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Sharma V, Singh TG. Hypoxia-inducible Factor-1α Pathway in Cerebral Ischemia: From Molecular Mechanisms to Therapeutic Targets. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2025; 24:208-218. [PMID: 39428931 DOI: 10.2174/0118715273324551241008111827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/22/2024]
Abstract
INTRODUCTION Ischemic injury to the brain can result in a variety of life-threatening conditions, mortality, or varying degrees of disability. Hypoxia-inducible factor 1α (HIF 1α), an oxygen- sensitive transcription factor that controls the adaptive metabolic response to hypoxia, is a critical constituent of cerebral ischemia. It participates in numerous processes, such as metabolism, proliferation, and angiogenesis, and plays a major role in cerebral ischemia. METHODS Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the pharmacological modulation of HIF-1α pathways for the treatment of cerebral ischemia. RESULTS Various signalling pathways, such as Mitogen-activated protein kinase (MAPK), Janus kinase/ signal transducers and activators (JAK/STAT), Phosphoinositide-3-kinase (PI3-K), and cAMPresponse element binding protein (CREB) play a vital role in modulation of HIF-1α pathway, which helps in preventing the pathogenesis of cerebral ischemia. CONCLUSION The pharmacological modulation of the HIF-1α pathway via various molecular signalling pathways, such as PI3-K, MAPK, CREB, and JAK/STAT activators, offer a promising prospect for future interventions and treatment for cerebral ischemia.
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Affiliation(s)
- Veerta Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Izquierdo-Bermejo S, Chamorro B, Martín-de-Saavedra MD, Lobete M, López-Muñoz F, Marco-Contelles J, Oset-Gasque MJ. In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke. Antioxidants (Basel) 2024; 13:946. [PMID: 39199193 PMCID: PMC11351736 DOI: 10.3390/antiox13080946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/27/2024] [Accepted: 07/30/2024] [Indexed: 09/01/2024] Open
Abstract
Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia-reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically.
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Affiliation(s)
- Sara Izquierdo-Bermejo
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain; (S.I.-B.); (B.C.); (M.D.M.-d.-S.); (M.L.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain
- Faculty of Health Sciences—HM Hospitals, Camilo José Cela University, Villafranca del Castillo, 28692 Madrid, Spain;
| | - Beatriz Chamorro
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain; (S.I.-B.); (B.C.); (M.D.M.-d.-S.); (M.L.)
- Faculty of Health Sciences—HM Hospitals, Camilo José Cela University, Villafranca del Castillo, 28692 Madrid, Spain;
| | - María Dolores Martín-de-Saavedra
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain; (S.I.-B.); (B.C.); (M.D.M.-d.-S.); (M.L.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain
| | - Miguel Lobete
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain; (S.I.-B.); (B.C.); (M.D.M.-d.-S.); (M.L.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain
| | - Francisco López-Muñoz
- Faculty of Health Sciences—HM Hospitals, Camilo José Cela University, Villafranca del Castillo, 28692 Madrid, Spain;
- HM Hospitals Health Research Institute, 28015 Madrid, Spain
- Neuropsychopharmacology Unit, “Hospital 12 de Octubre” Research Institute, 28041 Madrid, Spain
| | - José Marco-Contelles
- Laboratory of Medicinal Chemistry, Institute of Organic Chemistry (CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain;
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Carlos III Health Institute (ISCIII), 28029 Madrid, Spain
| | - María Jesús Oset-Gasque
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, Ciudad Universitaria, 28040 Madrid, Spain; (S.I.-B.); (B.C.); (M.D.M.-d.-S.); (M.L.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain
- Instituto Universitario de Investigación en Neuroquímica, Complutense University of Madrid, Ciudad Universitaria, 28040 Madrid, Spain
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Jearjaroen P, Thangwong P, Tocharus C, Lungkaphin A, Chaichompoo W, Srijun J, Suksamrarn A, Tocharus J. Hexahydrocurcumin Attenuates Neuronal Injury and Modulates Synaptic Plasticity in Chronic Cerebral Hypoperfusion in Rats. Mol Neurobiol 2024; 61:4304-4317. [PMID: 38087168 DOI: 10.1007/s12035-023-03821-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 11/20/2023] [Indexed: 07/11/2024]
Abstract
Dementia is the most common age-related problem due predominantly to Alzheimer's disease (AD) and vascular dementia (VaD). It has been shown that these contributors are associated with a high amount of oxidative stress that leads to changes in neurological function and cognitive impairment. The aim of study was to explore the mechanism by which hexahydrocurcumin (HHC) attenuates oxidative stress, amyloidogenesis, phosphorylated Tau (pTau) expression, neuron synaptic function, and cognitive impairment and also the potential mechanisms involved in induced permanent occlusion of bilateral common carotid arteries occlusion (BCCAO) or 2-vessel occlusion (2VO) in rats. After surgery, rats were treated with HHC (40 mg/kg) or piracetam (600 mg/kg) by oral gavage daily for 4 weeks. The results showed that HHC or piracetam attenuated oxidative stress by promoting nuclear factor erythroid 2-related factor 2 (Nrf2) activity, and alleviated expression of synaptic proteins (pre- and post-synaptic proteins) mediated by the Wingless/Integrated (Wnt)/β-catenin signaling pathway. Moreover, HHC or piracetam also improved synaptic plasticity via the brain-derived neurotrophic factor (BDNF)/Tyrosine receptor kinase B (TrkB)/cAMP responsive element binding protein (CREB) signaling pathway. In addition, HHC reduced amyloid beta (Aβ) production and pTau expression and improved memory impairment as evidenced by the Morris water maze. In conclusion, HHC exerted remarkable improvement in cognitive function in the 2VO rats possibly via the attenuation of oxidative stress, improvement in synaptic function, attenuation of amyloidogenesis, pTau, and neuronal injury, thereby improving cognitive performance.
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Affiliation(s)
- Pranglada Jearjaroen
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Phakkawat Thangwong
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Jaranwit Srijun
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Functional Food Research Center for Well-being, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Rabinovitz R, Eynan M. CNS-oxygen toxicity and blood glucose levels in MnSOD enzyme knockdown mice. Respir Physiol Neurobiol 2023; 316:104122. [PMID: 37481014 DOI: 10.1016/j.resp.2023.104122] [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: 05/27/2023] [Revised: 07/04/2023] [Accepted: 07/18/2023] [Indexed: 07/24/2023]
Abstract
Many studies have been conducted in the search for the mechanism underlying CNS-oxygen toxicity (OT), which may be fatal when diving with a closed-circuit apparatus. We investigated the influence of hyperbaric oxygen (HBO) on blood glucose level (BGL) in Mn-superoxide dismutase (SOD2) knockdown mice regarding CNS-OT in particular under stress conditions such as hypoglycemia or hyperglycemia. Two groups of mice were used: SOD2 knockdown (Heterozygous, HET) mice and their WT family littermates. Animals were exposed to HBO from 2 up to 5 atmosphere absolute (ATA). Blood samples were drawn before and after each exposure for measurement of BGL. The mice were sacrificed following the final exposure, which was at 5 ATA. We used RT-PCR and Western blot to measure levels of glucose transporter 1 (GLUT1) and hypoxia inducible factor (HIF)1a in the cortex and hippocampus. In the hypoglycemic condition, the HET mice were more sensitive to oxidative stress than the WT. In addition, following exposure to sub-toxic HBO, which does not induce CNS-OT, BGL were higher in the HET mice compared with the WT. The expression of mRNA of GLUT1 and HIF-1a decreased in the hippocampus in the HET mice, while the protein level decreased in the HET and WT following HBO exposure. The results suggest that the higher BGL following HBO exposure especially at SOD2 HET mice is in part due to reduction in GLUT1 as a consequence of lower HIF-1a expression. This may add part to the puzzle of the understanding the mechanism leading to CNS-OT.
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Affiliation(s)
- Ricarina Rabinovitz
- Israel Naval Medical Institute, Israel Defense Forces Medical Corps, Haifa, Israel
| | - Mirit Eynan
- Israel Naval Medical Institute, Israel Defense Forces Medical Corps, Haifa, Israel.
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Liu Y, Li YP, Xiao LM, Chen LK, Zheng SY, Zeng EM, Xu CH. Extracellular Vesicles Derived from Bone Mesenchymal Stem Cells Carrying circ_0000075 Relieves Cerebral Ischemic Injury by Competitively Inhibiting miR-218-5p and Up-regulating E3 Ubiquitin Ligase SMURF2. Mol Neurobiol 2023; 60:2801-2818. [PMID: 36732429 DOI: 10.1007/s12035-022-03192-9] [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: 08/17/2022] [Accepted: 12/23/2022] [Indexed: 02/04/2023]
Abstract
Extracellular vesicle (EV)-encapsulated circRNAs have the potential role in affecting brain disorders. However, the role of circ_0000075 in cerebral ischemic injury remains unclear. Here, we tried to investigate the mechanism of bone marrow mesenchymal stem cell (BMSC)-derived EVs carrying circ_0000075 in the control of cerebral ischemic injury. Initially, a mouse model with cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO), followed by the determination of circ_0000075 expression. Then, neurons were isolated and subjected to oxygen-glucose deprivation/reperfusion. BMSCs were isolated for extraction of EVs. The correlation among circ_0000075, microRNA (miR)-218-5p, and Smad ubiquitination regulatory factor 2 (SMURF2) was detected with their roles in cerebral ischemic injury analyzed in vivo and in vitro. circ_0000075 was down-regulated in MCAO mice and engineered RVG-EVs were internalized by neurons to up-regulate circ_0000075 expression. Treatment of RVG-circ_0000075-EVs reduced brain tissue damage, increased neuronal count, and significantly curtailed apoptosis rate, suppressing cerebral ischemic injury in vitro and in vivo. miR-218-5p was targeted by circ_0000075 in neurons, which promoted SMURF2 expression. A negative correlation between SMURF2 and transcriptional regulator Yin Yang 1 (YY1) was identified. In vitro experiments further proved that circ_ 00,000 75 could down-regulate the expression of YY1 through SMURF2, and finally relieving cerebral ischemic injury. Collectively, engineered EVs delivered circ_0000075 into brain tissues and increased circ_0000075 expression, which down-regulated miR-218-5p and up-regulated SMURF2, thus alleviating cerebral ischemic injury.
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Affiliation(s)
- Yue Liu
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - You-Ping Li
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Li-Min Xiao
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Li-Ke Chen
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Su-Yue Zheng
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Er-Ming Zeng
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China
| | - Chun-Hua Xu
- Department of Neurosurgery, Jiangxi Province, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Nanchang, 330006, People's Republic of China.
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Waseem A, Rashid S, Rashid K, Khan MA, Khan R, Haque R, Seth P, Raza SS. Insight into the transcription factors regulating Ischemic Stroke and Glioma in Response to Shared Stimuli. Semin Cancer Biol 2023; 92:102-127. [PMID: 37054904 DOI: 10.1016/j.semcancer.2023.04.006] [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: 11/23/2022] [Revised: 03/28/2023] [Accepted: 04/09/2023] [Indexed: 04/15/2023]
Abstract
Cerebral ischemic stroke and glioma are the two leading causes of patient mortality globally. Despite physiological variations, 1 in 10 people who have an ischemic stroke go on to develop brain cancer, most notably gliomas. In addition, glioma treatments have also been shown to increase the risk of ischemic strokes. Stroke occurs more frequently in cancer patients than in the general population, according to traditional literature. Unbelievably, these events share multiple pathways, but the precise mechanism underlying their co-occurrence remains unknown. Transcription factors (TFs), the main components of gene expression programmes, finally determine the fate of cells and homeostasis. Both ischemic stroke and glioma exhibit aberrant expression of a large number of TFs, which are strongly linked to the pathophysiology and progression of both diseases. The precise genomic binding locations of TFs and how TF binding ultimately relates to transcriptional regulation remain elusive despite a strong interest in understanding how TFs regulate gene expression in both stroke and glioma. As a result, the importance of continuing efforts to understand TF-mediated gene regulation is highlighted in this review, along with some of the primary shared events in stroke and glioma.
