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Huang HJ, Tseng YJ, Lee IJ, Lo YL, Lin AMY. Involvement of EGFR-AKT signaling in hemin-induced neurotoxicity. Exp Biol Med (Maywood) 2025; 250:10554. [PMID: 40444141 PMCID: PMC12121490 DOI: 10.3389/ebm.2025.10554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 04/24/2025] [Indexed: 06/02/2025] Open
Abstract
Intracerebral hemorrhage (ICH), as bleeding from ruptured vessels within the brain, is the second leading neuropathological problem following ischemic stroke. In the present study, the involvement of epithelial growth factor receptor (EGFR)-tyrosine kinase (TK) signaling underlying ICH-related neurodegeneration was investigated using afatinib, a clinically available EGFR-tyrosine kinase inhibitor (EGFR-TKI). We employed hemin (a breakdown product of hemoglobin) to mimic the pathophysiology of ICH in primary cultured cortical neurons. Using a lactate dehydrogenase (LDH) assay, incubation of hemin concentration- and time-dependently induced neuronal death. Simultaneous incubation of afatinib (10 nM) significantly inhibited hemin (30 μM)-induced neuronal death. Immunofluorescent data demonstrated that co-treatment of afatinib for 1 h attenuated hemin (30 μM)-induced elevation in phosphorylated-EGFR (p-EGFR) immunoreactivity and neurite impairment. Western blot assay demonstrated that co-incubation of afatinib for 16 h diminished hemin-induced elevation in p-EGFR and p-AKT, tumor necrosis factor-α and cyclooxygenase 2 (two proinflammatory biomarkers) as well as heme oxygenase-1 (HO-1, an enzyme catalyzing heme/hemin), glutathione hydroperoxidase 4 and receptor-interacting protein 3 (two biomarkers of ferroptosis and necroptosis). In addition, co-treatment of afatinib for 24 h inhibited hemin-induced NO production in the culture medium. In conclusion, our study shows that afatinib via blocking EGFR-AKT signaling inhibits hemin-induced EGFR-AKT activation, neuroinflammation, HO-1 expression and programed cell death, suggesting that EGFR-AKT signaling is involved in hemin-induced neurotoxicity and may be a druggable target for ICH.
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Affiliation(s)
- Hui-Ju Huang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yang-Jie Tseng
- Ph.D. Program in Regulatory Science and Policy, National Yang-Ming Chiao-Tung University, Taipei, Taiwan
| | - I-Jung Lee
- Pharmaceutical Botany Research Laboratory, Yokohama University of Pharmacy, Yokohama, Japan
| | - Yu-Li Lo
- Institute of Pharmacology, National Yang-Ming Chiao-Tung University, Taipei, Taiwan
| | - Anya Maan-Yuh Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Ph.D. Program in Regulatory Science and Policy, National Yang-Ming Chiao-Tung University, Taipei, Taiwan
- Department of Pharmacy, National Yang-Ming Chiao-Tung University, Taipei, Taiwan
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Lin Q, Huang E, Fan K, Zhang Z, Shangguan H, Zhang W, Fang W, Ou Q, Liu X. Cerebrospinal Fluid Neutrophil Gelatinase-Associated Lipocalin as a Novel Biomarker for Postneurosurgical Bacterial Meningitis: A Prospective Observational Cohort Study. Neurosurgery 2024; 95:1418-1428. [PMID: 38856216 DOI: 10.1227/neu.0000000000003021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
BACKGROUND AND OBJECTIVES Postneurosurgical bacterial meningitis (PNBM) was a significant clinical challenge, as early identification remains difficult. This study aimed to explore the potential of neutrophil gelatinase-associated lipocalin (NGAL) as a novel biomarker for the early diagnosis of PNBM in patients who have undergone neurosurgery. METHODS A total of 436 postneurosurgical adult patients were enrolled in this study. Clinical information, cerebrospinal fluid (CSF), and blood samples were collected. After the screening, the remaining 267 patients were divided into the PNBM and non-PNBM groups, and measured CSF and serum NGAL levels to determine the diagnostic utility of PNBM. Subsequently, patients with PNBM were categorized into gram-positive and gram-negative bacterial infection groups to assess the effectiveness of CSF NGAL in differentiating between these types of infections. We analyzed the changes in CSF NGAL expression before and after anti-infection treatment in PNBM. Finally, an additional 60 patients were included as an independent validation cohort to further validate the diagnostic performance of CSF NGAL. RESULTS Compared with the non-PNBM group, CSF NGAL was significantly higher in the PNBM group (305.1 [151.6-596.5] vs 58.5 [30.7-105.8] ng/mL; P < .0001). The area under the curve of CSF NGAL for diagnosing PNBM was 0.928 (95% CI: 0.897-0.960), at a threshold of 119.7 ng/mL. However, there was no significant difference in serum NGAL between the 2 groups (142.5 [105.0-248.6] vs 161.9 [126.6-246.6] ng/mL, P = .201). Furthermore, CSF NGAL levels were significantly higher in patients with gram-negative bacterial infections than those with gram-positive bacteria ( P = .023). In addition, CSF NGAL levels decrease after treatment compared with the initial stage of infection ( P < .0001). Finally, in this validation cohort, the threshold of 119.7 ng/mL CSF NGAL shows good diagnostic performance with a sensitivity and specificity of 90% and 80%, respectively. CONCLUSION CSF NGAL holds promise as a potential biomarker for the diagnosis, early drug selection, and efficacy monitoring of PNBM.
