bims-heshmo 2021-02-21 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–02–21
twenty papers selected by
Andreia Luís, Ludwig Boltzmann Institute

Ophiopogonin A Alleviates Hemorrhagic Shock-Induced Renal Injury via Induction of Nrf2 Expression.
ER stress preconditioning ameliorates liver damage after hemorrhagic shock and reperfusion.
Genome-wide landscape of mRNAs, microRNAs, lncRNAs, and circRNAs in hemorrhagic shock-induced ALI/ARDS in rats.
Extracellular Vesicles as an Emerging Frontier in Spinal Cord Injury Pathobiology and Therapy.
Hypobaria-Induced Oxidative Stress Facilitates Homocysteine Transsulfuration and Promotes Glutathione Oxidation in Rats with Mild Traumatic Brain Injury.
Cardioprotective Effect of Echinatin Against Ischemia/Reperfusion Injury: Involvement of Hippo/Yes-Associated Protein Signaling.
Critical roles of sphingosine kinase 1 in the regulation of neuroinflammation and neuronal injury after spinal cord injury.
Sodium butyrate relieves lung ischemia-reperfusion injury by inhibiting NF-κB and JAK2/STAT3 signaling pathways.
Transfer of lncRNA UCA1 by hUCMSCs-derived exosomes protects against hypoxia/reoxygenation injury through impairing miR-143-targeted degradation of Bcl-2.
S-1-propenylcysteine improves TNF-α-induced vascular endothelial barrier dysfunction by suppressing the GEF-H1/RhoA/Rac pathway.
Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways.
Restoration of NRF2 attenuates myocardial ischemia reperfusion injury through mediating microRNA-29a-3p/CCNT2 axis.
Neohesperidin alleviated pathological damage and immunological imbalance in rat myocardial ischemia-reperfusion injury via inactivation of JNK and NF-κB p65.
Trauma-induced lung injury is associated with infiltration of activated TLR expressing myeloid cells.
Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36.
Plasma concentrations of syndecan-1 are dependent on kidney function.
Mast cell activation, TLR4-NF-κB/TNF-α pathway variation in rats' intestinal ischemia-reperfusion injury and Tongxinluo's therapeutic effect.
Neuroprotective roles of HAX-1 in ischemic neuronal injury.
Glutaredoxin 2 protects cardiomyocytes from hypoxia/reoxygenation-induced injury by suppressing apoptosis, oxidative stress, and inflammation via enhancing Nrf2 signaling.
Schizandrin B attenuates hypoxia/reoxygenation injury in H9c2 cells by activating the AMPK/Nrf2 signaling pathway.

Front Physiol. 2020 ;11 619740

Ophiopogonin A Alleviates Hemorrhagic Shock-Induced Renal Injury via Induction of Nrf2 Expression.

Xiaoming Sheng, Yang Yang, JiaJia Liu, Junbo Yu, Qingsong Guo, Wei Guan, Fan Liu.

  Ophiopogonin, including Ophiopogonin A, B, C, D, is an effective active component of traditional Chinese medicine Ophiopogon japonicus which has a wide range of pharmacological effects such as protecting myocardial ischemia, resisting myocardial infarction, immune regulation, lowering blood glucose, and anti-tumor. However, the functions of ophiopogonin A on hemorrhagic shock (HS)-induced renal injury remain unclear. First, this study constructed an HS rat model and hypoxia HK-2 cell model to assess the effects of ophiopogonin A in vivo and in vitro. In vivo, HE and TUNEL staining show that ophiopogonin A dose-dependently inhibits HS-induced tissue damage and apoptosis. Moreover, ophiopogonin A dose-dependently downregulates the levels of blood urea nitrogen (BUN), creatinine (Cr), KIM-1, NGAL, iNOS, TNF-α, IL-1β, and IL-6 in HS rats kidney tissues, and decreases the number of MPO-positive cells. In vitro, we get similar results that ophiopogonin A dose-dependently improves hypoxia-induced HK-2 cell apoptosis and damage. In addition, ophiopogonin A dose-dependently increases the expression of NF E2-related factor 2 (Nrf2), while knockdown of Nrf2 reverses the functions of ophiopogonin A in vivo and in vitro. Furthermore, ophiopogonin A dose-dependently promotes the phosphorylation of ERK in HS kidney tissues and hypoxia-treated HK-2 cells, suggesting that ophiopogonin A functions via the p-ERK/ERK signaling pathway.

Keywords:  Nrf2; hemorrhagic shock-induced renal injury; ophiopogonin A; p-ERK/ERK; renal injury

DOI:  https://doi.org/10.3389/fphys.2020.619740
Exp Ther Med. 2021 Mar;21(3): 248

ER stress preconditioning ameliorates liver damage after hemorrhagic shock and reperfusion.

David Peter Obert, Alexander Karl Wolpert, Nathan Lewis Grimm, Sebastian Korff.