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Affiliation(s)
- Arshi Waseem
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Lucknow-226003, India
| | - Sumaiya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Khalid Rashid
- Department of Cancer Biology, Vontz Center for Molecular Studies, Cincinnati, OH 45267-0521
| | | | - Rehan Khan
- Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City,Mohali, Punjab 140306, India
| | - Rizwanul Haque
- Department of Biotechnology, Central University of South Bihar, Gaya -824236, India
| | - Pankaj Seth
- Molecular and Cellular Neuroscience, Neurovirology Section, National Brain Research Centre, Manesar, Haryana-122052, India
| | - Syed Shadab Raza
- Laboratory for Stem Cell & Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Sarfarazganj, Lucknow-226003, India; Department of Stem Cell Biology and Regenerative Medicine, Era's Lucknow Medical College Hospital, Era University, Sarfarazganj, Lucknow-226003, India
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Luo M, Yu J, Xin C, Hu M, Tao T, Wan G, Chen J, Zhang J. Expression of hypoxia-inducing factor-1α and matrix metalloproteinase-9 in the recipient parasylvian cortical arteries with different hemodynamic sources in adult moyamoya disease. Front Surg 2023; 10:1080395. [PMID: 36998597 PMCID: PMC10043197 DOI: 10.3389/fsurg.2023.1080395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/09/2023] [Indexed: 03/16/2023] Open
Abstract
ObjectiveIn our latest research, we have demonstrated that the recipient parasylvian cortical arteries (PSCAs) with hemodynamic sources from the middle cerebral artery (M-PSCAs) has a higher risk of postoperative cerebral hyperperfusion (CHP) syndrome than those from non-M-PSCAs in adult moyamoya disease (MMD) patient. However, whether there are differences between M-PSCAs and non-M-PSCAs in vascular specimens characteristics has not been studied. In this study, we further investigate the vascular specimen of recipient PSCAs by histological and immunohistochemical methods.Methods50 vascular specimens of recipient PSCAs were obtained from 50 adult MMD patients during the combined bypass surgeries in our departments of Zhongnan hospital. 4 recipient PSCAs samples were also obtained in the same way from the middle cerebral artery occlusion patients. The samples were received the pathological sectioning, hematoxylin and eosin staining, and immunohistochemistry, then the vascular wall thickness, matrix metalloproteinase-9 (MMP-9) and hypoxia-inducing factor-1α (HIF-1α) were analyzed.ResultsM-PSCAs adult MMD patients had a thinner intima than non-M-PSCAs in the recipient PSCAs specimens. In recipient non-M-PSCAs vascular specimens, the immunoreactivity indicating HIF-1α and matrix metalloproteinase-9 (MMP-9) was significantly higher than M-PSCAs groups. The logistic regression analyses showed that the M-PSCAs was an independent risk factor of postoperative cerebral hyperperfusion (CHP) syndrome (OR 6.235, 95% CI1.018-38.170, P = 0.048) in MMD.ConclusionOur results indicate that M-PSCAs adult MMD patients had thinner intima than non-MCAs adult MMD patients in the PSCAs. More importantly, HIF-1α and MMP-9 were overexpressed in non-M-PSCAs vascular specimens.
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Nor Nazli NA, Muthuraju S, Ahmad F, Mohamed Yusoff AA, Jaafar H, Shamsuddin S, Abdullah JM. Characterisation of Primary Human Hippocampal Astrocyte Cell Culture Following Exposure to Hypoxia. Malays J Med Sci 2023; 30:92-106. [PMID: 36875187 PMCID: PMC9984107 DOI: 10.21315/mjms2023.30.1.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/01/2022] [Indexed: 03/05/2023] Open
Abstract
Background The present study aimed to understand the characterisation of human hippocampal astrocyte following hypoxia exposure. Based on the preliminary screening, 15 min was chosen as the time point and the cells were exposed to different oxygen percentages. Methods The Trypan blue viability assay used to examine cell death. Immunofluorescence assay, glial fibrillary acidic protein (GFAP) was used to portray the morphology of astrocytes. The hypoxia-inducible factor 1 (HIF-1) staining was performed to confirm hypoxia induced cell death and there was a dramatic expression of HIF-1α displayed in exposed astrocyte cells compared to the control. In molecular level, genes were chosen, such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH), GFAP, HIF-1α and B-cell lymphoma 2 (Bcl-2) and ran the reverse transcription-polymerase chain reaction (RT-PCR). Results Microscope revealed a filamentous and clear nucleus appearance in a control whereas the rupture nuclei with no rigid structure of the cell were found in the 3% oxygen. The control and hypoxia cells were also stained with the annexin V-fluorescein isothiocyanate (annexin V-FITC). Fluorescence microscope reveals astrocyte cells after hypoxia showed higher expression of nuclei but not in control. Merging PI and FITC showed the differences of nuclei expression between the control and hypoxia. In the molecular analysis, there were significant changes of GFAP, HIF-1α and Bcl-2 in hypoxia exposed cells when compared to the control group. Conclusion Cells that were exposed to hypoxia (3% oxygen for 15 min) clearly showed damage. General view of human hippocampal astrocyte genomic response to hypoxia was obtained.
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Affiliation(s)
- Nurul Atikah Nor Nazli
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Sangu Muthuraju
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Farizan Ahmad
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Hasnan Jaafar
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Shaharum Shamsuddin
- Department of Biomedicine, School of Health Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Jafri Malin Abdullah
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.,Brain and Behaviour Cluster, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia
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Nitric oxide promotes cerebral ischemia/reperfusion injury through upregulating hypoxia-inducible factor1-α-associated inflammation and apoptosis in rats. Neurosci Lett 2023; 795:137034. [PMID: 36584806 DOI: 10.1016/j.neulet.2022.137034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/09/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022]
Abstract
Nitric oxide (NO) was one of the key factors to sustain hypoxia-inducible factor-1- α (HIF-1α) activation during hypoxia. However, the mechanism by which NO production promotes upregulation of HIF-1α to cause cerebral ischemia/reperfusion (I/R) injury remains unclear. The present study investigated whether eliminating NO would decrease HIF-1α level, and then reduce the subsequent inflammatory actions as well as neuronal apoptotic death in middle cerebral artery occlusion (MCAO) rats. Our results revealed that HIF-1α was correlated with 3-NT, a marker for nitrosative/oxidative stress, in the brain of MCAO rats. Treatment with NOS inhibitor L-NAME suppressed HIF-1α/3-NT double-positive cells, suggesting that HIF-1α was correlated with NO overproduction during cerebral I/R. Furthermore, pro-inflammatory cytokines TNF-α, IL-1β and NF-κB p65 were significantly increased and colocalized with HIF-1α in the brain of MCAO rats, all of which could be attenuated by NO inhibition, suggesting that eliminating NO reduced MCAO-induced HIF-1α upregulation, which in turn exerted anti-inflammatory actions. Accordingly, cleaved caspase-3, as well as HIF-1α and TUNEL double-positive cells in ischemic brain were also decreased by L-NAME treatment. These results suggest that NO accumulation after cerebral ischemia leads to HIF-1α upregulation, which may activate pro-inflammatory cytokines, resulting in neuronal apoptotic death. These findings demonstrate a novel mechanism of NO-induced cerebral I/R injury.
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Xu S, Zhang N, Cao L, Liu L, Deng H, Hua S, Zhang Y. Tetramethylpyrazine Attenuates Oxygen-glucose Deprivation-induced Neuronal Damage through Inhibition of the HIF-1α/BNIP3 Pathway: from Network Pharmacological Finding to Experimental Validation. Curr Pharm Des 2023; 29:543-554. [PMID: 36790003 DOI: 10.2174/1381612829666230215100507] [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: 08/26/2022] [Revised: 12/23/2022] [Accepted: 01/02/2023] [Indexed: 02/16/2023]
Abstract
AIMS A network pharmacological analysis combined with experimental validation was used to investigate the neuroprotective mechanism of the natural product Tetramethylpyrazine(TMP). BACKGROUND Protecting neurons is critical for acute ischemic stroke treatment. Tetramethylpyrazine is a bioactive component extracted from Chuanxiong. The neuroprotective potential of TMP has been reported, but a systematic analysis of its mechanism has not been performed. OBJECTIVE Based on the hints of network pharmacology and bioinformatics analysis, the mechanism by which TMP alleviates oxygen-glucose deprivation-induced neuronal damage through inhibition of the HIF-1α/BNIP3 pathway was verified. METHOD In this study, we initially used network pharmacology and bioinformatics analyses to elucidate the mechanisms involved in TMP's predictive targets on a system level. The HIF-1α/BNIP3 pathway mediating the cellular response to hypoxia and apoptosis was considered worthy of focus in the bioinformatic analysis. An oxygen-glucose deprivation (OGD)-induced PC12 cell injury model was established for functional and mechanical validation. Cell viability, lactate dehydrogenase leakage, intracellular reactive oxygen species, percentage of apoptotic cells, and Caspase-3 activity were determined to assess the TMP's protective effects. Transfection with siRNA/HIF-1α or pcDNA/HIF-1α plasmids to silence or overexpress hypoxia-inducible factor 1α(HIF-1α). The role of HIF-1α in OGD-injured cells was observed first. After that, TMP's regulation of the HIF-1α/BNIP3 pathway was investigated. The pcDNA3.1/HIF-1α-positive plasmids were applied in rescue experiments. RESULT The results showed that TMP dose-dependently attenuated OGD-induced cell injury. The expression levels of HIF-1α, BNIP3, and the Bax/Bcl-2 increased significantly with increasing OGD duration. Overexpression of HIF-1α decreased cell viability, increased BNIP3 expression, and Bax/Bcl-2 ratio; siRNA-HIF-1α showed the opposite effect. TMP treatment suppressed HIF-1α, BNIP3 expression, and the Bax/Bcl-2 ratio and was reversed by HIF-1α overexpression. CONCLUSION Our study shows that TMP protects OGD-damaged PC12 cells by inhibiting the HIF-1α/BNIP3 pathway, which provides new insights into the mechanism of TMP and its neuroprotective potential.
