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Sadeghzadeh J, Roqanian S, Jafarzadeh J, Zangbar HS, Nakhjiri E, Kalan AE, Farhoudi M, Ahmadian S, Shahabi P, Shahpasand K. Anti-cis P-tau attenuates tauopathy and enhances cognitive function following global cerebral ischemia in mice. Int Immunopharmacol 2025; 158:114834. [PMID: 40378437 DOI: 10.1016/j.intimp.2025.114834] [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: 12/21/2024] [Revised: 04/14/2025] [Accepted: 05/07/2025] [Indexed: 05/18/2025]
Abstract
Global cerebral ischemia/reperfusion (GCI/R) induces widespread neuronal degeneration, accompanied by tauopathy in the hippocampus and profound cognitive impairment. Tau, a microtubule-associated protein highly expressed in neurons, becomes neurotoxic upon hyperphosphorylation, disrupting mitochondrial integrity and destabilizing microtubule architecture. Despite extensive efforts, no practical therapeutic approach has emerged to counter tau-related pathology. This study established a murine GCI/R model using three cycles of bilateral common carotid artery occlusion (5 min per cycle) with 5-min reperfusion intervals. The presence of cis P-tau and cognitive deficits in the hippocampus was confirmed following GCI/R. Treatment with a cis P-tau-targeted monoclonal antibody effectively prevented cognitive deterioration and attenuated ultrastructural brain damage. These findings demonstrate that GCI/R promotes pathogenic tau formation and contributes to cognitive dysfunction. Targeting cis P-tau may represent a viable therapeutic strategy to mitigate neurodegeneration and support cognitive recovery following global cerebral ischemic injury.
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Affiliation(s)
- Jafar Sadeghzadeh
- Department of Neuroscience and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shaqayeq Roqanian
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Jaber Jafarzadeh
- Department of Community Nutrition, Faculty of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Soltani Zangbar
- Department of Neuroscience and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elnaz Nakhjiri
- Department of Physiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Ebrahimi Kalan
- Department of Neuroscience and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Farhoudi
- Neurosciences Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahin Ahmadian
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Parviz Shahabi
- Department of Physiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Koorosh Shahpasand
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Peng J, He J, Lin L, Li Y, Xia Y. Neural Stem Cell Extracellular Vesicles Carrying YBX1 Inhibited Neuronal Pyroptosis Through Increasing m6A-modified GPR30 Stability and Expression in Ischemic Stroke. Transl Stroke Res 2025; 16:262-279. [PMID: 37966628 DOI: 10.1007/s12975-023-01210-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 10/12/2023] [Accepted: 10/26/2023] [Indexed: 11/16/2023]
Abstract
Neural stem cell-derived extracellular vesicles (NSC-derived EVs) alleviated ischemic stroke (IS) by suppressing the activation of nucleotide-binding domain leucine-rich repeats family protein 3 (NLRP3) inflammasome and neuronal pyroptosis. However, the specific mechanism needs further investigation. qRT-qPCR, Western blotting, and immunofluorescence detected related gene expression. Immunofluorescent analyzed the expression of Ki-67, βIII-Tubulin (Tuj1), and GFAP. Lactate dehydrogenase (LDH) release and IL-1β and IL-18 levels were analyzed by LDH and ELISA kits. TTC staining evaluated the infarction of brain tissues. Flow cytometric analysis measured caspase-1 activity. M6A methylated RNA immunoprecipitation PCR (MeRIP-PCR) measured methylation levels of G protein-coupled receptor 30 (GPR30). RIP and Co-IP analyzed the interactions of Y box binding protein (YBX1)/GPR30, YBX1/IGF2BP1 and NLRP3/speckle-type POZ protein (SPOP), as well as the ubiquitination levels of NLRP3. NSC-derived EVs inhibited the ischemia-reperfusion (I/R) injury of rats and the neuronal pyroptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Knockdown of EVs carrying YBX1 or GPR30 silencing abolished these inhibiting effects. GPR30 mRNA and IGF2BP1 protein were enriched by YBX1 antibody. YBX1 enhanced the stability of m6A-modified GPR30 by interacting with IGF2BP1 and thus promoting GPR30 expression. Knockdown of IGF2BP1 suppressed the binding between YBX1 and GPR30 mRNA. GPR30 promoted NLRP3 ubiquitination by interacting with SPOP. EVs carrying YBX1 could reduce the infarction of brain tissues and inhibit neuronal pyroptosis in rats with I/R injury. NSC-derived EVs carrying YBX1 increased the stability of m6A-modified GPR30 by interacting with IGF2BP1; the upregulation of GPR30 inhibited the activation of NLRP3 inflammasome through promoting NLRP3 ubiquitination by SPOP, ultimately suppressing the neuronal pyroptosis in IS.
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Affiliation(s)
- Jun Peng
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Hainan Province, Haikou, 570208, People's Republic of China
| | - Jun He
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Hainan Province, Haikou, 570208, People's Republic of China
| | - Long Lin
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Hainan Province, Haikou, 570208, People's Republic of China
| | - You Li
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Hainan Province, Haikou, 570208, People's Republic of China
| | - Ying Xia
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Hainan Province, Haikou, 570208, People's Republic of China.
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Peng J, He J, Hu X, Xia Y. GPR30 Inhibits Neuronal Apoptosis After Subarachnoid Hemorrhage by Activating the Wnt/β-Catenin Pathway in a m6A-dependent Manner. Mol Neurobiol 2025:10.1007/s12035-025-04867-9. [PMID: 40131697 DOI: 10.1007/s12035-025-04867-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 03/18/2025] [Indexed: 03/27/2025]
Abstract
Neuronal apoptosis is associated with early brain injury after subarachnoid hemorrhage (SAH). In this study, the regulatory effects of GPR30 on neuronal apoptosis after SAH, METTL14 expression, and the Wnt/β-catenin pathway were investigated. SAH models were constructed in vitro in neurons and in vivo in rats. We found that the GPR30 protein was downregulated in OxyHB-stimulated neurons and SAH rat brain tissue. The GPR30 agonist G1 decreased iNOS levels and apoptosis in OxyHB-stimulated neurons. G1 increased m6A levels in OxyHB-stimulated neurons, increased the expression of METTL14 and Bcl-2, and reduced Caspase-3 and Bax levels. The GPR30 inhibitor G15 had the opposite effect as G1. METTL14 overexpression increased m6A levels in OxyHB-stimulated neurons; increased the expression of METTL14, Wnt1, β-catenin, and Bcl-2; decreased Caspase-3 and Bax levels; and inhibited apoptosis. The Wnt inhibitor IWR-1 abrogated the effects of METTL14 overexpression in OxyHB-stimulated neurons. In vivo, the results revealed that G1 decreased the mNSS, cerebral edema score, and caspase-3, IL-6, IL-1β, Bax, and p-β-catenin expression; inhibited apoptosis and nitric oxide production; and increased GPR30, IFN-γ, TGF-β1, METTL14, Wnt1, and β-catenin expression. G15 had the opposite effect of G1. METTL14 knockdown abrogated the effects of G1 in SAH model rats. Our results suggest that GPR30 inhibits neuronal apoptosis after SAH via Wnt/β-catenin pathway regulation and METTL14-mediated m6A modification, providing a new therapeutic target for SAH.
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Affiliation(s)
- Jun Peng
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, No.43, Renmin Avenue, Meilan District, Haikou, 570000, China
| | - Jun He
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, No.43, Renmin Avenue, Meilan District, Haikou, 570000, China
| | - Xiqi Hu
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, No.43, Renmin Avenue, Meilan District, Haikou, 570000, China
| | - Ying Xia
- Department of Neurosurgery, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, No.43, Renmin Avenue, Meilan District, Haikou, 570000, China.
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Liu P, Xu J, Chen Y, Xu Q, Zhang W, Hu B, Li A, Zhu Q. Electrophysiological Signatures in Global Cerebral Ischemia: Neuroprotection Via Chemogenetic Inhibition of CA1 Pyramidal Neurons in Rats. J Am Heart Assoc 2024; 13:e036146. [PMID: 39673154 PMCID: PMC11935537 DOI: 10.1161/jaha.124.036146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/19/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND Although there has been limited research into the perturbation of electrophysiological activity in the brain after ischemia, the activity signatures during ischemia and reperfusion remain to be fully elucidated. We aim to comprehensively describe these electrophysiological signatures and interrogate their correlation with ischemic damage during global cerebral ischemia and reperfusion. METHODS AND RESULTS We used the 4-vessel occlusion method of inducing global cerebral ischemia in rats. We used in vivo electrophysiological techniques to simultaneously record single units, scalp electroencephalogram, and local field potentials in awake animals. Neuronal damage and astrocyte reactivation were examined by immunofluorescence, immunoblotting, and quantitative real-time reverse-transcription polymerase chain reaction under chemogenetic inhibition of glutamatergic neurons. Electroencephalogram/local field potentials power and phase-amplitude coupling of the theta and low-gamma bands were reduced during ischemia and the acute phase of reperfusion. The firing rate of single units was enhanced by ischemia-reperfusion, and the phase relationship between the local field potentials theta band and neuronal firing was altered. Precise inhibition of hippocampus CA1 pyramidal neuron hyperactivity by chemogenetics rescued the firing dysfunction, ischemic neuronal damage, and A1 astrocyte activation. CONCLUSIONS Our results provide a comprehensive description of the characteristics of electrophysiological activity that accompany ischemia-reperfusion and highlight the significance of this activity in ischemic damage.
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Affiliation(s)
- Penglai Liu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Jiang Xu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Yilan Chen
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Qi Xu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Wei Zhang
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Bin Hu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Anan Li
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
| | - Qiuju Zhu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouChina
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5
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Han K, Choi G, Kim TJ. Fluorescence-based techniques for investigating estrogen receptor dynamics. BMB Rep 2024; 57:472-483. [PMID: 39219049 PMCID: PMC11608856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/03/2024] [Accepted: 07/17/2024] [Indexed: 09/04/2024] Open
Abstract
Understanding estrogen receptor (ER) signaling pathways is crucial for uncovering the mechanisms behind estrogen-related diseases, such as breast cancer, and addressing the effects of environmental estrogenic disruptors. Traditionally, ER signaling involves genomic events, including ligand binding, receptor dimerization, and transcriptional modulation within cellular nuclei. However, recent research have revealed ERs also participate in non-genomic signaling pathways, adding complexity to their functions. Researchers use advanced fluorescence-based techniques, leveraging fluorescent probes (FPb) to study ER dynamics in living cells, such as spatial distribution, expression kinetics, and functional activities. This review systematically examines the application of fluorescent probes in ER signaling research, covering the visualization of ER, ligandreceptor interactions, receptor dimerization, estrogen response elements (EREs)-mediated transcriptional activation, and G-proteincoupled estrogen receptor (GPER) signaling. Our aim is to provide researchers with valuable insights for employing FPb in their explorations of ER signaling. [BMB Reports 2024; 57(11): 472-483].
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Affiliation(s)
- Kiseok Han
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea
| | - Gyuho Choi
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea
| | - Tae-Jin Kim
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea
- Department of Biological Sciences, Pusan National University, Busan 46241, Korea
- Institute of Systems Biology, Pusan National University, Busan 46241, Korea
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Wang L, Gao F, Chen L, Sun W, Liu H, Yang W, Zhang X, Bai J, Wang R. Remote Ischemia Postconditioning Mitigates Hippocampal Neuron Impairment by Modulating Cav1.2-CaMKIIα-Aromatase Signaling After Global Cerebral Ischemia in Ovariectomized Rats. Mol Neurobiol 2024; 61:6511-6527. [PMID: 38321351 PMCID: PMC11339123 DOI: 10.1007/s12035-024-03930-1] [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: 10/11/2023] [Accepted: 01/05/2024] [Indexed: 02/08/2024]
Abstract
Brain-derived estrogen (BDE2) is gaining attention as an endogenous neurotransmitter. Recent research has revealed that selectively removing the aromatase gene, the pivotal enzyme responsible for BDE2 synthesis, in forebrain neurons or astrocytes can lead to synaptic loss and cognitive impairment. It is worth noting that remote ischemia post-conditioning (RIP), a non-invasive technique, has been shown to activate natural protective mechanisms against severe ischemic events. The aim of our study was to investigate whether RIP triggers aromatase-BDE2 signaling, shedding light on its neuroprotective mechanisms after global cerebral ischemia (GCI) in ovariectomized rats. Our findings are as follows: (1) RIP was effective in mitigating ischemic damage in hippocampal CA1 neurons and improved cognitive function after GCI. This was partially due to increased Aro-BDE2 signaling in CA1 neurons. (2) RIP intervention efficiently enhanced pro-survival kinase pathways, such as AKT, ERK1/2, CREB, and suppressed CaMKIIα signaling in CA1 astrocytes induced by GCI. Remarkably, inhibiting CaMKIIα activity led to elevated Aro-BDE2 levels and replicated the benefits of RIP. (3) We also identified the positive mediation of Cav1.2, an LVGCC calcium channel, on CaMKIIα-Aro/BDE2 pathway response to RIP intervention. (4) Significantly, either RIP or CaMKIIα inhibition was found to alleviate reactive astrogliosis, which was accompanied by increased pro-survival A2-astrocyte protein S100A10 and decreased pro-death A1-astrocyte marker C3 levels. In summary, our study provides compelling evidence that Aro-BDE2 signaling is a critical target for the reparative effects of RIP following ischemic insult. This effect may be mediated through the CaV1.2-CaMKIIα signaling pathway, in collaboration with astrocyte-neuron interactions, thereby maintaining calcium homeostasis in the neuronal microenvironment and reducing neuronal damage after ischemia.