  The mismatch of oxygen supply and demand during hemorrhagic shock disturbs endoplasmic reticulum (ER) homeostasis. The resulting accumulation of unfolded proteins in the ER lumen, which is a condition that is defined as ER stress, triggers the unfolded protein response (UPR). Since the UPR influences the extent of organ damage following hemorrhagic shock/reperfusion (HS/R) and mediates the protective effects of stress preconditioning before ischemia-reperfusion injury, the current study investigated the mechanisms of ER stress preconditioning and its impact on post-hemorrhagic liver damage. Male C56BL/6-mice were injected intraperitoneally with the ER stress inductor tunicamycin (TM) or its drug vehicle 48 h prior to being subjected to a 90 min pressure-controlled hemorrhagic shock (30±5 mmHg). A period of 14 h after hemorrhagic shock induction, mice were sacrificed. Hepatocellular damage was quantified by analyzing hepatic transaminases and hematoxylin-eosin stained liver tissue sections. Additionally, the topographic expression patterns of the ER stress marker binding immunoglobulin protein (BiP), UPR signaling pathways, and the autophagy marker Beclin1 were evaluated. TM injection significantly increased BiP expression and modified the topographic expression patterns of the UPR signaling proteins. In addition, immunohistochemical analysis of Beclin1 revealed an increased pericentral staining intensity following TM pretreatment. The histologic analysis of hepatocellular damage demonstrated a significant reduction in cell death areas in HS/R+TM (P=0.024). ER stress preconditioning influences the UPR and alleviates post-hemorrhagic liver damage. The beneficial effects were, at least partially, mediated by the upregulation of BiP and autophagy induction. These results underscore the importance of the UPR in the context of HS/R and may help identify novel therapeutic targets.

Keywords:  binding immunoglobulin protein; hemorrhage; ischemia-reperfusion injury; tunicamycin; unfolded protein response

DOI:  https://doi.org/10.3892/etm.2021.9679
J Trauma Acute Care Surg. 2021 Feb 17.

Genome-wide landscape of mRNAs, microRNAs, lncRNAs, and circRNAs in hemorrhagic shock-induced ALI/ARDS in rats.

Zhiwei Wang, Panpan Chang, Jingjing Ye, Wei Ma, Jing Zhou, Peng Zhang, Xiaokun Chen, Bo Jia, Ming Zheng, Wei Huang, Tianbing Wang.

BACKGROUND: Hemorrhagic shock (HS) can develop into multiple organ dysfunction syndrome (MODS), among which acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) usually lead to poor outcomes. The underlying molecular mechanisms of HS-induced ALI/ARDS remain unclear. This study sought to investigate gene expression profiles and predict ceRNA regulatory networks in an HS-induced ALI/ARDS preclinical model.
METHODS: SD rats were subjected to a fixed volume of hemorrhage (HS, 40% estimated total blood volume) or not (sham) randomly. After 8 hours of observation, left lung tissue was harvested to evaluate lung injury. Right lung was collected for RNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed and the lncRNA/circRNA-miRNA-mRNA linkages were predicted using the ceRNA theory. Quantitative real-time polymerase chain reaction was used to validate the RNA sequencing findings.
RESULTS: HS lungs showed noticeable ALI/ARDS features, and 437 mRNAs, 31 miRNAs, 734 lncRNAs, and 29 circRNAs were differentially expressed. In GO and KEGG pathway analyses, the differentially expressed transcripts were enriched in the following terms: the metabolic pathways, signal transduction pathways, necroptosis, DNA damage recognition and repair, inflammatory cell migration and chemotaxis, the NOD-like receptor signaling pathway, the JAK-STAT signaling pathway, the MAPK signaling pathway, PI3K-Akt signaling, etc. And this study identified lncRNA-miRNA-mRNA linkages with 12 lncRNAs, 5 miRNAs, 15 mRNAs, and circRNA-miRNA-mRNA linkages with 10 circRNAs, 16 miRNAs, 39 mRNAs. These networks might play important regulatory roles.
CONCLUSIONS: This is the first high-throughput analysis of gene expression profiles in HS-induced ALI/ARDS. It shows that metabolism, cell signaling, DNA damage and repair, and necroptosis related RNAs altered, and inflammatory response associated RNAs and pathways have pivotal roles in HS-induced ALI/ARDS progression. It also prompts some important RNAs and regulatory networks for future research.
LEVEL OF EVIDENCE: basic science paper.

DOI: https://doi.org/10.1097/TA.0000000000003119
Trends Neurosci. 2021 Feb 10. pii: S0166-2236(21)00016-3. [Epub ahead of print]

Extracellular Vesicles as an Emerging Frontier in Spinal Cord Injury Pathobiology and Therapy.

Dipankar Dutta, Niaz Khan, Junfang Wu, Steven M Jay.

  Extracellular vesicles (EVs) are membrane-delimited particles that are secreted by nearly all cell types. EVs mediate crucial physiological functions and pathophysiological processes in the CNS. As carriers of diverse bioactive cargoes (e.g., proteins, lipids, and nucleic acids) that can be modified in response to external stimuli, EVs have emerged as pathological mediators following neurotrauma such as spinal cord injury (SCI). We discuss the roles of endogenous EVs in the CNS as well as crosstalk with peripheral EVs in relation to neurotrauma, with a particular focus on SCI. We then summarize the status of EV-based therapeutic advances in preclinical animal models for these conditions. Finally, we discuss new bioengineering strategies that are poised to enhance CNS-specific therapeutic capabilities of EVs.

Keywords:  exosomes; neural regeneration; neurotrauma

DOI:  https://doi.org/10.1016/j.tins.2021.01.003
J Cent Nerv Syst Dis. 2021 ;13 1179573520988193

Hypobaria-Induced Oxidative Stress Facilitates Homocysteine Transsulfuration and Promotes Glutathione Oxidation in Rats with Mild Traumatic Brain Injury.

Flaubert Tchantchou, Catriona Miller, Molly Goodfellow, Adam Puche, Gary Fiskum.

