Publications by authors named "Ji Young Yoo"

122 Publications

Effect-site concentration of remifentanil for smooth emergence from propofol-remifentanil anesthesia in patients using double lumen tube.

J Clin Anesth 2021 Apr 28;72:110297. Epub 2021 Apr 28.

Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon-si, 16499, Gyeonggi-do, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jclinane.2021.110297DOI Listing
April 2021

MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44.

Sci Rep 2021 Apr 28;11(1):9219. Epub 2021 Apr 28.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St., MSE R117B, Houston, TX, 77030, USA.

Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3' UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.
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http://dx.doi.org/10.1038/s41598-021-88615-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080729PMC
April 2021

Oncolytic herpes simplex virus infects myeloma cells and .

Mol Ther Oncolytics 2021 Mar 18;20:519-531. Epub 2021 Feb 18.

Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Monrovia, CA 91016, USA.

Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138/CD38 plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target.
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http://dx.doi.org/10.1016/j.omto.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940704PMC
March 2021

Neuregulin 1/ErbB4/Akt signaling attenuates cytotoxicity mediated by the APP-CT31 fragment of amyloid precursor protein.

Exp Mol Pathol 2021 Mar 6;120:104622. Epub 2021 Mar 6.

Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon 301-746, Republic of Korea. Electronic address:

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal and synaptic loss. The cytoplasmic tail of amyloid precursor protein (APP) undergoes sequential cleavage at a specific intracellular caspase site to generate the cytoplasmic terminal 31 (CT31) fragment. The APP-CT31 fragment is a potent inducer of apoptosis. The cytotoxicity of APP-CT31 in SH-SY5Y cells was evaluated by the lactate dehydrogenase (LDH) assay. TUNEL staining was used to detect apoptotic signals in SH-SY5Y cells and primary cortical neurons. The expression of apoptosis-related proteins, such as p53, PUMA (p53 up-regulated modulator of apoptosis), and cleaved was investigated by immunofluorescence analysis and Western blotting. In this study, we investigated the neuroprotective effect of neuregulin 1 (NRG1) against cytotoxicity induced by APP-CT31. Our data showed that CT31 induced cytotoxicity and apoptosis in SH-SY5Y cells and primary cortical neurons. NRG1 attenuated the neurotoxicity induced by the expression of APP-CT31. We also showed that APP-CT31 altered the expression of p53 and cleaved caspase 3. However, treatment with NRG1 rescued the APP-CT31-induced upregulation of p53 and cleaved caspase 3 expression. The protective effect of NRG1 was abrogated by inhibition of the ErbB4 receptor and Akt. These results indicate an important role of ErbB4/Akt signaling in NRG1-mediated neuroprotection, suggesting that endogenous NRG1/ErbB4 signaling represents a valuable therapeutic target in AD.
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http://dx.doi.org/10.1016/j.yexmp.2021.104622DOI Listing
March 2021

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

Ann Neurol 2021 May 22;89(5):926-941. Epub 2021 Mar 22.

Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.

Objective: Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRAS mutation induces sporadic bAVMs in mice.

Methods: Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRAS . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRAS -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor.

Results: The viral-mediated KRAS overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment.

Interpretation: Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.
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http://dx.doi.org/10.1002/ana.26059DOI Listing
May 2021

Inhibiting protein phosphatase 2A increases the antitumor effect of protein arginine methyltransferase 5 inhibition in models of glioblastoma.

Neuro Oncol 2021 Feb 8. Epub 2021 Feb 8.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Background: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor treating fields, the median survival of Glioblastoma (GBM) patients is less than 15 months. Protein Arginine Methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. LB100, a first-in-class small molecular inhibitor of Protein Phosphatase 2A (PP2A) can sensitize therapy-resistant tumor cells. Here, we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition.

Methods: Patient-derived primary GBM neurospheres (GBMNS), transfected with PRMT5 target-specific siRNA were treated with LB100 and subjected to in vitro assays including PP2A activity and western blot. The intracranial mouse xenograft model was used to test the in vivo antitumor efficacy of combination treatment.