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Affiliation(s)
- Shixin Xu
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Nannan Zhang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Dongcheng District Community Health Service Management Center, Beijing, China
| | - Lanlan Cao
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Lu Liu
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Binhai New Area Hospital of TCM. Tian Jin, Fourth Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Deng
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Shengyu Hua
- Institute of traditional Chinese medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yunsha Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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11
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Zhou W, Tao T, Yu W, Wu W, Hui Z, Xu H, Li Y, Zhang Y, Yang X. Recombinant Adenovirus-Mediated HIF-lα Ameliorates Neurological Dysfunction by Improving Energy Metabolism in Ischemic Penumbra After Cerebral Ischemia-Reperfusion in Rats. Neuropsychiatr Dis Treat 2023; 19:775-784. [PMID: 37051416 PMCID: PMC10085005 DOI: 10.2147/ndt.s389022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Background Hypoxia inducible factor-1α (HIF-1α) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1ɑ on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model. Methods Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1α (AdHIF-1α) group. The AdHIF-1α group and the Ad group were injected with AdHIF-1α and Ad in the lateral ventricle. The mNSS was performed at post-ischemia day 0 (P0) and P1, P14 and P28. At P14, the cerebral infarct volume was compared. At P28, HE staining, Nissl stains and TUNEL staining were performed. The expression of HIF-1α, GLUT1 and PFKFB3 were evaluated by Western Blot and immunohistochemistry. High performance liquid chromatography (HPLC) was used to determine the expression of GLUT1 and PFKFB3, and the level of energy metabolites: ATP, ADP and AMP. Results mNSS scores in the AdHIF-1α group were consistently lower than those in the CIR and Ad groups from P14 (P < 0.05) and Ad groups (P < 0.05). The cerebral infarct volume was reduced in the AdHIF-1α group compared with that in CIR group and Ad group (P < 0.05). At P28, HE showed better pathological changes in AdHIF-1α group. The number of Nissl bodies was increased in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The number of apoptotic cells in the AdHIF-1α group was fewer than that in the CIR and Ad groups (P < 0.05). The expression of HIF-1α, GLUT1 and PFKFB3 was significantly higher in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The ATP, ADP and AMP in the ischemic penumbra were also higher in the AdHIF-1α group (P < 0.05). Conclusion HIF-lα promoted neurological function recovery and decreased cerebral infarct volume in rats after cerebral ischemia-reperfusion injury by improving energy metabolism.
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Affiliation(s)
- Wenmei Zhou
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Tao Tao
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
- Correspondence: Tao Tao, Tel +86 13985162824, Email
| | - Wenfeng Yu
- Department of Human Anatomy, Basic Medical College, Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China
| | - Wanfu Wu
- Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA
| | - Zhirong Hui
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Hongliang Xu
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Yaqi Li
- Emergency Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
| | - Ying Zhang
- Department of Chinese Traditional Medicine, Zunyi Medical and Pharmaceutical College, Zunyi, Guizhou, 563006, People’s Republic of China
| | - Xiaohui Yang
- Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China
- Department of Rehabilitation Medicine, The Affiliated Hospital Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of China
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12
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Chen H, Ma D, Yue F, Qi Y, Dou M, Cui L, Xing Y. The Potential Role of Hypoxia-Inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases. Curr Neuropharmacol 2022; 20:1651-1666. [PMID: 34325641 PMCID: PMC9881070 DOI: 10.2174/1570159x19666210729123137] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/19/2021] [Accepted: 07/16/2021] [Indexed: 11/22/2022] Open
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a heterodimer protein composed of an oxygenregulated functional subunit, HIF-1α, and a structural subunit, HIF-1β, belonging to the basic helixloop- helix family. Strict regulation of HIF-1 protein stability and subsequent transcriptional activity involves various molecular interactions and is primarily controlled by post-transcriptional modifications. Hypoxia, owing to impaired cerebral blood flow, has been implicated in a range of central nervous system (CNS) diseases by exerting a deleterious effect on brain function. As a master oxygen- sensitive transcription regulator, HIF-1 is responsible for upregulating a wide spectrum of target genes involved in glucose metabolism, angiogenesis, and erythropoiesis to generate the adaptive response to avoid, or at least minimize, hypoxic brain injury. However, prolonged, severe oxygen deprivation may directly contribute to the role-conversion of HIF-1, namely, from neuroprotection to the promotion of cell death. Currently, an increasing number of studies support the fact HIF-1 is involved in a variety of CNS-related diseases, such as intracranial atherosclerosis, stroke, and neurodegenerative diseases. This review article chiefly focuses on the effect of HIF-1 on the pathogenesis and mechanism of progression of numerous CNS-related disorders by mediating the expression of various downstream genes and extensive biological functional events and presents robust evidence that HIF-1 may represent a potential therapeutic target for CNS-related diseases.
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Affiliation(s)
- Hongxiu Chen
- Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing, China; ,Beijing Diagnostic Center of Vascular Ultrasound, Beijing, China; ,Center of Vascular Ultrasonography, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 45 Changchun Road, Xicheng District, Beijing, 100053, China; ,Hongxiu Chen and Di Ma contributed equally to this work.
| | - Di Ma
- Department of Neurology, The First Hospital of Jilin University, Changchun, China,Hongxiu Chen and Di Ma contributed equally to this work.
| | - Feixue Yue
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yajie Qi
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Manman Dou
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Liuping Cui
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yingqi Xing
- Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing, China; ,Beijing Diagnostic Center of Vascular Ultrasound, Beijing, China; ,Center of Vascular Ultrasonography, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 45 Changchun Road, Xicheng District, Beijing, 100053, China; ,Address correspondence to this author at the Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing Diagnostic Center of Vascular Ultrasound, Center of Vascular Ultrasonography, Beijing Institute of Brain Disorders, 45 Changchun Road, Xicheng District, Beijing, 100053, China; E-mail: This work is recommended by Pro Jiachun Feng, The First Hospital of Jilin University.
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13
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Neuroprotective strategies for acute ischemic stroke: Targeting oxidative stress and prolyl hydroxylase domain inhibition in synaptic signalling. BRAIN DISORDERS 2022. [DOI: 10.1016/j.dscb.2022.100030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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McKinley MJ, Deede J, Markowitz B. Use of a Novel Portable Non-powered Suction Device in Patients With Oropharyngeal Dysphagia During a Choking Emergency. Front Med (Lausanne) 2022; 8:742734. [PMID: 35186960 PMCID: PMC8847721 DOI: 10.3389/fmed.2021.742734] [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: 11/05/2021] [Accepted: 12/24/2021] [Indexed: 11/18/2022] Open
Abstract
Choking remains a leading cause of accidental death and morbidity worldwide. Currently, there is no device to assist in the resuscitation of a choking victim when standard maneuvers fail. A novel portable non-powered suction device (LifeVac; LifeVac LLC, Nesconset, NY) has been developed and may have potential use in patients with oropharyngeal dysphagia who are at increased risk of choking. The device is FDA registered and distributed worldwide. This case series provides a summary of self-reported data regarding the use of the suction device in adult patients with oropharyngeal dysphagia during real-world choking emergencies recorded between January 2014 and July 2020. Over a 6-year monitoring period the device has been reported to be successful in the resuscitation of 38 out of 39 patients with oropharyngeal dysphagia during choking emergencies. Although the obstruction was removed with the device from the 39th patient, resuscitation was not successful and he succumbed to his injuries. This portable, non-powered suction device may be useful in resuscitating patients with oropharyngeal dysphagia who are choking. The reported cases describe successful use of the device in real-world settings with minimal risk. Resuscitating patients with oropharyngeal dysphagia using this device may be a viable option when abdominal thrusts or back blows fail to resolve a choking emergency.
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Affiliation(s)
| | - Jennifer Deede
- ProHEALTH Care Associates, Lake Success, NY, United States
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15
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Filchenko I, Korostovtseva L, Bochkarev M, Sviryaev Y. Brain damage in sleep-disordered breathing: the role of glia. Zh Nevrol Psikhiatr Im S S Korsakova 2022; 122:15-22. [DOI: 10.17116/jnevro202212201115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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16
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Zhang HT, Wang XZ, Zhang QM, Zhao H. Neuroprotection of chromobox 7 knockout in the mouse after cerebral ischemia-reperfusion injury via nuclear factor E2-related factor 2/hemeoxygenase-1 signaling pathway. Hum Exp Toxicol 2022; 41:9603271221094660. [PMID: 35435747 DOI: 10.1177/09603271221094660] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. METHODS The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress-related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. RESULTS At 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. CONCLUSION Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.
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Affiliation(s)
- Hai-Tao Zhang
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, China
| | - Xi-Zeng Wang
- The Third Department of Surgery, Xintai Hospital of Traditional Chinese Medicine, Xintai, China
| | - Qing-Mei Zhang
- Department of Nursing, Shandong Liaocheng Veteran Hospital, Liaocheng City, China
| | - Han Zhao
- Department of Neurosurgery, 230965Taian Central Hospital, Taian, China
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17
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[Effects of lentivirus-mediated RNA interference of HIF-1α and PTEN on oxygen-glucose deprivation injury in primary cultured rat neurons]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:1795-1800. [PMID: 35012910 PMCID: PMC8752430 DOI: 10.12122/j.issn.1673-4254.2021.12.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To observe the effects of lentivirus-mediated RNA interference (RNAi) of hypoxia-inducible factor 1α (HIF-1α) and phosphatase and tensin homolog on chromosome ten (PTEN) on oxygen-glucose deprivation (OGD) injury in primary cultured rat neurons. METHODS Primary cultures of neonatal SD rat neurons were infected by lentiviral vectors carrying short hairpin RNA (shRNA) targeting HIF-1α or PTEN followed 4 days later by hypoxic exposure, and the control neurons were infected with the empty virus only with or without subsequent hypoxic exposure. Twenty-four hours after hypoxia, the interference efficiency was assessed with qRT-PCR, and lactate dehydrogenase (LDH) assay and AnnexinV-FITC/ PI assay were performed to detect neuronal damage and apoptosis. The expressions of the related proteins were determined with Western blotting. RESULTS Lentivirus-mediated RNAi effectively silenced the mRNA expression of the target genes. HIF-1α silencing obviously aggravated the hypoxia-induced damage and apoptosis of the neurons, enhanced the expression of PTEN protein and significantly lowered the expressions of p-PTEN, p-AKT, NR2A and VEGFa (P < 0.05). PTEN silencing significantly alleviated hypoxia-induced damage and apoptosis of the neurons and increased the cellular expressions of p-PTEN and p-AKT (P < 0.05) without obviously affecting the expressions of HIF-1α, NR2A or VEGFa (P>0.05). CONCLUSION An up-regulated expression of HIF-1α causes down-regulation of PTEN expression to protect primary cultured rat neurons against OGD injury.
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Abstract
Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF-1α is the main molecule that responds to hypoxia. HIF-1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF-1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF-1α target, including biological factors, non-coding RNA, hypoxic-ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF-1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.
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Affiliation(s)
- Peiliang Dong
- Institute of Traditional Chinese Medicine, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Qingna Li
- College of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
| | - Hua Han
- College of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China
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Rahmati M, Ferns GA, Mobarra N. The lower expression of circulating miR-210 and elevated serum levels of HIF-1α in ischemic stroke; Possible markers for diagnosis and disease prediction. J Clin Lab Anal 2021; 35:e24073. [PMID: 34708885 PMCID: PMC8649366 DOI: 10.1002/jcla.24073] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/25/2021] [Accepted: 10/08/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Stroke, either due to ischemia or hemorrhage, causes acute neurological damages to the brain. There is shortage of reliable biomarkers for ischemic stroke (IS), and we therefore investigated the serum concentrations of microRNA-210 (miR-210) and hypoxia inducible factor-1α (HIF-1α), as possible diagnostic and/or prognostic markers for IS. METHODS Serum samples were acquired from 52 IS patients and their healthy counterparts at five time points: upon admission, 24 and 48 h after admission, upon discharge and 3 months later. Serum levels of miR-210 and HIF-1α were respectively analyzed using real time RT-PCR and ELISA. Diagnostic and prognostic accuracy tests were performed to assess the value of suggested biomarkers. RESULTS IS patients demonstrated higher levels of serum HIF-1α and lower miR-210 in comparison to the healthy subjects. MiR-210 was suggested to be a weak diagnostic biomarker at the time of admission (AUC = 0.61; p = 0.05), while HIF-1α was an acceptable diagnostic marker for IS (AUC = 0.73; p < 0.0001). The higher expression of miR-210 and lower levels of HIF-1α were associated with better survivals in IS patients. CONCLUSIONS Serum miR-210 is a weak diagnostic marker of IS. Serum HIF-1α is a better biomarker in diagnosing IS patients but further work in larger groups, including those with hemorrhagic stroke is necessary to confirm its diagnostic utility. Similarly, the prognostic potentiality of miR-210 and HIF-1α was acceptable but needs bigger sample size and longer follow-up to be statistically confirmed.