   Background: United States service members injured in combat theatre are often aeromedically evacuated within a few days to regional military hospitals. Animal and epidemiological research indicates that early exposure to flight hypobaria may worsen brain and other injuries. The mechanisms by which secondary exposure to hypobaria worsen trauma outcomes are not well elucidated. This study tested the hypothesis that hypobaria-induced oxidative stress and associated changes in homocysteine levels play a role in traumatic brain injury (TBI) pathological progression caused by hypobaria.
Methods: Male Sprague Dawley rats were exposed to a 6 h hypobaria 24 h after mild TBI by the controlled cortical impact. Plasma and brain tissues were assessed for homocysteine levels, oxidative stress markers or glutathione metabolism, and behavioral deficits post-injury in the absence and presence of hypobaria exposure.
Results: We found that hypobaria after TBI increased oxidative stress markers, altered homocysteine metabolism, and promoted glutathione oxidation. Increased glutathione metabolism was driven by differential upregulation of glutathione metabolizing genes. These changes correlated with increased anxiety-like behavior.
Conclusion: These data provide evidence that hypobaria exposure after TBI increases oxidative stress and alters homocysteine elimination likely through enhanced glutathione metabolism. This pathway may represent a compensatory mechanism to attenuate free radical formation. Thus, hypobaria-induced enhancement of glutathione metabolism represents a potential therapeutic target for TBI management.

Keywords:  Hypobaria; glutathione; homocysteine; oxidative stress; traumatic brain injury

DOI:  https://doi.org/10.1177/1179573520988193
Front Pharmacol. 2020 ;11 593225

Cardioprotective Effect of Echinatin Against Ischemia/Reperfusion Injury: Involvement of Hippo/Yes-Associated Protein Signaling.

Jieting Niu, Yanguang Li, Xiang Song, Yunfeng Liu, Ying Li, Ya Li.

  Background: Echinatin (Ech) has been reported to exert antioxidant and anti-inflammatory activities. In this study, we aimed to characterize the functional role of Ech in myocardial ischemic/reperfusion (MI/R) injury and elucidate its underlying mechanism of action. Method: We established in vivo and in vitro models of MI/R injury to determine the effect of Ech on MI/R injury. Gene expression was examined using quantitative real-time polymerase chain reaction and western blotting. Myocardial infarction was assessed using tetrazolium chloride staining and the degree of myocardial injury was evaluated by measuring lactate dehydrogenase (LDH) and creatine kinase-myocardial band (CK-MB) levels. Cell apoptosis was detected using the terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) assay. The viability of H9c2 cells was determined using Cell Counting Kit-8 assay. Results: MI/R induced myocardial infarction, which was mitigated by Ech treatment. Moreover, Ech treatment resulted in a marked decline of LDH and CK-MB levels in the serum and myocardium of MI/R rats. Ech treatment also restrained cardiomyocyte apoptosis in vivo and in vitro, as evidenced by reduction in LDH release, the number of TUNEL-positive cells, and caspase-3 activity. Furthermore, Ech administration inhibited MI/R-induced activation of Hippo/Yes-associated protein signaling in vivo and in vitro, as indicated by inhibition of mammalian sterile 20-like protein kinase 1, large tumor suppressor one, and YAP phosphorylation and promotion of YAP nuclear translocation. However, silencing of YAP counteracted the protective effect of Ech on hypoxia/reoxygenation-induced myocardial injury in vitro. Conclusion: Ech exerted its protective effect against MI/R injury at least partially by suppressing the Hippo/YAP signaling pathway, providing novel insights into the remission of MI/R injury.

Keywords:  caspase-3; echinatin; hippo/yes kinase-associated protein signaling; lactate dehydrogenase; myocardial ischemia/reperfusion injury

DOI:  https://doi.org/10.3389/fphar.2020.593225
J Neuroinflammation. 2021 Feb 18. 18(1): 50

Critical roles of sphingosine kinase 1 in the regulation of neuroinflammation and neuronal injury after spinal cord injury.

Chenjian Wang, Tianzhen Xu, Brittany Bolduc Lachance, Xiqiang Zhong, Guangjie Shen, Tao Xu, Chengxuan Tang, Xiaofeng Jia.

   BACKGROUND: The pathological process of traumatic spinal cord injury (SCI) involves excessive activation of microglia leading to the overproduction of proinflammatory cytokines and causing neuronal injury. Sphingosine kinase 1 (Sphk1), a key enzyme responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P), plays an important role in mediating inflammation, cell proliferation, survival, and immunity.
METHODS: We aim to investigate the mechanism and pathway of the Sphk1-mediated neuroinflammatory response in a rodent model of SCI. Sixty Sprague-Dawley rats were randomly assigned to sham surgery, SCI, or PF543 (a specific Sphk1 inhibitor) groups. Functional outcomes included blinded hindlimb locomotor rating and inclined plane test.
RESULTS: We discovered that Sphk1 is upregulated in injured spinal cord tissue of rats after SCI and is associated with production of S1P and subsequent NF-κB p65 activation. PF543 attenuated p65 activation, reduced inflammatory response, and relieved neuronal damage, leading to improved functional recovery. Western blot analysis confirmed that expression of S1P receptor 3 (S1PR3) and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) are activated in microglia of SCI rats and mitigated by PF543. In vitro, we demonstrated that Bay11-7085 suppressed NF-κB p65 and inhibited amplification of the inflammation cascade by S1P, reducing the release of proinflammatory TNF-α. We further confirmed that phosphorylation of p38 MAPK and activation of NF-κB p65 is inhibited by PF543 and CAY10444. p38 MAPK phosphorylation and NF-κB p65 activation were enhanced by exogenous S1P and inhibited by the specific inhibitor SB204580, ultimately indicating that the S1P/S1PR3/p38 MAPK pathway contributes to the NF-κB p65 inflammatory response.
CONCLUSION: Our results demonstrate a critical role of Sphk1 in the post-traumatic SCI inflammatory cascade and present the Sphk1/S1P/S1PR3 axis as a potential target for therapeutic intervention to control neuroinflammation, relieve neuronal damage, and improve functional outcomes in SCI.

