Establishment and characterization of a mouse model for studying kidney repair in diabetes.

The prognosis of acute kidney injury (AKI) is markedly worse in patients with diabetes. Diabetes not only exaggerates the severity of AKI but also prevent kidney repair or recovery from AKI. Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Specifically, diabetes increases AKI severity, making it difficult to induce the same level of AKI in diabetic and nondiabetic animals to compare their kidney repair. Here, we have identified a time window of 4 days immediately after the completion of streptozotocin (STZ) treatment in mice when blood glucose has yet to rise. Within this time window, renal ischemia-reperfusion injury (IRI) induced the same level of AKI in STZ-treated mice [127.2 ± 12.82 mg/dL blood urea nitrogen (BUN), 2.275 ± 0.4728 serum creatinine] and vehicle solution-treated mice (128.6 ± 11.83 mg/dL BUN, 2.087 ± 0.4748 mg/dL serum creatinine]. By days 5-6, the post-AKI kidney entered into the phase of kidney repair when diabetic hyperglycemia started in STZ-treated mice, providing the opportunity to study the effect of diabetes on kidney repair without affecting initial AKI. In this model, kidney repair was indeed impaired by diabetes (116.5 ± 8.052 mg/dL BUN and 1.382 ± 0.2732 mg/dL serum creatinine in IR + vehicle group; 136.6 ± 8.740 mg/dL BUN and 1.916 ± 0.3756 mg/dL serum creatinine in IR + STZ group). The impairment was associated with decreased tubular cell proliferation and increased tubular cell senescence, peritubular capillary (PTC) rarefaction, inflammation, and 40.90% more interstitial fibrosis.NEW & NOTEWORTHY Little is known about the cellular and molecular basis of defective kidney repair in diabetes. One obstacle in studying kidney repair in diabetes is the lack of suitable animal models. Here, we report a mouse model to investigate the effect of diabetes on kidney repair without affecting initial injury and found that the repair defect is associated with decreased renal tubular cell proliferation and increased tubular cell senescence, PTC rarefaction, inflammation, and interstitial fibrosis.

Dynamic changes in the real-time glomerular filtration rate and kidney injury markers in different acute kidney injury models.

In this study, we dynamically monitored the glomerular filtration rate and other assessment of renal function and markers of injury in various mice models of acute kidney injury. Male C57BL/6 mice were utilized to establish acute kidney injury models of sepsis, ischemia reperfusion, cisplatin, folic acid, aristolochic acid and antibiotic. In addition to the real time glomerular filtration rate, renal LCN-2 and HAVCR-1 mRNA expression levels, and serum creatinine, urea nitrogen and cystatin c levels were also used to evaluate renal function. In addition, the protein levels of LCN-2 and HAVCR-1 in renal, serum and urine were measured. Our results demonstrated that the changes in biomarkers always lagged the real time glomerular filtration rate during the progression and recovery of renal injury. Cystatin-c can reflect renal injury earlier than other markers, but it remains higher in the recovery stage. Perhaps the glomerular filtration rate does not reflect the greater injury caused by vancomycin plus piperacillin.

Targeting ferroptosis by natural products in pathophysiological conditions.

Ferroptosis is a form of cell death that is induced by iron-mediated accumulation of lipid peroxidation. The involvement of ferroptosis in different pathophysiological conditions has offered new perspectives on potential therapeutic interventions. Natural products, which are widely recognized for their significance in drug discovery and repurposing, have shown great promise in regulating ferroptosis by targeting various ferroptosis players. In this review, we discuss the regulatory mechanisms of ferroptosis and its implications in different pathological conditions. We dissect the interactions between natural products and ferroptosis in cancer, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury, liver injury, and cardiomyopathy, with an emphasis on the relevance of ferroptosis players to disease targetability.

The use of ultrasound for noninvasive monitoring of anesthetic effects in renal ischemia-reperfusion injury.