Results: We found that PRMT5-depletion increased PP2A activity in GBMNS. LB100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5 intact GBMNS. LB100 enhanced G1 cell cycle arrest induced by PRMT5-depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged survival, while LB100 treatment alone had no survival benefit.

Conclusion: Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone.
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http://dx.doi.org/10.1093/neuonc/noab014DOI Listing
February 2021

Lightwand-Guided Insertion of Flexible Reinforced Laryngeal Mask Airway: Comparison with Standard Digital Manipulation Insertion.

Med Sci Monit 2021 Jan 11;27:e928538. Epub 2021 Jan 11.

Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, Gyeonggi, South Korea.

BACKGROUND The flexibility of the long flexometallic tube makes insertion of the flexible reinforced laryngeal mask airway (f-LMA) difficult. We compared the usefulness of rigid lightwand-guided f-LMA insertion with standard digital manipulation. MATERIAL AND METHODS Fifty-four patients (aged 19-70 years) were randomly divided into a control group (digital manipulation technique) or the lightwand group (lightwand-guided insertion technique). The insertion profiles, oropharyngeal leak pressure (OLP), peak inspiratory pressure (PIP), expiratory tidal volume, and ventilatory score were measured in patients with neutral, extension, rotation, flexion, and re-neutral head-neck positions in turn. RESULTS The success rate and ease of insertion did not differ between groups, but the insertion time was longer in the lightwand group. The fiberoptic laryngeal view was significantly better in the lightwand group than in the control group. However, the OLP, PIP, expiratory tidal volume, and ventilatory scores were not significantly different between groups according to head-neck positions. The extension posture was associated with a significant negative effect on ventilation, but ventilation returned to initial levels with the other postures. CONCLUSIONS Lightwand-guided f-LMA insertion showed a better fiberoptic laryngeal view than standard digital manipulation, but no improvement in the ventilatory state was observed due to position. Therefore, lightwand-guided insertion could facilitate correct placement of the f-LMA, but it has limited clinical usefulness.
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http://dx.doi.org/10.12659/MSM.928538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812698PMC
January 2021

Antitussive effect of a magnesium infusion during anesthetic emergence in patients with double-lumen endotracheal tube: a randomized controlled trial.

J Thorac Dis 2020 Oct;12(10):5691-5699

Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, Korea.

Background: A double-lumen endotracheal tube (DLT) inserted into the bronchus can stimulate the respiratory tracts, causing coughing. Opioids have been introduced to prevent emergence cough. However, the administration of a significant opioid dose at the end of surgery may result in undesirable events. Magnesium, common intracellular ion, suppress bronchial smooth muscle contraction and have antitussive effect. We investigated the antitussive effects of a magnesium infusion during anesthetic emergence in patients who underwent thoracic surgery requiring one-lung ventilation (OLV) anesthesia with a DLT.

Methods: One-hundred forty patients undergoing OLV anesthesia with a DLT were enrolled in this prospective, randomized double-blinded trial. In combination with a low dose of remifentanil, patients were randomly allocated to receive either magnesium sulphate (infusion of 15 mg/kg/hour after a single bolus of 30 mg/kg) or normal saline during the operation and emergence. Primary outcomes were the severity and incidence of cough during emergence.

Results: The severity of cough was assessed by the cough severity grading score: 0, no cough; 1, single cough; 2, cough persistence <5 seconds; 3, cough persistence ≥5 seconds. There was a significant difference in the severity score of cough between the groups [median (IQR): 2 (0 to 3) in control group 0 (0 to 1) in magnesium group, P=0.003]. However, there was no significant difference in the overall incidence of cough between both groups [42 (64.6%) in control group 31 (47.7%) in magnesium group, P=0.077].

Conclusions: Magnesium attenuated the severity of cough during emergence after OLV anesthesia using a DLT without adverse events.
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http://dx.doi.org/10.21037/jtd-20-1977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656382PMC
October 2020

Neuregulin-1 inhibits CoCl-induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in SH-SY5Y cells and the hippocampus of mice.