Keywords:  M1 microglia; NF-κB p65 activation; S1P/S1PR3/p38 MAPK pathway; Sphk1; Spinal cord injury

DOI:  https://doi.org/10.1186/s12974-021-02092-4
Eur Rev Med Pharmacol Sci. 2021 Jan;pii: 24409. [Epub ahead of print]25(1): 413-422

Sodium butyrate relieves lung ischemia-reperfusion injury by inhibiting NF-κB and JAK2/STAT3 signaling pathways.

X-D Ying, G Wei, H An.

OBJECTIVE: Ischemia-reperfusion (IR) is the main cause of acute lung injury (ALI) in clinical lung transplantation, extracorporeal circulation, lung sleeve resection, trauma and cardiopulmonary resuscitation. The inflammatory response and oxidative stress following IR are factors that cause and aggravate its secondary damage. The purpose of this study was to investigate the efficacy and mechanism of sodium butyrate (NaB) on lung ischemia-reperfusion injury (LIRI).
MATERIALS AND METHODS: We used male C57BL/6 mice to construct the LIRI model and administered the mice with NaB. By examining the expression of inflammatory factors and oxidative stress-related molecules in mouse lung tissue, we investigated the effects of NaB on inflammation and oxidative stress in lung tissue after IR. In addition, the changes in the activity of the NF-κB and JAK2/STAT3 signaling pathways were also examined to determine the mechanism of NaB.
RESULTS: The expression levels of the inflammatory factors (IL-1β, IL-6 and TNF-α) in lung tissue of mice after IR were significantly increased, while NaB reduced the expression of inflammatory factors. In addition, the oxidative stress level of mouse lung tissue after IR increased significantly, showing the decrease of antioxidant molecules SOD1/2, catalase (CAT), and Peroxiredoxin 1 (Prdx1), while the intake of NaB increased the antioxidant level of mouse lung tissue. The activities of NF-κB and JAK2/STAT3 signaling pathways were significantly increased in lung tissue after IR, whereas NaB inhibited the activity of NF-κB and JAK2/STAT3 signaling pathways.
CONCLUSIONS: NaB relieves LIRI by inhibiting NF-κB and JAK2/STAT3 signaling pathways to reduce inflammation and oxidative stress levels in lung tissue of mice after IR.

DOI: https://doi.org/10.26355/eurrev_202101_24409
Aging (Albany NY). 2021 Feb 11. 13

Transfer of lncRNA UCA1 by hUCMSCs-derived exosomes protects against hypoxia/reoxygenation injury through impairing miR-143-targeted degradation of Bcl-2.

Liwei Diao, Qinghua Zhang.

  Ischemia results in neuronal damage via alterations in gene transcription and protein expression. Long noncoding RNAs (LncRNAs) are pivotal in the regulation of target protein expression in hypoxia/reoxygenation (H/R). In this study, we observed the function of exosomes-carried lncRNA UCA1 in H/R-induced injury of cardiac microvascular endothelial cells (CMECs). In H/R cell model, CMECs were co-cultured with human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-ex). The loss-of-function experiments were conducted to assess the effect of lncRNA UCA1 on H/R injury by assessing the biological behaviors of CMECs. The relationship among lncRNA UCA1, miR-143 and Bcl-2 were verified. An ischemia-reperfusion (I/R) rat model was established. Then hUCMSC-ex was injected into I/R rats to identify its effects on apoptosis and autophagy. Functional rescue experiments were performed to verify the sponge system. In vitro and in vivo experiments showed that hUCMSC-ex protected I/R rats and H/R CMECs against injury. Silencing UCA1 in hUCMSC-ex or miR-143 overexpression aggravated H/R injury in CMECs. LncRNA UCA1 competitively bound to miR-143 to upregulate Bcl-2. And hUCMSCs-ex/si-UCA1+inhi-miR-143 treatment protected CMECs against H/R injury and inhibited hyperautophagy. Together, hUCMSC-ex-derived lncRNA UCA1 alleviates H/R injury through the miR-143/Bcl-2/Beclin-1 axis. Hence, this study highlights a stem cell-based approach against I/R injury.

Keywords:  exosome; human umbilical cord mesenchymal stem cell; hypoxia/reoxygenation; ischemia-reperfusion; lncRNA UCA1

DOI:  https://doi.org/10.18632/aging.202520
Cell Commun Signal. 2021 Feb 15. 19(1): 17

S-1-propenylcysteine improves TNF-α-induced vascular endothelial barrier dysfunction by suppressing the GEF-H1/RhoA/Rac pathway.

Kayo Kunimura, Satomi Miki, Miyuki Takashima, Jun-Ichiro Suzuki.

