bims-heshmo 2021-03-21 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021‒03‒21
twelve papers selected by
Andreia Luís
Ludwig Boltzmann Institute

Exosomal LINC00174 derived from vascular endothelial cells attenuates myocardial I/R injury via p53-mediated autophagy and apoptosis.
Cardiomyocyte protective effects of thyroid hormone during hypoxia/reoxygenation injury through activating of IGF-1-mediated PI3K/Akt signalling.
miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury.
The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia-reperfusion in vivo.
Glycocalyx components affect platelet function, whole blood coagulation, and fibrinolysis: an in vitro study suggesting a link to trauma-induced coagulopathy.
Splenectomy is associated with altered leukocyte kinetics after severe trauma.
MicroRNA-877-5p alleviates ARDS via enhancing PI3K/Akt path by targeting CDKN1B both in vivo and in vitro.
Expression of Lactate Dehydrogenase A and B isoforms in the mouse kidney.
Hemostatic Strategies in Trauma.
Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression.
Systemic and local cardiac inflammation after experimental long bone fracture, traumatic brain injury and combined trauma in mice.
Intestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies.

Mol Ther Nucleic Acids. 2021 Mar 05. 23 1304-1322

Exosomal LINC00174 derived from vascular endothelial cells attenuates myocardial I/R injury via p53-mediated autophagy and apoptosis.

Qiang Su, Xiang-Wei Lv, Yu-Li Xu, Ru-Ping Cai, Ri-Xin Dai, Xi-Heng Yang, Wei-Kun Zhao, Bing-Hui Kong.

  In this study, we aim to investigate the regulation of specific long non-coding RNAs (lncRNAs) on the progression of ischemia/reperfusion (I/R) injury. We identified and characterized the exosomes derived from mouse primary aortic endothelial cells. Subsequently, we found that these exosomes expressed typical exosomal markers and high levels of LINC00174, which significantly ameliorated I/R-induced myocardial damage and suppressed the apoptosis, vacuolation, and autophagy of myocardial cells. Mechanistic approaches revealed that LINC00174 directly interacted with SRSF1 to suppress the expression of p53, thus restraining the transcription of myocardin and repressing the activation of the Akt/AMPK pathway that was crucial for autophagy initiation in I/R-induced myocardial damage. Moreover, this molecular mechanism was verified by in vivo study. In summary, exosomal LINC00174 generated from vascular endothelial cells repressed p53-mediated autophagy and apoptosis to mitigate I/R-induced myocardial damage, suggesting that targeting LINC00174 may be a novel strategy to treat I/R-induced myocardial infarction.

Keywords:  LINC00174; apoptosis; autophagy; ischemia/reperfusion injury; p53; vascular endothelial cells

DOI:  https://doi.org/10.1016/j.omtn.2021.02.005
J Cell Mol Med. 2021 Mar 16.

Cardiomyocyte protective effects of thyroid hormone during hypoxia/reoxygenation injury through activating of IGF-1-mediated PI3K/Akt signalling.

Bin Zeng, Lei Liu, Xiaoting Liao, Caixia Zhang.

  Ischaemia/reperfusion (I/R) injury is a common clinical condition that results in apoptosis and oxidative stress injury. Thyroid hormone was previously reported to elicit cardiac myocyte hypertrophy and promote cardiac function after cardiac injury. We used an in vivo mouse model of I/R injury and in vitro primary cardiomyocyte culture assays to investigate the effects of thyroid hormone on cardiomyocytes during hypoxia/reoxygenation (H/R) injury. The results showed that T3 pretreatment in vivo significantly improved left ventricular function after I/R injury. In vitro, T3 pretreatment decreased cell apoptosis rate, inhibited caspase-3 activity and decreased the Bax/Bcl-2 ration induced by H/R injury. T3 pretreatment significantly attenuated the loss of mitochondrial membrane potential. Furthermore, it was observed that T3 diminished the expression of NCX1 protein and decreased SERCA2a protein expression in H/R-induced cardiomyocytes, and T3 prevented intracellular Ca2+ increase during H/R injury. Also, T3 increased the expression of IGF-1, and PI3K/Akt signalling in cardiomyocytes under H/R-induced injury, and that the protective effect of T3 against H/R-induced injury was blocked by the PI3K inhibitor LY294002. IGF-1 receptor (IGF-1R) inhibitor GSK1904529A significantly inhibited the expression of IGF-1R and PI3K/Akt signalling. In summary, T3 pretreatment protects cardiomyocytes against H/R-induced injury by activating the IGF-1-mediated PI3K/Akt signalling pathway.

