bims-heshmo Biomed News
on Trauma hemorrhagic shock — molecular basis
Issue of 2022‒01‒23
fifteen papers selected by
Andreia Luís
Ludwig Boltzmann Institute
  1. Circ_ZNF512-Mediated miR-181d-5p Inhibition Limits Cardiomyocyte Autophagy and Promotes Myocardial Ischemia/Reperfusion Injury through an EGR1/mTORC1/TFEB-Based Mechanism.
  2. HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma.
  3. Vagus Nerve Stimulation Attenuates Acute Skeletal Muscle Injury Induced by Hepatic Ischemia/Reperfusion Injury in Rats.
  4. Significance of initial hemoglobin levels in severe trauma patients without prehospital fluid administration: a single-center study in Japan.
  5. FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.
  6. miR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1.
  7. Integration of Metabolomic and Clinical Data Improves the Prediction of Intensive Care Unit Length of Stay Following Major Traumatic Injury.
  8. Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury.
  9. Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart.
  10. HMGB1-Mediated Neutrophil Extracellular Trap Formation Exacerbates Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury.
  11. miR-210 Regulates Apoptotic Cell Death during Cellular Hypoxia and Reoxygenation in a Diametrically Opposite Manner.
  12. Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury.
  13. Quercetin Liposomal Nanoformulation for Ischemia and Reperfusion Injury Treatment.
  14. Mitochondrial redox signaling in O2-sensing chemoreceptor cells.
  15. Fluid Overload Phenotypes in Critical Illness-A Machine Learning Approach.
  1. J Med Chem. 2022 Jan 18.
    Circ_ZNF512-Mediated miR-181d-5p Inhibition Limits Cardiomyocyte Autophagy and Promotes Myocardial Ischemia/Reperfusion Injury through an EGR1/mTORC1/TFEB-Based Mechanism.
    Chen Huang, Liliang Shu, Hualu Zhang, Xiaohua Zhu, Gongcheng Huang, Jing Xu.
      Studies have shown that circRNAs are important regulatory molecules involved in cell physiology and pathology. Herein, we analyzed the role of circ_ZNF512 in cardiomyocyte autophagy of myocardial ischemia/reperfusion (I/R) injury. A mouse model was induced by ligation of the left anterior descending artery followed by reperfusion. An in vitro model was also developed in cultured cardiomyocytes following hypoxia/reoxygenation (H/R) injury. It was established that EGR1 expression was increased in myocardial tissues of I/R mice and H/R-induced cardiomyocytes. Silencing of circ_ZNF512 attenuated its binding to miR-181d-5p, which in turn impaired the EGR1 expression by targeting its 3'-UTR, thus promoting the autophagy of cardiomyocytes and suppressing cell apoptosis to alleviate myocardial tissue injury. Additionally, the circ_ZNF512/miR-181d-5p/EGR1 crosstalk activated the mTORC1/TFEB signaling pathway, increasing mTORC1 expression while suppressing TFEB expression. Together, circ_ZNF512 knockdown protects against myocardial I/R injury, which may be a potential therapeutic approach for preventing myocardial I/R injury.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c00745
  2. Biomolecules. 2022 Jan 08. pii: 101. [Epub ahead of print]12(1):
    HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma.
    Zhangsheng Yang, Milomir O Simovic, Peter R Edsall, Bin Liu, Tomas S Cancio, Andriy I Batchinsky, Leopoldo C Cancio, Yansong Li.
      Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 h after admission. In total, 45 (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 h after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01 (2-O, 3-O desulfated heparin). Animals were cannulated, then recovered for 5-7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels along with severe tissue damage and high mortality. CX-01 inhibited systemic HMGB1 activity, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage.
    Keywords:  HMGB1; hemorrhagic shock; inflammation; multiple organ failure; trauma
    DOI:  https://doi.org/10.3390/biom12010101
  3. Front Pharmacol. 2021 ;12 756997
    Vagus Nerve Stimulation Attenuates Acute Skeletal Muscle Injury Induced by Hepatic Ischemia/Reperfusion Injury in Rats.
    Ying Xin, Yifeng Zhang, Simin Deng, Xinqun Hu.
