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Ali M, Wollenhaupt-Aguiar B, Sehmbi M, Minuzzi L, Bock NA, Frey BN. Peripheral neurofilament light chain and intracortical myelin in bipolar I disorder. J Affect Disord 2025; 374:184-190. [PMID: 39800065 DOI: 10.1016/j.jad.2025.01.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 01/07/2025] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Neurofilament light chain (NfL) is a cytoskeletal protein that supports neuronal structure. Blood NfL levels are reported to be higher in diseases where myelin is damaged. Studies investigating intracortical myelin (ICM) in bipolar disorder (BD) have reported deficits in ICM maturation over age. This study investigated the association between ICM and peripheral blood NfL levels in BD. METHODS NfL was quantified using a high sensitivity ELISA kit in 72 BD and 71 healthy control (HC) participants. t-test was used to determine group difference in NfL levels between BD and HC, and ridge regression was performed to analyze NfL and ICM association in six brain regions that demonstrated ICM deficits including the dorsolateral motor cortex, dorsomedial motor cortex, dorsolateral premotor cortex, dorsomedial premotor cortex, caudal dorsolateral prefrontal cortex, caudal dorsomedial prefrontal cortex, and age in BD only. Regions within the occipital lobe and cingulum was also analyzed as control regions. RESULTS BD individuals had higher serum NfL concentration compared to HC (p = 0.001). The ridge regression analysis including the six brain regions and age explained 26 % of the variance in NfL concentration, while the occipital lobe and cingulum along with age explained only 7 % and 2 % of the variance, respectively. LIMITATIONS This was a cross-sectional correlational study so causation cannot be inferred. Also, this study focused on a limited number of brain regions previously associated with changes in ICM in BD. CONCLUSION This study corroborates previous research, which found increased NfL in CSF and blood in BD compared to HC. This demonstrates the potential utility of NfL as a marker of brain morphology deficits in BD.
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Affiliation(s)
- Mohammad Ali
- MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada; Centre for Clinical Neurosciences, McMaster University, Canada
| | - Bianca Wollenhaupt-Aguiar
- Centre for Clinical Neurosciences, McMaster University, Canada; Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada
| | - Manpreet Sehmbi
- MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada
| | - Luciano Minuzzi
- Centre for Clinical Neurosciences, McMaster University, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada; Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada
| | - Nicholas A Bock
- Department of Psychology, Neuroscience, and Behaviour, McMaster University, Hamilton, ON, Canada
| | - Benicio N Frey
- Centre for Clinical Neurosciences, McMaster University, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada; Mood Disorders Treatment and Research Centre and Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, ON, Canada.
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Wang L, Gu T, Yu C, Gao Y, Xuan T, Shen K, Wang G, Wang Z. Kaempferol attenuates experimental autoimmune neuritis through TNFR1/JNK/p38 signaling pathway inhibition. Int Immunopharmacol 2025; 147:113951. [PMID: 39752756 DOI: 10.1016/j.intimp.2024.113951] [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: 11/25/2024] [Revised: 12/14/2024] [Accepted: 12/23/2024] [Indexed: 01/29/2025]
Abstract
Kaempferol (Kae) is a flavonoid that has antioxidant, anti-inflammatory and neuroprotective effects. In recent years, there have been increasing reports on viral infection-induced Guillain-Barré syndrome (GBS) with high rates of disability and fatality. Therefore, in order to search for effective peripheral nerve injury repair drugs, we used rats with experimental autoimmune neuritis (EAN) as the typical animal model for GBS, and implemented Kae treatment intervention on EAN rats. Real-time quantitative polymerase chain reaction (qPCR), western blotting (WB) and immunofluorescence (IF) were utilized to detect the changes of inflammatory factors and signaling pathway proteins in peripheral nerve of rats. The impact of Kae on peripheral nerve damage in EAN rats was evaluated in multiple dimensions by clinical symptom score and neuroelectrophysiology examination, and the protective impact and mechanism of Kae on peripheral nerve injury were revealed. Our results showed that Kae increased the expression of sciatic myelin basic protein (MBP), decreased the expression of peripheral nerve macrophage infiltration and inflammatory cytokines, including TNF-α, IL-1β and IL-6, and down-regulated the expression levels of TNFR1. Additionally, it suppressed the activation of the JNK and p38 pathways. It can alleviate sciatic nerve symptoms and pathological injury in EAN rats. Therefore, we believe that Kae can be used as an adjunct drug in the treatment of GBS.
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MESH Headings
- Animals
- Neuritis, Autoimmune, Experimental/drug therapy
- Neuritis, Autoimmune, Experimental/immunology
- Kaempferols/pharmacology
- Kaempferols/therapeutic use
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Rats
- p38 Mitogen-Activated Protein Kinases/metabolism
- Male
- Sciatic Nerve/drug effects
- Sciatic Nerve/injuries
- Sciatic Nerve/metabolism
- Anti-Inflammatory Agents/therapeutic use
- Anti-Inflammatory Agents/pharmacology
- Cytokines/metabolism
- Signal Transduction/drug effects
- MAP Kinase Signaling System/drug effects
- Rats, Inbred Lew
- Guillain-Barre Syndrome/drug therapy
- Guillain-Barre Syndrome/immunology
- Disease Models, Animal
- Female
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Affiliation(s)
- Li Wang
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Tao Gu
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Chunguang Yu
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Yingying Gao
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Tingting Xuan
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Kaichun Shen
- The First Clinical Medical School, Ningxia Medical University, Yinchuan 750004, China
| | - Guowei Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, Chongqing 400016, China.
| | - Zhenhai Wang
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan 750004, China; Diagnosis and Treatment Engineering Technology Research Center of Nervous System Diseases of Ningxia, Yinchuan 750004, China; Neurology Center, General Hospital of Ningxia Medical University, Yinchuan 750004, China.
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Langhnoja J, Buch L, Pillai P. Neurotrophomodulatory effect of TNF-α through NF-κB in rat cortical astrocytes. Cytotechnology 2025; 77:37. [PMID: 39776978 PMCID: PMC11700960 DOI: 10.1007/s10616-024-00698-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
Tumor necrosis factor alpha (TNF-α) is a well-known pro-inflammatory cytokine originally recognized for its ability to induce apoptosis and cell death. However, recent research has revealed that TNF-α also plays a crucial role as a mediator of cell survival, influencing a wide range of cellular functions. The signaling of TNF-α is mediated through two distinct receptors, TNFR1 and TNFR2, which trigger various intracellular pathways, including NF-κB, JNK, and caspase signaling cascades. Both TNFR1 and TNFR2 are expressed in astrocytes, which are specialized glial cells essential for maintaining the structural and functional integrity of the central nervous system (CNS). Astrocytes support neuronal function by regulating brain homeostasis, maintaining synaptic function, and supplying metabolic substrates. In addition, astrocytes are known to secrete a variety of growth factors and neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5. These neurotrophins play a critical role in supporting neuronal survival, synaptic plasticity, and myelination within the brain. The present study focuses on the role of TNF-α in modulating neurotrophin expression and secretion in rat cortical astrocytes. We demonstrate that TNF-α induces the upregulation of neurotrophins, particularly NGF and BDNF, in cultured astrocytes. This effect is accompanied by an increase in the expression of their respective receptors (TrkA & TrkB), further suggesting a functional modulation of neurotrophic signaling pathways. Notably, we show that the modulation of neurotrophin expression by TNF-α is mediated via the NF-κB signaling pathway. Additionally, we observed that TNF-α also regulates the secretion levels of NGF and BDNF into the culture media of astrocytes in a dose-dependent manner, indicating that TNF-α can modulate both the production and release of these growth factors. Taken together, our findings highlight a previously underexplored neuroprotective role of TNF-α in astrocytes. Specifically, we propose that TNF-α, through the upregulation of neurotrophins, may contribute to maintaining neuronal health and supporting neuroprotection under disease conditions.
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Affiliation(s)
- Jaldeep Langhnoja
- Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat India
| | - Lipi Buch
- Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat India
| | - Prakash Pillai
- Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat India
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Wang LW, Hsiung CW, Chang CP, Lin MT, Chen SJ. Neuroserpin normalization by mesenchymal stem cell therapy after encephalopathy of prematurity in neonatal rats. Pediatr Res 2024:10.1038/s41390-024-03412-z. [PMID: 39085403 DOI: 10.1038/s41390-024-03412-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Hypoxic-ischemia (HI), infection/inflammation and reperfusion injury are pathogenic factors of encephalopathy of prematurity, which involves maturational/neurotrophic disturbances in oligodendrocyte progenitor cells (OPC) and neurons/axons. Mesenchymal stem cells (MSCs) might facilitate neuroserpin production, which is neurotrophic for OPC/neurons. This study investigated MSC effects on developmental disturbances after lipopolysaccharide (LPS)-sensitized HI/reperfusion (LHIR) injury and the relation to neuroserpin expression. METHODS Postnatal day 2 (P2) rat pups received intraperitoneal LPS (5 µg/kg) injection followed by HI (unilateral common-carotid-artery ligation and 6.5% oxygen exposure for 90 min) and post-HI reperfusion (release of ligation). MSCs (5 × 104 cells) were injected into the left lateral ventricle at 24 h post-LHIR. Neurological tests and brain tissue examinations were performed between P5 and P56. RESULTS After LHIR injury, MSC therapy significantly reduced cell death in subplate neurons, attenuated axonal damage, and facilitated synaptophysin synthesis in the cortex. It also alleviated OPC maturation arrest and preserved the complexity of myelinated axons in the white matter, leading to cognitive, motor and behavioral functional improvements. These beneficial effects were linked to restored neuroserpin expression in subplate neurons. CONCLUSIONS MSC therapy ameliorated developmental disturbances after LHIR injury through protection of neuroserpin expression, serving as a promising approach for treating encephalopathy of prematurity. IMPACT Neuroserpin is secreted by subplate neurons and may regulate the development of neurons and oligodendrocyte-axon contact for myelination in the premature brain. LPS-sensitized hypoxic-ischemia/reperfusion (LHIR) injury caused the developmental disturbances of neurons/axons and oligodendrocytes, and lowered neuroserpin levels in a neonatal rat model simulating encephalopathy of prematurity. Mesenchymal stem cell therapy alleviated the developmental disturbances after LHIR injury through protection of neuroserpin expression in subplate neurons, offering a new perspective on potential treatment for encephalopathy of prematurity.
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Affiliation(s)
- Lan-Wan Wang
- Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan, ROC.
- Department of Biotechnology and Food Technology, Southern Taiwan University of Science and Technology, Tainan, Taiwan, ROC.
- School of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC.
| | - Chien-Wei Hsiung
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan, ROC
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Ching-Ping Chang
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan, ROC
| | - Mao-Tsun Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan, ROC
| | - Shyi-Jou Chen
- Department of Pediatrics, Tri-service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
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Singh A, Ravendranathan N, Frisbee JC, Singh KK. Complex Interplay between DNA Damage and Autophagy in Disease and Therapy. Biomolecules 2024; 14:922. [PMID: 39199310 PMCID: PMC11352539 DOI: 10.3390/biom14080922] [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: 06/25/2024] [Revised: 07/19/2024] [Accepted: 07/26/2024] [Indexed: 09/01/2024] Open
Abstract
Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations.