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Affiliation(s)
- Mina Rahmati
- Department of BiochemistryMetabolic Disorders Research CenterFaculty of MedicineGolestan University of Medical SciencesGorganIran
| | - Gordon A. Ferns
- Brighton and Sussex Medical SchoolDivision of Medical EducationBrightonUK
| | - Naser Mobarra
- Department of Clinical BiochemistrySchool of MedicineMashhad University of Medical SciencesMashhadIran
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Wang K, Lei L, Cao J, Qiao Y, Liang R, Duan J, Feng Z, Ding Y, Ma Y, Yang Z, Zhang E. Network pharmacology-based prediction of the active compounds and mechanism of Buyang Huanwu Decoction for ischemic stroke. Exp Ther Med 2021; 22:1050. [PMID: 34434264 PMCID: PMC8353622 DOI: 10.3892/etm.2021.10484] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 02/09/2021] [Indexed: 02/06/2023] Open
Abstract
Buyang Huanwu Decoction (BYHWD) is used to promote blood circulation and is widely used in Chinese clinical practice for the treatment and prevention of ischemic cerebral vascular diseases. However, the mechanism and active compounds of BYHWD used to treat ischemic stroke are not well understood. The current study aimed to identify the potential active components of BYHWD and explore its mechanism using network pharmacology and bioinformatics analyses. The compounds of BYHWD were obtained from public databases. Oral bioavailability and drug-likeness were screened using the absorption, distribution, metabolism and excretion (ADME) criteria. Components of BYHWD, alongside the candidate targets of each component and the known therapeutic targets of ischemic stroke were collected. A network of target gene compounds and cerebral ischemia compounds was established using network pharmacology data sources. The enrichment of key targets and pathways was analyzed using STRING and DAVID databases. Moreover, three of key targets [IL6, VEGFA and hypoxia-inducible-factor-1α (HIF-1α)] were verified using western blot analysis. Network analysis determined 102 compounds in seven herbal medicines that were subjected to ADME screening. A total of 42 compounds as well as 79 genes formed the principal pathways associated with ischemic stroke. The 16 key compounds identified were baicalein, beta-carotene, baicalin, kaempferol, luteolin, quercetin, hydroxysafflor yellow A, isorhamnetin, bifendate, formononetin, calycosin, astragaloside IV, stigmasterol, sitosterol, Z-ligustilide, and dihydrocapsaicin. The core genes in this network were IL6, TNF, VEGFA, HIF-1α, MAPK1, MAPK3, JUN, STAT3, IL1B and IL10. Furthermore, the TNF, IL17, apoptosis, PI3K-Akt, toll-like receptor, MAPK, NF-κB and HIF-1 signaling pathways were identified to be associated with ischemic stroke. Compared with the control group (no treatment), BYHWD significantly inhibited the expression of IL6 and increase the expression of HIF-1α and VEGFA. Network pharmacology analyses can help to reveal close interactions between multi-components and multi-targets and enhance understanding of the potential effects of BYHWD on ischemic stroke.
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Affiliation(s)
- Kai Wang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P.R. China
| | - Lu Lei
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jinyi Cao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yi Qiao
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
- Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China
| | - Ruimin Liang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P.R. China
| | - Jialin Duan
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Zhijun Feng
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yi Ding
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yang Ma
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Zhifu Yang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Enhu Zhang
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P.R. China
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Zhang HT, Wang XZ, Zhang QM, Zhao H. Neuroprotection of chromobox 7 knockout in the mouse after cerebral ischemia-reperfusion injury via nuclear factor E2-related factor 2/hemeoxygenase-1 signaling pathway. Hum Exp Toxicol 2021; 40:S178-S186. [PMID: 34353139 DOI: 10.1177/09603271211036122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. METHODS The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress-related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. RESULTS At 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. CONCLUSION Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.
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Affiliation(s)
- Hai-Tao Zhang
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, China
| | - Xi-Zeng Wang
- The Third Department of Surgery, Xintai Hospital of Traditional Chinese Medicine, Xintai, China
| | - Qing-Mei Zhang
- Department of Nursing, Shandong Liaocheng Veteran Hospital, Liaocheng City, China
| | - Han Zhao
- Department of Neurosurgery, 230965Taian Central Hospital, Taian, China
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22
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Lan YL, Zhu Y, Chen G, Zhang J. The Promoting Effect of Traumatic Brain Injury on the Incidence and Progression of Glioma: A Review of Clinical and Experimental Research. J Inflamm Res 2021; 14:3707-3720. [PMID: 34377008 PMCID: PMC8350857 DOI: 10.2147/jir.s325678] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 07/23/2021] [Indexed: 12/16/2022] Open
Abstract
The role of traumatic brain injury in the development of glioma is highly controversial since first presented. This is not unexpected because traumatic brain injuries are overwhelmingly more common than glioma. However, the causes of post-traumatic glioma have been long discussed and still warrant further research. In this review, we have presented an overview of previous cohort studies and case–control studies. We have summarized the roles of microglial cells, macrophages, astrocytes, and stem cells in post-traumatic glioma formation and development, and reviewed various carcinogenic factors involved during traumatic brain injury, especially those reported in experimental studies indicating a relationship with glioma progression. Besides, traumatic brain injury and glioma share several common pathways, including inflammation and oxidative stress; however, the exact mechanism underlying this co-occurrence is yet to be discovered. In this review, we have summarized current epidemiological studies, clinical reports, pathophysiological research, as well as investigations evaluating the probable causes of co-occurrence and treatment possibilities. More efforts should be directed toward elucidating the relationship between traumatic brain injury and glioma, which could likely lead to promising pharmacological interventions towards designing therapeutic strategies.
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Affiliation(s)
- Yu-Long Lan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.,Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China.,Department of Neurosurgery, Shenzhen People's Hospital, Shenzhen, People's Republic of China
| | - Yongjian Zhu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Gao Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Jianmin Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
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23
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Sompol P, Gollihue JL, Kraner SD, Artiushin IA, Cloyd RA, Chishti EA, Koren SA, Nation GK, Abisambra JF, Huzian O, Nagy LI, Santha M, Hackler L, Puskas LG, Norris CM. Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology. Aging Cell 2021; 20:e13416. [PMID: 34117818 PMCID: PMC8282246 DOI: 10.1111/acel.13416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 03/30/2021] [Accepted: 05/19/2021] [Indexed: 12/27/2022] Open
Abstract
Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.
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Affiliation(s)
- Pradoldej Sompol
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Jenna L. Gollihue
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Susan D. Kraner
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Irina A. Artiushin
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Ryan A. Cloyd
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Emad A. Chishti
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Shon A. Koren
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Grant K. Nation
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
| | - Jose F. Abisambra
- Center for Translational Research in Neurodegenerative Disease University of Florida Gainesville FL USA
| | | | | | | | | | | | - Christopher M. Norris
- Sanders‐Brown Center on Aging University of Kentucky College of Medicine Lexington KY USA
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24
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Pradillo JM, Hernández-Jiménez M, Fernández-Valle ME, Medina V, Ortuño JE, Allan SM, Proctor SD, Garcia-Segura JM, Ledesma-Carbayo MJ, Santos A, Moro MA, Lizasoain I. Influence of metabolic syndrome on post-stroke outcome, angiogenesis and vascular function in old rats determined by dynamic contrast enhanced MRI. J Cereb Blood Flow Metab 2021; 41:1692-1706. [PMID: 34152893 PMCID: PMC8221771 DOI: 10.1177/0271678x20976412] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Stroke affects primarily aged and co-morbid people, aspects not properly considered to date. Since angiogenesis/vasculogenesis are key processes for stroke recovery, we purposed to determine how different co-morbidities affect the outcome and angiogenesis/vasculogenesis, using a rodent model of metabolic syndrome, and by dynamic enhanced-contrast imaging (DCE-MRI) to assess its non-invasive potential to determine these processes. Twenty/twenty-two month-old corpulent (JCR:LA-Cp/Cp), a model of metabolic syndrome and lean rats were used. After inducing the experimental ischemia by transient MCAO, angiogenesis was analyzed by histology, vasculogenesis by determination of endothelial progenitor cells in peripheral blood by flow cytometry and evaluating their pro-angiogenic properties in culture and the vascular function by DCE-MRI at 3, 7 and 28 days after tMCAO. Our results show an increased infarct volume, BBB damage and an impaired outcome in corpulent rats compared with their lean counterparts. Corpulent rats also displayed worse post-stroke angiogenesis/vasculogenesis, outcome that translated in an impaired vascular function determined by DCE-MRI. These data confirm that outcome and angiogenesis/vasculogenesis induced by stroke in old rats are negatively affected by the co-morbidities present in the corpulent genotype and also that DCE-MRI might be a technique useful for the non-invasive evaluation of vascular function and angiogenesis processes.
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Affiliation(s)
- Jesús M Pradillo
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
| | - Macarena Hernández-Jiménez
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
| | - María E Fernández-Valle
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
| | - Violeta Medina
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
| | - Juan E Ortuño
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.,Biomedical Image Technologies (BIT), ETSI Telecomunicación, Universidad Politécnica de Madrid, Spain
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Spencer D Proctor
- Division of Human Nutrition, Metabolic and Cardiovascular Diseases Laboratory, Agricultural, Food and Nutritional Science Li Ka Shing (LKS) Centre for Health Research Innovation, University of Alberta, Edmonton, Canada
| | - Juan M Garcia-Segura
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
| | - María J Ledesma-Carbayo
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.,Biomedical Image Technologies (BIT), ETSI Telecomunicación, Universidad Politécnica de Madrid, Spain
| | - Andrés Santos
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.,Biomedical Image Technologies (BIT), ETSI Telecomunicación, Universidad Politécnica de Madrid, Spain
| | - María A Moro
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
| | - Ignacio Lizasoain
- Neurovascular Research Unit, Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid and Instituto de Investigación Hospital 12 de Octubre i+12, Madrid, Spain
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25
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Pan Z, Ma G, Kong L, Du G. Hypoxia-inducible factor-1: Regulatory mechanisms and drug development in stroke. Pharmacol Res 2021; 170:105742. [PMID: 34182129 DOI: 10.1016/j.phrs.2021.105742] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/13/2021] [Accepted: 06/23/2021] [Indexed: 12/14/2022]
Abstract
Stroke is an acute cerebrovascular disease caused by sudden rupture of blood vessels in the brain or blockage of blood vessels, which has now become one of the main causes of adult death. During stroke, hypoxia-inducible factor-1 (HIF-1), as an important regulator under hypoxia conditions, is involved in the pathological process of stroke by regulating multi-pathways, such as glucose metabolism, angiogenesis, erythropoiesis, cell survival. However, the roles of HIF-1 in stroke are still controversial, which are related with ischemic time and degree of ischemia. The regulatory mechanisms of HIF-1 in stroke include inflammation, autophagy, oxidative stress, apoptosis and energy metabolism. The potential drugs targeting HIF-1 have attracted more attention, such as HIF-1 inhibitors, HIF-1 stabilizers and natural products. Based on the role of HIF-1 in stroke, HIF-1 is expected to be a potential target for stroke treatment. Resolving when and what interventions for HIF-1 to take during stroke will provide novel strategies for stroke treatment.