OBJECTIVE: Compared with the use of ultrasound for noninvasive monitoring of the anesthetic sodium pentobarbital versus tribromoethanol in an animal model of renal ischemia-reperfusion injury in rats. METHODS: Adult rats were randomly assigned to a renal ischemia-reperfusion injury model, and preoperative anesthetics were administered as either sodium pentobarbital or tribromoethanol. Color Doppler ultrasound and spectral Doppler ultrasound were used to detect changes in respiratory rate and heart rate during and after the surgery, as well as measure renal hemodynamic parameters including peak systolic velocity, end-diastolic velocity, and resistance index. RESULTS: The frequency of changes in respiration and heart rate was significantly higher in the sodium pentobarbital anesthesia group compared to the tribromoethanol anesthesia group. The peak systolic velocity and end-diastolic velocity values in the sodium pentobarbital anesthesia group were significantly lower than those in the tribromoethanol group. However, the resistance index in the sodium pentobarbital group was higher than that in the tribromoethanol group. CONCLUSION: Ultrasound can be used to dynamically monitor the effects of anesthesia during the experiment, including changes in respiratory rate and heart rate, as well as semi-quantitatively monitor hemodynamic changes in the kidneys, which indirectly reflects whole-body hemodynamic changes in rats.

Novel Models for Assessing and Pathophysiology of Hepatic Ischemia-Reperfusion Injury Mechanisms.

Hepatic ischemia-reperfusion injury (IRI) is a major cause of postoperative hepatic dysfunction and liver failure involving cellular damage to previously ischemic tissues to which blood flow is restored. The reestablishment of blood flow is essential for salvaging ischemic tissues. The reperfusion itself, however, can paradoxically lead to further cellular damage, which involves a multi-factorial process resulting in extensive tissue damage, which can threaten the function and viability of the liver and other organ systems. The following review outlines multiple models for in-lab analysis of the various hepatic IRI mechanisms, including murine, porcine, cell lines, and machine perfusion models.

[Analysis of nerve excitability in the dentate gyrus of the hippocampus in cerebral ischaemia-reperfusion mice].

Ischemic stroke often leads to cognitive dysfunction, which delays the recovery process of patients. However, its pathogenesis is not yet clear. In this study, the cerebral ischemia-reperfusion model was built as the experimental object, and the hippocampal dentate gyrus (DG) was the target brain area. TTC staining was used to evaluate the degree of cerebral infarction, and nerve cell membrane potentials and local field potentials (LFPs) signals were collected to explore the mechanism of cognitive impairment in ischemia-reperfusion mice. The results showed that the infarcted area on the right side of the brain of the mice in the model group was white. The resting membrane potential, the number of action potential discharges, the post-hyperpolarization potential and the maximum ascending slope of the hippocampal DG nerve cells in the model mice were significantly lower than those in the control group ( P < 0.01); the peak time, half-wave width, threshold and maximum descending slope of the action potential were significantly higher than those in the control group ( P < 0.01). The time-frequency energy values of LFPs signals in the θ and γ bands of mice in the ischemia and reperfusion groups were significantly reduced ( P < 0.01), and the time-frequency energy values in the reperfusion group were increased compared with the ischemia group ( P < 0.01). The signal complexity of LFPs in the ischemia and reperfusion group was significantly reduced ( P < 0.05), and the signal complexity in the reperfusion group was increased compared with the ischemia group ( P < 0.05). In summary, cerebral ischemia-reperfusion reduced the excitability of nerve cells in the DG area of the mouse hippocampus; cerebral ischemia reduced the discharge activity and signal complexity of nerve cells, and the electrophysiological indicators recovered after reperfusion, but it failed to reach the healthy state during the experiment period.

Spatially Resolved Transcriptomic Analysis of Acute Kidney Injury in a Female Murine Model.