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Affiliation(s)
- Aman Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
| | - Naresh Ravendranathan
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
| | - Jefferson C. Frisbee
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
| | - Krishna K. Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
- Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
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Dong A, Gao Z, Wang H, Wu R, Wang W, Jin X, Ji Y, Yang F, Zhu T, Jiang Z, Xu Y, Guo J, Ji L. Acupuncture Alleviates Chronic Ischemic White Matter Injury in SHR Rats via JNK-NMDAR Circuit. Mol Neurobiol 2024; 61:3144-3160. [PMID: 37976026 DOI: 10.1007/s12035-023-03759-0] [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: 09/11/2023] [Accepted: 10/31/2023] [Indexed: 11/19/2023]
Abstract
To study the protective mechanism of acupuncture at "Jiangya Recipe" on chronic ischemic white matter injury in spontaneously hypertensive rats (SHR) and the regulation of Jun N-terminal kinase-N-methyl-D-aspartate receptor (JNK-NMDAR) loop. A hypertensive white matter injury model was established in 46 male SHR rats aged 11 weeks by bilateral common carotid artery tapering (SHR-2VGO). In the SHR sham operation group, only bilateral common carotid arteries were isolated and in the SHR-2VGO modeling group, 36 rats were used for microcoil spring clip implantation to narrow the common carotid arteries and then, after 2 weeks of modeling, rats with impaired motor function were removed, and SHR-2VGO rats with successful final models were randomly divided into the model group, JNK blocking group, and acupuncture group. The sham operation group, model group, and JNK blocking group underwent the same grasping fixation, and the acupuncture group received acupuncture at acupoints "Jiangya Fang" once daily. In the JNK blocker group, an injection cannula was implanted into the lateral ventricle and sp600125 was injected into the lateral ventricle at 4.5 ul/day for 4 weeks. One week after the end of the intervention, white matter lesions were detected by MRI DWI and T2 imaging, and the learning and memory ability of rats was tested by Y-Maze and Passive Avoidance. Myelin density was detected by luxol fast blue (LFB) staining, also axon arrangement, myelin integrity, and thickness of neurons were detected by electron microscopy; neuronal morphology and the number of Nissl bodies in the hippocampus were detected by Nissl staining, dendritic spine density changes were detected by Golgi staining, and JNK, NMDAR1, and N-methyl-D-receptor 2B (NMDAR2B) in DG, CA3 region of hippocampus were detected by immunohistochemistry, protein expression of p-JNK/JNK, p-NMDAR1/NMDAR1, NMDAR2B, GSK3β protein expression in the fimbria of hippocampus was detected by Western blot. The Y maze test of SHR-2VGO+Acu and SHR-2VGO+ sp600125 group showed that the spontaneous alternating reaction rate increased significantly. At the same time, the incubation period increased significantly and the number of errors decreased significantly in Passive Avoidance. MRI T2WI showed that the white matter high signal of the corpus callosum, internal capsule and hippocampal fimbria in the SHR-2VGO+ sp600125 and SHR-2VGO+Acu groups was significantly lower than that in the SHR-2VGO model group, and the striatum and anterior commissure were not obvious. DWI showed that the SHR-2VGO model group had scattered high signal and limited diffusion movement in both the internal capsule and striatum, but the difference between groups was not obvious. Compared with SHR-2VGO rats, LFB staining of SHR-2VGO + sp600125 and SHR-2VGO +Acu groups showed significant relaxation of myelin porosity in corpus callosum, striatum, inner capsule, anterior commissure and hippocampal fimbria, and electron microscopy showed improved axonal myelin integrity and thickness in corpus callosum region. Also, the number of blue patchy Nissl bodies increased, and the number and complexity of dendritic spines increased significantly in Golgi staining. Immunohistochemical detection showed that JNK levels in DG and CA3 region were increased and NMDAR1 and NMDAR2B levels were decreased in SHR-2VGO+Acu and SHR-2VGO+ sp600125 groups. Meanwhile, protein expressions of GSK3β, NMDAR1/p-NMDAR1 and NMDAR2B in fimbria of hippocampus were increased, and JNK/P-JNK protein expression decreased. Acupuncture can increase the density and thickness of myelin sheath in white matter areas of corpus callosum, anterior commissure and hippocampal fimbria, increase the number and length of hippocampal neuronal dendrites, and improve hypertensive white matter injury and cognitive decline through JNK-NMDAR pathway.
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Affiliation(s)
- Aiai Dong
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Zhen Gao
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Haijun Wang
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Ronglin Wu
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Weifeng Wang
- Shanxi University of Traditional Chinese Medicine Affiliated Hospital of Acupuncture and Massage, Taiyuan, 030006, China
| | - Xiaofei Jin
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Yufang Ji
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Faming Yang
- Shanxi University of Traditional Chinese Medicine Affiliated Hospital of Acupuncture and Massage, Taiyuan, 030006, China
| | - Tao Zhu
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Ziwen Jiang
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Yongrong Xu
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Jilong Guo
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China
| | - Laixi Ji
- Shanxi University of Traditional Chinese Medicine, Jinzhong, 030619, China.
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Ali M, Husnudinov R, Wollenhaupt-Aguiar B, Frey BN. The association of blood biomarkers with cerebral white matter and myelin content in bipolar disorder: a systematic review. REVISTA BRASILEIRA DE PSIQUIATRIA (SAO PAULO, BRAZIL : 1999) 2023; 46:e20233267. [PMID: 38712923 PMCID: PMC11189111 DOI: 10.47626/1516-4446-2023-3267] [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: 06/30/2023] [Accepted: 09/21/2023] [Indexed: 05/08/2024]
Abstract
OBJECTIVES Evidence from diffusion tensor imaging (DTI) and postmortem studies has demonstrated white-matter (WM) deficits in bipolar disorder (BD). Changes in peripheral blood biomarkers have also been observed; however, studies evaluating the potential relationship between brain alterations and the periphery are scarce. The objective of this systematic review is to investigate the relationship between blood-based biomarkers and WM in BD. METHODS PubMed, Embase, and PsycINFO were used to conduct literature searches. Cross-sectional or longitudinal studies reporting original data which investigated both a blood-based biomarker and WM (by neuroimaging) in BD were included. RESULTS Of 3,750 studies retrieved, 23 were included. Several classes of biomarkers were found to have a significant relationship with WM in BD. These included cytokines and growth factors (interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-a], and insulin-like growth factor binding protein 3 [IGFBP-3]), innate immune system (natural killer cells [NK]), metabolic markers (lipid hydroperoxidase, cholesterol, triglycerides), the kynurenine (Kyn) pathway (5-hydroxyindoleacetic acid, kynurenic acid [Kyna]), and various gene polymorphisms (serotonin-transporter-linked promoter region). CONCLUSION This systematic review revealed that blood-based biomarkers are associated with markers of WM deficits observed in BD. Longitudinal studies investigating the potential clinical utility of these specific biomarkers are encouraged.
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Affiliation(s)
- Mohammad Ali
- Neuroscience Graduate Program, McMaster University, Hamilton, ON, Canada
- Centre for Clinical Neurosciences, McMaster University, St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada
| | - Renata Husnudinov
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Bianca Wollenhaupt-Aguiar
- Centre for Clinical Neurosciences, McMaster University, St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada
- Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Benicio N. Frey
- Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
- Women's Health Concerns Clinic, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada
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Fabres RB, Cardoso DS, Aragón BA, Arruda BP, Martins PP, Ikebara JM, Drobyshevsky A, Kihara AH, de Fraga LS, Netto CA, Takada SH. Consequences of oxygen deprivation on myelination and sex-dependent alterations. Mol Cell Neurosci 2023; 126:103864. [PMID: 37268283 DOI: 10.1016/j.mcn.2023.103864] [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: 01/20/2023] [Revised: 05/07/2023] [Accepted: 05/25/2023] [Indexed: 06/04/2023] Open
Abstract
Oxygen deprivation is one of the main causes of morbidity and mortality in newborns, occurring with a higher prevalence in preterm infants, reaching 20 % to 50 % mortality in newborns in the perinatal period. When they survive, 25 % exhibit neuropsychological pathologies, such as learning difficulties, epilepsy, and cerebral palsy. White matter injury is one of the main features found in oxygen deprivation injury, which can lead to long-term functional impairments, including cognitive delay and motor deficits. The myelin sheath accounts for much of the white matter in the brain by surrounding axons and enabling the efficient conduction of action potentials. Mature oligodendrocytes, which synthesize and maintain myelination, also comprise a significant proportion of the brain's white matter. In recent years, oligodendrocytes and the myelination process have become potential therapeutic targets to minimize the effects of oxygen deprivation on the central nervous system. Moreover, evidence indicate that neuroinflammation and apoptotic pathways activated during oxygen deprivation may be influenced by sexual dimorphism. To summarize the most recent research about the impact of sexual dimorphism on the neuroinflammatory state and white matter injury after oxygen deprivation, this review presents an overview of the oligodendrocyte lineage development and myelination, the impact of oxygen deprivation and neuroinflammation on oligodendrocytes in neurodevelopmental disorders, and recent reports about sexual dimorphism regarding the neuroinflammation and white matter injury after neonatal oxygen deprivation.
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Affiliation(s)
- Rafael Bandeira Fabres
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre 90035-003, Brazil
| | - Débora Sterzeck Cardoso
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | | | - Bruna Petrucelli Arruda
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | - Pamela Pinheiro Martins
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | - Juliane Midori Ikebara
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | | | - Alexandre Hiroaki Kihara
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil
| | - Luciano Stürmer de Fraga
- Departamento de Fisiologia, Universidade Federal do Rio Grande do Sul (UFRGS), Sarmento Leite, 500, Porto Alegre 90050-170, Brazil
| | - Carlos Alexandre Netto
- Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos, 2600, Porto Alegre 90035-003, Brazil
| | - Silvia Honda Takada
- Neurogenetics Laboratory, Universidade Federal do ABC, Alameda da Universidade, s/n, São Bernardo do Campo 09606-045, Brazil.
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Fan H, Sheng S, Li D, Li J, Wang G, Zhang F. Heat-killed Lactobacillus murinus confers neuroprotection against dopamine neuronal loss by targeting NLRP3 inflammasome. Bioeng Transl Med 2023; 8:e10455. [PMID: 36925673 PMCID: PMC10013757 DOI: 10.1002/btm2.10455] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/12/2022] [Accepted: 11/08/2022] [Indexed: 11/24/2022] Open
Abstract
The intestinal flora has become very active in studies related to Parkinson's disease (PD) in recent years. The microbe-gut-brain axis is closely related to the maintenance of brain homeostasis as well as PD pathogenesis. Alterations in gut bacteria can contribute to neuroinflammation and dopamine (DA) neurodegeneration. Lactobacillus murinus, a gram-positive bacterium, is a commensal gut bacteria present in the mammalian gut and considered as a potential probiotic due to its beneficial effects, including anti-inflammatory and antibacterial actions. In this study, the effects of live L. murinus and heat-killed L. murinus on DA neuronal damage in rats and the underlying mechanisms were investigated. Data showed that heat-killed L. murinus ameliorated 6-hydroxydopamine-induced motor dysfunctions and loss of substantia nigra DA neurons, while no protection was shown in live L. murinus treatment. At the same time, heat-killed L. murinus reduced the activation of NLRP3 inflammasome in microglia and the secretion of pro-inflammatory factors, thus inhibiting the development of neuroinflammation. Furthermore, heat-killed L. murinus failed to display its original neuroprotective properties in NLRP3 inflammasome knockout mice. Together, heat-killed L. murinus conferred neuroprotection against DA neuronal loss via the inhibition of microglial NLRP3 inflammasome activation. These findings provide a promising potential for future applications of L. murinus, and also beneficial strategy for PD treatment.