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Affiliation(s)
- Zirong Pan
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Guodong Ma
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Linglei Kong
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
| | - Guanhua Du
- Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
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26
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Yang K, Zeng L, Ge A, Chen Y, Wang S, Zhu X, Ge J. Exploring the Regulatory Mechanism of Hedysarum Multijugum Maxim.- Chuanxiong Rhizoma Compound on HIF-VEGF Pathway and Cerebral Ischemia-Reperfusion Injury's Biological Network Based on Systematic Pharmacology. Front Pharmacol 2021; 12:601846. [PMID: 34248611 PMCID: PMC8267578 DOI: 10.3389/fphar.2021.601846] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 05/17/2021] [Indexed: 01/02/2023] Open
Abstract
Background: Clinical research found that Hedysarum Multijugum Maxim.-Chuanxiong Rhizoma Compound (HCC) has definite curative effect on cerebral ischemic diseases, such as ischemic stroke and cerebral ischemia-reperfusion injury (CIR). However, its mechanism for treating cerebral ischemia is still not fully explained. Methods: The traditional Chinese medicine related database were utilized to obtain the components of HCC. The Pharmmapper were used to predict HCC’s potential targets. The CIR genes were obtained from Genecards and OMIM and the protein-protein interaction (PPI) data of HCC’s targets and IS genes were obtained from String database. After that, the DAVID platform was applied for Gene Ontology (GO) enrichment analysis and pathway enrichment analysis. Finally, a series of animal experiments were carried out to further explore the mechanism of HCC intervention in CIR. Results: The prediction results of systematic pharmacology showed that HCC can regulate CIR-related targets (such as AKT1, MAPK1, CASP3, EGFR), biological processes (such as angiogenesis, neuronal axonal injury, blood coagulation, calcium homeostasis) and signaling pathways (such as HIF-1, VEGF, Ras, FoxO signaling). The experiments showed that HCC can improve the neurological deficit score, decrease the volume of cerebral infarction and up-regulate the expression of HIF-1α/VEGF and VEGFR protein and mRNA (p < 0.05). Conclusion: HCC may play a therapeutic role by regulating CIR-related targets, biological processes and signaling pathways found on this study.
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Affiliation(s)
- Kailin Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Liuting Zeng
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Anqi Ge
- Galactophore Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yi Chen
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Shanshan Wang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China
| | - Xiaofei Zhu
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China.,School of Graduate, Central South University, Changsha, China
| | - Jinwen Ge
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China.,Shaoyang University, Shaoyang, China
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27
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Wang M, Bai Y, Chi H, Lin P, Wu Y, Cui J, Wang Y, Sun J, Lang MF. miR-451 protects against ischemic stroke by targeting Phd3. Exp Neurol 2021; 343:113777. [PMID: 34058227 DOI: 10.1016/j.expneurol.2021.113777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/10/2021] [Accepted: 05/27/2021] [Indexed: 12/19/2022]
Abstract
Ischemic stroke still remains a therapeutic challenge due to its complex pathogenesis and implications. By screening biomarkers in the peripheral blood of ischemic stroke patients, miR-451 was identified as a differentially expressed miRNA along the disease course of ischemic stroke. To investigate the role of miR-451, middle cerebral artery occlusion (MCAO) was performed as an ischemic stroke model in mice. Intracerebroventricular administration of miR-451 mimic in the MCAO mice significantly decreased infarct size, while miR-451 inhibitor significantly increased infarct size. To understand the molecular mechanism of the protective effect of miR-451, Phd3 (also Egln3) was validated as a new miR-451 target. Either fewer or more Phd3-positive cells were observed in brain sections from mice receiving miR-451 mimic or inhibitor, respectively. In addition, the levels of p53 (a known Phd3 target) were significantly downregulated when the levels of Phd3 were reduced, suggesting its participation in reducing apoptosis after the miR-451 administration. Indeed, reduced apoptosis upon miR-451 mimic administration was detected by TUNEL staining. In conclusion, this study demonstrated a new protective role of miR-451 in cerebral ischemia and identified Phd3 as a novel miR-451 target, linking the mechanism to the involvement of p53 in the regulation of apoptosis during the pathogenesis of ischemic stroke.
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Affiliation(s)
- Mengmeng Wang
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China; Medical College, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China; Graduate School, Dalian University, Dalian, Liaoning 116622, China
| | - Ying Bai
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China.
| | - Haitao Chi
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Ping Lin
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Yu Wu
- Medical College, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China
| | - Jiahui Cui
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Yi Wang
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Jing Sun
- College of Environmental and Chemical Engineering, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China
| | - Ming-Fei Lang
- Medical College, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China.
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28
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Loginova M, Mishchenko T, Savyuk M, Guseva S, Gavrish M, Krivonosov M, Ivanchenko M, Fedotova J, Vedunova M. Double-Edged Sword of Vitamin D3 Effects on Primary Neuronal Cultures in Hypoxic States. Int J Mol Sci 2021; 22:5417. [PMID: 34063823 PMCID: PMC8196622 DOI: 10.3390/ijms22115417] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/03/2021] [Accepted: 05/17/2021] [Indexed: 01/23/2023] Open
Abstract
The use of vitamin D3 along with traditional therapy opens up new prospects for increasing the adaptive capacity of nerve cells to the effects of a wide range of stress factors, including hypoxia-ischemic processes. However, questions about prophylactic and therapeutic doses of vitamin D3 remain controversial. The purpose of our study was to analyze the effects of vitamin D3 at different concentrations on morpho-functional characteristics of neuron-glial networks in hypoxia modeling in vitro. We showed that a single administration of vitamin D3 at a high concentration (1 µM) in a normal state has no significant effect on the cell viability of primary neuronal cultures; however, it has a pronounced modulatory effect on the functional calcium activity of neuron-glial networks and causes destruction of the network response. Under hypoxia, the use of vitamin D3 (1 µM) leads to total cell death of primary neuronal cultures and complete negation of functional neural network activity. In contrast, application of lower concentrations of vitamin D3 (0.01 µM and 0.1 µM) caused a pronounced dose-dependent neuroprotective effect during the studied post-hypoxic period. While the use of vitamin D3 at a concentration of 0.1 µM maintained cell viability, preventive administration of 0.01 µM not only partially preserved the morphological integrity of primary neuronal cells but also maintained the functional structure and activity of neuron-glial networks in cultures. Possible molecular mechanisms of neuroprotective action of vitamin D3 can be associated with the increased expression level of transcription factor HIF-1α and maintaining the relationship between the levels of BDNF and TrkB expression in cells of primary neuronal cultures.
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Affiliation(s)
- Maria Loginova
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
| | - Tatiana Mishchenko
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
| | - Maria Savyuk
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
| | - Svetlana Guseva
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
| | - Maria Gavrish
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
| | - Mikhail Krivonosov
- Department of Applied Mathematics, Institute of Information Technologies, Mathematics and Mechanics (ITMM), Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.K.); (M.I.)
| | - Mikhail Ivanchenko
- Department of Applied Mathematics, Institute of Information Technologies, Mathematics and Mechanics (ITMM), Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.K.); (M.I.)
| | - Julia Fedotova
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
- Laboratory of Neuroendocrinology, I.P. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Emb. Makarova, 199034 St. Petersburg, Russia
| | - Maria Vedunova
- Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603022 Nizhny Novgorod, Russia; (M.L.); (T.M.); (M.S.); (S.G.); (M.G.); (J.F.)
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29
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Liori S, Arfaras-Melainis A, Bistola V, Polyzogopoulou E, Parissis J. Cognitive impairment in heart failure: clinical implications, tools of assessment, and therapeutic considerations. Heart Fail Rev 2021; 27:993-999. [PMID: 33939080 DOI: 10.1007/s10741-021-10118-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/26/2021] [Indexed: 10/21/2022]
Abstract
Cognitive impairment (CI) is an important comorbidity in patients with heart failure (HF). Its prevalence parallels the severity of heart failure, while it is an independent prognostic marker of adverse events. Various factors contribute to cognitive decline in HF, influencing self-care. There are no standardized screening methods for the diagnosis and management of these patients. The aim of the present manuscript is to provide an overview of the impact of cognitive impairment in HF, describe the utility of assessment tools and imaging methods for the evaluation of CI, and propose a comprehensive diagnostic and management approach.
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Affiliation(s)
- Sotiria Liori
- Heart Failure Unit and University Clinic of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
| | - Angelos Arfaras-Melainis
- Heart Failure Unit and University Clinic of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Vasiliki Bistola
- Heart Failure Unit and University Clinic of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Eftihia Polyzogopoulou
- Heart Failure Unit and University Clinic of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - John Parissis
- Heart Failure Unit and University Clinic of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
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30
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Kong L, Ma Y, Wang Z, Liu N, Ma G, Liu C, Shi R, Du G. Inhibition of hypoxia inducible factor 1 by YC-1 attenuates tissue plasminogen activator induced hemorrhagic transformation by suppressing HMGB1/TLR4/NF-κB mediated neutrophil infiltration in thromboembolic stroke rats. Int Immunopharmacol 2021; 94:107507. [PMID: 33657523 DOI: 10.1016/j.intimp.2021.107507] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/27/2021] [Accepted: 02/11/2021] [Indexed: 12/13/2022]
Abstract
Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke after thrombolytic therapy and seriously affects the prognosis of stroke. Due to the limited therapeutic window and hemorrhagic complications, tissue plasminogen activator (t-PA) is underutilized in acute ischemic stroke. Currently, there are no clinically effective drugs to decrease the incidence of t-PA-induced HT. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that maintains oxygen homeostasis and mediates neuroinflammation under hypoxia. However, the effect of HIF-1 on t-PA-induced HT is not clear. The aim of this study was to investigate the role of HIF-1 in t-PA-induced HT by applying YC-1, an inhibitor of HIF-1. In the present study, we found that HIF-1 expression was significantly increased in ischemic brain tissue after delayed t-PA treatment and was mainly localized in neurons and endothelial cells. Inhibition of HIF-1 by YC-1 improved infarct volume and neurological deficits. YC-1 inhibited matrix metalloproteinase protein expression, increased tight junction protein expression, and ameliorated BBB disruption and the occurrence of HT. Furthermore, YC-1 suppressed the release of inflammatory factors, neutrophil infiltration and the activation of the HMGB1/TLR4/NF-κB signaling pathway. These results demonstrated that inhibition of HIF-1 could protect BBB integrity by suppressing HMGB1/TLR4/NF-κB-mediated neutrophil infiltration, thereby reducing the risk of t-PA-induced HT. Thus, HIF-1 may be a potential therapeutic target for t-PA-induced HT.