   BACKGROUND: Vascular endothelial barrier function is maintained by cell-to-cell junctional proteins and contributes to vascular homeostasis. Various risk factors such as inflammation disrupt barrier function through down-regulation of these proteins and promote vascular diseases such as atherosclerosis. Previous studies have demonstrated that aged garlic extract (AGE) and its sulfur-containing constituents exert the protective effects against several vascular diseases such as atherosclerosis. In this study, we examined whether AGE and its sulfur-containing constituents improve the endothelial barrier dysfunction elicited by a pro-inflammatory cytokine, Tumor-necrosis factor-α (TNF-α), and explored their mode of action on TNF-α signaling pathway.
METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with test substances in the presence of TNF-α for various time periods. The endothelial permeability was measured by using a transwell permeability assay. The localization of cell-to-cell junctional proteins and actin cytoskeletons were visualized by immunostaining. RhoA and Rac activities were assessed by using GTP-binding protein pulldown assay. Gene and protein expression levels of signaling molecules were analyzed by real-time PCR and western blotting, respectively.
RESULTS: We found that AGE and its major sulfur-containing constituent, S-1-propenylcysteine (S1PC), reduced hyperpermeability elicited by TNF-α in HUVECs. In addition, S1PC inhibited TNF-α-induced production of myosin light chain (MLC) kinase and inactivation of MLC phosphatase through the suppression of the Rac and RhoA signaling pathways, respectively, which resulted in the dephosphorylation of MLC2, a key factor of actin remodeling. Moreover, S1PC inhibited the phosphorylation and activation of guanine nucleotide exchange factor-H1 (GEF-H1), a common upstream key molecule and activator of Rac and RhoA. These effects of S1PC were accompanied by its ability to prevent the disruption of junctional proteins on the cell-cell contact regions and the increase of actin stress fibers induced by TNF-α.
CONCLUSIONS: The present study suggested that AGE and its major constituent, S1PC, improve endothelial barrier disruption through the protection of junctional proteins on plasma membrane. Video abstract.

Keywords:  Actin remodeling; Adherens junction; Aged garlic extract; GEF-H1; Rac; RhoA; S-1-propenylcysteine; TNF-α; Tight junction; Vascular endothelial barrier function

DOI:  https://doi.org/10.1186/s12964-020-00692-w
Drug Des Devel Ther. 2021 ;15 501-513

Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways.

Jin Zhang, Changsong Wang, Kai Kang, Haitao Liu, Xiaowei Liu, Xiaonan Jia, Kaijiang Yu.

   Purpose: Sepsis, a destructive inflammatory response syndrome, is the principal reason to induce death in the intensive care unit. Loganin has been proved to possess the property of anti-inflammation, antioxidant, neuroprotection, and sedation. The primary aim of this study was to evaluate whether Loganin could alleviate acute kidney injury (AKI) during sepsis and investigate the latent mechanisms.
Methods: Septic AKI models were established by cecal ligation and puncture (CLP) surgery in mice and given Loganin (20, 40, 80 mg/kg) by gavage. Lipopolysaccharides (LPS)-stimulated human kidney proximal tubular (HK2) cells incubated in Loganin (5, 10, 20 μ M) were used to explore the accurate mechanisms. Survival rate, renal function (creatinine and blood urea nitrogen), and renal pathological changes were detected in septic mice. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), mitochondrial membrane potential, mitochondrial calcium overload, and nuclear factor E2-related factor 2 (Nrf2)/heme-oxygenase 1 (HO-1) pathway activation in vivo and in vitro were determined by commercial kits and Western blot. Cell apoptosis, apoptotic-related protein (cleaved caspase-3, Bcl-2, and Bax) expression and protein kinase B (AKT) phosphorylation in vivo and in vitro were measured by TUNEL staining and Western blot. Finally, AKT blockage by 10 μM LY294002 or Nrf2 inhibition by10 μ M ML385 were utilized to prove the involvement of AKT and Nrf2/HO-1 pathway in AKI during sepsis.
Results: We found Loganin treatment (20, 40, 80 mg/kg) mitigated septic AKI reflected by elevated renal function and palliative pathological changes. Oxidative stress and apoptosis in the kidney and LPS-treated HK2 cells were also inhibited by Loganin administration, which was accompanied by AKT and Nrf2/HO-1 pathway activation. Besides, the protective effects of Loganin could be diminished by AKT or Nrf2 blockage, indicating the involvement of AKT and Nrf2/HO-1 pathway.
Conclusion: The results suggested that the protective effects of Loganin on AKI during sepsis might be mediated by AKT and Nrf2/HO-1 pathway signaling activation in kidney proximal tubular cells.

Keywords:  AKT; Loganin; Nrf2/HO-1; acute kidney injury; sepsis

DOI:  https://doi.org/10.2147/DDDT.S294266
Biofactors. 2021 Feb 18.

Restoration of NRF2 attenuates myocardial ischemia reperfusion injury through mediating microRNA-29a-3p/CCNT2 axis.

Ran Tian, Xin Guan, Hao Qian, Liang Wang, Zhujun Shen, Ligang Fang, Zhenyu Liu.

  Accumulated studies have been implemented for comprehending the mechanism of myocardial ischemia reperfusion injury (MI/RI). Nuclear factor erythroid-2 related factor 2 (NRF2)-mediated transcription activity in MI/RI has not been completely interpreted from the perspective of microRNA-29a-3p (miR-29a-3p) and cyclin T2 (CCNT2). Therein, this study intends to decode the mechanism of NRF2/miR-29a-3p/CCNT2 axis in MI/RI. Rat MI/RI models were established by right anterior descending coronary artery ligation. Rats were injected with NRF2 or CCNT2 overexpression plasmids or miR-29a-3p agomir to explore their effects on MI/RI. Hypoxia/reoxygenation (H/R) cardiomyocytes were established and transfected with restored NRF2 or miR-29a-3p or CCNT2 for further exploration of their roles. NRF2, miR-29a-3p, and CCNT2 expression in myocardial tissues in rats with MI/RI and in cardiomyocytes in H/R injury were detected. ChIP assay verified the relationship between miR-29a-3p and NRF2, and the bioinformatics software and dual-luciferase reporter experiment verified the interaction between miR-29a-3p and CCNT2. NRF2 and miR-29a-3p were down-regulated while CCNT2 was up-regulated in myocardial tissues in rats with MI/RI and in H/R-treated cardiomyocytes. Restoration of NRF2 or miR-29a-3p improved hemodynamics and myocardial injury and suppressed serum inflammation and cardiomyocyte apoptosis via CCNT2 in rats with MI/RI. Upregulation of NRF2 or miR-29a-3p inhibited LDH and CK-MB activities, oxidative stress, and apoptosis and promoted viability of cardiomyocytes with H/R injury. NRF2 bound to the promoter of miR-29a-3p and CCNT2 was targeted by miR-29a-3p. This study elucidates that up-regulating NRF2 or miR-29a-3p attenuates MI/RI via inhibiting CCNT2, which may renew the existed knowledge of MI/RI-related mechanism and provide a novel guidance toward MI/RI treatment.

