bims-heshmo 2021-08-29 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–08–29
fourteen papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Chronic critical illness after hypothermia in trauma patients.
Hypothermia in Trauma.
[The lethal triad of hemorrhage].
Protective Effects of FK 506 Against Hemorrhagic Shock-Induced Microvascular Hyperpermeability.
N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats.
The Interplay between Autophagy and NLRP3 Inflammasome in Ischemia/Reperfusion Injury.
Impact of Idarucizumab and Andexanet Alfa on DOAC Plasma Concentration and ClotPro® Clotting Time: An Ex Vivo Spiking Study in A Cohort of Trauma Patients.
Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact.
Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion.
Decreased Spp1 Expression in Acute Myocardial Infarction after Ischemia and Reperfusion Injury.
Ferroptosis, a New Insight Into Acute Lung Injury.
Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice.
Perturbations in cardiac metabolism in a human model of acute myocardial ischaemia.
Extracellular Vesicles in Acute Kidney Injury and Clinical Applications.

Trauma Surg Acute Care Open. 2021 ;6(1): e000747

Chronic critical illness after hypothermia in trauma patients.

David Miranda, Rebecca Maine, Mackenzie Cook, Scott Brakenridge, Lyle Moldawer, Saman Arbabi, Grant O'Keefe, Bryce Robinson, Eileen M Bulger, Ronald Maier, Joseph Cuschieri.

   Objectives: Chronic critical illness (CCI) is a phenotype that occurs frequently in patients with severe injury. Previous work has suggested that inflammatory changes leading to CCI occur early following injury. However, the modifiable factors associated with CCI are unknown. We hypothesized that hypothermia, an early modifiable factor, is associated with CCI.
Methods: To determine the association of hypothermia and CCI, a secondary analysis of the Inflammation and Host Response to Injury database was performed, and subsequently validated on a similar cohort of patients from a single level 1 trauma center from January 2015 to December 2019. Hypothermia was defined as initial body temperature ≤34.5°C. CCI was defined as death or sustained multiorgan failure ≥14 days after injury. Data were analyzed using univariable analyses with Student's t-test and Pearson's χ2 test, and logistic regression. An arrayed genomic analysis of the transcriptome of circulating immune cells was performed in these patients.
Results: Of the initial 1675 patients, 254 had hypothermia and 1421 did not. On univariable analysis, 120/254 (47.2%) of patients with hypothermia had CCI, compared with 520/1421 (36.6%) without hypothermia who had CCI, p<0.001. On multivariable logistic regression, hypothermia was independently associated with CCI, OR 1.61 (95% CI 1.17 to 2.21) but not mortality. Subsequent validation in 1264 patients of which 172 (13.6%) were hypothermic, verified that hypothermia was independently associated with CCI on multivariable logistic regression, OR 1.84 (95% CI 1.21 to 2.41). Transcriptomic analysis in hypothermic and non-hypothermic patients revealed unique cellular-specific genomic changes to only circulating monocytes, without any distinct effect on neutrophils or lymphocytes.
Conclusions: Hypothermia is associated with the development of CCI in severely injured patients. There are transcriptomic changes which indicate that the changes induced by hypothermia may be associated with persistent CCI. Thus, early reversal of hypothermia following injury may prevent the CCI.
Level of evidence: III.

Keywords:  multiple organ failure; multiple trauma

DOI:  https://doi.org/10.1136/tsaco-2021-000747
Int J Environ Res Public Health. 2021 Aug 18. pii: 8719. [Epub ahead of print]18(16):

Hypothermia in Trauma.

Michiel J van Veelen, Monika Brodmann Maeder.

  Hypothermia in trauma patients is a common condition. It is aggravated by traumatic hemorrhage, which leads to hypovolemic shock. This hypovolemic shock results in a lethal triad of hypothermia, coagulopathy, and acidosis, leading to ongoing bleeding. Additionally, hypothermia in trauma patients can deepen through environmental exposure on the scene or during transport and medical procedures such as infusions and airway management. This vicious circle has a detrimental effect on the outcome of major trauma patients. This narrative review describes the main factors to consider in the co-existing condition of trauma and hypothermia from a prehospital and emergency medical perspective. Early prehospital recognition and staging of hypothermia are crucial to triage to proper care to improve survival. Treatment of hypothermia should start in an early stage, especially the prevention of further cooling in the prehospital setting and during the primary assessment. On the one hand, active rewarming is the treatment of choice of hypothermia-induced coagulation disorder in trauma patients; on the other hand, accidental or clinically induced hypothermia might improve outcomes by protecting against the effects of hypoperfusion and hypoxic injury in selected cases such as patients suffering from traumatic brain injury (TBI) or traumatic cardiac arrest.