BACKGROUND: Single-cell sequencing technologies have advanced our understanding of kidney biology and disease, but the loss of spatial information in these datasets hinders our interpretation of intercellular communication networks and regional gene expression patterns. New spatial transcriptomic sequencing platforms make it possible to measure the topography of gene expression at genome depth. METHODS: We optimized and validated a female bilateral ischemia-reperfusion injury model. Using the 10× Genomics Visium Spatial Gene Expression solution, we generated spatial maps of gene expression across the injury and repair time course, and applied two open-source computational tools, Giotto and SPOTlight, to increase resolution and measure cell-cell interaction dynamics. RESULTS: An ischemia time of 34 minutes in a female murine model resulted in comparable injury to 22 minutes for males. We report a total of 16,856 unique genes mapped across our injury and repair time course. Giotto, a computational toolbox for spatial data analysis, enabled increased resolution mapping of genes and cell types. Using a seeded nonnegative matrix regression (SPOTlight) to deconvolute the dynamic landscape of cell-cell interactions, we found that injured proximal tubule cells were characterized by increasing macrophage and lymphocyte interactions even 6 weeks after injury, potentially reflecting the AKI to CKD transition. CONCLUSIONS: In this transcriptomic atlas, we defined region-specific and injury-induced loss of differentiation markers and their re-expression during repair, as well as region-specific injury and repair transcriptional responses. Lastly, we created an interactive data visualization application for the scientific community to explore these results (http://humphreyslab.com/SingleCell/).

TBC1Domain Family Member 25 deficiency aggravates cerebral ischemia-reperfusion injury via TAK1-JNK/p38 pathway.

TBC1Domain Family Member 25 (TBC1D25) is a protein that contains a TBC/RAB-GTPase activating protein (GAP) domain, which was shown to participate in autophagy in previous studies. However, the role of TBC1D25 in cerebral ischemia-reperfusion (I/R) injury remains unknown. In this study, we found that the mRNA and protein expression levels of TBC1D25 decreased in mouse brain after I/R injury and primary cortical neurons treated with oxygen and glucose deprivation/reoxygenation (OGD/R). Then TBC1D25 knockout (KO) mice were applied to demonstrate that TBC1D25 ablation aggravated cerebral I/R-induced neuronal loss and infarct size. In addition, neuronal apoptosis and inflammation were significantly potentiated in the TBC1D25-KO group. In in vitro OGD/R model, TBC1D25 knockdown can attenuate neuronal cell viability and aggravate the process of inflammation and apoptosis. Conversely, over-expression of TBC1D25 in primary neurons ameliorated the aforementioned processes. Mechanistically, RNA-sequencing (RNA-seq) analysis revealed mitogen-activated protein kinase (MAPK) signaling pathway was the most significant pathway that contributed to TBC1D25-mediated brain I/R injury process. Through experimental verification, TBC1D25 deficiency increased the phosphorylation of the transforming growth factor-ß-activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK)/p38 axis in neurons during the brain I/R injury. Furthermore, we found that TAK1 blockade abrogated the apoptosis and inflammatory response produced by TBC1D25 knockdown in vitro. In conclusion, this study is the first to demonstrate the functional significance of TBC1D25 in the pathophysiology of brain I/R injury, and the protective mechanism of TBC1D25 is dependent on the TAK1-JNK/p38 pathway.

Necroptosis: the release of damage-associated molecular patterns and its physiological relevance.

Regulated necrosis, termed necroptosis, is negatively regulated by caspase-8 and is dependent on the kinase activity of RIPK1 and RIPK3. Necroptosis leads to rapid plasma membrane permeabilization and to the release of cell contents and exposure of damage-associated molecular patterns (DAMPs). We are only beginning to identify the necroptotic DAMPs, their modifications, and their potential role in the regulation of inflammation. In this review, we discuss the physiological relevance of necroptosis and its role in the modulation of inflammation. For example, during viral infection, RIPK3-mediated necroptosis acts as a backup mechanism to clear pathogens. Necroptosis is also involved in apparently immunologically silent maintenance of T cell homeostasis. In contrast, the induction of necroptosis in skin, intestine, systemic inflammatory response syndrome, and ischemia reperfusion injury provoke a strong inflammatory response, which might be triggered by emission of DAMPs from necroptotic cells, showing the detrimental side of necroptosis.

Preoperative fasting confers protection against intestinal ischaemia/reperfusion injury by modulating gut microbiota and their metabolites in a mouse model.