Keywords:  cyclin T2; hypoxia/reoxygenation; microRNA-29a-3p; myocardial infarction; myocardial ischemia reperfusion injury; nuclear factor erythroid-2 related factor 2

DOI:  https://doi.org/10.1002/biof.1712
Biosci Biotechnol Biochem. 2021 Feb 18. 85(2): 251-261

Neohesperidin alleviated pathological damage and immunological imbalance in rat myocardial ischemia-reperfusion injury via inactivation of JNK and NF-κB p65.

Aihua Li, Xin Zhang, Qiuping Luo.

  Neohesperidin (NEO) exerts antiviral, antioxidant, anti-inflammation, and antitumor effects in some diseases. The purpose of this study was to investigate the effect and mechanism of NEO on myocardial ischemia-reperfusion (I/R) injury. Results indicated that NEO suppressed the levels of serum inflammatory cytokines, myocardial damage markers, and oxidative stress markers, and increased the levels of antioxidant in myocardial I/R rats. NEO also inhibited cell apoptosis. Besides, NEO also inhibited the phosphorylation of c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) p65. Furthermore, the protective effects of NEO on myocardial tissue damage, inflammatory cytokines, myocardial injury markers, oxidative stress markers, cell apoptosis, spleen, thymus and liver indices, and phagocytic indices were reversed by JNK activator and NF-κB activator, respectively. In conclusion, NEO alleviates myocardial damage, oxidative stress, cell apoptosis, and immunological imbalance in I/R injury via the inactivation of JNK and NF-κB, making NEO a potential agent for myocardial I/R therapy.

Keywords:  JNK; NF-κB; myocardial ischemia-reperfusion injury; neohesperidin

DOI:  https://doi.org/10.1093/bbb/zbaa064
Cytokine. 2021 Feb 10. pii: S1043-4666(21)00037-5. [Epub ahead of print]141 155457

Trauma-induced lung injury is associated with infiltration of activated TLR expressing myeloid cells.

Meenakshi Rani, Shannon R Sayyadioskoie, Eva M Galvan, Susannah E Nicholson, Martin G Schwacha.

   INTRODUCTION: Traumatic injury with hemorrhage (TH) induces an inflammatory response in the lung resulting in lung injury involving activation of immune cells including myeloid cells (i.e., monocytes, granulocytes and macrophages), in part through TLRs. TLRs, via the recognition of damage associated molecular patterns (DAMPs), are a key link between tissue injury and inflammation. Nonetheless, the role of TLRs in myeloid cell activation and TH-induced lung injury remains ill defined.
METHODS: C57BL/6 male mice were subjected to TH or sham treatment (n = 4-6 /group). Lung tissues were collected two hrs. after injury. Single cells were isolated from the lungs by enzymatic digestion and myeloid cell TLR expression and activation (i.e., cytokine production) were assessed using flow cytometry techniques.
RESULTS: The injury was associated with a profound change in the lung myeloid cell population. TH markedly increased lung CD11b+ monocyte numbers and Gr1+ granulocyte numbers as compared to sham mice. The number of cells expressing TLR2, TLR4, and TLR9 were increased 4-7 fold in the TH mice. Activation for elevated cytokine (TNFα, IL-10) production was observed in the lung monocyte population of the TH mice.
CONCLUSIONS: Trauma-induced lung injury is associated with infiltration of the lungs with TLR expressing myeloid cells that are activated for elevated cytokine responses. This elevation in TLR expression may contribute to DAMP-mediated pulmonary complications of an inflammatory nature and warrants further investigation.

Keywords:  Cytokines; Inflammation; Injury; Receptors

DOI:  https://doi.org/10.1016/j.cyto.2021.155457
Brain Behav Immun. 2021 Feb 12. pii: S0889-1591(21)00043-X. [Epub ahead of print]

Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36.

Qian Li, Xi Lan, Xiaoning Han, Frederick Durham, Jieru Wan, Abigail Weiland, Raymond C Koehler, Jian Wang.

  Hematoma size after intracerebral hemorrhage (ICH) significantly affects patient outcome. However, our knowledge of endogenous mechanisms that underlie hematoma clearance and the potential role of the anti-inflammatory cytokine interleukin-10 (IL-10) is limited. Using organotypic hippocampal slice cultures and a collagenase-induced ICH mouse model, we investigated the role of microglial IL-10 in phagocytosis ex vivo and hematoma clearance in vivo. In slice culture, exposure to hemoglobin induced IL-10 expression in microglia and enhanced phagocytosis that depended on IL-10-regulated expression of CD36. Following ICH, IL-10-deficient mice had more severe neuroinflammation, brain edema, iron deposition, and neurologic deficits associated with delayed hematoma clearance. Intranasal administration of recombinant IL-10 accelerated hematoma clearance and improved neurologic function. Additionally, IL-10-deficient mice had weakened in vivo phagocytic ability owing to decreased expression of microglial CD36. Moreover, loss of IL-10 significantly increased monocyte-derived macrophage infiltration and enhanced brain inflammation in vivo. These results indicate that IL-10 regulates microglial phagocytosis and monocyte-derived macrophage infiltration after ICH and that CD36 is a key phagocytosis effector regulated by IL-10. Leveraging the innate immune response to ICH by augmenting IL-10 signaling may provide a useful strategy for accelerating hematoma clearance and improving neurologic outcome in clinical translation studies.

