bims-heshmo 2021-03-07 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021‒03‒07
fifteen papers selected by
Andreia Luís
Ludwig Boltzmann Institute

Sevoflurane preconditioning activates HGF/Met-mediated autophagy to attenuate hepatic ischemia-reperfusion injury in mice.
SET8 mitigates hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway.
Myocardial ischemia-reperfusion induced cardiac extracellular vesicles harbour proinflammatory features and aggravate heart injury.
AST-120 Improves Cardiac Dysfunction in Acute Kidney Injury Mice via Suppression of Apoptosis and Proinflammatory NF-κB/ICAM-1 Signaling.
Renal Tubular Epithelial TRPA1 Acts as An Oxidative Stress Sensor to Mediate Ischemia-Reperfusion-Induced Kidney Injury through MAPKs/NF-κB Signaling.
SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway.
Oxidative Stress Evaluation in Ischemia Reperfusion Models: Characteristics, Limits and Perspectives.
Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury.
Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies.
Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry.
Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation.
Role of AMPK in the protective effects exerted by triiodothyronine in ischemic-reperfused myocardium.
The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation-Where Have We Gone So Far?
Txnip C247S mutation protects the heart against acute myocardial infarction.
Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade.

Cell Signal. 2021 Feb 24. pii: S0898-6568(21)00054-1. [Epub ahead of print] 109966

Sevoflurane preconditioning activates HGF/Met-mediated autophagy to attenuate hepatic ischemia-reperfusion injury in mice.

Xiaoyu Xiao, Dezhao Liu, Sufang Chen, Xiang Li, Mian Ge, Wenqi Huang.

  Sevoflurane (SEV) preconditioning plays a protective effect against liver ischemia reperfusion (IR) injury, while the role of autophagy in SEV-mediated hepatoprotection and the precise mechanism is unclear. In the current study, mice were pretreated with SEV or autophagy inhibitor before liver IR injury. In vitro, primary rat hepatocytes were pretreated with SEV and then exposed to hypoxia/reoxygenation (H/R). Liver function was measured by biochemical and histopathological examinations, and markers associated with inflammation, oxidation, apoptosis and autophagy were subsequently measured. We found that SEV preconditioning dramatically reduced hepatic damage, alleviated cell inflammatory response, oxidative stress and apoptosis in mice suffering hepatic IR injury, whereas these protective effects were abolished by the autophagy inhibitor 3-MA. In addition, pretreatment with SEV markedly activated HGF/Met signaling pathway regulation. Besides, pretreatment with an hepatocyte growth factor (HGF) inhibitor or knocking down HGF expression significantly downregulated phosphorylated met (p-met) and autophagy levels, and abolished the protective effects of SEV against hepatic IR or hepatocyte H/R injury. Conversely, HGF overexpression efficiently increased the p-met and autophagy levels and strengthened the protective effects of SEV. These results indicated that sevoflurane preconditioning ameliorates hepatic IR injury by activating HGF/Met-mediated autophagy.

Keywords:  Autophagy; Hepatic ischemia-reperfusion injury; Hepatocyte growth factor; Met; Sevoflurane preconditioning

DOI:  https://doi.org/10.1016/j.cellsig.2021.109966
Life Sci. 2021 Mar 01. pii: S0024-3205(21)00271-X. [Epub ahead of print] 119286

SET8 mitigates hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway.

Yunhai Luo, Zuotian Huang, Tong Mou, Junliang Pu, Tingting Li, Zhongtang Li, Hang Yang, Ping Yan, Zhongjun Wu, Qiao Wu.