      Vagus nerve stimulation (VNS) has a protective effect on distal organ injury after ischemia/reperfusion (I/R) injury. We aimed to investigate the protective efficacy of VNS on hepatic I/R injury-induced acute skeletal muscle injury and explore its underlying mechanisms. To test this hypothesis, male Sprague-Dawley rats were randomly divided into three groups: sham group (sham operation, n = 6); I/R group (hepatic I/R with sham VNS, n = 6); and VNS group (hepatic I/R with VNS, n = 6). A hepatic I/R injury model was prepared by inducing hepatic ischemia for 1 h (70%) followed by hepatic reperfusion for 6 h. VNS was performed during the entire hepatic I/R process. Tissue and blood samples were collected at the end of the experiment for biochemical assays, molecular biological preparations, and histological examination. Our results showed that throughout the hepatic I/R process, VNS significantly reduced inflammation, oxidative stress, and apoptosis, while significantly increasing the protein levels of silent information regulator 1 (SIRT1) and decreasing the levels of acetylated forkhead box O1 and Ac-p53, in the skeletal muscle. These data suggest that VNS can alleviate hepatic I/R injury-induced acute skeletal muscle injury by suppressing inflammation, oxidative stress, and apoptosis, potentially via the SIRT1 pathway.
    Keywords:  hepatic injury; ischemia reperfusion; remote organs; skeletal muscle injury; vagus nerve stimulation
    DOI:  https://doi.org/10.3389/fphar.2021.756997
  4. Trauma Surg Acute Care Open. 2021 ;6(1): e000831
    Significance of initial hemoglobin levels in severe trauma patients without prehospital fluid administration: a single-center study in Japan.
    Yasuyuki Kawai, Hidetada Fukushima, Hideki Asai, Keisuke Takano, Akinori Okuda, Yusuke Tada, Naoki Maegawa, Francesco Bolstad.
      Objectives: Hemoglobin (Hb) levels have been considered to remain stable in the early stages of bleeding due to trauma. However, several studies have reported that rapid compensatory fluid shifts cause Hb dilution earlier than previously thought. These reports are from Western countries where it is standard protocol to administer fluids during an emergency, making it almost impossible to eliminate the effect of prehospital intravenous fluid administration on Hb levels. This study aimed to determine the relationship between Hb levels and severity of injury on arrival at the hospital in severe trauma patients without prehospital intravenous fluid administration.Methods: This single-center observational retrospective study included patients with Abbreviated Injury Scale scores of 3 or above between 2008 and 2014. In Japan, prehospital life-saving technicians were not allowed to administer intravenous fluids until 2014. We investigated whether the difference between the measured blood Hb level at arrival and the corresponding standard blood Hb level for each age group and sex reported in the national survey was associated with the severity of injury and the need for hemostasis.
    Results: In total, 250 patients were included in this study (median age, 46 years; male patients, 183). The median time from injury to arrival at the hospital was 45 min, and there was no statistical correlation with the initial Hb level on arrival (ρ=0.092, p=0.14). When the study subjects were stratified into four groups according to the initial Hb levels, lower Hb levels correlated with higher rates of requirement for hemostatic interventions (p=0.02) and mortality (p=0.02). In addition, lower Hb levels were associated with the need for hemostasis.
    Conclusion: In severe trauma patients without prehospital intravenous fluid administration, decreased Hb levels on arrival may be associated with the severity of trauma and with the need for hemostasis.
    Level of evidence: Level IV.
    Keywords:  clinical assessment; emergency department; emergency treatment; hemorrhage
    DOI:  https://doi.org/10.1136/tsaco-2021-000831
  5. Cell Signal. 2022 Jan 17. pii: S0898-6568(22)00009-2. [Epub ahead of print] 110249
    FUNDC1 activates the mitochondrial unfolded protein response to preserve mitochondrial quality control in cardiac ischemia/reperfusion injury.
    Haizhe Ji, Jin Wang, David Muid, Wei Song, Yinong Jiang, Hao Zhou.