Keywords:  IL-10; hematoma clearance; intracerebral hemorrhage; macrophage; microglia

DOI:  https://doi.org/10.1016/j.bbi.2021.02.001
Acta Anaesthesiol Scand. 2021 Feb 17.

Plasma concentrations of syndecan-1 are dependent on kidney function.

Robert G Hahn, Markus Zdolsek, Joachim Zdolsek.

   BACKGROUND: Elevated plasma concentrations of syndecan-1 and heparan sulfate in studies of trauma, sepsis, and major surgery are commonly assumed to indicate acute glycocalyx degradation. We explored a possible role of the kidneys for these elevations.
METHODS: Plasma and urine concentrations of syndecan-1, heparan sulfate, and biomarkers of inflammation were measured over 5 h in 15 hospital patients treated for post-burn injury. The renal clearances of syndecan-1 and heparan sulfate (CLR ) were calculated and their influence on the plasma concentration predicted by simulation.
RESULTS: The urine/plasma concentration ratio was 0.9 (0.3-3.0) for syndecan-1 and 2.8 (2.0-4.3) for heparan sulfate. The CLR varied 250-fold for syndecan-1 and 10-fold for heparan sulfate. Multiple linear regression analysis showed that CLR for syndecan-1 was positively associated with the creatinine clearance (P< 0.0032) and the urine flow (P< 0.015). CLR for heparan sulfate increased with interleukin-6 (P< 0.003) and the urine flow (P< 0.01). Simulations suggested that a change in CLR from the mean of the highest three to the lowest three values would double plasma syndecan-1 within 4 h and cause a 7-fold rise after 24 h. A similar change in CLR for heparan sulfate would triple the plasma level within 24 h, even if no increased shedding of the glycocalyx takes place.
CONCLUSIONS: The renal elimination of syndecan-1 and heparan sulfate varied greatly. A change in kidney function, which is common after trauma and major surgery, might alone induce several-fold changes in their plasma concentrations.

Keywords:  Glycocalyx; heparan sulfate; kidney function; renal clearance; syndecan-1

DOI:  https://doi.org/10.1111/aas.13801
Pak J Pharm Sci. 2020 Jul;33(4): 1599-1608

Mast cell activation, TLR4-NF-κB/TNF-α pathway variation in rats' intestinal ischemia-reperfusion injury and Tongxinluo's therapeutic effect.

Zhang Junxiu, Feng Yu, Hu Yanyan, Zhang Yin, Liu Yi, Yang Minghui, Li Shaodan.

This study was designed to investigate mast cell activation and related TLR4-NF-κB/TNF-α pathway variation in 3 and 7 days' rats intestinal I/R injury, and TXL's intervention effect. Rat intestine I/R injury was carried out using superior mesenteric artery occlusion model with 30 min ischemia followed 3 or 7 days' reperfusion. Rats were administered TXL ultrafine power of 0.4, 0.8 and 1.6g/kg/d respectively for 3 or 7 days after modeling. Mast cell activation was determined by immunofluorescent double staining. TLR4, ANGPTL4 and microRNA126 were determined by RT-PCR. PECAM-1, NF-κB p65, TNF-α and VE-Cadherin were determined by immunohistochemical staining. Intestine I/R induced massively mast cell activation and overexpressed TLR4, NF-κB, TNF-α, PECAM-1, miR126 in 3 and 7 days. VE-cadherin and ANGPTL4 expression was reduced. TXL treatment attenuated mast cell activation and inhibited TLR4, NF-κB, TNF-α, PECAM-1 over-expression in 3 and 7 days, protected VE-cadherin and ANGPTL4 protein. Inflammation boomed in rats' intestine I/R injury for 3 and 7 days, characterized by mast cell and related TLR4-NF-κB/TNF-α pathway activation, accompanied with endothelial barrier dysfunction and enhanced vascular permeability. TXL treatment attenuated inflammation, protected endothelial barrier function. TXL treat intestine I/R injury, according with "Treat different diseases with the same method" in TCM theory.
Exp Neurol. 2021 Feb 15. pii: S0014-4886(21)00047-9. [Epub ahead of print] 113642

Neuroprotective roles of HAX-1 in ischemic neuronal injury.

Xin Sui, Hideyuki Yoshioka, Yuichiro Fukumoto, Kazuya Kanemaru, Hiroyuki Kinouchi.