Keywords:  ECLS; cardiac arrest; coagulation; emergency preservation resuscitation; extracorporeal life support; hemorrhage; hypothermia; lethal triad; trauma; traumatic brain injury

DOI:  https://doi.org/10.3390/ijerph18168719
Rev Infirm. 2021 Aug-Sep;70(273):pii: S1293-8505(21)00195-0. [Epub ahead of print]70(273): 16-18

[The lethal triad of hemorrhage].

Rachel Borowko, Pierre-Olivier Vignon, Noémie Lutz, Aline Maillot, Hugues Lefort.

  Coagulopathy, acidosis and hypothermia form the lethal triad in trauma patients with acute hemorrhage. The prevention of this chain reaction relies on an adapted management from the first care in pre-hospital situation: rapid arrest of bleeding, fight against hypothermia, limited vascular filling with an early recourse to vasoactive amines. Pre-hospital transfusion is still rare, whereas in the hospital, an adapted transfusion strategy can wait for or support a surgical or radiological hemostasis procedure.

Keywords:  acidose; acidosis; coagulopathie; coagulopathy; hemorrhage; hypothermia; hypothermie; hémorragie; resuscitation; réanimation; trauma; traumatisme

DOI:  https://doi.org/10.1016/j.revinf.2021.06.003
Clin Exp Pharmacol Physiol. 2021 Aug 25.

Protective Effects of FK 506 Against Hemorrhagic Shock-Induced Microvascular Hyperpermeability.

Binu Tharakan, Felicia A Hunter, Ed W Childs.

Microvascular hyperpermeability, the excessive leakage of fluid and proteins from the intravascular space to the interstitium is a devastating clinical concern in hemorrhagic shock (HS), sepsis, burn etc. Previous studies have shown that HS-induced microvascular hyperpermeability is associated with activation of the mitochondria-mediated 'intrinsic' apoptotic signaling cascade and caspase-3 mediated disruption of the endothelial cell barrier. In this study, our objective was to test if FK506, an immunomodulator that is also known to protect mitochondria, would protect barrier functions and decrease vascular hyperpermeability following HS by acting on this pathway. FK506 (25µM was given 10 minutes prior to the shock period in a rat model of HS. The HS model was a nontraumatic/fixed pressure model of hypovolemic shock developed by withdrawing blood to reduce the mean arterial pressure to 40 mm Hg for 60 minutes. The mesenteric post-capillary venules were monitored for changes in permeability using intravital microscopic imaging. The changes in mitochondrial transmembrane potential (MTP) were determined using the cationic dye JC-1, that was superfused on the mesenteric vasculature followed by intravital imaging. The mesenteric Caspase-3 activity was measured fluorometrically. HS induced a significant increase in hyperpermeability compared to the sham-control group and FK506 treatment decreased HS-induced hyperpermeability significantly (p<0.05). FK506 dampened HS-induced loss of MTP and elevation of caspase-3 activity significantly (p<0.05). FK506 has protective effects against HS-induced microvascular hyperpermeability. The maintenance of the MTP and protection against caspase-3 mediated endothelial cell barrier disruption are possible mechanisms by which FK506 attenuates HS-induced hyperpermeability. FK506, currently used in clinical settings as an immunomodulator, needs to be explored further for its therapeutic usefulness against HS-induced vascular hyperpermeability and associated complications.

DOI: https://doi.org/10.1111/1440-1681.13578
Biomed Res Int. 2021 ;2021 1156031

N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats.

Cristiane Busnardo, Aline Fassini, Bruno Rodrigues, José Antunes-Rodrigues, Carlos C Crestani, Fernando M A Corrêa.

Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.