      The mitochondrial unfolded protein response (UPRmt) is an adaptive transcriptional response involving the activation of proteases, chaperones, and antioxidant enzymes and serves to degrade abnormal or unfolded proteins and restore mitochondrial function. Although the cardioprotective action of the UPRmt has been verified in myocardial ischemia/reperfusion (I/R) injuries, the upstream signals involved remain unclear. Here, we explored the regulatory mechanisms underlying UPRmt in the reperfused mouse heart. UPRmt was slightly activated by I/R injury. UPRmt activation (using oligomycin) and inhibition (with the protease inhibitor AEBSF) respectively alleviated and augmented the reperfusion-mediated myocardial damage. Gene expression analysis demonstrated that oxidative stress was partly inhibited by UPRmt through upregulation of mitochondria-localized, not cytoplasmic, antioxidant enzymes. Contributing to cardiomyocyte survival under I/R, the transcription of pro-apoptotic proteins Bcl2 and c-IAP was also stimulated by UPRmt. Moreover, UPRmt upregulated mitochondrial fusion-related, but not fission-related, genes and stimulated the expression of mitochondrial biogenesis markers in reperfused hearts. Finally, we found that FUN14 domain containing 1 (FUNDC1)-mediated mitophagy induces the mitochondrial DNA decrease, triggering UPRmt. These results demonstrate that FUNDC1 functions upstream of the UPRmt to maintain mitochondrial quality control during myocardial I/R injury.
    Keywords:  Cardiomyocyte; FUNDC1; Mitochondrial unfolded protein response; Mitophagy; Myocardial I/R injury
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110249
  6. Front Mol Biosci. 2021 ;8 789927
    miR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1.
    Wenqiang Tao, Fen Liu, Jianguo Zhang, Shangmiao Fu, Hui Zhan, Kejian Qian.
      Renal ischemia-reperfusion (IR) is frequently observed in patients who are critically ill, yet there are no reliable or effective approaches for the treatment of this condition. Ferroptosis, a form of programmed cell death, is regulated by key genes such as glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HMOX1) and participates in the injury of renal tubular epithelial cells during IR. This study aimed to investigate the miRNA-mRNA regulatory networks involved in ferroptosis following renal IR. Using bioinformatics analysis, HMOX1 was found to be significantly upregulated during the early stages of renal IR injury, and microRNA-3587 (miR-3587) was identified as a putative regulator of HMOX1. When a miR-3587 inhibitor was applied in a hypoxia-reoxygenation (HR) model system using renal tubular epithelial cells, HO-1 protein (encoded by HMOX1) expression was significantly increased relative to that observed in the HR group, with concomitant increases in GPX4 protein levels, enhanced cell viability, a reduction in malondialdehyde content, decreased Fe2+ level, and the restoration of normal mitochondrial membrane potential. Transmission electron microscopy showed a reduced or absent mitochondrial crest and a damaged mitochondrial outer membrane. Targeting of HMOX1 by miR-3587 was confirmed by luciferase reporter gene assay. In conclusion, these preliminary results indicate that inhibition of miR-3587 promotes HO-1 upregulation, thereby protecting renal tissues from IR-induced ferroptosis.
    Keywords:  acute kidney injury; ferroptosis; heme oxygenase-1; ischemia-reperfusion; microRNA
    DOI:  https://doi.org/10.3389/fmolb.2021.789927
  7. Metabolites. 2021 Dec 31. pii: 29. [Epub ahead of print]12(1):
    Integration of Metabolomic and Clinical Data Improves the Prediction of Intensive Care Unit Length of Stay Following Major Traumatic Injury.
    Animesh Acharjee, Jon Hazeldine, Alina Bazarova, Lavanya Deenadayalu, Jinkang Zhang, Conor Bentley, Dominic Russ, Janet M Lord, Georgios V Gkoutos, Stephen P Young, Mark A Foster.