  AIMS: Hepatic ischemia/reperfusion (I/R) injury is a critical factor affecting the prognosis of liver surgery. The aim of this study is to explore the effects of SET8 on hepatic I/R injury and the putative mechanisms.MAIN METHODS: The expression of SET8 and MARK4 in I/R group and sham group were detected both in vivo and in vitro. In addition, mouse and RAW 264.7 cells were transfected with MARK4 siRNA and SET8 siRNA knockdown of MARK4 and SET8, respectively. The expression of SET8, MARK4 and NLRP3-associated proteins were detected after different treatments. The pathology of liver and the serologic detection were detected after different treatments.
KEY FINDINGS: Our present study identified SET domain-containing protein 8 (SET8) as an efficient protein, which can negatively regulate hepatic I/R-mediated inflammatory response and ameliorate hepatic I/R injury by suppressing microtubule affinity-regulating kinase 4 (MARK4)/ NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway. The data showed that MARK4 deficiency inhibited hypoxia/reoxygenation (H/R)-induced NLRP3 inflammasome activation, while SET8 deficiency showed the opposite effect. We further demonstrated that SET8 restrained NLRP3 inflammasome activation by inhibiting MARK4. Moreover, we verified SET8 made protective effect on hepatic I/R injury.
SIGNIFICANCE: SET8 plays an essential role in hepatic ischemia/reperfusion injury in mice by suppressing MARK4/NLRP3 inflammasome pathway. Our results may offer a new strategy to mitigate hepatic I/R injury.

Keywords:  Hepatic ischemia/reperfusion; Inflammation; Microtubule affinity-regulating kinase 4; NLRP3; SET domain-containing protein 8

DOI:  https://doi.org/10.1016/j.lfs.2021.119286
J Extracell Vesicles. 2021 Feb;10(4): e12072

Myocardial ischemia-reperfusion induced cardiac extracellular vesicles harbour proinflammatory features and aggravate heart injury.

Xinyu Ge, Qingshu Meng, Lu Wei, Jing Liu, Mimi Li, Xiaoting Liang, Fang Lin, Yuhui Zhang, Yinzhen Li, Zhongmin Liu, Huimin Fan, Xiaohui Zhou.

  Extracellular vesicles (EVs) curb important biological functions. We previously disclosed that ischemia-reperfusion (IR) induces increased release of EVs (IR-EVs) in the heart. However, the role of IR-EVs in IR pathological process remains poorly understood. Here we found that adoptive transfer of IR-EVs aggravated IR induced heart injury, and EV inhibition by GW4869 reduced the IR injury. Our in vivo and in vitro investigations substantiated that IR-EVs facilitated M1-like polarization of macrophages with increased expression of proinflammatory cytokines. Further, we disclosed the miRNA profile in cardiac EVs and confirmed the enrichment of miRNAs, such as miR-155-5p in IR-EVs compared to EVs from the sham heart (S-EVs). In particular, IR-EVs transferred miR-155-5p to macrophages and enhanced the inflammatory response through activating JAK2/STAT1 pathway. Interestingly, IR-EVs not only boosted the local inflammation in the heart, but even triggered systemic inflammation in distant organs. Taken together, we newly identify an IR-EVs-miR-155-5p-M1 polarization axis in the heart post IR. The EVs derived from IR-injured heart contribute to both local and systemic inflammation. Importantly, EV inhibition by GW4869 is supposed to be a promising therapeutic strategy for IR injury.

Keywords:  extracellular vesicles; heart injury; inflammation; ischemia‐reperfusion injury; macrophage polarization; miRNAs

DOI:  https://doi.org/10.1002/jev2.12072
J Inflamm Res. 2021 ;14 505-518

AST-120 Improves Cardiac Dysfunction in Acute Kidney Injury Mice via Suppression of Apoptosis and Proinflammatory NF-κB/ICAM-1 Signaling.

Wen-Ching Shen, Yu-Hsiang Chou, Li-Shian Shi, Zhi-Wei Chen, Hai-Jian Tu, Xin-Yi Lin, Guei-Jane Wang.

