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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Relation between quantitative coronary CTA and myocardial ischemia by adenosine stress myocardial CT perfusion

Background: Coronary-computed tomography angiography (CTA) has limited accuracy to predict myocardial ischemia. Besides luminal area stenosis, other coronary plaque morphology and composition parameters may help to assess ischemia. With the integration of coronary CTA and adenosine stress CT myocardial perfusion (CTP), reliable information regarding coronary anatomy and function can be derived in one procedure. This analysis aimed to investigate the association between coronary stenosis severity, plaque composition and morphology and the presence of ischemia measured with adenosine stress myocardial CTP. Methods and Results: 84 patients (age, 62 ± 10 years; 48% men) who underwent sequential coronary CTA and adenosine stress myocardial CT perfusion were analyzed. Automated quantification was performed in all coronary lesions (quantitative CTA). Downstream myocardial ischemia was assessed by visual analysis of the rest and stress CTP images and defined as a summed difference score of ≥1. One or more coronary plaques were present in 146 coronary arteries of which 31 (21%) were ischemia-related. Of the lesions with a stenosis percentage <50%, 50%-70%, and >70%, respectively, 9% (6/67), 18% (9/51), and 57% (16/28) demonstrated downstream ischemia. Furthermore, mean plaque burden, plaque volume, lesion length, maximal plaque thickness, and dense calcium volume were significantly higher in ischemia-related lesions, but only stenosis severity (%) (OR 1.06; 95% CI 1.02-1.10; P = .006) and lesion length (mm) (OR 1.26; 95% CI 1.02-1.55; P = .029) were independent correlates. Conclusions: Increasing stenosis percentage by quantitative CTA is positively correlated to myocardial ischemia measured with adenosine stress myocardial CTP. However, stenosis percentage remains a moderate determinant. Lumen area stenosis and lesion length were independently associated with ischemia, adjusted for coronary plaque volume, mean plaque burden, maximal lesion thickness, and dense calcium volume.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Cardioprotection by modulation of mitochondrial respiration during ischemia–reperfusion: Role of apoptosis-inducing factor

Highlights: •Blockade of electron transport prevents the loss of AIF from mitochondria during IR. •Blockade of electron transport decreases caspase-independent cell death during IR. •Mitochondrial AIF content is down-regulated in Harlequin mice. •Blockade of electron transport protects Harlequin mouse hearts during IR. •Amobarbital protection is partially dependent on mitochondrial AIF content. -- Abstract: The transient, reversible blockade of electron transport (BET) during ischemia or at the onset of reperfusion protects mitochondria and decreases cardiac injury. Apoptosis inducing factor (AIF) is located within the mitochondrial intermembrane space. A release of AIF from mitochondria into cytosol and nucleus triggers caspase-independent cell death. We asked if BET prevents the loss of AIF from mitochondria as a mechanism of protection in the buffer perfused heart. BET during ischemia with amobarbital, a rapidly reversible inhibitor of mitochondrial complex I, attenuated a release of AIF from mitochondria into cytosol, in turn decreasing the formation of cleaved and activated PARP-1. These results suggest that BET-mediated protection may occur through prevention of the loss of AIF from mitochondria during ischemia–reperfusion. In order to further clarify the role of mitochondrial AIF in BET-mediated protection, Harlequin (Hq) mice, a genetic model with mitochondrial AIF deficiency, were used to test whether BET could still decrease cell injury in Hq mouse hearts during reperfusion. BET during ischemia protected Hq mouse hearts against ischemia–reperfusion injury and improved mitochondrial function in these hearts during reperfusion. Thus, cardiac injury can still be decreased in the presence of down-regulated mitochondrial AIF content. Taken together, BET during ischemia protects both hearts with normal mitochondrial AIF content and hearts with mitochondrial AIF deficiency. Although preservation of mitochondrial AIF content plays a key role in reducing cell injury during reperfusion, the protection derived from the BET is not fully dependent on AIF-driven mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels

