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Zhou Y, Feng Y, Zhao Y, Wu Y, Li M, Yang X, Wu X, Chen X. Oral 7,8-Dihydroxyflavone Protects Retinal Ganglion Cells by Modulating the Gut-Retina Axis and Inhibiting Ferroptosis via the Indoleacrylic Acid-AhR-ALDH1A3-FSP1 Pathway. CNS Neurosci Ther 2025; 31:e70442. [PMID: 40365730 PMCID: PMC12076127 DOI: 10.1111/cns.70442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/23/2025] [Accepted: 05/05/2025] [Indexed: 05/15/2025] Open
Abstract
OBJECTIVES 7,8-Dihydroxyflavone (7,8-DHF) activates the TrkB receptor, offering neuroprotection, yet its pharmacological limitations restrict its safe and effective delivery to the eye and brain, impeding clinical translation. This study explores the protective effects of oral 7,8-DHF on retinal ganglion cells (RGCs) by inhibiting ferroptosis and investigates the involvement of the gut-retina axis, particularly the Indoleacrylic acid (IDA)-AhR-ALDH1A3-FSP1 pathway, with potential clinical implications. METHODS To evaluate the neuroprotective effects of oral 7,8-DHF, retinal 3D cultures were used for axon regeneration and GCL cell apoptosis, and ONC models for RGC survival and electrophysiology. Mechanisms were investigated by assessing ferroptosis-related proteins via Western blotting, screening differential metabolites in PC12 cells, analyzing mitochondrial changes with TEM, evaluating gut microbiota shifts, and examining metabolite changes in retina and feces. RESULTS Oral 7,8-DHF enhanced RGC survival and retinal function in the ONC model by inhibiting ferroptosis, independent of TrkB activation. This effect was blocked by antibiotics and AHR, ALDH1A3, and FSP1 inhibitors. Metabolomics showed increased IDA in retina and feces, with IDA inhibiting ferroptosis in PC12 cells and promoting axonal regeneration in retinal explants. Western blot revealed upregulation of nAhR and ALDH1A3, while non-FSP1 ferroptosis proteins were unaffected. 7,8-DHF also altered gut microbiota, increasing Parasutterella, which correlated with higher IDA levels. CONCLUSIONS 7,8-DHF regulates the gut microbiota to increase IDA levels in the intestine, which subsequently leads to the accumulation of IDA in the retina. This activates the AhR-ALDH1A3-FSP1 axis in the retina, thereby inhibiting retinal ferroptosis and exerting neuroprotective effects.
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Affiliation(s)
- Yanping Zhou
- Department of OphthalmologyZhongshan Hospital of Fudan UniversityShanghaiChina
| | - Yifan Feng
- Department of OphthalmologyZhongshan Hospital of Fudan UniversityShanghaiChina
| | - Yingxi Zhao
- Department of OphthalmologyEye Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Yu Wu
- Department of OphthalmologyTaizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical UniversityTaizhouZhejiangChina
| | - Min Li
- Department of OphthalmologyZhongshan Hospital of Fudan UniversityShanghaiChina
| | - Xi Yang
- Department of OphthalmologyZhongshan Hospital of Fudan UniversityShanghaiChina
| | - Xinyuan Wu
- Department of OphthalmologyZhongshan Hospital of Fudan UniversityShanghaiChina
| | - Xiangwu Chen
- Department of OphthalmologyZhongshan Hospital of Fudan UniversityShanghaiChina
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Chen Z, Liu X, Feng X, Lyu A, Zhou W. A systematic pharmacological strategy-based to decode the synergistic mechanism of 7,4'-dihydroxyflavone in combination with vitamin D3 against asthma. JOURNAL OF ETHNOPHARMACOLOGY 2025; 344:119513. [PMID: 39971017 DOI: 10.1016/j.jep.2025.119513] [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: 11/26/2024] [Revised: 01/24/2025] [Accepted: 02/16/2025] [Indexed: 02/21/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE 7,4'-dihydroxyflavone (74DHF), extracted from Gancao (Rhizoma Glycyrrhizae), has demonstrated to mediate the asthma pathology, while Vitamin D3 (VD3) plays a role in asthma treatment due to its immunomodulatory effects. However, the potential molecular or systems mechanism of 74DHF in combination with VD3 against asthma has not yet been elucidated. AIM OF THE STUDY The current study not only deepens our understanding of the complex synergistic mechanism of 74DHF andVD3 against asthma but also proposes a promising strategy to promote the development of combination therapy. MATERIALS AND METHODS This study employed a systems pharmacology-based approach integrating target fishing, data integration, bioinformatics analysis, network analysis, Gene Ontology (GO) enrichment analysis, pathway analysis, and in vitro experiment validation to elucidate the pharmacological mechanisms of the combination of 74DHF and VD3 for asthma treatment. RESULTS Our investigation revealed 47 overlapping targets, 20 core targets, 10 optimal common GO processes, and 10 key pathways closely associated with asthma in the combination of 74DHF and VD3. The combined treatment of 74DHF and VD3 inhibited the inflammatory response (TNF-α and IL-6) induced by LPS in macrophages and epithelial to mesenchymal transition (EMT) related genes expression (CDH1 and ACTA2) in bronchial epithelial cells under the stimulation of TGF-β1. CONCLUSION The present study deciphered the molecular mechanism of combined therapeutic effect of 74DHF and VD3 on asthma on systemic and cellular level.