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Affiliation(s)
- Qingwen Lin
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Er Huang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Kengna Fan
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Zeqin Zhang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Huangcheng Shangguan
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Weiqing Zhang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Wenhua Fang
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Qishui Ou
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
| | - Xiaofeng Liu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
- Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University, Fuzhou , China
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Eom JW, Lee JY, Kwon Y, Kim YH. An increase of lysosomes through EGF-triggered endocytosis attenuated zinc-mediated lysosomal membrane permeabilization and neuronal cell death. Cell Death Dis 2024; 15:823. [PMID: 39537601 PMCID: PMC11560978 DOI: 10.1038/s41419-024-07192-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 10/20/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
In the context of acute brain injuries, where zinc neurotoxicity and oxidative stress are acknowledged contributors to neuronal damage, we investigated the pivotal role of lysosomes as a potential protective mechanism. Our research commenced with an exploration of epidermal growth factor (EGF) and its impact on lysosomal dynamics, particularly its neuroprotective potential against zinc-induced cytotoxicity. Using primary mouse cerebrocortical cultures, we observed the rapid induction of EGFR endocytosis triggered by EGF, resulting in a transient increase in lysosomal vesicles. Furthermore, EGF stimulated lysosomal biogenesis, evident through elevated expression of lysosomal-associated membrane protein 1 (LAMP-1) and the induction and activation of prominent lysosomal proteases, particularly cathepsin B (CTSB). This process of EGFR endocytosis was found to promote lysosomal augmentation, thus conferring protection against zinc-induced lysosomal membrane permeabilization (LMP) and subsequent neuronal death. Notably, the neuroprotective effects and lysosomal enhancement induced by EGF were almost completely reversed by the inhibition of clathrin-mediated and caveolin-mediated endocytosis pathways, along with the disruption of retrograde trafficking. Furthermore, tyrosine kinase inhibition of EGFR nullified EGFR endocytosis, resulting in the abrogation of EGF-induced lysosomal upregulation and neuroprotection. An intriguing aspect of our study is the successful replication of EGF's neuroprotective effects through the overexpression of LAMP-1, which significantly reduced zinc-induced LMP and cell death, demonstrated in both primary mouse cerebrocortical neuronal cultures and human embryonic kidney (HEK) cells. Our research extended beyond zinc-induced neurotoxicity, as we observed EGF's protective effects against other oxidative stressors linked to intracellular zinc release, including hydrogen peroxide (H2O2) and 1-methyl-4-phenylpyridinium ion (MPP+). Collectively, our findings unveil the intricate interplay between EGF-triggered EGFR endocytosis, lysosomal upregulation, an increase in the regulatory capacity for zinc homeostasis, and the subsequent alleviation of zinc-induced neurotoxicity. These results present promising avenues for therapeutic interventions to enhance neuroprotection by targeting lysosomal augmentation.
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Affiliation(s)
- Jae-Won Eom
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea
| | - Jin-Yeon Lee
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea
| | - Yeabin Kwon
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea
| | - Yang-Hee Kim
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, 05006, Republic of Korea.
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Gu YQ, Zhou X, Yao LH, Wang Q, Zhou CN, Liu ZD. Relationship between serum neutrophil gelatinase-associated lipocalin levels and cognitive impairment, anxiety, and depressive symptoms in acute ischemic stroke. World J Psychiatry 2024; 14:1467-1473. [DOI: 10.5498/wjp.v14.i10.1467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/31/2024] [Accepted: 09/14/2024] [Indexed: 10/17/2024] Open
Abstract
BACKGROUND Acute ischemic stroke (AIS) is a significant global health issue with increasing incidence owing to aging populations and rising cardiovascular risk factors. In addition to physical impairments, AIS frequently leads to neuropsychiatric complications, such as cognitive impairment, anxiety, and depressive symptoms, which adversely affect patients’ quality of life and rehabilitation. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a potential biomarker for various conditions, including AIS. This study investigated the association between serum NGAL levels at admission and neuropsychiatric complications in patients with AIS.
AIM To investigate the relationship between serum NGAL levels at admission and neuropsychiatric complications in patients with AIS.
METHODS Between January 2022 and December 2023, 150 patients with AIS were enrolled. Serum NGAL levels were measured at admission using an enzyme-linked immunosorbent assay. Cognitive function was assessed using the Mini-Mental State Examination, while anxiety and depressive symptoms were evaluated using the Hospital Anxiety and Depression Scale at discharge. The relationship between serum NGAL levels and cognitive impairment, anxiety, and depressive symptoms was analyzed using multivariate logistic regression, adjusted for potential confounders of age, sex, body mass index, smoking status, hypertension, diabetes mellitus, dyslipidemia, previous stroke, and stroke severity.