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Affiliation(s)
- Lu Wang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Fujia Gao
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Lingling Chen
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Wuxiang Sun
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Huiyu Liu
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Wei Yang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Xin Zhang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Jing Bai
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China
| | - Ruimin Wang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, 063210, Hebei, China.
- Dementia and Dyscognitive Key Lab., North China University of Science and Technology, International Science & Technology Cooperation Base of Geriatric Medicine of China, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China.
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, Hebei, China.
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Poitras M, Doiron A, Plamondon H. Selective estrogen receptor activation prior to global cerebral ischemia in female rats impacts microglial activation and anxiety-like behaviors without effects on CA1 neuronal injury. Behav Brain Res 2024; 470:115094. [PMID: 38844057 DOI: 10.1016/j.bbr.2024.115094] [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: 04/16/2024] [Revised: 06/03/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024]
Abstract
Estrogen receptor (ER) activation by 17-ß estradiol (E2) can attenuate neuronal injury and behavioral impairments following global cerebral ischemia (GCI) in rodents. This study sought to further examine the discrete roles of ERs through characterization of the effects of selective ER activation on post-ischemic pro-inflammatory microglial activation, hippocampal neuronal injury, and anxiety-like behaviors. Forty-six ovariectomized (OVX) adult female Wistar rats received daily s.c injections (100 μg/kg/day) of propylpyrazole triol (PPT; ERα agonist), diarylpropionitrile (DPN; ERβ agonist), G-1 (G-protein coupled ER agonist; GPER), E2 (activating all receptors), or vehicle solution (VEH) for 21 days. After final injection, rats underwent GCI via 4-vessel occlusion (n=8 per group) or sham surgery (n=6, vehicle injections). The Open Field Test (OFT), Elevated Plus Maze (EPM), and Hole Board Test (HBT) assessed anxiety-like behaviors. Microglial activation (Iba1, CD68, CD86) in the basolateral amygdala (BLA), CA1 of the hippocampus, and paraventricular nucleus of the hypothalamus (PVN) was determined 8 days post-ischemia. Compared to sham rats, Iba1 activation and CA1 neuronal injury were increased in all ischemic groups except DPN-treated rats, with PPT-treated ischemic rats also showing increased PVN Iba1-ir expression. Behaviorally, VEH ischemic rats showed slightly elevated anxiety in the EPM compared to sham counterparts, with no significant effects of agonists. While no changes were observed in the OFT, emotion regulation via grooming in the HBT was increased in G-1 rats compared to E2 rats. Our findings support selective ER activation to regulate post-ischemic microglial activation and coping strategies in the HBT, despite minimal impact on hippocampal injury.
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Affiliation(s)
- Marilou Poitras
- Cerebro Vascular Accidents and Behavioral Recovery Laboratory, School of Psychology, University of Ottawa, Ottawa, Canada
| | - Alexandra Doiron
- Cerebro Vascular Accidents and Behavioral Recovery Laboratory, School of Psychology, University of Ottawa, Ottawa, Canada
| | - Hélène Plamondon
- Cerebro Vascular Accidents and Behavioral Recovery Laboratory, School of Psychology, University of Ottawa, Ottawa, Canada.
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Zhang Y, Tan X, Tang C. Estrogen-immuno-neuromodulation disorders in menopausal depression. J Neuroinflammation 2024; 21:159. [PMID: 38898454 PMCID: PMC11188190 DOI: 10.1186/s12974-024-03152-1] [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: 04/20/2024] [Accepted: 06/11/2024] [Indexed: 06/21/2024] Open
Abstract
A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression.
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Affiliation(s)
- Yuling Zhang
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan, China
| | - Xiying Tan
- Department of Neurology, Xinxiang City First People's Hospital, Xinxiang, 453000, Henan, China
| | - Chaozhi Tang
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan, China.
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9
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Zheng H, Triplett KD, Prossnitz ER, Hall PR, Daly SM. G protein-coupled estrogen receptor agonist G-1 decreases ADAM10 levels and NLRP3-inflammasome component activation in response to Staphylococcus aureus alpha-hemolysin. Microbiologyopen 2024; 13:e23. [PMID: 38867416 PMCID: PMC11168966 DOI: 10.1002/mbo3.1423] [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: 01/08/2024] [Revised: 05/20/2024] [Accepted: 05/30/2024] [Indexed: 06/14/2024] Open
Abstract
The G protein-coupled estrogen receptor, also known as GPER1 or originally GPR30, is found in various tissues, indicating its diverse functions. It is typically present in immune cells, suggesting its role in regulating immune responses to infectious diseases. Our previous studies have shown that G-1, a selective GPER agonist, can limit the pathogenesis mediated by Staphylococcus aureus alpha-hemolysin (Hla). It aids in clearing bacteria in a mouse skin infection model and restricts the surface display of the Hla receptor, ADAM10 (a disintegrin and metalloprotease 10) in HaCaT keratinocytes. In this report, we delve into the modulation of GPER in human immune cells in relation to the NLRP3 inflammasome. We used macrophage-like differentiated THP-1 cells for our study. We found that treating these cells with G-1 reduces ATP release, decreases the activity of the caspase-1 enzyme, and lessens cell death following Hla intoxication. This is likely due to the reduced levels of ADAM10 and NLRP3 proteins, as well as the decreased display of the ADAM10 receptor in the G-1-treated THP-1 cells. Our studies, along with our previous work, suggest the potential therapeutic use of G-1 in reducing Hla susceptibility in humans. This highlights the importance of GPER in immune regulation and its potential as a therapeutic target.
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Affiliation(s)
- Huayu Zheng
- Department of Pharmaceutical SciencesUniversity of New Mexico Health Sciences Center, College of PharmacyAlbuquerqueNew MexicoUSA
| | - Kathleen D. Triplett
- Department of Pharmaceutical SciencesUniversity of New Mexico Health Sciences Center, College of PharmacyAlbuquerqueNew MexicoUSA
| | - Eric R. Prossnitz
- Department of Internal Medicine, School of Medicine, Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism and University of New Mexico Comprehensive Cancer CenterUniversity of New Mexico Health Sciences CenterAlbuquerqueNew MexicoUSA
| | - Pamela R. Hall
- Department of Pharmaceutical SciencesUniversity of New Mexico Health Sciences Center, College of PharmacyAlbuquerqueNew MexicoUSA
| | - Seth M. Daly
- Department of Pharmaceutical SciencesUniversity of New Mexico Health Sciences Center, College of PharmacyAlbuquerqueNew MexicoUSA
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Machado GDB, Schnitzler AL, Fleischer AW, Beamish SB, Frick KM. G protein-coupled estrogen receptor (GPER) in the dorsal hippocampus regulates memory consolidation in gonadectomized male mice, likely via different signaling mechanisms than in female mice. Horm Behav 2024; 161:105516. [PMID: 38428223 PMCID: PMC11065565 DOI: 10.1016/j.yhbeh.2024.105516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 02/12/2024] [Accepted: 02/20/2024] [Indexed: 03/03/2024]
Abstract
Studies in ovariectomized (OVX) female rodents suggest that G protein-coupled estrogen receptor (GPER) is a key regulator of memory, yet little is known about its importance to memory in males or the cellular mechanisms underlying its mnemonic effects in either sex. In OVX mice, bilateral infusion of the GPER agonist G-1 into the dorsal hippocampus (DH) enhances object recognition and spatial memory consolidation in a manner dependent on rapid activation of c-Jun N-terminal kinase (JNK) signaling, cofilin phosphorylation, and actin polymerization in the DH. However, the effects of GPER on memory consolidation and DH cell signaling in males are unknown. Thus, the present study first assessed effects of DH infusion of G-1 or the GPER antagonist G-15 on object recognition and spatial memory consolidation in gonadectomized (GDX) male mice. As in OVX mice, immediate post-training bilateral DH infusion of G-1 enhanced, whereas G-15 impaired, memory consolidation in the object recognition and object placement tasks. However, G-1 did not increase levels of phosphorylated JNK (p46, p54) or cofilin in the DH 5, 15, or 30 min after infusion, nor did it affect phosphorylation of ERK (p42, p44), PI3K, or Akt. Levels of phospho-cAMP-responsive element binding protein (CREB) were elevated in the DH 30 min following G-1 infusion, indicating that GPER in males activates a yet unknown signaling mechanism that triggers CREB-mediated gene transcription. Our findings show for the first time that GPER in the DH regulates memory consolidation in males and suggests sex differences in underlying signaling mechanisms.
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Affiliation(s)
- Gustavo D B Machado
- University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI 53211, United States of America
| | - Alexis L Schnitzler
- University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI 53211, United States of America
| | - Aaron W Fleischer
- University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI 53211, United States of America
| | - Sarah B Beamish
- University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI 53211, United States of America
| | - Karyn M Frick
- University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI 53211, United States of America.
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Gu Y, Hu ZF, Zheng DW, Yang YQ, Dong XL, Chen WF. Baohuoside I suppresses the NLRP3 inflammasome activation via targeting GPER to fight against Parkinson's disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155435. [PMID: 38394727 DOI: 10.1016/j.phymed.2024.155435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/16/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Accumulating evidence indicates the crucial role of microglia-mediated inflammation and the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in the pathogenesis of Parkinson's disease (PD). Baohuoside I, a natural flavonoid extracted from Herba Epimedii, has been shown to possess anti-inflammatory effects, but its potential neuroprotective effects and mechanism against PD have not been documented. STUDY DESIGN AND METHODS The anti-inflammatory effects of Baohuoside I were evaluated by LPS-induced BV2 cells or primary microglia isolated from wide type or G protein-coupled estrogen receptor (GPER) gene knockout mice. The underlying mechanism related to GPER-mediated NLRP3 inflammasome inhibition was further explored using LPS-induced GPER+/+ or GPER-/- mouse models of PD. The neuroprotective effects of Baohuoside I were detected through western blot analysis, real-time PCR, molecular docking, mouse behavioral tests, immunofluorescence, and immunohistochemistry. RESULTS Baohuoside I significantly alleviated LPS-induced neuroinflammation by inhibiting the activation of NF-κB signal and the increase of pyroptosis levels as evidenced by the downregulated expression of pyroptosis-related proteins (NLRP3, ASC, pro-Caspase-1, IL-1β) in microglia cells. Intragastric administration of Baohuoside I protected against LPS-induced motor dysfunction and loss of dopaminergic neurons, reduced pro-inflammatory cytokines expressions, and inhibited microglial (Iba-1) and astrocyte (GFAP) activation in the nigrostriatal pathway in LPS-induced mouse model of PD. Pretreatment with GPER antagonist G15 in microglia cells or GPER gene deletion in mice significantly blocked the inhibitory effects of Baohuoside I on LPS-induced neuroinflammation and activation of the NLRP3/ASC/Caspase-1 pathway. Molecular docking further indicated that Baohuoside I might bind to GPER directly with a binding energy of -10.4 kcal/mol. CONCLUSION Baohuoside I provides neuroprotective effects against PD by inhibiting the activation of the NF-κB signal and NLRP3/ASC/Caspase-1 pathway. The molecular target for its anti-inflammatory effects is proved to be GPER in the PD mouse model. Baohuoside I may be a valuable anti-neuroinflammatory agent and a drug with well-defined target for the treatment of PD.