DOI: https://doi.org/10.1155/2021/1156031
Int J Mol Sci. 2021 Aug 16. pii: 8773. [Epub ahead of print]22(16):

The Interplay between Autophagy and NLRP3 Inflammasome in Ischemia/Reperfusion Injury.

Shuangyu Lv, Huiyang Liu, Honggang Wang.

  Ischemia/reperfusion (I/R) injury is characterized by a limited blood supply to organs, followed by the restoration of blood flow and reoxygenation. In addition to ischemia, blood flow recovery can also lead to very harmful injury, especially inflammatory injury. Autophagy refers to the transport of cellular materials to the lysosomes for degradation, leading to the conversion of cellular components and offering energy and macromolecular precursors. It can maintain the balance of synthesis, decomposition and reuse of the intracellular components, and participate in many physiological processes and diseases. Inflammasomes are a kind of protein complex. Under physiological and pathological conditions, as the cellular innate immune signal receptors, inflammasomes sense pathogens to trigger an inflammatory response. TheNLRP3 inflammasome is the most deeply studied inflammasome and is composed of NLRP3, the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18 mediated by caspase-1 and promotes a further inflammatory process. Studies have shown that autophagy and the NLRP3 inflammasome play an important role in the process of I/R injury, but the relevant mechanisms have not been fully explained, especially how the interaction between autophagy and the NLRP3 inflammasome participates in I/R injury, which remains to be further studied. Therefore, we reviewed the recent studies about the interplay between autophagy and the NLRP3 inflammasome in I/R injury and analyzed the mechanisms to provide the theoretical references for further research in the future.

Keywords:  NLRP3 inflammasome; autophagy; ischemia/reperfusion injury; mitophagy; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms22168773
J Clin Med. 2021 Aug 06. pii: 3476. [Epub ahead of print]10(16):

Impact of Idarucizumab and Andexanet Alfa on DOAC Plasma Concentration and ClotPro® Clotting Time: An Ex Vivo Spiking Study in A Cohort of Trauma Patients.

Daniel Oberladstätter, Christoph J Schlimp, Johannes Zipperle, Marcin F Osuchowski, Wolfgang Voelckel, Oliver Grottke, Herbert Schöchl.

  Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® ecarin clotting time (ECA-CT), we added the reversal agent Idarucizumab in vitro and these two analyses were repeated. Likewise, the baseline plasma concentration of apixaban, edoxaban, and rivaroxaban as well as ClotPro® Russell's viper venom test clotting time (RVV-CT) were measured and reanalyzed following Andexanet alfa spiking. We analyzed fifty blood samples from 37 patients and 10 healthy volunteers. Idarucizumab decreased the measured dabigatran plasma concentration from 323.9 ± 185.4 ng/mL to 5.9 ± 2.3 ng/mL and ECA-CT from 706.2 ± 344.6 s to 70.6 ± 20.2 s, (all, p < 0.001). Andexanet alfa decreased the apixaban concentration from 165.1 ± 65.5 ng/mL to 9.8 ± 8.1 ng/mL, edoxaban from 152.4 ± 79.0 ng/mL to 36.4 ± 19.2 ng/mL, and rivaroxaban from 153.2 ± 111.8 ng/mL to 18.1 ± 9.1 ng/mL (all p < 0.001). Andexanet alfa shortened the RVV-CT of patients with apixaban from 239.2 ± 71.7 s to 151.1 ± 30.2 s, edoxaban from 288.2 ± 65.0 s to 122.7 ± 37.1 s, and rivaroxaban from 225.9 ± 49.3 s to 103.7 ± 12.1 s (all p < 0.001). In vitro spiking of dabigatran-containing blood with Idarucizumab substantially reduced the plasma concentration and ecarin-test clotting time. Andexanet alfa lowered the concentration of the investigated factor Xa-inhibitors but did not normalize the RVV-CT. In healthy volunteers' blood, Idarucizumab spiking had no impact on ECA-CT. Andexanet alfa spiking of non-anticoagulated blood prolonged RVV-CT (p = 0.001), potentially as a consequence of a competitive antagonism with human factor Xa.