RESULTS The mean age of the participants was 65.4 ± 10.2 years, and 58% were males. Prevalence rates of cognitive impairment, anxiety, and depressive symptoms at discharge were 34.7%, 28.0%, and 32.0%, respectively. Serum NGAL levels were significantly higher in patients with cognitive impairment (median: 5.6 ng/mL vs 3.2 ng/mL, P < 0.001), anxiety (median: 5.1 ng/mL vs 3.5 ng/mL, P = 0.002), and depressive symptoms (median: 5.4 ng/mL vs 3.3 ng/mL, P < 0.001), compared to those without these conditions. Multivariate logistic regression analysis showed that higher serum NGAL levels at admission were independently associated with cognitive impairment [odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.18-1.71, P < 0.001], anxiety (OR = 1.28, 95%CI: 1.09-1.51, P = 0.003), and depressive symptoms (OR = 1.39, 95%CI: 1.16-1.67, P < 0.001) after adjusting for potential confounders.
CONCLUSION Elevated serum NGAL levels were independently associated with cognitive impairment, anxiety, and depressive symptoms in patients with AIS; and may function as potential biomarkers for patients at risk.
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Affiliation(s)
- You-Quan Gu
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xuan Zhou
- Department of Neurology, The First Clinical Medical College of Lanzhou University, Lanzhou 730099, Gansu Province, China
| | - Li-He Yao
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Qiang Wang
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Chao-Ning Zhou
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Zhao-Dong Liu
- Department of Neurology, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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Laohavisudhi K, Sriwichaiin S, Attachaipanich T, Wittayachamnankul B, Chattipakorn N, Chattipakorn S. Mechanistic insights into Lipocalin-2 in ischemic stroke and hemorrhagic brain injury: Integrating animal and clinical studies. Exp Neurol 2024; 379:114885. [PMID: 38996863 DOI: 10.1016/j.expneurol.2024.114885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/21/2024] [Accepted: 07/08/2024] [Indexed: 07/14/2024]
Abstract
Brain injuries, including strokes and traumatic brain injuries (TBI), are a major global health concern, contributing significantly to both mortality and long-term disability. Recent research has identified lipocalin-2 (LCN2), a glycoprotein secreted by various brain cells, as a key factor in influencing brain injury outcomes. Evidence from animal and clinical studies firmly establishes the pivotal role of LCN2 in driving the inflammatory responses triggered by damage to brain tissue. Furthermore, increased LCN2 promotes cellular differentiation, blood-brain barrier breakdown, and decreases cell viability. Interventions with LCN2 inhibitors attenuated brain injury through a reduction in the inflammation process and enhanced cellular viability. Potential mechanisms of LCN2 involve several pathways including the Janus kinase-2 (JAK2)-signal transducers and the transcription-3 (STAT3) signaling, hypoxia-inducible factor 1-alpha (HIF-1α)-LCN2-vascular endothelial growth factor alpha (VEGFα), and the PKR-like ER kinase (PERK) pathways. LCN2 itself interacts with diverse inflammatory cytokines in TBI and intracranial hemorrhage (ICH), resulting in disruption of the blood-brain barrier, increased programmed cell death, and an imbalance in iron homeostasis. Clinical studies have also shown that increased LCN2 level can act as a prognostic biomarker of outcomes following brain injuries. Therefore, this review aims to comprehensively evaluate the role and underlying mechanisms of LCN2 in brain injuries, including stroke and TBI, and explore potential therapeutic interventions targeting LCN2 in these conditions.
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Affiliation(s)
- Korsin Laohavisudhi
- Department of Emergency Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Sirawit Sriwichaiin
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Tanawat Attachaipanich
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Borwon Wittayachamnankul
- Department of Emergency Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand
| | - Siriporn Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand.
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Durand NC, Kim HG, Patel VN, Turnbull MT, Siegel JL, Hodge DO, Tawk RG, Meschia JF, Freeman WD, Zubair AC. Mesenchymal Stem Cell Therapy in Acute Intracerebral Hemorrhage: A Dose-Escalation Safety and Tolerability Trial. Neurocrit Care 2024; 41:59-69. [PMID: 38114796 PMCID: PMC11335835 DOI: 10.1007/s12028-023-01897-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 11/15/2023] [Indexed: 12/21/2023]
Abstract
BACKGROUND We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells. METHODS Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg. RESULTS Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe. CONCLUSIONS Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH.