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Affiliation(s)
- Yu Gu
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Zi-Fan Hu
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Dan-Wen Zheng
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Yan-Qing Yang
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiao-Li Dong
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, China; Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China
| | - Wen-Fang Chen
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
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12
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Tan XX, Dai HY, Yao J, Wang JJ, Dai YC, Zhang TH, Qiu LL, Sun J. Hippocampal estrogens rescued the decline of synaptic plasticity after surgery and anesthesia by inhibiting microglia overactivation. Behav Brain Res 2024; 459:114794. [PMID: 38056710 DOI: 10.1016/j.bbr.2023.114794] [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: 07/22/2023] [Revised: 10/30/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Elderly patients experience postoperative cognitive impairment frequently; therefore, effective interventions are urgently needed. Central nervous inflammation characterized by microglia may promote the progression of POCD by reducing synaptic plasticity. Notably, clinical studies revealed that the incidence of female patients was significantly lower than that of male patients. Besides, the brain estrogens have an anti-inflammatory effect and regulate the microglia at the same times. This study aimed to determine whether suppressing microglia overactivation by hippocampal estrogens can rescue the decrease of synaptic plasticity after surgery and anesthesia. METHODS Exploratory laparotomy was used to establish the POCD model in 15-month-old male or female C57BL/6 J mice and animal behavioral tests were performed to test hippocampal-dependent memory capacity. Western blot and immunofluorescence were used to detect the microglial activation and plasticity related protein expressions. Elisa was used to detect the content of estrogens in the hippocampus. Estrogens and estrogen receptor inhibitor were used to replenish the estrogens in the brain and inhibit the effect of estrogens. RESULTS Surgery and anesthesia did not cause POCD in female mice (P > 0.05), while the cognitive function decreased significantly after estrogen receptor inhibitor was given(P < 0.05). Male mice experienced cognitive dysfunction after surgery and anesthesia, and their cognitive function improved after estrogens supplementation (P < 0.05). Given estrogens and estrogen receptor inhibitors at the same time, the cognitive function of male mice could not be saved (P < 0.05). By correlation analysis, there was a negative correlation between the content of hippocampal estrogens and microglia (P < 0.05). The number or degree of activation of microglia affected the synaptic plasticity, which ultimately regulated the cognitive function of mice. CONCLUSION Hippocampal estrogens rescued the decline of synaptic plasticity after surgery and anesthesia by inhibiting microglia overactivation.
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Affiliation(s)
- Xiao-Xiang Tan
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Hong-Yu Dai
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Juan Yao
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Jia-Jia Wang
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Yu-Chen Dai
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Tian-Hao Zhang
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China
| | - Li-Li Qiu
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China.
| | - Jie Sun
- Department of Anesthesiology, Surgery and Pain Management, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu Province, China.
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Sun Q, Li G, Zhao F, Dong M, Xie W, Liu Q, Yang W, Cui R. Role of estrogen in treatment of female depression. Aging (Albany NY) 2024; 16:3021-3042. [PMID: 38309292 PMCID: PMC10911346 DOI: 10.18632/aging.205507] [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: 07/18/2023] [Accepted: 11/28/2023] [Indexed: 02/05/2024]
Abstract
Depression is a neurological disorder that profoundly affects human physical and mental health, resulting in various changes in the central nervous system. Despite several prominent hypotheses, such as the monoaminergic theory, hypothalamic-pituitary-adrenal (HPA) axis theory, neuroinflammation, and neuroplasticity, the current understanding of depression's pathogenesis remains incomplete. Importantly, depression is a gender-dimorphic disorder, with women exhibiting higher incidence rates than men. Given estrogen's pivotal role in the menstrual cycle, it is reasonable to postulate that its fluctuating levels could contribute to the pathogenesis of depression. Estrogen acts by binding to a diversity of receptors, which are widely distributed in the central nervous system. An abundance of research has established that estrogen and its receptors play a crucial role in depression, spanning pathogenesis and treatment. In this comprehensive review, we provide an in-depth analysis of the fundamental role of estrogen and its receptors in depression, with a focus on neuroinflammation, neuroendocrinology, and neuroplasticity. Furthermore, we discuss potential mechanisms underlying the therapeutic effects of estrogen in the treatment of depression, which may pave the way for new antidepressant drug development and alternative treatment options.
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Affiliation(s)
- Qihan Sun
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Guangquan Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Fangyi Zhao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Mengmeng Dong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Wei Xie
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Qianqian Liu
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Wei Yang
- Department of Neurology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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14
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Ma Y, Sun W, Bai J, Gao F, Ma H, Liu H, Hu J, Xu C, Zhang X, Liu Z, Yuan T, Sun C, Huang Y, Wang R. Targeting blood brain barrier-Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats. CNS Neurosci Ther 2024; 30:e14613. [PMID: 38379185 PMCID: PMC10879645 DOI: 10.1111/cns.14613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 11/16/2023] [Accepted: 11/26/2023] [Indexed: 02/22/2024] Open
Abstract
AIMS Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. METHODS Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RESULTS RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well. CONCLUSION Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.
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Affiliation(s)
- Yuxuan Ma
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Wuxiang Sun
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
| | - Jing Bai
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
| | - Fujia Gao
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Haoran Ma
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Huiyu Liu
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Jiewei Hu
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
| | - Chao Xu
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Xin Zhang
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Zixuan Liu
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
| | - Tao Yuan
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
| | - Chenxu Sun
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
| | - Yuanyuan Huang
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
| | - Ruimin Wang
- International Science & Technology Cooperation Base of GeriatricSchool of Public Health of North China University of Science and TechnologyTangshanHebeiChina
- School of Basic Medical ScienceNorth China University of Science and TechnologyTangshanHebeiChina
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15
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Ping D, Qi J, Li M, Sun X, Peng Y, Liu C. Fuzheng Huayu recipe alleviates liver fibrosis via inhibiting NLRP3 inflammasome activation in macrophages. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117001. [PMID: 37544346 DOI: 10.1016/j.jep.2023.117001] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 07/26/2023] [Accepted: 08/02/2023] [Indexed: 08/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fuzheng Huayu recipe (FZHY) is a commonly used Traditional Chinese Medicine formula for treating liver fibrosis in clinical settings. Despite its widespread use, the specific curative effects and underlying pharmacological mechanisms of FZHY in treating liver fibrosis are not yet fully understood. AIM AND STUDY This study aims to investigate the antifibrotic mechanism of FZHY treatment by exploring its effects on the activation of NOD-like receptor protein 3 (NLRP3) inflammasome in macrophages. MATERIALS AND METHODS In order to investigate the impact of FZHY on the activation and priming of NLRP3 inflammasome in clinical trials and animal experiments using immunohistochemistry and Western blotting. Twenty-four C57BL/6 mice were used to induce liver fibrosis by feeding a diet that contained 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). To study inflammasome function, Lipopolysaccharide (LPS)/adenine triphosphate (ATP) induced NLRP3 inflammasome activation was induced in bone marrow-derived macrophages (BMDMs) isolated from wild mice. The effects of macrophage NLRP3 inflammasome activation on the function of hepatic stellate cells (HSCs) were explored by treating primary HSCs with preconditioned media from BMDMs culture. RESULTS FZHY treatment resulted in the downregulation of NLRP3 protein expression and inhibition of its priming and activation in both human fibrotic livers and DDC-induced liver fibrosis. Furthermore, FZHY was observed to block the activation of the NLRP3 inflammasome pathway, which can lead to excessive inflammatory cytokine release in supernatants and cell lysates in response to LPS and ATP. Lastly, treatment with FZHY was able to inhibit the activation of HSCs induced by supernatants from macrophages. CONCLUSIONS FZHY has been shown to potentially prevent NLRP3 inflammasome activation in macrophages which can result in the suppression of HSCs activation. Ultimately, these effects may lead to the improvement of liver fibrosis. The ability of FZHY to act on this novel mechanism represents an important aspect of its therapeutic potential for liver fibrosis.
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Affiliation(s)
- Dabing Ping
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jingshu Qi
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Meng Li
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xin Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yuan Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, 201203, China.
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16
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OKAMOTO M, MIURA A, ITO R, KAMADA T, MIZUKAMI Y, KAWAMOTO K. G-protein-coupled estrogen receptor prevents nuclear factor-kappa B promoter activation by Helicobacter pylori cytotoxin-associated gene A in gastric cancer cells. J Vet Med Sci 2023; 85:1348-1354. [PMID: 37952974 PMCID: PMC10788165 DOI: 10.1292/jvms.23-0054] [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: 01/30/2023] [Accepted: 10/20/2023] [Indexed: 11/14/2023] Open
Abstract
Helicobacter pylori is a well-known pathogen that causes chronic gastritis, leading to the development of gastric cancer. This bacterium has also been detected in dogs, and symptoms similar to those in humans have been reported. The cytotoxin-associated gene A (CagA) is involved in pathogenesis through aberrant activation of host signal transduction, including the nuclear factor-kappa B (NF-κB) pathway. We have previously shown the anti-inflammatory effect of the G-protein-coupled estrogen receptor (GPER) via inhibiting of NF-κB activation in several cells. Therefore, here, we investigated the effect of GPER on CagA-mediated NF-κB promoter activity and showed that CagA overexpression in gastric cancer cells activated the NF-κB reporter and induced interleukin 8 (il-8) expression, both of which were inhibited by the GPER agonist.
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Affiliation(s)
- Mariko OKAMOTO
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Atsushi MIURA
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Ryota ITO
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Toshiki KAMADA
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
| | - Yoichi MIZUKAMI
- Institute of Gene Research, Yamaguchi University Science
Research Center, Yamaguchi, Japan
| | - Keiko KAWAMOTO
- Laboratory of Immunology and Infection Control, Department
of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Kanagawa,
Japan
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17
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Dong W, Peng Q, Liu Z, Xie Z, Guo X, Li Y, Chen C. Estrogen plays an important role by influencing the NLRP3 inflammasome. Biomed Pharmacother 2023; 167:115554. [PMID: 37738797 DOI: 10.1016/j.biopha.2023.115554] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/16/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023] Open
Abstract
The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important part of the natural immune system that plays an important role in many diseases. Estrogen is a sex hormone that plays an important role in controlling reproduction and regulates many physiological and pathological processes. Recent studies have indicated that estrogen is associated with disease progression. Estrogen can ameliorate some diseases (e. g, sepsis, mood disturbances, cerebral ischemia, some hepatopathy, Parkinson's disease, amyotrophic lateral sclerosis, inflammatory bowel disease, spinal cord injury, multiple sclerosis, myocardial ischemia/reperfusion injury, osteoarthritis, and renal fibrosis) by inhibiting the NLRP3 inflammasome. Estrogen can also promote the development of diseases (e.g., ovarian endometriosis, dry eye disease, and systemic lupus erythematosus) by upregulating the NLRP3 inflammasome. In addition, estrogen has a dual effect on the development of cancers and asthma. However, the mechanism of these effects is not summarized. This article reviewed the progress in understanding the effects of estrogen on the NLRP3 inflammasome and its mechanisms in recent years to provide a theoretical basis for an in-depth study.
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Affiliation(s)
- Wanglin Dong
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Qianwen Peng
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Zhuoxin Liu
- Clinical College of Medicine, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Zhenxing Xie
- School of Basic Medical Science, Henan University, Jinming Avenue, Kaifeng, Henan 475004, China.
| | - Xiajun Guo
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Yuanyuan Li
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Chaoran Chen
- Institute of Nursing and Health, College of Nursing and Health, Henan University, Kaifeng, Henan, China.
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Hu J, Huang Y, Gao F, Sun W, Liu H, Ma H, Yuan T, Liu Z, Tang L, Ma Y, Zhang X, Bai J, Wang R. Brain-derived estrogen: a critical player in maintaining cognitive health of aged female rats, possibly involving GPR30. Neurobiol Aging 2023; 129:15-27. [PMID: 37257405 DOI: 10.1016/j.neurobiolaging.2023.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 04/11/2023] [Accepted: 04/17/2023] [Indexed: 06/02/2023]
Abstract
Brain-derived estrogen is an endogenous neuroprotective agent, whether and how might this protective function with aging, especially postmenopausal drops in circulating estrogen, remain unclear. We herein subjected 6, 14, and 18 Mon female rats to mimic natural aging, and found that estrogen synthesis is more active in the healthy aged brain, as evidenced by the highest levels of mRNA and protein expression of aromatase, the key enzyme of E2 biosynthesis, among the three groups. Aromatase knockout in forebrain neurons (FBN-Aro-/-) impaired hippocampal and cortical neurons, and cognitive function in 18 Mon rats, compared to wild-type controls. Furthermore, estrogen nuclear receptors (ERα/β) displayed opposite changes, with a significant ERα decrease and ERβ increase, while membrane receptor GPR30 expressed stably in hippocampus during aging. Intriguingly, GPR30, but not ERα and ERβ, was decreased by FBN-Aro-/-. The results indicate that GPR30 is more sensitive to brain local E2 synthesis. Our findings provide evidence of a critical role for brain-derived estrogen in maintaining healthy brain function in older individuals, possibly involving GPR30.