Keywords:  Andexanet alfa; DOAC; ECA-test; Idarucizumab; RVV-test; reversal

DOI:  https://doi.org/10.3390/jcm10163476
Oxid Med Cell Longev. 2021 ;2021 1370862

Melatonin Attenuates Cardiac Ischemia-Reperfusion Injury through Modulation of IP3R-Mediated Mitochondria-ER Contact.

Wenya Li, Botao Liu, Lin Wang, Jilie Liu, Xiuhui Yang, Jia Zheng.

Although the interplay between mitochondria and ER has been identified as a crucial regulator of cellular homeostasis, the pathogenic impact of alterations in mitochondria-ER contact sites (MERCS) during myocardial postischemic reperfusion (I/R) injury remains incompletely understood. Therefore, in our study, we explored the beneficial role played by melatonin in protecting cardiomyocytes against reperfusion injury via stabilizing mitochondria-ER interaction. In vitro exposure of H9C2 rat cardiomyocytes to hypoxia/reoxygenation (H/R) augmented mitochondrial ROS synthesis, suppressed both mitochondrial potential and ATP generation, and increased the mitochondrial permeability transition pore (mPTP) opening rate. Furthermore, H/R exposure upregulated the protein content of CHOP and caspase-12, two markers of ER stress, and enhanced the transcription of main MERCS tethering proteins, namely, Fis1, BAP31, Mfn2, and IP3R. Interestingly, all the above changes could be attenuated or reversed by melatonin treatment. Suggesting that melatonin-induced cardioprotection works through normalization of mitochondria-ER interaction, overexpression of IP3R abolished the protective actions offered by melatonin on mitochondria-ER fitness. These results expand our knowledge on the cardioprotective actions of melatonin during myocardial postischemic reperfusion damage and suggest that novel, more effective treatments for acute myocardial reperfusion injury might be achieved through modulation of mitochondria-ER interaction in cardiac cells.

DOI: https://doi.org/10.1155/2021/1370862
Antioxidants (Basel). 2021 Jul 22. pii: 1168. [Epub ahead of print]10(8):

Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion.

Małgorzata Trocha, Mariusz G Fleszar, Paulina Fortuna, Łukasz Lewandowski, Kinga Gostomska-Pampuch, Tomasz Sozański, Anna Merwid-Ląd, Małgorzata Krzystek-Korpacka.

  A possibility of repurposing sitagliptin, a well-established antidiabetic drug, for alleviating injury caused by ischemia-reperfusion (IR) is being researched. The aim of this study was to shed some light on the molecular background of the protective activity of sitagliptin during hepatic IR. The expression and/or concentration of inflammation and oxidative stress-involved factors have been determined in rat liver homogenates using quantitative RT-PCR and Luminex® xMAP® technology and markers of nitrative and halogenative stress were quantified using targeted metabolomics (LC-MS/MS). Animals (n = 36) divided into four groups were treated with sitagliptin (5 mg/kg) (S and SIR) or saline solution (C and IR), and the livers from IR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). The midkine expression (by 2.2-fold) and the free 3-nitrotyrosine (by 2.5-fold) and IL-10 (by 2-fold) concentration were significantly higher and the Nox4 expression was lower (by 9.4-fold) in the IR than the C animals. As compared to IR, the SIR animals had a lower expression of interleukin-6 (by 4.2-fold) and midkine (by 2-fold), a lower concentration of 3-nitrotyrosine (by 2.5-fold) and a higher Nox4 (by 2.9-fold) and 3-bromotyrosine (by 1.4-fold). In conclusion, IR disturbs the oxidative, nitrative and halogenative balance and aggravates the inflammatory response in the liver, which can be attenuated by low doses of sitagliptin.

Keywords:  NADPH oxidase (NOX); bromotyrosine; dipeptidylpeptidase-4 antagonists; drug repurposing; hepatoprotection; liver transplantation; midkine; nitrotyrosine

DOI:  https://doi.org/10.3390/antiox10081168
Cardiol Res Pract. 2021 ;2021 3925136

Decreased Spp1 Expression in Acute Myocardial Infarction after Ischemia and Reperfusion Injury.

Ling Li, Jungang Huang, Zongkai Zhao, Zhuzhi Wen, Kang Li, Tianjiao Ma, Lisui Zhang, Junmeng Zheng, Shi Liang.