Keywords:  Akt signalling pathway; Ca2+ homeostasis; PI3K; apoptosis; mitochondrial membrane potential; triiodothyronine

DOI:  https://doi.org/10.1111/jcmm.16389
Basic Res Cardiol. 2021 Mar 19. 116(1): 19

miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury.

Ji-Hye Jung, Gentaro Ikeda, Yuko Tada, Daniel von Bornstädt, Michelle R Santoso, Christine Wahlquist, Siyeon Rhee, Young-Jun Jeon, Anthony C Yu, Connor G O'brien, Kristy Red-Horse, Eric A Appel, Mark Mercola, Joseph Woo, Phillip C Yang.

  Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.

Keywords:  Cell cycle re-entry; EVs; Endogenous cardiac repair mechanism; IPSCs; MiRNAs; Myocardial Infarction

DOI:  https://doi.org/10.1007/s00395-021-00858-8
Sci Rep. 2021 Mar 17. 11(1): 6152

The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia-reperfusion in vivo.

Khairat Bahgat Youssef El Baradie, Mohammad B Khan, Bharati Mendhe, Jennifer Waller, Frederick O'Brien, Mark W Hamrick.

Acute ischemia-reperfusion injury in skeletal muscle is a significant clinical concern in the trauma setting. The mitochondrial permeability transition inhibitor NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal muscle are, however, not well understood. We first used an in vitro model of muscle cell ischemia in which primary human skeletal myoblasts were exposed to hypoxic conditions (1% O2 and 5% CO2) for 6 h. Cells were treated with NIM-811 (0-20 µM). MTS assay was used to quantify cell survival and LDH assay to quantify cytotoxicity 2 h after treatment. Results indicate that NIM-811 treatment of ischemic myotubes significantly increased cell survival and decreased LDH in a dose-dependent manner. We then examined NIM-811 effects in vivo using orthodontic rubber bands (ORBs) for 90 min of single hindlimb ischemia. Mice received vehicle or NIM-811 (10 mg/kg BW) 10 min before reperfusion and 3 h later. Ischemia and reperfusion were monitored using laser speckle imaging. In vivo data demonstrate that mice treated with NIM-811 showed increased gait speed and improved Tarlov scores compared to vehicle-treated mice. The ischemic limbs of female mice treated with NIM-811 showed significantly lower levels of MCP-1, IL-23, IL-6, and IL-1α compared to limbs of vehicle-treated mice. Similarly, male mice treated with NIM-811 showed significantly lower levels of MCP-1 and IL-1a. These findings are clinically relevant as MCP-1, IL-23, IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after ischemia-reperfusion injury.

DOI: https://doi.org/10.1038/s41598-021-85753-x
BMC Anesthesiol. 2021 Mar 19. 21(1): 83

Glycocalyx components affect platelet function, whole blood coagulation, and fibrinolysis: an in vitro study suggesting a link to trauma-induced coagulopathy.

Martin W Britten, Laura Lümers, Kenji Tominaga, Jürgen Peters, Daniel Dirkmann.