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Affiliation(s)
- Ziyi Chen
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518020, China; Department of Respirology & Allergy. Third Affiliated Hospital of Shenzhen University. Shenzhen University, Shenzhen, 518020, China; Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China
| | - Xiaoyu Liu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518020, China; Department of Respirology & Allergy. Third Affiliated Hospital of Shenzhen University. Shenzhen University, Shenzhen, 518020, China
| | - Xiaoyang Feng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, China
| | - Aiping Lyu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong.
| | - Wei Zhou
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy & Immunology, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518020, China; Department of Respirology & Allergy. Third Affiliated Hospital of Shenzhen University. Shenzhen University, Shenzhen, 518020, China.
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Filisola-Villaseñor JG, Arroyo-Sánchez BI, Navarro-González LJ, Morales-Ríos E, Olin-Sandoval V. Ornithine decarboxylase and its role in cancer. Arch Biochem Biophys 2025; 765:110321. [PMID: 39870288 DOI: 10.1016/j.abb.2025.110321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/03/2025] [Accepted: 01/24/2025] [Indexed: 01/29/2025]
Abstract
Cancer is among the leading causes of death worldwide. The effectiveness of conventional chemotherapy has some drawbacks, therefore, there is an urgency to develop novel strategies to fight this disease. Ornithine decarboxylase (ODC) is the most finely tuned enzyme of the polyamine (PA) biosynthesis pathway as it is regulated at different levels: transcriptional, translational, post-translational, and by feedback inhibition. In cancer, this enzyme is overexpressed due to its regulation by the protooncogene c-Myc, thus it has been proposed as a drug target against this disease. This review describes information regarding the biochemistry and regulation of the ODC at different levels and its role in cancer. Moreover, we discuss the molecules aiming on the inhibition of the ODC activity that have been tested as therapeutic options. ODC remains as a therapeutic opportunity that needs to be more explored.
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Affiliation(s)
| | - Beatriz Irene Arroyo-Sánchez
- Department of Biotechnology and Bioengineering, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Luis Janiel Navarro-González
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico
| | - Edgar Morales-Ríos
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
| | - Viridiana Olin-Sandoval
- Department of Biotechnology and Bioengineering, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
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Wei X, Li M, You J, Luo J, Zhai J, Zhang J, Feng J, Wang H, Zhou Y. A Procedural Overview of the Involvement of Small Molecules in the Nervous System in the Regulation of Bone Healing. Int J Nanomedicine 2025; 20:1263-1284. [PMID: 39906525 PMCID: PMC11792627 DOI: 10.2147/ijn.s505677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
Clinically, a multitude of factors can contribute to the development of bone defects. In the process of bone healing, the nervous system plays a vital role in bone regeneration. Small molecules from the nervous system, such as neurotrophic factors and neuropeptides, have been found to stimulate osteoblast proliferation and differentiation by activating signaling pathways associated with bone calcification and angiogenesis. These small molecules play a crucial regulatory role at various stages of bone healing. The systematic release mechanism of small molecules within the nervous system through diverse bone tissue engineering materials holds significant clinical implications for the controlled regulation of the bone healing process. This review provides an overview of the involvement of various nervous system small molecules at different stages of bone healing and discusses their regulatory mechanisms, aiming to establish a theoretical foundation for programmed regulation in bone regeneration and design of replacement materials in bone tissue engineering.
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Affiliation(s)
- Xuyan Wei
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Mucong Li
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiaqian You
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiaxin Luo
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jingjie Zhai
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiameng Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jian Feng
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Hanchi Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Yanmin Zhou
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
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Lim SY, Scarlett CO, Yapici S, Ferrazzano P, Cengiz P. Pharmacokinetics of 7,8-dihydroxyflavone in neonatal mice with hypoxia-ischemia related brain injury. Front Pharmacol 2025; 15:1508696. [PMID: 39881861 PMCID: PMC11775835 DOI: 10.3389/fphar.2024.1508696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Introduction 7,8-Dihydroxyflavone (7,8-DHF) is a promising translational therapy in several brain injury models, including the neonatal hypoxia-ischemia (HI) model in mice. However, the neuroprotective effect of 7,8-DHF was only observed in female, but not male, neonatal mice with HI brain injury. It is unknown whether HI-induced physiological changes affect brain distribution of 7,8-DHF differently for male versus female mice. We aimed to evaluate the impact of sex on the pharmacokinetics of 7,8-DHF in plasma and brain neonatal mice following experimentally induced HI brain injury. Methods Left-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5 mg/kg intraperitoneal injection of 7,8-DHF. A liquid chromatography-tandem mass spectrometry method was developed to quantitate the drug concentration in plasma samples, as well as in samples from the left and right brain hemispheres. A nonlinear mixed-effects model was used to analyze the plasma and brain concentration-time data. A semi-quantitative approach was used to evaluate the concentrations of two active O-methylated metabolites of 7,8-DHF (8H7M-flavone and 7H8M-flavone) in both plasma and brain samples. Results Our PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3 h after the IP injection. Sex was not significantly associated with the PK of 7,8-DHF; however, HI brain injury was associated with a 21% reduction in clearance (p < 0.01). The distribution of 7,8-DHF to the brain was rapid; however, the extent of brain distribution was low with the right and left brain-to-plasma partition coefficients being 8.6% and 9.9%, respectively. Additionally, both O-methylated metabolites of 7,8-DHF were detected in the plasma and brain. Conclusion The plasma and brain PK of 7,8-DHF in neonatal mice were similar between males and females. The low extent of 7,8-DHF brain distribution and the potential effects of the active metabolites should be considered in future studies evaluating the therapeutic effects of 7,8-DHF.