  Purpose: Acute kidney injury (AKI) is a devastating disorder associated with considerably high morbidity and mortality. Reports have shown that AST-120, an oral charcoal adsorbent, can reduce oxidative stress by lowering serum indoxyl sulfate levels. The effects of AST-120 and indoxyl sulfate on kidney injury and cardiac dysfunction were investigated in vivo and in vitro.Patients and Methods: Patients were tracked for enrollment upon receiving a diagnosis of AKI. Plasma was collected to determine the renal and inflammatory parameters. Renal ischemia/reperfusion (I/R) induced AKI or sham operation was performed in C57BL/6J mice. Animals were divided into sham, AKI+vehicle, and AKI+AST-120 groups. Plasma and tissues were assembled after 48 h to assess apoptotic and inflammatory responses. We also conducted human umbilical vein endothelial cell (HUVECs) and HL-1 cardiomyocyte culture studies to determine the underlying mechanisms of indoxyl sulfate's effects. Echocardiography, histopathology, biochemical indexes, ELISA, terminal dUTP nick-end labeling (TUNEL) and Western blot analysis were performed.
Results: The cohort included 25 consecutive patients with AKI and 25 non-AKI. Plasma levels of creatinine, indoxyl sulfate, IL-1β and ICAM-1 were significantly higher in patients with AKI than in non-AKI controls. Plasma levels of blood urea nitrogen, creatinine, indoxyl sulfate, IL-1β and renal tubular injury were increased in mice after renal I/R and were decreased by AST-120 treatment. In addition, AST-120 therapy not only improved the parameters assessed by echocardiography but also substantially attenuated the elevation of plasma BNP. Oral administration of AST-120 significantly downregulated NF-κB/ICAM-1 expression and reduced cell apoptosis in both kidney and heart after renal I/R injury.
Conclusion: Our investigations demonstrated that AST-120 administration improves cardiac dysfunction in AKI mice via the suppression of apoptosis and proinflammatory NF-κB/ICAM-1 signaling.

Keywords:  AST-120; NF-κB; acute kidney injury; apoptosis; cardiac dysfunction; inflammation

DOI:  https://doi.org/10.2147/JIR.S283378
Int J Mol Sci. 2021 Feb 25. pii: 2309. [Epub ahead of print]22(5):

Renal Tubular Epithelial TRPA1 Acts as An Oxidative Stress Sensor to Mediate Ischemia-Reperfusion-Induced Kidney Injury through MAPKs/NF-κB Signaling.

Chung-Kuan Wu, Chia-Lin Wu, Tzong-Shyuan Lee, Yu Ru Kou, Der-Cherng Tarng.

  Oxidative stress and inflammation play important roles in the pathophysiology of acute kidney injury (AKI). Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+-permeable ion channel that is sensitive to reactive oxygen species (ROS). The role of TRPA1 in AKI remains unclear. In this study, we used human and animal studies to assess the role of renal TRPA1 in AKI and to explore the regulatory mechanism of renal TRPA1 in inflammation via in vitro experiments. TRPA1 expression increased in the renal tubular epithelia of patients with AKI. The severity of tubular injury correlated well with tubular TRPA1 or 8-hydroxy-2'-deoxyguanosine expression. In an animal model, renal ischemia-reperfusion injury (IR) increased tubular TRPA1 expression in wild-type (WT) mice. Trpa1-/- mice displayed less IR-induced tubular injury, oxidative stress, inflammation, and dysfunction in kidneys compared with WT mice. In the in vitro model, TRPA1 expression increased in renal tubular cells under hypoxia-reoxygenation injury (H/R) conditions. We demonstrated that H/R evoked a ROS-dependent TRPA1 activation, which elevated intracellular Ca2+ level, increased NADPH oxidase activity, activated MAPK/NF-κB signaling, and increased IL-8. Renal tubular TRPA1 may serve as an oxidative stress sensor and a crucial regulator in the activation of signaling pathways and promote the subsequent transcriptional regulation of IL-8. These actions might be evident in mice with IR or patients with AKI.

Keywords:  TRPA1; acute kidney injury; inflammation; oxidative stress; renal tubule cells

DOI:  https://doi.org/10.3390/ijms22052309
Mol Ther Nucleic Acids. 2021 Mar 05. 23 1066-1077

SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway.

Fengwei Li, Lei Zhang, Hui Xue, Jianbing Xuan, Shu Rong, Kui Wang.