BACKGROUND: Intestinal ischaemia/reperfusion (I/R) injury is a grave surgical event with high morbidity and mortality. Preoperative fasting might confer protection against intestinal I/R injury by altering the composition of gut microbiota and their respective metabolites. METHODS: An intestinal I/R mouse model was established and subjected to preoperative fasting for 24 h or fed ad libitum. Intestinal I/R injury was assessed using histological examination and survival analysis. Faecal samples were collected for 16S rDNA sequencing and metabolomic analysis. Faecal transplantation of fasted and non-fasted mice and humans was conducted to evaluate the effects of gut microbiota on intestinal I/R. Murine small intestinal cells wecre subjected to oxygen and glucose deprivation/reoxygenation as an in vitro I/R model. RESULTS: Preoperative fasting protected against intestinal I/R injury and improved survival in mice (P<0.001). In addition, 16S rDNA sequencing revealed that preoperative fasting increased the diversity and restructured the composition of the gut microbiota after intestinal I/R. Mice that received microbiota from fasted mice and humans showed less intestinal damage than those that received microbiota from fed subjects. Metabolomic analysis showed that the profiles of gut microbial metabolites differed between fasted and fed groups. Specifically, the concentration of petroselinic acid was significantly higher in the fasted group (P=0.009). Treatment of intestinal I/R mice with petroselinic acid alleviated intestinal injury in vivo and decreased cell apoptosis by mediating AMP-activated protein kinase-mammalian target of rapamycin-P70S6K signaling in vitro. CONCLUSIONS: Preoperative fasting protected against intestinal I/R injury by modulating gut microbiota and petroselinic acid, suggesting a novel therapeutic strategy.

7,8-Dihydroxyflavone alleviates apoptosis and inflammation induced by retinal ischemia-reperfusion injury via activating TrkB/Akt/NF-kB signaling pathway.

Retinal ischemia-reperfusion injury (RIRI) is of common occurrence in retinal and optic nerve diseases. The BDNF/TrkB signaling pathway has been examined to be neuroprotective in RIRI. In this study, we investigated the role of a potent selective TrkB agonist 7,8-dihydroxyfavone (DHF) in rat retinas with RIRI. Our results showed that RIRI inhibited the conversion of BDNF precursor (proBDNF) to mature BDNF (mBDNF) and increased the level of neuronal cell apoptosis. Compared with RIRI, DHF+RIRI reduced proBDNF level and at the same time increased mBDNF level. Moreover, DHF administration effectively activated TrkB signaling and and downstream Akt and Erk signaling pathways which increased nerve cell survival. The combined effects of mBDNF/proBDNF increase and TrkB signaling activation lead to reduction of apoptosis level and protection of retinas with RIRI. Moreover, it was also found that astrocytes labeled by GFAP were activated in RIRI and NF-kB mediated the increased expressions of inflammatory factors and these effects were partially reversed by DHF administration. Besides, we also used RNA sequencing to analyze the differently expressed genes (DEGs) and their enriched (Kyoto Encyclopedia of Genes and Genomes) KEGG pathways between Sham, RIRI, and DHF+RIRI. It was found that 1543 DEGs were differently expressed in RIRI and 619 DEGs were reversed in DHF+RIRI. The reversed DEGs were typically enriched in PI3K-Akt signaling pathway, Jak-STAT signaling pathway, NF-kB signaling pathway, and Apoptosis. To sum up, the DHF administration alleviated apoptosis and inflammation induced by RIRI via activating TrkB signaling pathway and may serve as a promising drug candidate for RIRI related ophthalmopathy.

Obesity-related IL-18 Impairs T-Regulatory Cell Function and Promotes Lung Ischemia-Reperfusion Injury.