Background: With the progress of shock therapy and the establishment and promotion of methods such as thrombolytic therapy and percutaneous coronary intervention (PCI), many tissues and organs have been reperfused after ischemia which may cause even worse disorder called ischemia-reperfusion injury (IRI). mRNAs have been found to have significant impacts on ischemia-reperfusion through various mechanisms. In view of the accessibility of mRNAs from blood, we aimed to find the association between mRNA and ischemia-reperfusion.
Methods: We used the GSE83472 dataset from the Gene Expression Omnibus (GEO) database to find differential RNA expression between ischemia-reperfusion tissue and control samples. In addition, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to find the biological property of 449 RNAs from GSE83472 via the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Besides, Gene Set Enrichment Analysis (GSEA), a tool to find the pathway orientation of a gene set, was used for further study in the four most significant KEGG pathways. Furthermore, we constructed a protein-protein interaction (PPI) network. In the end, we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting to measure and compare the expression of Spp1 in patients who accepted percutaneous coronary intervention.
Results: The bioinformatics analyses suggested that Spp1 was a hub gene in reperfusion after ischemia. The qRT-PCR result showed that the Spp1 expression was significantly downregulated in ischemia-reperfusion cells after PCI compared with normal samples and so as the western blotting.
Conclusion: Spp1 might play an essential role in acute myocardial infarction after ischemia and reperfusion injury.

DOI: https://doi.org/10.1155/2021/3925136
Front Pharmacol. 2021 ;12 709538

Ferroptosis, a New Insight Into Acute Lung Injury.

Xiaofang Yin, Guisong Zhu, Qian Wang, Yuan Dong Fu, Juan Wang, Biao Xu.

  Acute lung injury (ALI), a common and critical illness with high morbidity and mortality, is caused by multiple causes. It has been confirmed that oxidative stress plays an important role in the development of ALI. Ferroptosis, a newly discovered programmed cell death in 2012, is characterized by iron-dependent lipid peroxidation and involved in many diseases. To date, compelling evidence reveals the emerging role of ferroptosis in the pathophysiological process of ALI. Here, we review the role of ferroptosis in the pathogenesis of ALI and its therapeutic potential in ALI.

Keywords:  acute lung injury; ferroptosis; ferrostatin-1; iASPP; iron metabolism; lipid peroxidation; lipoxstatin-1

DOI:  https://doi.org/10.3389/fphar.2021.709538
Biochem Biophys Res Commun. 2021 Aug 13. pii: S0006-291X(21)01155-4. [Epub ahead of print]573 164-170

Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice.

Kentaro Nakata, Mikio Okazaki, Dai Shimizu, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Daiki Ousaka, Toshiaki Ohara, Akihiro Matsukawa, Masahiro Nishibori, Shinichi Toyooka.

  During ischemia reperfusion (IR) injury, high mobility group box 1 (HMGB1), a chromatin binding protein, is released from necrotic cells and triggers inflammatory responses. We assessed the therapeutic effect of a neutralizing anti-HMGB1 monoclonal antibody (mAb) on lung IR injury. A murine hilar clamp model of IR was used, where mice were divided into sham and IR groups with intravenous administration of anti-HMGB 1 mAb or control mAb. We analyzed the effect of anti-HMGB1 mAb against IR injury by assessing lung oxygenation, lung injury score, neutrophil infiltration, expression of proinflammatory cytokines and chemokines, levels of mitogen-activated protein kinase (MAPK) signaling, and measurement of apoptotic cells. Anti-HMGB1 mAb significantly decreased the plasma level of HMGB1 elevated by IR. The severity of IR injury represented by oxygenation capacity, lung injury score, and neutrophil infiltration was significantly improved by anti-HMGB1 mAb treatment. The expression of proinflammatory factors, including IL-1β, IL-6, IL-12, TNF-α, CXCL-1, and CXCL-2, and phosphorylation of p38 MAPK were both significantly reduced by anti-HMGB1 mAb treatment. Furthermore, anti-HMGB1 mAb treatment suppressed apoptosis, as determined through TUNEL assays. Overall, anti-HMGB1 mAb ameliorated lung IR injury by reducing inflammatory responses and apoptosis. Our findings indicate that anti-HMGB1 mAb has potential for use as a therapeutic to improve IR injury symptoms during lung transplantation.