Advances in quantitative mass spectrometry (MS)-based proteomics have sparked efforts to characterize the proteomes of tumor samples to provide complementary and unique information inaccessible by genomics. Tumor samples are usually not accrued with proteomic characterization in mind, raising concerns regarding effects of undocumented sample ischemia on protein abundance and phosphosite stoichiometry. Here we report the effects of cold ischemia time on clinical ovarian cancer samples and patient-derived basal and luminal breast cancer xenografts. Tumor tissues were excised and collected prior to vascular ligation, subjected to accurately defined ischemia times up to 60 min, and analyzed by quantitative proteomics and phosphoproteomics using isobaric tags and high-performance, multidimensional LC-MS/MS. No significant changes were detected at the protein level in each tumor type after 60 minutes of ischemia, and the majority of the >25,000 phosphosites detected were also stable. However, large, reproducible increases and decreases in protein phosphorylation at specific sites were observed in up to 24% of the phosphoproteome starting as early as 5 minutes post-excision. Early and sustained activation of stress response, transcriptional regulation and cell death pathways were observed in common across tumor types. Tissue-specific changes in phosphosite stability were also observed suggesting idiosyncratic effects of ischemia in particular lineages. Our study provides insights into the information that may be obtained by proteomic characterization of tumor samples after undocumented periods of ischemia, and suggests caution especially in interpreting activation of stress pathways in such samples as they may reflect sample handling rather than tumor physiology.

Environmental Molecular Sciences Laboratory↗
DOE OSTI2019

Coronary vascular age: An alternate means for predicting stress-induced myocardial ischemia in patients with suspected coronary artery disease

Background: Coronary artery calcium (CAC) can be used to estimate vascular age in adults, providing a convenient transformation of CAC from Agatston units into a year’s scale. We investigated the role of coronary vascular age in predicting stress-induced myocardial ischemia in subjects with suspected coronary artery disease (CAD). Methods: A total of 717 subjects referred to CAC scoring and {sup 82}Rb PET/CT stress-rest myocardial perfusion imaging for suspected CAD were studied. CAC score was measured according to the Agatston method and coronary vascular age by equating estimated CAD risk for chronological age and CAC using the formula 39.1 + 7.25 × ln(CAC + 1). Results: Stress-induced ischemia was present in 105 (15%) patients. Mean chronological age, CAC score, and coronary vascular age were higher (all P < .001) in patients with ischemia compared to those without. At incremental analysis, the global Chi square increased from 41.26 to 68.77 (P < .001) when chronological age was added to clinical variables. Including vascular age in the model, the global Chi square further increased from 68.77 to 106.38 (P < .001). Adding chronological age to clinical data, continuous net reclassification improvement (cNRI) was 0.57, while adding vascular age to clinical data and chronological age cNRI was 0.62. At decision curve analysis, the model including vascular age was associated with the highest net benefit compared to the model including only clinical data, to the model including chronological age and clinical data, and to a strategy considering that all patients had ischemia. The model including vascular age also showed the largest reduction in false-positive rate without missing any ischemic patients. Conclusions: In subjects with suspected CAD, coronary vascular age is strongly associated with stress-induced ischemia. The communication of a given vascular age would have a superior emotive impact improving observance of therapies and healthier lifestyles.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca{sup 2+} permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MicroRNA-182-5p attenuates cerebral ischemia-reperfusion injury by targeting Toll-like receptor 4

Highlights: • We investigated whether miRNA-mediated neuroprotection acts via TLR4. • We found that TLR4 is a direct target of miR-182-5p. • miR-182-5p is a candidate for cerebral ischemia-reperfusion injury treatment. Cerebral ischemia-reperfusion-induced microglial activation causes neuronal death through the release of inflammatory cytokines. Increasing evidence suggests that microRNAs (miRNAs) exert a neuroprotective effect by modulating the inflammatory process in cerebral ischemia-reperfusion injury. Furthermore, Toll-like receptor 4 (TLR4) is increasingly being considered to have a significant role in the regulation of inflammation. However, whether miRNAs mediate their neuroprotective effects by regulating TLR4-mediated inflammatory responses remains unknown. To explore this gap in the literature, we conducted both in vitro and in vivo experiments. In vitro: BV2 cells were activated by oxygen-glucose deprivation (OGD). TLR4 and inflammatory cytokine (TNF-a, IL-6, and IL-1β) transcription and translation expression levels were assessed using RT-PCR, ELISA, and western blot. BV2 cells were transfected with miR-182-5p mimics, inhibitors, siTLR4, or negative control (NC) using lipofectamine 2000 reagent. To confirm whether TLR4 is a direct target of miR-182-5p, we performed a luciferase reporter assay. In BV2 cells, we observed that OGD upregulated TLR4 expression, but downregulated miR-182-5p expression. We determined that miR-182-5p inhibited TLR4 by directly binding to its 3′-UTR. Furthermore, miR-182-5p suppressed the release of TNF-a, IL-6, and IL-1β. In vivo: A middle cerebral artery occlusion (MCAO) rat model was used to mimic cerebral ischemia-reperfusion. Iba1 and TLR4 double staining was used to demonstrate that the target of miR-182-5p in microglial cells, and the mediator of the anti-inflammatory effect, is TLR4. TTC staining was performed to evaluate the infarct volume. Compared to the animals treated with miR-182-5p NC and normal saline, rats treated with miR-182-5p mimics demonstrated significantly enhanced neurological functions. TTC staining results were consistent with neurological function test findings. In summary, our data suggested that miR-182-5p exhibits potential neuroprotective effects in the cerebral ischemia-reperfusion injury via the regulation of the TLR4-mediated inflammatory response.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Peripheral Stent Thrombosis Leading to Acute Limb Ischemia and Major Amputation: Incidence and Risk Factors in the Aortoiliac and Femoropopliteal Arteries