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Affiliation(s)
- Sin Yin Lim
- Pharmacy Practice and Translational Research Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States
| | - Cameron O. Scarlett
- Analytical Instrumentation Center, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States
| | - Sefer Yapici
- Waisman Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Peter Ferrazzano
- Waisman Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Pelin Cengiz
- Waisman Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
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Jang K, Garraway SM. TrkB Agonist (7,8-DHF)-Induced Responses in Dorsal Root Ganglia Neurons Are Decreased after Spinal Cord Injury: Implication for Peripheral Pain Mechanisms. eNeuro 2025; 12:ENEURO.0219-24.2024. [PMID: 39753357 PMCID: PMC11728855 DOI: 10.1523/eneuro.0219-24.2024] [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: 05/27/2024] [Revised: 11/08/2024] [Accepted: 12/04/2024] [Indexed: 01/15/2025] Open
Abstract
Brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) are known to contribute to both protective and pronociceptive processes. However, their contribution to neuropathic pain after spinal cord injury (SCI) needs further investigation. In a recent study utilizing TrkBF616A mice, it was shown that systemic pharmacogenetic inhibition of TrkB signaling with 1NM-PP1 (1NMP) immediately after SCI delayed the onset of pain hypersensitivity, implicating maladaptive TrkB signaling in pain after SCI. To examine potential neural mechanisms underlying the behavioral outcome, patch-clamp recording was performed in small-diameter dissociated thoracic (T) dorsal root ganglia (DRG) neurons to evaluate TrkB signaling in uninjured mice and after T10 contusion SCI. Bath-applied 7,8-dihydroxyflavone (7,8-DHF), a selective TrkB agonist, induced a robust inward current in neurons from uninjured mice, which was attenuated by 1NMP treatment. SCI also decreased 7,8-DHF-induced current while increasing the latency to its peak amplitude. Western blot revealed a concomitant decrease in TrkB expression in DRGs adjacent to the spinal lesion. Analyses of cellular and membrane properties showed that SCI increased neuronal excitability, evident by an increase in resting membrane potential and the number of spiking neurons. However, SCI did not increase spontaneous firing in DRG neurons. These results suggest that SCI induced changes in TrkB activation in DRG neurons even though these alterations are likely not contributing to pain hypersensitivity by nociceptor hyperexcitability. Overall, this reveals complex interactions involving TrkB signaling and provides an opportunity to investigate other, presumably peripheral, mechanisms by which TrkB contributes to pain hypersensitivity after SCI.
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Affiliation(s)
- Kyeongran Jang
- Department of Cell Biology, School of Medicine, Emory University, Atlanta, Georgia 30322
| | - Sandra M Garraway
- Department of Cell Biology, School of Medicine, Emory University, Atlanta, Georgia 30322
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Shi M, Yang J, Liu Y, Zhao H, Li M, Yang D, Xie Q. Huanglian Wendan Decoction Improves Insomnia in Rats by Regulating BDNF/TrkB Signaling Pathway Through Gut Microbiota-Mediated SCFAs and Affecting Microglia Polarization. Mol Neurobiol 2025; 62:1047-1066. [PMID: 38954253 DOI: 10.1007/s12035-024-04330-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 06/21/2024] [Indexed: 07/04/2024]
Abstract
Insomnia is a typical type of sleep disorder. Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) with the effects of regulating Qi, drying dampness and resolving phlegm, calming the mind, and relieving irritation. This study aims to investigate the effect of HWD on insomnia in rats and its mechanism. Para-chlorophenylalanine (PCPA)-induced insomnia in rats was used for in vivo experiments and then treated with HWD. Behavioral tests, Western blot, real-time PCR, immunofluorescent staining, 16S rRNA sequencing were conducted. The content of SCFAs was determined by GC-MS. Acetic acid-pretreated rat hippocampal nerve cells were used for in vitro experiments. The results showed that HWD significantly improved the learning memory ability, decreased sleep latency, and prolonged sleep duration in insomniac rats. HWD reduced TNF-α and IL-6 levels and increased IL-10 and Foxp3 levels. HWD also promoted the polarization of macrophages from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. In addition, HWD increased the expression levels of BDNF and TrkB in the hippocampus. Administration of the TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) confirmed the mechanism by which HWD activates BDNF/TrkB signaling to ameliorate insomnia. Furthermore, HWD restored gut microbiota richness and diversity and promoted short-chain fatty acid (SCFA) production in insomniac rats. In vitro experiments confirmed that the acetic acid-treated SCFA group could activate the BDNF/TrkB signaling pathway in neuronal cells, further promoting neuronal cell growth. In conclusion, HWD alleviated insomnia by maintaining gut microbiota homeostasis, promoting SCFA production, reducing neuroinflammatory response and microglia activation, and activating BDNF/TrkB signaling pathway.