  Hematopoietic cell-specific protein 1 associated protein X-1 (HAX-1) is a novel mitochondrial protein that regulates oxidative stress-induced apoptosis. However, the roles of HAX-1 in ischemic neuronal injury have not been thoroughly elucidated. In this study, the expression and roles of HAX-1 after ischemic stress were investigated using in vivo and in vitro models. The effect of oxidative stress on the regulation of HAX-1 was examined using knockout mice lacking nicotinamide-adenine dinucleotide phosphate oxidase 2 (NOX2), which is a major source of reactive oxygen species (ROS) after cerebral ischemia. Male C57BL/6 J mice were subjected to transient forebrain ischemia induced by 22-min occlusion of the bilateral common carotid arteries, and striatum samples were analyzed. For in vitro ischemic experiments, oxygen and glucose deprivation (OGD) in a rat pheochromocytoma cell line was utilized. Western blotting and immunofluorescence analysis revealed HAX-1 expression in neuronal mitochondria, which was significantly decreased after ischemia in vivo and in vitro. In NOX2 knockout mice, ischemia-induced decrease in HAX-1 expression and ischemic neuronal injury was significantly alleviated compared to those in wild-type mice. Inhibition of HAX-1 using small interfering RNA significantly increased injury in cultured cells after OGD. These findings suggest that HAX-1 has a neuroprotective effect against ischemic neuronal injury, and downregulation of HAX-1 by NOX2-produced ROS induces apoptosis after cerebral ischemia.

Keywords:  Apoptosis; Brain ischemia; HAX-1; Mitochondria; NADPH oxidase

DOI:  https://doi.org/10.1016/j.expneurol.2021.113642
Int Immunopharmacol. 2021 Feb 10. pii: S1567-5769(21)00064-3. [Epub ahead of print]94 107428

Glutaredoxin 2 protects cardiomyocytes from hypoxia/reoxygenation-induced injury by suppressing apoptosis, oxidative stress, and inflammation via enhancing Nrf2 signaling.

Chengliang Li, Hong Xin, Yingpeng Shi, Jianjun Mu.

  Glutaredoxin 2 (GRX2) plays a cytoprotective role under various pathological conditions. However, whether GRX2 plays a role during myocardial ischemia-reperfusion injury has not been fully elucidated. In this work, we aimed to explore the detailed role and mechanism of GRX2 in modulating hypoxia/reoxygenation (H/R)-induced cardiac injury in vitro. H/R treatment resulted in a significant increase in GRX2 expression in cardiomyocytes. GRX2 knockdown enhanced the sensitivity of cardiomyocytes to H/R-induced apoptosis, oxidative stress, and inflammation, while GRX2 up-regulation exerted a cardioprotective role in H/R-injured cardiomyocytes. Further investigations revealed that GRX2 up-regulation enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling associated with upregulation of the phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β). Akt inhibition markedly abolished GRX2-mediated activation of Nrf2, while GSK-3β inhibition reversed GRX2-knockdown-mediated inhibition of Nrf2. In addition, Nrf2 inhibition markedly abrogated GRX2-mediated protective effects against H/R-induced apoptosis, oxidative stress and inflammation. Overall, this work indicates that GRX2 protects cardiomyocytes from H/R-induced apoptosis, oxidative stress, and inflammation by enhancing Nrf2 activation via modulation of the Akt/GSK-3β axis. Our study highlights a potential relevance of GRX2 in myocardial ischemia-reperfusion injury; it may serve as an attractive target for cardioprotection.

Keywords:  Cardiomyocyte; GRX2; Hypoxia/reoxygenation; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.intimp.2021.107428
Exp Ther Med. 2021 Mar;21(3): 220

Schizandrin B attenuates hypoxia/reoxygenation injury in H9c2 cells by activating the AMPK/Nrf2 signaling pathway.

Bo Zhao, Guang-Ping Li, Jian-Jun Peng, Li-Hui Ren, Li-Cheng Lei, Hui-Ming Ye, Zuo-Yan Wang, Sheng Zhao.

  Schizandrin B exhibits prominent antioxidant and anti-inflammatory effects, and plays an important role in ameliorating myocardial ischemia/reperfusion injury. However, the underlying protective mechanisms remain to be elucidated. The aim of the present study was to explore the cardioprotective effects of schizandrin B against hypoxia/reoxygenation (H/R)-induced H9c2 cell injury, focusing on the role of the adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in this process. The results showed that schizandrin B attenuated the H/R-induced decrease in cell viability and the increase in lactate dehydrogenase release, as well as the apoptosis rate in H9c2 cells. Schizandrin B also mitigated H/R-induced oxidative stress, as illustrated by the decrease in intracellular reactive oxygen species generation, malondialdehyde content and NADPH oxidase 2 expression, and the increase in antioxidant enzyme superoxide dismutase and glutathione peroxidase activities. In addition, schizandrin B reversed the H/R-induced upregulation of pro-inflammatory cytokines [interleukin (IL)-1β (IL-1β) tumor necrosis factor-α, IL-6 and IL-8] and the downregulation of anti-inflammatory cytokines (transforming growth factor-β and IL-10) in the culture supernatant. Notably, schizandrin B increased the expression of Nrf2, NAD(P)H: Quinone oxidoreductase (NQO-1) and heme oxygenase-1 (HO-1) in H/R-treated H9c2 cells, activating the Nrf2 signaling pathway. The cardioprotection of schizandrin B against H/R injury was inhibited by Nrf2 knockdown induced byNrf-2-specific small interfering RNA (siRNA; si-Nrf2) transfection. Furthermore, schizandrin B enhanced phosphorylated (p)-AMPK expression, while AMPK knockdown induced by AMPK-specific siRNA(si-AMPK) transfection remarkably eliminated schizandrin B-induced cardioprotection and reduced Nrf2 expression in H/R-treated H9c2 cells. Taken together, these results suggested that schizandrin B exerts cardioprotection on H/R injury in H9c2 cells due to its antioxidant and anti-inflammatory activities via activation of the AMPK/Nrf2 pathway.

Keywords:  adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2signaling pathway; inflammation; myocardial ischemia/reperfusion injury; oxidative stress; schizandrin B

DOI:  https://doi.org/10.3892/etm.2021.9651