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Affiliation(s)
- Hong‐Xia Fan
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal CenterZunyi Medical UniversityZunyiGuizhouChina
| | - Shuo Sheng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal CenterZunyi Medical UniversityZunyiGuizhouChina
| | - Dai‐Di Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal CenterZunyi Medical UniversityZunyiGuizhouChina
| | - Jing‐Jie Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal CenterZunyi Medical UniversityZunyiGuizhouChina
| | - Guo‐Qing Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal CenterZunyi Medical UniversityZunyiGuizhouChina
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education and Key Laboratory of Basic Pharmacology of Guizhou Province and Laboratory Animal CenterZunyi Medical UniversityZunyiGuizhouChina
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10
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Xu J, Ji T, Li G, Zhang H, Zheng Y, Li M, Ma J, Li Y, Chi G. Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen-glucose deprivation conditions. J Neuroinflammation 2022; 19:314. [PMID: 36572898 PMCID: PMC9793555 DOI: 10.1186/s12974-022-02678-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Brain lactate concentrations are enhanced in response to cerebral ischemia and promote the formation of reactive astrocytes, which are major components of the neuroinflammatory response and functional recovery, following cerebral ischemia. NDRG2 is upregulated during reactive astrocyte formation. However, its regulation and function are unclear. We studied the relationship between lactate and NDRG2 in astrocytes under conditions of ischemia or oxygen-glucose deprivation (OGD). METHODS We examined astrocytic NDRG2 expression after middle cerebral artery occlusion (MCAO) using western blot and immunofluorescence staining. Under hypoxia conditions, we added exogenous L-lactate sodium (lactate) to cultured primary astrocytes to explore the effects of lactate on the ubiquitination modification of NDRG2. We profiled the transcriptomic features of NDRG2 silencing in astrocytes after 8 h of OGD conditions as well as exogenous lactate treatment by performing RNA-seq. Finally, we evaluated the molecular mechanisms of NDRG2 in regulating TNFα under OGD conditions using western blot and immunohistochemistry. RESULTS Reactive astrocytes strongly expressed NDRG2 in a rat model of MCAO. We also showed that lactate stabilizes astrocytic NDRG2 by inhibiting its ubiquitination. NDRG2 inhibition in astrocytes increased inflammation and upregulated immune-associated genes and signaling pathways. NDRG2 knockdown induced TNFα expression and secretion via c-Jun phosphorylation. CONCLUSIONS We revealed that under OGD conditions, lactate plays an important anti-inflammatory role and inhibits TNFα expression by stabilizing NDRG2, which is beneficial for neurological functional recovery. NDRG2 may be a new therapeutic target for cerebral ischemia.
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Affiliation(s)
- Jinying Xu
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China ,grid.430605.40000 0004 1758 4110Department of Burn Surgery, The First Hospital of Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Tong Ji
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China ,grid.64924.3d0000 0004 1760 5735Department of Pathogenic Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Guichen Li
- grid.430605.40000 0004 1758 4110Department of Neurology, The First Hospital of Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Haiying Zhang
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Yangyang Zheng
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China ,grid.410645.20000 0001 0455 0905Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao, 266071 Shandong People’s Republic of China
| | - Meiying Li
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Jie Ma
- grid.64924.3d0000 0004 1760 5735School of Pharmaceutical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Yulin Li
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China
| | - Guangfan Chi
- grid.64924.3d0000 0004 1760 5735The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021 Jilin People’s Republic of China
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11
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Kang N, Shin W, Jung S, Bang M, Lee SH. The Effect of TNF-alpha rs1800629 Polymorphism on White Matter Structures and Memory Function in Patients With Schizophrenia: A Pilot Study. Psychiatry Investig 2022; 19:1027-1036. [PMID: 36588437 PMCID: PMC9806513 DOI: 10.30773/pi.2021.0326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/06/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE This study investigated the effect of TNF-α rs1800629 polymorphism on white matter integrity and memory function in patients with schizophrenia. METHODS Fifty-five participants with schizophrenia were enrolled in this study. They were genotyped for TNF-α rs1800629 polymorphism and underwent diffusion tensor imaging. Memory function was assessed using the Rey-Kim memory test. Participants with schizophrenia were grouped into GG homozygotes and A-allele carriers. RESULTS Compared to GG homozygotes, A-allele carriers had significantly lower scores for immediate and delayed recall and recognition of verbal memory and showed significantly lower fractional anisotropy in extensive brain regions. Lower total scores in immediate and delayed recall of verbal memory, immediate recall of visual memory, and figure copy of visual memory were significantly correlated with decreased mean fractional anisotropy in the white matter tracts of the corresponding brain regions. CONCLUSION Our findings suggest that the A-allele, which is associated with higher levels of TNF-α expression, correlates with lower connectivity of the fronto-temporal white matter compared to that in GG homozygotes. Impaired fronto-temporal connectivity may be associated with genetic vulnerability to schizophrenia, leading to verbal and visual memory deficits in patients with schizophrenia.
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Affiliation(s)
- Naok Kang
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Wonsuk Shin
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sra Jung
- Department of Psychiatry, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Minji Bang
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Psychiatry, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
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12
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Favrais G, Bokobza C, Saliba E, Chalon S, Gressens P. Alteration of the Oligodendrocyte Lineage Varies According to the Systemic Inflammatory Stimulus in Animal Models That Mimic the Encephalopathy of Prematurity. Front Physiol 2022; 13:881674. [PMID: 35928559 PMCID: PMC9343871 DOI: 10.3389/fphys.2022.881674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Abstract
Preterm birth before the gestational age of 32 weeks is associated with the occurrence of specific white matter damage (WMD) that can compromise the neurological outcome. These white matter abnormalities are embedded in more global brain damage defining the encephalopathy of prematurity (EoP). A global reduction in white matter volume that corresponds to chronic diffuse WMD is the most frequent form in contemporary cohorts of very preterm infants. This WMD partly results from alterations of the oligodendrocyte (OL) lineage during the vulnerability window preceding the beginning of brain myelination. The occurrence of prenatal, perinatal and postnatal events in addition to preterm birth is related to the intensity of WMD. Systemic inflammation is widely recognised as a risk factor of WMD in humans and in animal models. This review reports the OL lineage alterations associated with the WMD observed in infants suffering from EoP and emphasizes the role of systemic inflammation in inducing these alterations. This issue is addressed through data on human tissue and imaging, and through neonatal animal models that use systemic inflammation to induce WMD. Interestingly, the OL lineage damage varies according to the inflammatory stimulus, i.e., the liposaccharide portion of the E.Coli membrane (LPS) or the proinflammatory cytokine Interleukin-1β (IL-1β). This discrepancy reveals multiple cellular pathways inducible by inflammation that result in EoP. Variable long-term consequences on the white matter morphology and functioning may be speculated upon according to the intensity of the inflammatory challenge. This hypothesis emerges from this review and requires further exploration.
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Affiliation(s)
- Geraldine Favrais
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
- Neonatology Unit, CHRU de Tours, Tours, France
- *Correspondence: Geraldine Favrais,
| | - Cindy Bokobza
- Inserm, NeuroDiderot, Université Paris Cité, Paris, France
| | - Elie Saliba
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
| | - Sylvie Chalon
- UMR 1253, iBrain, Inserm, Université de Tours, Tours, France
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13
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Enhanced Microglia Activation and Glioma Tumor Progression by Inflammagen Priming in Mice with Tumor Necrosis Factor Receptor Type 2 Deficiency. Life (Basel) 2021; 11:life11090961. [PMID: 34575110 PMCID: PMC8465392 DOI: 10.3390/life11090961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/25/2022] Open
Abstract
Despite the fact that accumulation of microglia, the resident macrophages of the central nervous system (CNS) are the main feature of glioblastoma, the role of microglia in the progression of glioma is still arguable. Based on the correlation of inflammation with tumor progression, in this study, we attempt to determine if peripheral inflammation aggravates glioma expansion and the activation of microglia associated with the tumor. Experimental animals were administered intraperitoneally by inflammagen lipopolysaccharide (LPS) for 7 days (LPS priming) before intracerebral implantation of glioma cells. Moreover, a reduced level of tumor necrosis factor receptor type 2 (TNFR2) that is restricted to immune cells, neurons, and microglia has been found in patients with glioblastoma through the clinic analysis of monocyte receptor expression. Thus, in addition to wildtype (WT) mice, heterogeneous TNFR2 gene deficiency (TNFR2+/−) mice and homogeneous TNFR2 gene knockout (TNFR2−/−) mice were used in this study. The results show that peripheral challenge by LPS, Iba1+- or CD11b+-microglia increase in numbers in the cortex and hippocampus of TNFR2−/− mice, when compared to WT or TNFR2+/− mice. We further conducted the intracerebral implantation of rodent glioma cells into the animals and found that the volumes of tumors formed by rat C6 glioma cells or mouse GL261 glioma cells were significantly larger in the cortex of TNFR2−/− mice when compared to that measured in LPS-primed WT or LPS-primed TNFR2+/− mice. Ki67+-cells were exclusively clustered in the tumor of LPS-primed TNFR2−/− mice. Microglia were also extensively accumulated in the tumor formed in LPS-primed TNFR2−/− mice. Accordingly, our findings demonstrate that aggravation of microglia activation by peripheral inflammatory challenge and a loss of TNFR2 function might lead to the promotion of glioma growth.
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Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease. Mediators Inflamm 2021; 2021:9999146. [PMID: 34158806 PMCID: PMC8187052 DOI: 10.1155/2021/9999146] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/04/2021] [Indexed: 12/14/2022] Open
Abstract
The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.
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15
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Du J, Zhang A, Li J, Liu X, Wu S, Wang B, Wang Y, Jia H. Doxorubicin-Induced Cognitive Impairment: The Mechanistic Insights. Front Oncol 2021; 11:673340. [PMID: 34055643 PMCID: PMC8158153 DOI: 10.3389/fonc.2021.673340] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/08/2021] [Indexed: 12/21/2022] Open
Abstract
Chemotherapy can significantly prolong the survival of patients with breast cancer; Nevertheless, the majority of patients receiving chemotherapy such as doxorubicin may have cognitive deficits that manifest as impairments in learning, reasoning, attention, and memory. The phenomenon of chemotherapy-induced cognitive decline is termed as chemotherapy-related cognitive impairment (CRCI) or chemo-brain. Doxorubicin (DOX), a commonly used drug in adjuvant chemotherapy for patients with breast cancer, has been reported to induce chemo-brain through a variety of mechanisms including DNA damage, oxidative stress, inflammation, dysregulation of apoptosis and autophagy, changes in neurotransmitter levels, mitochondrial dysfunction, glial cell interactions, neurogenesis inhibition, and epigenetic factors. These mechanisms do not operate independently but are inter-related, coordinately contributing to the development of chemo-brain. Here we review the relationships of these mechanisms and pathways in attempt to provide mechanistic insights into the doxorubicin-induced cognitive impairment.