  BACKGROUND: The mechanisms of trauma induced coagulopathy (TIC) are considered multifactorial. Amongst others, however, shedding of the endothelial glycocalyx resulting in increased concentrations of glycocalyx fragments in plasma might also play a role. Thus, we hypothesized that shedded glycocalyx components affect coagulation and may act as humoral mediators of TIC.METHODS: To investigate effects of heparan sulfate, chondroitin sulfate, syndecan-1, versican, and thrombomodulin we added these fragments to in vitro assays of whole blood from healthy volunteers to yield concentrations observed in trauma patients. Platelet function, whole blood coagulation, and fibrinolysis were measured by standard coagulation tests, impedance aggregometry (IA), and viscoelastic tests (VET). To assess dose-response relationships, we performed IA with increasing concentrations of versican and VET with increasing concentrations of thrombomodulin.
RESULTS: Intrinsically activated clotting times (i.e., activated partial thromboplastin time and intrinsically activated VET with and without heparinase) were unaffected by any glycocalyx fragment. Thrombomodulin, however, significantly and dose-dependently diminished fibrinolysis as assessed by VET with exogenously added rt-PA, and increased rt-PA-induced lysis Indices after 30 (up to 108% of control, p < 0,0001), 45 (up to 368% of control, p < 0,0001), and 60 min (up to 950% of control, p < 0,0001) in VET. Versican impaired platelet aggregation in response to arachidonic acid (up to - 37,6%, p < 0,0001), ADP (up to - 14,5%, p < 0,0001), and collagen (up to - 31,8%, p < 0,0001) in a dose-dependent manner, but did not affect TRAP-6 induced platelet aggregation. Clotting time in extrinsically activated VET was shortened by heparan sulfate (- 7,2%, p = 0,024), chondroitin sulfate (- 11,6%, p = 0,016), versican (- 13%, p = 0,012%), and when combined (- 7,2%, p = 0,007).
CONCLUSIONS: Glycocalyx components exert distinct inhibitory effects on platelet function, coagulation, and fibrinolysis. These data do not support a 'heparin-like auto-anticoagulation' by shed glycosaminoglycans but suggest a possible role of versican in trauma-induced thrombocytopathy and of thrombomodulin in trauma-associated impairment of endogenous fibrinolysis.

Keywords:  Glycosaminoglycans; Shock; Syndecan-1; Thrombomodulin; Versicans

DOI:  https://doi.org/10.1186/s12871-021-01300-1
Eur J Med Res. 2021 Mar 15. 26(1): 26

Splenectomy is associated with altered leukocyte kinetics after severe trauma.

Michel Paul Johan Teuben, Arne Hollman, Taco Blokhuis, Roman Pfeifer, Roy Spijkerman, Henrik Teuber, Hans-Christoph Pape, Luke Petrus Hendrikus Leenen.

  BACKGROUND: Inadequate activation of the innate immune system after trauma can lead to severe complications such as Acute Respiratory Distress Syndrome and Multiple Organ Dysfunction Syndrome. The spleen is thought to modulate the cellular immune system. Furthermore, splenectomy is associated with improved outcome in severely injured trauma patients. We hypothesized that a splenectomy alters the cellular immune response in polytrauma.METHODS: All adult patients with an ISS ≥ 16 and suffering from splenic or hepatic injuries were selected from our prospective trauma database. Absolute leukocyte numbers in peripheral blood were measured. White blood cell kinetics during the first 14 days were compared between splenectomized patients, patients treated surgically for liver trauma and nonoperatively treated individuals.
RESULTS: A total of 129 patients with a mean ISS of 29 were included. Admission characteristics and leukocyte numbers were similar in all groups, except for slightly impaired hemodynamic status in patients with operatively treated liver injuries. On admission, leukocytosis occurred in all groups. During the first 24 h, leukopenia developed gradually, although significantly faster in the operatively treated patients. Thereafter, leukocyte levels normalized in all nonoperatively treated cases whereas leukocytosis persisted in operatively treated patients. This effect was significantly more prominent in splenectomized patients than all other conditions.
CONCLUSIONS: This study demonstrates that surgery for intra-abdominal injuries is associated with an early drop in leucocyte numbers in peripheral blood. Moreover, splenectomy in severely injured patients is associated with an altered cellular immune response reflected by a persistent state of prominent leukocytosis after trauma.