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Affiliation(s)
- Jiewei Hu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Yuanyuan Huang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Fujia Gao
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Wuxiang Sun
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Huiyu Liu
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Haoran Ma
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Tao Yuan
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Zixuan Liu
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Lei Tang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Yuxuan Ma
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Xin Zhang
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Jing Bai
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
| | - Ruimin Wang
- Neurobiology Institute, Key Laboratory of Dementia and Cognitive Dysfunction, School of Public Health of North China University of Science and Technology, Tangshan, Hebei, China; School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, China.
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19
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Huang Y, Sun W, Gao F, Ma H, Yuan T, Liu Z, Liu H, Hu J, Bai J, Zhang X, Wang R. Brain-Derived Estrogen Regulates Neurogenesis, Learning and Memory with Aging in Female Rats. BIOLOGY 2023; 12:760. [PMID: 37372046 DOI: 10.3390/biology12060760] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/18/2023] [Accepted: 05/18/2023] [Indexed: 06/29/2023]
Abstract
Although 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month (Mon) female rats. Female forebrain neuronal aromatase knockout (FBN-ARO-KO) rats and letrozole-treated rats were also employed. We demonstraed that (1) the number of neural stem cells declined over 14-Mon age, and the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. KO rats showed declines in astrocyte A2 subtype and elevation in A1 subtype at 18 Mon; (2) neurogenesis sharply dropped from 1-Mon age; (3) KO suppressed dentate gyrus (DG) neurogenesis at 1, 6 and 18 Mon. Additionally, KO and letrozole treatment led to declined neurogenesis at 1-Mon age, compared to age-matched WT controls; (4) FBN-ARO-KO inhibited CREB-BDNF activation, and decreased protein levels of neurofilament, spinophilin and PSD95. Notably, hippocampal-dependent spatial learning and memory was impaired in juvenile (1 Mon) and adulthood (6 Mon) KO rats. Taken together, we demonstrated that BDE2 plays a pivotal role for hippocampal neurogenesis, as well as learning and memory during female aging, especially in juvenile and middle age.
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Affiliation(s)
- Yuanyuan Huang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- School of Basic Medical Science, North China University of Science and Technology, Tangshan 063210, China
| | - Wuxiang Sun
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- School of Basic Medical Science, North China University of Science and Technology, Tangshan 063210, China
| | - Fujia Gao
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Haoran Ma
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Tao Yuan
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Zixuan Liu
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- School of Basic Medical Science, North China University of Science and Technology, Tangshan 063210, China
| | - Huiyu Liu
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Jiewei Hu
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- School of Basic Medical Science, North China University of Science and Technology, Tangshan 063210, China
| | - Jing Bai
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- School of Basic Medical Science, North China University of Science and Technology, Tangshan 063210, China
| | - Xin Zhang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Ruimin Wang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- School of Basic Medical Science, North China University of Science and Technology, Tangshan 063210, China
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20
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Prossnitz ER, Barton M. The G protein-coupled oestrogen receptor GPER in health and disease: an update. Nat Rev Endocrinol 2023:10.1038/s41574-023-00822-7. [PMID: 37193881 DOI: 10.1038/s41574-023-00822-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2023] [Indexed: 05/18/2023]
Abstract
Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.
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Affiliation(s)
- Eric R Prossnitz
- Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
| | - Matthias Barton
- Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
- Andreas Grüntzig Foundation, Zürich, Switzerland.
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21
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Chiarini A, Gui L, Viviani C, Armato U, Dal Prà I. NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes. Biomedicines 2023; 11:biomedicines11040999. [PMID: 37189617 DOI: 10.3390/biomedicines11040999] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/29/2023] Open
Abstract
Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3’s and other inflammasomes’ regulation, while minimizing failure risks in candidate drug trials.
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22
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Arterburn JB, Prossnitz ER. G Protein-Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications. Annu Rev Pharmacol Toxicol 2023; 63:295-320. [PMID: 36662583 PMCID: PMC10153636 DOI: 10.1146/annurev-pharmtox-031122-121944] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein-coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.
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Affiliation(s)
- Jeffrey B Arterburn
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, USA
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA;
| | - Eric R Prossnitz
- University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA;
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, and Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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23
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Anti-Inflammatory Actions of G-Protein-Coupled Estrogen Receptor 1 (GPER) and Brain-Derived Estrogen Following Cerebral Ischemia in Ovariectomized Rats. BIOLOGY 2023; 12:biology12010099. [PMID: 36671793 PMCID: PMC9855882 DOI: 10.3390/biology12010099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/13/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023]
Abstract
Global cerebral ischemia can elicit rapid innate neuroprotective mechanisms that protect against delayed neuronal death. Brain-derived 17β-estradiol (BDE2), an endogenous neuroprotectant, is synthesized from testosterone by the enzyme aromatase (Aro) and is upregulated by brain ischemia and inflammation. Our recent study revealed that G1, a specific G-protein-coupled estrogen receptor 1 (GPER) agonist, exerts anti-inflammatory and anti-apoptotic roles after global cerebral ischemia (GCI). Herein, we aimed to elucidate whether G1 modulates the early inflammatory process and the potential underlying mechanisms in the ovariectomized rat hippocampal CA1 region. G1 was found to markedly reduce pro-inflammatory (iNOS, MHCII, and CD68) and to enhance anti-inflammatory (CD206, Arginase 1, IL1RA, PPARγ, and BDNF) markers after 1 and 3 days of reperfusion after GCI. Intriguingly, the neuroprotection of G1 was blocked by the Aro inhibitor, letrozole. Conversely, the GPER antagonist, G36, inhibited Aro-BDE2 signaling and exacerbated neuronal damage. As a whole, this work demonstrates a novel anti-inflammatory role of GPER, involving a synergistic mediation with BDE2 during the early stage of GCI.
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24
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Jiao Y, Gao P, Dong L, Ding X, Meng Y, Qian J, Gao T, Wang R, Jiang T, Zhang Y, Kong D, Wu Y, Chen S, Xu S, Tang D, Luo P, Wu M, Meng L, Wen D, Wu C, Zhang G, Shi X, Yu W, Rong W. Molecular identification of bulbospinal ON neurons by GPER, which drives pain and morphine tolerance. J Clin Invest 2023; 133:e154588. [PMID: 36346677 PMCID: PMC9797334 DOI: 10.1172/jci154588] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
The rostral ventromedial medulla (RVM) exerts bidirectional descending modulation of pain attributable to the activity of electrophysiologically identified pronociceptive ON and antinociceptive OFF neurons. Here, we report that GABAergic ON neurons specifically express G protein-coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, but their ablation abrogated, pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain, and ameliorated morphine analgesia through desensitizing μ-type opioid receptor-mediated (MOR-mediated) activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia, and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly indicate that GPER is a marker for GABAergic ON cells and illuminate the mechanisms underlying hormonal regulation of pain and analgesia, thus highlighting GPER as a promising target for the treatment of pain and opioid tolerance.
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Affiliation(s)
- Yingfu Jiao
- Department of Anatomy and Physiology and
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Po Gao
- Department of Anatomy and Physiology and
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Dong
- Department of Anatomy and Physiology and
| | | | - Youqiang Meng
- Department of Anatomy and Physiology and
- Department of Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Chongming Branch, Shanghai University of Medicine and Health Sciences Affiliated Chongming Hospital, Shanghai, China
| | | | - Ting Gao
- Department of Anatomy and Physiology and
| | - Ruoxi Wang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Jiang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunchun Zhang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dexu Kong
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Wu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sihan Chen
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Saihong Xu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Tang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Luo
- Department of Anatomy and Physiology and
| | - Meimei Wu
- Department of Anatomy and Physiology and
| | - Li Meng
- Department of Anatomy and Physiology and
| | - Daxiang Wen
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changhao Wu
- School of Biosciences and Medicine, University of Surrey, Guildford, United Kingdom
| | | | - Xueyin Shi
- Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weifeng Yu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weifang Rong
- Department of Anatomy and Physiology and
- Department of Anesthesiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Nong FF, Liang YQ, Xing SP, Xiao YF, Chen HH, Wen B. Alcohol promotes epithelial mesenchymal transformation-mediated premetastatic niche formation of colorectal cancer by activating interaction between laminin-γ2 and integrin-β1. World J Gastroenterol 2022; 28:5154-5174. [PMID: 36188720 PMCID: PMC9516679 DOI: 10.3748/wjg.v28.i35.5154] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/23/2022] [Accepted: 08/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a common malignant tumor. Alcohol consumption is positively correlated with CRC malignant metastasis; however, the mechanism is unclear. The interaction between laminin-γ2 (LAMC2) and integrin-β1 (ITGB1) plays a role in premetastatic niche signaling, which may induce epithelial mesenchymal transformation (EMT) and lead to metastasis.
AIM To investigate the effects of alcohol on CRC metastasis from the molecular mechanism of the premetastatic niche.
METHODS The interaction between LAMC2 and ITGB1 was measured by Duolink assay, and the expression levels of LAMC2, ITGB1 and focal adhesion kinase (FAK), snail, fibronectin, N-cadherin and special AT-rich sequence binding protein 1 (SATB1) were measured by quantitative real-time polymerase chain reaction, immunohistochemistry and western blotting. Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6 levels were measured via enzyme-linked immunosorbent assay, histopathological assessment via hematoxylin eosin staining, and determination of aberrant crypt foci via methylene blue.
RESULTS The lymph node metastasis rate was higher in the alcohol group than non-alcohol group. There was a significant increase in interaction signals between LAMC2 and ITGB1, and an increase in phosphorylate-FAK/FAK, snail, fibronectin, N-cadherin and SATB1, whereas E-cadherin was reduced in the alcohol group compared to the non-alcohol group in both animal and clinical samples. Serum IL-1β, TNF-α and IL-6 were higher in alcohol group than in non-alcohol group. Alcohol may promote CRC metastasis by influencing the molecular mechanism of the premetastatic niche.
CONCLUSION Our study suggests that alcohol promotes EMT-mediated premetastatic niche formation of CRC by activating the early interaction between LAMC2 and ITGB1 and lead to CRC metastasis.
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Affiliation(s)
- Fei-Fei Nong
- Pi-Wei Institute, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Yu-Qi Liang
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Shang-Ping Xing
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Yin-Fang Xiao
- Pi-Wei Institute, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Hui-Hui Chen
- Pi-Wei Institute, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
| | - Bin Wen
- Pi-Wei Institute, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510000, Guangdong Province, China
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26
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Gupta K, Vishwakarma J, Garg A, Pandey R, Jain V, Gupta R, Das U, Roy S, Bandyopadhyay S. Arsenic Induces GSK3β-dependent p-tau, neuronal apoptosis and cognitive impairment via an interdependent hippocampal ERα and IL-1/IL-1R1 mechanism in female rats. Toxicol Sci 2022; 190:79-98. [PMID: 35993674 DOI: 10.1093/toxsci/kfac087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Arsenic is an environmental contaminant with potential neurotoxicity. We previously reported that arsenic promoted hippocampal neuronal apoptosis, inducing cognitive loss. Here, we correlated it with tau pathology. We observed that environmentally relevant arsenic exposure increased tau phosphorylation and the principal tau kinase, glycogen synthase kinase-3 beta (GSK3β), in the female rat hippocampal neurons. We detected the same in primary hippocampal neurons. Since a regulated estrogen receptor (ER) level and inflammation contributed to normal hippocampal functions, we examined their levels following arsenic exposure. Our ER screening data revealed that arsenic down-regulated hippocampal neuronal ERα. We also detected an up-regulated hippocampal interleukin-1 (IL-1) and its receptor, IL-1R1. Further, co-treating arsenic with the ERα agonist, 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), or IL-1R antagonist (IL-1Ra) resulted in reduced GSK3β and p-tau, indicating involvement of decreased ERα and increased IL-1/IL-1R1 in tau hyperphosphorylation. We then checked whether ERα and IL-1/IL-1R1 had linkage, and detected that while PPT reduced IL-1 and IL-1R1, the IL-1Ra restored ERα, suggesting their arsenic-induced interdependence. We finally correlated this pathway with apoptosis and cognition. We observed that PPT, IL-1Ra and the GSK3β inhibitor, LiCl, reduced hippocampal neuronal cleaved caspase-3 and TUNEL+ve apoptotic count, and decreased the number of errors during learning and increased the saving-memory for Y-Maze Test and retention performance for Passive avoidance test in arsenic-treated rats. Thus, our study reveals a novel mechanism of arsenic-induced GSK3β-dependent tau pathology via interdependent ERα and IL-1/IL-1R1 signaling. It also envisages the protective role of ERα agonist and IL-1 inhibitor against arsenic-induced neurotoxicity.