  The hepatoprotection of histone deacetylase sirtuin 1 (SIRT1) has been identified to attenuate ischemia-reperfusion (IR)-triggered inflammation and liver damage. This study was performed to characterize the function of SIRT1 in hepatic IR injury. In in vivo assays on liver-specific knockout mice of SIRT1, we first validated the effect of SIRT1 knockout on liver damage and XBP1/NLRP3 inflammasome activation. Next, we examined whether knockdown of XBP1/NLRP3 or miR-182 agomir could reverse the effect of SIRT1 knockout. In in vitro assays, NCTC1469 cells subjected to hypoxia/reoxygenation (H/R) were transduced with small interfering RNA (siRNA)/activator of SIRT1 or miR-182 agomir to confirm the effect of SIRT1 on NCTC1469 cell behaviors as well as the regulation of miR-182 and the XBP1/NLRP3 signaling pathway. Hepatic IR injury was appreciably aggravated in SIRT1 knockout mice, and SIRT1 knockdown abolished the inhibition of XBP1/NLRP3 inflammasome activation, which was reversed by NLRP3 knockdown, XBP1 knockdown, or miR-182 agomir. Mechanistically, miR-182 expression was positively regulated by SIRT1 in hepatic IR injury in mice, and miR-182 inhibited the expression of XBP1 by binding to the 3' untranslated region (UTR) of XBP1. The histone deacetylase SIRT1 inhibits the downstream XBP1/NLRP3 inflammatory pathway by activating miR-182, thus alleviating hepatic IR injury in mice.

Keywords:  NLRP3; SIRT1; XBP1; hepatic ischemia-reperfusion injury; miR-182

DOI:  https://doi.org/10.1016/j.omtn.2020.11.015
Int J Mol Sci. 2021 Feb 27. pii: 2366. [Epub ahead of print]22(5):

Oxidative Stress Evaluation in Ischemia Reperfusion Models: Characteristics, Limits and Perspectives.

Pauline Chazelas, Clara Steichen, Frédéric Favreau, Patrick Trouillas, Patrick Hannaert, Raphaël Thuillier, Sébastien Giraud, Thierry Hauet, Jérôme Guillard.

  Ischemia reperfusion injury is a complex process consisting of a seemingly chaotic but actually organized and compartmentalized shutdown of cell function, of which oxidative stress is a key component. Studying oxidative stress, which results in an imbalance between reactive oxygen species (ROS) production and antioxidant defense activity, is a multi-faceted issue, particularly considering the double function of ROS, assuming roles as physiological intracellular signals and as mediators of cellular component damage. Herein, we propose a comprehensive overview of the tools available to explore oxidative stress, particularly in the study of ischemia reperfusion. Applying chemistry as well as biology, we present the different models currently developed to study oxidative stress, spanning the vitro and the silico, discussing the advantages and the drawbacks of each set-up, including the issues relating to the use of in vitro hypoxia as a surrogate for ischemia. Having identified the limitations of historical models, we shall study new paradigms, including the use of stem cell-derived organoids, as a bridge between the in vitro and the in vivo comprising 3D intercellular interactions in vivo and versatile pathway investigations in vitro. We shall conclude this review by distancing ourselves from "wet" biology and reviewing the in silico, computer-based, mathematical modeling, and numerical simulation options: (a) molecular modeling with quantum chemistry and molecular dynamic algorithms, which facilitates the study of molecule-to-molecule interactions, and the integration of a compound in a dynamic environment (the plasma membrane...); (b) integrative systemic models, which can include many facets of complex mechanisms such as oxidative stress or ischemia reperfusion and help to formulate integrated predictions and to enhance understanding of dynamic interaction between pathways.

Keywords:  ROS; animal models; antioxidant factors; ischemia-reperfusion injury; molecular modeling models; organoids; oxidative stress

DOI:  https://doi.org/10.3390/ijms22052366
Acta Pharm Sin B. 2021 Feb;11(2): 394-405

Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury.

Xu Jing, Dandan Ren, Fei Gao, Ye Chen, Xiao Wu, Yue Han, Qingsheng Han, Liang Li, Xiaojie Wang, Wei Tang, Yan Zhang.