Keywords:  Inflammation; Leukocytes; Spleen; Splenectomy; Trauma

DOI:  https://doi.org/10.1186/s40001-021-00497-8
Int Immunopharmacol. 2021 Mar 15. pii: S1567-5769(21)00166-1. [Epub ahead of print]95 107530

MicroRNA-877-5p alleviates ARDS via enhancing PI3K/Akt path by targeting CDKN1B both in vivo and in vitro.

Kaili Li, Zuoting Huang, Shijing Tian, Yi Chen, Yuan Yuan, Jianghan Yuan, Xuan Zou, Fachun Zhou.

  Acute respiratory distress syndrome (ARDS) is a public health problem with high morbidity and mortality worldwide due to lacking known characteristic biomarkers and timely intervention. Pulmonary edema caused by inflammation and pulmonary microvascular endothelial cell disfunction is the main pathophysiological change of ARDS. Circulating microRNAs (miRNAs) are differentially expressed between subjects who did and did not develop ARDS. Many miRNAs have been exemplified to be involved in ARDS and could represent the novel therapeutic targets, but the role of microRNA-877-5p (miR-877-5p) in ARDS and its regulatory mechanisms are still unknown. Herein, we explore the underlying function of miR-877-5p toward anesis of ARDS and addressed that miRNA-877 can reduce the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 thus attenuating the damage of pulmonary microvascular endothelial cells (HPMECs). Have further evaluated the protein expression, we detected that miR-877-5p contributed to the relief of ARDS by suppressing Cyclin-dependent kinase inhibitor 1B (CDKN1B), which serves as a regulator of endothelial cell polarization and migration through phosphatidylinositol-3-kinase and AKT (PI3K/Akt) signaling pathway. Besides, we noticed that CDKN1B restrains cell differentiation by inhibiting Cdk2 (cyclin-dependent kinase 2), instead of Cdk4 (cyclin-dependent kinase 4), during which the nuclear translocation of CDKN1B may participate. Together, our works testified that miR-877-5p might suppress inflammatory responses and promote HPMECs regeneration via targeting CDKN1B by modulation of Cdk2 and PI3K/Akt path. These molecules likely modulating ARDS progression may inform biomarkers and therapeutic development.

Keywords:  (Acute respiratory distress syndrome) ARDS; (Cyclin-dependent kinase inhibitor 1B) CDKN1B; Cdk2; Endothelial barrier; PI3K/Akt signaling pathway; microRNA-877-5p

DOI:  https://doi.org/10.1016/j.intimp.2021.107530
Am J Physiol Renal Physiol. 2021 Mar 15.

Expression of Lactate Dehydrogenase A and B isoforms in the mouse kidney.

Gunars Osis, Amie M Traylor, Laurence M Black, Daryll Spangler, James F George, Abolfazl Zarjou, Jill W Verlander, Anupam Agarwal.