Mol Brain 2020 11 13;13(1):153. Epub 2020 Nov 13.

Department of Anatomy and Neuroscience, College of Medicine, Eulji University, 143-5Jung-Gu, Yongdu-Dong, Daejeon, 301-746, Republic of Korea.

Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl is thought to represent a compensatory response against oxidative stress in an acute hypoxic state. We further demonstrated that pretreatment with Neuregulin-1 (NRG1) rescued CoCl-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl-induced apoptosis and cell death. NRG1 inhibited the CoCl-induced release of cleaved caspase-3 and reduction in Bcl-X levels. Our novel finding suggests that NRG1 may play a protective role in hypoxia through the inhibition of oxidative stress and thereby maintain normal EAAC1 expression levels.
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http://dx.doi.org/10.1186/s13041-020-00686-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664014PMC
November 2020

Targeted delivery of small noncoding RNA for glioblastoma.

Cancer Lett 2021 Mar 8;500:274-280. Epub 2020 Nov 8.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. Electronic address:

Aberrant expression of certain genes and microRNAs (miRNAs) has been shown to drive cancer development and progression, thus the modification of aberrant gene and miRNA expression presents an opportunity for therapeutic targeting. Ectopic modulation of a single dysregulated miRNA has the potential to revert therapeutically unfavorable gene expression in cancer cells by targeting multiple genes simultaneously. Although the use of noncoding RNA-based cancer therapy is a promising approach, the lack of a feasible delivery platform for small noncoding RNAs has hindered the development of this therapeutic modality. Recently, however, there has been an evolution in RNA nanotechnology, in which small noncoding RNA is loaded onto nanoparticles derived from the pRNA-3WJ viral RNA motif of the bacteriophage phi29. Preclinical studies have shown the capacity of this technology to specifically target tumor cells by conjugating these nanoparticles with ligands specific for cancer cells and resulting in the endocytic delivery of siRNA and miRNA inhibitors directly into the cell. Here we provide a systematic review of the various strategies, which have been utilized for miRNA delivery with a specific focus on the preclinical evaluation of promising RNA nanoparticles for glioblastoma (GBM) targeted therapy.
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http://dx.doi.org/10.1016/j.canlet.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855548PMC
March 2021

Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity.

Clin Cancer Res 2021 Jan 21;27(2):542-553. Epub 2020 Oct 21.

Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas.

Purpose: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy.

Experimental Design: Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models ( = 9-10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of antitumor immune response ( = 3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition .

Results: Gene Ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV)-related pathways in infected cells (FDR = 2.97E-57). Mechanistically, we identified reduced expression of transporters expressed on EV implicated in cisplatin efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy.

Conclusions: To our knowledge, this is the first report to show HSV-induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2210DOI Listing
January 2021

Early-life stress induces EAAC1 expression reduction and attention-deficit and depressive behaviors in adolescent rats.

Cell Death Discov 2020 8;6:73. Epub 2020 Aug 8.

Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon, 34824 Republic of Korea.

Neonatal maternal separation (NMS), as an early-life stress (ELS), is a risk factor to develop emotional disorders. However, the exact mechanisms remain to be defined. In the present study, we investigated the mechanisms involved in developing emotional disorders caused by NMS. First, we confirmed that NMS provoked impulsive behavior, orienting and nonselective attention-deficit, abnormal grooming, and depressive-like behaviors in adolescence. Excitatory amino acid carrier 1 (EAAC1) is an excitatory amino acid transporter expressed specifically by neurons and is the route for the neuronal uptake of glutamate/aspartate/cysteine. Compared with that in the normal control group, EAAC1 expression was remarkably reduced in the ventral hippocampus and cerebral cortex in the NMS group. Additionally, EAAC1 expression was reduced in parvalbumin-positive hippocampal GABAergic neurons in the NMS group. We also found that EAAC1-knockout (EAAC1-/-) mice exhibited impulsive-like, nonselective attention-deficit, and depressive-like behaviors compared with WT mice in adolescence, characteristics similar to those of the NMS behavior phenotype. Taken together, our results revealed that ELS induced a reduction in EAAC1 expression, suggesting that reduced EAAC1 expression is involved in the pathophysiology of attention-deficit and depressive behaviors in adolescence caused by NMS.
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http://dx.doi.org/10.1038/s41420-020-00308-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415155PMC
August 2020

Strategies to Modulate MicroRNA Functions for the Treatment of Cancer or Organ Injury.