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Affiliation(s)
- Keerti Gupta
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jitendra Vishwakarma
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Asmita Garg
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rukmani Pandey
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Veena Jain
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.,Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
| | - Raksha Gupta
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.,DAV PG College, Nasirabad, Buxipur, Gorakhpur, Uttar Pradesh, 273001, India
| | - Uttara Das
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Somendu Roy
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.,Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India
| | - Sanghamitra Bandyopadhyay
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
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27
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Chen J, Ding Q, Jiao X, Wang B, Sun Z, Zhang Y, Zhao J. Dexmedetomidine attenuates hippocampal neuroinflammation in postoperative neurocognitive disorders by inhibiting microRNA-329-3p and activating the CREB1/IL1RA axis. Psychopharmacology (Berl) 2022; 239:2171-2186. [PMID: 35412062 DOI: 10.1007/s00213-022-06091-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 02/14/2022] [Indexed: 11/24/2022]
Abstract
RATIONALE Due to its anti-inflammatory effect, dexmedetomidine (DEX) can confer neuroprotection in postoperative neurocognitive disorders (NCD). Here, the mechanism responsible for this effect of DEX is rarely ascertained. OBJECTIVES Our research was implemented to figure out mechanism governing the protection of DEX against hippocampal neuroinflammation in postoperative NCD. METHODS Exploratory laparotomy was applied for generating a postoperative NCD mouse model before bilateral hippocampal injection with microRNA (miR)-329-3p-agomir and intraperitoneal injection with DEX. Cognitive function of mice was evaluated by water maze test and fear conditioning test. Immunofluorescence was performed to assess microglial activation in hippocampus. After cell transfection and DEX treatment, mouse microglial cells (BV-2) were stimulated by lipopolysaccharide (LPS). IL-1β, IL-6, and TNF-α levels and the number of phagocytes were assessed by ELISA and flow cytometry. Dual-luciferase reporter assay was adopted to assess the relationship between miR-329-3p and CREB1. RESULTS miR-329-3p expression was reduced in the postoperative NCD mice after DEX treatment. DEX treatment or miR-329-3p downregulation caused attenuated cognitive dysfunction and microglia activation as well as reduced IL-1β, IL-6, and TNF-α levels in the hippocampus of the postoperative NCD mice. Mechanistically, miR-329-3p inversely targeted CREB1 that activated IL1RA in LPS-induced BV-2 cells. DEX treatment, miR-329-3p inhibition, or CREB1 or IL1RA upregulation curtailed the release of proinflammatory proteins and the number of phagocytes in LPS-induced BV-2 cells. CONCLUSIONS Collectively, our data provided the novel insight of the neuroprotective mechanism of DEX in postoperative NCD pertaining to the miR-329-3p/CREB1/IL1RA axis.
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Affiliation(s)
- Jinquan Chen
- Anesthesia Operation Center, The First Peoples Hospital of Xianyang, Xianyang, 712000, People's Republic of China
| | - Qian Ding
- Anesthesia Operation Center, Xi´an International Medical Center Hospital, No. 777, Xitai Road, 710100, Xi´an, People's Republic of China
| | - Xiangxue Jiao
- Anesthesia Operation Center, The First Peoples Hospital of Xianyang, Xianyang, 712000, People's Republic of China
| | - Binrong Wang
- Anesthesia Operation Center, Xi´an International Medical Center Hospital, No. 777, Xitai Road, 710100, Xi´an, People's Republic of China
| | - Zhenzhong Sun
- Department of Anesthesiology, Guangdong Armed Police Corps Hospital, Guangzhou, 510507, People's Republic of China
| | - Yutao Zhang
- Anesthesia Operation Center, Xi´an International Medical Center Hospital, No. 777, Xitai Road, 710100, Xi´an, People's Republic of China
| | - Juan Zhao
- Anesthesia Operation Center, Xi´an International Medical Center Hospital, No. 777, Xitai Road, 710100, Xi´an, People's Republic of China.
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Lu Y, Wang J, Tang F, Pratap UP, Sareddy GR, Dhandapani KM, Capuano A, Arvanitakis Z, Vadlamudi RK, Brann DW. Regulation and Role of Neuron-Derived Hemoglobin in the Mouse Hippocampus. Int J Mol Sci 2022; 23:5360. [PMID: 35628182 PMCID: PMC9140924 DOI: 10.3390/ijms23105360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 11/17/2022] Open
Abstract
Hemoglobin (Hb) is the oxygen transport protein in erythrocytes. In blood, Hb is a tetramer consisting of two Hb-alpha (Hb-α) chains and two Hb-beta (Hb-β) chains. A number of studies have also shown that Hb-α is also expressed in neurons in both the rodent and human brain. In the current study, we examined for age-related regulation of neuronal Hb-α and hypoxia in the hippocampus and cerebral cortex of intact male and female mice. In addition, to confirm the role and functions of neuronal Hb-α, we also utilized lentivirus CRISPR interference-based Hb-α knockdown (Hb-α CRISPRi KD) in the non-ischemic and ischemic mouse hippocampus and examined the effect on neuronal oxygenation, as well as induction of hypoxia-inducible factor-1α (HIF-1α) and its downstream pro-apoptotic factors, PUMA and NOXA, and on neuronal survival and neurodegeneration. The results of the study revealed an age-related decrease in neuronal Hb-α levels and correlated increase in hypoxia in the hippocampus and cortex of intact male and female mice. Sex differences were observed with males having higher neuronal Hb-α levels than females in all brain regions at all ages. In vivo Hb-α CRISPRi KD in the mouse hippocampus resulted in increased hypoxia and elevated levels of HIF-1α, PUMA and NOXA in the non-ischemic and ischemic mouse hippocampus, effects that were correlated with a significant decrease in neuronal survival and increased neurodegeneration. As a whole, these findings indicate that neuronal Hb-α decreases with age in mice and has an important role in regulating neuronal oxygenation and neuroprotection.
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Affiliation(s)
- Yujiao Lu
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (Y.L.); (K.M.D.)
| | - Jing Wang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (J.W.); (F.T.)
| | - Fulei Tang
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (J.W.); (F.T.)
| | - Uday P. Pratap
- Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, TX 78229, USA; (U.P.P.); (G.R.S.); (R.K.V.)
| | - Gangadhara R. Sareddy
- Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, TX 78229, USA; (U.P.P.); (G.R.S.); (R.K.V.)
| | - Krishnan M. Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (Y.L.); (K.M.D.)
| | - Ana Capuano
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; (A.C.); (Z.A.)
| | - Zoe Arvanitakis
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA; (A.C.); (Z.A.)
| | - Ratna K. Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health, San Antonio, TX 78229, USA; (U.P.P.); (G.R.S.); (R.K.V.)
| | - Darrell W. Brann
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (J.W.); (F.T.)
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Zhao Y, Wu J, Li D, Liu J, Chen W, Hou Z, Liu K, Jiang L, Chen X, Wang L, Hu B, Zong F, Wang Y, Wang Y. Human ESC-derived immunity- and matrix- regulatory cells ameliorated white matter damage and vascular cognitive impairment in rats subjected to chronic cerebral hypoperfusion. Cell Prolif 2022; 55:e13223. [PMID: 35437845 PMCID: PMC9136497 DOI: 10.1111/cpr.13223] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/24/2022] [Accepted: 03/03/2022] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVES This study investigated the ability of immunity- and matrix- regulatory cells (IMRCs) to improve cognitive function in a rat model of vascular cognitive impairment. MATERIALS AND METHODS A chronic cerebral hypoperfusion (CCH) model was established in rats via permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). The rats then received intravenous injections of IMRCs or saline. A single injection of different doses of IMRCs (1 × 106 cells/rat, 2 × 106 cells/rat, or 4 × 106 cells/rat) was administered via tail vein 72 h after establishment of the model. To evaluate functional recovery, the rats were subjected to behavioural tests after 30 days of CCH. Imaging, western blotting, immunofluorescence staining, and quantitative real-time PCR were used to analyse neuroinflammation and white matter injury after 14 and 40 days of CCH. RNA sequencing (RNA-seq) was used to profile gene expression changes in copine 1 (CPNE1) in response to IMRCs treatment. RESULTS Intravenous injection of 4 × 106 IMRCs alleviated white matter damage and ameliorated cognitive deficits in rats subjected to CCH. Immunofluorescence staining suggested that activation of microglia and astrocytes was reduced, and RNA sequencing showed that CPNE1 expression was significantly elevated following treatment with IMRCs. CONCLUSIONS Intravenous injection of IMRCs protected against CCH-induced white matter injury and cognitive impairment inhibition of microglial activation and regulation of microglia polarization.
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DeLeon C, Pemberton K, Green M, Kalajdzic V, Rosato M, Xu F, Arnatt C. Novel GPER Agonist, CITFA, Increases Neurite Growth in Rat Embryonic (E18) Hippocampal Neurons. ACS Chem Neurosci 2022; 13:1119-1128. [PMID: 35353510 DOI: 10.1021/acschemneuro.1c00811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Numerous studies have reported neuroprotective and procognitive effects of estrogens. The estrogen 17β-estradiol (E2) activates both the classical nuclear estrogen receptors ERα and ERβ as well as the G protein-coupled estrogen receptor (GPER). The differential effects of targeting the classical estrogen receptors over GPER are not well-understood. A limited number of selective GPER compounds have been described. In this study, 10 novel compounds were synthesized and exhibited half-maximal effective concentration values greater than the known GPER agonist G-1 in calcium mobilization assays performed in nonadherent HL-60 cells. Of these compounds, 2-cyclohexyl-4-isopropyl-N-((5-(tetrahydro-2H-pyran-2-yl)furan-2-yl)methyl)aniline, referred to as CITFA, significantly increased axonal and dendritic growth in neurons extracted from embryonic day 18 (E18) fetal rat hippocampal neurons. Confirmation of the results was performed by treating E18 hippocampal neurons with known GPER-selective antagonist G-36 and challenging with either E2, G-1, or CITFA. Results from these studies revealed an indistinguishable difference in neurite outgrowth between the treatment and control groups, exhibiting that neurite outgrowth in response to G-1 and CITFA originates from GPER activation and can be abolished with pretreatment of an antagonist. Subsequent docking studies using a homology model of GPER showed unique docking poses between G-1 and CIFTA. While docking poses differed between the ligands, CIFTA exhibited more favorable distance, bond angle, and strain for hydrogen-bonding and hydrophobic interactions.
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Affiliation(s)
- Chelsea DeLeon
- The Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States
| | - Kyle Pemberton
- The Department of Biology, College of Arts and Sciences, Saint Louis University, St. Louis, Missouri 63103, United States
- The Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, Missouri 63104, United States
| | - Michael Green
- The Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States
| | - Vanja Kalajdzic
- The Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States
| | - Martina Rosato
- The Department of Biology, College of Arts and Sciences, Saint Louis University, St. Louis, Missouri 63103, United States
- The Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, Missouri 63104, United States
| | - Fenglian Xu
- The Department of Biology, College of Arts and Sciences, Saint Louis University, St. Louis, Missouri 63103, United States
- The Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, Missouri 63104, United States
- The Department of Pharmacology and Physiology, Saint Louis University, St. Louis, Missouri 63103, United States
| | - Christopher Arnatt
- The Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States
- The Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, Missouri 63104, United States
- The Department of Pharmacology and Physiology, Saint Louis University, St. Louis, Missouri 63103, United States
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Dehydroepiandrosterone exacerbates nigericin-induced abnormal autophagy and pyroptosis via GPER activation in LPS-primed macrophages. Cell Death Dis 2022; 13:372. [PMID: 35440074 PMCID: PMC9018772 DOI: 10.1038/s41419-022-04841-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Abstract
As a widely acknowledged FDA-approved dietary supplement or over-the-counter medicines, dehydroepiandrosterone (DHEA) exerts anti-inflammatory and immunomodulatory function. Pyroptosis is an important form of programmed cell death (PCD), and which acts a key role in the body's anti-infection and inflammatory responses. But the effects and mechanisms of DHEA on pyroptosis remain unclear. Here, we found that DHEA inhibited the NLRP3 inflammasome components expression by blocking inflammatory signals in lipopolysaccharide (LPS)-primed macrophages, and prevented the bacterial toxin nigericin (Nig)-induced NLRP3 inflammasome assembly. However, DHEA exacerbated NLRP3-independent cell death in Nig-treated inflammatory macrophages. During this process, DHEA induced the abnormal autophagy, which reflected as the blocking of autophagic flux and the accumulation of autophagy receptor p62 (SQSTM1) protein. In addition, DHEA caused a burst of reactive oxygen species (ROS) and activated extracellular signal-regulated kinase (ERK) phosphorylation in LPS plus Nig-stimulated macrophages but not in LPS-treated macrophages. Mechanistically, the present study certified that the activation of G protein-coupled estrogen receptor (GPER) signal mediated the cell death induced by DHEA in Nig-stimulated inflammatory macrophages, as GPER specific inhibitor G15 alleviated the abnormal autophagy and ultimately prevented the gasdermin D (GSDMD)-mediated pyroptosis induced by DHEA. Collectively, DHEA can exacerbate Nig-induced abnormal autophagy and pyroptosis via activation of GPER in LPS-primed macrophages, which prompts us the potential application value of DHEA in anti-infection or anti-tumor immunity.