Rationale: Primary graft dysfunction (PGD) is a severe form of acute lung injury, leading to increased early morbidity and mortality after lung transplant. Obesity is a major health problem, and recipient obesity is one of the most significant risk factors for developing PGD. Objectives: We hypothesized that T-regulatory cells (Tregs) are able to dampen early ischemia-reperfusion events and thereby decrease the risk of PGD, whereas that action is impaired in obese recipients. Methods: We evaluated Tregs, T cells, and inflammatory markers, plus clinical data, in 79 lung transplant recipients and 41 liver or kidney transplant recipients and studied two groups of mice on a high-fat diet (HFD), which did ("inflammatory" HFD) or did not ("healthy" HFD) develop low-grade inflammation with decreased Treg function. Measurements and Main Results: We identified increased levels of IL-18 as a previously unrecognized mechanism that impairs Tregs' suppressive function in obese individuals. IL-18 decreases levels of FOXP3, the key Treg transcription factor, decreases FOXP3 di- and oligomerization, and increases the ubiquitination and proteasomal degradation of FOXP3. IL-18-treated Tregs or Tregs from obese mice fail to control PGD, whereas IL-18 inhibition ameliorates lung inflammation. The IL-18-driven impairment in Tregs' suppressive function before transplant was associated with an increased risk and severity of PGD in clinical lung transplant recipients. Conclusions: Obesity-related IL-18 induces Treg dysfunction that may contribute to the pathogenesis of PGD. Evaluation of Tregs' suppressive function together with evaluation of IL-18 levels may serve as a screening tool to identify obese individuals with an increased risk of PGD before transplant.

Combination of constraint-induced movement therapy with fasudil amplifies neurogenesis after focal cerebral ischemia/reperfusion in rats.

PURPOSE: Spontaneous axonal plasticity and functional restoration after stroke may be limited by Nogo-A, a myelin-associated inhibitor, via activation of the Rho/Rho-associated protein kinase (ROCK) pathway. Constraint-induced movement therapy (CIMT) is a rehabilitation technique based on neuroplasticity and neural recombination. We recently reported that CIMT promoted neurogenesis after cerebral ischemia/reperfusion in part by inhibiting the Nogo-A-RhoA-ROCK pathway. Here, we examine the hypothesis that CIMT combined with the ROCK inhibitor fasudil further amplifies neurogenesis during stroke recovery. METHODS: Four groups of rats were randomized as follows: Cerebral ischemia-reperfusion (IR), Fasudil, CIMT and CIMT + Fasudil. Seven days after stroke, CIMT and/or intraperitoneal infusion of fasudil were initiated and continued for 3 weeks. The behavioral outcomes and immunohistochemical markers of neurogenesis were quantified. RESULTS: Compared with other groups, the combination of CIMT with fasudil after IR significantly improved motor and memory function recovery. In addition, BrdU, BrdU/doublecortin and BrdU/GFAP all increased significantly in the brain tissue of the combined treatment group compared to the CIMT or Fasudil group. CONCLUSION: These results suggest that the effects of CIMT on neurogenesis are amplified by fasudil during the recovery phase after stroke.

Role of Mitochondrial Pathways in Cell Apoptosis during He-Patic Ischemia/Reperfusion Injury.

Hepatic ischemia-reperfusion injury is a major cause of post-operative hepatic dysfunction and liver failure after transplantation. Mitochondrial pathways can be either beneficial or detrimental to hepatic cell apoptosis during hepatic ischemia/reperfusion injury, depending on multiple factors. Hepatic ischemia/reperfusion injury may be induced by opened mitochondrial permeability transition pore, released apoptosis-related proteins, up-regulated B-cell lymphoma-2 gene family proteins, unbalanced mitochondrial dynamics, and endoplasmic reticulum stress, which are integral parts of mitochondrial pathways. In this review, we discuss the role of mitochondrial pathways in apoptosis that account for the most deleterious effect of hepatic ischemia/reperfusion injury.

Arbutin protects brain against middle cerebral artery occlusion-reperfusion (MCAo/R) injury.