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Affiliation(s)
- Min Shi
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan, China
| | - Jie Yang
- Traditional Chinese Medicine Department, Chengdu Eighth People's Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, 610000, Sichuan, China
| | - Ying Liu
- Department of Cardiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China
| | - Huan Zhao
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan, China
| | - Man Li
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan, China
| | - Dongdong Yang
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan, China.
| | - Quan Xie
- Department of Rehabilitation, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan, China.
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Dong X, Pei G, Yang Z, Huang S. Flavonoid chrysin activates both TrkB and FGFR1 receptors while upregulates their endogenous ligands such as brain derived neurotrophic factor to promote human neurogenesis. Cell Prolif 2025; 58:e13732. [PMID: 39331585 DOI: 10.1111/cpr.13732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 07/12/2024] [Accepted: 07/30/2024] [Indexed: 09/29/2024] Open
Abstract
Neurogenesis is the process of generating new neurons from neural stem cells (NSCs) and plays a crucial role in neurological diseases. The process involves a series of steps, including NSC proliferation, migration and differentiation, which are regulated by multiple pathways such as neurotrophic Trk and fibroblast growth factor receptors (FGFR) signalling. Despite the discovery of numerous compounds capable of modulating individual stages of neurogenesis, it remains challenging to identify an agent that can regulate multiple cellular processes of neurogenesis. Here, through screening of bioactive compounds in dietary functional foods, we identified a flavonoid chrysin that not only enhanced the human NSCs proliferation but also facilitated neuronal differentiation and neurite outgrowth. Further mechanistic study revealed the effect of chrysin was attenuated by inhibition of neurotrophic tropomyosin receptor kinase-B (TrkB) receptor. Consistently, chrysin activated TrkB and downstream ERK1/2 and AKT. Intriguingly, we found that the effect of chrysin was also reduced by FGFR1 blockade. Moreover, extended treatment of chrysin enhanced levels of brain-derived neurotrophic factor, as well as FGF1 and FGF8. Finally, chrysin was found to promote neurogenesis in human cerebral organoids by increasing the organoid expansion and folding, which was also mediated by TrkB and FGFR1 signalling. To conclude, our study indicates that activating both TrkB and FGFR1 signalling could be a promising avenue for therapeutic interventions in neurological diseases, and chrysin appears to be a potential candidate for the development of such treatments.
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Affiliation(s)
- Xiaoxu Dong
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Gang Pei
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Zhuo Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Shichao Huang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
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Gao AYL, Inglebert Y, Shi R, Ilie A, Popic J, Mustian J, Sonenberg N, Orlowski J, McKinney RA. Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167529. [PMID: 39341363 DOI: 10.1016/j.bbadis.2024.167529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/31/2024] [Accepted: 09/24/2024] [Indexed: 10/01/2024]
Abstract
Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the SLC9A6 gene encoding the recycling endosomal pH regulator (Na+, K+)/H+ exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of Nhe6 knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spines density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.
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MESH Headings
- Animals
- Neuronal Plasticity/drug effects
- Mice
- Flavones/pharmacology
- Mice, Knockout
- Receptor, trkB/metabolism
- Receptor, trkB/agonists
- Receptor, trkB/genetics
- Sodium-Hydrogen Exchangers/metabolism
- Sodium-Hydrogen Exchangers/genetics
- Hippocampus/metabolism
- Hippocampus/drug effects
- Hippocampus/pathology
- Endosomes/metabolism
- Endosomes/drug effects
- Receptors, AMPA/metabolism
- Receptors, AMPA/genetics
- Receptors, AMPA/agonists
- Mental Retardation, X-Linked/pathology
- Mental Retardation, X-Linked/genetics
- Mental Retardation, X-Linked/drug therapy
- Mental Retardation, X-Linked/metabolism
- Dendritic Spines/metabolism
- Dendritic Spines/drug effects
- Dendritic Spines/pathology
- Male
- Synaptic Transmission/drug effects
- Microcephaly
- Genetic Diseases, X-Linked
- Epilepsy
- Intellectual Disability
- Ocular Motility Disorders
- Ataxia
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Affiliation(s)
- Andy Y L Gao
- Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
| | - Yanis Inglebert
- Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
| | - Roy Shi
- Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
| | - Alina Ilie
- Department of Physiology, McGill University, Montreal, Canada
| | - Jelena Popic
- Department of Biochemistry, McGill University, Montreal, Canada
| | - Jamie Mustian
- Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
| | - Nahum Sonenberg
- Department of Biochemistry, McGill University, Montreal, Canada
| | - John Orlowski
- Department of Physiology, McGill University, Montreal, Canada
| | - R Anne McKinney
- Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada.