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Affiliation(s)
- Nisha C Durand
- Center for Regenerative Biotherapeutics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
- Human Cellular Therapy Laboratory, Mayo Clinic, Jacksonville, FL, USA.
| | - H G Kim
- Clinical Research Intern Scholar Program, Mayo Clinic, Jacksonville, FL, USA
| | - Vishal N Patel
- Division of Neuroradiology, Mayo Clinic, Jacksonville, FL, USA
| | - Marion T Turnbull
- Research Collaborator in the Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
| | - Jason L Siegel
- Department of Critical Care Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - David O Hodge
- Biostatistics Unit, Mayo Clinic, Jacksonville, FL, USA
| | - Rabih G Tawk
- Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, USA
| | | | - W David Freeman
- Department of Critical Care Medicine, Mayo Clinic, Jacksonville, FL, USA
- Department of Neurologic Surgery, Mayo Clinic, Jacksonville, FL, USA
- Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
| | - Abba C Zubair
- Center for Regenerative Biotherapeutics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
- Department of Laboratory Medicine and Pathology, Center for Regenerative Biotherapeutics, Mayo Clinic, Jacksonville, FL, USA
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Zhang LC, Li N, Chen JL, Sun J, Xu M, Liu WQ, Zuo ZF, Shi LL, Wang TH, Luo XY. Molecular network mechanism in cerebral ischemia-reperfusion rats treated with human urine stem cells. Heliyon 2024; 10:e27508. [PMID: 38560254 PMCID: PMC10979071 DOI: 10.1016/j.heliyon.2024.e27508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
Objective To explore the effect of human urine-derived stem cells (husc) in improving the neurological function of rats with cerebral ischemia-reperfusion (CIR), and report new molecular network by bioinformatics, combined with experiment validation. Methods After CIR model was established, and husc were transplanted into the lateral ventricle of rats，neurological severe score (NSS) andgene network analysis were performed. Firstly, we input the keywords "Cerebral reperfusion" and "human urine stem cells" into Genecard database and merged data with findings from PubMed so as to get their targets genes, and downloaded them to make Venny intersection plot. Then, Gene ontology (GO) analysis, kyoto encyclopedia of genes and genomes (KEGG) pathway analysis and protein-protein interaction (PPI) were performed to construct molecular network of core genes. Lastly, the expressional level of core genes was validated via quantitative real-time polymerase chain reaction (qRT-PCR), and localized by immunofluorescence. Results Compared with the Sham group, the neurological function of CIR rats was significantly improved after the injection of husc into the lateral ventricle; at 14 days, P = 0.028, which was statistically significant. There were 258 overlapping genes between CIR and husc, and integrated with 252 genes screened from PubMed and CNKI. GO enrichment analysis were mainly involved neutrophil degranulation, neutrophil activation in immune response and platelet positive regulation of degranulation, Hemostasis, blood coagulation, coagulation, etc. KEGG pathway analysis was mainly involved in complement and coagulation cascades, ECM-receptor. Hub genes screened by Cytoscape consist ofCD44, ACTB, FN1, ITGB1, PLG, CASP3, ALB, HSP90AA1, EGF, GAPDH. Lastly, qRT-PCR results showed statistic significance (P < 0.05) in ALB, CD44 and EGF before and after treatment, and EGF immunostaining was localized in neuron of cortex. Conclusion husc transplantation showed a positive effect in improving neural function of CIR rats, and underlying mechanism is involved in CD44, ALB, and EGF network.
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Affiliation(s)
- Lang-Chun Zhang
- Department of Neurosurgery, Xiang Ya Hospital of Central South University, Changsha, 410078, China
- Animal Canter Department of Anatomy, Kunming Medical University, Kunming, 650500, China
| | - Na Li
- Animal Canter Department of Anatomy, Kunming Medical University, Kunming, 650500, China
| | - Ji-Lin Chen
- Animal Canter Department of Anatomy, Kunming Medical University, Kunming, 650500, China
| | - Jie Sun
- Animal Canter Department of Anatomy, Kunming Medical University, Kunming, 650500, China
| | - Min Xu
- Animal Canter Department of Anatomy, Kunming Medical University, Kunming, 650500, China
| | - Wen-Qiang Liu
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, 121000, China
| | - Zhong-Fu Zuo
- Department of Anatomy, Jinzhou Medical University, Jinzhou, China
| | - Lan-Lan Shi
- Department of Neurosurgery, Xiang Ya Hospital of Central South University, Changsha, 410078, China
| | - Ting-Hua Wang
- Department of Neurosurgery, Xiang Ya Hospital of Central South University, Changsha, 410078, China
| | - Xiang-Yin Luo
- Department of Neurosurgery, Xiang Ya Hospital of Central South University, Changsha, 410078, China
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8
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Lv S, Zhao K, Li R, Meng C, Li G, Yin F. EGFR-Activated JAK2/STAT3 Pathway Confers Neuroprotection in Spinal Cord Ischemia-Reperfusion Injury: Evidence from High-Throughput Sequencing and Experimental Models. Mol Neurobiol 2024; 61:646-661. [PMID: 37656314 DOI: 10.1007/s12035-023-03548-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 07/24/2023] [Indexed: 09/02/2023]
Abstract
This study aimed to investigate the molecular mechanisms underlying spinal cord ischemia-reperfusion (SCI/R) injury. Through RNA-Seq high-throughput sequencing and bioinformatics analysis, we found that EGFR was downregulated in the spinal cord of SCI/R mice and may function via mediating the JAK2/STAT3 signaling pathway. In vitro cell experiments indicated that overexpression of EGFR activated the JAK2/STAT3 signaling pathway and reduced neuronal apoptosis levels. In vivo animal experiments further confirmed this conclusion, suggesting that EGFR inhibits SCI/R-induced neuronal apoptosis by activating the JAK2/STAT3 signaling pathway, thereby improving SCI/R-induced spinal cord injury in mice. This study revealed the molecular mechanisms of SCI/R injury and provided new therapeutic strategies for treating neuronal apoptosis.
