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Kanayama T, Hatakeyama M, Akiyama N, Otsu Y, Onodera O, Shimohata T, Kanazawa M. Oxygen-glucose-deprived peripheral blood mononuclear cells act on hypoxic lesions after ischemia-reperfusion injury. Exp Neurol 2025; 385:115121. [PMID: 39710242 DOI: 10.1016/j.expneurol.2024.115121] [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: 08/21/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Despite advances in reperfusion therapies, ischemic stroke remains a major cause of long-term disability due to residual hypoxic lesions persisting after macrovascular reperfusion. These residual hypoxic lesions, caused by microvascular dysfunction, represent an important therapeutic target. We previously demonstrated that oxygen-glucose-deprived peripheral blood mononuclear cells (OGD-PBMCs) migrate to ischemic brain regions and promote functional recovery after stroke. This recovery occurs through mechanisms involving hypoxia-inducible factor-1α, exosomal miR-155-5p, and vascular endothelial growth factor (VEGF). However, it remains unclear whether OGD-PBMCs target hypoxic regions. METHODS We evaluated cerebral blood flow using a laser speckle flow imaging system. Next, we utilized pimonidazole to investigate the presence of hypoxic lesions after ischemia-reperfusion injury in a rat suture occlusion model in immunohistochemical analyses. We also compared levels of a cell surface receptor in human PBMCs by flow cytometric analysis under normoxic and OGD conditions. RESULTS We found persistent pimonidazole-positive hypoxic lesions at 10- and 28-days post-reperfusion despite restored gross cerebral perfusion. Treatment with the C-X-C motif chemokine receptor 4 (CXCR4) inhibitor AMD3100 before and after OGD-PBMCs administration reduced the number of OGD-PBMCs in the brain parenchyma compared to the control group (P = 0.018). Administered OGD-PBMCs localized within these hypoxic regions via the stromal cell-derived factor-1/CXCR4 chemotactic axis. OGD-PBMCs enhanced VEGF expression, specifically within hypoxic lesions, compared to the phosphate-buffered saline group (P < 0.01). Furthermore, OGD-PBMCs reduced the number of pimonidazole-positive hypoxic cells in the ischemic core on 28 days. These findings demonstrate that OGD-PBMCs selectively migrate to and modulate the microenvironment of hypoxic lesions following cerebral ischemia-reperfusion injury. CONCLUSION Targeting these residual hypoxic regions may underline the therapeutic effects of OGD-PBMC treatment and represent a promising strategy for improving stroke recovery despite successful recanalization.
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Affiliation(s)
- Takeshi Kanayama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata 951-8585, Japan
| | - Masahiro Hatakeyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata 951-8585, Japan
| | - Natsuki Akiyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata 951-8585, Japan
| | - Yutaka Otsu
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata 951-8585, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata 951-8585, Japan
| | - Takayoshi Shimohata
- Department of Neurology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata 951-8585, Japan.
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Yamagami K, Samata B, Doi D, Tsuchimochi R, Kikuchi T, Amimoto N, Ikeda M, Yoshimoto K, Takahashi J. Progranulin enhances the engraftment of transplanted human iPS cell-derived cerebral neurons. Stem Cells Transl Med 2024; 13:1113-1128. [PMID: 39340829 PMCID: PMC11555480 DOI: 10.1093/stcltm/szae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 07/12/2024] [Indexed: 09/30/2024] Open
Abstract
Cerebral organoids (COs) in cell replacement therapy offer a viable approach to reconstructing neural circuits for individuals suffering from stroke or traumatic brain injuries. Successful transplantation relies on effective engraftment and neurite extension from the grafts. Earlier research has validated the effectiveness of delaying the transplantation procedure by 1 week. Here, we hypothesized that brain tissues 1 week following a traumatic brain injury possess a more favorable environment for cell transplantation when compared to immediately after injury. We performed a transcriptomic comparison to differentiate gene expression between these 2 temporal states. In controlled in vitro conditions, recombinant human progranulin (rhPGRN) bolstered the survival rate of dissociated neurons sourced from human induced pluripotent stem cell-derived COs (hiPSC-COs) under conditions of enhanced oxidative stress. This increase in viability was attributable to a reduction in apoptosis via Akt phosphorylation. In addition, rhPGRN pretreatment before in vivo transplantation experiments augmented the engraftment efficiency of hiPSC-COs considerably and facilitated neurite elongation along the host brain's corticospinal tracts. Subsequent histological assessments at 3 months post-transplantation revealed an elevated presence of graft-derived subcerebral projection neurons-crucial elements for reconstituting neural circuits-in the rhPGRN-treated group. These outcomes highlight the potential of PGRN as a neurotrophic factor suitable for incorporation into hiPSC-CO-based cell therapies.
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Affiliation(s)
- Keitaro Yamagami
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Department of Neurosurgery, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Bumpei Samata
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Daisuke Doi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Ryosuke Tsuchimochi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
- Department of Neurosurgery, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuhiro Kikuchi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Naoya Amimoto
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Megumi Ikeda
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Koji Yoshimoto
- Department of Neurosurgery, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Takahashi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Minatoguchi S, Satake A, Murase H, Yoshizumi R, Komaki H, Baba S, Yasuda S, Ojio S, Tanaka T, Okura H, Minatoguchi S. Elevated plasma progranulin levels in the acute phase are correlated with recovery of left ventricular function in the chronic phase in patients with acute myocardial infarction. PLoS One 2024; 19:e0313014. [PMID: 39514465 PMCID: PMC11548716 DOI: 10.1371/journal.pone.0313014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Progranulin is a secreted glycoprotein that regulates inflammation and wound healing. However, plasma progranulin levels in the acute phase and their clinical significance in patients with acute myocardial infarction (AMI) remain to be elucidated. OBJECTIVE We aimed to investigate the relationship between the increase in plasma progranulin levels in the acute phase and the recovery of left ventricular function in the chronic phase in AMI patients. METHOD AND RESULT Eighteen AMI patients were followed up for 6 months. Blood samples were collected from the antecubital vein on day 0 (on admission) and day 7 in the acute phase. The control group consisted of patients without significant coronary artery stenosis, as assessed by cardiac catheterization (n = 16). Plasma progranulin levels were measured by enzyme-linked immunosorbent assay. Echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI to evaluate left ventricular ejection fraction using the modified Simpson's method. Plasma progranulin levels in the AMI group on day 0 (69.5 ± 24.6 ng/mL) were similar to those in the control group (84.2 ± 47.1 ng/mL). There was a significant increase in progranulin levels in the AMI group on day 7 (104.2 ± 52.0 ng/mL) compared with day 0. The increase in plasma progranulin levels in the acute phase was positively correlated with the increase in left ventricular ejection fraction between the acute and chronic phases. Among various factors, only plasma progranulin levels were favorably correlated with left ventricular functional recovery in the chronic phase. CONCLUSION The increase in plasma progranulin levels in the acute phase may serve as a predictive biomarker and a contributer for the recovery of left ventricular function in the chronic phase in patients with AMI.
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Affiliation(s)
- Shingo Minatoguchi
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Atsushi Satake
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Hirotaka Murase
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Ryo Yoshizumi
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Hisaaki Komaki
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Shinya Baba
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Shinji Yasuda
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Shinsuke Ojio
- Department of Cardiology, Gifu Municipal Hospital, Gifu, Japan
| | - Toshiki Tanaka
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyuki Okura
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
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Nguyen JN, Mohan EC, Pandya G, Ali U, Tan C, Kofler JK, Shapiro L, Marrelli SP, Chauhan A. CD13 facilitates immune cell migration and aggravates acute injury but promotes chronic post-stroke recovery. J Neuroinflammation 2023; 20:232. [PMID: 37817190 PMCID: PMC10566099 DOI: 10.1186/s12974-023-02918-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/01/2023] [Indexed: 10/12/2023] Open
Abstract
INTRODUCTION Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown. METHODS CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8-12 weeks) male wild-type and global CD13 knockout (KO) mice were used for this study. Mice underwent 60 min of middle cerebral artery occlusion (MCAO) followed by reperfusion. For acute studies, the mice were euthanized at either 24- or 72 h post-stroke. For chronic studies, the Y-maze, Barnes maze, and the open field were performed on day 7 and day 28 post-stroke. Mice were euthanized at day 30 post-stroke and the brains were collected for assessment of inflammation, white matter injury, tissue loss, and angiogenesis. Flow cytometry was performed on days 3 and 7 post-stroke to quantify infiltrated monocytes and neutrophils and CXCL12/CXCR4 signaling. RESULTS Brain CD13 expression and infiltrated CD13+ monocytes and neutrophils increased acutely after the stroke. The brain CD13+lectin+ blood vessels increased on day 15 after the stroke. Similarly, an increase in the percentage area CD13 was observed in human stroke patients at the subacute time after stroke. Deletion of CD13 resulted in reduced infarct volume and improved neurological recovery after acute stroke. However, CD13KO mice had significantly worse memory deficits, amplified gliosis, and white matter damage compared to wild-type animals at chronic time points. CD13-deficient mice had an increased percentage of CXCL12+cells but a reduced percentage of CXCR4+cells and decreased angiogenesis at day 30 post-stroke. CONCLUSIONS CD13 is involved in the trans-migration of monocytes and neutrophils after stroke, and acutely, led to decreased infarct size and improved behavioral outcomes. However, loss of CD13 led to reductions in post-stroke angiogenesis by reducing CXCL12/CXCR4 signaling.
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Affiliation(s)
- Justin N Nguyen
- University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Eric C Mohan
- University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Gargee Pandya
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Uzma Ali
- Baylor University, Waco, TX, USA
| | - Chunfeng Tan
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Julia K Kofler
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Linda Shapiro
- Center for Vascular Biology, The University of Connecticut Health Center, Farmington, CT, USA
| | - Sean P Marrelli
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA
| | - Anjali Chauhan
- Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA.
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Purrahman D, Shojaeian A, Poniatowski ŁA, Piechowski-Jóźwiak B, Mahmoudian-Sani MR. The Role of Progranulin (PGRN) in the Pathogenesis of Ischemic Stroke. Cell Mol Neurobiol 2023; 43:3435-3447. [PMID: 37561339 PMCID: PMC11410000 DOI: 10.1007/s10571-023-01396-8] [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: 12/11/2022] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Stroke is a life-threatening medical condition and is a leading cause of disability. Cerebral ischemia is characterized by a distinct inflammatory response starting with the production of various cytokines and other inflammation-related agents. Progranulin (PGRN), a multifunctional protein, is critical in diverse physiological reactions, such as cell proliferation, inflammation, wound healing, and nervous system development. A mature PGRN is anti-inflammatory, while granulin, its derivative, conversely induces pro-inflammatory cytokine expression. PGRN is significantly involved in the brain tissue and its damage, for example, improving mood and cognitive disorders caused by cerebral ischemia. It may also have protective effects against nerve and spinal cord injuries by inhibiting neuroinflammatory response and apoptosis or it may be related to the proliferation, accumulation, differentiation, and activation of microglia. PGRN is a neurotrophic factor in the central nervous system. It may increase post-stroke neurogenesis of the subventricular zone (SVZ), which is particularly important in improving long-term brain function following cerebral ischemia. The neurogenesis enhanced via PGRN in the ischemic brain SVZ may be attributed to the induction of PI3K/AKT and MAPK/ERK signaling routes. PGRN can also promote the proliferation of neural stem/progenitor cells through PI3K/AKT signaling pathway. PGRN increases hippocampal neurogenesis, reducing anxiety and impaired spatial learning post-cerebral ischemia. PGRN alleviates cerebral ischemia/reperfusion injury by reducing endoplasmic reticulum stress and suppressing the NF-κB signaling pathway. PGRN can be introduced as a potent neuroprotective agent capable of improving post-ischemia neuronal actions, mainly by reducing and elevating the inflammatory and anti-inflammatory cytokines. Expression, storage, cleavage, and function of progranulin (PGRN) in the pathogenesis of ischemic stroke.