Focal ischemia causes irreversible brain damage if cerebral blood flow is not restored promptly. Acute phase excitotoxicity and pro-oxidant and inflammatory events in the sub-chronic phase elicit coagulative necrosis, vascular injury, cerebral oedema, and neurobehavioral deficits. Earlier, in pre-clinical studies arbutin protected behavioral functions and improved therapeutic outcomes in different models of brain and metabolic disorders. Arbutin is natural hydroquinone that might protect against ischemia-reperfusion (I/R) injury. In this study, cerebro-protective effects of arbutin were evaluated in the middle cerebral artery occlusion-reperfusion (MCAo/R) mouse model. Mice were administered arbutin (50, 100 mg/kg, i.p.) for 21 days, and subjected to MCAo/R or sham surgery on day 14. Results showed brain infarction, blood-brain barrier dysfunction, oedema, and neurological deficits 24 h post-MCAo/R injury that were prevented by arbutin. Behavioral evaluations over the sub-chronic phase revealed MCAo/R triggered spatial and working memory deficits. Arbutin protected the memory against MCAo/R injury and decreased hydroxy-2'-deoxyguanosine, protein carbonyls, inflammatory cytokines (tumor necrosis factor-α, myeloperoxidase, matrix metalloproteinase-9, inducible nitric oxide synthase), and enhanced glutathione levels in the ischemia ipsilateral hemisphere. Arbutin decreased brain acetylcholinesterase activity, glutamate, and enhanced GABA levels against MCAo/R. Arbutin can alleviate I/R pathogenesis and protects neurobehavioral functions in the MCAo/R mouse model.

Influence of ischemia-reperfusion injury on endothelial function in men and women with similar serum estradiol concentrations.

Prior data suggest that, relative to the early follicular phase, women in the late follicular phase are protected against endothelial ischemia-reperfusion (I/R) injury when estradiol concentrations are highest. In addition, endothelial I/R injury is consistently observed in men with naturally low endogenous estradiol concentrations that are similar to those of women in the early follicular phase. Therefore, the purpose of this study was to determine whether the vasodeleterious effect of I/R injury differs between women in the early follicular phase of the menstrual cycle and age-matched men. We tested the hypothesis that I/R injury would attenuate endothelium-dependent vasodilation to the same extent in women and age-matched men with similar circulating estradiol concentrations. Endothelium-dependent vasodilation was assessed via brachial artery flow-mediated dilation (duplex ultrasound) in young healthy men (n = 22) and women (n = 12) before (pre-I/R) and immediately after (post-I/R) I/R injury, which was induced via 20 min of arm circulatory arrest followed by 20-min reperfusion. Serum estradiol concentrations did not differ between sexes (men 115.0 ± 33.9 pg·mL-1 vs. women 90.5 ± 40.8 pg·mL-1; P = 0.2). The magnitude by which I/R injury attenuated endothelium-dependent vasodilation did not differ between men (pre-I/R 5.4 ± 2.4% vs. post-I/R 3.0 ± 2.7%) and women (pre-I/R 6.1 ± 2.8% vs. post-I/R 3.7 ± 2.7%; P = 0.9). Our data demonstrate that I/R injury similarly reduces endothelial function in women in the early follicular phase of the menstrual cycle and age-matched men with similar estradiol concentrations.

(Pro)renin receptor in the kidney: function and significance.

(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.

Effect of ischemia-reperfusion on outcomes after open mesenteric bypass for chronic mesenteric ischemia.