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Affiliation(s)
- Linglei Kong
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yinzhong Ma
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Zhiyuan Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Nannan Liu
- Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Guodong Ma
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Chengdi Liu
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Ruili Shi
- Department of Physiology, Baotou Medical College, Baotou 014060, China.
| | - Guanhua Du
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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31
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Liu H, Sun S, Liu B. Smurf2 exerts neuroprotective effects on cerebral ischemic injury. J Biol Chem 2021; 297:100537. [PMID: 33722608 PMCID: PMC8363835 DOI: 10.1016/j.jbc.2021.100537] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 02/20/2021] [Accepted: 03/10/2021] [Indexed: 11/17/2022] Open
Abstract
The present study aimed to explore specific mechanisms involved in mediating the neuroprotective effects of Smad ubiquitination regulatory factor 2 (Smurf2) in cerebral ischemic injury. A middle cerebral artery occlusion (MCAO) mouse model and an oxygen–glucose deprivation (OGD)–treated neuron model were developed. The expression of Smurf2, Yin Yang 1 (YY1), hypoxia-inducible factor-1 alpha (HIF1α), and DNA damage–inducible transcript 4 gene (DDIT4) was analyzed. Thereafter, the expression of Smurf2, YY1, HIF1α, and DDIT4 was altered in the MCAO mice and OGD-treated neurons. Apoptosis in tissues and cerebral infarction were assessed. In neurons, the expression of apoptosis-related proteins, viability, and apoptosis were assessed, followed by evaluation of lactate dehydrogenase leakage rate. The interaction between Smurf2 and YY1 was analyzed by coimmunoprecipitation assay and that between YY1 ubiquitination by in vivo ubiquitination experiment. The results showed downregulation of Smurf2 and upregulation of YY1, HIF1α, and DDIT4 in both MCAO mice and OGD-treated neurons. Smurf2 elevated YY1 ubiquitination and degradation, and YY1 increased HIF1α expression to promote DDIT4 in neurons. Overexpressed Smurf2 or downregulated YY1, HIF1α, or DDIT4 reduced the volume of cerebral infarction and apoptosis in MCAO mice, while enhancing cell viability and reducing apoptosis and lactate dehydrogenase leakage in OGD-treated neurons. In summary, our findings elucidated a neuroprotective role of Smurf2 in cerebral ischemic injury via inactivation of the YY1/HIF1α/DDIT4 axis.
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Affiliation(s)
- Haibin Liu
- Department of Paediatrics, Linyi People's Hospital, Linyi, China
| | - Shengtao Sun
- Department of Paediatrics, Linyi People's Hospital, Linyi, China
| | - Bing Liu
- Department of Paediatrics, Linyi People's Hospital, Linyi, China.
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McAleese CE, Choudhury C, Butcher NJ, Minchin RF. Hypoxia-mediated drug resistance in breast cancers. Cancer Lett 2020; 502:189-199. [PMID: 33278499 DOI: 10.1016/j.canlet.2020.11.045] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/23/2020] [Accepted: 11/26/2020] [Indexed: 02/07/2023]
Abstract
Tissue hypoxia in solid tumors is caused by several pathological changes associated with tumor growth, including altered microvasculature structure, increased diffusional distances, and tumor-associated anemia. As the oxygen tension decreases, tumor cells adapt to the limited oxygen supply. Previous studies have shown that such adaptation leads to an aggressive phenotype that is resistant to many anti-cancer therapies. Induction of hypoxia inducible factors (HIFs) mediates many proteomic and genomic changes associated with tumor hypoxia. In breast cancers, HIFs not only predict poor prognosis, but also promote metastasis and drug resistance. Several studies have proposed HIF-1α as a druggable target in drug-resistant breast cancers, leading to the synthesis and development of small molecule inhibitors. Disappointingly, however, none of these small molecule inhibitors have progressed to clinical use. In this review, we briefly discuss the role of HIF-1α in breast cancer drug resistance and summarize the current and future approaches to targeting this transcription factor in breast cancer treatment.
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Affiliation(s)
- Courtney E McAleese
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Chandra Choudhury
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Neville J Butcher
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia
| | - Rodney F Minchin
- School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
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Zhang H, Liu Y, Cheng L, Ma X, Luo X. Exendin-4 induces a novel extended effect of ischemic tolerance via crosstalk with IGF-1R. Brain Res Bull 2020; 169:145-155. [PMID: 33197537 DOI: 10.1016/j.brainresbull.2020.11.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 10/09/2020] [Accepted: 11/11/2020] [Indexed: 11/15/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist exendin-4 (Ex-4), a drug that has been used in the clinical treatment of type 2 diabetes mellitus, also confers a neuroprotective effect against stroke. Although GLP-1 analogs were reported to induce sustained insulin secretion and glucose tolerance improved after cessation of treatment, no study has revealed whether Ex-4 exerts sustained neuroprotection against stroke and the underlying mechanism after treatment cessation. In this study, mice were pretreated with Ex-4 for 7 days, and middle cerebral artery occlusion (MCAO) was performed on different days after cessation of Ex-4 treatment. Ex-4 ameliorated neurological dysfunction and reduced the infarct volume induced by MCAO. These protective effects lasted for 6 days after the cessation of Ex-4 treatment and were associated with sustained upregulation of PI3K, AKT, mTOR, and HIF-1α levels, as well as HIF-1α downstream genes. Knockdown of GLP-1R or HIF-1α in the brain by short hairpin RNA abolished Ex-4 treatment-mediated neuroprotection. In normal mice, Ex-4 treatment led to instant upregulation of p-PI3K, p-AKT, p-mTOR, and HIF-1α expression levels, which quickly returned to normal after cessation of Ex-4 treatment, while the expression levels of insulin growth factor-1 receptor (IGF-1R) remained high for 6 days after Ex-4 cessation. Additionally, Ex-4 did not directly induce IGF-1 production, which was only induced by MCAO. Ex-4 induces extended cerebral ischemic tolerance. This neuroprotective effect is associated with activation of GLP-1R and upregulation of IGF-1R in the brain, and the latter then activates the PI3K/AKT/mTOR/HIF-1 signaling pathway via binding to IGF-1 secreted from the ischemic brain.
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Affiliation(s)
- Huinan Zhang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China
| | - Yunhan Liu
- Department of Neurology Impatient, the Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Liusiyuan Cheng
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China
| | - Xue Ma
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China.
| | - Xiaoxing Luo
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China.
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Ma J, Wang C, Sun Y, Pang L, Zhu S, Liu Y, Zhu L, Zhang S, Wang L, Du L. Comparative study of oral and intranasal puerarin for prevention of brain injury induced by acute high-altitude hypoxia. Int J Pharm 2020; 591:120002. [PMID: 33141084 DOI: 10.1016/j.ijpharm.2020.120002] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/12/2020] [Accepted: 10/18/2020] [Indexed: 12/18/2022]
Abstract
Human activities in the areas of high altitude have increased significantly recently. Brain is highly sensitive to changing of oxygen pressure due to high altitude, and this physiological response may lead to serious brain injury, such as learning and memory disabilities. Puerarin is a phytoestrogen with many pharmacological activities, such as treatment of neurological disorders. However, most of current drugs can not easily enter brain through the blood-brain barrier (BBB). The nose-to-brain route can bypass BBB for brain-targeting. Here, thermosensitive in situ hydrogels (TISGs) of puerarin were prepared with poloxamers 407, poloxamers 188 and propylene glycol to improve bioavailability and brain targeting. In vitro drug release in simulated nasal fluids, rheological properties and cilia toxicity of puerarin TISGs were explored. The pharmacodynamics and pharmacokinetics of puerarin by intranasal (i.n.) and oral (p.o.) administrations were also evaluated. The viscosity of puerarin TISGs tended to increase obviously with increased temperature. The puerarin release profile and transmucosal process of puerarin TISGs could be described with the first-order kinetics equation, depending on drug diffusion. The cilia toxicity of puerarin TISGs was not obvious. Rat models of hypobarism/hypoxia-induced brain injury were established with a hypobaric simulation chamber. Morris water maze and open filed tests indicated that puerarin TISGs improved the spatial memory and spontaneous exploratory behavior of the rats suffering from hypoxia-induced brain injury. Furthermore, puerarin TISGs decreased the level of oxidative stress cytokines (malondialdehyde (MDA) and glutathione (GSH)) in the peripheral circulation, alleviated the cerebral histological lesions, and relieved the expression of hypoxia-inducible factor-1α (HIF-1α). Intranasal puerarin TISGs were absorbed quickly with a shorter Tmax (10.0 ± 5.7 min) compared to that of oral puerarin (36 ± 13.4 min). In addition, the relative bioavailability of i.n. puerarin TISGs was high to 300% compared to oral administration of puerarin. The area under the curve (AUC) of brain after i.n. administration of puerarin TISGs was 954.5 ± 335.1 h.ng/mL, while no puerarin was detected in the brain after oral administration. Therefore, i.n. puerarin TISGs led to excellent brain targeting effect. Puerarin TISGs are an effective neuroprotector formulation for prevention of brain injury induced by acute high-altitude hypoxia.
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Affiliation(s)
- Jinqiu Ma
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Chenyun Wang
- Chinese PLA General Hospital, Beijing 100853, China
| | - Yunbo Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lulu Pang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Siqing Zhu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Yijing Liu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Lin Zhu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Shouguo Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lin Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Lina Du
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
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Zhang Q, Liao Y, Liu Z, Dai Y, Li Y, Li Y, Tang Y. Interleukin-17 and ischaemic stroke. Immunology 2020; 162:179-193. [PMID: 32935861 DOI: 10.1111/imm.13265] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 07/22/2020] [Accepted: 08/26/2020] [Indexed: 12/26/2022] Open
Abstract
Interleukin-17 (IL-17) is a cytokine family that includes 6 members, IL-17A through IL-17F, most of them are reported to have pro-inflammatory role. Through binding to their receptors (IL-17Rs), IL-17 activates the intracellular signalling pathways to play an important role in autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). Ischaemic stroke is a complex pathophysiological process mainly caused by regional cerebral ischaemia. Inflammatory factors contribute to the physiological process of stroke that leads to poor prognosis. IL-17 plays a crucial role in promoting inflammatory response and inducing secondary injury in post-stroke. Though immune cells and inflammatory factors have been reported to be involved in the damage of stroke, the functions of IL-17 in this process need to be elucidated. This review focuses on the pathological modulation and the mechanism of IL-17 family in ischaemic stroke and seeking to provide new insights for future therapies.
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Affiliation(s)
- Qiaohui Zhang
- Chinese Medical Institute, Beijing University of Chinese Medicine, Beijing, China
| | - Yan Liao
- Chinese Medical Institute, Beijing University of Chinese Medicine, Beijing, China
| | - Zhenquan Liu
- School of Chinese Materia Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Yajie Dai
- Chinese Medical Institute, Beijing University of Chinese Medicine, Beijing, China
| | - Yunxin Li
- Chinese Medical Institute, Beijing University of Chinese Medicine, Beijing, China
| | - Yue Li
- School of Chinese Materia Medical, Beijing University of Chinese Medicine, Beijing, China
| | - Yibo Tang
- Chinese Medical Institute, Beijing University of Chinese Medicine, Beijing, China
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Lin JP, Wei Y, Fan XJ, Zhang MH, Wu MQ, Li W, Wang P, Xiong W. The mechanisms of pei-yuan-tong-nao capsule as a therapeutic agent against cerebrovascular disease. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2020. [DOI: 10.4103/wjtcm.wjtcm_45_20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Yang T, Lu Z, Wang L, Zhao Y, Nie B, Xu Q, Han X, Li T, Zhao J, Cheng W, Wang B, Wu A, Zhu H, Meng W, Shang H, Zhao M. Dynamic Changes in Brain Glucose Metabolism and Neuronal Structure in Rats with Heart Failure. Neuroscience 2020; 424:34-44. [DOI: 10.1016/j.neuroscience.2019.10.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 10/02/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022]
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Protein Arginine Methyltransferases in Cardiovascular and Neuronal Function. Mol Neurobiol 2019; 57:1716-1732. [PMID: 31823198 DOI: 10.1007/s12035-019-01850-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 12/01/2019] [Indexed: 12/16/2022]
Abstract
The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a type of post-translational modification which is important for numerous cellular processes, including mRNA splicing, DNA repair, signal transduction, protein interaction, and transport. PRMTs have been extensively associated with various pathologies, including cancer, inflammation, and immunity response. However, the role of PRMTs has not been well described in vascular and neurological function. Aberrant expression of PRMTs can alter its metabolic products, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). Increased ADMA levels are recognized as an independent risk factor for cardiovascular disease and mortality. Recent studies have provided considerable advances in the development of small-molecule inhibitors of PRMTs to study their function under normal and pathological states. In this review, we aim to elucidate the particular roles of PRMTs in vascular and neuronal function as a potential target for cardiovascular and neurological diseases.