Pharmacol Rev 2020 07;72(3):639-667

Departments of Neurosurgery (T.J.L., K.K., J.Y.Y., D.H.K., B.K.) and Anesthesiology (X.Y., H.K.E.), McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.

Cancer and organ injury-such as that occurring in the perioperative period, including acute lung injury, myocardial infarction, and acute gut injury-are among the leading causes of death in the United States and impose a significant impact on quality of life. MicroRNAs (miRNAs) have been studied extensively during the last two decades for their role as regulators of gene expression, their translational application as diagnostic markers, and their potential as therapeutic targets for disease treatment. Despite promising preclinical outcomes implicating miRNA targets in disease treatment, only a few miRNAs have reached clinical trials. This likely relates to difficulties in the delivery of miRNA drugs to their targets to achieve efficient inhibition or overexpression. Therefore, understanding how to efficiently deliver miRNAs into diseased tissues and specific cell types in patients is critical. This review summarizes current knowledge on various approaches to deliver therapeutic miRNAs or miRNA inhibitors and highlights current progress in miRNA-based disease therapy that has reached clinical trials. Based on ongoing advances in miRNA delivery, we believe that additional therapeutic approaches to modulate miRNA function will soon enter routine medical treatment of human disease, particularly for cancer or perioperative organ injury. SIGNIFICANCE STATEMENT: MicroRNAs have been studied extensively during the last two decades in cancer and organ injury, including acute lung injury, myocardial infarction, and acute gut injury, for their regulation of gene expression, application as diagnostic markers, and therapeutic potentials. In this review, we specifically emphasize the pros and cons of different delivery approaches to modulate microRNAs, as well as the most recent exciting progress in the field of therapeutic targeting of microRNAs for disease treatment in patients.
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http://dx.doi.org/10.1124/pr.119.019026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300323PMC
July 2020

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation.

Cancers (Basel) 2020 Apr 23;12(4). Epub 2020 Apr 23.

Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.
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http://dx.doi.org/10.3390/cancers12041040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225935PMC
April 2020

Oncolytic HSV-Infected Glioma Cells Activate NOTCH in Adjacent Tumor Cells Sensitizing Tumors to Gamma Secretase Inhibition.

Clin Cancer Res 2020 05 5;26(10):2381-2392. Epub 2020 Mar 5.

The Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas.

Purpose: To examine the effect of oncolytic herpes simplex virus (oHSV) on NOTCH signaling in central nervous system tumors.

Experimental Design: Bioluminescence imaging, reverse phase protein array proteomics, fluorescence microscopy, reporter assays, and molecular biology approaches were used to evaluate NOTCH signaling. Orthotopic glioma-mouse models were utilized to evaluate effects .

Results: We have identified that herpes simplex virus-1 (HSV-1; oncolytic and wild-type)-infected glioma cells induce NOTCH signaling, from inside of infected cells into adjacent tumor cells (inside out signaling). This was canonical NOTCH signaling, which resulted in activation of RBPJ-dependent transcriptional activity that could be rescued with dnMAML. High-throughput screening of HSV-1-encoded cDNA and miRNA libraries further uncovered that HSV-1 miR-H16 induced NOTCH signaling. We further identified that factor inhibiting HIF-1 (FIH-1) is a direct target of miR-H16, and that FIH-1 downregulation by virus encoded miR-H16 induces NOTCH activity. FIH-1 binding to Mib1 has been reported, but this is the first report that shows FIH-1 sequester Mib1 to suppress NOTCH activation. We observed that FIH-1 degradation induced NOTCH ligand ubiquitination and NOTCH activity. REMBRANDT and The Cancer Genome Atlas data analysis also uncovered a significant negative regulation between FIH-1 and NOTCH. Furthermore, combination of oHSV with NOTCH-blocking gamma secretase inhibitor (GSI) had a therapeutic advantage in two different intracranial glioma models treated with oncolytic HSV, without affecting safety profile of the virus .