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Affiliation(s)
- Jiajia Du
- Department of First Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Aoxue Zhang
- Department of First Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Jing Li
- Department of First Clinical Medicine, Shanxi Medical University, Taiyuan, China
| | - Xin Liu
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Shuai Wu
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Bin Wang
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanhong Wang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China
| | - Hongyan Jia
- Department of Breast Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
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16
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Li Q, Zhao Y, Huang Z, Guo Y, Long J, Luo L, You W, Sweeney JA, Li F, Gong Q. Microstructural white matter abnormalities in pediatric and adult obsessive-compulsive disorder: A systematic review and meta-analysis. Brain Behav 2021; 11:e01975. [PMID: 33270358 PMCID: PMC7882176 DOI: 10.1002/brb3.1975] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 11/09/2020] [Accepted: 11/15/2020] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To identify the most prominent and replicable fractional anisotropy (FA) alterations of white matter associated with obsessive-compulsive disorder (OCD) in tract-based spatial statistics (TBSS) studies. METHODS We reviewed previous TBSS studies (n = 20) in OCD and performed a meta-analysis (n = 16) of FA differences. RESULTS No between-group differences in FA were detected in the pooled meta-analysis. However, reduced FA was identified in the genu and anterior body of corpus callosum (CC) in adult OCD. FA reductions in the anterior body of CC were associated with a later age of onset in adult patients with OCD. For pediatric OCD, decreased FA in earlier adolescence and increased FA in later adolescence were seemingly related to an altered trajectory of brain maturation. CONCLUSIONS Absent in the pooled sample but robust in adults, disrupted microstructural organization in the anterior part of CC indicates a bias of deficits toward connections in interhemispheric connections of rostral neocortical regions, which could lead to deficits of interhemispheric communication and thus contribute to cognitive and emotional deficits in adult OCD. The correlation between FA in the anterior body of CC and older illness onset suggests that patients with later adult onset of illness may represent a biologically distinct subgroup. For pediatric OCD, alterations in neurodevelopmental maturation may contribute to inconsistent patterns of FA alteration relative to controls during adolescence. While most studies of OCD have emphasized alterations of within hemisphere fronto-striatal circuits, these results indicate that between hemisphere connectivity of this circuitry may also represent important pathophysiology of the illness.
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Affiliation(s)
- Qian Li
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - Youjin Zhao
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - Zixuan Huang
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Medical Imaging Technology Department, West China School of MedicineSichuan UniversityChengduChina
| | - Yi Guo
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - Jingyi Long
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - Lekai Luo
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - Wanfang You
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - John A. Sweeney
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Department of PsychiatryUniversity of CincinnatiCincinnatiOHUSA
| | - Fei Li
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC), Department of RadiologyWest China Hospital of Sichuan UniversityChengduChina
- Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengduChina
- Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan UniversityChengduChina
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Benedetti F, Poletti S, Vai B, Mazza MG, Lorenzi C, Brioschi S, Aggio V, Branchi I, Colombo C, Furlan R, Zanardi R. Higher baseline interleukin-1β and TNF-α hamper antidepressant response in major depressive disorder. Eur Neuropsychopharmacol 2021; 42:35-44. [PMID: 33191075 DOI: 10.1016/j.euroneuro.2020.11.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 10/18/2020] [Accepted: 11/06/2020] [Indexed: 01/06/2023]
Abstract
Raised pro-inflammatory immune/inflammatory setpoints, leading to an increased production of peripheral cytokines, have been associated with Major Depressive Disorder (MDD) and with failure to respond to first-line antidepressant drugs. However, the usefulness of these biomarkers in clinical psychopharmacology has been questioned because single findings did not translate into the clinical practice, where patients are prescribed treatments upon clinical need. We studied a panel of 27 inflammatory biomarkers in a sample of 108 inpatients with MDD, treated with antidepressant monotherapy for 4 weeks upon clinical need in a specialized hospital setting, and assessed the predictive effect of baseline peripheral measures of inflammation on antidepressing efficacy (response rates and time-lagged pattern of decrease of depression severity) using a machine-learning approach with elastic net penalized regression, and multivariate analyses in the context of the general linear model. When considering both categorical and continuous measures of response, baseline levels of IL-1β predicted non-response to antidepressants, with the predicted probability to respond being highly dispersed at low levels of IL-1β, and stratifying toward non-response when IL-1β is high. Significant negative effects were also detected for TNF-α, while IL-12 weakly predicted response. These findings support the usefulness of inflammatory biomarkers in the clinical psychopharmacology of depression, and add to ongoing research efforts aiming at defining reliable cutoff values to identify depressed patients in clinical settings with high inflammation, and low probability to respond.
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Affiliation(s)
- Francesco Benedetti
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy.
| | - Sara Poletti
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy
| | - Benedetta Vai
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy; Fondazione Centro San Raffaele, Milano, Italy
| | - Mario Gennaro Mazza
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy
| | - Cristina Lorenzi
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
| | - Silvia Brioschi
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
| | - Veronica Aggio
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy
| | - Igor Branchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy
| | - Cristina Colombo
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy
| | - Roberto Furlan
- Vita-Salute San Raffaele University, Milano, Italy; Clinical Neuroimmunology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy
| | - Raffaella Zanardi
- Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy
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18
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Lee YS, Choi JY, Mankhong S, Moon S, Kim S, Koh YH, Kim JH, Kang JH. Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia-reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis. Cell Death Dis 2020; 11:1072. [PMID: 33318474 PMCID: PMC7736319 DOI: 10.1038/s41419-020-03293-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 12/19/2022]
Abstract
Hypoxia-reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer's disease (AD) pathologies. Therefore, we investigated the roles of hypoxia-reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aβ) production. H/R increased nuclear-cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1-HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aβ40 and Aβ42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1.
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Affiliation(s)
- Young-Sun Lee
- Department of Pharmacology, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.,Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, 22212, Republic of Korea
| | - Ji-Young Choi
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Chungcheongbuk-do, 28159, Republic of Korea
| | - Sakulrat Mankhong
- Department of Pharmacology, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.,Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, 22212, Republic of Korea
| | - Sohee Moon
- Department of Pharmacology, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.,Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, 22212, Republic of Korea
| | - Sujin Kim
- Department of Pharmacology, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.,Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.,Department of Kinesiology, Inha University, Incheon, 22212, Republic of Korea
| | - Young Ho Koh
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Chungcheongbuk-do, 28159, Republic of Korea
| | - Ji-Hye Kim
- Department of Emergency Medicine, Inha University Hospital, Incheon, 22332, Republic of Korea
| | - Ju-Hee Kang
- Department of Pharmacology, College of Medicine, Inha University, Incheon, 22212, Republic of Korea. .,Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.
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19
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Hu J, Zhang YM, Miao YF, Zhu L, Yi XL, Chen H, Yang XJ, Wan MH, Tang WF. Effects of Yue-Bi-Tang on water metabolism in severe acute pancreatitis rats with acute lung-kidney injury. World J Gastroenterol 2020; 26:6810-6821. [PMID: 33268963 PMCID: PMC7684462 DOI: 10.3748/wjg.v26.i43.6810] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The complications acute lung injury and acute kidney injury caused by severe inflammation are the main reasons of high mortality of severe acute pancreatitis (SAP). These two complications can both lead to water metabolism and acid-base balance disorders, which could act as additional critical factors affecting the disease trend. Aquaporins (AQPs), which can regulate the transmembrane water transport, have been proved to participate in the pathophysiological process of SAP and the associated complications, such as acute lung injury and acute kidney injury. Thus, exploring herbs that can effectively regulate the expression of AQP in SAP could benefit the prognosis of this disease.
AIM To determine whether Yue-Bi-Tang (YBT) can regulate the water metabolism in rats with severe acute pancreatitis via regulating the expression of aquaporins.
METHODS Sprague-Dawley rats were randomly divided into three groups, sham operation group (SOG), model group (MG), and treatment group (TG). SAP was induced with 3.5% sodium taurocholate in the MG and TG. Rats in the TG were administered with YBT while SOG and MG rats were given the same volume of saline. Blood and tissue samples were harvested to detect serum inflammatory cytokines, histopathological changes, malondialdehyde and superoxide dismutase in the lung, and protein and mRNA expression of kidney injury molecule-1, α-smooth muscle actin, and vimentin in the kidney, and AQP1 and 4 in the lung, pancreas, and kidney.
RESULTS The serum interleukin-10, tumor necrosis factor α, and creatinine levels were higher in the MG than in the SOG. Tumor necrosis factor α level in the TG was lower than that in the MG. Malondialdehyde level in lung tissues was higher than in the SOG. The pathological scores and edema scores of the pancreas, lung, and kidney tissues in the MG were all higher than those in the SOG and TG. The protein expression of AQP4 in lung tissues and AQP1 in kidney tissues in the MG were higher than those in the SOG and TG. The expression of vimentin was significantly higher in the MG than in the SOG. The expression of AQP1 mRNA in the lung and kidney, and AQP4 mRNA in the kidney was up-regulated in the MG compared to the SOG.
CONCLUSION YBT might regulate water metabolism to reduce lung and kidney edema of SAP rats via decreasing AQP expression, and alleviate the tissue inflammatory injury.
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Affiliation(s)
- Jing Hu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Mei Zhang
- Department of Traditional Chinese Medicine, Xiang’an Hospital of Xiamen University, Xiamen 361101, Fujian Province, China
| | - Yi-Fan Miao
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Lin Yi
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Chen
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xi-Jing Yang
- Animal Experiment Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mei-Hua Wan
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Fu Tang
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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20
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Wang Y, Meagher RB, Ambati S, Ma P, Phillips BG. Patients with obstructive sleep apnea have suppressed levels of soluble cytokine receptors involved in neurodegenerative disease, but normal levels with airways therapy. Sleep Breath 2020; 25:1641-1653. [PMID: 33037528 PMCID: PMC8376707 DOI: 10.1007/s11325-020-02205-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 08/13/2020] [Accepted: 09/26/2020] [Indexed: 12/14/2022]
Abstract
Purpose Obstructive sleep apnea (OSA) results in systemic intermittent hypoxia. By one model, hypoxic stress signaling in OSA patients alters the levels of inflammatory soluble cytokines TNF and IL6, damages the blood brain barrier, and activates microglial targeting of neuronal cell death to increase the risk of neurodegenerative disorders and other diseases. However, it is not yet clear if OSA significantly alters the levels of the soluble isoforms of TNF receptors TNFR1 and TNFR2 and IL6 receptor (IL6R) and co-receptor gp130, which have the potential to modulate TNF and IL6 signaling. Methods Picogram per milliliter levels of the soluble isoforms of these four cytokine receptors were estimated in OSA patients, in OSA patients receiving airways therapy, and in healthy control subjects. Triplicate samples were examined using Bio-Plex fluorescent bead microfluidic technology. The statistical significance of cytokine data was estimated using the nonparametric Wilcoxon rank-sum test. The clustering of these high-dimensional data was visualized using t-distributed stochastic neighbor embedding (t-SNE). Results OSA patients had significant twofold to sevenfold reductions in the soluble serum isoforms of all four cytokine receptors, gp130, IL6R, TNFR1, and TNFR2, as compared with control individuals (p = 1.8 × 10−13 to 4 × 10−8). Relative to untreated OSA patients, airways therapy of OSA patients had significantly higher levels of gp130 (p = 2.8 × 10−13), IL6R (p = 1.1 × 10−9), TNFR1 (p = 2.5 × 10−10), and TNFR2 (p = 5.7 × 10−9), levels indistinguishable from controls (p = 0.29 to 0.95). The data for most airway-treated patients clustered with healthy controls, but the data for a few airway-treated patients clustered with apneic patients. Conclusions Patients with OSA have aberrantly low levels of four soluble cytokine receptors associated with neurodegenerative disease, gp130, IL6R, TNFR1, and TNFR2. Most OSA patients receiving airways therapy have receptor levels indistinguishable from healthy controls, suggesting a chronic intermittent hypoxia may be one of the factors contributing to low receptor levels in untreated OSA patients. Electronic supplementary material The online version of this article (10.1007/s11325-020-02205-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ye Wang
- Department of Statistics, University of Georgia, Athens, GA, 30602, USA
| | - Richard B Meagher
- Department of Genetics, University of Georgia, Athens, GA, 30602, USA.