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Intracellular Neuroprotective Mechanisms in Neuron-Glial Networks Mediated by Glial Cell Line-Derived Neurotrophic Factor. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1036907. [PMID: 31827666 PMCID: PMC6885812 DOI: 10.1155/2019/1036907] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 10/19/2019] [Indexed: 12/28/2022]
Abstract
Glial cell line-derived neurotrophic factor (GDNF) has a pronounced neuroprotective effect in various nervous system pathologies, including ischaemic brain damage and neurodegenerative diseases. In this work, we studied the effect of GDNF on the ultrastructure and functional activity of neuron-glial networks during acute hypoxic exposure, a key damaging factor in numerous brain pathologies. We analysed the molecular mechanisms most likely involved in the positive effects of GDNF. Hypoxia modelling was performed on day 14 of culturing primary hippocampal cells obtained from mouse embryos (E18). GDNF (1 ng/ml) was added to the culture medium 20 min before oxygen deprivation. Acute hypoxia-induced irreversible changes in the ultrastructure of neurons and astrocytes led to the loss of functional Сa2+ activity and neural network disruption. Destructive changes in the mitochondrial apparatus and its functional activity characterized by an increase in the basal oxygen consumption rate and respiratory chain complex II activity during decreased stimulated respiration intensity were observed 24 hours after hypoxic injury. At a concentration of 1 ng/ml, GDNF maintained the functional metabolic network activity in primary hippocampal cultures and preserved the structure of the synaptic apparatus and number of mature chemical synapses, confirming its neuroprotective effect. GDNF maintained the normal structure of mitochondria in neuronal outgrowth but not in the soma. Analysis of the possible GDNF mechanism revealed that RET kinase, a component of the receptor complex, and the PI3K/Akt pathway are crucial for the neuroprotective effect of GDNF. The current study also revealed the role of GDNF in the regulation of HIF-1α transcription factor expression under hypoxic conditions.
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Lynch MA. Can the emerging field of immunometabolism provide insights into neuroinflammation? Prog Neurobiol 2019; 184:101719. [PMID: 31704314 DOI: 10.1016/j.pneurobio.2019.101719] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 10/18/2019] [Accepted: 10/30/2019] [Indexed: 12/29/2022]
Abstract
In the past few years it has become increasingly clear that an understanding of the interaction between metabolism and immune function can provide an insight into cellular responses to challenges. Significant progress has been made in terms of how macrophages are metabolically re-programmed in response to inflammatory stimuli but, to date, little emphasis has been placed on evaluating equivalent changes in microglia. The need to make progress is driven by the fact that, while microglial activation and the cell's ability to adopt an inflammatory phenotype is necessary to fulfil the neuroprotective function of the cell, persistent activation of microglia and the associated neuroinflammation is at the heart of several neurodegenerative diseases. Understanding the metabolic changes that accompany microglial responses may broaden our perspective on how dysfunction might arise and be tempered. This review will evaluate the current literature that addresses the interplay between inflammation and metabolic reprogramming in microglia, reflecting on the parallels that exist with macrophages. It will consider the changes that take place with age including those that have been reported in neurons and astrocytes with the development of non-invasive imaging techniques, and reflect on the literature that is currently available relating to metabolic reprogramming of microglia with age and in neurodegeneration. Finally it will consider the possibility that manipulating microglial metabolism may provide a valuable approach to modulating neuroinflammation.
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Affiliation(s)
- Marina A Lynch
- Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
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Ghosh MK, Chakraborty D, Sarkar S, Bhowmik A, Basu M. The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports. Signal Transduct Target Ther 2019; 4:42. [PMID: 31637020 PMCID: PMC6799849 DOI: 10.1038/s41392-019-0075-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 12/16/2022] Open
Abstract
Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide. Although these conditions have different physiological incidences, ~10% of ischemic stroke patients develop cerebral cancer, especially glioma, in the postischemic stages. Additionally, the high proliferation, venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism, including ischemic stroke. Surprisingly, these events share several common pathways, viz. hypoxia, cerebral inflammation, angiogenesis, etc., but the proper mechanism behind this co-occurrence has yet to be discovered. The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population. Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer, and the reverse is also partially true. Based on clinical and neurosurgical experience, the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy. The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells (CSCs). Cancer cells in stroke patients have already metastasized, but early-stage cancer patients also suffer stroke for multiple reasons. Therefore, stroke is an early manifestation of cancer. Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients, and vice-versa. The intricate mechanisms for stroke with and without cancer are different. This review summarizes the current clinical reports, pathophysiology, probable causes of co-occurrence, prognoses, and treatment possibilities.
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Affiliation(s)
- Mrinal K. Ghosh
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Kolkata 700032 and CN-06, Sector-V, Salt Lake, Kolkata, 700091 India
| | - Dipankar Chakraborty
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Kolkata 700032 and CN-06, Sector-V, Salt Lake, Kolkata, 700091 India
| | - Sibani Sarkar
- Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), 4 Raja S.C. Mullick Road, Kolkata 700032 and CN-06, Sector-V, Salt Lake, Kolkata, 700091 India
| | - Arijit Bhowmik
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata, 700 026 India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, South 24, Paraganas, 743372 India
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Zhou DR, Eid R, Miller KA, Boucher E, Mandato CA, Greenwood MT. Intracellular second messengers mediate stress inducible hormesis and Programmed Cell Death: A review. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:773-792. [PMID: 30716408 DOI: 10.1016/j.bbamcr.2019.01.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 01/25/2019] [Accepted: 01/29/2019] [Indexed: 12/11/2022]
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Morphological changes of telocytes in camel efferent ductules in response to seasonal variations during the reproductive cycle. Sci Rep 2019; 9:4507. [PMID: 30872789 PMCID: PMC6418092 DOI: 10.1038/s41598-019-41143-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 02/27/2019] [Indexed: 01/15/2023] Open
Abstract
Telocytes (TCs) are a distinct stromal cell type described in many organs. The present study investigated the existence of TCs within the efferent ductules in camel and the changes that occur in their morphology and activity during active and inactive reproductive seasons. TCs in the camel had a cell body and multiple telopodes (TPs), and most TCs had indented nuclei that exhibited prominent intranucleolar chromatin. TCs exhibited seasonal differences which were evaluated by histochemistry, immunohistochemistry (IHC), Transimition electron microscopy (TEM) and scanning electron microscopy (SEM). The presence of TCs in camel efferent ductules has been confirmed by CD34 positive immunostaing. In addition to the expression of the vascular endothelial growth factor (VEGF) which was stronger in the summer season. TCs exhibited stronger immunoreactivity for progesterone and oestrogen alpha receptors (ESR1) in the spring than in the summer. In addition, TCs showed strong positive immunostaining for both vimentin and androgen receptor (AR). Several ultrastructural changes were observed in TCs during the two seasons. TPs in the summer season had delicate ramifications whereas, in the spring, TPs displayed fine arborization and became more corrugated. TCs acquired signs of exaggerated secretory activities in the spring; TPs became expanded and packed with secretory vesicles. Thus, we conclude that, hormonal alterations during the reproductive cycle impact the morphology and secretory behavior of TCs.
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Liang X, Liu X, Lu F, Zhang Y, Jiang X, Ferriero DM. HIF1α Signaling in the Endogenous Protective Responses after Neonatal Brain Hypoxia-Ischemia. Dev Neurosci 2019; 40:1-10. [PMID: 30836371 PMCID: PMC6728223 DOI: 10.1159/000495879] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 11/27/2018] [Indexed: 12/21/2022] Open
Abstract
Hypoxia-inducible factor 1α (HIF1α) is a key regulator of oxygen homeostasis, and its target genes mediate adaptive, protective, and pathological processes. The role of HIF1α in neuronal survival is controversial and the brain maturation stage is important in determining its function in brain ischemia or hypoxia-ischemia (HI). In this study, we used neuron-specific HIF1α knockout mice at postnatal day 9 (P9), and immature cortical neurons (days 7-8 in vitro) treated with the HIF1α inhibitor 2-methoxyestradiol (2ME2) or stabilizer dimethyloxalylglycine (DMOG), to examine the function of neuronal HIF1α in neonatal HI in vivo (Vannucci model) and in vitro (oxygen glucose deprivation, OGD). Inhibition of HIF1α with 2ME2 in primary neurons or deletion of neuronal HIF1α in P9 mice increased both necrotic and apoptotic cell death following HI, as evaluated by the protein levels of 145/150-kDa and 120-kDa spectrin breakdown products 24 h after HI. DMOG attenuated neuronal death right after OGD. Acute pharmacological manipulation of HIF1α synchronously regulated the expression of its targets, vascular endothelial growth factor (VEGF) and erythropoietin (Epo), in the same manner. The in vivo findings agree with our previous data using the same HIF1α-deficient mice at an earlier age. This study confirms the role of neuronal HIF1α signaling in the endogenous protective responses following HI in the developing brain.
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Affiliation(s)
- Xiao Liang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuemei Liu
- Central Laboratory, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Fuxin Lu
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Yunling Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangning Jiang
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Donna M Ferriero
- Department of Pediatrics, University of California San Francisco, San Francisco, California, USA,
- Department of Neurology, University of California San Francisco, San Francisco, California, USA,
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Davis CK, Jain SA, Bae ON, Majid A, Rajanikant GK. Hypoxia Mimetic Agents for Ischemic Stroke. Front Cell Dev Biol 2019; 6:175. [PMID: 30671433 PMCID: PMC6331394 DOI: 10.3389/fcell.2018.00175] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 12/10/2018] [Indexed: 12/27/2022] Open
Abstract
Every year stroke claims more than 6 million lives worldwide. The majority of them are ischemic stroke. Small molecule-based therapeutics for ischemic stroke has attracted a lot of attention, but none has been shown to be clinically useful so far. Hypoxia-inducible factor-1 (HIF-1) plays a crucial role in the transcriptional adaptation of cells to hypoxia. Small molecule-based hypoxia-mimetic agents either stabilize HIF-1α via HIF-prolyl hydroxylases (PHDs) inhibition or through other mechanisms. In both the cases, these agents have been shown to confer ischemic neuroprotection in vitro and in vivo. The agents which act via PHD inhibition are mainly classified into iron chelators, iron competitors, and 2 oxoglutarate (2OG) analogs. This review discusses HIF structure and key players in the HIF-1 degradation pathway as well as the genes, proteins and chemical molecules that are connected to HIF-1 and how they affect cell survival following ischemic injury. Furthermore, this review gives a summary of studies that used PHD inhibitors and other HIF-1α stabilizers as hypoxia-mimetic agents for the treatment of ischemic injury.