Conclusions: To our knowledge this is the first report to identify impact of HSV-1 on NOTCH signaling and highlights the significance of combining oHSV and GSI for glioblastoma therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325527PMC
May 2020

Neuregulin 1/ErbB4 signaling attenuates neuronal cell damage under oxygen-glucose deprivation in primary hippocampal neurons.

Anat Cell Biol 2019 Dec 31;52(4):462-468. Epub 2019 Dec 31.

Department of Anatomy and Neuroscience, Eulji University College of Medicine, Daejeon, Korea.

The hippocampus is one of the most important brain areas of cognition. This region is particularly sensitive to hypoxia and ischemia. Neuregulin-1 (NRG1) has been shown to be able to protect against focal cerebral ischemia. The aim of the present study was to investigate the neuroprotective effect of NRG1 in primary hippocampal neurons and its underlying mechanism. Our data showed oxygen-glucose deprivation (OGD)-induced cytotoxicity and overexpression of ErbB4 in primary hippocampal neurons. Moreover, pretreatment with NRG1 could inhibit OGD-induced overexpression of ErbB4. In addition, NRG1 significantly attenuated neuronal death induced by OGD. The neuroprotective effect of NRG1 was blocked in ischemic neurons after pretreatment with AG1478, an inhibitor of ErbB4, but not after pretreatment with AG879, an inhibitor of ErbB2. These results indicate an important role of ErbB4 in NRG1-mediated neuroprotection, suggesting that endogenous ErbB4 might serve as a valuable therapeutic target for treating global cerebral ischemia.
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http://dx.doi.org/10.5115/acb.19.210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952697PMC
December 2019

Neuregulin-1 Protects Neuronal Cells Against Damage due to CoCl2-Induced Hypoxia by Suppressing Hypoxia-Inducible Factor-1α and P53 in SH-SY5Y Cells.

Int Neurourol J 2019 Nov 30;23(Suppl 2):S111-118. Epub 2019 Nov 30.

Department of Anatomy and Neuroscience, Eulji University College of Medicine, Daejeon, Korea.

Purpose: Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer disease. Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain. The aim of the present study was to investigate the neuroprotective effect and the regulating hypoxic inducible factor of NRG1 in cobalt chloride (CoCl2) induced hypoxia.

Methods: Hypoxia was induced in SH-SY5Y cells by CoCl2 treatment. SH-SY5Y cells were pretreated with NRG1 and then treated with CoCl2. Western blotting, immunocytochemistry, and lactate dehydrogenase (LDH) release assays were performed to examine neuroprotective properties of NRG1 in SH-SY5Y cells.

Results: Our data showed that CoCl2 induced cytotoxicity and changes of hypoxia-inducible factor-1α (HIF-1α) and p53 expression in SH-SY5Y cells. However, pretreatment with NRG1 inhibited CoCl2-induced accumulation of HIF-1α and p53 stability. In addition, NRG1 significantly attenuated cell death of SH-SY5Y induced by CoCl2.

Conclusion: NRG1 can regulate HIF-1α and p53 to protect neurons against hypoxic damage.
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http://dx.doi.org/10.5213/inj.1938190.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905208PMC
November 2019

Pdlim4 is essential for CCR7-JNK-mediated dendritic cell migration and F-actin-related dendrite formation.

FASEB J 2019 10 9;33(10):11035-11044. Epub 2019 Jul 9.

Department of Biotechnology, CHA University, Seongnam, South Korea.