| | - Suresh Ambati
- Department of Genetics, University of Georgia, Athens, GA, 30602, USA
| | - Ping Ma
- Department of Statistics, University of Georgia, Athens, GA, 30602, USA
| | - Bradley G Phillips
- Clinical and Administrative Pharmacy, University of Georgia, Athens, GA, 30602, USA.,Clinical and Translational Research Unit, University of Georgia, Athens, GA, 30602, USA
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21
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Huang P, Zhou Q, Lin Q, Lin L, Wang H, Chen X, Jiang S, Fu H, Deng Y. Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β-catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide. Brain Pathol 2020; 30:495-514. [PMID: 31622511 PMCID: PMC8018074 DOI: 10.1111/bpa.12798] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/10/2019] [Indexed: 02/05/2023] Open
Abstract
Neuroinflammation is thought to play a pivotal role in the pathogenesis of periventricular white matter (PWM) damage (PWMD) induced by neonatal sepsis. Because the complement cascade is implicated in inflammatory response, this study was carried out to determine whether C3a is involved in PWMD, and, if so, whether it would induce axonal hypomyelination. Furthermore, we explored if C3a would act through its C3a receptor (C3aR) and thence inhibit maturation of oligodendrocyte precursor cells (OPCs) via the WNT/β-catenin signal pathway. Sprague Dawley (SD) rats aged 1 day were intraperitoneally injected with lipopolysaccharide (LPS) (1 mg/kg). C3a was upregulated in activated microglia and astrocytes in the PWM up to 7 days after LPS injection. Concomitantly, enhanced C3aR expression was observed in NG2+ oligodendrocytes (OLs). Myelin proteins including CNPase, PLP, MBP and MAG were significantly reduced in the PWM of 28-day septic rats. The number of PLP+ and MBP+ cells was markedly decreased. By electron microscopy, myelin sheath thickness was thinner and the average g-ratios were higher. This was coupled with an increase in number of NG2+ cells and decreased number of CC1+ cells. Olig1, Olig2 and SOX10 protein expression was significantly reduced in the PWM after LPS injection. Very strikingly, C3aRa administration for the first 7 days could reverse the above-mentioned pathological alterations in the PWM of septic rats. When incubated with C3a, expression of MBP, CNPase, PLP, MAG, Olig1, Olig2, SOX10 and CC1 in primary cultured OPCs was significantly downregulated as opposed to increased NG2. Moreover, WNT/β-catenin signaling pathway was found to be implicated in inhibition of OPCs maturation and differentiation induced by C3a in vitro. As a corollary, it is speculated that C3a in the PWM of septic rats is closely associated with the disorder of OPCs differentiation and maturation through WNT/β-catenin signaling pathway, which would contribute ultimately to axonal hypomyelination.
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Affiliation(s)
- Peixian Huang
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
| | - Qiuping Zhou
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
- School of MedicineSouth China University of TechnologyGuangzhou510006GuangdongChina
| | - Qiongyu Lin
- Department of critical care medicineJieyang People's HospitalJieyang522000GuangdongChina
| | - Lanfen Lin
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
- Department of critical care medicineGuangdong Second Provincial General HospitalGuangzhou510317GuangdongChina
| | - Huifang Wang
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
- Affiliated South China HospitalSourthern Medical University (Guangdong Provincial People's Hospital)Guangzhou510515GuangdongChina
| | - Xuan Chen
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
- Shantou University Medical CollegeShantou5105063GuangdongChina
| | - Shuqi Jiang
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
- School of MedicineSouth China University of TechnologyGuangzhou510006GuangdongChina
| | - Hui Fu
- Department of AnatomyWuhan University School of Basic Medical SciencesWuhan430072HubeiChina
| | - Yiyu Deng
- Department of Critical Care and EmergencyGuangdong Provincial People's Hospital, Guangdong Academy of Medical SciencesGuangzhou510080GuangdongChina
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22
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Furlan R, Melloni E, Finardi A, Vai B, Di Toro S, Aggio V, Battistini L, Borsellino G, Manfredi E, Falini A, Colombo C, Poletti S, Benedetti F. Natural killer cells protect white matter integrity in bipolar disorder. Brain Behav Immun 2019; 81:410-421. [PMID: 31254622 DOI: 10.1016/j.bbi.2019.06.037] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 06/08/2019] [Accepted: 06/25/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Bipolar Disorder (BD) associates with disrupted white matter (WM) microstructure and functional connectivity, and with a perturbation of the immune system. Higher cytokines, and reduced T cells, correlated with WM disruption and fMRI responses. A core component of the innate immune system, natural killer (NK) cells were detected in brain parenchyma, but never studied in BD. METHODS We studied Diffusion Tensor Imaging (DTI) measures of water diffusion, fMRI corticolimbic functional response and connectivity, and multi-parameter cytofluorometry analysis of NK (CD56+) subpopulations, in 30 inpatients with active Bipolar Disorder type I. NK cells were also obtained in 36 healthy controls. RESULTS Patients had significantly higher circulating counts of CD56+GMCSF+, CD56+INFγ+, and CD56+IL17+. NK cell levels positively associated to fractional anisotropy (FA) measures. CD56+TNFα+, CD56+INFγ+, and CD56+GMCSF+ directly correlated with FA, and inversely with radial (RD) and mean (MD) diffusivity. Duration of lithium treatment associated with higher CD56+TNFα+, CD56+IL2+, and CD56+IL4+, and positively associated with FA in tracts were NKs had significant effects. A mediation model suggested a partial mediation of CD56+TNFα+ cells, higher in patients on lithium, on the effects of lithium on FA. Frequencies of the same cytokine-producing NK cells also influenced fMRI cortico-limbic functional connectivity during processing of both, emotional and non-emotional stimuli. DISCUSSION Higher circulating cytokine-producing NK cells associated with lithium treatment, and with DTI measures of WM integrity, partially mediating the effect of lithium on WM. The same cells associated with fMRI responses and connectivity, thus suggesting an effect on structural and functional connectomics in BD.
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Affiliation(s)
- Roberto Furlan
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Elisa Melloni
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Annamaria Finardi
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Benedetta Vai
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Sara Di Toro
- Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Veronica Aggio
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | | | | | | | - Andrea Falini
- University Vita-Salute San Raffaele, Italy; Department of Neuroradiology, San Raffaele Scientific Institute, Milano, Italy
| | - Cristina Colombo
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Sara Poletti
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy
| | - Francesco Benedetti
- University Vita-Salute San Raffaele, Italy; Psychiatry & Clinical Psychobiology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy.
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C1 Esterase Inhibitor Reduces BBB Leakage and Apoptosis in the Hypoxic Developing Mouse Brain. Neuromolecular Med 2019; 22:31-44. [DOI: 10.1007/s12017-019-08560-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 07/31/2019] [Indexed: 12/18/2022]
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24
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Wang YM, Song Z, Qu Y, Lu LQ. Down-regulated miR-21 promotes learning-memory recovery after brain injury. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:916-921. [PMID: 31933901 PMCID: PMC6945147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 01/20/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND MicroRNA is anendogenous non-coding single strand RNA which consists of 22 nt. It post-transcriptionally regulates gene expression and development. MicroRNA 21 plays an important role in repairing injured brain tissues. Thus, in this research, we explored the function of miR-21 in learning-memory recovery after brain injury. METHOD 3 days old newborn SD rats were separated into three groups: Sham operation group (Sham), inflammation-sensitized hypoxic-ischemic brain injury (LPS+HI) group and miR-21 inhibitor group. 28 days later, the learning and memory capability was assayed by water maze. H&E staining and Nissl's staining were used to assay pathologic changes and TUNEL was used to assay neuron apoptosis in brain tissue. RESULTS Water maze assay showed that the capability of positioning navigation in the IH-HI group was worse than in the Sham group and miR-21 inhibition group, and the Sham group wass better than miR-21 group. Both of the comparisons had statistical significance (P < 0.05). H&E staining in the sham group showed that the neurons were arranged well in hippocampus. In LPS+HI group, some neurons in hippocampus had vacuolar degeneration and the neurons were not well arranged well. In the hippocampus of miR-21 inhibitor group, the neuron cell layers were decreased but the neurons were arranged better than in the LPS+HI group. Nissl's staining in LPS+HI group showed neuronal edema, neurons decreased, and Nissl's bodies decreased in the cytoplasm compared with the sham group. However, compared with the LPS+HI group, Nissl's staining in miR-21 inhibitor group showed that the neuronal edema was alleviated and neurons were better arranged. TUNEL assay showed that the apoptosis rate of LPS+HI group was higher than in the miR-21 inhibitor group and miR-21 inhibitor group was higher than the sham group. CONCLUSION Down-regulated miR-21 can alleviate LPS+HI injury in the brain.
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Affiliation(s)
- You-Meng Wang
- Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical CollegeChengdu, PR China
| | - Zhen Song
- Molecular Bioinformatics, Institute of Computer Science, Johann Wolfgang Goethe-University Frankfurt Am MainGermany
| | - Yi Qu
- West China Second University HospitalChengdu, PR China
| | - Li-Qun Lu
- Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical CollegeChengdu, PR China
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25
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Ferrucci M, Biagioni F, Ryskalin L, Limanaqi F, Gambardella S, Frati A, Fornai F. Ambiguous Effects of Autophagy Activation Following Hypoperfusion/Ischemia. Int J Mol Sci 2018; 19:ijms19092756. [PMID: 30217100 PMCID: PMC6163197 DOI: 10.3390/ijms19092756] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 01/07/2023] Open
Abstract
Autophagy primarily works to counteract nutrient deprivation that is strongly engaged during starvation and hypoxia, which happens in hypoperfusion. Nonetheless, autophagy is slightly active even in baseline conditions, when it is useful to remove aged proteins and organelles. This is critical when the mitochondria and/or proteins are damaged by toxic stimuli. In the present review, we discuss to that extent the recruitment of autophagy is beneficial in counteracting brain hypoperfusion or, vice-versa, its overactivity may per se be detrimental for cell survival. While analyzing these opposite effects, it turns out that the autophagy activity is likely not to be simply good or bad for cell survival, but its role varies depending on the timing and amount of autophagy activation. This calls for the need for an appropriate autophagy tuning to guarantee a beneficial effect on cell survival. Therefore, the present article draws a theoretical pattern of autophagy activation, which is hypothesized to define the appropriate timing and intensity, which should mirrors the duration and severity of brain hypoperfusion. The need for a fine tuning of the autophagy activation may explain why confounding outcomes occur when autophagy is studied using a rather simplistic approach.
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Affiliation(s)
- Michela Ferrucci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
| | | | - Larisa Ryskalin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
| | - Fiona Limanaqi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
| | | | | | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
- IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli (IS), Italy.