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Affiliation(s)
- Shijie Lv
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Kunchi Zhao
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Ran Li
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Chunyang Meng
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China
| | - Guangchun Li
- Department of Orthopedics, Jilin Province People's Hospital, Changchun, 130021, People's Republic of China
| | - Fei Yin
- Department of Spine Surgery, China-Japan Union Hospital of Jilin University, No. 126, Xiantai Street, Changchun, 130033, People's Republic of China.
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Wang R, Bai J. Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury. Neural Regen Res 2024; 19:35-42. [PMID: 37488841 PMCID: PMC10479866 DOI: 10.4103/1673-5374.375304] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 03/08/2023] [Accepted: 04/07/2023] [Indexed: 07/26/2023] Open
Abstract
Traumatic spinal cord injury is a devastating disorder characterized by sensory, motor, and autonomic dysfunction that severely compromises an individual's ability to perform activities of daily living. These adverse outcomes are closely related to the complex mechanism of spinal cord injury, the limited regenerative capacity of central neurons, and the inhibitory environment formed by traumatic injury. Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury. A number of therapeutic agents have been shown to improve the injury environment, mitigate secondary damage, and/or promote regeneration and repair. Among them, the spinal cord microcirculation has become an important target for the treatment of spinal cord injury. Drug interventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury. These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neurons, axons, and glial cells. This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury, including its structure and histopathological changes. Further, it summarizes the progress of drug therapies targeting the spinal cord microcirculation after spinal cord injury.
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Affiliation(s)
- Rongrong Wang
- Department of Spine and Spinal Cord Surgery, Beijing Bo’ai Hospital, China Rehabilitation Research Center, Beijing, China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, China
| | - Jinzhu Bai
- Department of Spine and Spinal Cord Surgery, Beijing Bo’ai Hospital, China Rehabilitation Research Center, Beijing, China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, China
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10
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Jung MA, Song HK, Jo K, Lee A, Hwang YH, Ji KY, Jung DH, Cai M, Lee JY, Pyun BJ, Kim T. Gleditsia sinensis Lam. aqueous extract attenuates nasal inflammation in allergic rhinitis by inhibiting MUC5AC production through suppression of the STAT3/STAT6 pathway. Biomed Pharmacother 2023; 161:114482. [PMID: 36921533 DOI: 10.1016/j.biopha.2023.114482] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/16/2023] Open
Abstract
Allergic rhinitis (AR), a chronic respiratory inflammatory disease, is among the most common chronic diseases reported worldwide. Mucus hypersecretion is a critical feature of AR pathogenesis. Although the Gleditsia sinensis extract has several beneficial effects on human health, its effects on allergic inflammation have not yet been investigated. In this study, we examined the effects of G. sinensis aqueous extract (GSAE) on nasal inflammation in an ovalbumin (OVA)-induced AR mouse model. GSAE was administered orally for 1 week and then the clinical nasal symptoms were evaluated. The levels of histamine, OVA-specific immunoglobulin (Ig) E, and interleukin (IL)-13 were measured in the serum using an enzyme-linked immunosorbent assay (ELISA). Inflammatory cells were then counted in the nasal lavage fluid (NALF) and histopathology in the nasal epithelium was evaluated. STAT3/STAT6 phosphorylation was examined in primary human nasal epithelial cells (HNEpCs) using western blot analysis. Oral administration of GSAE to OVA-induced AR mice alleviated nasal clinical symptoms and reduced OVA-specific immunoglobulin E, interleukin (IL)-13, and histamine levels. The accumulation of eosinophils in nasal lavage fluid, nasal mucosa, mast cells, goblet cells, and mucin 5AC (MUC5AC) in the nasal epithelium was also inhibited by GSAE. Treatment with GSAE inhibited the production of MUC5AC in IL-4/IL-13-stimulated primary human nasal epithelial cells through the signal transducer and activator of transcription (STAT)3/STAT6 signaling pathway. These results indicated that GSAE reduces nasal inflammation suggesting that it is a potential treatment option for AR.
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Affiliation(s)
- Myung-A Jung
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Hyun-Kyung Song
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Kyuhyung Jo
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Ami Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Youn-Hwan Hwang
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Kon-Young Ji
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea; Center for Companion Animal New Drug Development, Jeonbuk Branch, Korea Institute of Toxicology (KIT), 30 Baekhak1-gil, Jeongeup-si 56212, the Republic of Korea
| | - Dong Ho Jung
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Mudan Cai
- KM Science Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Joo Young Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea
| | - Bo-Jeong Pyun
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea.
| | - Taesoo Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero Yuseong-gu, Daejeon 34054, the Republic of Korea.