      Recent advances in emergency medicine and the co-ordinated delivery of trauma care mean more critically-injured patients now reach the hospital alive and survive life-saving operations. Indeed, between 2008 and 2017, the odds of surviving a major traumatic injury in the UK increased by nineteen percent. However, the improved survival rates of severely-injured patients have placed an increased burden on the healthcare system, with major trauma a common cause of intensive care unit (ICU) admissions that last ≥10 days. Improved understanding of the factors influencing patient outcomes is now urgently needed. We investigated the serum metabolomic profile of fifty-five major trauma patients across three post-injury phases: acute (days 0-4), intermediate (days 5-14) and late (days 15-112). Using ICU length of stay (LOS) as a clinical outcome, we aimed to determine whether the serum metabolome measured at days 0-4 post-injury for patients with an extended (≥10 days) ICU LOS differed from that of patients with a short (<10 days) ICU LOS. In addition, we investigated whether combining metabolomic profiles with clinical scoring systems would generate a variable that would identify patients with an extended ICU LOS with a greater degree of accuracy than models built on either variable alone. The number of metabolites unique to and shared across each time segment varied across acute, intermediate and late segments. A one-way ANOVA revealed the most variation in metabolite levels across the different time-points was for the metabolites lactate, glucose, anserine and 3-hydroxybutyrate. A total of eleven features were selected to differentiate between <10 days ICU LOS vs. >10 days ICU LOS. New Injury Severity Score (NISS), testosterone, and the metabolites cadaverine, urea, isoleucine, acetoacetate, dimethyl sulfone, syringate, creatinine, xylitol, and acetone form the integrated biomarker set. Using metabolic enrichment analysis, we found valine, leucine and isoleucine biosynthesis, glutathione metabolism, and glycine, serine and threonine metabolism were the top three pathways differentiating ICU LOS with a p < 0.05. A combined model of NISS and testosterone and all nine selected metabolites achieved an AUROC of 0.824. Differences exist in the serum metabolome of major trauma patients who subsequently experience a short or prolonged ICU LOS in the acute post-injury setting. Combining metabolomic data with anatomical scoring systems allowed us to discriminate between these two groups with a greater degree of accuracy than that of either variable alone.
    Keywords:  ICU length of stay; inflammation; metabolomics; omics integration
    DOI:  https://doi.org/10.3390/metabo12010029
  8. Antioxidants (Basel). 2021 Dec 27. pii: 57. [Epub ahead of print]11(1):
    Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury.
    Hyang-Mi Lee, Ji Woong Choi, Min Sik Choi.
      Ischemia-reperfusion injury (IRI) is a process in which damage is induced in hypoxic tissue when oxygen supply is resumed after ischemia. During IRI, restoration of reduced nitric oxide (NO) levels may alleviate reperfusion injury in ischemic organs. The protective mechanism of NO is due to anti-inflammatory effects, antioxidant effects, and the regulation of cell signaling pathways. On the other hand, it is generally known that S-nitrosylation (SNO) mediates the detrimental or protective effect of NO depending on the action of the nitrosylated target protein, and this is also applied in the IRI process. In this review, the effect of each change of NO and SNO during the IRI process was investigated.
    Keywords:  ischemia-reperfusion injury; nitric oxide; protein S-nitrosylation
    DOI:  https://doi.org/10.3390/antiox11010057
  9. Cells. 2022 Jan 13. pii: 258. [Epub ahead of print]11(2):
    Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart.
    Jihoon Nah, Eun-Ah Sung, Peiyong Zhai, Daniela Zablocki, Junichi Sadoshima.
      Autosis is a unique form of cell death with characteristic morphological and biochemical features caused by dysregulated autophagy. Autosis is observed in the heart during the late phase of ischemia/reperfusion (I/R), when marked accumulation of autophagosomes is induced. We previously showed that the excessive accumulation of autophagosomes promotes autosis in cardiomyocytes. Although the inhibition of autophagic flux via the upregulation of Rubicon induces the accumulation of autophagosomes during I/R, it appears that additional mechanisms exacerbating autophagosome accumulation are required for the induction of autosis. Here, we show that Tfeb contributes to the induction of autosis during the late phase of I/R in the heart. During myocardial reperfusion, Tfeb is activated and translocated into the nucleus, which in turn upregulates genes involved in autophagy and lysosomal function. The overexpression of Tfeb enhanced cardiomyocyte death induced by a high dose of TAT-Beclin 1, an effect that was inhibited by the downregulation of Atg7. Conversely, the knockdown of Tfeb attenuated high-dose TAT-Beclin1-induced death in cardiomyocytes. Although the downregulation of Tfeb in the heart significantly decreased the number of autophagic vacuoles and inhibited autosis during I/R, the activation of Tfeb activity via 3,4-dimethoxychalcone, an activator of Tfeb, aggravated myocardial injury during I/R. These findings suggest that Tfeb promotes cardiomyocyte autosis during the late phase of reperfusion in the heart.