PurposeTo report the real-world incidence and risk factors of stent thrombosis in the aortoiliac and femoropopliteal arteries in case of bare nitinol stent (BNS) or covered nitinol stent (CNS) placement from a single-centre retrospective audit.Materials and MethodsMedical records of consecutive patients treated with peripheral stent placement for claudication or critical limb ischemia were audited for definite stent thrombosis defined as imaging confirmed stent thrombosis that presented as acute limb-threatening ischemia. Cases were stratified between aortoiliac and femoropopliteal anatomy. Cox regression analysis was employed to adjust for baseline clinical and procedural confounders and identify predictors of stent thrombosis and major limb loss.Results256 patients (n = 277 limbs) were analysed over a 5-year period (2009–2014) including 117 aortoiliac stents (34 CNS; 12.8 ± 5.0 cm and 83 BNS; 7.8 ± 4.0 cm) and 160 femoropopliteal ones (60 CNS; 21.1 ± 11.0 cm and 100 BNS; 17.5 ± 11.9 cm). Median follow-up was 1 year. Overall stent thrombosis rate was 6.1% (17/277) after a median of 43 days (range 2–192 days) and affected almost exclusively the femoropopliteal segment (12/60 in the CNS cohort vs. 4/100 in the BNS; p = 0.001). Annualized stent thrombosis rates (per 100 person-years) were 12.5% in case of CNS and 1.4% in case of BNS (HR 6.3, 95% CI 2.4–17.9; p = 0.0002). Corresponding major amputations rates were 8.7 and 2.5%, respectively (HR 4.5, 95% CI 2.7–27.9; p = 0.0006). On multivariable analysis, critical leg ischemia and CNS placement were the only predictors of stent thrombosis. Diabetes, critical leg ischemia, femoropopliteal anatomy, long stents and CNS were independent predictors of major amputations.ConclusionsPlacement of long femoropopliteal covered nitinol stents is associated with an increased incidence of acute stent thrombosis and ensuing major amputation. Risks are significantly lower in the aortoiliac vessels and with use of bare nitinol stents.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Percutaneous Mechanical Thromboembolectomy in Acute Lower Limb Ischemia

Purpose: To analyze the immediate outcome of percutaneous mechanical thromboembolectomy in acute infrainguinal leg ischemia in a consecutive cohort of patients with acute lower limb ischemia. Material and Method: We retrospectively analyzed the data of 156 acute infrainguinal ischemic events in 148 patients. Patients presented with acute limb ischemia Rutherford category I in 68 cases (44%), Rutherford category II A in 64 instances (41%) and Rutherford II B in 24 instances (15%). In 62 cases (39.7%), the occlusion site started below the knee joint level, in 94 (60.3%) cases above. As a basic technique, an intervention was started by manual aspiration but if aspiration failed, an additional device was added. Most frequently, a rotational thrombectomy device (Rotarex, Straub Medical, Wangs, Switzerland) was used. An antegrade access to the femoral artery was the preferred access to the limb (154/156). Results: In 145 of 156 incidents, a technical success was achieved (93%). Aspiration was used in 153 cases (98%). Rotational thrombectomy by use of the Rotarex catheter was added in 60 cases (38%). Directional atherectomy was applied in a total of five patients. As main technical complications, a downward embolization occurred (n = 11). There were four surgical groin revisions. Five patients died during the early follow-up with four not related to the intervention. Clinically, 135 patients (86.5%) showed an improvement in their clinical situation. Conclusion: Acute lower limb ischemia can be successfully treated by mechanical thromboembolectomy only by combining aspiration embolectomy with rotational thrombectomy in most cases but manual aspiration alone will frequently fail especially above the knee joint level.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Stronger correlation with myocardial ischemia of high-sensitivity troponin T than other biomarkers