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Affiliation(s)
- Daryush Purrahman
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Shojaeian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Łukasz A Poniatowski
- Department of Neurosurgery, Dietrich-Bonhoeffer-Klinikum, Salvador-Allende-Straße 30, 17036, Neubrandenburg, Germany
| | - Bartłomiej Piechowski-Jóźwiak
- Neurological Institute, Cleveland Clinic Abu Dhabi, 59 Hamouda Bin Ali Al Dhaheri Street, Jazeerat Al Maryah, PO Box 112412, Abu Dhabi, United Arab Emirates
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Otsu Y, Hatakeyama M, Kanayama T, Akiyama N, Ninomiya I, Omae K, Kato T, Onodera O, Fukushima M, Shimohata T, Kanazawa M. Oxygen-Glucose Deprived Peripheral Blood Mononuclear Cells Protect Against Ischemic Stroke. Neurotherapeutics 2023; 20:1369-1387. [PMID: 37335500 PMCID: PMC10480381 DOI: 10.1007/s13311-023-01398-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/25/2023] [Indexed: 06/21/2023] Open
Abstract
Stroke is the leading cause of severe long-term disability. Cell therapy has recently emerged as an approach to facilitate functional recovery in stroke. Although administration of peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation (OGD-PBMCs) has been shown to be a therapeutic strategy for ischemic stroke, the recovery mechanisms remain largely unknown. We hypothesised that cell-cell communications within PBMCs and between PBMCs and resident cells are necessary for a polarising protective phenotype. Here, we investigated the therapeutic mechanisms underlying the effects of OGD-PBMCs through the secretome. We compared levels of transcriptomes, cytokines, and exosomal microRNA in human PBMCs by RNA sequences, Luminex assay, flow cytometric analysis, and western blotting under normoxic and OGD conditions. We also performed microscopic analyses to assess the identification of remodelling factor-positive cells and evaluate angiogenesis, axonal outgrowth, and functional recovery by blinded examination by administration of OGD-PBMCs after ischemic stroke in Sprague-Dawley rats. We found that the therapeutic potential of OGD-PBMCs was mediated by a polarised protective state through decreased levels of exosomal miR-155-5p, and upregulation of vascular endothelial growth factor and a pluripotent stem cell marker stage-specific embryonic antigen-3 through the hypoxia-inducible factor-1α axis. After administration of OGD-PBMCs, microenvironment changes in resident microglia by the secretome promoted angiogenesis and axonal outgrowth, resulting in functional recovery after cerebral ischemia. Our findings revealed the mechanisms underlying the refinement of the neurovascular unit by secretome-mediated cell-cell communications through reduction of miR-155-5p from OGD-PBMCs, highlighting the therapeutic potential carrier of this approach against ischemic stroke.
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Affiliation(s)
- Yutaka Otsu
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Masahiro Hatakeyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Takeshi Kanayama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Natsuki Akiyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Itaru Ninomiya
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Kaoru Omae
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, 1-5-4 Minatojima-Minamimachi, Kobe, 650-0047, Japan
| | - Taisuke Kato
- Department of System Pathology for Neurological Disorders, Brain Science Branch, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan
| | - Masanori Fukushima
- Foundation of Learning Health Society Institute, 8F, Nagoya Mitsui Bussan Bldg. 1-16-21 Meiekiminami, Nakamura-ku, Nagoya, 450-003, Japan
| | - Takayoshi Shimohata
- Department of Neurology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuoku, Niigata, 951-8585, Japan.
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Ninomiya I, Koyama A, Otsu Y, Onodera O, Kanazawa M. Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke. Front Cell Neurosci 2023; 17:1225504. [PMID: 37636590 PMCID: PMC10457112 DOI: 10.3389/fncel.2023.1225504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/31/2023] [Indexed: 08/29/2023] Open
Abstract
Theoretically, direct chemical reprogramming of somatic cells into neurons in the infarct area represents a promising regenerative therapy for ischemic stroke. Previous studies have reported that human fibroblasts and astrocytes transdifferentiate into neuronal cells in the presence of small molecules without introducing ectopic transgenes. However, the optimal combination of small molecules for the transdifferentiation of macrophages into neurons has not yet been determined. The authors hypothesized that a combination of small molecules could induce the transdifferentiation of monocyte-derived macrophages into neurons and that the administration of this combination may be a regenerative therapy for ischemic stroke because monocytes and macrophages are directly involved in the ischemic area. Transcriptomes and morphologies of the cells were compared before and after stimulation using RNA sequencing and immunofluorescence staining. Microscopic analyses were also performed to identify cell markers and evaluate functional recovery by blinded examination following the administration of small molecules after ischemic stroke in CB-17 mice. In this study, an essential combination of six small molecules [CHIR99021, Dorsomorphin, Forskolin, isoxazole-9 (ISX-9), Y27632, and DB2313] that transdifferentiated monocyte-derived macrophages into neurons in vitro was identified. Moreover, administration of six small molecules after cerebral ischemia in model animals generated a new neuronal layer in the infarct cortex by converting macrophages into neuronal cells, ultimately improving neurological function. These results suggest that altering the transdifferentiation of monocyte-derived macrophages by the small molecules to adjust their adaptive response will facilitate the development of regenerative therapies for ischemic stroke.
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Affiliation(s)
- Itaru Ninomiya
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Akihide Koyama
- Department of Legal Medicine, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan
| | - Yutaka Otsu
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
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Ahn W, Chi G, Kim S, Son Y, Zhang M. Substance P Reduces Infarct Size and Mortality After Ischemic Stroke, Possibly Through the M2 Polarization of Microglia/Macrophages and Neuroprotection in the Ischemic Rat Brain. Cell Mol Neurobiol 2023; 43:2035-2052. [PMID: 36112332 PMCID: PMC11412183 DOI: 10.1007/s10571-022-01284-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/08/2022] [Indexed: 12/12/2022]
Abstract
Substance-P (SP) is an 11 amino acid neuropeptide that is known to stimulate the peripheral mobilization of bone marrow mesenchymal stem cells and M2 polarization in monocytes/macrophages in a variety of acute and chronic tissue injuries. To examine the role of SP in protection and recovery from acute ischemic brain injury, experimental ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAo) in rats for 1 h with subsequent reperfusion. Two injections of SP, immediately and one day post-tMCAo, resulted in approximately threefold lower mortality and 40% less infarct volume than those of saline-treated rats at seven days post-tMCAo. At 4.5 h, SP markedly increased CD11b/c+CD163+/CD 206+ cells in the blood, which were concomitantly decreased in the bone marrow, suggesting that SP preferentially mobilized M2-polarized monocytes. After two days, SP increased the expression of neuroprotective and anti-inflammatory genes in the ischemic brain and induced neuronal survival in the brain penumbra. Additionally, SP markedly increased CD68+CD163+ and CD68+CD206+ M2 microglia/macrophages in the ischemic brain during seven days post-tMCAo. Furthermore, SP preserved the blood‒brain barrier in the ischemic brain, which was confirmed by the abundant levels of SMI71+ brain endothelial cells that colocalized with α-SMA+ pericytes. The beneficial effects of SP on functional recovery and tissue preservation were maintained for six weeks. Collectively, SP treatment in the early phase of ischemic stroke markedly suppressed the destructive inflammatory response and improved the microenvironment for tissue protection and repair.
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Affiliation(s)
- Woosung Ahn
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
| | - Guangfan Chi
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
| | - Sumin Kim
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
| | - Youngsook Son
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea.
| | - Mingzi Zhang
- Department of Genetics and Biotechnology, College of Life Science and Graduate School of Biotechnology, Kyung Hee University, Seocheon-dong, Kiheung-gu 446-701, Yongin-Si, Republic of Korea
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Qiao C, Liu Z, Qie S. The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery. Biomolecules 2023; 13:biom13030571. [PMID: 36979506 PMCID: PMC10046452 DOI: 10.3390/biom13030571] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/23/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery.
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Affiliation(s)
- Chenye Qiao
- Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China
| | - Zongjian Liu
- Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China
| | - Shuyan Qie
- Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China
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Saeedi-Boroujeni A, Purrahman D, Shojaeian A, Poniatowski ŁA, Rafiee F, Mahmoudian-Sani MR. Progranulin (PGRN) as a regulator of inflammation and a critical factor in the immunopathogenesis of cardiovascular diseases. J Inflamm (Lond) 2023; 20:1. [PMID: 36658641 PMCID: PMC9851114 DOI: 10.1186/s12950-023-00327-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/15/2023] [Indexed: 01/20/2023] Open
Abstract
Immune dysregulation has been identified as a critical cause of the most common types of cardiovascular diseases (CVDs). Notably, the innate and adaptive immune responses under physiological conditions are typically regulated with high sensitivity to avoid the exacerbation of inflammation, but any dysregulation can probably be associated with CVDs. In this respect, progranulin (PGRN) serves as one of the main components of the regulation of inflammatory processes, which significantly contributes to the immunopathogenesis of such disorders. PGRN has been introduced among the secreted growth factors as one related to wound healing, inflammation, and human embryonic development, as well as a wide variety of autoimmune diseases. The relationship between the serum PGRN and TNF-α ratio with the spontaneous bacterial peritonitis constitute one of the independent predictors of these conditions. The full-length PGRN can thus effectively reduce the calcification of valve interstitial cells, and the granulin precursor (GRN), among the degradation products of PGRN, can be beneficial. Moreover, it was observed that, PGRN protects the heart against ischemia-reperfusion injury. Above all, PGRN also provides protection in the initial phase following myocardial ischemia-reperfusion injury. The protective impact of PGRN on this may be associated with the early activation of the PI3K/Akt signaling pathway. PGRN also acts as a protective factor in hyperhomocysteinemia, probably by down-regulating the wingless-related integration site Wnt/β-catenin signaling pathway. Many studies have further demonstrated that SARS-CoV-2 (COVID-19) has dramatically increased the risks of CVDs due to inflammation, so PGRN has drawn much more attention among scholars. Lysosomes play a pivotal role in the inflammation process, and PGRN is one of the key regulators in their functioning, which contributes to the immunomodulatory mechanism in the pathogenesis of CVDs. Therefore, investigation of PGRN actions can help find new prospects in the treatment of CVDs. This review aims to summarize the role of PGRN in the immunopathogenesis of CVD, with an emphasis on its treatment.
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Affiliation(s)
- Ali Saeedi-Boroujeni
- Department of Microbiology, School of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Daryush Purrahman
- grid.411230.50000 0000 9296 6873Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Shojaeian
- grid.411950.80000 0004 0611 9280Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Łukasz A. Poniatowski
- grid.491786.50000 0001 0211 9062Department of Neurosurgery, Dietrich-Bonhoeffer-Klinikum, Neubrandenburg, Germany
| | - Fatemeh Rafiee
- grid.469309.10000 0004 0612 8427Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Science, Zanjan, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- grid.411230.50000 0000 9296 6873Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran ,grid.411230.50000 0000 9296 6873Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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11
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Zhao L, Xu DG, Hu YH. The Regulation of Microglial Cell Polarization in the Tumor Microenvironment: A New Potential Strategy for Auxiliary Treatment of Glioma-A Review. Cell Mol Neurobiol 2023; 43:193-204. [PMID: 35137327 PMCID: PMC11415204 DOI: 10.1007/s10571-022-01195-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 01/09/2022] [Indexed: 01/07/2023]
Abstract
Glioma is the most common primary tumor of the central nervous system and normally should be treated by synthetic therapy, mainly with surgical operation assisted by radiotherapy and chemotherapy; however, the therapeutic effect has not been satisfactory, and the 5-year survival rates of anaplastic glioma and glioblastoma are 29.7% and 5.5%, respectively. To identify a more efficient strategy to treat glioma, in recent years, the influence of the inflammatory microenvironment on the progression of glioma has been studied. Various immunophenotypes exist in microglial cells, each of which has a different functional property. In this review, references about the phenotypic conversion of microglial cell polarity in the microenvironment were briefly summarized, and the differences in polarized state and function, their influences on glioma progression under different physiological and pathological conditions, and the interactive effects between the two were mainly discussed. Certain signaling molecules and regulatory pathways involved in the microglial cell polarization process were investigated, and the feasibility of targeted regulation of microglial cell conversion to an antitumor phenotype was analyzed to provide new clues for the efficient auxiliary treatment of neural glioma.