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Pandey R, Garg A, Gupta K, Shukla P, Mandrah K, Roy S, Chattopadhyay N, Bandyopadhyay S. Arsenic Induces Differential Neurotoxicity in Male, Female, and E2-Deficient Females: Comparative Effects on Hippocampal Neurons and Cognition in Adult Rats. Mol Neurobiol 2022; 59:2729-2744. [PMID: 35175559 DOI: 10.1007/s12035-022-02770-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 02/03/2022] [Indexed: 02/06/2023]
Abstract
We earlier reported that arsenic induced hippocampal neuronal loss, causing cognitive dysfunctions in male rats. This neuronal damage mechanism involved an altered bone morphogenetic protein (BMP2)/Smad and brain-derived neurotrophic factor (BDNF)/TrkB signaling. Susceptibility to toxicants is often sex-dependent, and hence we studied the comparative effects of arsenic in adult male and female rats. We observed that a lower dose of arsenic reduced learning-memory ability, examined through passive avoidance and Y-maze tests, in male but not female rats. Again, male rats exhibited greater learning-memory loss at a higher dose of arsenic. Supporting this, arsenic-treated male rats demonstrated larger reduction in the hippocampal NeuN and %-surviving neurons, together with increased apoptosis and altered BMP2/Smad and BDNF/TrkB pathways compared to their female counterparts. Since the primary female hormone, estrogen (E2), regulates normal brain functions, we next probed whether endogenous E2 levels in females offered resistance against arsenic-induced neurotoxicity. We used ovariectomized (OVX) rat as the model for E2 deficiency. We primarily identified that OVX itself induced hippocampal neuronal damage and cognitive decline, involving an increased BMP2/Smad and reduced BDNF/TrkB. Further, these effects appeared greater in arsenic + OVX compared to arsenic + sham (ovary intact) or OVX rats alone. The OVX-induced adverse effects were significantly reduced by E2 treatment. Overall, our study suggests that adult males could be more susceptible than females to arsenic-induced neurotoxicity. It also indicates that endogenous E2 regulates hippocampal BMP and BDNF signaling and restrains arsenic-induced neuronal dysfunctions in females, which may be inhibited in E2-deficient conditions, such as menopause or ovarian failure.
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Affiliation(s)
- Rukmani Pandey
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
- Department of Psychiatry, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York City, USA
| | - Asmita Garg
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Keerti Gupta
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Pallavi Shukla
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
- Division of Microbial Technology, CSIR-National Botanical Research Institute, Lucknow, 226001, India
| | - Kapil Mandrah
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
- Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
| | - Somendu Roy
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
- Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India
| | - Naibedya Chattopadhyay
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
- Division of Endocrinology, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, Uttar Pradesh, India
| | - Sanghamitra Bandyopadhyay
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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He F, Ye B, Chen J, Li C. Effect of EGCG on inflammatory reaction in rats suffered cerebral ischemia/reperfusion injury. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2021; 46:1325-1331. [PMID: 35232900 PMCID: PMC10930569 DOI: 10.11817/j.issn.1672-7347.2021.210245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVES Epigallocatechin gallate (EGCG) is the main bioactive component of polyphenols in tea, which has a variety of biological effects. The neurologic injury caused by cerebral ischemia/reperfusion (I/R) is closely related to the inflammatory reaction. The pro-inflammatory factor interleukin-1β (IL-1β) and the anti-inflammatory factor interleukin-10 (IL-10) play important roles in the regulation of inflammatory reaction. This study aims to explore the effect of EGCG on water content, myeloperoxidase (MPO) activity, IL-1β and IL-10 in brain tissues of rats suffered cerebral I/R injury. METHODS Middle cerebral artery occlusion model of SD rats was established by suture embolic method. After ischemia for 1.5 h, the nylon thread was pulled out and reperfusion was performed for 24.0 h. SD rats were randomly divided into 5 groups: a sham group, an I/R group, a EGCG1 group (I/R+12.5 mg/kg EGCG), a EGCG2 (I/R+25.0 mg/kg EGCG), and a EGCG3 group (I/R+50.0 mg/kg EGCG). The sham group was the same as the I/R group except that the middle cerebral artery was not blocked. The water content in brain tissues of rats was measured by dry and wet weight method, and MPO activity was detected by colorimetry. The levels of IL-1β and IL-10 mRNA were determined by RT-PCR, and the contents of IL-1β and IL-10 were determined by ELISA. In addition, primary cultured cortical neurons of SD rats were randomly divided into 3 groups: a control group, an oxygen-glucose deprivation/reperfusion (OGD/R) group, and an OGD/R+EGCG group (OGD/R+50.0 μmol/L EGCG). The effects of EGCG on the levels of IL-1β and IL-10 protein in neurons were assessed by Western blotting. RESULTS Compared with the sham group, water content, MPO activity, the contents of IL-1β and IL-10 were significantly increased (P<0.05 or P<0.01), the mRNA expression of IL-1β and IL-10 were obviously up-regulated (both P<0.01) in cerebral tissues of rats in the I/R group. Compared with the I/R group, water content and MPO activity in cerebral tissues of rats were significantly decreased (both P<0.01), the content of IL-1β (P<0.01) were significantly decreased and IL-10 (P<0.01) were significantly increased in the EGCG3 group. Compared with the I/R group, the mRNA expression of IL-1β was obviously down-regulated and the mRNA expression of IL-10 was obviously up-regulated in the EGCG2 and the EGCG3 group (P<0.05 or P<0.01). Compared with the control group, the protein levels of IL-1β and IL-10 in neurons were significantly increased in the OGD/R group (both P<0.01). Compared with the OGD/R group, the protein expression of IL-1β was obviously down-regulated and the protein expression of IL-10 was obviously up-regulated in neurons in the OGD/R+EGCG group (both P<0.01). CONCLUSIONS EGCG can inhibit the inflammatory reaction induced by cerebral I/R, which may be related to down-regulating the expression of pro-inflammatory factor IL-1β and up-regulating anti-inflammatory factor IL-10.
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Affiliation(s)
- Fang He
- Department of Basic Medicine, Suzhou Vocational Health College, Suzhou Jiangsu 215009.
| | - Bei Ye
- Department of Basic Medicine, Suzhou Vocational Health College, Suzhou Jiangsu 215009
| | - Jianzhen Chen
- Department of Basic Medicine, Suzhou Vocational Health College, Suzhou Jiangsu 215009
| | - Chang Li
- Department of Thoracic Surgery, First Affiliated Hospital of Soochow University, Suzhou Jiangsu 215006, China
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Reddy V, McCarthy M, Raval AP. Xenoestrogens impact brain estrogen receptor signaling during the female lifespan: A precursor to neurological disease? Neurobiol Dis 2021; 163:105596. [PMID: 34942334 DOI: 10.1016/j.nbd.2021.105596] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/08/2021] [Accepted: 12/18/2021] [Indexed: 02/07/2023] Open
Abstract
Xenoestrogens, foreign synthetic chemicals mimicking estrogens, are lurking in our surroundings. Climate change may alter their toxicity and bioavailability. Since xenoestrogens have extremely high lipid solubility and are structurally similar to natural endogenous estrogens, they can bind to estrogen receptors (ERs) -alpha (ER-α) and -beta (ER-β). Scientific evidence accumulated over the past decades have suggested that natural 17β-estradiol (E2; a potent estrogen), via activation of its receptors, plays a pivotal role in regulation of brain development, differentiation, metabolism, synaptic plasticity, neuroprotection, cognition, anxiety, body temperature, feeding and sexual behavior. In the brain, ER-β is predominantly expressed in the various regions, including cerebral cortex and hippocampus, that have been shown to play a key role in cognition. Therefore, disturbances in function of ER-β mediated E2 signaling by xenoestrogens can lead to deleterious effects that potentiate a variety of neurological diseases starting from prenatal to post-menopause in women. The goal of this review is to identify the possible neurological effects of xenoestrogens that can alter estrogen receptor-mediated signaling in the brain during different stages of the female lifespan.
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Affiliation(s)
- Varun Reddy
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA; Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Micheline McCarthy
- Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Ami P Raval
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA; Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
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Yan J, Xu W, Lenahan C, Huang L, Wen J, Li G, Hu X, Zheng W, Zhang JH, Tang J. CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage. Stroke 2021; 52:4021-4032. [PMID: 34719258 PMCID: PMC8607924 DOI: 10.1161/strokeaha.120.033285] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 07/11/2021] [Accepted: 07/30/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND PURPOSE Neuronal pyroptosis is a type of regulated cell death triggered by proinflammatory signals. CCR5 (C-C chemokine receptor 5)-mediated inflammation is involved in the pathology of various neurological diseases. This study investigated the impact of CCR5 activation on neuronal pyroptosis and the underlying mechanism involving cAMP-dependent PKA (protein kinase A)/CREB (cAMP response element binding)/NLRP1 (nucleotide-binding domain leucine-rich repeat pyrin domain containing 1) pathway after experimental intracerebral hemorrhage (ICH). METHODS A total of 194 adult male CD1 mice were used. ICH was induced by autologous whole blood injection. Maraviroc (MVC)-a selective antagonist of CCR5-was administered intranasally 1 hour after ICH. To elucidate the underlying mechanism, a specific CREB inhibitor, 666-15, was administered intracerebroventricularly before MVC administration in ICH mice. In a set of naive mice, rCCL5 (recombinant chemokine ligand 5) and selective PKA activator, 8-Bromo-cAMP, were administered intracerebroventricularly. Short- and long-term neurobehavioral assessments, Western blot, Fluoro-Jade C, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunofluorescence staining were performed. RESULTS The brain expression of CCL5 (chemokine ligand 5), CCR5, PKA-Cα (protein kinase A-Cα), p-CREB (phospho-cAMP response element binding), and NLRP1 was increased, peaking at 24 hours after ICH. CCR5 was expressed on neurons, microglia, and astrocytes. MVC improved the short- and long-term neurobehavioral deficits and decreased neuronal pyroptosis in ipsilateral brain tissues at 24 hours after ICH, which were accompanied by increased PKA-Cα and p-CREB expression, and decreased expression of NLRP1, ASC (apoptosis-associated speck-like protein containing a CARD), C-caspase-1, GSDMD (gasdermin D), and IL (interleukin)-1β/IL-18. Such effects of MVC were abolished by 666-15. At 24 hours after injection in naive mice, rCCL5 induced neurological deficits, decreased PKA-Cα and p-CREB expression in the brain, and upregulated NLRP1, ASC, C-caspase-1, N-GSDMD, and IL-1β/IL-18 expression. Those effects of rCCL5 were reversed by 8-Bromo-cAMP. CONCLUSIONS CCR5 activation promoted neuronal pyroptosis and neurological deficits after ICH in mice, partially through the CCR5/PKA/CREB/NLRP1 signaling pathway. CCR5 inhibition with MVC may provide a promising therapeutic approach in managing patients with ICH.
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Affiliation(s)
- Jun Yan
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China (J.Y.)
| | - Weilin Xu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China (W.X.)
| | - Cameron Lenahan
- Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM (C.L.)
| | - Lei Huang
- Department of Neurosurgery (L.H., J.H.Z.), Loma Linda University, CA
- Department of Physiology and Pharmacology (L.H., J.H.Z., J.T.), Loma Linda University, CA
| | - Jing Wen
- Department of Rheumatism, First Affiliated Hospital of Guangxi Medical University, Nanning, China (J.W.)
| | - Gaigai Li
- Department of Neurology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, China (G.L.)
| | - Xin Hu
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China (X.H.)
| | - Wen Zheng
- Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha, China (W.Z.)
| | - John H. Zhang
- Department of Neurosurgery (L.H., J.H.Z.), Loma Linda University, CA
- Department of Physiology and Pharmacology (L.H., J.H.Z., J.T.), Loma Linda University, CA
- Department of Anesthesiology (J.H.Z.), Loma Linda University, CA
| | - Jiping Tang
- Department of Physiology and Pharmacology (L.H., J.H.Z., J.T.), Loma Linda University, CA
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Wnuk A, Przepiórska K, Pietrzak BA, Kajta M. Posttreatment Strategy Against Hypoxia and Ischemia Based on Selective Targeting of Nonnuclear Estrogen Receptors with PaPE-1. Neurotox Res 2021; 39:2029-2041. [PMID: 34797527 PMCID: PMC8639538 DOI: 10.1007/s12640-021-00441-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/03/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
Newly synthesized Pathway Preferential Estrogen-1 (PaPE-1) selectively activates membrane estrogen receptors (mERs), namely, mERα and mERβ, and has been shown to evoke neuroprotection; however, its effectiveness in protecting brain tissue against hypoxia and ischemia has not been verified in a posttreatment paradigm. This is the first study showing that a 6-h delayed posttreatment with PaPE-1 inhibited hypoxia/ischemia-induced neuronal death, as indicated by neutral red uptake in mouse primary cell cultures in vitro. The effect was accompanied by substantial decreases in neurotoxicity and neurodegeneration in terms of LDH release and Fluoro-Jade C staining of damaged cells, respectively. The mechanisms of the neuroprotective action of PaPE-1 also involved apoptosis inhibition demonstrated by normalization of both mitochondrial membrane potential and expression levels of apoptosis-related genes and proteins such as Fas, Fasl, Bcl2, FAS, FASL, BCL2, BAX, and GSK3β. Furthermore, PaPE-1-evoked neuroprotection was mediated through a reduction in ROS formation and restoration of cellular metabolic activity that had become dysregulated due to hypoxia and ischemia. These data provide evidence that targeting membrane non-GPER estrogen receptors with PaPE-1 is an effective therapy that protects brain neurons from hypoxic/ischemic damage, even when applied with a 6-h delay from injury onset.