Background: Acute myocardial infarction (AMI) is considered a major cause of death and disability. Myocardial perfusion scintigraphy (MPS) as a non-invasive diagnostic imaging procedure and certain biomarkers associated with myocardial ischemia (ISCH), such as ischemia-modified albumin (IMA), neuropeptide Y (NPY), N-terminal pro b-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hsTnT) could probably aid in the detection of myocardial infarction. Methods: Between December 2011 and June 2012, we prospectively analyzed patients who underwent a MPS study with the clinical question of myocardial ISCH. An exercise test was performed along with a MPS. Blood was drawn from the patients before exercise and the within 3 minutes from achieving maximum load and was analyzed for the aforementioned biomarkers. Results: A total of 71 patients (56 men and 15 women) were enrolled with a mean age of 61 ± 12 years. Twenty-six patients (36.6%) showed reduced uptake on stress MPS images that normalized at rest, a finding consistent with ISCH. Between ISCH and non-ISCH groups, only hsTnT levels showed a significant difference with the highest levels pertaining to the former group both before (0.0075 ng/ml vs 0.0050 ng/ml, P = 0.023) and after stress exercise (0.0085 vs 0.0050, P = 0.015). The most prominent differences were seen in higher stages of the Bruce protocol (stress duration > 9.05 minutes – P < 0.017). None of the IMA, NPY, and NP-pro BNP showed significant differences in time between the two groups. Conclusions: Although IMA, NPY, and NT-pro BNP may not detect minor ischemic myocardial insults, serum hsTnT holds a greater ability of detecting not only myocardial infarction but also less severe ischemia. Further studies with larger cohorts of patients are warranted in order to better define the role of hsTnT as a screening tool for myocardial ischemia.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2018

Apixaban attenuates ischemia-induced myocardial fibrosis by inhibition of Gq/PKC signaling

Highlights: • Apixaban attenuates ischemia-induced myocardial fibrosis. • Ischemia-induced myocardial fibrosis shows higher thrombin level. • Thrombin induced collagen deposition in cardiac fibroblasts. • Thrombin induced collagen deposition by activation of Gq/PKC signaling. • Inhibition of Gq/PKC blunts ischemia-induced myocardial fibrosis. It was previously found that patients with symptom of myocardial dysfunction had increased levels of thrombin. Apixaban is one of the novel oral anticoagulant drugs widely used in clinic. As the inhibitor of FXa (prothrombin), it inhibits prothrombin conversion into thrombin leading to thrombin deficiency in vivo. However, the effects of apixaban on myocardial fibrosis were still unclear, and the concomitant molecular mechanisms remain to be investigated. Here, we showed that myocardial fibrosis-bearing mice induced by continuous myocardial ischemia (MI) had higher levels of thrombin. Orally administration of apixaban significantly abrogated fibrosis condition and thrombin levels. In vitro, thrombin induced collagen deposition in primary cardiac fibroblasts in a dose-dependent manner. Mechanistic experiments showed that thrombin induced collagen deposition by activation of the Par-1-coupled Gq/PKC signaling. Genetic ablation of Gq or pharmacological inhibition of PKC effectively blunted thrombin-induced collagen deposition in cardiac fibroblasts. Moreover, administration of PKC inhibitor or Gq antagonist obviously blocked MI-induced myocardial fibrosis in mice. To conclude, apixaban attenuates MI-induced myocardial fibrosis by inhibition of thrombin-dependent Par-1/Gq/PKC signaling axis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Attenuation of zinc-enhanced inflammatory M1 phenotype of microglia by peridinin protects against short-term spatial-memory impairment following cerebral ischemia in mice