  Recent studies have shown that programmed cell death 4 (PDCD4) modulates distinct signal transduction pathways in different pathological conditions. Despite acute and chronic immune responses elicited by ischemia contributing to the functional deterioration of the kidney, the contributions and mechanisms of PDCD4 in acute kidney injury (AKI) have remained unclear. Using two murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI, we found that PDCD4 deficiency markedly ameliorated renal dysfunction and inflammatory responses in AKI mice. Consistently, upregulation of PDCD4 was also confirmed in the kidneys from patients with biopsy confirmed acute tubular necrosis from a retrospective cohort study. Moreover, we found that overexpression of Fgr, a member of the tyrosine kinase family, dramatically aggravated renal injury and counteracted the protective effects of PDCD4 deficiency in AKI mice. We discovered that FGR upregulated NOTCH1 expression through activating STAT3. Most importantly, we further found that systemic administration of ponatinib, a tyrosine kinase inhibitor, significantly ameliorated AKI in mice. In summary, we identified that PDCD4 served as an important regulator, at least in part, of FGR/NOTCH1-mediated tubular apoptosis and inflammation in AKI mice. Furthermore, our findings suggest that ponatinib-mediated pharmacologic targeting of this pathway had therapeutic potential for mitigating AKI.

Keywords:  Acute kidney injury; Cell death; FGR; Inflammation; Ischemia–reperfusion injury; NOTCH1; PDCD4; Tyrosine kinase

DOI:  https://doi.org/10.1016/j.apsb.2020.10.024
Int J Mol Sci. 2021 Feb 13. pii: 1864. [Epub ahead of print]22(4):

Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies.

Norbert Nemeth, Katalin Peto, Zsuzsanna Magyar, Zoltan Klarik, Gabor Varga, Mihai Oltean, Anna Mantas, Zoltan Czigany, Rene H Tolba.

  Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular-pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.

Keywords:  hemorheology; hepatic ischemia-reperfusion; microcirculation; preventive and therapeutic strategies

DOI:  https://doi.org/10.3390/ijms22041864
Sci Rep. 2021 Mar 04. 11(1): 5135

Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry.

Aleksandra Aljakna Khan, Nasim Bararpour, Marie Gorka, Timothée Joye, Sandrine Morel, Christophe A Montessuit, Silke Grabherr, Tony Fracasso, Marc Augsburger, Brenda R Kwak, Aurélien Thomas, Sara Sabatasso.

Diagnostics of myocardial infarction in human post-mortem hearts can be achieved only if ischemia persisted for at least 6-12 h when certain morphological changes appear in myocardium. The initial 4 h of ischemia is difficult to diagnose due to lack of a standardized method. Developing a panel of molecular tissue markers is a promising approach and can be accelerated by characterization of molecular changes. This study is the first untargeted metabolomic profiling of ischemic myocardium during the initial 4 h directly from tissue section. Ischemic hearts from an ex-vivo Langendorff model were analysed using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) at 15 min, 30 min, 1 h, 2 h, and 4 h. Region-specific molecular changes were identified even in absence of evident histological lesions and were segregated by unsupervised cluster analysis. Significantly differentially expressed features were detected by multivariate analysis starting at 15 min while their number increased with prolonged ischemia. The biggest significant increase at 15 min was observed for m/z 682.1294 (likely corresponding to S-NADHX-a damage product of nicotinamide adenine dinucleotide (NADH)). Based on the previously reported role of NAD+/NADH ratio in regulating localization of the sodium channel (Nav1.5) at the plasma membrane, Nav1.5 was evaluated by immunofluorescence. As expected, a fainter signal was observed at the plasma membrane in the predicted ischemic region starting 30 min of ischemia and the change became the most pronounced by 4 h. Metabolomic changes occur early during ischemia, can assist in identifying markers for post-mortem diagnostics and improve understanding of molecular mechanisms.

DOI: https://doi.org/10.1038/s41598-021-84523-z
Cell Death Discov. 2021 Mar 02. 7(1): 44

Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation.

Ji Zhang, Jiasi Zhang, Haiqiang Ni, Yanfeng Wang, Gaurav Katwal, Yuanyuan Zhao, Kailun Sun, Mengqin Wang, Qingwen Li, Gen Chen, Yun Miao, Nianqiao Gong.