Keywords:  Anti-High mobility box1 antibody; High mobility box1; Ischemia reperfusion injury; Lung transplantation

DOI:  https://doi.org/10.1016/j.bbrc.2021.08.015
Metabolomics. 2021 Aug 23. 17(9): 76

Perturbations in cardiac metabolism in a human model of acute myocardial ischaemia.

Sanoj Chacko, Mamas A Mamas, Magdi El-Omar, David Simon, Sohaib Haseeb, Farzin Fath-Ordoubadi, Bernard Clarke, Ludwig Neyses, Warwick B Dunn.

   INTRODUCTION: Acute myocardial ischaemia and the transition from reversible to irreversible myocardial injury are associated with abnormal metabolic patterns. Advances in metabolomics have extended our capabilities to define these metabolic perturbations on a metabolome-wide scale.
OBJECTIVES: This study was designed to identify cardiac metabolic changes in serum during the first 5 min following early myocardial ischaemia in humans, applying an untargeted metabolomics approach.
METHODS: Peripheral venous samples were collected from 46 patients in a discovery study (DS) and a validation study (VS) (25 for DS, 21 for VS). Coronary sinus venous samples were collected from 7 patients (4 for DS, 3 for VS). Acute myocardial ischaemia was induced by transient coronary occlusion during percutaneous coronary intervention (PCI). Plasma samples were collected at baseline (prior to PCI) and at 1 and 5 min post-coronary occlusion. Samples were analyzed by Ultra Performance Liquid Chromatography-Mass Spectrometry in an untargeted metabolomics approach.
RESULTS: The study observed changes in the circulating levels of metabolites at 1 and 5 min following transient coronary ischaemia. Both DS and VS identified 54 and 55 metabolites as significant (P < 0.05) when compared to baseline levels, respectively. Fatty acid beta-oxidation and anaerobic respiration, lysoglycerophospholipids, arachidonic acid, docosahexaenoic acid, tryptophan metabolism and sphingosine-1-phosphate were identified as mechanistically important.
CONCLUSION: Using an untargeted metabolomics approach, the study identified important cardiac metabolic changes in peripheral and coronary sinus plasma, in a human model of controlled acute myocardial ischaemia. Distinct classes of metabolites were shown to be involved in the rapid cardiac response to ischemia and provide insights into diagnostic and interventional targets.

Keywords:  Acute myocardial ischemia; Coronary sinus serum; Metabolism; Metabolomics; PCI

DOI:  https://doi.org/10.1007/s11306-021-01827-x
Int J Mol Sci. 2021 Aug 18. pii: 8913. [Epub ahead of print]22(16):

Extracellular Vesicles in Acute Kidney Injury and Clinical Applications.

Sekyung Oh, Sang-Ho Kwon.

  Acute kidney injury (AKI)--the sudden loss of kidney function due to tissue damage and subsequent progression to chronic kidney disease--has high morbidity and mortality rates and is a serious worldwide clinical problem. Current AKI diagnosis, which relies on measuring serum creatinine levels and urine output, cannot sensitively and promptly report on the state of damage. To address the shortcomings of these traditional diagnosis tools, several molecular biomarkers have been developed to facilitate the identification and ensuing monitoring of AKI. Nanosized membrane-bound extracellular vesicles (EVs) in body fluids have emerged as excellent sources for discovering such biomarkers. Besides this diagnostic purpose, EVs are also being extensively exploited to deliver therapeutic macromolecules to damaged kidney cells to ameliorate AKI. Consequently, many successful AKI biomarker findings and therapeutic applications based on EVs have been made. Here, we review our understanding of how EVs can help with the early identification and accurate monitoring of AKI and be used therapeutically. We will further discuss where current EV-based AKI diagnosis and therapeutic applications fall short and where future innovations could lead us.

Keywords:  acute kidney injury; apoptotic bodies; biomarkers; exosomes; extracellular vesicles; injury repair; liquid biopsy; mesenchymal stem cells; microvesicles

DOI:  https://doi.org/10.3390/ijms22168913