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26
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Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs). Brain Sci 2018; 8:brainsci8080147. [PMID: 30087289 PMCID: PMC6119922 DOI: 10.3390/brainsci8080147] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 07/25/2018] [Accepted: 08/01/2018] [Indexed: 12/13/2022] Open
Abstract
Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality and morbidity in neonates, with survivors suffering significant neurological sequelae including cerebral palsy, epilepsy, intellectual disability and autism spectrum disorders. While hypothermia is used clinically to reduce neurological injury following HIE, it is only used for term infants (>36 weeks gestation) in tertiary hospitals and improves outcomes in only 30% of patients. For these reasons, a more effective and easily administrable pharmacological therapeutic agent, that can be used in combination with hypothermia or alone when hypothermia cannot be applied, is urgently needed to treat pre-term (≤36 weeks gestation) and term infants suffering HIE. Several recent studies have demonstrated that cationic arginine-rich peptides (CARPs), which include many cell-penetrating peptides [CPPs; e.g., transactivator of transcription (TAT) and poly-arginine-9 (R9; 9-mer of arginine)], possess intrinsic neuroprotective properties. For example, we have demonstrated that poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer (R18D) are neuroprotective in vitro following neuronal excitotoxicity, and in vivo following perinatal hypoxia-ischemia (HI). In this paper, we review studies that have used CARPs and other peptides, including putative neuroprotective peptides fused to TAT, in animal models of perinatal HIE. We critically evaluate the evidence that supports our hypothesis that CARP neuroprotection is mediated by peptide arginine content and positive charge and that CARPs represent a novel potential therapeutic for HIE.
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27
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Concepcion KR, Zhang L. Corticosteroids and perinatal hypoxic-ischemic brain injury. Drug Discov Today 2018; 23:1718-1732. [PMID: 29778695 DOI: 10.1016/j.drudis.2018.05.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/13/2018] [Accepted: 05/11/2018] [Indexed: 01/15/2023]
Abstract
Perinatal hypoxic-ischemic (HI) brain injury is the major cause of neonatal mortality and severe long-term neurological morbidity. Yet, the effective therapeutic interventions currently available are extremely limited. Corticosteroids act on both mineralocorticoid (MR) and glucocorticoid (GR) receptors and modulate inflammation and apoptosis in the brain. Neuroinflammatory response to acute cerebral HI is a major contributor to the pathophysiology of perinatal brain injury. Here, we give an overview of current knowledge of corticosteroid-mediated modulations of inflammation and apoptosis in the neonatal brain, focusing on key regulatory cells of the innate and adaptive immune response. In addition, we provide new insights into targets of MR and GR in potential therapeutic strategies that could be beneficial for the treatment of infants with HI brain injury.
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Affiliation(s)
- Katherine R Concepcion
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
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28
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Guo X, Jiang H, Chen J, Zhang BF, Hu Q, Yang S, Yang J, Zhang J. RP105 ameliorates hypoxia̸reoxygenation injury in cardiac microvascular endothelial cells by suppressing TLR4̸MAPKs̸NF-κB signaling. Int J Mol Med 2018; 42:505-513. [PMID: 29693119 DOI: 10.3892/ijmm.2018.3621] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Accepted: 12/05/2017] [Indexed: 11/10/2022] Open
Abstract
The radioprotective 105 kDa protein (RP105) has been implicated in the pathological process of multiple cardiovascular diseases through its functional and physical interactions with Toll‑like receptor 4 (TLR4). However, the effects of RP105 on cardiac microvascular endothelial cells (CMECs) in response to hypoxia̸reoxygenation (H̸R) injury have not been extensively investigated. The aim of the present study was to elucidate the potential roles of RP105 in the protection of CMECs against H̸R injury, and investigate the underlying mechanisms. CMECs isolated from Sprague‑Dawley rats were transduced with adenoviral vectors encoding RP105 or green fluorescent protein (GFP). At 48 h post‑transfection, CMECs were subjected to hypoxia for 4 h and reoxygenation for 2 h (H̸R) to simulate the in vivo ischemia̸reperfusion model. The mRNA and protein levels of RP105 were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. The effects of RP105 on CMEC proliferation, migration and apoptosis were measured by GFP‑8, Transwell chamber and flow cytometry assays, respectively. The secretion of interleukin (IL)‑6 and tumor necrosis factor (TNF)‑α in the culture medium was measured by ELISA. Moreover, the expression level of TLR4, p38 mitogen‑activated protein kinase (MAPK), extracellular-signal-regulated kinase 1̸2, c-Jun N-terminal kinase, nuclear factor (NF)‑κB̸p65, IL‑6, TNF‑α and intercellular adhesion melecule‑1 was evaluated by western blot analysis. The results demonstrated that RP105 was minimally expressed in CMECs subjected to H̸R injury. Overexpression of RP105 via adenoviral vectors was able to significantly protect CMECs against H̸R injury, as evidenced by the promotion of cell proliferation and migration, as well as the amelioration of inflammation and apoptosis. These beneficial effects were at least partly mediated through inhibition of TLR4̸MAPKs̸NF‑κB signaling. Therefore, RP105 may be a promising candidate for prevention against CMECs‑associated H̸R injury.
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Affiliation(s)
- Xin Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jing Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Bo-Fang Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qi Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Shuo Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jian Yang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei 443000, P.R. China
| | - Jing Zhang
- Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei 443000, P.R. China
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Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-κB signaling pathway after LPS treatment in neonatal rats. Oncotarget 2018; 8:31638-31654. [PMID: 28404943 PMCID: PMC5458236 DOI: 10.18632/oncotarget.15780] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 01/25/2017] [Indexed: 12/31/2022] Open
Abstract
Hypoxic-ischemic and inflammatory (HII) induces the disruption of blood–brain barrier (BBB) which leads to inflammatory responses and neuronal cell death, resulting in brain secondary damage. Previous studies showed that melatonin produced potent neuroprotective effects in neonatal hypoxic-ischaemic models. However, the relationship between BBB disruption and melatonin in HII was still unclear. The present study therefore investigated the beneficial effects of melatonin on BBB after HII and the underlying mechanisms. HII animal model was conducted by receiving lipopolysaccharide followed by 90 min hypoxia-ischaemia in postnatal day 2 Sprague–Dawley rat pups. Melatonin was injected intraperitoneally 1 h before lipopolysaccharide injection and then once a day for 1 week to evaluate the long-term effects. In this study, we demonstrated that melatonin administration inhibited the disruption of BBB permeability and improved the white matter recovery in HII model rats. Melatonin significantly attenuated the degradation of junction proteins and the neuroprotective role was related to the inhibition of microglial toll-like receptor 4/ nuclear factor-kappa B signaling pathway both in vivo and in vitro. Taken together, our data demonstrated that therapeutic strategies targeting inflammation might be suitable for the therapy of preserving BBB integrity after HII.
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Necrostatin-1 Improves Long-term Functional Recovery Through Protecting Oligodendrocyte Precursor Cells After Transient Focal Cerebral Ischemia in Mice. Neuroscience 2018; 371:229-241. [DOI: 10.1016/j.neuroscience.2017.12.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 12/04/2017] [Accepted: 12/06/2017] [Indexed: 11/22/2022]
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Yin X, Zhao J, Jiang H, Li L, Jiang J, Xi H, Peng X, Yin X, Shi X, Zhang L. Impact of Xenon on CLIC4 and Bcl-2 Expression in Lipopolysaccharide and Hypoxia-Ischemia-Induced Periventricular White Matter Damage. Neonatology 2018. [PMID: 29518790 DOI: 10.1159/000487220] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Premature birth is a significant health care burden. Xenon (Xe) is a general anesthetic with neuroprotective effects. OBJECTIVES Here, we investigate the neuroprotective role of Xe in a lipopolysaccharide (LPS)- and hypoxia-ischemia (HI)-induced white matter damage (WMD) model. METHODS Three-day-old Sprague-Dawley rats were randomly divided into a sham group (group A, n = 24), an LPS + HI group (group B, n = 24), and an LPS + HI + Xe group (group C, n = 72). The onset of Xe inhalation started at 0, 2, and 5 h in subgroups C1, C2, and C3, respectively. Next, we performed TUNEL and hematoxylin and eosin (HE) staining; and examined the expression of CLIC4 and Bcl-2 in brain tissues. RESULTS HE staining revealed distorted cytoarchitecture, tangled nerve fibers, and pyknosis in group B, while Xe treatment improved these histological alterations in the group C pups. Following LPS and HI insult, the number of apoptotic cells significantly increased in group B at 48 and 72 h (p < 0.05), and Xe significantly alleviated apoptosis (p < 0.001) at 24, 48, and 72 h, respectively. Similarly, CLIC4 mRNA expression was significantly increased in group B (p < 0.05), and Xe produced a marked reduction in CLIC4 mRNA expression in group C subgroups (p < 0.05). Western blotting demonstrated enhanced Bcl-2 expression in group C when compared to group B (p < 0.05). CONCLUSIONS These results demonstrate that LPS and HI successfully induced WMD, and Xe decreased neuronal apoptosis via Bcl-2- and CLIC4-mediated pathways. Moreover, the therapeutic time window of Xe extended for up to 5 h. These findings suggest that Xe can be used as a protective treatment for WMD in premature infants.
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Li B, Concepcion K, Meng X, Zhang L. Brain-immune interactions in perinatal hypoxic-ischemic brain injury. Prog Neurobiol 2017; 159:50-68. [PMID: 29111451 PMCID: PMC5831511 DOI: 10.1016/j.pneurobio.2017.10.006] [Citation(s) in RCA: 162] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 10/26/2017] [Indexed: 01/07/2023]
Abstract
Perinatal hypoxia-ischemia remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as behavioral, social, attentional, cognitive and functional motor deficits. An ever-increasing body of evidence shows that the immune response to acute cerebral hypoxia-ischemia is a major contributor to the pathophysiology of neonatal brain injury. Hypoxia-ischemia provokes an intravascular inflammatory cascade that is further augmented by the activation of resident immune cells and the cerebral infiltration of peripheral immune cells response to cellular damages in the brain parenchyma. This prolonged and/or inappropriate neuroinflammation leads to secondary brain tissue injury. Yet, the long-term effects of immune activation, especially the adaptive immune response, on the hypoxic-ischemic brain still remain unclear. The focus of this review is to summarize recent advances in the understanding of post-hypoxic-ischemic neuroinflammation triggered by the innate and adaptive immune responses and to discuss how these mechanisms modulate the brain vulnerability to injury. A greater understanding of the reciprocal interactions between the hypoxic-ischemic brain and the immune system will open new avenues for potential immunomodulatory therapy in the treatment of neonatal brain injury.
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Affiliation(s)
- Bo Li
- The Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
| | - Katherine Concepcion
- The Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Xianmei Meng
- The Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
| | - Lubo Zhang
- The Lawrence D. Longo, MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA
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Victores AJ, Chen M, Smith A, Lane AP. Olfactory loss in chronic rhinosinusitis is associated with neuronal activation of c-Jun N-terminal kinase. Int Forum Allergy Rhinol 2017; 8:415-420. [PMID: 29193850 DOI: 10.1002/alr.22053] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/22/2017] [Accepted: 11/07/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND Olfactory inflammation in chronic rhinosinusitis (CRS) is associated with cytokines that may result in the death of olfactory sensory neurons. The principal signaling molecules involved in the apoptotic pathway are c-Jun N-terminal kinases (JNK). Although the JNK pathway has emerged as a key player in programmed cell death in neuroinflammation, its specific role in CRS-associated olfactory loss has not been thoroughly investigated. METHODS JNK activation was studied in human tissue samples from 9 control and 11 CRS patients by immunohistochemical staining for phosphorylated c-Jun. A mouse model of inducible olfactory cytokine expression was used to experimentally control inflammation and assess JNK activation over time. RESULTS In patients with CRS, activation of c-Jun is significantly increased relative to non-CRS control subjects, and there is an associated loss of sensory neurons. In the olfactory inflammation mouse model, prolonged induction of inflammation results in elevation of c-Jun expression and neuronal apoptosis. CONCLUSION Activation of neuronal JNK is a feature of chronic olfactory inflammation that is associated with neuronal apoptosis. Given that inhibition of JNK activity is neuroprotective in other settings, antagonism of this pathway may have therapeutic potential in the management of inflammatory olfactory loss or other disorders linked to olfactory neuronal apoptosis.