  Cellular metabolic rates in the kidney are critical for maintaining renal function. In a hypoxic milieu, cells rely on glycolysis to meet energy needs, resulting in the generation of pyruvate and NADH. In the absence of oxidative phosphorylation, the continuation of glycolysis is dependent on the regeneration of NAD+ from NADH accompanied by the fermentation of pyruvate to lactate. This reaction is catalyzed by lactate dehydrogenase (LDH) isoform A (LDHA), while isoform B (LDHB) catalyzes the opposite reaction. LDH is widely used as a potential injury marker, yet the precise isoform-specific cellular localization of the enzyme along the nephron has not been characterized. By combining immunohistochemistry and single-cell RNA sequencing data on healthy mouse kidneys we identified that LDHA is primarily expressed in proximal segments while LDHB is expressed in the distal parts of the nephron. In vitro studies in mouse and human renal proximal tubule cells show an increase in LDHA following hypoxia with no change in LDHB. We observed that the overall expression of both LDHA and LDHB decreased following renal ischemia-reperfusion injury (IRI) as well as in the adenine-diet induced model of chronic kidney disease. Single-nucleus RNA sequencing analyses of kidneys following IRI revealed a significant decline in the number of cells expressing Ldha and Ldhb, however, cells that were positive showed increased average expression post-injury which subsided during the recovery phase. These data provide information on the cell-specific expression of LDHA and LDHB in the normal kidney as well as following acute and chronic kidney disease.

Keywords:  lactate; metabolism; nephron; proximal tubule; pyruvate

DOI:  https://doi.org/10.1152/ajprenal.00628.2020
AACN Adv Crit Care. 2021 Mar 15. 32(1): 51-63

Hemostatic Strategies in Trauma.

Paul Thurman.

  Bleeding is a leading cause of early death from trauma. Consequently, effective hemostasis can improve the odds of survival after severe traumatic injury. Understanding the pathophysiology of trauma-induced coagulopathy can provide insights into effective strategies to assess and halt hemorrhage. Both physical assessment and appropriate laboratory studies are important in the diagnosis and evaluation of coagulopathy to identify the most effective mechanical and pharmacological strategies to achieve hemostasis. This article uses a case study approach to explore evidence-based techniques to evaluate hemorrhage and strategies to promote hemostasis.

Keywords:  acute traumatic coagulopathy; hemorrhage; trauma-induced coagulopathy

DOI:  https://doi.org/10.4037/aacnacc2021473
Front Immunol. 2021 ;12 622601

Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression.

Christian B Bergmann, Nadine Beckmann, Christen E Salyer, Marc Hanschen, Peter A Crisologo, Charles C Caldwell.

  In sepsis and trauma, pathogens and injured tissue provoke a systemic inflammatory reaction which can lead to overwhelming inflammation. Concurrent with the innate hyperinflammatory response is adaptive immune suppression that can become chronic. A current key issue today is that patients who undergo intensive medical care after sepsis or trauma have a high mortality rate after being discharged. This high mortality is thought to be associated with persistent immunosuppression. Knowledge about the pathophysiology leading to this state remains fragmented. Immunosuppressive cytokines play an essential role in mediating and upholding immunosuppression in these patients. Specifically, the cytokines Interleukin-10 (IL-10), Transforming Growth Factor-β (TGF-β) and Thymic stromal lymphopoietin (TSLP) are reported to have potent immunosuppressive capacities. Here, we review their ability to suppress inflammation, their dynamics in sepsis and trauma and what drives the pathologic release of these cytokines. They do exert paradoxical effects under certain conditions, which makes it necessary to evaluate their functions in the context of dynamic changes post-sepsis and trauma. Several drugs modulating their functions are currently in clinical trials in the treatment of other pathologies. We provide an overview of the current literature on the effects of IL-10, TGF-β and TSLP in sepsis and trauma and suggest therapeutic approaches for their modulation.

Keywords:  IL-10; chronic critical illness; immunosuppression; thymic stromal lymphopoietin; transforming growth factor β

DOI:  https://doi.org/10.3389/fimmu.2021.622601
J Orthop Translat. 2021 May;28 39-46

Systemic and local cardiac inflammation after experimental long bone fracture, traumatic brain injury and combined trauma in mice.

Ina Lackner, Birte Weber, Melanie Haffner-Luntzer, Simona Hristova, Florian Gebhard, Charles Lam, Kazuhito Morioka, Ralph S Marcucio, Theodore Miclau, Miriam Kalbitz.