Ischemia-reperfusion (IR) injury to the renal epithelia is associated with endoplasmic reticulum stress (ERS) and mitochondria dysfunction, which lead to oxidative stress-induced acute kidney injury (AKI). X-box binding protein 1 (XBP1), an ERS response protein, could play a prominent role in IR-induced AKI. In this study, we revealed that XBP1 and its downstream target HRD1 participated in the crosstalk between ERS and mitochondrial dysfunction via regulation of NRF2/HO-1-mediated reactive oxidative stress (ROS) signaling. Mice with reduced expression of XBP1 (heterozygous Xbp1±) were resistant to IR-induced AKI due to the enhanced expression of NRF2/HO-1 and diminished ROS in the kidney. Downregulation of XBP1 in renal epithelial cells resulted in reduced HRD1 expression and increased NRF2/HO-1 function, accompanied with enhanced antioxidant response. Furthermore, HRD1 served as an E3-ligase to facilitate the downregulation of NRF2 through ubiquitination-degradation pathway, and the QSLVPDI motif on NRF2 constituted an active site for its interaction with HRD1. Thus, our findings unveil an important physiological role for XBP1/HRD1 in modulating the antioxidant function of NRF2/HO-1 in the kidney under stress conditions. Molecular therapeutic approaches that target XBP1-HRD1-NRF2 pathway may represent potential effective means to treat renal IR injury.

DOI: https://doi.org/10.1038/s41420-021-00425-z
J Mol Endocrinol. 2021 Feb 01. pii: JME-20-0314.R1. [Epub ahead of print]

Role of AMPK in the protective effects exerted by triiodothyronine in ischemic-reperfused myocardium.

Romina Hermann, Victoria Evangelina Mestre Cordero, María de Las Mercedes Fernández Pazos, Mailen Florencia Córdoba, Federico Joaquín Reznik, Débora Elisabet Vélez, Andrea Lorena Fellet, María Gabriela Marina Prendes.

Recent studies have provided evidence that triiodothyronine (T3) might play an effective role in the recovery of ischemic myocardium, through the preservation of mitochondrial function and the improvement of energy substrate metabolism. To this respect, it has been suggested that T3 could activate AMP-activated protein kinase (AMPK), the cellular 'fuel-gauge' enzyme, although its role has yet to be elucidated. The aim of the present study was to investigate the effects produced by acute treatment with T3 (60 nM) and the pharmacological inhibition of AMPK by compound C, on isolated rat left atria subjected to 75 min simulated ischemia-75 min reperfusion. Results showed that T3 increased AMPK activation during simulated ischemia-reperfusion, while compound C prevented it. At the end of simulated reperfusion, acute T3 treatment increased contractile function recovery and cellular viability conservation. Mitochondrial ultrastructure was better preserved in the presence of T3, as well as mitochondrial ATP production rate and tissue ATP content. Calcium retention capacity, parameter widely used as an indicator of the resistance of mitochondrial permeability transition pore (MPTP) to opening, and GSK-3 phosphorylation, a master switch enzyme that limits MPTP opening, were increased by T3 administration. All these beneficial effects exerted by T3 acute treatment were prevented when compound C was co-administrated. The present study provided original evidence that T3 enhances intrinsic activation of AMPK during myocardial ischemia-reperfusion, being this enzyme involved, at least in part, in the protective effects exerted by T3, contributing to mitochondrial structure and function preservation, post-ischemic contractile recovery and conservation cellular viability.

DOI: https://doi.org/10.1530/JME-20-0314
Int J Mol Sci. 2021 Feb 22. pii: 2157. [Epub ahead of print]22(4):

The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation-Where Have We Gone So Far?

Anila Duni, Vassilios Liakopoulos, Vasileios Koutlas, Charalampos Pappas, Michalis Mitsis, Evangelia Dounousi.

  The damage of the endothelial glycocalyx as a consequence of ischemia and/or reperfusion injury (IRI) following kidney transplantation has come at the spotlight of research due to potential associations with delayed graft function, acute rejection as well as long-term allograft dysfunction. The disintegration of the endothelial glycocalyx induced by IRI is the crucial event which exposes the denuded endothelial cells to further inflammatory and oxidative damage. The aim of our review is to present the currently available data regarding complex links between shedding of the glycocalyx components, like syndecan-1, hyaluronan, heparan sulphate, and CD44 with the activation of intricate immune system responses, including toll-like receptors, cytokines and pro-inflammatory transcription factors. Evidence on modes of protection of the endothelial glycocalyx and subsequently maintenance of endothelial permeability as well as novel nephroprotective molecules such as sphingosine-1 phosphate (S1P), are also depicted. Although advances in technology are making the visualization and the analysis of the endothelial glycocalyx possible, currently available evidence is mostly experimental. Ongoing progress in understanding the complex impact of IRI on the endothelial glycocalyx, opens up a new era of research in the field of organ transplantation and clinical studies are of utmost importance for the future.