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Affiliation(s)
- Andrew J Victores
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mengfei Chen
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Amy Smith
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Andrew P Lane
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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van Tilborg E, de Theije CGM, van Hal M, Wagenaar N, de Vries LS, Benders MJ, Rowitch DH, Nijboer CH. Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury. Glia 2017; 66:221-238. [PMID: 29134703 PMCID: PMC5765410 DOI: 10.1002/glia.23256] [Citation(s) in RCA: 183] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/17/2017] [Accepted: 10/20/2017] [Indexed: 12/11/2022]
Abstract
Infants born prematurely are at high risk to develop white matter injury (WMI), due to exposure to hypoxic and/or inflammatory insults. Such perinatal insults negatively impact the maturation of oligodendrocytes (OLs), thereby causing deficits in myelination. To elucidate the precise pathophysiology underlying perinatal WMI, it is essential to fully understand the cellular mechanisms contributing to healthy/normal white matter development. OLs are responsible for myelination of axons. During brain development, OLs are generally derived from neuroepithelial zones, where neural stem cells committed to the OL lineage differentiate into OL precursor cells (OPCs). OPCs, in turn, develop into premyelinating OLs and finally mature into myelinating OLs. Recent studies revealed that OPCs develop in multiple waves and form potentially heterogeneous populations. Furthermore, it has been shown that myelination is a dynamic and plastic process with an excess of OPCs being generated and then abolished if not integrated into neural circuits. Myelination patterns between rodents and humans show high spatial and temporal similarity. Therefore, experimental studies on OL biology may provide novel insights into the pathophysiology of WMI in the preterm infant and offers new perspectives on potential treatments for these patients.
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Affiliation(s)
- Erik van Tilborg
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Caroline G M de Theije
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Maurik van Hal
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Nienke Wagenaar
- Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Linda S de Vries
- Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Manon J Benders
- Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - David H Rowitch
- Department of Pediatrics, Eli and Edythe Broad Center for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, California.,Department of Paediatrics, Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
| | - Cora H Nijboer
- Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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35
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Subedi L, Venkatesan R, Kim SY. Neuroprotective and Anti-Inflammatory Activities of Allyl Isothiocyanate through Attenuation of JNK/NF-κB/TNF-α Signaling. Int J Mol Sci 2017; 18:ijms18071423. [PMID: 28671636 PMCID: PMC5535914 DOI: 10.3390/ijms18071423] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Revised: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 12/23/2022] Open
Abstract
Allyl isothiocyanate (AITC), present in Wasabia japonica (wasabi), is an aliphatic isothiocyanate derived from the precursor sinigrin, which is a glucosinolate present in vegetables of the Brassica family. Traditionally, it has been used to treat rheumatic arthralgia, blood circulation, and pain. This study focuses on its anti-apoptotic activity through the regulation of lipopolysaccharide (LPS)-induced neuroinflammation. Furthermore, we assessed its neuroprotective efficacy, which it achieves through the upregulation of nerve growth factor (NGF) production. Pretreatment with AITC significantly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, decreased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO) production in activated microglia, and increased the nerve growth factor (NGF) and neurite outgrowth in neuroblastoma cells. AITC inhibited the nuclear factor (NF-κB-mediated transcription by modulating mitogen activated protein kinase (MAPK) signaling, particularly downregulating c-Jun N-terminal kinase (JNK) phosphorylation, which was followed by a reduction in the TNF-α expression in activated microglia. This promising effect of AITC in controlling JNK/NF-κB/TNF-α cross-linking maintains the Bcl-2 gene family and protects neuroblastoma cells from activated microglia-induced toxicity. These findings provide novel insights into the anti-neuroinflammatory effects of AITC on microglial cells, which may have clinical significance in neurodegeneration.
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Affiliation(s)
- Lalita Subedi
- Laboratory of Pharmacognosy, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
| | - Ramu Venkatesan
- Laboratory of Pharmacognosy, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
| | - Sun Yeou Kim
- Laboratory of Pharmacognosy, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.
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Adipogenic miR-27a in adipose tissue upregulates macrophage activation via inhibiting PPARγ of insulin resistance induced by high-fat diet-associated obesity. Exp Cell Res 2017; 355:105-112. [PMID: 28365247 DOI: 10.1016/j.yexcr.2017.03.060] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 03/03/2017] [Accepted: 03/28/2017] [Indexed: 01/05/2023]
Abstract
Chronic low degree inflammation caused by macrophage activation is a crucial factor underlying insulin resistance induced by obesity. To illustrate the mechanism of regulating of macrophage activation in adipose tissue, the role of adipogenic miR-27a activating M1 macrophage polarization via blocking PPARγ was evaluated. Obese mice model and miR-27a overexpression or knockdown mice model were established and related biochemical index were examined. Raw264.7 and 3T3-L1 were cultured and co-cultured for mimicking the microenvironment of local inflammation. Macrophage infiltration was observed. MiR-27a and cytokines levels in serum and adipose tissue were measured. Macrophage polarization markers and protein expression in insulin or inflammatory signaling pathways were observed. Impaired glucose tolerance and insulin tolerance was observed in 4w, 8w and 12w of high fat diet and miR-27a overexpression mice. Concurrently, miR-27a was increased in serum in a time-dependent manner, along with M1 cytokines and M1 macrophages increasing in adipose tissue clearly. Insulin signaling pathway was blocked, and PPARγ was suppressed. However, NF-κB was activated. On the other hand, activated macrophages and hypertrophic adipocytes induced by miR-27a could increase the ratio of Raw264.7 migration, including improving cytokines generation, and blocking PPARγ expression markedly. The present studies are conducted to clarify that miR-27a has increased along with up-regulation in the process of proinflammatory cytokines generation, macrophage influx and M1 macrophage polarization in obesity. These indicate that miR-27a gives the novel target of intervention for inflammation and insulin resistance in obesity.
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Skladnev NV, Ganeshan V, Kim JY, Burton TJ, Mitrofanis J, Stone J, Johnstone DM. Widespread brain transcriptome alterations underlie the neuroprotective actions of dietary saffron. J Neurochem 2016; 139:858-871. [PMID: 27696408 DOI: 10.1111/jnc.13857] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/21/2016] [Accepted: 09/21/2016] [Indexed: 12/21/2022]
Abstract
Dietary saffron has shown promise as a neuroprotective intervention in clinical trials of retinal degeneration and dementia and in animal models of multiple CNS disorders, including Parkinson's disease. This therapeutic potential makes it important to define the relationship between dose and protection and the mechanisms involved. To explore these two issues, mice were pre-conditioned by providing an aqueous extract of saffron (0.01% w/v) as their drinking water for 2, 5 or 10 days before administration of the parkinsonian neurotoxin MPTP (50 mg/kg). Five days of saffron pre-conditioning provided the greatest benefit against MPTP-induced neuropathology, significantly mitigating both loss of functional dopaminergic cells in the substantia nigra pars compacta (p < 0.01) and abnormal neuronal activity in the caudate-putamen complex (p < 0.0001). RNA microarray analysis of the brain transcriptome of mice pre-conditioned with saffron for 5 days revealed differential expression of 424 genes. Bioinformatics analysis identified enrichment of molecular pathways (e.g. adherens junction, TNFR1 and Fas signaling) and expression changes in candidate genes (Cyr61, Gpx8, Ndufs4, and Nos1ap) with known neuroprotective actions. The apparent biphasic nature of the dose-response relationship between saffron and measures of neuroprotection, together with the stress-inducible nature of many of the up-regulated genes and pathways, lend credence to the idea that saffron, like various other phytochemicals, is a hormetic stimulus, with functions beyond its strong antioxidant capacity. These findings provide impetus for a more comprehensive evaluation of saffron as a neuroprotective intervention.
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Affiliation(s)
- Nicholas V Skladnev
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Physiology, University of Sydney, Sydney, NSW, Australia
| | - Varshika Ganeshan
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Physiology, University of Sydney, Sydney, NSW, Australia
| | - Ji Yeon Kim
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Physiology, University of Sydney, Sydney, NSW, Australia.,School of Medicine, University of Queensland Centre for Clinical Research, Brisbane, Qld, Australia
| | - Thomas J Burton
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Physiology, University of Sydney, Sydney, NSW, Australia
| | - John Mitrofanis
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Anatomy & Histology, University of Sydney, Sydney, NSW, Australia
| | - Jonathan Stone
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Physiology, University of Sydney, Sydney, NSW, Australia
| | - Daniel M Johnstone
- Bosch Institute, University of Sydney, Sydney, NSW, Australia.,Discipline of Physiology, University of Sydney, Sydney, NSW, Australia
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Zhu J, Qu Y, Lin Z, Zhao F, Zhang L, Huang Y, Jiang C, Mu D. Loss of PINK1 inhibits apoptosis by upregulating α-synuclein in inflammation-sensitized hypoxic-ischemic injury in the immature brains. Brain Res 2016; 1653:14-22. [PMID: 27742469 DOI: 10.1016/j.brainres.2016.10.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 09/04/2016] [Accepted: 10/10/2016] [Indexed: 01/23/2023]
Abstract
The incidence of preterm birth is rising worldwide. Among preterm infants, many face a lifetime of neurologic impairments. Recent studies have revealed that systemic inflammation can sensitize the immature brain to hypoxic-ischemic (HI) injury. Therefore, it is important to identify the mechanisms involved in inflammation-sensitized HI injury in immature brains. PTEN-induced putative kinase 1 (PINK1) is a regulatory protein that is highly expressed in the brain. We have previously found that PINK1 gene knockout can protect matured brains from HI injury in postnatal day 10 mice. However, the mechanisms are unknown. In this study, we employed an inflammation-sensitized HI injury model using postnatal day 3 mice to study the roles and mechanisms that PINK1 plays in the immature brains. Lipopolysaccharide (LPS) was injected intraperitoneally into the mice before HI treatment to set up the model. We found that PINK1-knockout mice had fewer brain infarcts and less cell apoptosis than did the wild-type mice. Furthermore, we found that α-synuclein was markedly higher in the PINK1-knockout mice than in the wild-type mice, and inhibition of α-synuclein through small interfering RNA (siRNA) reversed the protective effect in the PINK1-knockout mice. Collectively, these findings indicate that loss of PINK1 plays a novel role in the protection of inflammation-sensitized HI brain damage.
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Affiliation(s)
- Jianghu Zhu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China; Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, China.
| | - Yi Qu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
| | - Zhenlang Lin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, China.
| | - Fengyan Zhao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
| | - Li Zhang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
| | - Yang Huang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
| | - Changan Jiang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China.
| | - Dezhi Mu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu 610041, China; Department of Pediatrics, University of California, San Francisco, USA.