  Background: Trauma is the leading cause of death and disability worldwide, especially in the young population. Cardiac injuries are an independent predictor for a poor overall outcome after trauma. The aim of the present study was to analyze systemic inflammation as well as local cardiac inflammation after experimental limb-, neuro- and combined trauma in mice.Methods: Male C57BL/6 mice received either a closed tibia fracture (Fx), isolated traumatic brain injury (TBI) or a combination of both (Fx + TBI). Control animals underwent sham procedure. After 6 and 24 h, systemic levels of inflammatory mediators were analyzed, respectively. Locally, cardiac inflammation and cardiac structural alterations were investigated in left ventricular tissue of mice 6 and 24 h after trauma.
Results: Mice showed enhanced systemic inflammation after combined trauma, which was manifested by increased levels of KC, MCP-1 and G-CSF. Locally, mice exhibited increased expression of inflammatory cytokines (IL-1β, TNF) in heart tissue, which was probably mediated via toll-like receptor (TLR) signaling. Furthermore, mice demonstrated a redistribution of connexin 43 in cardiac tissue, which appeared predominantly after combined trauma. Besides inflammation and structural cardiac alterations, expression of glucose transporter 4 (GLUT4) mRNA was increased in the heart early after TBI and after combination of TBI and limb fracture, indicating a modification of energy metabolism. Early after combination of TBI and tibia fracture, nitrosative stress was increased, manifested by elevation of nitrotyrosine in cardiac tissue. Finally, mice showed a trend of increased systemic levels of cardiac troponin I and heart-fatty acid binding protein (HFABP) after combined trauma, which was associated with a significant decrease of troponin I and HFABP mRNA expression in cardiac tissue after TBI and combination of TBI and limb fracture.
Conclusion: Mice exhibited early cardiac alterations as well as alterations in cardiac glucose transporter expression, indicating a modification of energy metabolism, which might be linked to increased systemic- and local cardiac inflammation after limb-, neuro- and combined trauma. These cardiac alterations might predispose individuals for secondary cardiac damage after trauma that might compromise cardiac function after TBI and long bone fracture.
Translational potential statement: Injuries to the head and extremities frequently occur after severe trauma. In our study, we analyzed the effects of closed tibia fracture, isolated TBI, and the combination of both injuries with regard to the development of post-traumatic secondary cardiac injuries.

Keywords:  Cytokines; Damage-associated molecular patterns; Heart-fatty acid binding protein; Secondary cardiac injury; Toll-like receptor; Troponin I

DOI:  https://doi.org/10.1016/j.jot.2020.12.003
Biomed Pharmacother. 2021 Mar 16. pii: S0753-3322(21)00267-5. [Epub ahead of print]138 111482

Intestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies.

Jun Wang, Wentong Zhang, Guosheng Wu.

  Intestinal ischemic reperfusion injury (IIRI) is a life-threatening condition with high morbidity and mortality in the clinic. IIRI was induced by intestinal ischemic diseases such as, small bowel transplantation, aortic aneurysm surgery, and strangulated hernias. Although related mechanisms have not been fully elucidated, during the last decade, researches have demonstrated that many factors are crucial in the pathological process, including oxidative stress (OS), epithelial barrier function disorder, and so on. Rats model, as the most applied animal IIRI model, provides specific targets for researches and therapeutic strategies. Moreover, various treatment strategies such as, anti-oxidative stress, anti-apoptosis, and anti-inflammation, have shown promising effects in alleviating IIRI. However, current researches cannot solve the clinical problems of IIRI, and specific treatment strategies are still needed to be exploited. This review focuses on a recommended experimental IIRI rat model and understanding of the involved mechanisms such as, OS, gut bacteria translocation, apoptosis, and necroptosis, aim at providing novel ideas for therapeutic strategies of IIRI.

Keywords:  Apoptosis; Gut microbiota; Intestinal ischemic reperfusion injury; Oxidative stress; Rats

DOI:  https://doi.org/10.1016/j.biopha.2021.111482