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Affiliation(s)
- Lei Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Dong-Gang Xu
- Institute of Military Cognition and Brain Science, Research Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China
| | - Yu-Hua Hu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, People's Republic of China.
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12
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González-Rodríguez M, Ait Edjoudi D, Cordero Barreal A, Ruiz-Fernández C, Farrag M, González-Rodríguez B, Lago F, Capuozzo M, Gonzalez-Gay MA, Mera Varela A, Pino J, Farrag Y, Gualillo O. Progranulin in Musculoskeletal Inflammatory and Degenerative Disorders, Focus on Rheumatoid Arthritis, Lupus and Intervertebral Disc Disease: A Systematic Review. Pharmaceuticals (Basel) 2022; 15:1544. [PMID: 36558994 PMCID: PMC9782117 DOI: 10.3390/ph15121544] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/02/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022] Open
Abstract
Progranulin (PGRN) is a glycoprotein formed by 593 amino acids encoded by the GRN gene. It has an important role in immunity and inflammatory response, as well as in tissue recovery. Its role in musculoskeletal inflammatory diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and intervertebral disc degeneration disease (IVDD), is, nowadays, an important target to investigate. The objective of this review is to systematically sum up all the recent findings concerning PGRN as a target in the development and resolution of the inflammatory diseases. PubMed was examined with the terms combinations (Progranulin) AND (Lupus Erythematosus, Systemic), (Progranulin) AND (Arthritis, Rheumatoid), and (Progranulin) AND (Intervertebral Disc Degeneration). PubMed was examined with the terms combinations (Atsttrin) AND (Lupus Erythematosus, Systemic), (Atsttrin) AND (Arthritis, Rheumatoid), and (Atsttrin) AND (Intervertebral Disc Degeneration). Moreover, research through Web of Science was performed searching the same items. The inclusion criteria were: studies whose main topic were progranulin, or atsttrin, with emphasis on the three selected diseases. On the other hand, the exclusion criteria were studies that only focused on diseases not related to RA, lupus or IVDD, in addition to the previous published literature reviews. Since few results were obtained, we did not filter by year. The records assessed for eligibility were 23, including all the studies with the information in state of art of progranulin and its capability to be a potential target or treatment for each one of the selected diseases. As these results are descriptive and not clinical trials, we did not perform risk of bias methods. Within these results, many studies have shown an anti-inflammatory activity of PGRN in RA. PGRN levels in serum and synovial fluids in RA patients were reported higher than controls. On the other hand, serum levels were directly correlated with SLE disease activity index, suggesting an important role of PGRN as a player in the progression of inflammatory diseases and a therapeutical approach for the recovery. This review has some limitations due to the small number of studies in this regard; therefore, we highlight the importance and the necessity of further investigation. No external funding was implicated in this systematical review.
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Affiliation(s)
- María González-Rodríguez
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
- International PhD School, University of Santiago de Compostela (EDIUS), 15706 Santiago de Compostela, Spain
| | - Djedjiga Ait Edjoudi
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Alfonso Cordero Barreal
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
- International PhD School, University of Santiago de Compostela (EDIUS), 15706 Santiago de Compostela, Spain
| | - Clara Ruiz-Fernández
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
- International PhD School, University of Santiago de Compostela (EDIUS), 15706 Santiago de Compostela, Spain
| | - Mariam Farrag
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Beatriz González-Rodríguez
- SESCAM (Servicio de Salud de Castilla La Mancha), Ophthalmology Department, University Hospital of Toledo, 45007 Toledo, Spain
| | - Francisca Lago
- Molecular and Cellular Cardiology Group, SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), Research Laboratory 7, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Maurizio Capuozzo
- National Health Service, Local Health Authority ASL 3 Napoli Sud, Department of Pharmacy, 80056 Naples, Italy
| | - Miguel Angel Gonzalez-Gay
- Hospital Universitario Marqués de Valdecilla, Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL, University of Cantabria, Avenida de Valdecilla s/n, 39008 Santander, Spain
| | - Antonio Mera Varela
- SERGAS, Servizo Galego de Saude, Santiago University Clinical Hospital, Division of Rheumatology, 15706 Santiago de Compostela, Spain
| | - Jesús Pino
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Yousof Farrag
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude), and IDIS (Instituto de Investigación Sanitaria de Santiago), NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain
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13
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Gaire BP. Microglia as the Critical Regulators of Neuroprotection and Functional Recovery in Cerebral Ischemia. Cell Mol Neurobiol 2022; 42:2505-2525. [PMID: 34460037 PMCID: PMC11421653 DOI: 10.1007/s10571-021-01145-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/25/2021] [Indexed: 12/13/2022]
Abstract
Microglial activation is considered as the critical pathogenic event in diverse central nervous system disorders including cerebral ischemia. Proinflammatory responses of activated microglia have been well reported in the ischemic brain and neuroinflammatory responses of activated microglia have been believed to be the potential therapeutic strategy. However, despite having proinflammatory roles, microglia can have significant anti-inflammatory roles and they are associated with the production of growth factors which are responsible for neuroprotection and recovery after ischemic injury. Microglia can directly promote neuroprotection by preventing ischemic infarct expansion and promoting functional outcomes. Indirectly, microglia are involved in promoting anti-inflammatory responses, neurogenesis, and angiogenesis in the ischemic brain which are crucial pathophysiological events for ischemic recovery. In fact, anti-inflammatory cytokines and growth factors produced by microglia can promote neuroprotection and attenuate neurobehavioral deficits. In addition, microglia regulate phagocytosis, axonal regeneration, blood-brain barrier protection, white matter integrity, and synaptic remodeling, which are essential for ischemic recovery. Microglia can also regulate crosstalk with neurons and other cell types to promote neuroprotection and ischemic recovery. This review mainly focuses on the roles of microglia in neuroprotection and recovery following ischemic injury. Furthermore, this review also sheds the light on the therapeutic potential of microglia in stroke patients.
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Affiliation(s)
- Bhakta Prasad Gaire
- Department of Neurology and Anesthesiology, Shock Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
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14
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Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. Nat Neurosci 2022; 25:1034-1048. [PMID: 35879464 DOI: 10.1038/s41593-022-01124-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 06/16/2022] [Indexed: 12/13/2022]
Abstract
Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood-brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
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15
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Zheng X, Mi T, Wang R, Zhang Z, Li W, Zhao J, Yang P, Xia H, Mao Q. Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury. Glia 2022; 70:1317-1336. [PMID: 35362178 DOI: 10.1002/glia.24175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 03/22/2022] [Accepted: 03/22/2022] [Indexed: 11/07/2022]
Abstract
Traumatic brain injury (TBI) can be progressive and can lead to the development of a long-term complication termed chronic traumatic encephalopathy. The mechanisms underlying the progressive changes are still unknown; however, studies have suggested that microglia-mediated neuroinflammation in response to TBI may play a fundamental role. This study aimed to determine whether progranulin (PGRN), a major modulator of microglial activity, plays a role in the progressive damage following TBI. PGRN-deficient and wild-type mice were subjected to controlled cortical impact and were observed neuropathologically after 3 days, 7 days, and 5 months. Compared to sham and wild-type mice, the PGRN-deficient mice showed overall stronger microgliosis and astrocytosis. The astrocytosis involved broader areas than the microgliosis and was more prominent in the basal ganglia, hippocampus, and internal capsule in PGRN-deficient mice. Ongoing neuronal death was uniquely observed in the hippocampal CA3 region of PGRN-deficient mice at 5 months after TBI, accompanying the regional chronic microgliosis and astrocytosis involving the CA3 commissural pathway. In addition, there was M1 microglial polarization in the pericontusional area with activated TLR4/MyD88/NF-κB signaling; however, the hippocampus showed only mild M1 polarization 7 days after TBI. Lastly, Morris water maze tests showed PGRN-deficient mice had poorer spatial learning and memory 5 months after TBI than wild-type or sham mice. The data indicated the PGRN deficiency caused TBI progression by promoting persistent microgliosis with microglial polarization and astrocytosis, as well as regional pathology in the hippocampus. The study suggests that PGRN should be evaluated as a potential therapy for TBI.
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Affiliation(s)
- Xiaojing Zheng
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Tiantian Mi
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Rong Wang
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Zihan Zhang
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Wenyan Li
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Junli Zhao
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Peiyan Yang
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Haibin Xia
- Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Qinwen Mao
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
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16
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Purrahman D, Mahmoudian-Sani MR, Saki N, Wojdasiewicz P, Kurkowska-Jastrzębska I, Poniatowski ŁA. Involvement of progranulin (PGRN) in the pathogenesis and prognosis of breast cancer. Cytokine 2022; 151:155803. [DOI: 10.1016/j.cyto.2022.155803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 12/26/2021] [Accepted: 01/09/2022] [Indexed: 12/19/2022]
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Sun S, Zhou J, Li Z, Wu Y, Wang H, Zheng Q, Adu-Nti F, Fan J, Tian Y. Progranulin promotes hippocampal neurogenesis and alleviates anxiety-like behavior and cognitive impairment in adult mice subjected to cerebral ischemia. CNS Neurosci Ther 2022; 28:775-787. [PMID: 35146924 PMCID: PMC8981488 DOI: 10.1111/cns.13810] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 12/14/2022] Open
Abstract
Aims Cerebral ischemia can lead to anxiety and cognitive impairment due to the loss of hippocampal neurons. Facilitation of endogenous neurogenesis in the hippocampus is a potential therapeutic strategy for alleviating ischemia‐induced anxiety and cognitive impairment. Progranulin (PGRN), a secretory glycoprotein, has been reported to have a mitogentic effect on many cell types. However, it is not clear whether PGRN enhances hippocampal neurogenesis and promotes functional recovery. Methods Adult male C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and injected intracerebroventricularly with recombinant mouse PGRN 30 min after pMCAO. Anxiety‐like behavior was detected by the open field and the elevated plus maze tests, and spatial learning and memory abilities were evaluated by Morris water maze. Neurogenesis was examined by double labeling of BrdU and neural stem cells or neurons markers. For mechanism studies, the level of ERK1/2 and AKT phosphorylation were assessed by western blotting. Results Progranulin significantly alleviated anxiety‐like behavior and spatial learning and memory impairment induced by cerebral ischemia in mice. Consistent with the functional recovery, PGRN promoted neural stem cells (NSCs) proliferation and neuronal differentiation in the dentate gyrus (DG) after cerebral ischemia. PGRN upregulated the expression of phosphorylated ERK1/2 and Akt in the DG after cerebral ischemia. Conclusions Progranulin alleviates ischemia‐induced anxiety‐like behavior and spatial learning and memory impairment in mice, probably via stimulation of hippocampal neurogenesis mediated by activation of MAPK/ERK and PI3K/Akt pathways. PGRN might be a promising candidate for coping with ischemic stroke‐induced mood and cognitive impairment in clinic.
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Affiliation(s)
- Siqi Sun
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.,College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Jinlong Zhou
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.,College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Zhongqi Li
- College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Yuzi Wu
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.,College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Hao Wang
- Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, China
| | - Qi Zheng
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.,College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Frank Adu-Nti
- College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Juan Fan
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.,College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Yingfang Tian
- Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.,College of Life Sciences, Shaanxi Normal University, Xi'an, China
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18
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Chitramuthu BP, Campos-García VR, Bateman A. Multiple Molecular Pathways Are Influenced by Progranulin in a Neuronal Cell Model-A Parallel Omics Approach. Front Neurosci 2022; 15:775391. [PMID: 35095393 PMCID: PMC8791029 DOI: 10.3389/fnins.2021.775391] [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: 09/13/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Progranulin (PGRN) is critical in supporting a healthy CNS. Its haploinsufficiency results in frontotemporal dementia, while in experimental models of age-related neurodegenerative diseases, the targeted expression of PGRN greatly slows the onset of disease phenotypes. Nevertheless, much remains unclear about how PGRN affects its target cells. In previous studies we found that PGRN showed a remarkable ability to support the survival of NSC-34 motor neuron cells under conditions that would otherwise lead to their apoptosis. Here we used the same model to investigate other phenotypes of PGRN expression in NSC-34 cells. PGRN significantly influenced morphological differentiation, resulting in cells with enlarged cell bodies and extended projections. At a molecular level this correlated with pathways associated with the cytoskeleton and synaptic differentiation. Depletion of PGRN led to increased expression of several neurotrophic receptors, which may represent a homeostatic mechanism to compensate for loss of neurotrophic support from PGRN. The exception was RET, a neurotrophic tyrosine receptor kinase, which, when PGRN levels are high, shows increased expression and enhanced tyrosine phosphorylation. Other receptor tyrosine kinases also showed higher tyrosine phosphorylation when PGRN was elevated, suggesting a generalized enhancement of receptor activity. PGRN was found to bind to multiple plasma membrane proteins, including RET, as well as proteins in the ER/Golgi apparatus/lysosome pathway. Understanding how these various pathways contribute to PGRN action may provide routes toward improving neuroprotective therapies.