    Keywords:  Tfeb; autophagic cell death; autosis; ischemia/reperfusion
    DOI:  https://doi.org/10.3390/cells11020258
  10. J Immunol. 2022 Jan 21. pii: ji2100593. [Epub ahead of print]
    HMGB1-Mediated Neutrophil Extracellular Trap Formation Exacerbates Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury.
    YaQing Zhan, YiHong Ling, Qiwen Deng, YuXin Qiu, JianTong Shen, HanJin Lai, ZhaoRong Chen, ChanYan Huang, LiQun Liang, Xiang Li, JianFeng Wu, WenQi Huang, ShiHong Wen.
      Influx of activated neutrophils into the lungs is the histopathologic hallmark of acute lung injury (ALI) after intestinal ischemia/reperfusion (I/R). Neutrophils can release DNA and granular proteins to form cytotoxic neutrophil extracellular traps (NETs), which promotes bystander tissue injury. However, whether NETs are responsible for the remote ALI after intestinal I/R and the mechanisms underlying the dissemination of harmful gut-derived mediators to the lungs are unknown. In the C57BL/6J mouse intestinal I/R model, DNase I-mediated degradation and protein arginine deiminase 4 (PAD4) inhibitor-mediated inhibition of NET treatments reduced NET formation, tissue inflammation, and pathological injury in the lung. High-mobility group protein B1 (HMGB1) blocking prevented NET formation and protected against tissue inflammation, as well as reduced cell apoptosis and improved survival rate. Moreover, recombinant human HMGB1 administration further drives NETs and concurrent tissue toxic injury, which in turn can be reversed by neutrophil deletion via anti-Ly6G Ab i.p. injection. Furthermore, global MyD88 deficiency regulated NET formation and alleviated the development of ALI induced by intestinal I/R. Thus, HMGB1 released from necroptotic enterocytes caused ALI after intestinal I/R by inducing NET formation. Targeting NETosis and the HMGB1 pathway might extend effective therapeutic strategies to minimize intestinal I/R-induced ALI.
    DOI:  https://doi.org/10.4049/jimmunol.2100593
  11. Biomedicines. 2021 Dec 25. pii: 42. [Epub ahead of print]10(1):
    miR-210 Regulates Apoptotic Cell Death during Cellular Hypoxia and Reoxygenation in a Diametrically Opposite Manner.
    Gurdeep Marwarha, Øystein Røsand, Nathan Scrimgeour, Katrine Hordnes Slagsvold, Morten Andre Høydal.
      Apoptotic cell death of cardiomyocytes is a characteristic hallmark of ischemia-reperfusion (I/R) injury. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxic stress. However, to date, no consensus has emerged with regards to the polarity of the miR-210-elicited cellular response, as miR-210 has been shown to exacerbate as well as attenuate hypoxia-driven apoptotic cell death. Herein, in AC-16 cardiomyocytes subjected to hypoxia-reoxygenation (H-R) stress, we unravel novel facets of miR-210 biology and resolve the biological response mediated by miR-210 into the hypoxia and reoxygenation temporal components. Using transient overexpression and decoy/inhibition vectors to modulate miR-210 expression, we elucidated a Janus role miR-210 in the cellular response to H-R stress, wherein miR-210 mitigated the hypoxia-induced apoptotic cell death but exacerbated apoptotic cell death during cellular reoxygenation. We further delineated the underlying cellular mechanisms that confer this diametrically opposite effect of miR-210 on apoptotic cell death. Our exhaustive biochemical assays cogently demonstrate that miR-210 attenuates the hypoxia-driven intrinsic apoptosis pathway, while significantly augmenting the reoxygenation-induced caspase-8-mediated extrinsic apoptosis pathway. Our study is the first to unveil this Janus role of miR-210 and to substantiate the cellular mechanisms that underlie this functional duality.