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Aladdin N, Ghareib SA. Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway. J Biochem Mol Toxicol 2024; 38:e70082. [PMID: 39651608 DOI: 10.1002/jbt.70082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 10/25/2024] [Accepted: 11/20/2024] [Indexed: 12/11/2024]
Abstract
Metabolic syndrome (MetS) is usually associated with cognitive impairment, neuropathic pain, and reduced brain-derived neurotrophic factor (BDNF) levels. BDNF via tropomyosin receptor kinase B (TrkB) exerts neuroprotection by activating protein kinase B (Akt) to inhibit glycogen synthase kinase-3β (GSK3β). Although Vitamin D3 (VitD3) has demonstrated favorable metabolic and neuronal outcomes in MetS, the precise molecular mechanisms underlying its neuroprotective effects remain poorly elucidated. We aimed to test the hypothesis that VitD3 mitigates MetS-induced cognition deficits and neuropathic pain via modulating the BDNF/TRKB/Akt/GS3Kβ signaling pathway. MetS was induced in male rats by 10% fructose-supplemented water and 3% salt-enriched diet. After 6 weeks, normal and MetS rats received either vehicle or VitD3 (10 µg/kg/day) for an additional 6 weeks. Glycemic status, lipid profile, and behavioral changes were assessed. The advanced glycation end products (AGEs), and markers of inflammation (TNF-α and NF-κB), oxidative stress (malondialdehyde), and apoptosis (caspase3), as well as BDNF, TrkB, PI3K, Akt, GSK3β, phosphorylated tau, and amyloid beta (Aβ) were assessed in the cerebral cortex. MetS rats had deteriorated glycemic and lipid profiles, higher AGEs, reduced levels of BDNF, TrkB, PI3K, and active Akt, along with increased GSK3β levels, inflammation, oxidative stress, and apoptosis. These changes were associated with higher levels of cognitive impairment markers phosphorylated tau and Aβ, as well as behavioral changes indicative of cognitive impairment and neuropathic pain. VitD3 improved the cognitive and behavioral alterations, while mitigating the associated molecular derangements. Our results indicate that VitD3 may exert neuroprotective effects by modulating the BDNF/TrkB/PI3K/Akt/GSK3β signaling pathway.
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Affiliation(s)
- Noha Aladdin
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Salah A Ghareib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
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11
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Verma H, Kaur S, Kaur S, Gangwar P, Dhiman M, Mantha AK. Role of Cytoskeletal Elements in Regulation of Synaptic Functions: Implications Toward Alzheimer's Disease and Phytochemicals-Based Interventions. Mol Neurobiol 2024; 61:8320-8343. [PMID: 38491338 DOI: 10.1007/s12035-024-04053-3] [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: 07/03/2023] [Accepted: 02/13/2024] [Indexed: 03/18/2024]
Abstract
Alzheimer's disease (AD), a multifactorial disease, is characterized by the accumulation of neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques. AD is triggered via several factors like alteration in cytoskeletal proteins, a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), amyloid precursor protein (APP), and post-translational modifications (PTMs) in the cytoskeletal elements. Owing to the major structural and functional role of cytoskeletal elements, like the organization of axon initial segmentation, dendritic spines, synaptic regulation, and delivery of cargo at the synapse; modulation of these elements plays an important role in AD pathogenesis; like Tau is a microtubule-associated protein that stabilizes the microtubules, and it also causes inhibition of nucleo-cytoplasmic transportation by disrupting the integrity of nuclear pore complex. One of the major cytoskeletal elements, actin and its dynamics, regulate the dendritic spine structure and functions; impairments have been documented towards learning and memory defects. The second major constituent of these cytoskeletal elements, microtubules, are necessary for the delivery of the cargo, like ion channels and receptors at the synaptic membranes, whereas actin-binding protein, i.e., Cofilin's activation form rod-like structures, is involved in the formation of paired helical filaments (PHFs) observed in AD. Also, the glial cells rely on their cytoskeleton to maintain synaptic functionality. Thus, making cytoskeletal elements and their regulation in synaptic structure and function as an important aspect to be focused for better management and targeting AD pathology. This review advocates exploring phytochemicals and Ayurvedic plant extracts against AD by elucidating their neuroprotective mechanisms involving cytoskeletal modulation and enhancing synaptic plasticity. However, challenges include their limited bioavailability due to the poor solubility and the limited potential to cross the blood-brain barrier (BBB), emphasizing the need for targeted strategies to improve therapeutic efficacy.