Highlights: • Peridinin suppressed zinc-enhanced inflammatory M1 phenotype of microglia. • Zinc-increased microglial ROS level was abolished by peridinin. • Peridinin protected mice from ischemia-induced deficits in short-term spatial memory. Activated microglia exhibit two opposite activation states, the inflammatory M1 and the anti-inflammatory M2 activation states. In the mammalian brain, ischemia elicits a massive release of zinc from hippocampal neurons, and the extracellular zinc primes M1 microglia—by inducing reactive oxygen species (ROS) generation—to enhance their production of proinflammatory cytokines, which ultimately results in short-term spatial memory impairment. Here, we examined how peridinin, a carotenoid in dinoflagellates, affects the zinc-enhanced inflammatory M1 phenotype of microglia. Treatment of microglia with 30–300 ng/mL peridinin caused a dose-dependent attenuation of zinc-enhanced interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα) secretion when M1 activation was induced by lipopolysaccharide exposure. Moreover, peridinin inhibited the increase in ROS levels in zinc-treated microglia without directly interacting with zinc. Notably, when mice were administrated peridinin (20–200 ng/animal) intracerebroventricularly 5 min before cerebral ischemia-reperfusion, the peridinin treatment not only suppressed the increase in expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, but also protected the mice against ischemia-induced short-term spatial-memory impairment. Our findings suggest that peridinin prevents extracellular zinc-enhanced proinflammatory cytokine secretion from M1 microglia by inhibiting the increase in microglial ROS levels, and that this anti-inflammatory effect of peridinin might result in protection against deficits in short-term spatial memory.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Tisp40 deficiency attenuates renal ischemia reperfusion injury induced apoptosis of tubular epithelial cells

Renal ischemia reperfusion (IR) is a major cause of acute kidney injury (AKI) and no effective treatments have been established. Tisp40 is a transcription factor of the CREB/ATF family and involves in cell apoptosis, proliferation and differentiation, but its role in renal IR remains unknown. Here, we investigated the role of Tisp40 in renal IR injury. In vivo, Tisp40 knockout (KO) and wild-type (WT) mice were subjected to thirty minutes of bilateral renal ischemia and 48 h reperfusion, the blood and kidneys were harvested for analysis. In vitro, Tisp40 overexpression and vector cells were subjected to hypoxia/reoxygenation (HR), the apoptosis rate and the expressions of related proteins were measured. Following IR, the expressions of Tisp40 protein, serum creatinine (sCr), blood urea nitrogen (BUN) and apoptosis of tubular cells were significantly increased in WT mice. However, Tisp40 deficiency significantly attenuated the increase of sCr, BUN and apoptosis of tubular cells. Following HR, apoptosis of tubular cells was increased in Tisp40 overexpression cells compared with vector cells. Mechanistically, Tisp40 promoted the expressions of C/EBP homologous protein (CHOP), Bax and Cleaved caspase3 and suppressed the expression of Bcl-2 in renal IR injury. In conclusion, Tisp40 aggravates tubular cells apoptosis in renal IR injury. - Highlights: • Tisp40 is induced in renal ischemia reperfusion. • Tisp40 knockout attenuates renal dysfunctions and tubular cell apoptosis. • Tisp40 overexpression increases tubular cell apoptosis in hypoxia/reoxygenation. • Tisp40 promotes CHOP mediated cell apoptosis in renal ischemia reperfusion.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of monoacylglycerol lipase inhibitor URB602 on lung ischemia-reperfusion injury in mice