Dendritic cells (DCs) are the most potent professional antigen (Ag)-presenting cells and inducers of T cell-mediated immunity. A previous microarray analysis identified PDZ and LIM domain protein 4 (Pdlim4) as a candidate marker for DC maturation. The aim of this study was to investigate whether Pdlim4 influences DC migration and maturation. Mouse bone marrow-derived DCs were transduced lentivirally with short hairpin RNA and examined by confocal microscopy, flow cytometry, ELISA, and Western blotting. Pdlim4 was highly induced in LPS-stimulated mature DCs (mDCs). -knockdown mDCs showed reduced expression of molecules associated with Ag presentation and T-cell costimulation, reduced cytokine production, and functional defects in their ability to activate T cells. Moreover, Pdlim4 was necessary for mDC migration C-C chemokine receptor type 7 (CCR7)-JNK in Transwell assays. The importance of Pdlim4 in DC migration was confirmed with an migration model in which C57BL/6 mice were injected with fluorescently labeled DCs in the footpad and migration to the popliteal lymph nodes was assessed by flow cytometry. Moreover, dendrite formation in mDCs was remarkably attenuated under knockdown. Taken together, these results demonstrate that Pdlim4 is necessary for DC migration CCR7-JNK, dendrite formation, and subsequent development of functional T-cell responses.-Yoo, J.-Y., Jung, N.-C., Lee, J.-H., Choi, S.-Y., Choi, H.-J., Park, S.-Y., Jang, J.-S., Byun, S.-H., Hwang, S.-U., Noh, K.-E., Park, Y., Lee, J., Song, J.-Y., Seo, H. G., Lee, H. S., Lim, D.-S. Pdlim4 is essential for CCR7-JNK-mediated dendritic cell migration and F-actin-related dendrite formation.
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http://dx.doi.org/10.1096/fj.201901031DOI Listing
October 2019

Pivotal role of microRNA-138 in human cancers.

Am J Cancer Res 2019 1;9(6):1118-1126. Epub 2019 Jun 1.

Department of Neurosurgery, University of Texas Health Science Center at Houston, McGovern Medical School Houston, TX 77030, USA.

Aberrant expression of certain microRNAs (miRNAs) has been implicated in cancers as a promising druggable target due to the fact that a modulation of the deregulated single miRNA seems to revert the therapeutically unfavorable gene expressions in cancer cell by targeting multiple genes. Global miRNA profiling from a number of patient cohorts in various type of human cancers has identified miR-138 as a signature of tumor suppressor that are down-regulated in most types of human cancer. As a tumor suppressor, miR-138 can inhibit oncogenic proteins by directly bind to their mRNAs. However, in rare cases of cancer stem cell population from glioblastoma, miR-138 seems to be down-regulated and plays an oncogenic function. This review will summarize accumulating evidence that has shown the expression and functional role of miR-138 in various human cancers with its target genes and pathways in a hope to find a better therapeutic option to treat human cancers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610051PMC
June 2019

Oncolytic Herpes Virus Armed with Vasculostatin in Combination with Bevacizumab Abrogates Glioma Invasion via the CCN1 and AKT Signaling Pathways.

Mol Cancer Ther 2019 08 15;18(8):1418-1429. Epub 2019 May 15.

Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Anti-VEGF treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab has also been reported to induce invasiveness of glioma. In this study, we examined the effects of rapid antiangiogenesis mediated by oncolytic virus (RAMBO), an oncolytic herpes simplex virus-1 expressing vasculostatin, on bevacizumab-induced glioma invasion. The effect of the combination of RAMBO and bevacizumab was assessed by cytotoxicity, migration, and invasion assays. For experiments, glioma cells were stereotactically inoculated into the brain of mice. RAMBO was intratumorally injected 7 days after tumor inoculation, and bevacizumab was administered intraperitoneally twice a week. RAMBO significantly decreased both the migration and invasion of glioma cells treated with bevacizumab. In mice treated with bevacizumab and RAMBO combination, the survival time was significantly longer and the depth of tumor invasion was significantly smaller than those treated with bevacizumab monotherapy. Interestingly, RAMBO decreased the expression of cysteine-rich protein 61 and phosphorylation of AKT, which were increased by bevacizumab. These results suggest that RAMBO suppresses bevacizumab-induced glioma invasion, which could be a promising approach to glioma therapy.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0799DOI Listing
August 2019

Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo.