OBJECTIVE: Significant physiologic perturbations can occur in patients with chronic mesenteric ischemia (CMI) undergoing open mesenteric bypass (OMB). These events have frequently been attributed to ischemia-reperfusion events and have been directly implicated in the occurrence of multiple organ dysfunction (MOD). Scoring systems (MOD score [MODS] and sequential organ failure assessment [SOFA]) have been derived within the critical care field to provide a composite metric for these pathophysiologic changes. The purpose of the present study was to describe the early pathophysiologic changes that occur after OMB for CMI and determine whether these are predictive of the outcomes. METHODS: Patients with CMI who had undergone elective OMB from 2002 to 2018 at a single institution were reviewed. Changes in the hemodynamic, pulmonary, hepatic, renal, and hematologic parameters in the first 96 hours postoperatively were analyzed. The MODSs and SOFA scores were calculated. Cox regression was used to determine the association of the MODSs and SOFA scores with the outcomes. RESULTS: The use of OMB was analyzed for 72 patients (age, 66 ± 11 years; 68% women; body mass index, 23.8 ± 6 kg/m2; 48 ± 34-lb weight loss in 59%). Previous mesenteric stent placement or bypass had been performed in 39% [stenting in 21; bypass in 8; (one patient had both)]. An antegrade configuration (93%) was most common (retrograde configuration, 7%), with revascularization of the superior mesenteric artery/celiac vessels in 85% (superior mesenteric artery only in 15%). Postoperative pathophysiologic and metabolic changes were common, and the mean MODSs and SOFA scores were 3.6 ± 2.4 (range, 1-10) and 4.0 ± 2.7 (range, 1-13), respectively. The median length of stay was 14 days (interquartile range, 9-21). The 30-day mortality was 4% (n = 3) and in-hospital morbidity was 53% (n = 38; gastrointestinal, 25%; infectious, 22%; cardiac, 18%; pulmonary, 18%; renal, 11%). The clinical follow-up period was 16 ± 20 months. The MODSs and SOFA scores correlated linearly with overall mortality (MODS: odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.7; P < .01; SOFA score: OR, 1.4; 95% CI, 1.2-1.7; P < .01 per unit), with a score of ≥5 the inflection point most predictive of mortality (MODS: OR, 3.9; 95% CI, 1.6-9.9; P ≤ .01; SOFA score: OR, 2.8; 95% CI, 1.2-6.6; P = .02). The 1- and 3-year primary bypass patency and freedom from reintervention was 91% ± 5% and 83% ± 7%, respectively, with no association with the MODSs or SOFA scores. The 1- and 3-year survival was 86% ± 4% and 71% ± 6% with significantly worse outcomes for patients with higher MODSs and/or SOFA scores. CONCLUSIONS: Most CMI patients undergoing OMB will experience significant metabolic derangements resulting from sequelae of the ischemia-reperfusion phenomenon postoperatively. These can be objectively assessed in the early postoperative period using simply applied scoring systems to reliably predict the early and long-term outcomes. A derivation of the MODS and/or SOFA score after OMB for CMI can identify the most vulnerable patients at the greatest risk of mortality.

MicroRNA mediated regulation of the major redox homeostasis switch, Nrf2, and its impact on oxidative stress-induced ischemic/reperfusion injury.

Ischemia/reperfusion injury (IRI) initiates from oxidative stress caused by lack of blood supply and subsequent reperfusion. It is often associated with sterile inflammation, cell death and microvascular dysfunction, which ultimately results in myocardial, cerebral and hepatic IRIs. Reportedly, deregulation of Nrf2 pathway plays a significant role in the oxidative stress-induced IRIs. Further, microRNAs (miRNAs/miRs) are proved to regulate the expression and activation of Nrf2 by targeting either the 3'-UTR or the upstream regulators of Nrf2. Additionally, compounds (crocin, ZnSO4 and ginsenoside Rg1) that modulate the levels of the Nrf2-regulating miRNAs were found to exhibit a protective effect against IRIs of different organs. Therefore, the current review briefs the impact of ischemia reperfusion (I/R) pathogenesis in various organs, role of miRNAs in the regulation of Nrf2 and the I/R protective effect of compounds that alter their expression.

Assessment of retinal oxygen metabolism, visual function, thickness and degeneration markers after variable ischemia/reperfusion in rats.

After total retinal ischemia induced experimentally by ophthalmic vessel occlusion followed by reperfusion, studies have reported alterations in retinal oxygen metabolism (MO2), delivery (DO2), and extraction fraction (OEF), as well as visual dysfunction and cell loss. In the current study, under variable durations of ischemia/reperfusion, changes in these oxygen metrics, visual function, retinal thickness, and degeneration markers (gliosis and apoptosis) were assessed and related. Additionally, the prognostic value of MO2 for predicting visual function and retinal thickness outcomes was reported. Sixty-one rats were divided into 5 groups of ischemia duration (0 [sham], 60, 90, 120, or 180 min) and 2 reperfusion durations (1 h, 7 days). Phosphorescence lifetime and blood flow imaging, electroretinography, and optical coherence tomography were performed. MO2 reduction was related to visual dysfunction, retinal thinning, increased gliosis and apoptosis after 7-days reperfusion. Impairment in MO2 after 1-h reperfusion predicted visual function and retinal thickness outcomes after 7-days reperfusion. Since MO2 can be measured in humans, findings from analogous studies may find value in the clinical setting.