Highlights: • URB602 prevent and treat -LIRI in mice in vivo. • URB602 attenuate LIRI by increasing 2-AG levels and reducing AA to LTB{sub 4}, PGI{sub 2} and TXB{sub 2}. Lung ischemia-reperfusion injury (LIRI) is a common and severe postoperative pathologic complication that often occurs when the oxygen supply disrupted to the lung tissue fallowed by reperfusion period, in most cases after lung transplantation and cardiopulmonary bypass. Endocannabinoids such as 2-arachidonoylglycerol (2-AG) have very important role as regulators of inflammation. Monoacylglycerol lipase (MAGL) is the main 2-AG-degrading enzyme, and the downstream metabolites of 2-AG play a role in the inflammation. Ischemia reperfusion (IR) was induced by clamping the left pulmonary hilum for 60 min, followed by 120 min of reperfusion in male C57BL/6 mice. Effects of URB602, a MAGL inhibitor, were evaluated in a preventive or therapeutic regimen (5 min before ischemia or reperfusion, respectively). Oxygenation index, wet-to-dry weight ratio and lung injury score were analyzed. Endocannabinoids including 2-AG, anandamide (AEA) and arachidonic acid (AA) levels, metabolites such as Prostaglandin I{sub 2} (PGI{sub 2}), Thromboxane B{sub 2} (TXB{sub 2}) and Leukotrienes B{sub 4} (LTB{sub 4}) and inflammatory markers (Interleukin 6 (IL-6) andTumor necrosis factor-α (TNF-α)) in lung tissues were measured by using mass spectrometry or ELISA analyses. We found that IR increased the wet-to-dry weight ratio of lung and lung injury score and decreased oxygenation index as compared to the sham group. Moreover, treatment with URB602 in preventive or therapeutic regimen reduced the wet-to-dry weight ratio and lung injury score while increased oxygenation index when compared with the IR group, with a more improvement in the preventive regimen group. In addition, treatment with URB602 before ischemia increased 2-AG level but decreased metabolites (AA, PGI{sub 2}, TXB{sub 2}, LTB{sub 4}) and inflammatory markers (IL-6, TNF-α). Thus, our study demonstrated that a pretreatment with URB602 significantly reduced IR-induced lung injury and inflammation. URB602 inhibited LIRI and inflammation by increasing 2-AG level and reducing downstream metabolites from AA to PGI{sub 2}, TXB{sub 2} and LTB{sub 4} in lung tissues.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Rearfoot Transcutaneous Oximetry is a Useful Tool to Highlight Ischemia of the Heel

PurposeTo demonstrate the usefulness of rearfoot transcutaneous oximetry to assess the peripheral arterial disease in diabetic patients with heel ulcer.MethodsFrom our database of 550 critical limb ischemia diabetic patients followed after a percutaneous transluminal angioplasty, we have selected patients with below the knee arterial disease. Patients were grouped according to the dorsal transcutaneous oximetry value (Group A < 30 mmHg; Group B ≥ 30 mmHg). Patients of Group B had a second oximetry performed at the rearfoot, close to the lesion localized in all cases at the heel. Finally, the analysis of the arterial pattern disease has been done.ResultsWe selected 191 patients: Group A (151 patients), dorsal transcutaneous oximetry of 11.8 ± 0.7 mmHg; Group B (40 patients), dorsal transcutaneous oximetry of 44.2 ± 10.1 mmHg. In Group B, rearfoot oximetry was 20.5 ± 5 mmHg, significantly lower than dorsal oximetry (p = 0.0179). The anterior tibial artery was involved in all patients of Group A. In Group B, the anterior tibial artery was involved in 15 subjects and never alone; the posterior tibial artery was involved in 20 subjects and in 11 cases alone. The peroneal artery was affected in 20 subjects and in 14 patients alone.ConclusionWhen a heel lesion is present and the transcutaneous oximetry recorded on the dorsum of the foot does not confirm the presence of critical limb ischemia (not ≤30 mmHg), a second oximetry recorded on the rearfoot is useful to point out ischemia of the peroneal artery and/or of the posterior tibial artery.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Roles of PTEN-induced putative kinase 1 and dynamin-related protein 1 in transient global ischemia-induced hippocampal neuronal injury

Recent studies showed that increased mitochondrial fission is an early event of cell death during cerebral ischemia and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, which may be regulated by PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulate mitochondrial fission. However, the roles of PINK1 and Drp1 in hippocampal injury caused by transient global ischemia (TGI) remain unknown. We therefore tested the hypothesis that TGI may induce PINK1 causing downregulation of Drp1 phosphorylation to enhance hippocampal neuronal survival, thus functioning as an endogenous neuroprotective mechanism. We found progressively increased PINK1 expression in the hippocampal CA1 subfield1-48 h following TGI, reaching the maximal level at 4 h. Despite lack of changes in the expression level of total Drp1 and phosphor-Drp1 at Ser637, TGI induced a time-dependent increase of Drp1 phosphorlation at Ser616 that peaked after 24 h. Notably, PINK1-siRNA increased p-Drp1(Ser616) protein level in hippocampal CA1 subfield 24 h after TGI. The PINK1 siRNA also aggravated the TGI-induced oxidative DNA damage with an increased 8-hydroxy-deoxyguanosine (8-OHdG) content in hippocampal CA1 subfield. Furthermore, PINK1 siRNA also augmented TGI-induced apoptosis as evidenced by the increased numbers of TUNEL-positive staining and enhanced DNA fragmentation. These findings indicated that PINK1 is an endogenous protective mediator vital for neuronal survival under ischemic insult through regulating Drp1 phosphorylation at Ser616. - Highlights: • Transient global ischemia increases expression of PINK1 and p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA decreases PINK1 expression but increases p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA augments oxidative stress and neuronal damage in hippocampal CA1 subfield.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The selective Nlrp3 inflammasome inhibitor Mcc950 attenuates lung ischemia-reperfusion injury