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Affiliation(s)
- Harkomal Verma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Village Ghudda, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Sharanjot Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Village Ghudda, Bathinda, Punjab, India
| | - Sukhchain Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Village Ghudda, Bathinda, Punjab, India
| | - Prabhakar Gangwar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Village Ghudda, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Village Ghudda, Bathinda, Punjab, India
| | - Anil Kumar Mantha
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Village Ghudda, VPO - Ghudda, Bathinda, 151 401, Punjab, India.
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12
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Li D, Zhao Z, Zhu L, Feng H, Song J, Fu J, Li J, Chen Z, Fu H. 7,8-DHF inhibits BMSC oxidative stress via the TRKB/PI3K/AKT/NRF2 pathway to improve symptoms of postmenopausal osteoporosis. Free Radic Biol Med 2024; 223:413-429. [PMID: 39155025 DOI: 10.1016/j.freeradbiomed.2024.08.014] [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: 06/28/2024] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 08/20/2024]
Abstract
Postmenopausal osteoporosis (PMO) is characterized by bone loss and microstructural damage, and it is most common in older adult women. Currently, there is no cure for PMO. The flavonoid chemical 7,8-dihydroxyflavone (7,8-DHF) specifically activates tropomyosin receptor kinase B (TRKB). Furthermore, 7,8-DHF has various biological characteristics, including anti-inflammatory and antioxidant effects. However, the specific implications and fundamental mechanisms of 7,8-DHF in PMO remain unclear. We used protein imprinting, flow cytometry, tissue staining, and other methods to estimate the preventive mechanisms of 7,8-DHF against hydrogen peroxide (H2O2)-induced apoptosis in primary mouse bone marrow mesenchymal stem cells (BMSCs), osteogenic differentiation ability, and bone mass in ovariectomized (OVX) mice. We found that 7,8-DHF effectively prevented H2O2-induced reductions in the viability and osteogenic differentiation capacity of primary BMSCs. Mechanistically, 7,8-DHF induced the TRKB to activate the PI3K/AKT/NRF2 pathway. In vivo experiments with the OVX mouse model confirmed that 7,8-DHF can inhibit oxidative stress and promote bone formation, indicating that 7,8-DHF improves the viability and osteogenic differentiation ability of BMSCs stimulated via H2O2 by activating the TRKB/PI3K/AKT and NRF2 pathways, thereby improving PMO.
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Affiliation(s)
- Dailuo Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Zihang Zhao
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Liyu Zhu
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Haoran Feng
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Junlong Song
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Jiawei Fu
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Jincheng Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Zhanzhi Chen
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Hailiang Fu
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
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13
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Zheng N, Luo S, Zhang X, Hu L, Huang M, Li M, McCaig C, Ding YQ, Lang B. Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF. J Adv Res 2024:S2090-1232(24)00382-5. [PMID: 39265888 DOI: 10.1016/j.jare.2024.08.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/27/2024] [Accepted: 08/31/2024] [Indexed: 09/14/2024] Open
Abstract
INTRODUCTION Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium, actively facilitates the formation and absorption of primary cilia. IFT172 is the largest component of the IFT-B complex, and its roles in Bardet-Biedl Syndrome (BBS) have been appreciated with unclear mechanisms. OBJECTIVES We performed a battery of behavioral tests with Ift172 haploinsufficiency (Ift172+/-) and WT littermates. We use RNA sequencing to identify the genes and signaling pathways that are differentially expressed and enriched in the hippocampus of Ift172+/- mice. Using AAV-mediated sparse labeling, electron microscopic examination, patch clamp and local field potential recording, western blot, luciferase reporter assay, chromatin immunoprecipitation, and neuropharmacological approach, we investigated the underlying mechanisms for the aberrant phenotypes presented by Ift172+/- mice. RESULTS Ift172+/- mice displayed excessive self-grooming, elevated anxiety, and impaired cognition. RNA sequencing revealed enrichment of differentially expressed genes in pathways relevant to axonogenesis and synaptic plasticity, which were further confirmed by less spine density and synaptic number. Ift172+/- mice demonstrated fewer parvalbumin-expressing neurons, decreased inhibitory synaptic transmission, augmented theta oscillation, and sharp-wave ripples in the CA1 region. Moreover, Ift172 haploinsufficiency caused less BDNF production and less activated BDNF-TrkB signaling pathway through transcription factor Gli3. Application of 7,8-Dihydroxyflavone, a potent small molecular TrkB agonist, fully restored BDNF-TrkB signaling activity and abnormal behavioral phenotypes presented by Ift172+/- mice. With luciferase and chip assays, we provided further evidence that Gli3 may physically interact with BDNF promoter I and regulate BDNF expression. CONCLUSIONS Our data suggest that Ift172 per se drives neurotrophic effects and, when defective, could cause neurodevelopmental disorders reminiscent of autism-like disorders.