Keywords:  endothelial glycocalyx; immune responses; inflammation; ischemia and/or reperfusion injury; kidney transplantation

DOI:  https://doi.org/10.3390/ijms22042157
J Mol Cell Cardiol. 2021 Feb 27. pii: S0022-2828(21)00048-1. [Epub ahead of print]

Txnip C247S mutation protects the heart against acute myocardial infarction.

Yoshinobu Nakayama, Nobuhiro Mukai, Bing F Wang, Kristen Yang, Parth Patwari, Richard N Kitsis, Jun Yoshioka.

  RATIONALE: Thioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo.OBJECTIVE: A single mutation of Txnip, C247S, abolishes the binding of Txnip with thioredoxin. Using a conditional and inducible approach with a mouse model of a mutant Txnip that does not bind thioredoxin, we tested whether the interaction of thioredoxin with Txnip is required for Txnip's pro-oxidative or cytotoxic effects in the heart.
METHODS AND RESULTS: Overexpression of Txnip C247S in cells resulted in a reduction in ROS, due to an inability to inhibit thioredoxin. Hypoxia (1% O2, 24 h)-induced killing effects of Txnip were decreased by lower levels of cellular ROS in Txnip C247S-expressing cells compared with wild-type Txnip-expressing cells. Then, myocardial ischemic injuries were assessed in the animal model. Cardiomyocyte-specific Txnip C247S knock-in mice had better survival with smaller infarct size following MI compared to control animals. The absence of Txnip's inhibition of thioredoxin promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage induced by myocardial infarction. Furthermore, an unbiased RNA sequencing screen identified that hypoxia-inducible factor 1 signaling pathway was involved in Txnip C247S-mediated cardioprotective mechanisms.
CONCLUSION: Txnip is a cysteine-containing redox protein that robustly regulates the thioredoxin system via a disulfide bond-switching mechanism in adult cardiomyocytes. Our results provide the direct in vivo evidence that regulation of redox state by Txnip is a crucial component for myocardial homeostasis under ischemic stress.

Keywords:  Cell death; Metabolism; Mitochondria; ROS

DOI:  https://doi.org/10.1016/j.yjmcc.2021.02.013
Immunity. 2021 Mar 01. pii: S1074-7613(21)00070-4. [Epub ahead of print]

Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade.

Stefan Roth, Jiayu Cao, Vikramjeet Singh, Steffen Tiedt, Gabriel Hundeshagen, Ting Li, Julia D Boehme, Dhruv Chauhan, Jie Zhu, Alessio Ricci, Oliver Gorka, Yaw Asare, Jun Yang, Mary S Lopez, Markus Rehberg, Dunja Bruder, Shengxiang Zhang, Olaf Groß, Martin Dichgans, Veit Hornung, Arthur Liesz.

  Loss of lymphocytes, particularly T cell apoptosis, is a central pathological event after severe tissue injury that is associated with increased susceptibility for life-threatening infections. The precise immunological mechanisms leading to T cell death after acute injury are largely unknown. Here, we identified a monocyte-T cell interaction driving bystander cell death of T cells in ischemic stroke and burn injury. Specifically, we found that stroke induced a FasL-expressing monocyte population, which led to extrinsic T cell apoptosis. This phenomenon was driven by AIM2 inflammasome-dependent interleukin-1β (IL-1β) secretion after sensing cell-free DNA. Pharmacological inhibition of this pathway improved T cell survival and reduced post-stroke bacterial infections. As such, this study describes inflammasome-dependent monocyte activation as a previously unstudied cause of T cell death after injury and challenges the current paradigms of post-injury lymphopenia.

Keywords:  AIM2; Fas; IL-1; T cell; burn; cell death; inflammasome; stroke; tissue injury

DOI:  https://doi.org/10.1016/j.immuni.2021.02.004