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Affiliation(s)
- Charles K. Davis
- School of Biotechnology, National Institute of Technology Calicut, Calicut, India
| | - Saurabh A. Jain
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
| | - Ok-Nam Bae
- College of Pharmacy, Hanyang University, Ansan, South Korea
| | - Arshad Majid
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom
| | - G. K. Rajanikant
- School of Biotechnology, National Institute of Technology Calicut, Calicut, India
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Ostrowski RP, Zhang JH. The insights into molecular pathways of hypoxia-inducible factor in the brain. J Neurosci Res 2018; 98:57-76. [PMID: 30548473 DOI: 10.1002/jnr.24366] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/16/2018] [Accepted: 11/20/2018] [Indexed: 12/12/2022]
Abstract
The objectives of this present work were to review recent developments on the role of hypoxia-inducible factor (HIF) in the survival of cells under normoxic versus hypoxic and inflammatory brain conditions. The dual nature of HIF effects appears well established, based on the accumulated evidence of HIF playing both the role of adaptive factor and mediator of cell demise. Cellular HIF responses depend on pathophysiological conditions, developmental phase, comorbidities, and administered medications. In addition, HIF-1α and HIF-2α actions may vary in the same tissues. The multiple roles of HIF in stem cells are emerging. HIF not only regulates expression of target genes and thereby influences resultant protein levels but also contributes to epigenetic changes that may reciprocally provide feedback regulations loops. These HIF-dependent alterations in neurological diseases and its responses to treatments in vivo need to be examined alongside with a functional status of subjects involved in such studies. The knowledge of HIF pathways might be helpful in devising HIF-mimetics and modulating drugs, acting on the molecular level to improve clinical outcomes, as exemplified here by clinical and experimental data of selected brain diseases, occasionally corroborated by the data from disorders of other organs. Because of complex role of HIF in brain injuries, prospective therapeutic interventions need to differentially target HIF responses depending on their roles in the molecular mechanisms of neurologic diseases.
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Affiliation(s)
- Robert P Ostrowski
- Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - John H Zhang
- Departments of Anesthesiology and Physiology, School of Medicine, Loma Linda University, Loma Linda, California
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Yang X, Zi XH. LncRNA SNHG1 alleviates OGD induced injury in BMEC via miR-338/HIF-1α axis. Brain Res 2018; 1714:174-181. [PMID: 30414401 DOI: 10.1016/j.brainres.2018.11.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 11/02/2018] [Accepted: 11/03/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Brain microvascular endothelial cell (BMEC) is an important therapeutic target for the inhibition of brain vascular dysfunction in ischemic stroke. Expression of long non-coding RNA SNHG1 is reportedly upregulated in BMEC after OGD. The present study aims to investigate the potential roles of SNHG1 in OGD-induced injury in BMEC. METHODS Mice primary brain microvascular endothelial cells (BMEC) were cultured under "normal" or "oxygen/glucose-deprived" (OGD) conditions. The expression of SNHG1 and miR-338 after OGD were examined by qPCR. shRNA against SNHG1 was used to knockdown SNHG1 in BMEC. MiR-338-3p mimic and inhibitor were used to change the expression of miR-338 in BMEC. The relationship between SNHG1 and miR-338, and the relationship between miR-338 and HIF-1α were clarified using RNA pull-down and luciferase reporter gene assays, respectively. RESULTS SNHG1 and miR-338 were upregulated in OGD induced BMEC. SNHG1 silence aggravated OGD-induced cell apoptosis by down-regulating Bcl-2, HIF-1α and VEGF-A, and upregulating caspase 3 activity and Bax. MiR-338 was upregulated in SNHG1-silenced BMEC. RNA pull-down assays showed that SNHG1 could be directly bound by miR-338. In addition, miR-338 overexpression reduced cell viability in OGD while miR-338 inhibition protected BMEC against OGD-induced injury. Furthermore, luciferase reporter assay showed that HIF-1α was a direct target of miR-338. CONCLUSIONS SNHG1 exerted protective effects against OGD induced injury via sponging miR-338, thus upregulating HIF-1α/VEGF-A in BMEC.
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Affiliation(s)
- Xia Yang
- Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Xiao-Hong Zi
- Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha 410013, PR China.
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Chen R, Lai UH, Zhu L, Singh A, Ahmed M, Forsyth NR. Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors. Front Cell Dev Biol 2018; 6:132. [PMID: 30364203 PMCID: PMC6192379 DOI: 10.3389/fcell.2018.00132] [Citation(s) in RCA: 186] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/21/2018] [Indexed: 12/11/2022] Open
Abstract
Hypoxia inducible factor (HIF) is the master oxygen sensor within cells and is central to the regulation of cell responses to varying oxygen levels. HIF activation during hypoxia ensures optimum ATP production and cell integrity, and is associated both directly and indirectly with reactive oxygen species (ROS) formation. HIF activation can either reduce ROS formation by suppressing the function of mitochondrial tricarboxylic acid cycle (TCA cycle), or increase ROS formation via NADPH oxidase (NOX), a target gene of HIF pathway. ROS is an unavoidable consequence of aerobic metabolism. In normal conditions (i.e., physioxia), ROS is produced at minimal levels and acts as a signaling molecule subject to the dedicated balance between ROS production and scavenging. Changes in oxygen concentrations affect ROS formation. When ROS levels exceed defense mechanisms, ROS causes oxidative stress. Increased ROS levels can also be a contributing factor to HIF stabilization during hypoxia and reoxygenation. In this review, we systemically review HIF activation and ROS formation in the brain during hypoxia and hypoxia/reoxygenation. We will then explore the literature describing how changes in HIF levels might provide pharmacological targets for effective ischaemic stroke treatment. HIF accumulation in the brain via HIF prolyl hydroxylase (PHD) inhibition is proposed as an effective therapy for ischaemia stroke due to its antioxidation and anti-inflammatory properties in addition to HIF pro-survival signaling. PHD is a key regulator of HIF levels in cells. Pharmacological inhibition of PHD increases HIF levels in normoxia (i.e., at 20.9% O2 level). Preconditioning with HIF PHD inhibitors show a neuroprotective effect in both in vitro and in vivo ischaemia stroke models, but post-stroke treatment with PHD inhibitors remains debatable. HIF PHD inhibition during reperfusion can reduce ROS formation and activate a number of cellular survival pathways. Given agents targeting individual molecules in the ischaemic cascade (e.g., antioxidants) fail to be translated in the clinic setting, thus far, HIF pathway targeting and thereby impacting entire physiological networks is a promising drug target for reducing the adverse effects of ischaemic stroke.
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Affiliation(s)
- Ruoli Chen
- School of Pharmacy, Keele University, Staffordshire, United Kingdom.,Institute for Science and Technology in Medicine, Keele University, Staffordshire, United Kingdom
| | - U Hin Lai
- School of Pharmacy, Keele University, Staffordshire, United Kingdom
| | - Lingling Zhu
- Department of Brain Protection and Plasticity, Institute of Basic Medical Sciences, Beijing, China
| | - Ayesha Singh
- School of Pharmacy, Keele University, Staffordshire, United Kingdom.,Institute for Science and Technology in Medicine, Keele University, Staffordshire, United Kingdom
| | - Muhammad Ahmed
- Institute for Science and Technology in Medicine, Keele University, Staffordshire, United Kingdom.,College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Nicholas R Forsyth
- Institute for Science and Technology in Medicine, Keele University, Staffordshire, United Kingdom
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Liu Y, Ran H, Xiao Y, Wang H, Chen Y, Chen W, Xu X. Knockdown of HIF-1α impairs post-ischemic vascular reconstruction in the brain via deficient homing and sprouting bmEPCs. Brain Pathol 2018; 28:860-874. [PMID: 30052311 DOI: 10.1111/bpa.12628] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 05/17/2018] [Indexed: 01/08/2023] Open
Abstract
Although the critical role of hypoxia inducible factor-1α (HIF-1α) in cerebral neovascularization after stroke has been well characterized, the details regarding the regulation of endothelial progenitor cell (EPC)-dependent neovascularization by HIF-1α are not completely understood. Using lentiviral shRNA to knockdown HIF-1α, we showed that HIF-1α plays a central role in bone marrow-derived EPC (bmEPC) homing and sprouting in the post-acute stage of ischemic Sprague Dawley (SD) rat brains. First, knockdown of HIF-1α decreased the homing of both endogenous and exogenous bmEPCs to the ischemic brain. Additionally, the knockdown impaired the incorporation and sprouting of bmEPCs in the ischemic brain. In vitro, knockdown of HIF-1α inhibited the spheroid sprouting and tube formation of bmEPCs. Mechanically, the HIF-1α-dependent recruitment of bmEPCs to the ischemic brain was relative to the CXCL12/CXCR4 axis and HMGB1, which were relative to astrocytes. In addition, the loss of HIF-1α resulted in deficient expression levels of VEGF-A, Flk-1, NRP1, and Dll4 in the ischemic brains, bmEPCs, and astrocytes. These findings suggested that HIF-1α implicates in bmEPC homing via CXCL12/CXCR4 and HMGB1 and that it promotes bmEPC sprouting via VEGF-A/flk1-NRP1/Dll4.
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Affiliation(s)
- Yang Liu
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China
| | - He Ran
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Yaping Xiao
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Hongjin Wang
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Yi Chen
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
| | - Weihai Chen
- Faculty of Psychology, Southwest University, Chongqing, China
| | - Xiaoyu Xu
- College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, China.,Chongqing Key Laboratory of New Drug Screening from Traditional Chinese Medicine, Chongqing, China.,Pharmacology of Chinese Materia Medica - the Key Discipline Constructed by the State Administration of Traditional Chinese Medicine, Chongqing, China
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Hao YH, Zhang J, Wang H, Wang HY, Dong J, Xu XP, Yao BW, Wang LF, Zhou HM, Zhao L, Peng RY. HIF-1α regulates COXIV subunits, a potential mechanism of self-protective response to microwave induced mitochondrial damages in neurons. Sci Rep 2018; 8:10403. [PMID: 29991768 PMCID: PMC6039499 DOI: 10.1038/s41598-018-28427-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 06/18/2018] [Indexed: 12/17/2022] Open
Abstract
Anxiety and speculation about potential health hazards of microwaves exposure are spreading in the past decades. Hypoxia-inducible factor-1α (HIF-1α), which can be activated by reactive oxygen species (ROS), played pivotal roles in protective responses against microwave in neuron-like cells. In this study, we established 30 mW/cm2 microwave exposed animal model, which could result in revisable injuries of neuronal mitochondria, including ultrastructure and functions, such as ROS generation and cytochrome c oxidase (COX) activity. We found that the ratio of COXIV-1/COXIV-2, two isoforms of COXIV, decreased at 1 d and increased from 3 d to 14 d. Similar expression changes of HIF-1α suggested that COXIV-1 and COXIV-2 might be regulated by HIF-1α. In neuron-like cells, 30 mW/cm2 microwave down-regulated COX activity from 30 min to 6 h, and then started to recover. And, both HIF-1α transcriptional activity and COXIV-1/COXIV-2 ratio were up-regulated at 6 h and 9 h after exposure. Moreover, HIF-1α inhibition down-regulated COXIV-1 expression, promoted ROS generation, impaired mitochondrial membrane potentials (MMP), as well as abolished microwave induced ATP production. In conclusion, microwave induced mitochondrial ROS production activated HIF-1α and regulated COXIV-1 expression to restore mitochondria functions. Therefore, HIF-1α might be a potential target to impair microwave induced injuries.
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Affiliation(s)
- Yan-Hui Hao
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Jing Zhang
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Hui Wang
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Hao-Yu Wang
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Ji Dong
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Xin-Ping Xu
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Bin-Wei Yao
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Li-Feng Wang
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Hong-Mei Zhou
- Department of Radiation Protection and Health Physics, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China
| | - Li Zhao
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China.
| | - Rui-Yun Peng
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, 100850, P.R. China.
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