additionally, the preservation solutions were supplemented with melatonin and glucosamine. The protective effects of the preservation solutions were assessed by biochemical and microscopical analysis at 2, 10, 24, and 72 h after preserving the rat kidneys with static cold storage. Lactate dehydrogenase (LDH) activity in preservation solutions was measured at 2, 10, 24, and 72. It was not detectable at 2 h of preservation in all groups and 10 h of preservation in modified UW+melatonin (mUW-m) and modified UW+glucosamine (mUW-g) groups. At the 72nd hour, the lowest LDH activity (0.91 IU/g (0.63-1.17)) was measured in the mUW-m group. In comparison to the UW group, histopathological damage score was low in modified UW (mUW), mUW-m, and mUW-g groups at 10, 24, and 72 hours. The mUW-m solution at low temperature was an effective and suitable solution to protect renal tissue for up to 72 h.
| S-EPMC9432748 | biostudies-literature
Project description:PurposeThe aim of this study was to determine whether spinal cord injuries (SCI) is associated with increased risk of ischemic bowel syndrome (IBS) in an Asian population by analyzing data from the National Health Insurance Research Database (NHIRD) in Taiwan.MethodsPatients aged ?20 years in the inpatient database with newly identified SCI from 2000 to 2011 were selected as the SCI cohort. For the non-SCI cohort, patients were selected based on a 1:4 risk-set sampling. Hospitalization with a new diagnosis of IBS during the follow-up was the main outcome measure. We used the standard univariable and multivariable Cox proportional hazard regression models to determine adjusted subhazard ratios (SHR) and 95% confidence interval (CI) in the SCI and non-SCI cohorts.ResultsPatients with SCI were at significant risk for IBS, with an adjusted SHR (aSHR) of 1.25, 95% CI = 1.04-1.51. Multivariable analysis showed individuals with SCI were associated with a greater risk of IBS than individuals without SCI among males (aSHR = 1.47, 95% CI = 1.16-1.86), all age groups (?49 y: aSHR = 2.15, 95% CI = 1.24-3.74; 50-65 y: aSHR = 1.82, 95% CI = 1.15-2.88; >65 y: aSHR = 1.39, 95% CI = 1.11-1.74) and those without comorbidities (aSHR = 1.41, 95% CI = 1.04-1.93). Comorbidities including diabetes, hypertension, heart failure, coronary artery disease (CAD), Stroke, and end stage renal disease (ESRD) significantly increased the risk of IBS.ConclusionPatients hospitalized for SCI have increased risks of developing IBS. Though the mechanism that predisposes SCI patients to IBS is unclear, we suggest that physicians promptly identify and treat correctable risk factors.
| S-EPMC5215787 | biostudies-literature
Project description:12-week-old rats, iron-replete or iron-deficient. Three groups of each condition. 230A and 230B chips used with cRNA derived from jejunal scrapes. Keywords: ordered
2005-07-11 | GSE2269 | GEO
Project description:BackgroundLiver transplantation (LT) is considered the standard treatment for end-stage liver disease, but ideal donors remain in limited supply, resulting in an unavoidable increase in the need to use grafts from marginal donors. The attenuation of ischemia-reperfusion injury (IRI) in such marginal donors is therefore crucial for reducing the possibility of the primary non-function of grafts and graft loss. Some reports have found that molecular-hydrogen showed antioxidant and anti-inflammatory effects in preventing IRI in some non-hepatic transplant models. Therefore, we investigated whether or not molecular-hydrogen could attenuate IRI in LT model rats.MethodsWe used a hydrogen-rich water bath to dissolve hydrogen into solution and graft tissues and performed isogenic and orthotopic LT in Lewis rats with University of Wisconsin (UW) solution. Blood and tissue samples were collected 6 h after the reperfusion. Hepatic enzymes in serum were measured. Pathological findings including the expressions of cytokines and heme oxygenase (HO)-1 in liver tissues were evaluated.ResultsThe concentration of hydrogen inside the graft tissues increased depending on the storage time, plateauing after 1 h. Serum liver enzyme levels were significantly lower and the histology score of liver damage markedly attenuated in the group given grafts preserved in hydrogen-rich UW solution than in the control group. The hydrogen-rich UW solution group also showed less oxidative damage and hepatocyte apoptosis than the control group, and the expression of proinflammatory cytokines tended to be lower while the protein levels of HO-1 were significantly increased (n = 3-12 per group, P < 0.05).ConclusionsStorage of liver grafts in hydrogen-rich UW solution resulted in superior functional and morphologic protection against IRI via the up-regulation of HO-1 expression.
| S-EPMC6368804 | biostudies-literature