    Keywords:  AC-16 cardiomyocytes; apoptosis; hypoxia; hypoxia-reoxygenation; miR-210
    DOI:  https://doi.org/10.3390/biomedicines10010042
  12. Front Med (Lausanne). 2021 ;8 757336
    Novel Targets and Therapeutic Strategies to Protect Against Hepatic Ischemia Reperfusion Injury.
    Xin-Li Mao, Yue Cai, Ya-Hong Chen, Yi Wang, Xiu-Xiu Jiang, Li-Ping Ye, Shao-Wei Li.
      Hepatic ischemia reperfusion injury (IRI), a fascinating topic that has drawn a lot of interest in the last few years, is a major complication caused by a variety of clinical situations, such as liver transplantation, severe trauma, vascular surgery, and hemorrhagic shock. The IRI process involves a series of complex events, including mitochondrial deenergization, metabolic acidosis, adenosine-5'-triphosphate depletion, Kupffer cell activation, calcium overload, oxidative stress, and the upregulation of pro-inflammatory cytokine signal transduction. A number of protective strategies have been reported to ameliorate IRI, including pharmacological therapy, ischemic pre-conditioning, ischemic post-conditioning, and machine reperfusion. However, most of these strategies are only at the stage of animal model research at present, and the potential mechanisms and exact therapeutic targets have yet to be clarified. IRI remains a main cause of postoperative liver dysfunction, often leading to postoperative morbidity or even mortality. Very recently, it was reported that the activation of peroxisome proliferator-activated receptor γ (PPARγ), a member of a superfamily of nuclear transcription factors activated by agonists, can attenuate IRI in the liver, and FAM3A has been confirmed to mediate the protective effect of PPARγ in hepatic IRI. In addition, non-coding RNAs, like LncRNAs and miRNAs, have also been reported to play a pivotal role in the liver IRI process. In this review, we presented an overview of the latest advances of treatment strategies and proposed potential mechanisms behind liver IRI. We also highlighted the role of several important molecules (PPARγ, FAM3A, and non-coding RNAs) in protecting against hepatic IRI. Only after achieving a comprehensive understanding of potential mechanisms and targets behind IRI can we effectively ameliorate IRI in the liver and achieve better therapeutic effects.
    Keywords:  injury; ischemia reperfusion; liver; novel target; therapeutic strategy
    DOI:  https://doi.org/10.3389/fmed.2021.757336
  13. Pharmaceutics. 2022 Jan 03. pii: 104. [Epub ahead of print]14(1):
    Quercetin Liposomal Nanoformulation for Ischemia and Reperfusion Injury Treatment.
    Margarida Ferreira-Silva, Catarina Faria-Silva, Manuela C Carvalheiro, Sandra Simões, H Susana Marinho, Paulo Marcelino, Maria Celeste Campos, Josbert M Metselaar, Eduarda Fernandes, Pedro V Baptista, Alexandra R Fernandes, Maria Luísa Corvo.
      Ischemia and reperfusion injury (IRI) is a common complication caused by inflammation and oxidative stress resulting from liver surgery. Current therapeutic strategies do not present the desirable efficacy, and severe side effects can occur. To overcome these drawbacks, new therapeutic alternatives are necessary. Drug delivery nanosystems have been explored due to their capacity to improve the therapeutic index of conventional drugs. Within nanocarriers, liposomes are one of the most successful, with several formulations currently in the market. As improved therapeutic outcomes have been demonstrated by using liposomes as drug carriers, this nanosystem was used to deliver quercetin, a flavonoid with anti-inflammatory and antioxidant properties, in hepatic IRI treatment. In the present work, a stable quercetin liposomal formulation was developed and characterized. Additionally, an in vitro model of ischemia and reperfusion was developed with a hypoxia chamber, where the anti-inflammatory potential of liposomal quercetin was evaluated, revealing the downregulation of pro-inflammatory markers. The anti-inflammatory effect of quercetin liposomes was also assessed in vivo in a rat model of hepatic IRI, in which a decrease in inflammation markers and enhanced recovery were observed. These results demonstrate that quercetin liposomes may provide a significant tool for addressing the current bottlenecks in hepatic IRI treatment.