Neuro Oncol 2019 09;21(9):1131-1140

Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas.

Background: Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors.

Methods: Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy.

Result: Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model.

Conclusion: This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.
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http://dx.doi.org/10.1093/neuonc/noz079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571492PMC
September 2019

Time to tracheal intubation over a fibreoptic bronchoscope using a silicone left double-lumen endobronchial tube versus polyvinyl chloride single-lumen tube with bronchial blocker: a randomized controlled non-inferiority trial.

J Thorac Dis 2019 Mar;11(3):901-908

Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, Korea.

Background: Direct insertion of a double-lumen endobronchial tube (DLT) over a fibreoptic bronchoscope (FOB) is considered more difficult and traumatic than that of a single-lumen tube (SLT). We hypothesized that time to intubation over an FOB using a silicone left DLT would be non-inferior to that using a polyvinyl chloride (PVC) SLT.

Methods: Eighty patients were enrolled in this open-label, randomized controlled, non-inferiority trial. Patients were randomly allocated to fibreoptic tracheal intubation with either a silicone DLT or PVC SLT (DLT and SLT groups, respectively). Time to tracheal intubation [time to insertion of FOB plus railroading (advancement over the FOB) time]; total time for correct tube and bronchial blocker positioning; difficulty of railroading; and the incidence of sore throat, swallowing difficulty, and hoarseness were compared between groups.

Results: The median time to intubation over the FOB was 20 s in the DLT group and 23 s in the SLT group. The upper limit of the confidence interval of this difference was below the non-inferiority margin of 10 s (median difference: -2 s; 95% confidence interval: -4 to 0 s). Railroading time was significantly shorter in the DLT group than in the SLT group (median time: 10 . 11 s; median difference: -1 s; 95% confidence interval: -3 to 0 s; P=0.03). Railroading over the FOB (rated on a four-point scale) was less difficult in the DLT group than in the SLT group (P<0.01).

Conclusions: Tracheal intubation using an FOB can be achieved at least as fast using the silicone DLT as using the PVC SLT. The silicone DLT exhibited superior railroading performance to the PVC SLT.
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http://dx.doi.org/10.21037/jtd.2019.01.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462687PMC
March 2019

Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin β1 Blocking Antibody OS2966.

Mol Cancer Ther 2019 06 29;18(6):1127-1136. Epub 2019 Mar 29.

The Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas.

Integrin β1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression and resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin β1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin β1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and bioluminescence imaging on mammary fat pad triple-negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and proinflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated antitumor efficacy in orthotopic xenograft models, including triple-negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve antitumor efficacy of conventional oHSV therapy.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548661PMC
June 2019

Suppression of HMGB1 Released in the Glioblastoma Tumor Microenvironment Reduces Tumoral Edema.

Mol Ther Oncolytics 2019 Mar 6;12:93-102. Epub 2018 Dec 6.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.

HMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection and . The impact of secreted HMGB1 on tumor growth and response to oncolytic viral therapy was evaluated by using HMGB1-blocking antibodies and in mice bearing intracranial tumors. IVIS and MRI imaging was utilized to visualize in real time virus spread, tumor growth, and changes in edema in mice. Our data showed that HMGB1 released in tumor microenvironment orchestrated increased vascular leakiness and edema. Further HMGB1 blocking antibodies rescued vascular leakiness and enhanced survival of intracranial glioma-bearing mice treated with oHSV.
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http://dx.doi.org/10.1016/j.omto.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350213PMC
March 2019

PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance.

Nat Commun 2018 11 27;9(1):5006. Epub 2018 Nov 27.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.