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Benedetti F, Poletti S, Hoogenboezem TA, Mazza E, Ambrée O, de Wit H, Wijkhuijs AJM, Locatelli C, Bollettini I, Colombo C, Arolt V, Drexhage HA. Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder. J Affect Disord 2016; 202:1-9. [PMID: 27253210 DOI: 10.1016/j.jad.2016.05.047] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/21/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND Bipolar Disorder (BD) is associated with elevated biomarkers of cell-mediated immune activation and inflammation and with signs of widespread disruption of white matter (WM) integrity in adult life. Consistent findings in animal models link WM damage in inflammatory diseases of the brain and serum levels of cytokines. METHODS With an exploratory approach, we tested the effects of 22 serum analytes, including pro- and anti-inflammatory cytokines and neurotrophic/hematopoietic factors, on DTI measures of WM microstructure in a sample of 31 patients with a major depressive episode in course of BD. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA). RESULTS The inflammation-related cytokines TNF-α, IL-8, IFN-γ and IL-10, and the growth factors IGFBP2 and PDGF-BB, shared the same significant associations with lower FA, and higher MD and RD, in large overlapping networks of WM fibers mostly located in the anterior part of the brain and including corpus callosum, cingulum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, uncinate, forceps, corona radiata, thalamic radiation, internal capsule. CONCLUSIONS Higher RD is thought to signify increased space between fibers, suggesting demyelination or dysmyelination. The pattern of higher RD and MD with lower FA suggests that inflammation-related cytokine and growth factor levels inversely associate with integrity of myelin sheaths. The activated inflammatory response system might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.
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Affiliation(s)
- Francesco Benedetti
- Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy.
| | - Sara Poletti
- Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy
| | | | - Elena Mazza
- Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy
| | - Oliver Ambrée
- Department of Psychiatry, University of Münster, Münster, Germany
| | - Harm de Wit
- Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands
| | | | - Clara Locatelli
- Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy
| | - Irene Bollettini
- Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy
| | - Cristina Colombo
- Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milano, University Vita-Salute San Raffaele, Milano, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), University Vita-Salute San Raffaele, Milano, Italy
| | - Volker Arolt
- Department of Psychiatry, University of Münster, Münster, Germany
| | - Hemmo A Drexhage
- Department of Immunology, Erasmus University Medical Centre, Rotterdam, Netherlands
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Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways. Int J Mol Sci 2016; 17:ijms17071051. [PMID: 27420048 PMCID: PMC4964427 DOI: 10.3390/ijms17071051] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/05/2016] [Accepted: 06/27/2016] [Indexed: 12/15/2022] Open
Abstract
Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p < 0.05). Furthermore, the levels of STC-1,p53, phosphorylated mitogen-activated protein kinase kinase (p-MEKK-1), c-Jun N-terminal kinase (p-JNK), extracellular signal-regulated kinase (p-ERK), IkB kinase (p-IKK), nuclear factor (NF) κB, apoptosis signal-regulating kinase 1 (ASK-1) and caspase-3 changed significantly in kidney cells isolated from a RIRI model when compared to those isolated from a sham control (p < 0.05). Meanwhile, STC-1 overexpression or silence caused significant changes of the levels of these ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and reduce of capase-3, p53, IL-6 and IFN-γ.
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Kaminska B, Mota M, Pizzi M. Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. Biochim Biophys Acta Mol Basis Dis 2016; 1862:339-51. [DOI: 10.1016/j.bbadis.2015.10.026] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/12/2015] [Accepted: 10/28/2015] [Indexed: 12/21/2022]
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Wong SY, Tan MGK, Banks WA, Wong WSF, Wong PTH, Lai MKP. Andrographolide attenuates LPS-stimulated up-regulation of C-C and C-X-C motif chemokines in rodent cortex and primary astrocytes. J Neuroinflammation 2016; 13:34. [PMID: 26860080 PMCID: PMC4748554 DOI: 10.1186/s12974-016-0498-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 02/01/2016] [Indexed: 01/04/2023] Open
Abstract
Background Andrographolide is the major bioactive compound isolated from Andrographis paniculata, a native South Asian herb used medicinally for its anti-inflammatory properties. In this study, we aimed to assess andrographolide’s potential utility as an anti-neuroinflammatory therapeutic. Methods The effects of andrographolide on lipopolysaccharide (LPS)-induced chemokine up-regulation both in mouse cortex and in cultured primary astrocytes were measured, including cytokine profiling, gene expression, and, in cultured astrocytes, activation of putative signaling regulators. Results Orally administered andrographolide significantly attenuated mouse cortical chemokine levels from the C-C and C-X-C subfamilies. Similarly, andrographolide abrogated a range of LPS-induced chemokines as well as tumor necrosis factor (TNF)-α in astrocytes. In astrocytes, the inhibitory actions of andrographolide on chemokine and TNF-α up-regulation appeared to be mediated by nuclear factor-κB (NF-κB) or c-Jun N-terminal kinase (JNK) activation. Conclusions These results suggest that andrographolide may be useful as a therapeutic for neuroinflammatory diseases, especially those characterized by chemokine dysregulation. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0498-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Siew Ying Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Kent Ridge, 117600, Singapore.
| | - Michelle G K Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Kent Ridge, 117600, Singapore. .,Department of Clinical Research, Singapore General Hospital, Outram, Singapore.
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. .,Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Seattle, WA, USA.
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Kent Ridge, 117600, Singapore. .,Immunology Program, Life Science Institute, National University of Singapore, Kent Ridge, Singapore.
| | - Peter T-H Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Kent Ridge, 117600, Singapore.
| | - Mitchell K P Lai
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Kent Ridge, 117600, Singapore.
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Lack of Proinflammatory Cytokine Interleukin-6 or Tumor Necrosis Factor Receptor-1 Results in a Failure of the Innate Immune Response after Bacterial Meningitis. Mediators Inflamm 2016; 2016:7678542. [PMID: 27057100 PMCID: PMC4749820 DOI: 10.1155/2016/7678542] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 01/04/2016] [Indexed: 12/27/2022] Open
Abstract
The most frequent pathogen that causes bacterial meningitis is the Gram-positive bacterium Streptococcus pneumoniae. By entering the brain, host cells will be activated and proinflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are released. The goal of the current study was to examine the interaction between IL-6 and TNFR1 as receptor for TNF-α and the innate immune response in vivo in a model of Streptococcus pneumoniae-induced meningitis. For the experiments IL-6(-/-), TNFR1(-/-), and TNFR1-IL-6(-/-) KO mice were used. Our results revealed higher mortality rates and bacterial burden after infection in TNFR1(-/-), IL-6(-/-), and TNFR1-IL-6(-/-) mice and a decreased immune response including lower neutrophil infiltration in the meninges of TNFR1(-/-) and TNFR1-IL-6(-/-) mice in contrast to IL-6(-/-) and wild type mice. Furthermore, the increased mortality of TNFR1(-/-) and TNFR1-IL-6(-/-) mice correlated with decreased glial cell activation compared to IL-6(-/-) or wild type mice after pneumococcal meningitis. Altogether, the results show the importance of TNFR1 and IL-6 in the regulation of the innate immune response. The lack of TNFR1 and IL-6 results in higher mortality by weakened immune defence, whereas the lack of TNFR1 results in more severe impairment of the innate immune response than the lack of IL-6 alone.
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Wang LY, Tu YF, Lin YC, Huang CC. CXCL5 signaling is a shared pathway of neuroinflammation and blood-brain barrier injury contributing to white matter injury in the immature brain. J Neuroinflammation 2016; 13:6. [PMID: 26738635 PMCID: PMC4704424 DOI: 10.1186/s12974-015-0474-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 12/30/2015] [Indexed: 12/17/2022] Open
Abstract
Background In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood–brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. Methods Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. Results On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreased myelination and increased astrogliosis) was observed on P12 compared with controls. Immunohistochemical analyses revealed increased CXCL5 expression in the white matter 6 and 24 h after insult. Immunofluorescence experiments revealed upregulated CXCL5 expression in the activated microglia and endothelial cells 24 h after insult. CXCL5 inhibition by SB225002, a selective nonpeptide inhibitor of CXCR2, significantly attenuated microglial activation and BBB damage, increased myelination, and reduced astrogliosis in the white matter after LPS-sensitized HI. In addition, CXCL5-sensitized HI or CXCL5 alone significantly induced BBB damage and white matter injury in association with different neuroinflammation mechanisms. CXCL5-sensitized HI-induced microglial activation and neutrophil infiltration, whereas CXCL5 alone predominately caused neutrophil infiltration. Conclusions CXCL5 is a potential biomarker for white matter injury in preterm infants. Pharmacological blockade of CXCL5 signaling that attenuates dysregulated neuroinflammation can be used a therapeutic strategy against white matter injury in the immature brain. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0474-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lin-Yu Wang
- Department of Pediatrics, Chi Mei Medical Center, Tainan, 710, Taiwan. .,Department of Childhood Education and Nursery, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
| | - Yi-Fang Tu
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan. .,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
| | - Yung-Chieh Lin
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan. .,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan.
| | - Chao-Ching Huang
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan. .,Department of Pediatrics, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan. .,Department of Pediatrics, Wan-Fang Hospital, Taipei Medical University, Taipei, 110, Taiwan.
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Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders. Antibodies (Basel) 2015. [DOI: 10.3390/antib4040369] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Effects of Etanercept against Transient Cerebral Ischemia in Diabetic Rats. BIOMED RESEARCH INTERNATIONAL 2015; 2015:189292. [PMID: 26665003 PMCID: PMC4668299 DOI: 10.1155/2015/189292] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/28/2015] [Indexed: 01/08/2023]
Abstract
Diabetes mellitus is known to exacerbate acute cerebral ischemic injury. Previous studies have demonstrated that infarction volumes caused by transient cerebral ischemia were greater in diabetic rats than in nondiabetic rats. Tumor necrosis factor-α (TNF-α) is a proinflammatory protein produced in the brain in response to cerebral ischemia that promotes apoptosis. Etanercept (ETN), a recombinant TNF receptor (p75)-Fc fusion protein, competitively inhibits TNF-α. Therefore, we evaluated the neuroprotective effects of chronic or acute treatment with ETN on cerebral injury caused by middle cerebral artery occlusion/reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. Furthermore, we evaluated the effects of ETN against the apoptosis and myeloperoxidase activity. Single administration of ETN before MCAO significantly suppressed exacerbation of cerebral damage in nondiabetic rats, as assessed by infarct volume. In contrast, the diabetic state markedly aggravated MCAO/Re-induced cerebral damage despite ETN treatment within 24 h before MCAO. However, the damage was improved by repeated administration of ETN at 900 μg/kg/daily in rats in an induced diabetic state. These results suggested that repeated administration of ETN can prevent exacerbation of cerebral ischemic injury in the diabetic state and is mainly attributed to anti-inflammatory effects.
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An Extended Way to Predict Neonatal Hypoxic Ischemic Encephalopathy. Pediatr Neonatol 2015; 56:283-4. [PMID: 26411926 DOI: 10.1016/j.pedneo.2015.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 08/14/2015] [Indexed: 11/23/2022] Open
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Shi H, Hu X, Leak RK, Shi Y, An C, Suenaga J, Chen J, Gao Y. Demyelination as a rational therapeutic target for ischemic or traumatic brain injury. Exp Neurol 2015; 272:17-25. [PMID: 25819104 DOI: 10.1016/j.expneurol.2015.03.017] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 03/15/2015] [Accepted: 03/18/2015] [Indexed: 12/11/2022]
Abstract
Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients.
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Affiliation(s)
- Hong Shi
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Anesthesiology of Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China
| | - Xiaoming Hu
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA
| | - Rehana K Leak
- Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA
| | - Yejie Shi
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA
| | - Chengrui An
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Jun Suenaga
- Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Jun Chen
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
| | - Yanqin Gao
- The State Key Laboratory of Medical Neurobiology, The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
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