    Keywords:  anti-inflammatory therapy; drug delivery nanosystems; hepatic ischemia and reperfusion injury; inflammation; liposomes; liver; quercetin
    DOI:  https://doi.org/10.3390/pharmaceutics14010104
  14. Antioxid Redox Signal. 2022 Jan 19.
    Mitochondrial redox signaling in O2-sensing chemoreceptor cells.
    Lin Gao, Patricia Ortega-Saenz, Alejandro Moreno-Dominguez, José López Barneo.
      SIGNIFICANCE: Acute responses to hypoxia are essential for the survival of mammals. The carotid body (CB), the main arterial chemoreceptor, contains glomus cells with O2-sensitive K+ channels, which are inhibited during hypoxia to trigger adaptive cardiorespiratory reflexes. Recent Advances: In this review, recent advances in molecular mechanisms of acute O2 sensing in CB glomus cells are discussed, with a special focus on the signaling role of mitochondria through regulating cellular redox status. These advances have been achieved thanks to the use of genetically engineering redox-sensitive protein roGFP probes, which allowed us to monitor rapid changes in ROS production in real time in different subcellular compartments during hypoxia. This methodology was used in combination with conditional knockout mice models, pharmacological approaches, and transcriptomic studies. We have proposed a mitochondria-to-membrane signaling model of acute O2 sensing in which H2O2 released in mitochondrial intermembrane space serves as a signaling molecule to inhibit K+ channels on the plasma membrane.CRITICAL ISSUES: Changes in mitochondrial reactive oxygen species (ROS) production during acute hypoxia are highly compartmentalized in sub-mitochondrial regions. The use of redox-sensitive probes targeted to specific compartments is essential to fully understand the role of mitochondrial ROS in acute O2 sensing.
    FUTURE DIRECTIONS: Further studies are needed to specify the ROS and to characterize the target(s) of ROS in chemoreceptor cells during acute hypoxia. These data may also contribute to a more complete understanding of the implication of ROS in acute responses to hypoxia in O2-sensing cells in other organs.
    DOI:  https://doi.org/10.1089/ars.2021.0255
  15. J Clin Med. 2022 Jan 11. pii: 336. [Epub ahead of print]11(2):
    Fluid Overload Phenotypes in Critical Illness-A Machine Learning Approach.
    Anna S Messmer, Michel Moser, Patrick Zuercher, Joerg C Schefold, Martin Müller, Carmen A Pfortmueller.
      BACKGROUND: The detrimental impact of fluid overload (FO) on intensive care unit (ICU) morbidity and mortality is well known. However, research to identify subgroups of patients particularly prone to fluid overload is scarce. The aim of this cohort study was to derive "FO phenotypes" in the critically ill by using machine learning techniques.METHODS: Retrospective single center study including adult intensive care patients with a length of stay of ≥3 days and sufficient data to compute FO. Data was analyzed by multivariable logistic regression, fast and frugal trees (FFT), classification decision trees (DT), and a random forest (RF) model.
    RESULTS: Out of 1772 included patients, 387 (21.8%) met the FO definition. The random forest model had the highest area under the curve (AUC) (0.84, 95% CI 0.79-0.86), followed by multivariable logistic regression (0.81, 95% CI 0.77-0.86), FFT (0.75, 95% CI 0.69-0.79) and DT (0.73, 95% CI 0.68-0.78) to predict FO. The most important predictors identified in all models were lactate and bicarbonate at admission and postsurgical ICU admission. Sepsis/septic shock was identified as a risk factor in the MV and RF analysis.
    CONCLUSION: The FO phenotypes consist of patients admitted after surgery or with sepsis/septic shock with high lactate and low bicarbonate.
    Keywords:  fluid overload; fluid resuscitation; intensive care; risk factors
    DOI:  https://doi.org/10.3390/jcm11020336
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