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Affiliation(s)
- Babykumari P Chitramuthu
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, and Centre for Translational Biology, Metabolic Disorders and Complications, McGill University Health Centre Research Institute, Montréal, QC, Canada
| | - Víctor R Campos-García
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, and Centre for Translational Biology, Metabolic Disorders and Complications, McGill University Health Centre Research Institute, Montréal, QC, Canada
| | - Andrew Bateman
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, and Centre for Translational Biology, Metabolic Disorders and Complications, McGill University Health Centre Research Institute, Montréal, QC, Canada
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Malicek D, Wittig I, Luger S, Foerch C. Proteomics-Based Approach to Identify Novel Blood Biomarker Candidates for Differentiating Intracerebral Hemorrhage From Ischemic Stroke-A Pilot Study. Front Neurol 2022; 12:713124. [PMID: 34975707 PMCID: PMC8719589 DOI: 10.3389/fneur.2021.713124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022] Open
Abstract
Background: A reliable distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is required for diagnosis-specific treatment and effective secondary prevention in patients with stroke. However, in resource-limited settings brain imaging, which is the current diagnostic gold standard for this purpose, is not always available in time. Hence, an easily accessible and broadly applicable blood biomarker-based diagnostic test differing stroke subtypes would be desirable. Using an explorative proteomics approach, this pilot study aimed to identify novel blood biomarker candidates for distinguishing IS from ICH. Material and Methods: Plasma samples from patients with IS and ICH were drawn during hospitalization and were analyzed by using liquid chromatography/mass spectrometry. Proteins were identified using the human reference proteome database UniProtKB, and label-free quantification (LFQ) data were further analyzed using bioinformatic tools. Results: Plasma specimens of three patients with IS and four patients with ICH with a median National Institute of Health Stroke Scale (NIHSS) of 12 [interquartile range (IQR) 10.5–18.5] as well as serum samples from two healthy volunteers were analyzed. Among 495 identified protein groups, a total of 368 protein groups exhibited enough data points to be entered into quantitative analysis. Of the remaining 22 top-listed proteins, a significant difference between IS and ICH was found for Carboxypeptidase N subunit 2 (CPN2), Coagulation factor XII (FXII), Plasminogen, Mannan-binding lectin serine protease 1, Serum amyloid P-component, Paraoxonase 1, Carbonic anhydrase 1, Fibulin-1, and Granulins. Discussion: In this exploratory proteomics-based pilot study, nine candidate biomarkers for differentiation of IS and ICH were identified. The proteins belong to the immune system, the coagulation cascade, and the apoptosis system, respectively. Further investigations in larger cohorts of patients with stroke using additional biochemical analysis methods, such as ELISA or Western Blotting are now necessary to validate these markers, and to characterize diagnostic accuracy with regard to the development of a point-of-care-system for use in resource-limited areas.
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Affiliation(s)
- David Malicek
- Department of Neurology, Goethe University/University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Ilka Wittig
- Functional Proteomics, Institute of Cardiovascular Physiology, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany
| | - Sebastian Luger
- Department of Neurology, Goethe University/University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christian Foerch
- Department of Neurology, Goethe University/University Hospital Frankfurt, Frankfurt am Main, Germany
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20
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Rizzo SA, Bartley O, Rosser AE, Newland B. Oxygen-glucose deprivation in neurons: implications for cell transplantation therapies. Prog Neurobiol 2021; 205:102126. [PMID: 34339808 DOI: 10.1016/j.pneurobio.2021.102126] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/16/2021] [Accepted: 07/29/2021] [Indexed: 12/25/2022]
Abstract
Cell replacement therapies hold the potential to restore neuronal networks compromised by neurodegenerative diseases (such as Parkinson's disease or Huntington's disease), or focal tissue damage (via a stroke or spinal cord injury). Despite some promising results achieved to date, transplanted cells typically exhibit poor survival in the central nervous system, thus limiting therapeutic efficacy of the graft. Although cell death post-transplantation is likely to be multifactorial in causality, growing evidence suggests that the lack of vascularisation at the graft site, and the resulting ischemic host environment, may play a fundamental role in the fate of grafted cells. Herein, we summarise data showing how the deprivation of either oxygen, glucose, or both in combination, impacts the survival of neurons and review strategies which may improve graft survival in the central nervous system.
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Affiliation(s)
| | - Oliver Bartley
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, Wales, UK
| | - Anne E Rosser
- Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, Wales, UK; Neuroscience and Mental Health Institute and B.R.A.I.N Unit, Cardiff University, School of Medicine, Hadyn Ellis Building, Maindy Road, CF24 4HQ, Cardiff, UK
| | - Ben Newland
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB, Wales, UK; Leibniz Institute for Polymer Research Dresden (IPF), Hohe Straße 6, 01069, Dresden, Germany.
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21
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Davis SE, Roth JR, Aljabi Q, Hakim AR, Savell KE, Day JJ, Arrant AE. Delivering progranulin to neuronal lysosomes protects against excitotoxicity. J Biol Chem 2021; 297:100993. [PMID: 34298019 PMCID: PMC8379502 DOI: 10.1016/j.jbc.2021.100993] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/08/2021] [Accepted: 07/19/2021] [Indexed: 01/18/2023] Open
Abstract
Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD), possibly due to loss of progranulin's neurotrophic and anti-inflammatory effects. Progranulin promotes neuronal growth and protects against excitotoxicity and other forms of injury. It is unclear if these neurotrophic effects are mediated through cellular signaling or through promotion of lysosomal function. Progranulin is a secreted proprotein that may activate neurotrophic signaling through cell-surface receptors. However, progranulin is efficiently trafficked to lysosomes and is necessary for maintaining lysosomal function. To determine which of these mechanisms mediates progranulin's protection against excitotoxicity, we generated lentiviral vectors expressing progranulin (PGRN) or lysosome-targeted progranulin (L-PGRN). L-PGRN was generated by fusing the LAMP-1 transmembrane and cytosolic domains to the C-terminus of progranulin. L-PGRN exhibited no detectable secretion, but was delivered to lysosomes and processed into granulins. PGRN and L-PGRN protected against NMDA excitotoxicity in rat primary cortical neurons, but L-PGRN had more consistent protective effects than PGRN. L-PGRN's protective effects were likely mediated through the autophagy-lysosomal pathway. In control neurons, an excitotoxic dose of NMDA stimulated autophagy, and inhibiting autophagy with 3-methyladenine reduced excitotoxic cell death. L-PGRN blunted the autophagic response to NMDA and occluded the protective effect of 3-methyladenine. This was not due to a general impairment of autophagy, as L-PGRN increased basal autophagy and did not alter autophagy after nutrient starvation. These data show that progranulin's protection against excitotoxicity does not require extracellular progranulin, but is mediated through lysosomes, providing a mechanistic link between progranulin's lysosomal and neurotrophic effects.
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Affiliation(s)
- Skylar E Davis
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA; Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jonathan R Roth
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA; Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Qays Aljabi
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA; Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ahmad R Hakim
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA; Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Katherine E Savell
- Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jeremy J Day
- Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Andrew E Arrant
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA; Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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22
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Xin WQ, Wei W, Pan YL, Cui BL, Yang XY, Bähr M, Doeppner TR. Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells, extracellular vesicles and microglia. World J Stem Cells 2021; 13:1030-1048. [PMID: 34567423 PMCID: PMC8422926 DOI: 10.4252/wjsc.v13.i8.1030] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/25/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammation plays an important role in the pathological process of ischemic stroke, and systemic inflammation affects patient prognosis. As resident immune cells in the brain, microglia are significantly involved in immune defense and tissue repair under various pathological conditions, including cerebral ischemia. Although the differentiation of M1 and M2 microglia is certainly oversimplified, changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia. Recent evidence indicates that both mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) regulate inflammation and modify tissue repair under preclinical stroke conditions. However, the precise mechanisms of these signaling pathways, especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia, have not been sufficiently unveiled. Hence, this review summarizes the state-of-the-art knowledge on MSC- and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways, including cytokines, neurotrophic factors, transcription factors, and microRNAs.
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Affiliation(s)
- Wen-Qiang Xin
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Wei Wei
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Yong-Li Pan
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Bao-Long Cui
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Xin-Yu Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mathias Bähr
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
| | - Thorsten R Doeppner
- Department of Neurology, University Medical Center Göttingen, Göttingen 37075, Germany
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23
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Yildirim F, Foddis M, Blumenau S, Müller S, Kajetan B, Holtgrewe M, Kola V, Beule D, Sassi C. Shared and oppositely regulated transcriptomic signatures in Huntington's disease and brain ischemia confirm known and unveil novel potential neuroprotective genes. Neurobiol Aging 2021; 104:122.e1-122.e17. [PMID: 33875290 DOI: 10.1016/j.neurobiolaging.2021.03.001] [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: 02/23/2020] [Revised: 02/13/2021] [Accepted: 03/02/2021] [Indexed: 11/20/2022]
Abstract
Huntington's disease and subcortical vascular dementia display similar dementing features, shaped by different degrees of striatal atrophy, deep white matter degeneration and tau pathology. To investigate the hypothesis that Huntington's disease transcriptomic hallmarks may provide a window into potential protective genes upregulated during brain acute and subacute ischemia, we compared RNA sequencing signatures in the most affected brain areas of 2 widely used experimental mouse models: Huntington's disease, (R6/2, striatum and cortex and Q175, hippocampus) and brain ischemia-subcortical vascular dementia (BCCAS, striatum, cortex and hippocampus). We identified a cluster of 55 shared genes significantly differentially regulated in both models and we screened these in 2 different mouse models of Alzheimer's disease, and 96 early-onset familial and apparently sporadic small vessel ischemic disease patients. Our data support the prevalent role of transcriptional regulation upon genetic coding variability of known neuroprotective genes (Egr2, Fos, Ptgs2, Itga5, Cdkn1a, Gsn, Npas4, Btg2, Cebpb) and provide a list of potential additional ones likely implicated in different dementing disorders and worth further investigation.
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Affiliation(s)
- Ferah Yildirim
- Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Marco Foddis
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Sonja Blumenau
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Susanne Müller
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Bentele Kajetan
- Berlin Institute of Health, BIH, Core Unit Bioinformatics, Berlin, Germany
| | - Manuel Holtgrewe
- Berlin Institute of Health, BIH, Core Unit Bioinformatics, Berlin, Germany
| | - Vasilis Kola
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health, BIH, Core Unit Bioinformatics, Berlin, Germany
| | - Celeste Sassi
- Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
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24
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Wang XM, Zeng P, Fang YY, Zhang T, Tian Q. Progranulin in neurodegenerative dementia. J Neurochem 2021; 158:119-137. [PMID: 33930186 DOI: 10.1111/jnc.15378] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/28/2021] [Accepted: 04/16/2021] [Indexed: 01/21/2023]
Abstract
Long-term or severe lack of protective factors is important in the pathogenesis of neurodegenerative dementia. Progranulin (PGRN), a neurotrophic factor expressed mainly in neurons and microglia, has various neuroprotective effects such as anti-inflammatory effects, promoting neuron survival and neurite growth, and participating in normal lysosomal function. Mutations in the PGRN gene (GRN) have been found in several neurodegenerative dementias, including frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Herein, PGRN deficiency and PGRN hydrolytic products (GRNs) in the pathological changes related to dementia, including aggregation of tau and TAR DNA-binding protein 43 (TDP-43), amyloid-β (Aβ) overproduction, neuroinflammation, lysosomal dysfunction, neuronal death, and synaptic deficit have been summarized. Furthermore, as some therapeutic strategies targeting PGRN have been developed in various models, we highlighted PGRN as a potential anti-neurodegeneration target in dementia.