Highlights: • The Nlrp3 inflammasome is activated by ROS during lung ischemia-reperfusion. • Mcc950 blocks Nlrp3 inflammasome activation and protects against lung ischemia-reperfusion injury. • The mechanism of Mcc950 is partially attributed to inhibition of the interaction between Nlrp3 and Nek7. Lung ischemia-reperfusion (IR) occurs in many circumstances and leads to impaired lung function. The NACHT, LRR and PYD domains-containing protein 3 (Nlrp3) inflammasome is reportedly activated during lung IR. Mcc950 is a recently developed Nlrp3 inhibitor. The aim of our study was to test the efficacy of Mcc950 on lung IR injury and to investigate the role of reactive oxygen species (ROS) in Nlrp3 inflammasome activation using a murine lung IR model. The results of the current study confirmed that Nlrp3 was upregulated and activated during lung IR, and inhibiting oxidative stress by the ROS scavenger edaravone attenuated Nlrp3 inflammasome activation. Mcc950 pretreatment significantly alleviated IR-induced lung injury by reducing production of the proinflammatory cytokines Il-1β and Il-18 and inhibiting neutrophil infiltration and cell apoptosis. Protein coimmunoprecipitation revealed that Mcc950 partially blocked the interaction between Nlrp3 and Nek7 (NimA-related protein kinase 7). Therefore, we conclude that ROS-dependent activation of the Nlrp3 inflammasome contributed to lung IR injury. Mcc950 significantly reduced lung IR injury by blocking Nlrp3 inflammasome activation, and the mechanism was partially attributed to inhibition of the interaction between Nlrp3 and Nek7. Thus, Mcc950 is a promising treatment for the prevention of lung IR injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Reverse triiodothyronine (rT3) attenuates ischemia-reperfusion injury

Highlights: • rT3 mitigates IR injury in vivo. • rT3 mitigates IR injury in vitro. • rT3 reduced IR induced oxidative stress. Hypothyroidism has been associated with better recovery from cerebral ischemia-reperfusion (IR) injury in humans. However, any therapeutic advantage of inducing hypothyroidism for mitigating IR injury without invoking the adverse effect of whole body hypothyroidism remains a challenge. We hypothesize that a deiodinase II (D2) inhibitor reverse triiodothyronine (rT3) may render brain specific hypometabolic state to ensue reduced damage during an acute phase of cerebral ischemia without affecting circulating thyroid hormone levels. Preclinical efficacy of rT3 as a neuroprotective agent was determined in rat model of middle cerebral artery occlusion (MCAO) induced cerebral IR and in oxygen glucose deprivation/reoxygenation (OGD/R) model in vitro. rT3 administration in rats significantly reduced neuronal injury markers, infarct size and neurological deficit upon ischemic insult. Similarly, rT3 increased cellular survival in primary cerebral neurons under OGD/R stress. Based on our results from both in vivo as well as in vitro models of ischemia reperfusion injury we propose rT3 as a novel therapeutic agent in reducing neuronal damage and improving stroke outcome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

(Phospho)Proteomic dataset of ischemia- and ultrasound- stimulated mouse cardiac endothelial cells in vitro

Cardiac endothelial cells respond to both ischemia and therapeutic ultrasound; the proteomic changes underlying these responses are unknown. This data article provides raw and processed data resulting from our global, unbiased phosphoproteomics investigation conducted on primary mouse cardiac endothelial cells exposed to ischemia (2-hour oxygen glucose deprivation) and ultrasound (250 kHz, 1.2 MPa) in vitro [1]. Proteins were extracted from cell lysates and enriched phosphopeptides were analyzed with a high mass accuracy liquid chromatrography (LC) - tandem mass spectrometry (MS/MS) proteomic platform, yielding multiple alterations in both total protein levels and phosphorylation events in response to ischemic injury and ultrasound. This dataset can be used as a reference for future studies on the cardiac endothelial response to ischemia and the mechanistic underpinnings of the cellular response to ultrasound, with the potential to yield clinically relevant therapeutic targets.

59 BASIC BIOLOGICAL SCIENCES↗