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Affiliation(s)
- Nanxi Zheng
- Department of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Department of Psychiatry, Fujian Medical University Affiliated Fuzhou Neuropsychiatric Hospital, Fuzhou 350005, China
| | - Shilin Luo
- Department of Neurology, Xiangya Hospital of Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorder, Central South University, Changsha, China; Engineering Research Center of Human Province in Cognitive Impairment Disorders, Changsha 410008, China
| | - Xin Zhang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Ling Hu
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 200433 Shanghai, China
| | - Muzhi Huang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Mingyu Li
- Department of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Colin McCaig
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD Aberdeen, Scotland, UK
| | - Yu-Qiang Ding
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 200433 Shanghai, China
| | - Bing Lang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
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Brenner M, Zink C, Witzinger L, Keller A, Hadamek K, Bothe S, Neuenschwander M, Villmann C, von Kries JP, Schindelin H, Jeanclos E, Gohla A. 7,8-Dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase. eLife 2024; 13:RP93094. [PMID: 38856179 PMCID: PMC11164532 DOI: 10.7554/elife.93094] [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] [Indexed: 06/11/2024] Open
Abstract
Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5'-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5'-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.
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Affiliation(s)
- Marian Brenner
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
| | - Christoph Zink
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
| | - Linda Witzinger
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
| | - Angelika Keller
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
| | - Kerstin Hadamek
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
| | - Sebastian Bothe
- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of WürzburgWürzburgGermany
| | | | - Carmen Villmann
- Institute of Clinical Neurobiology, University Hospital, University of WürzburgWürzburgGermany
| | | | - Hermann Schindelin
- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of WürzburgWürzburgGermany
| | - Elisabeth Jeanclos
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
| | - Antje Gohla
- Institute of Pharmacology and Toxicology, University of WürzburgWürzburgGermany
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15
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Enkavi G, Girych M, Moliner R, Vattulainen I, Castrén E. TrkB transmembrane domain: bridging structural understanding with therapeutic strategy. Trends Biochem Sci 2024; 49:445-456. [PMID: 38433044 DOI: 10.1016/j.tibs.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/19/2024] [Accepted: 02/09/2024] [Indexed: 03/05/2024]
Abstract
TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the receptor for brain-derived neurotrophic factor (BDNF) and is a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding of the structure and function of TrkB, including its transmembrane domain (TMD). TrkB interacts with membrane cholesterol, which bidirectionally regulates TrkB signaling. Additionally, TrkB has recently been recognized as a binding target of antidepressant drugs. A variety of different antidepressants, including typical and rapid-acting antidepressants, as well as psychedelic compounds, act as allosteric potentiators of BDNF signaling through TrkB. This suggests that TrkB is the common target of different antidepressant compounds. Although more research is needed, current knowledge suggests that TrkB is a promising target for further drug development.
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Affiliation(s)
- Giray Enkavi
- Department of Physics, University of Helsinki, Helsinki, Finland
| | - Mykhailo Girych
- Department of Physics, University of Helsinki, Helsinki, Finland
| | - Rafael Moliner
- Neuroscience Center/HiLIFE, University of Helsinki, Helsinki, Finland
| | - Ilpo Vattulainen
- Department of Physics, University of Helsinki, Helsinki, Finland.
| | - Eero Castrén
- Neuroscience Center/HiLIFE, University of Helsinki, Helsinki, Finland.
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16
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Chanana V, Zafer D, Kintner DB, Chandrashekhar JH, Eickhoff J, Ferrazzano PA, Levine JE, Cengiz P. TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury. Biol Sex Differ 2024; 15:30. [PMID: 38566248 PMCID: PMC10988865 DOI: 10.1186/s13293-024-00596-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of learning disabilities and memory deficits in children. In both human and animal studies, female neonate brains are less susceptible to HI than male brains. Phosphorylation of the nerve growth factor receptor TrkB has been shown to provide sex-specific neuroprotection following in vivo HI in female mice in an estrogen receptor alpha (ERα)-dependent manner. However, the molecular and cellular mechanisms conferring sex-specific neonatal neuroprotection remain incompletely understood. Here, we test whether female neonatal hippocampal neurons express autonomous neuroprotective properties and assess the ability of testosterone (T) to alter this phenotype. METHODS We cultured sexed hippocampal neurons from ERα+/+ and ERα-/- mice and subjected them to 4 h oxygen glucose deprivation and 24 h reoxygenation (4-OGD/24-REOX). Sexed hippocampal neurons were treated either with vehicle control (VC) or the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following in vitro ischemia. End points at 24 h REOX were TrkB phosphorylation (p-TrkB) and neuronal survival assessed by immunohistochemistry. In addition, in vitro ischemia-mediated ERα gene expression in hippocampal neurons were investigated following testosterone (T) pre-treatment and TrkB antagonist therapy via q-RTPCR. Multifactorial analysis of variance was conducted to test for significant differences between experimental conditions. RESULTS Under normoxic conditions, administration of 3 µM 7,8-DHF resulted an ERα-dependent increase in p-TrkB immunoexpression that was higher in female, as compared to male neurons. Following 4-OGD/24-REOX, p-TrkB expression increased 20% in both male and female ERα+/+ neurons. However, with 3 µM 7,8-DHF treatment p-TrkB expression increased further in female neurons by 2.81 ± 0.79-fold and was ERα dependent. 4-OGD/24-REOX resulted in a 56% increase in cell death, but only female cells were rescued with 3 µM 7,8-DHF, again in an ERα dependent manner. Following 4-OGD/3-REOX, ERα mRNA increased ~ 3 fold in female neurons. This increase was blocked with either the TrkB antagonist ANA-12 or pre-treatment with T. Pre-treatment with T also blocked the 7,8-DHF- dependent sex-specific neuronal survival in female neurons following 4-OGD/24-REOX. CONCLUSIONS OGD/REOX results in sex-dependent TrkB phosphorylation in female neurons that increases further with 7,8-DHF treatment. TrkB phosphorylation by 7,8-DHF increased ERα mRNA expression and promoted cell survival preferentially in female hippocampal neurons. The sex-dependent neuroprotective actions of 7,8-DHF were blocked by either ANA-12 or by T pre-treatment. These results are consistent with a model for a female-specific neuroprotective pathway in hippocampal neurons in response to hypoxia. The pathway is activated by 7,8-DHF, mediated by TrkB phosphorylation, dependent on ERα and blocked by pre-exposure to T.