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Affiliation(s)
- Xiao-Ming Wang
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zeng
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan, China
| | - Ying-Yan Fang
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, China
| | - Teng Zhang
- Department of Neurology, Shanxian Central Hospital, The Affiliated Huxi Hospital of Jining Medical College, Heze, China
| | - Qing Tian
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan, China
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25
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Hummel R, Lang M, Walderbach S, Wang Y, Tegeder I, Gölz C, Schäfer MKE. Single intracerebroventricular progranulin injection adversely affects the blood-brain barrier in experimental traumatic brain injury. J Neurochem 2021; 158:342-357. [PMID: 33899947 DOI: 10.1111/jnc.15375] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/17/2021] [Accepted: 04/18/2021] [Indexed: 12/23/2022]
Abstract
Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor with protective effects in animal models of ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury (TBI). Administration of recombinant (r) PGRN prevents exaggerated brain pathology after TBI in Grn-deficient mice, suggesting that local injection of recombinant progranulin (rPGRN) provides therapeutic benefit in the acute phase of TBI. To test this hypothesis, we subjected adult male C57Bl/6N mice to the controlled cortical impact model of TBI, administered a single dose of rPGRN intracerebroventricularly (ICV) shortly before the injury, and examined behavioral and biological effects up to 5 days post injury (dpi). The anti-inflammatory bioactivity of rPGRN was confirmed by its capability to inhibit the inflammation-induced hypertrophy of murine primary microglia and astrocytes in vitro. In C57Bl/6N mice, however, ICV administration of rPGRN failed to attenuate behavioral deficits over the 5-day observation period. (Immuno)histological gene and protein expression analyses at 5 dpi did not reveal a therapeutic benefit in terms of brain injury size, brain inflammation, glia activation, cell numbers in neurogenic niches, and neuronal damage. Instead, we observed a failure of TBI-induced mRNA upregulation of the tight junction protein occludin and increased extravasation of serum immunoglobulin G into the brain parenchyma at 5 dpi. In conclusion, single ICV administration of rPGRN had not the expected protective effects in the acute phase of murine TBI, but appeared to cause an aggravation of blood-brain barrier disruption. The data raise questions about putative PGRN-boosting approaches in other types of brain injuries and disease.
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Affiliation(s)
- Regina Hummel
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Manuel Lang
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Simona Walderbach
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Yong Wang
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Irmgard Tegeder
- Institute of Clinical Pharmacology, Medical Faculty, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christina Gölz
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Michael K E Schäfer
- Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Focus Program Translational Neurosciences (FTN) of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Research Center for Immunotherapy (FZI) of the Johannes Gutenberg-University Mainz, Mainz, Germany
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26
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Horinokita I, Hayashi H, Yoshizawa R, Ichiyanagi M, Imamura Y, Iwatani Y, Takagi N. Possible involvement of progranulin in the protective effect of elastase inhibitor on cerebral ischemic injuries of neuronal and glial cells. Mol Cell Neurosci 2021; 113:103625. [PMID: 33933589 DOI: 10.1016/j.mcn.2021.103625] [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: 03/03/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 10/21/2022] Open
Abstract
In a previous study, we demonstrated that neutrophil elastase is activated in the brain parenchyma after cerebral ischemia, which enzyme cleaves progranulin (PGRN), an anti-inflammatory factor. In that study, we also found that sivelestat, a selective neutrophil elastase inhibitor, attenuates ischemia-induced inflammatory responses. However, it was not clear whether this anti-inflammatory effect was due to the direct effect of sivelestat. In this study, we evaluated the effects of sivelestat or recombinant PGRN (rPGRN) on cell injuries in cultured neurons, astrocytes, and microglia under oxygen/glucose deprivation (OGD) conditions. We demonstrated that OGD-induced neuronal cell injury, astrocyte activation, and increased proinflammatory cytokines caused by microglial activation, were suppressed by rPGRN treatment, whereas sivelestat had no effect on any of these events. These results indicate that the anti-inflammatory responses after in vivo cerebral ischemia were not due to the direct action of sivelestat but due to the suppression of PGRN cleavage by inhibition of elastase activity. It was also suggested that the pleiotropic effect of rPGRN could be attributed to the differentiation of M1 microglia into anti-inflammatory type M2 microglia. Therefore, the inhibition of PGRN cleavage by sivelestat could contribute to the establishment of a new therapeutic approach for cerebral ischemia.
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Affiliation(s)
- Ichiro Horinokita
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Hideki Hayashi
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Rihona Yoshizawa
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Mika Ichiyanagi
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Yui Imamura
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Yui Iwatani
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | - Norio Takagi
- Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
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27
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Ma DC, Zhang NN, Zhang YN, Chen HS. Salvianolic Acids for Injection alleviates cerebral ischemia/reperfusion injury by switching M1/M2 phenotypes and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia in vivo and in vitro. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113776. [PMID: 33421597 DOI: 10.1016/j.jep.2021.113776] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/22/2020] [Accepted: 12/30/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE After cerebral ischemia/reperfusion injury, pro-inflammatory M1 and anti-inflammatory M2 phenotypes of microglia are involved in neuroinflammation, in which activation of NLRP3 inflammasome and subsequent pyroptosis play essential roles. Salvianolic Acids for Injection (SAFI) is Chinese medicine injection which composed of multiple phenolic acids extracted from Radix Salviae Miltiorrhizae, and has been reported to generate neuroprotective effects after cerebral ischemic insult in clinical and animal studies. AIM OF THE STUDY The present study was designed to investigate whether SAFI exerts neuroprotective effects by switching microglial phenotype and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia. MATERIALS AND METHODS The middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) model in co-cultured primary neurons and primary microglia were utilized. The neuroprotective effect of SAFI was evaluated through measuring neurological deficit scores, neuropathological changes, inflammatory factors, cell phenotype markers, and related proteins of NLRP3 inflammasome/pyroptosis axis. RESULTS The results showed that SAFI treatment was able to: (1) produce a significant increase in neurological deficit scores and decrease in infarct volumes, and alleviate histological injury and neuronal apoptosis in cerebral cortex in MCAO/R model; (2) increase neuronal viability and reduce neuronal apoptosis in the OGD model; (3) reshape microglial polarization patterns from M1-like phenotype to M2-like phenotype; (4) inhibit the activation of the NLRP3 inflammasome and the expression of proteins related to NLRP3 inflammasome/pyroptosis axis in vivo and in vitro. CONCLUSION These findings indicate that SAFI exert neuroprotective effect, probably via reducing neuronal apoptosis, switching microglial phenotype from M1 towards M2, and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia.
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Affiliation(s)
- Dai-Chao Ma
- Graduate College, Liaoning University of Traditional Chinese Medicine, China; Department of Neurology, General Hospital of Northern Theater Command, China
| | - Nan-Nan Zhang
- Department of Neurology, General Hospital of Northern Theater Command, China
| | - Yi-Na Zhang
- Department of Neurology, General Hospital of Northern Theater Command, China
| | - Hui-Sheng Chen
- Department of Neurology, General Hospital of Northern Theater Command, China.
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28
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Liu Y, Ren J, Kang M, Zhai C, Cheng Q, Li J, Wu Y, Ruan X, Zhou J, Fan J, Tian Y. Progranulin promotes functional recovery and neurogenesis in the subventricular zone of adult mice after cerebral ischemia. Brain Res 2021; 1757:147312. [PMID: 33539798 DOI: 10.1016/j.brainres.2021.147312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 11/20/2022]
Abstract
Progranulin (PGRN), a secreted glycosylated protein, has been reported to attenuate ischemia-induced cerebral injury through anti-inflammation, attenuation of blood-brain barrier disruption and neuroprotection. However, the effect of PGRN on neurogenesis in the subventricular zone (SVZ) after cerebral ischemia remains unclear. In this study, adult C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (pMCAO), and different doses of recombinant mouse PGRN (r-PGRN, 0.3 ng, 1 ng, 5 ng) were intracerebroventricularly administered 30 min after pMCAO. Results showed that 1 ng r-PGRN markedly reduced infarct volume and rescued functional deficits 24 h after pMCAO. Meanwhile, 1 ng r-PGRN increased SVZ cell proliferation, as shown by a high number of bromodeoxyuridine-positive (BrdU+) cells and Ki-67+ cells in the ischemic ipsilateral SVZ 7 d after pMCAO. Additionally, PGRN increased the percentage of BrdU+/Doublecortin (DCX)+ cells in the ipsilateral SVZ 14 d after pMCAO and increased the percentage of new neurons (BrdU+/NeuN+ cells) in the peri-infarct striatum 28 d after pMCAO, suggesting that PGRN promotes neuronal differentiation. PGRN also upregulated phosphorylation of ERK1/2 and Akt in the ipsilateral SVZ 3 d after pMCAO. Our data indicate that PGRN treatment promotes acute functional recovery; most importantly, it also stimulates neurogenesis in the SVZ, which could be beneficial for long-term recovery after cerebral ischemia. The increase in neurogenesis could be associated with activation of the MAPK/ERK and PI3K/Akt pathways. These results suggest a potential new strategy utilizing PGRN in ischemic stroke therapy.
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Affiliation(s)
- Yingxun Liu
- Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Junrong Ren
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Mengsi Kang
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Chenyang Zhai
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Qiangqiang Cheng
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Jin Li
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Yuzi Wu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Xiaofei Ruan
- Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, Shaanxi 710062, China
| | - Jinlong Zhou
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Juan Fan
- Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, Shaanxi 710062, China; College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
| | - Yingfang Tian
- Key Laboratory of Modern Teaching Technology, Ministry of Education, Shaanxi Normal University, Xi'an, Shaanxi 710062, China; College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
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29
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Nikitin D, Choi S, Mican J, Toul M, Ryu WS, Damborsky J, Mikulik R, Kim DE. Development and Testing of Thrombolytics in Stroke. J Stroke 2021; 23:12-36. [PMID: 33600700 PMCID: PMC7900387 DOI: 10.5853/jos.2020.03349] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/28/2020] [Indexed: 12/16/2022] Open
Abstract
Despite recent advances in recanalization therapy, mechanical thrombectomy will never be a treatment for every ischemic stroke because access to mechanical thrombectomy is still limited in many countries. Moreover, many ischemic strokes are caused by occlusion of cerebral arteries that cannot be reached by intra-arterial catheters. Reperfusion using thrombolytic agents will therefore remain an important therapy for hyperacute ischemic stroke. However, thrombolytic drugs have shown limited efficacy and notable hemorrhagic complication rates, leaving room for improvement. A comprehensive understanding of basic and clinical research pipelines as well as the current status of thrombolytic therapy will help facilitate the development of new thrombolytics. Compared with alteplase, an ideal thrombolytic agent is expected to provide faster reperfusion in more patients; prevent re-occlusions; have higher fibrin specificity for selective activation of clot-bound plasminogen to decrease bleeding complications; be retained in the blood for a longer time to minimize dosage and allow administration as a single bolus; be more resistant to inhibitors; and be less antigenic for repetitive usage. Here, we review the currently available thrombolytics, strategies for the development of new clot-dissolving substances, and the assessment of thrombolytic efficacies in vitro and in vivo.