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Affiliation(s)
- A Wnuk
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smętna Street 12, 31-343, Krakow, Poland.
| | - K Przepiórska
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smętna Street 12, 31-343, Krakow, Poland
| | - B A Pietrzak
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smętna Street 12, 31-343, Krakow, Poland
| | - M Kajta
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Pharmacology, Laboratory of Neuropharmacology and Epigenetics, Smętna Street 12, 31-343, Krakow, Poland.
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Nuclear Receptors in Myocardial and Cerebral Ischemia-Mechanisms of Action and Therapeutic Strategies. Int J Mol Sci 2021; 22:ijms222212326. [PMID: 34830207 PMCID: PMC8617737 DOI: 10.3390/ijms222212326] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Nearly 18 million people died from cardiovascular diseases in 2019, of these 85% were due to heart attack and stroke. The available therapies although efficacious, have narrow therapeutic window and long list of contraindications. Therefore, there is still an urgent need to find novel molecular targets that could protect the brain and heart against ischemia without evoking major side effects. Nuclear receptors are one of the promising targets for anti-ischemic drugs. Modulation of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) by their ligands is known to exert neuro-, and cardioprotective effects through anti-apoptotic, anti-inflammatory or anti-oxidant action. Recently, it has been shown that the expression of aryl hydrocarbon receptor (AhR) is strongly increased after brain or heart ischemia and evokes an activation of apoptosis or inflammation in injury site. We hypothesize that activation of ERs and PPARs and inhibition of AhR signaling pathways could be a promising strategy to protect the heart and the brain against ischemia. In this Review, we will discuss currently available knowledge on the mechanisms of action of ERs, PPARs and AhR in experimental models of stroke and myocardial infarction and future perspectives to use them as novel targets in cardiovascular diseases.
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Sumien N, Cunningham JT, Davis DL, Engelland R, Fadeyibi O, Farmer GE, Mabry S, Mensah-Kane P, Trinh OTP, Vann PH, Wilson EN, Cunningham RL. Neurodegenerative Disease: Roles for Sex, Hormones, and Oxidative Stress. Endocrinology 2021; 162:6360925. [PMID: 34467976 PMCID: PMC8462383 DOI: 10.1210/endocr/bqab185] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Indexed: 02/08/2023]
Abstract
Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50 and 70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. The characteristic of sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate nicotinamide adenine dinucleotide-phosphate (NADPH) oxidase (NOX)-generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared with aged men, mediating the observed sex differences. Understanding of these signaling cascades could provide therapeutic targets for neurodegenerative diseases.
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Affiliation(s)
- Nathalie Sumien
- Department of Pharmacology & Neuroscience, Center for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - J Thomas Cunningham
- Department of Physiology & Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Delaney L Davis
- Department of Pharmacology & Neuroscience, Center for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Rachel Engelland
- Department of Pharmaceutical Sciences, School of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Oluwadarasimi Fadeyibi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - George E Farmer
- Department of Physiology & Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Steve Mabry
- Department of Pharmaceutical Sciences, School of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Paapa Mensah-Kane
- Department of Pharmacology & Neuroscience, Center for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Oanh T P Trinh
- Department of Pharmacology & Neuroscience, Center for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Philip H Vann
- Department of Pharmacology & Neuroscience, Center for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - E Nicole Wilson
- Department of Pharmaceutical Sciences, School of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Rebecca L Cunningham
- Department of Pharmaceutical Sciences, School of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
- Correspondence: Rebecca L. Cunningham, PhD, Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3400 Camp Bowie Boulevard, Fort Worth, TX, USA, 76107-2699.
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Yang S, Yin Z, Zhu G. A review of the functions of G protein-coupled estrogen receptor 1 in vascular and neurological aging. Eur J Pharmacol 2021; 908:174363. [PMID: 34297966 DOI: 10.1016/j.ejphar.2021.174363] [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: 03/09/2021] [Revised: 07/11/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023]
Abstract
Aging-related diseases, especially vascular and neurological disorders cause huge economic burden. How to delay vascular and neurological aging is one of the insurmountable questions. G protein-coupled estrogen receptor 1 (GPER) has been extensively investigated in recent years due to its multiple biological responses. In this review, the function of GPER in aging-related diseases represented by vascular diseases, and neurological disorders were discussed. Apart from that, activation of GPER was also found to renovate the aging brain characterized by memory decline, but in a manner different from another two nuclear estrogen receptors estrogen receptor (ER)α and ERβ. This salutary effect would be better clarified from the aspects of synaptic inputs and transmission. Furthermore, we carefully described molecular mechanisms underpinning GPER-mediated effects. This review would update our understanding of GPER in the aging process. Targeting GPER may represent a promising strategy in the aging-related disorders.
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Affiliation(s)
- Shaojie Yang
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China
| | - Zhe Yin
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China
| | - Guoqi Zhu
- Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China.
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Wang L, Liu J, Xu J, Zhang W, Wang R. Coupling of GPR30 mediated neurogenesis and protection with astroglial Aromatase-STAT3 signaling in rat hippocampus after global cerebral ischemia. Mol Cell Endocrinol 2021; 535:111394. [PMID: 34274445 DOI: 10.1016/j.mce.2021.111394] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 07/09/2021] [Accepted: 07/11/2021] [Indexed: 11/28/2022]
Abstract
Our previous study revealed that G-protein-coupled estrogen receptor-30 (GPR30) agonist G1 serves as a viable alternative neuroprotectant of 17β-estradiol (E2) to attenuate neuroinflammation and improve cognitive function after global cerebral ischemia (GCI). Aromatase, the key enzyme of E2 biosynthesis, is widely expressed in animal and human brain, and its expression and activity are mediated by selective estrogen receptor modulators. In the present study, we explored the long-term protective and reparative effects of G1 in ovariectomized rats after GCI. We used the aromatase inhibitor letrozole to elucidate whether G1 and brain-derived E2 together induce beneficial effects. Our results showed that G1 administration for 28 days a) significantly increased neurogenesis in the hippocampal sub-granular zone and CA1 regions; b) declined CA1 neuronal impairment in a long-term fashion; c) enhanced expression of synaptic proteins and cognitive function; d) and prevented reactive astrocytes loss, wherein aromatase and brain-derived estrogen levels were markedly increased. Additionally, expression and activation of transducer and activator of transcription 3 (STAT3) were increased in CA1 astrocytes of G1-treated animals. Letrozole abolished all of the observed benefits of G1. Our results suggest that GPR30 activation mediates long-term neuroprotection and neurogenesis in the hippocampus following GCI, with potential mechanism coupling with the activation of astroglial aromatase-STAT3 signaling.
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Affiliation(s)
- Lu Wang
- School of Public Health of North China University of Science and Technology, Tangshan, Hebei, 063210, China; Dementia and Dyscognitive Key Lab, Tangshan, Hebei, 063000, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, 063000, China
| | - Jiahao Liu
- School of Public Health of North China University of Science and Technology, Tangshan, Hebei, 063210, China; Dementia and Dyscognitive Key Lab, Tangshan, Hebei, 063000, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, 063000, China
| | - Jing Xu
- Dementia and Dyscognitive Key Lab, Tangshan, Hebei, 063000, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, 063000, China; School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, 063210, China
| | - Wenli Zhang
- School of Public Health of North China University of Science and Technology, Tangshan, Hebei, 063210, China; Dementia and Dyscognitive Key Lab, Tangshan, Hebei, 063000, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, 063000, China
| | - Ruimin Wang
- School of Public Health of North China University of Science and Technology, Tangshan, Hebei, 063210, China; Dementia and Dyscognitive Key Lab, Tangshan, Hebei, 063000, China; International Science & Technology Cooperation Base of Geriatric Medicine, Tangshan, Hebei, 063000, China; School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei, 063210, China.
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Guo S, Wang R, Hu J, Sun L, Zhao X, Zhao Y, Han D, Hu S. Photobiomodulation Promotes Hippocampal CA1 NSC Differentiation Toward Neurons and Facilitates Cognitive Function Recovery Involving NLRP3 Inflammasome Mitigation Following Global Cerebral Ischemia. Front Cell Neurosci 2021; 15:731855. [PMID: 34489645 PMCID: PMC8417562 DOI: 10.3389/fncel.2021.731855] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Our recent study revealed that photobiomodulation (PBM) inhibits delayed neuronal death by preserving mitochondrial dynamics and function following global cerebral ischemia (GCI). In the current study, we clarified whether PBM exerts effective roles in endogenous neurogenesis and long-lasting neurological recovery after GCI. Adult male rats were treated with 808 nm PBM at 20 mW/cm2 irradiance for 2 min on cerebral cortex surface (irradiance ∼7.0 mW/cm2, fluence ∼0.8 J/cm2 on the hippocampus) beginning 3 days after GCI for five consecutive days. Cognitive function was evaluated using the Morris water maze. Neural stem cell (NSC) proliferation, immature neurons, and mature neurons were examined using bromodeoxyuridine (BrdU)-, doublecortin (DCX)-, and NeuN-staining, respectively. Protein expression, such as NLRP3, cleaved IL1β, GFAP, and Iba1 was detected using immunofluorescence staining, and ultrastructure of astrocyte and microglia was observed by transmission electron microscopy. The results revealed that PBM exerted a markedly neuroprotective role and improved spatial learning and memory ability at 58 days of ischemia/reperfusion (I/R) but not at 7 days of reperfusion. Mechanistic studies revealed that PBM suppressed reactive astrocytes and maintained astrocyte regeneration at 7 days of reperfusion, as well as elevated neurogenesis at 58 days of reperfusion, as evidenced by a significant decrease in the fluorescence intensity of GFAP (astrocyte marker) but unchanged the number of BrdU-GFAP colabeled cells at the early timepoint, and a robust elevation in the number of DCX-NeuN colabeled cells at the later timepoint in the PBM-treated group compared to the GCI group. Notably, PBM treatment protected the ultrastructure of astrocyte and microglia cells at 58 days but not 7 days of reperfusion in the hippocampal CA1 region. Furthermore, PBM treatment significantly attenuated the GCI-induced immunofluorescence intensity of NLRP3 (an inflammasome component), cleaved IL1β (reflecting inflammasome activation) and Iba1, as well as the colocalization of NLRP3/GFAP or cleaved IL-1β/GFAP, especially in animals subjected to I/R at 58 days. Taken together, PBM treatment performed postischemia exerted a long-lasting protective effect on astrocytes and promoted endogenous neurogenesis in the hippocampal CA1 region, which might contribute to neurological recovery after GCI.
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Affiliation(s)
- Sihan Guo
- School of Life Sciences, Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
| | - Ruimin Wang
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Jiewei Hu
- Neurobiology Institute, School of Public Health, North China University of Science and Technology, Tangshan, China
| | - Liping Sun
- School of Life Sciences, Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
| | - Xinru Zhao
- School of Life Sciences, Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
| | - Yufeng Zhao
- School of Life Sciences, Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
| | - Dong Han
- School of Life Sciences, Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
| | - Shuqun Hu
- School of Life Sciences, Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
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Finney CA, Shvetcov A, Westbrook RF, Morris MJ, Jones NM. The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury 24 h after hippocampal silent infarct in male Sprague-Dawley rats. Horm Behav 2021; 134:105016. [PMID: 34242875 DOI: 10.1016/j.yhbeh.2021.105016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 06/03/2021] [Accepted: 06/05/2021] [Indexed: 02/07/2023]
Abstract
Silent infarcts (SI) are subcortical cerebral infarcts occurring in the absence of typical ischemia symptoms and are linked to cognitive decline and dementia development. There are no approved treatments for SI. One potential treatment is tamoxifen, a selective estrogen receptor modulator. It is critical to establish whether treatments effectively target the early consequences of SI to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 h later against cognitive deficits and injury responses including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). SI led to subtle cognitive impairment on the object place task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but increased apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI increased ERα and decreased ERβ in the hippocampus, which were mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that SI rats given tamoxifen were indistinguishable from controls. Further, SI rats were significantly different from all other groups, an effect associated with low levels of ERα and increased apoptosis, gliosis, inflammation, ERβ, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI 24 h after injury. Tamoxifen mitigates apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.