Engineered oncolytic viruses are used clinically to destroy cancer cells and have the ability to boost anticancer immunity. Phosphatase and tensin homolog deleted on chromosome 10 loss is common across a broad range of malignancies, and is implicated in immune escape. The N-terminally extended isoform, phosphatase and tensin homolog deleted on chromosome 10 alpha (PTENα), regulates cellular functions including protein kinase B signaling and mitochondrial adenosine triphosphate production. Here we constructed HSV-P10, a replicating, PTENα expressing oncolytic herpesvirus, and demonstrate that it inhibits PI3K/AKT signaling, increases cellular adenosine triphosphate secretion, and reduces programmed death-ligand 1 expression in infected tumor cells, thus priming an adaptive immune response and overcoming tumor immune escape. A single dose of HSV-P10 resulted in long term survivors in mice bearing intracranial tumors, priming anticancer T-cell immunity leading to tumor rejection. This implicates HSV-P10 as an oncolytic and immune stimulating therapeutic for anticancer therapy.
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http://dx.doi.org/10.1038/s41467-018-07344-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258708PMC
November 2018

A comparison of the Macintosh laryngoscope, McGrath video laryngoscope, and Pentax Airway Scope in paediatric nasotracheal intubation.

Sci Rep 2018 11 26;8(1):17365. Epub 2018 Nov 26.

Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, Republic of Korea.

We evaluated the performance of the McGrath video laryngoscope and Pentax Airway Scope in comparison with the Macintosh laryngoscope for nasotracheal intubation in paediatric patients. For this, 108 patients were enrolled in an open-label, randomized controlled trial. Patients were randomly allocated to one of three groups based on use of the Macintosh laryngoscope, McGrath video laryngoscope, or Pentax Airway Scope. Time to intubation, the intubation difficulty, and the quality of navigation were compared among groups. The median nasotracheal intubation time [interquartile range] in the Macintosh group (33.5 [28.3-39.8] s) was significantly shorter than those of the McGrath (39.0 [32.0-43.0] s) and Pentax groups (43.0 [35.0-52.0] s). The difficulty of nasotracheal intubation was similar among all groups. When navigating and aligning the tube from the oropharynx into the glottic inlet, the cuff inflation method was required in significantly fewer patients for the Macintosh group (11.1%) than for the McGrath (48.6%) and Pentax (51.4%) groups. Thus, compared to the McGrath video laryngoscope and Pentax Airway Scope, the Macintosh laryngoscope allowed shorter nasotracheal intubation times and better facilitated tracheal navigation, requiring less use of the cuff inflation method to navigate the tracheal tube into the glottic inlet.
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http://dx.doi.org/10.1038/s41598-018-35857-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255773PMC
November 2018

An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma.

Nat Biotechnol 2018 Nov 26. Epub 2018 Nov 26.

Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1 NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.
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http://dx.doi.org/10.1038/nbt.4302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535376PMC
November 2018

Neuregulin1 Attenuates HO-Induced Reductions in EAAC1 Protein Levels and Reduces HO-Induced Oxidative Stress.

Neurotox Res 2019 Feb 17;35(2):401-409. Epub 2018 Oct 17.

Department of Anatomy and Neuroscience, College of Medicine, Eulji University, 143-5, Yongdu-Dong, Jung-Gu, Daejeon, 34824, Republic of Korea.

Neuregulin 1 (NRG1) exhibits potent neuroprotective properties. The aim of the present study was to investigate the antioxidative effects and underlying mechanisms of NRG1 against HO-induced oxidative stress in primary rat cortical neurons. The expression level of the excitatory amino acid carrier 1 (EAAC1) protein was measured by Western blotting and immunocytochemistry. The levels of lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity, GPx activity, and mitochondrial membrane potential (∆ψm) were determined to examine cell death and the antioxidant properties of NRG1 in primary rat cortical neurons. HO reduced the expression of EAAC1 in a dose-dependent manner. We found that pretreatment with NRG1 attenuated the HO-induced reduction in EAAC1 expression. Moreover, NRG1 reduced the cell death and oxidative stress induced by HO. In addition, NRG1 attenuated HO-induced reductions in antioxidant enzyme activity and ∆ψm. Our data indicate a role for NRG1 in protecting against oxidative stress via the regulation of EAAC1. These observations may provide novel insights into the mechanisms of NRG1 activity during oxidative stress and may reveal new therapeutic targets for regulating the oxidative stress associated with various neurological diseases.
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http://dx.doi.org/10.1007/s12640-018-9965-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331506PMC
February 2019