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Affiliation(s)
- Dmitri Nikitin
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Seungbum Choi
- Molecular Imaging and Neurovascular Research Laboratory, Department of Neurology, Dongguk University College of Medicine, Goyang, Korea
| | - Jan Mican
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic.,Department of Neurology, St. Anne's Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Martin Toul
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Wi-Sun Ryu
- Department of Neurology, Dongguk University Ilsan Hospital, Goyang, Korea
| | - Jiri Damborsky
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Robert Mikulik
- International Centre for Clinical Research, St. Anne's Hospital, Brno, Czech Republic.,Department of Neurology, St. Anne's Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Dong-Eog Kim
- Molecular Imaging and Neurovascular Research Laboratory, Department of Neurology, Dongguk University College of Medicine, Goyang, Korea.,Department of Neurology, Dongguk University Ilsan Hospital, Goyang, Korea
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Gururaj S, Sampognaro PJ, Argouarch AR, Kao AW. Progranulin Adsorbs to Polypropylene Tubes and Disrupts Functional Assays: Implications for Research, Biomarker Studies, and Therapeutics. Front Neurosci 2021; 14:602235. [PMID: 33381010 PMCID: PMC7768044 DOI: 10.3389/fnins.2020.602235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/16/2020] [Indexed: 11/19/2022] Open
Abstract
Progranulin (PGRN) is a tightly regulated, secreted glycoprotein involved in a wide range of biological processes that is of tremendous interest to the scientific community due to its involvement in neoplastic, neurodevelopmental, and neurodegenerative diseases. In particular, progranulin haploinsufficiency leads to frontotemporal dementia. While performing experiments with a HIS-tagged recombinant human (rh) PGRN protein, we observed a measurable depletion of protein from solution due to its adsorption onto polypropylene (PPE) microcentrifuge tubes. In this study, we have quantified the extent of rhPGRN adsorption to PPE tubes while varying experimental conditions, including incubation time and temperature. We found that ∼25–35% of rhPGRN becomes adsorbed to the surface of PPE tubes even after a short incubation period. We then directly showed the deleterious impact of PGRN adsorption in functional assays and have recommended alternative labware to minimize these effects. Although the risk of adsorption of some purified proteins and peptides to polymer plastics has been characterized previously, this is the first report of rhPGRN adsorption. Moreover, since PGRN is currently being studied and utilized in both basic science laboratories to perform in vitro studies and translational laboratories to survey PGRN as a quantitative dementia biomarker and potential replacement therapy, the reported observations here are broadly impactful and will likely significantly affect the design and interpretation of future experiments centered on progranulin biology.
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Affiliation(s)
- Sushmitha Gururaj
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
| | - Paul J Sampognaro
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
| | - Andrea R Argouarch
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
| | - Aimee W Kao
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
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31
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Otsu Y, Namekawa M, Toriyabe M, Ninomiya I, Hatakeyama M, Uemura M, Onodera O, Shimohata T, Kanazawa M. Strategies to prevent hemorrhagic transformation after reperfusion therapies for acute ischemic stroke: A literature review. J Neurol Sci 2020; 419:117217. [PMID: 33161301 DOI: 10.1016/j.jns.2020.117217] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/09/2020] [Accepted: 10/29/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Reperfusion therapies by tissue plasminogen activator (tPA) and mechanical thrombectomy (MT) have ushered in a new era in the treatment of acute ischemic stroke (AIS). However, reperfusion therapy-related HT remains an enigma. AIM To provide a comprehensive review focused on emerging concepts of stroke and therapeutic strategies, including the use of protective agents to prevent HT after reperfusion therapies for AIS. METHODS A literature review was performed using PubMed and the ClinicalTrials.gov database. RESULTS Risk of HT increases with delayed initiation of tPA treatment, higher baseline glucose level, age, stroke severity, episode of transient ischemic attack within 7 days of stroke onset, and hypertension. At a molecular level, HT that develops after thrombolysis is thought to be caused by reactive oxygen species, inflammation, remodeling factor-mediated effects, and tPA toxicity. Modulation of these pathophysiological mechanisms could be a therapeutic strategy to prevent HT after tPA treatment. Clinical mechanisms underlying HT after MT are thought to involve smoking, a low Alberta Stroke Program Early CT Score, use of general anesthesia, unfavorable collaterals, and thromboembolic migration. However, the molecular mechanisms are yet to be fully investigated. Clinical trials with MT and protective agents have also been planned and good outcomes are expected. CONCLUSION To fully utilize the easily accessible drug-tPA-and the high recanalization rate of MT, it is important to reduce bleeding complications after recanalization. A future study direction could be to investigate the recovery of neurological function by combining reperfusion therapies with cell therapies and/or use of pleiotropic protective agents.
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Affiliation(s)
- Yutaka Otsu
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masaki Namekawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masafumi Toriyabe
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Medical Technology, Graduate School of Health Sciences, Niigata University, Niigata, Japan
| | - Itaru Ninomiya
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masahiro Hatakeyama
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masahiro Uemura
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Takayoshi Shimohata
- Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
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Vazifehkhah S, Khanizadeh AM, Mojarad TB, Nikbakht F. The possible role of progranulin on anti-inflammatory effects of metformin in temporal lobe epilepsy. J Chem Neuroanat 2020; 109:101849. [DOI: 10.1016/j.jchemneu.2020.101849] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/11/2020] [Accepted: 07/12/2020] [Indexed: 12/21/2022]
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Wang Y, Wang X, Li Y, Chen D, Liu Z, Zhao Y, Tu L, Wang S. Regulation of progranulin expression and location by sortilin in oxygen-glucose deprivation/reoxygenation injury. Neurosci Lett 2020; 738:135394. [PMID: 32949659 DOI: 10.1016/j.neulet.2020.135394] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
Progranulin is a secreted glycoprotein expressed in neurons and microglial cells that is involved in maintaining physiological functions. Many studies have found that progranulin may play a protective role against ischemic brain injury, but little is known about how the expression level and cellular localization status of progranulin is regulated after hypoxia-ischemia. Research has confirmed that sortilin, encoded by SORT1, can bind with progranulin and deliver a mature secretory isoform of progranulin to lysosomes, and progranulin is then cleaved. In the present study, we aimed to figure out whether sortilin could affect the expression and cellular localization of progranulin and regulate cell apoptosis during hypoxia-ischemia. In this study, oxygen-glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons was used to mimic hypoxic-ischemic episodes. After OGD/R, the neuroprotective effects of progranulin against hypoxia-ischemia were examined, and primary cortical neurons were transduced with a SORT1 knockdown lentivirus to inhibit the expression of sortilin. The results showed that sortilin inhibition increased PGRN expression and alleviated cell injury induced by hypoxia-ischemia. Additionally, sortilin inhibition was associated with less PGRN localization in lysosomes. All of these findings suggest that sortilin can regulate the expression of PGRN, most likely by transporting it to lysosomes and affecting the cell injury in hypoxia-ischemia.
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Affiliation(s)
- Yan Wang
- Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China
| | - Xiaoqing Wang
- Department of Nuclear Medicine, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong, China
| | - Yingbo Li
- Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China
| | - Di Chen
- Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China
| | - Zhao Liu
- Chongqing General Hospotal, University of Chinese Academy of Science, China
| | - Yu Zhao
- Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China
| | - Liu Tu
- Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China
| | - Shali Wang
- Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, China.
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34
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Secretory leukocyte protease inhibitor and progranulin as possible regulators of cervical remodeling in pregnancy. J Reprod Immunol 2020; 143:103241. [PMID: 33157500 DOI: 10.1016/j.jri.2020.103241] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/13/2020] [Accepted: 10/18/2020] [Indexed: 11/21/2022]
Abstract
Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R2 = 0.75) and interleukin-8 (R2 = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.
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Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review. Int J Mol Sci 2020; 21:ijms21176194. [PMID: 32867222 PMCID: PMC7503631 DOI: 10.3390/ijms21176194] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 12/12/2022] Open
Abstract
Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.
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36
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Xu B, Chen X, Ding Y, Chen C, Liu T, Zhang H. Abnormal angiogenesis of placenta in progranulin‑deficient mice. Mol Med Rep 2020; 22:3482-3492. [PMID: 32945448 PMCID: PMC7453605 DOI: 10.3892/mmr.2020.11438] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/16/2020] [Indexed: 12/23/2022] Open
Abstract
Progranulin (PGRN) is a secreted growth factor involved in pleiotropic functions, particularly angiogenesis. A distinctly different placental expression of PGRN has been reported between normal pregnancies and pregnancies with complications, such as pre‑eclampsia or fetal growth restriction. However, the role of PGRN in placental vascular development remains to be elucidated. In the present study, PGRN‑knockout mice (PGRN‑/‑) were used to investigate the role of PGRN in the development of placental blood vessels and placental formation. Placental weights and pup body weights were significantly lower in the PGRN‑/‑ mice compared with the wild‑type mice. Reduced labyrinthine layer areas and aberrant vascularization were also observed via hematoxylin and eosin staining of PGRN‑/‑ mice at embryonic day 14.5 (E14.5) and E17.5. In addition, the morphological data obtained via immunohistochemistry, immunofluorescence staining and western blotting demonstrated decreased expression levels of the blood vessel markers α‑smooth muscle actin and CD31 in PGRN‑/‑ placentas. Furthermore, vasodilator endothelial nitric oxide synthase was reduced in the PGRN‑/‑ placenta. These results indicated that PGRN serves an essential role in the normal angiogenesis of the placental labyrinth in mice.
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Affiliation(s)
- Bairuo Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xingyou Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yubin Ding
- College of Public Health and Health Management, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chang Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Taihang Liu
- College of Public Health and Health Management, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hua Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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37
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Sasaki T, Shimazawa M, Kanamori H, Yamada Y, Nishinaka A, Kuse Y, Suzuki G, Masuda T, Nakamura S, Hosokawa M, Minatoguchi S, Hara H. Effects of progranulin on the pathological conditions in experimental myocardial infarction model. Sci Rep 2020; 10:11842. [PMID: 32678228 PMCID: PMC7367277 DOI: 10.1038/s41598-020-68804-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Progranulin is a secreted growth factor associated with multiple physiological functions in ischemic pathophysiology. However, it is still not fully understood how progranulin is involved in ischemic lesion and cardiac remodeling after myocardial infarction (MI). In this study, we investigated the effects of progranulin on myocardial ischemia and reperfusion injury. We investigated progranulin expression using Western blotting and immunostaining after permanent left coronary artery (LCA) occlusion in mice. Infarct size and the number of infiltrating neutrophils were measured 24 h after permanent LCA occlusion. Recombinant mouse progranulin was administered before LCA occlusion. In addition, we evaluated cardiac function using cardiac catheterization and echocardiography, and fibrosis size by Masson's trichrome staining after myocardial ischemia/reperfusion in rabbits. Recombinant human progranulin was administered immediately after induction of reperfusion. Progranulin expression increased in the myocardial ischemic area 1, 3, and 5 days after permanent LCA occlusion in mice. The administration of recombinant mouse progranulin significantly attenuated infarct size and infiltrating neutrophils 24 h after permanent LCA occlusion in mice. We also found that administration of recombinant human progranulin ameliorated the deterioration of cardiac dysfunction and fibrosis after myocardial ischemia/reperfusion in rabbits. These findings suggest that progranulin may protect myocardial ischemia/reperfusion injury.
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Affiliation(s)
- Takahiro Sasaki
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
| | - Masamitsu Shimazawa
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
| | - Hiromitsu Kanamori
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshihisa Yamada
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Anri Nishinaka
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
| | - Yoshiki Kuse
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
| | - Genjiro Suzuki
- Dementia Research Project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Tomomi Masuda
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
| | - Shinsuke Nakamura
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan
| | - Masato Hosokawa
- Dementia Research Project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Shinya Minatoguchi
- Department of Circulatory and Respiratory Advanced Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- Heart Failure Center, Gifu Municipal Hospital, Gifu, Japan
| | - Hideaki Hara
- Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
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Ma DC, Zhang NN, Zhang YN, Chen HS. Kv1.3 channel blockade alleviates cerebral ischemia/reperfusion injury by reshaping M1/M2 phenotypes and compromising the activation of NLRP3 inflammasome in microglia. Exp Neurol 2020; 332:113399. [PMID: 32652099 DOI: 10.1016/j.expneurol.2020.113399] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/01/2020] [Accepted: 07/04/2020] [Indexed: 12/17/2022]
Abstract
After cerebral ischemia/reperfusion injury, pro-inflammatory M1-like and anti-inflammatory M2-like phenotypes of microglia are involved in neuroinflammation, in which NLRP3 inflammasome plays an essential role. Kv1.3 channel has been recognized as neuro-immunomodulatory target, but it is not clear as to its role in the neuroinflammation after cerebral ischemic injury. The current study aimed to investigate the issue. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen-glucose deprivation/ reoxygenation (OGD/R) in primary microglia were utilized to mimic disease state of ischemic stroke. Treatment with PAP-1, a Kv1.3 channel blocker, produced a significant improvement in neurological deficit scores and a decrease in infarct volume in MCAO/R model. An increased number of M2-like phenotypic microglia and a reduced number of M1-like phenotypic microglia were observed by immunofluorescent staining in the in vivo model, which was further validated by flow cytometry in vitro. Western blot showed that PAP-1 treatment profoundly reduced cleavage of caspase-1 and IL-1β in vivo and in vitro. Furthermore, PAP-1 administration reduced the number of NLRP3+/Iba1+ cells and NLRP3 protein levels in vivo, while reduced mRNA and protein expression levels of NLRP3 in vitro. Reduced mRNA expression levels of IL-1β in vitro and protein level of IL-1β in vivo were also observed. Taken together, our findings suggested that Kv1.3 channel blockade effectively alleviated cerebral ischemic injury, possibly by reshaping microglial phenotypic response from M1 towards M2, compromising the activation of NLRP3 inflammasome in microglia, and inhibiting release of IL-1β.