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11
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Zhang Q, Li Z, Xie L, Cao S, Cui Z, Shi B, Chen Y. Serum neutrophil gelatinase-associated lipocalin as a potential biomarker for cognitive decline in spinal cord injury. Front Neurol 2023; 14:1120446. [PMID: 36949855 PMCID: PMC10025340 DOI: 10.3389/fneur.2023.1120446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 02/13/2023] [Indexed: 03/08/2023] Open
Abstract
Objective Neutrophil gelatinase-associated lipoprotein (NGAL), a protein encoded by the lipocalcin-2 (LCN2) gene, has been reported to be involved in multiple processes of innate immunity, but its relationship with spinal cord injury (SCI) remains unclear. This study set out to determine whether NGAL played a role in the development of cognitive impairment following SCI. Methods At the Neck-Shoulder and Lumbocrural Pain Hospital, a total of 100 SCI patients and 72 controls were enrolled in the study through recruitment. Through questionnaires, baseline data on the participants' age, gender, education level, lifestyle choices (drinking and smoking) and underlying illnesses (hypertension, diabetes, coronary heart disease, and hyperlipidemia) were gathered. The individuals' cognitive performance was evaluated using the Montreal Cognitive Scale (MoCA), and their serum NGAL levels were discovered using ELISA. Results The investigation included 72 controls and 100 SCI patients. The baseline data did not differ substantially between the two groups, however the SCI group's serum NGAL level was higher than the control group's (p < 0.05), and this elevated level was adversely connected with the MoCA score (p < 0.05). According to the results of the ROC analysis, NGAL had a sensitivity of 58.24% and a specificity of 86.72% for predicting cognitive impairment following SCI. Conclusions The changes in serum NGAL level could serve as a biomarker for cognitive impairment in SCI patients, and this holds true even after taking in account several confounding variables.
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Affiliation(s)
- Qinghao Zhang
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ziteng Li
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- School of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Liangyu Xie
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Shengnan Cao
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhonghao Cui
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Bin Shi
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuanzhen Chen
- Bone Biomechanics Engineering Laboratory of Shandong Province, Shandong Medicinal Biotechnology Center (School of Biomedical Sciences), Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
- *Correspondence: Yuanzhen Chen
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12
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Simats A, Ramiro L, Valls R, de Ramón H, García-Rodríguez P, Orset C, Artigas L, Sardon T, Rosell A, Montaner J. Ceruletide and Alpha-1 Antitrypsin as a Novel Combination Therapy for Ischemic Stroke. Neurotherapeutics 2022; 19:513-527. [PMID: 35226340 PMCID: PMC9226209 DOI: 10.1007/s13311-022-01203-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2022] [Indexed: 12/29/2022] Open
Abstract
Ischemic stroke is a primary cause of morbidity and mortality worldwide. Beyond the approved thrombolytic therapies, there is no effective treatment to mitigate its progression. Drug repositioning combinational therapies are becoming promising approaches to identify new uses of existing drugs to synergically target multiple disease-response mechanisms underlying complex pathologies. Here, we used a systems biology-based approach based on artificial intelligence and pattern recognition tools to generate in silico mathematical models mimicking the ischemic stroke pathology. Combinational treatments were acquired by screening these models with more than 5 million two-by-two combinations of drugs. A drug combination (CA) formed by ceruletide and alpha-1 antitrypsin showing a predicted value of neuroprotection of 92% was evaluated for their synergic neuroprotective effects in a mouse pre-clinical stroke model. The administration of both drugs in combination was safe and effective in reducing by 39.42% the infarct volume 24 h after cerebral ischemia. This neuroprotection was not observed when drugs were given individually. Importantly, potential incompatibilities of the drug combination with tPA thrombolysis were discarded in vitro and in vivo by using a mouse thromboembolic stroke model with t-PA-induced reperfusion, revealing an improvement in the forepaw strength 72 h after stroke in CA-treated mice. Finally, we identified the predicted mechanisms of action of ceruletide and alpha-1 antitrypsin and we demonstrated that CA modulates EGFR and ANGPT-1 levels in circulation within the acute phase after stroke. In conclusion, we have identified a promising combinational treatment with neuroprotective effects for the treatment of ischemic stroke.
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Affiliation(s)
- Alba Simats
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona, 08035, Spain
| | - Laura Ramiro
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona, 08035, Spain
| | | | - Helena de Ramón
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona, 08035, Spain
| | - Paula García-Rodríguez
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona, 08035, Spain
| | - Cyrille Orset
- Inserm UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Université Caen-Normandie, GIP Cyceron, Caen, France
| | | | | | - Anna Rosell
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona, 08035, Spain
| | - Joan Montaner
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, Barcelona, 08035, Spain.
- Stroke Research Program, Institute of Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC, University of Seville, Seville, Spain.
- Department of Neurology, Hospital Universitario Virgen Macarena, Seville, Spain.