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Yin J, Wan J, Zhu J, Zhou G, Pan Y, Zhou H. Global trends and prospects about inflammasomes in stroke: a bibliometric analysis. Chin Med 2021; 16:53. [PMID: 34233704 PMCID: PMC8265129 DOI: 10.1186/s13020-021-00464-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/30/2021] [Indexed: 02/08/2023] Open
Abstract
Background Sterile inflammation is a key pathological process in stroke. Inflammasome activation has been implicated in various inflammatory diseases, including ischemic stroke and hemorrhagic stroke. Hence, targeting inflammasomes is a promising approach for the treatment of stroke. Methods We applied bibliometric methods and techniques. The Web of Science Core Collection was searched for studies indexed from database inception to November 26, 2020. We generated various visual maps to display publications, authors, sources, countries, and keywords. Results Our literature search yielded 427 publications related to inflammasomes involved in stroke, most of which consisted of original research articles and reviews. In particular, we found that there was a substantial increase in the number of relevant publications in 2018. Furthermore, most of the publications with the highest citation rates were published in 2014. Relatively, the field about inflammasomes in stroke developed rapidly in 2014 and 2018. Many institutions contributed to these publications, including those from China, the United States, and worldwide. We found that NLR family pyrin domain containing 3 (NLRP3) was the most studied, followed by NLRP1, NLRP2, and NLRC4 among the inflammasomes associated with stroke. Analysis of keywords suggested that the most studied mechanisms involved dysregulation of extracellular pH, efflux of Ca2+ ions, dysfunction of K+/Na+ ATPases, mitochondrial dysfunction, and damage to mitochondrial DNA. Conclusions Given the potential diagnostic and therapeutic implications, the specific mechanisms of inflammasomes contributing to stroke warrant further investigation. We used bibliometric methods to objectively present the global trend of inflammasomes in stroke, and to provide important information for relevant researchers.
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Affiliation(s)
- Junjun Yin
- Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, Zhejiang, China
| | - Jiayang Wan
- Peking University First Hospital, Beijing, 100034, China
| | - Jiaqi Zhu
- Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, Zhejiang, China
| | - Guoying Zhou
- Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, Zhejiang, China
| | - Yuming Pan
- Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, Zhejiang, China
| | - Huifen Zhou
- Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, Zhejiang, China.
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Dinh QN, Vinh A, Arumugam TV, Drummond GR, Sobey CG. G protein-coupled estrogen receptor 1: a novel target to treat cardiovascular disease in a sex-specific manner? Br J Pharmacol 2021; 178:3849-3863. [PMID: 33948934 DOI: 10.1111/bph.15521] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/23/2021] [Accepted: 04/28/2021] [Indexed: 12/19/2022] Open
Abstract
As an agonist of the classical nuclear receptors, estrogen receptor-α and -β (NR3A1/2), estrogen has been assumed to inhibit the development of cardiovascular disease in premenopausal women. Indeed, reduced levels of estrogen after menopause are believed to contribute to accelerated morbidity and mortality rates in women. However, estrogen replacement therapy has variable effects on cardiovascular risk in postmenopausal women, including increased serious adverse events. Interestingly, preclinical studies have shown that selective activation of the novel membrane-associated G protein-coupled estrogen receptor, GPER, can promote cardiovascular protection. These benefits are more evident in ovariectomised than intact females or in males. It is therefore possible that selective targeting of the GPER in postmenopausal women could provide cardiovascular protection with fewer adverse effects that are caused by conventional 'receptor non-specific' estrogen replacement therapy. This review describes new data regarding the merits of targeting GPER to treat cardiovascular disease with a focus on sex differences.
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Affiliation(s)
- Quynh Nhu Dinh
- Department of Physiology, Anatomy and Microbiology and Centre for Cardiovascular Biology and Disease Research, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Antony Vinh
- Department of Physiology, Anatomy and Microbiology and Centre for Cardiovascular Biology and Disease Research, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Thiruma V Arumugam
- Department of Physiology, Anatomy and Microbiology and Centre for Cardiovascular Biology and Disease Research, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Department of Physiology, Anatomy and Microbiology and Centre for Cardiovascular Biology and Disease Research, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher G Sobey
- Department of Physiology, Anatomy and Microbiology and Centre for Cardiovascular Biology and Disease Research, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
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Qin Y, Wang C, Xu S, Wu C, Wang S, Pan D, Ye G. G protein-coupled receptor 30 activation protects hepatic ischemia-reperfusion injury of liver tissue through inhibiting NLRP3 in the rat model. J Histotechnol 2020; 44:27-36. [PMID: 33210578 DOI: 10.1080/01478885.2020.1826175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
One of the most prominent characteristics of hepatic ischemia-reperfusion injury (HI/R) is an intense inflammatory reaction, which plays a key role in inflammatory injury induced by ischemia-reperfusion. Nucleotide-binding oligomerization domain-containing protein (NOD-), leucine-rich repeat (LRR), and pyrin domains-containing protein 3 (NLRP3) are involved in the inflammatory injury of ischemia-reperfusion as an important pattern recognition receptor for innate immunity. G protein-coupled receptor 30 (GPR30) is a newly identified as 7-transmembrane G protein-coupled receptor and can be activated by many stimulations including estrogen. The current study aims to explore whether GPR30 agonist (G1) can alleviate hepatic ischemia-reperfusion injury HI/R by inhibiting NLRP3. An induced HI/R rat model was generated, blood and liver samples were gathered and subjected to histological examination, biochemical assays, Western blot assays, and qRT-PCR. Our results indicated GPR30 agonist (G1) pretreatment or NLRP3 silencing significantly decreased the serum levels of Interleukin 1β (IL-1β), alanine aminotransferase (ALT) and aspartate aminotransferase, improved histological alterations and hepatocyte apoptosis. Moreover, G1 pretreatment or NLRP3 silencing downregulated the protein level of Caspase-1 and pro-Interleukin 1β (pro-IL-1β) while G1 pretreatment upregulated the expression of GPR30 (p < 0.05). In conclusion, the salutary effects of GPR30 agonists on HI/R are mediated at least in part through downregulating NLRP3 expression. GPR30 may be used as a therapy target of HI/R.
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Affiliation(s)
- Yong Qin
- Department of Hepatobiliary Surgery, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
| | - ChaoJun Wang
- Department of Ultrasound, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
| | - ShengQian Xu
- Department of Hepatobiliary Surgery, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
| | - ChengJun Wu
- Department of Hepatobiliary Surgery, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
| | - Shi Wang
- Department of Hepatobiliary Surgery, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
| | - DeBiao Pan
- Department of Hepatobiliary Surgery, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
| | - GuanXiong Ye
- Department of Hepatobiliary Surgery, People's Hospital of LiShui, the Sixth Affiliated Hospital of Wenzhou Medical University, the First Affiliated Hospital of LiShui University, Lishui, Zhengjiang, China
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McCarthy M, Raval AP. The peri-menopause in a woman's life: a systemic inflammatory phase that enables later neurodegenerative disease. J Neuroinflammation 2020; 17:317. [PMID: 33097048 PMCID: PMC7585188 DOI: 10.1186/s12974-020-01998-9] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023] Open
Abstract
The peri-menopause or menopausal transition—the time period that surrounds the final years of a woman’s reproductive life—is associated with profound reproductive and hormonal changes in a woman’s body and exponentially increases a woman’s risk of cerebral ischemia and Alzheimer’s disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.
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Affiliation(s)
- Micheline McCarthy
- Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Ami P Raval
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Leonard M. Miller School of Medicine, University of Miami, 1420 NW 9th Avenue, Neurology Research Building, Room # 203H, Miami, FL, 33136, USA. .,Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
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Habib P, Harms J, Zendedel A, Beyer C, Slowik A. Gonadal Hormones E2 and P Mitigate Cerebral Ischemia-Induced Upregulation of the AIM2 and NLRC4 Inflammasomes in Rats. Int J Mol Sci 2020; 21:ijms21134795. [PMID: 32645874 PMCID: PMC7370209 DOI: 10.3390/ijms21134795] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022] Open
Abstract
Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β and IL-18 by inflammasomes. However, the role of AIM2 and NLRC4 inflammasomes and the influence of the neuroprotective steroids 17β-estradiol (E2) and progesterone (P) on their regulation after ischemic stroke have not yet been conclusively elucidated. To address the latter, we subjected a total of 65 rats to 1 h of transient Middle Cerebral Artery occlusion (tMCAO) followed by a reperfusion period of 72 h. Moreover, we evaluated the expression and regulation of AIM2 and NLRC4 in glial single-cell cultures (astroglia and microglia) after oxygen–glucose deprivation (OGD). The administration of E2 and P decreased both infarct sizes and neurological impairments after cerebral ischemia in rats. We detected a time-dependent elevation of gene and protein levels (Western Blot/immunohistochemistry) of the AIM2 and NLRC4 inflammasomes in the post-ischemic brains. E2 or P selectively mitigated the stroke-induced increase of AIM2 and NLRC4. While both inflammasomes seemed to be exclusively abundant in neurons under physiological and ischemic conditions in vivo, single-cell cultures of cortical astrocytes and microglia equally expressed both inflammasomes. In line with the in vivo data, E and P selectively reduced AIM2 and NLRC4 in primary cortical astrocytes and microglial cells after OGD. In conclusion, the post-ischemic elevation of AIM2 and NLRC4 and their down-regulation by E2 and P may shed more light on the anti-inflammatory effects of both gonadal hormones after stroke.
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Affiliation(s)
- Pardes Habib
- Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany;
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
| | - Julie Harms
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany; (J.H.); (A.Z.); (C.B.)
| | - Adib Zendedel
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany; (J.H.); (A.Z.); (C.B.)
| | - Cordian Beyer
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany; (J.H.); (A.Z.); (C.B.)
- JARA Brain, RWTH Aachen University, 52074 Aachen, Germany
| | - Alexander Slowik
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany; (J.H.); (A.Z.); (C.B.)
- Correspondence: ; Tel.: +49-241-80-89112
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Macêdo DS, Sanders LLO, das Candeias R, Montenegro CDF, de Lucena DF, Chaves Filho AJM, Seeman MV, Monte AS. G Protein-Coupled Estrogen Receptor 1 (GPER) as a Novel Target for Schizophrenia Drug Treatment. SCHIZOPHRENIA BULLETIN OPEN 2020; 1. [DOI: 10.1093/schizbullopen/sgaa062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
AbstractThe observation that a person’s sex influences the onset age of schizophrenia, the course of the disease, and antipsychotic treatment response suggests a possible role for estrogen receptors in the pathophysiology of schizophrenia. Indeed, treatment with adjunctive estrogen or selective estrogen receptor modulators (SERMs) are known to reduce schizophrenia symptoms. While estrogen receptors (ER)α and ERβ have been studied, a third and more recently discovered estrogen receptor, the G protein-coupled estrogen receptor 1 (GPER), has been largely neglected. GPER is a membrane receptor that regulates non-genomic estrogen functions, such as the modulation of emotion and inflammatory response. This review discusses the possible role of GPER in brain impairments seen in schizophrenia and in its potential as a therapeutic target. We conducted a comprehensive literature search in the PubMed/MEDLINE database, using the following search terms: “Schizophrenia,” “Psychosis,” “GPER1 protein,” “Estrogen receptors,” “SERMS,” “GPER1 agonism, “Behavioral symptoms,” “Brain Inflammation.” Studies involving GPER in schizophrenia, whether preclinical or human studies, have been scarce, but the results are encouraging. Agonism of the GPER receptor could prove to be an essential mechanism of action for a new class of “anti-schizophrenia” drugs.
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Affiliation(s)
- Danielle S Macêdo
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Lia Lira Olivier Sanders
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
- Centro Universitário Christus-Unichristus, Fortaleza, CE, Brazil
| | - Raimunda das Candeias
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Cyntia de Freitas Montenegro
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
- Centro Universitário Christus-Unichristus, Fortaleza, CE, Brazil
| | - David Freitas de Lucena
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Adriano José Maia Chaves Filho
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Mary V Seeman
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Aline Santos Monte
- Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
- Health Science Institute, University of International Integration of Afro-Brazilian Lusophony—UNILAB, Redenção, CE, Brazil
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