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Affiliation(s)
- Dai-Chao Ma
- Graduate College, Liaoning University of Traditional Chinese Medicine, China; Department of neurology, General Hospital of Northern Theater Command, China
| | - Nan-Nan Zhang
- Department of neurology, General Hospital of Northern Theater Command, China
| | - Yi-Na Zhang
- Department of neurology, General Hospital of Northern Theater Command, China
| | - Hui-Sheng Chen
- Department of neurology, General Hospital of Northern Theater Command, China.
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Hosseini M, Wilson RH, Crouzet C, Amirhekmat A, Wei KS, Akbari Y. Resuscitating the Globally Ischemic Brain: TTM and Beyond. Neurotherapeutics 2020; 17:539-562. [PMID: 32367476 PMCID: PMC7283450 DOI: 10.1007/s13311-020-00856-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cardiac arrest (CA) afflicts ~ 550,000 people each year in the USA. A small fraction of CA sufferers survive with a majority of these survivors emerging in a comatose state. Many CA survivors suffer devastating global brain injury with some remaining indefinitely in a comatose state. The pathogenesis of global brain injury secondary to CA is complex. Mechanisms of CA-induced brain injury include ischemia, hypoxia, cytotoxicity, inflammation, and ultimately, irreversible neuronal damage. Due to this complexity, it is critical for clinicians to have access as early as possible to quantitative metrics for diagnosing injury severity, accurately predicting outcome, and informing patient care. Current recommendations involve using multiple modalities including clinical exam, electrophysiology, brain imaging, and molecular biomarkers. This multi-faceted approach is designed to improve prognostication to avoid "self-fulfilling" prophecy and early withdrawal of life-sustaining treatments. Incorporation of emerging dynamic monitoring tools such as diffuse optical technologies may provide improved diagnosis and early prognostication to better inform treatment. Currently, targeted temperature management (TTM) is the leading treatment, with the number of patients needed to treat being ~ 6 in order to improve outcome for one patient. Future avenues of treatment, which may potentially be combined with TTM, include pharmacotherapy, perfusion/oxygenation targets, and pre/postconditioning. In this review, we provide a bench to bedside approach to delineate the pathophysiology, prognostication methods, current targeted therapies, and future directions of research surrounding hypoxic-ischemic brain injury (HIBI) secondary to CA.
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Affiliation(s)
- Melika Hosseini
- Department of Neurology, School of Medicine, University of California, Irvine, USA
| | - Robert H Wilson
- Department of Neurology, School of Medicine, University of California, Irvine, USA
- Beckman Laser Institute, University of California, Irvine, USA
| | - Christian Crouzet
- Department of Neurology, School of Medicine, University of California, Irvine, USA
- Beckman Laser Institute, University of California, Irvine, USA
| | - Arya Amirhekmat
- Department of Neurology, School of Medicine, University of California, Irvine, USA
| | - Kevin S Wei
- Department of Neurology, School of Medicine, University of California, Irvine, USA
| | - Yama Akbari
- Department of Neurology, School of Medicine, University of California, Irvine, USA.
- Beckman Laser Institute, University of California, Irvine, USA.
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Abstract
Ischemic strokes occur when a major cerebral artery or its branches are occluded, resulting in activation of inflammatory processes that cause secondary tissue injury, breakdown of the blood–brain barrier, edema or hemorrhage. Treatments that inhibit inflammatory processes may thus be highly beneficial. A key regulator of the inflammatory process is the nuclear factor kappa B (NF-κB) pathway. In its active form, NF-κB regulates expression of proinflammatory and proapoptotic genes. The molecules that interact with NF-κB, and the subunits that compose NF-κB itself, represent therapeutic targets that can be modulated to decrease inflammation. This review focuses on our current understanding of the NF-κB pathway and the potential benefits of inhibiting NF-κB in ischemia-reperfusion injury of the brain.
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Rabenstein M, Vay SU, Blaschke S, Walter HL, Ladwig A, Fink GR, Rueger MA, Schroeter M. Crosstalk between stressed brain cells: direct and indirect effects of ischemia and aglycemia on microglia. J Neuroinflammation 2020; 17:33. [PMID: 31980036 PMCID: PMC6982395 DOI: 10.1186/s12974-020-1697-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND In cerebral ischemia, microglia have a dichotomous role in keeping the balance between pro- and anti-inflammatory mediators to avoid deleterious chronic inflammation and to leverage repair processes. METHODS We examined functional and inflammatory markers in primary rat microglia in vitro after oxygen-glucose deprivation (OGD) or glucose deprivation (aglycemia). We then investigated the preconditioning effect of OGD or aglycemia upon a subsequent strong inflammatory stimulus, here lipopolysaccharides (LPS). Moreover, an "in vitro brain model" of neurons and glia, differentiated from primary rat neural stem cells, was exposed to OGD or aglycemia. Conditioned medium (CM) of this neuronal/glial co-culture was then used to condition microglia, followed by LPS as a "second hit." RESULTS OGD or aglycemia at sublethal doses did not significantly affect microglia function, including the expression of inflammatory markers. However, preconditioning with either OGD or aglycemia led to a decreased pro-inflammatory response to a subsequent stimulus with LPS. Interestingly, the anti-inflammatory markers IGF-1 and IL-10 were additionally reduced after such preconditioning, while expression of CD206 remained unaffected. Treatment with CM from the neuronal/glial co-culture alone did not affect the expression of inflammatory markers in microglia. In contrast, treatment with CM increased the expression of both pro- and anti-inflammatory markers in microglia upon a second hit with LPS. Interestingly, this effect could be attenuated in microglia treated with CM from neuronal/glia co-cultures preconditioned with OGD or aglycemia. CONCLUSIONS Data suggest specific and distinct microglia signatures in response to metabolic stress. While metabolic stress directly and indirectly applied to microglia did not mitigate their subsequent response to inflammation, preconditioning with metabolic stress factors such as OGD and aglycemia elicited a decreased inflammatory response to a subsequent inflammation stimulus.
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Affiliation(s)
- Monika Rabenstein
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
| | - Sabine Ulrike Vay
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
| | - Stefan Blaschke
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
- Research Centre Juelich, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Juelich, Germany
| | - Helene Luise Walter
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
| | - Anne Ladwig
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
| | - Gereon Rudolf Fink
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
- Research Centre Juelich, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Juelich, Germany
| | - Maria Adele Rueger
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany
- Research Centre Juelich, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Juelich, Germany
| | - Michael Schroeter
- Department of Neurology, Faculty of Medicine and University Hospital, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany.
- Research Centre Juelich, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Juelich, Germany.
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Abstract
Increased microvessel density in the peri-infarct region has been reported and has been correlated with longer survival times in ischemic stroke patients and has improved outcomes in ischemic animal models. This raises the possibility that enhancement of angiogenesis is one of the strategies to facilitate functional recovery after ischemic stroke. Blood vessels and neuronal cells communicate with each other using various mediators and contribute to the pathophysiology of cerebral ischemia as a unit. In this mini-review, we discuss how angiogenesis might couple with axonal outgrowth/neurogenesis and work for functional recovery after cerebral ischemia. Angiogenesis occurs within 4 to 7 days after cerebral ischemia in the border of the ischemic core and periphery. Post-ischemic angiogenesis may contribute to neuronal remodeling in at least two ways and is thought to contribute to functional recovery. First, new blood vessels that are formed after ischemia are thought to have a role in the guidance of sprouting axons by vascular endothelial growth factor and laminin/β1-integrin signaling. Second, blood vessels are thought to enhance neurogenesis in three stages: 1) Blood vessels enhance proliferation of neural stem/progenitor cells by expression of several extracellular signals, 2) microvessels support the migration of neural stem/progenitor cells toward the peri-infarct region by supplying oxygen, nutrients, and soluble factors as well as serving as a scaffold for migration, and 3) oxygenation induced by angiogenesis in the ischemic core is thought to facilitate the differentiation of migrated neural stem/progenitor cells into mature neurons. Thus, the regions of angiogenesis and surrounding tissue may be coupled, representing novel treatment targets.
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Affiliation(s)
- Masahiro Hatakeyama
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Itaru Ninomiya
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
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Wang C, Zhang L, Ndong JDLC, Hettinghouse A, Sun G, Chen C, Zhang C, Liu R, Liu CJ. Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice. J Neuroinflammation 2019; 16:238. [PMID: 31775776 PMCID: PMC6882111 DOI: 10.1186/s12974-019-1630-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/31/2019] [Indexed: 02/08/2023] Open
Abstract
PURPOSE Spinal cord injury (SCI) often results in significant and catastrophic dysfunction and disability and imposes a huge economic burden on society. This study aimed to determine whether progranulin (PGRN) plays a role in the progressive damage following SCI and evaluate the potential for development of a PGRN derivative as a new therapeutic target in SCI. METHODS PGRN-deficient (Gr-/-) and wild-type (WT) littermate mice were subjected to SCI using a weight-drop technique. Local PGRN expression following injury was evaluated by Western blotting and immunofluorescence. Basso Mouse Scale (BMS), inclined grid walking test, and inclined plane test were conducted at indicated time points to assess neurological recovery. Inflammation and apoptosis were examined by histology (Hematoxylin and Eosin (H&E) staining and Nissl staining, TUNEL assays, and immunofluorescence), Western blotting (from whole tissue protein for iNOS/p-p65/Bax/Bcl-2), and ex vivo ELISA (for TNFα/IL-1β/IL-6/IL-10). To identify the prophylactic and therapeutic potential of targeting PGRN, a PGRN derived small protein, Atsttrin, was conjugated to PLGA-PEG-PLGA thermosensitive hydrogel and injected into intrathecal space prior to SCI. BMS was recorded for neurological recovery and Western blotting was applied to detect the inflammatory and apoptotic proteins. RESULTS After SCI, PGRN was highly expressed in activated macrophage/microglia and peaked at day 7 post-injury. Grn-/- mice showed a delayed neurological recovery after SCI at day 21, 28, 35, and 42 post-injury relative to WT controls. Histology, TUNEL assay, immunofluorescence, Western blotting, and ELISA all indicated that Grn-/- mice manifested uncontrolled and expanded inflammation and apoptosis. Administration of control-released Atsttrin could improve the neurological recovery and the pro-inflammatory/pro-apoptotic effect of PGRN deficiency. CONCLUSION PGRN deficiency exacerbates SCI by promoting neuroinflammation and cellular apoptosis, which can be alleviated by Atsttrin. Collectively, our data provide novel evidence of using PGRN derivatives as a promising therapeutic approach to improve the functional recovery for patients with spinal cord injury.
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Affiliation(s)
- Chao Wang
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA.,Department of Spine Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Lu Zhang
- Department of Spine Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Jean De La Croix Ndong
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA
| | - Aubryanna Hettinghouse
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA
| | - Guodong Sun
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA
| | - Changhong Chen
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA
| | - Chen Zhang
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA
| | - Ronghan Liu
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY, 10003, USA. .,Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA.
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Hatakeyama M, Kanazawa M, Ninomiya I, Omae K, Kimura Y, Takahashi T, Onodera O, Fukushima M, Shimohata T. A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation. Sci Rep 2019; 9:16819. [PMID: 31728010 PMCID: PMC6856386 DOI: 10.1038/s41598-019-53418-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
Cell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.