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13
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Patel D, Wairkar S. Biotechnology-based therapeutics for management of cerebral stroke. Eur J Pharmacol 2021; 913:174638. [PMID: 34801531 DOI: 10.1016/j.ejphar.2021.174638] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/05/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Cerebral stroke, commonly caused due to hindrance in blood flow, is broadly classified into two categories-ischemic and haemorrhagic strokes. The onset of stroke triggers multiple mechanisms causing inflammation, generation of free radicals and protein damage leading to apoptosis of neuronal cells. The current therapies available for cerebral strokes involve use of complex surgical treatments and tissue plasminogen activator which increases the risk of internal bleeding, brain edema and cerebral damage, thereby restricting their use in clinical setting. The alarming need to develop safe, effective, target specific systems which, promote neuronal growth and reduce cerebral inflammation can be accomplished with use of biotechnological approaches. The article gives an insight to biotechnology-based advancements for tissue plasminogen activators, cell penetrating peptides, growth factors, ribonucleic acid systems and monoclonal antibodies for cerebral stroke. We also emphasis on challenges and future perspective of biotechnology-based therapeutics for better management of stroke.
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Affiliation(s)
- Dhrumi Patel
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, Maharashtra, 400056, India
| | - Sarika Wairkar
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, Maharashtra, 400056, India.
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14
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Hu QP, Yan HX, Peng F, Feng W, Chen FF, Huang XY, Zhang X, Zhou YY, Chen YS. Genistein protects epilepsy-induced brain injury through regulating the JAK2/STAT3 and Keap1/Nrf2 signaling pathways in the developing rats. Eur J Pharmacol 2021; 912:174620. [PMID: 34752743 DOI: 10.1016/j.ejphar.2021.174620] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 01/07/2023]
Abstract
BACKGROUND Epilepsy is a common chronic neurological disease. Recurrent seizures can cause irreversible brain damage. This study aimed to explore the regulation of Genistein on JAK2/STAT3 and Keap1/Nrf2 signaling pathway and the protective effects on brain injury after epilepsy. METHODS Pentylenetetrazole (PTZ) was used to induce epilepsy in developing rats and Genistein was used for pretreatment of epilepsy. The seizure latency, grade scores and duration of the first generalized tonic-clonic seizure (GTCs) were recorded. Hippocampus tissue was sampled at 24 h post-epilepsy. Immunofluorescence staining was used to observe mature neurons, activated microglia and astrocytes in the hippocampal CA1 region. Western blot and qRT-PCR were used to determine the protein and mRNA levels of JAK2, STAT3, TNF-α, IL-1β, Keap1, Nrf2, HO-1, NQO1, caspase3, Bax and Bcl2 in the hippocampus. RESULTS Immunofluorescence showed that the number of neurons significantly decreased, and activated microglia and astrocytes significantly increased after epilepsy; Western blot and q-PCR showed that the expressions of JAK2, STAT3, TNF-α, IL-1β, Keap1, caspase3 and Bax significantly increased, while Nrf2, HO-1, NQO1 and Bcl-2 were significantly reduced after epilepsy. These effects were reversed by Genistein treatment. Moreover, Genistein was found to prolong seizure latency and reduce seizure intensity score and duration of generalized tonic-clonic seizures(GTCs) CONCLUSIONS: Genistein can activate the Keap1/Nrf2 antioxidant stress pathway and attenuate the activation of microglia and astrocytes. Genistein also inhibits the JAK2-STAT3 inflammation pathway and expression of apoptotic proteins, and increases the number of surviving neurons, thus having a protective effect on epilepsy-induced brain damage.
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Affiliation(s)
- Qing-Peng Hu
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Hong-Xia Yan
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Fang Peng
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Wei Feng
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Fen-Fang Chen
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiang-Yi Huang
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xin Zhang
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yang-Yu Zhou
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Yi-Shui Chen
- Department of Pediatrics, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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15
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Cui Q, Ma YH, Yu HY, Zhang YL, Qin XD, Ge SQ, Zhang GW. Systematic analysis of the mechanism of hydroxysafflor yellow A for treating ischemic stroke based on network pharmacology technology. Eur J Pharmacol 2021; 908:174360. [PMID: 34302817 DOI: 10.1016/j.ejphar.2021.174360] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/14/2021] [Accepted: 07/19/2021] [Indexed: 01/18/2023]
Abstract
In this study, we analyzed the mechanism of hydroxysafflor yellow A (HSYA) for treating ischemic stroke (IS) based on network pharmacology tools, and verified the kernel targets via animal experiments. The targets of HSYA were collected via PharmMapper server and the IS-related targets were searched using Genecards, Online Mendelian Inheritance in Man, Therapeutic Target, and Disgenet databases. The targets identified from the above two steps were overlapped to acquire candidate targets involved in the effects of HSYA for treating IS. Subsequently, the Database for Annotation, Visualization, and Integrated Discovery was used for gene ontology analysis and the Kyoto encyclopedia of genes and genomes pathway analysis. Cytoscape 3.7.1 was applied to establish the component-target-pathway network. Potential core targets were obtained by protein-protein interaction analysis. Furthermore, Autodock Vina was used to identify core genes, and animal experiments was used to verify the expression level of core genes. On the basis of the modified neurologic severity score and the results of 2,3,5-Triphenyltetrazolium chloride and Hematoxylin-eosin staining, we confirmed that HSYA reduced the infarct volume in rats and protected neuronal cells in the hippocampal region after IS. Western blot and immunohistochemical staining showed that HSYA increased the expression of epidermal growth factor receptor, hypoxia inducible factor 1 alpha, and endothelial nitric oxide synthase (P < 0.05). The effects of HSYA on IS are mediated through several targets and pathways related to the regulation of oxidative stress and the renewal of cell and blood vessels while improving post-ischemic brain impairment.