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Affiliation(s)
- Masahiro Hatakeyama
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata, 951-8585, Japan
| | - Masato Kanazawa
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata, 951-8585, Japan.
| | - Itaru Ninomiya
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata, 951-8585, Japan
| | - Kaoru Omae
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, 2-2 Minatojima-Minamimachi, Kobe, 650-0047, Japan
| | - Yasuko Kimura
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, 2-2 Minatojima-Minamimachi, Kobe, 650-0047, Japan
| | - Tetsuya Takahashi
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata, 951-8585, Japan
| | - Osamu Onodera
- Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuoku, Niigata, 951-8585, Japan
| | - Masanori Fukushima
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, 2-2 Minatojima-Minamimachi, Kobe, 650-0047, Japan
| | - Takayoshi Shimohata
- Department of Neurology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
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Nikbakht F, Belali R, Rasoolijazi H, Mohammad Khanizadeh A. 2-Deoxyglucose protects hippocampal neurons against kainate-induced temporal lobe epilepsy by modulating monocyte-derived macrophages (mo-MΦ) and progranulin production in the hippocampus. Neuropeptides 2019; 76:101932. [PMID: 31227312 DOI: 10.1016/j.npep.2019.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/04/2023]
Abstract
Inflammation is an important factor in the pathology of epilepsy with the hallmarks of resident microglia activation and infiltration of circulating monocytes in the damaged area. In the case of recovery and tissue repair, some monocytes change to macrophages (mo-MΦ) to enhance tissue repair. 2-deoxyglucose (2DG) is an analog of glucose capable of protecting the brain, and progranulin is a neurotrophic factor produced mainly by microglia and has an inflammation modulator effect. This study attempted to evaluate if one of the neuroprotective mechanisms of 2-DG is comprised of increasing monocyte-derived macrophages (mo-MΦ) and progranulin production. Status epilepticus (SE) was induced by i.c.v. injection of kainic acid (KA).2DG (125/mg/kg/day) was administered intraperitoneally. Four days later, animals were sacrificed. Their brain sections were then stained with Cresyl violet and Fluoro-Jade B to count the number of necrotic and degenerating neurons in CA3 and Hilus of dentate gyrus of the hippocampus. Lastly, immunohistochemistry was used to detect CD11b + monocyte, macrophage cells, and Progranulin level was evaluated by Western blotting. The histological analysis showed that 2DG can reduce the number of necrotic and degenerating neurons in CA3 and Hilar areas. Following KA administration, a great number of cD11b+ cells with monocyte morphology were observed in the hippocampus. 2DG not only reduced cD11b+ monocyte cells but was able to convert them to cells with the morphology of macrophages (mo-MΦ). 2DG also caused a significant increase in progranulin level in the hippocampus. Because macrophages and microglia are the most important sources of progranulin, it appears that 2DG caused the derivation of monocytes to macrophages and these cells produced progranulin with a subsequent anti-inflammation effect. In summary, it was concluded that 2DG is neuroprotective and probably one of its neuroprotective mechanisms is by modulating monocyte-derived macrophages by progranulin production.
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Affiliation(s)
- Farnaz Nikbakht
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Rafie Belali
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Homa Rasoolijazi
- Department of Anatomy, Iran University of Medical Sciences, Tehran, Iran
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Mangin G, Poittevin M, Charriaut-Marlangue C, Giannesini C, Merkoulova-Rainon T, Kubis N. Glatiramer acetate reduces infarct volume in diabetic mice with cerebral ischemia and prevents long-term memory loss. Brain Behav Immun 2019; 80:315-327. [PMID: 30953775 DOI: 10.1016/j.bbi.2019.04.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 02/18/2019] [Accepted: 04/02/2019] [Indexed: 12/15/2022] Open
Abstract
Stroke is currently the second leading cause of death in industrialized countries and the second cause of dementia after Alzheimer's disease. Diabetes is an independent risk factor for stroke that exacerbates the severity of lesions, disability and cognitive decline. There is increasing evidence that sustained brain inflammation may account for this long-term prejudicial outcome in diabetic patients in particular. We sought to demonstrate that experimental permanent middle cerebral artery occlusion (pMCAo) in the diabetic mouse aggravates stroke, induces cognitive decline, and is associated with exacerbated brain inflammation, and that these effects can be alleviated and/or prevented by the immunomodulator, glatiramer acetate (GA). Male diabetic C57Bl6 mice (streptozotocin IP) subjected to permanent middle cerebral artery occlusion (pMCAo), were treated by the immunomodulator, GA (Copaxone®) (1 mg/kg daily, sc) until 3 or 7 days post stroke. Infarct volume, brain pro- and anti-inflammatory mediators, microglial/macrophage density, and neurogenesis were monitored during the first week post stroke. Neurological sensorimotor deficit, spatial memory and brain deposits of Aβ40 and Aβ42 were assessed until six weeks post stroke. In diabetic mice with pMCAo, proinflammatory mediators (IL-1β, MCP1, TNFα and CD68) were significantly higher than in non-diabetic mice. In GA-treated mice, the infarct volume was reduced by 30% at D3 and by 40% at D7 post stroke (P < 0.05), sensorimotor recovery was accelerated as early as D3, and long-term memory loss was prevented. Moreover, proinflammatory mediators significantly decreased between D3 (COX2) and D7 (CD32, TNFα, IL-1β), and neurogenesis was significantly increased at D7. Moreover, GA abrogates the accumulation of insoluble Aβ40. This work is the first one to evidence that the immunomodulatory drug GA reduces infarct volume and proinflammatory mediators, enhances early neurogenesis, accelerates sensorimotor recovery, and prevents long-term memory loss in diabetic mice with pMCAo.
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Affiliation(s)
- Gabrielle Mangin
- Université Paris Diderot, Sorbonne Paris Cité & CART, INSERM U965, F-75475 Paris, France
| | - Marine Poittevin
- Université Paris Diderot, Sorbonne Paris Cité & CART, INSERM U965, F-75475 Paris, France
| | | | - Claire Giannesini
- Service de Neurologie, AP-HP, Hôpital Saint Antoine, 75012 Paris, France
| | | | - Nathalie Kubis
- Université Paris Diderot, Sorbonne Paris Cité & CART, INSERM U965, F-75475 Paris, France; Service de Physiologie Clinique, AP-HP, Hôpital Lariboisière, 75475 Paris, France.
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Kanazawa M, Takahashi T, Ishikawa M, Onodera O, Shimohata T, Del Zoppo GJ. Angiogenesis in the ischemic core: A potential treatment target? J Cereb Blood Flow Metab 2019; 39:753-769. [PMID: 30841779 PMCID: PMC6501515 DOI: 10.1177/0271678x19834158] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.
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Affiliation(s)
- Masato Kanazawa
- 1 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Tetsuya Takahashi
- 1 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Masanori Ishikawa
- 1 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Osamu Onodera
- 1 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Takayoshi Shimohata
- 2 Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Gregory J Del Zoppo
- 3 Department of Medicine (Division of Hematology), University of Washington, Seattle, WA, USA.,4 Department of Neurology, University of Washington, Seattle, WA, USA
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The role of progranulin (PGRN) in the modulation of anti-inflammatory response in asthma. Cent Eur J Immunol 2019; 44:97-101. [PMID: 31114443 PMCID: PMC6526594 DOI: 10.5114/ceji.2019.83267] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 01/28/2019] [Indexed: 01/04/2023] Open
Abstract
Asthma is one of the most common chronic diseases. Epidemiological studies show that asthma will develop among around 40% of children under six years old with symptoms of bronchial obstruction. Diagnosis of asthma is complicated, especially in the paediatric population. As a result, a lot of research is being carried out to establish the pathophysiology and to find new biomarkers of this disease. Progranulin (PGRN) is a recently discovered growth factor with many biological functions. PGRN has anti-inflammatory properties because it inhibits neutrophil degranulation and blocks tumor necrosis factor α (TNF-α) transmission. The underlying mechanisms are still being researched, but TNF-α is considered to be a cytokine responsible for neutrophilic inflammation in the airways and bronchial hyperresponsiveness. Therefore, PGRN, by lowering TNF-α concentration and stimulating regulatory T-cell (Treg) proliferation, relieves symptoms of bronchial inflammatory diseases. This article attempts to verify the current knowledge about basic pathophysiological mechanisms in asthma. We also summarise the most recent research advances in the role of PGRN in the respiratory system.
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Can B, Oz S, Sahinturk V, Musmul A, Alatas İO. Effects of Conivaptan versus Mannitol on Post-Ischemic Brain Injury and Edema. Eurasian J Med 2019; 51:42-48. [PMID: 30911255 DOI: 10.5152/eurasianjmed.2019.18368] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Objective The aim of this study was to compare the effects of conivaptan, an arginine vasopressin antagonist, and mannitol, a sugar alcohol, on cerebral ischemia-induced brain injury and edema in rats. Materials and Methods Fifty-eight 8-week-old male Sprague Dawley rats were randomly divided into five groups: control, ischemia-reperfusion (I/R)+saline, I/R+mannitol, I/R+10 mg/ml conivaptan, and I/R+20 mg/ml conivaptan. Cerebral ischemia was induced by common carotid artery occlusion for 30 minutes. Saline, mannitol, or conivaptan were administered intravenously at the onset of reperfusion. Blood and brain tissue samples were taken at the 6th hour of reperfusion. The electrolytes (Na+-K+-Cl-), osmolality, arginine vasopressin, albumin, progranulin (PGRN), neuron-specific enolase (NSE), and myeloperoxidase activity were measured in rat serum samples. Brain frontal/hippocampal sections were stained with hematoxylin-eosin and TUNEL techniques to evaluate histopathological changes. Results Statistical analyses revealed that conivaptan caused significant changes in the electrolyte, NSE, and PGRN levels and osmolality when compared with mannitol. Conivaptan treatment showed positive effects on serum biochemistry and tissue histology. Conclusion Our findings revealed that conivaptan shows more diuretic activity than mannitol and triggers neither any damages nor edema in the brain tissue. This study may provide beneficial information for the development of treatment strategies for ischemia-related cerebrovascular diseases.
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Affiliation(s)
- Betul Can
- Department of Medical Biochemistry, Eskisehir Osmangazi University School of Medicine, Eskisehir, Turkey
| | - Semih Oz
- Department of Health Services, Eskisehir Osmangazi University Vocational School of Health Services, Eskisehir, Turkey
| | - Varol Sahinturk
- Department of Histology and Embryology, Eskisehir Osmangazi University School of Medicine, Eskisehir, Turkey
| | - Ahmet Musmul
- Department of Medical Services and Techniques, Eskisehir Osmangazi University Vocational School of Health Services, Eskisehir, Turkey
| | - İbrahim Ozkan Alatas
- Department of Medical Biochemistry, Eskisehir Osmangazi University School of Medicine, Eskisehir, Turkey
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Cui Y, Hettinghouse A, Liu CJ. Progranulin: A conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases. Cytokine Growth Factor Rev 2019; 45:53-64. [PMID: 30733059 DOI: 10.1016/j.cytogfr.2019.01.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 01/29/2019] [Indexed: 12/14/2022]
Abstract
Progranulin (PGRN), a widely expressed glycoprotein with pleiotropic function, has been linked to a host of physiological processes and diverse pathological states. A series of contemporary preclinical disease models and clinical trials have evaluated various therapeutic strategies targeting PGRN, highlighting PGRN as a promising therapeutic target. Herein we summarize available knowledge of PGRN targeting in various kinds of diseases, including common neurological diseases, inflammatory autoimmune diseases, cancer, tissue repair, and rare lysosomal storage diseases, with a focus on the functional domain-oriented drug development strategies. In particular, we emphasize the role of extracellular PGRN as a non-conventional, extracellular matrix bound, growth factor-like conductor orchestrating multiple membrane receptors and intracellular PGRN as a chaperone/co-chaperone that mediates the folding and traffic of its various binding partners.
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Affiliation(s)
- Yazhou Cui
- Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA; Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Jinan, 250062, China
| | - Aubryanna Hettinghouse
- Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA
| | - Chuan-Ju Liu
- Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA; Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA.
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