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Affiliation(s)
- Qian Cui
- College of Traditional Chinese Medicine, Hebei University, Baoding, Hebei, 071002, China
| | - Yu-Hui Ma
- Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, China
| | - Hao-Yu Yu
- College of Traditional Chinese Medicine, Hebei University, Baoding, Hebei, 071002, China
| | - Yu-Liang Zhang
- College of Traditional Chinese Medicine, Hebei University, Baoding, Hebei, 071002, China
| | - Xiu-de Qin
- Shenzhen TCM Hospital, Shenzhen, Guangdong, 518000, China
| | - Shao-Qin Ge
- College of Traditional Chinese Medicine, Hebei University, Baoding, Hebei, 071002, China
| | - Guo-Wei Zhang
- College of Traditional Chinese Medicine, Hebei University, Baoding, Hebei, 071002, China.
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16
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Dekens DW, Eisel ULM, Gouweleeuw L, Schoemaker RG, De Deyn PP, Naudé PJW. Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases. Ageing Res Rev 2021; 70:101414. [PMID: 34325073 DOI: 10.1016/j.arr.2021.101414] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.
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Affiliation(s)
- Doortje W Dekens
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Ulrich L M Eisel
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Leonie Gouweleeuw
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Regien G Schoemaker
- Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands
| | - Peter P De Deyn
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Laboratory of Neurochemistry and Behaviour, Biobank, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Petrus J W Naudé
- Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences (GELIFES), University of Groningen, Groningen, the Netherlands; Department of Psychiatry and Mental Health and Neuroscience Institute, Brain Behaviour Unit, University of Cape Town, Cape Town, South Africa.
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17
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Liu HW, Hu ZL, Li H, Tan QF, Tong J, Zhang YQ. Knockdown of lncRNA ANRIL suppresses the production of inflammatory cytokines and mucin 5AC in nasal epithelial cells via the miR-15a-5p/JAK2 axis. Mol Med Rep 2020; 23:145. [PMID: 33325534 PMCID: PMC7751488 DOI: 10.3892/mmr.2020.11784] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/08/2020] [Indexed: 12/13/2022] Open
Abstract
The incidence of allergic rhinitis (AR) is increasing worldwide. Human nasal epithelial cells (HNECs) are the key cells in the occurrence of AR. Antisense non-coding RNA in the INK4 locus (ANRIL) was discovered to be involved in the progression of AR. However, the mechanism by which ANRIL mediates the progression of AR remains to be determined. The present study aimed to further explore the mechanism by which ANRIL regulates AR. Thereby, HNECs were treated with IL-13 to mimic AR in vitro. The mRNA expression levels of ANRIL, microRNA (miR)-15a-5p, JAK2, mucin 5AC (MUC5AC), granulocyte-macrophage colony-stimulating factor (GM-CSF) and eotaxin-1, and protein expression levels of JAK2, STAT3 and phosphorylated-STAT3 in HNECs were analyzed using reverse transcription-quantitative PCR and western blotting, respectively. ELISAs were used to detect the secretory levels of inflammatory cytokines and mucin in cell supernatants. In addition, a dual luciferase reporter assay was used to confirm the downstream target of ANRIL and the target gene of miR-15a-5p. The results revealed that the secretory levels of eotaxin-1, GM-CSF and MUC5AC were significantly upregulated by IL-13 in the supernatant of HNECs. The expression levels of ANRIL and JAK2 were also upregulated in IL-13-induced HNECs, while the expression levels of miR-15a-5p were downregulated. In addition, ANRIL was identified to bind to miR-15a-5p. The IL-13-induced upregulation of eotaxin-1, GM-CSF and MUC5AC mRNA expression and secretory levels was significantly inhibited by the genetic knockdown of ANRIL, while the miR-15a-5p inhibitor effectively reversed this effect. JAK2 was also discovered to be directly targeted by miR-15a-5p. The overexpression of JAK2 significantly suppressed the therapeutic effect of miR-15a-5p mimics on IL-13-induced inflammation in vitro. In conclusion, the findings of the present study suggested that the genetic knockdown of ANRIL may suppress the production of inflammatory cytokines and mucin in IL-13-treated HNECs via regulation of the miR-15a-5p/JAK2 axis. Thus, ANRIL may serve as a novel target for AR treatment.
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Affiliation(s)
- Huo-Wang Liu
- Department of Otolaryngology-Head and Neck Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Zhong-Liang Hu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410007, P.R. China
| | - Hao Li
- Department of Otolaryngology-Head and Neck Surgery, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Qi-Feng Tan
- Department of Otolaryngology-Head and Neck Surgery, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Jing Tong
- Department of Otolaryngology-Head and Neck Surgery, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Yong-Quan Zhang
- Department of Otolaryngology-Head and Neck Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
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