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Affiliation(s)
- Vishal Chanana
- Waisman Center, University of Wisconsin, Madison, WI, USA
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Wisconsin, 1500 Highland Ave - T505, Madison, WI, 53705-9345, USA
| | - Dila Zafer
- Waisman Center, University of Wisconsin, Madison, WI, USA
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Wisconsin, 1500 Highland Ave - T505, Madison, WI, 53705-9345, USA
| | - Douglas B Kintner
- Waisman Center, University of Wisconsin, Madison, WI, USA
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Wisconsin, 1500 Highland Ave - T505, Madison, WI, 53705-9345, USA
| | - Jayadevi H Chandrashekhar
- Waisman Center, University of Wisconsin, Madison, WI, USA
- University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Jens Eickhoff
- Department of Statistics and Bioinformatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Peter A Ferrazzano
- Waisman Center, University of Wisconsin, Madison, WI, USA
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Wisconsin, 1500 Highland Ave - T505, Madison, WI, 53705-9345, USA
| | - Jon E Levine
- Department of Neuroscience, University of Wisconsin, Madison, WI, USA
- Wisconsin National Primate Research Center, Madison, WI, USA
| | - Pelin Cengiz
- Waisman Center, University of Wisconsin, Madison, WI, USA.
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Wisconsin, 1500 Highland Ave - T505, Madison, WI, 53705-9345, USA.
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Kang JY, Gu JY, Baek DC, Son CG, Lee JS. A Capsicum annuum L. seed extract exerts anti-neuroexcitotoxicity in HT22 hippocampal neurons. Food Funct 2024; 15:2144-2153. [PMID: 38305768 DOI: 10.1039/d3fo04501c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
The hippocampal memory deficit stands out as a primary symptom in neurodegenerative diseases, including Alzheimer's disease. While numerous therapeutic candidates have been proposed, they primarily serve to delay disease progression. Given the irreversible brain atrophy or injury associated with these conditions, current research efforts are concentrated on preventive medicine strategies. Herein, we investigated whether the extracts of Capsicum annuum L. seeds (CSE) and Capsicum annuum L. pulp (CPE) have preventive properties against glutamate-induced neuroexcitotoxicity (one of the main causes of Alzheimer's disease) in HT22 hippocampal neuronal cells. Pretreatment with CSE demonstrated significant anti-neuroexcitotoxic activity, whereas CPE did not exhibit such effects. Specifically, CSE pretreatment dose-dependently inhibited the elevation of excitotoxic elements (intracellular calcium influx and reactive oxygen species; ROS) and apoptotic elements (p53 and cleaved caspase-3). In addition, the glutamate-induced alterations of neuronal activity indicators (brain-derived neurotrophic factor; BDNF and cAMP response element-binding protein phosphorylation; CREB) were significantly attenuated by CSE treatment. We also found that luteolin is the main bioactive compound corresponding to the anti-neuroexcitotoxic effects of CSE. Our results strongly suggest that Capsicum annuum L. seeds (but not its pulp) could be candidates for neuro-protective resources especially under conditions of neuroexcitotoxicity. Its underlying mechanisms may involve the amelioration of ROS-mediated cell death and BDNF-related neuronal inactivity and luteolin would be an active compound.
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Affiliation(s)
- Ji-Yun Kang
- Institute of Bioscience & Integrative Medicine, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea.
| | - Ji-Yeon Gu
- Institute of Bioscience & Integrative Medicine, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea.
| | - Dong-Cheol Baek
- Institute of Bioscience & Integrative Medicine, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea.
| | - Chang-Gue Son
- Institute of Bioscience & Integrative Medicine, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea.
- Research Center for CFS/ME, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea
| | - Jin-Seok Lee
- Institute of Bioscience & Integrative Medicine, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea.
- Research Center for CFS/ME, Daejeon Hospital of Daejeon University, Daejeon, Republic of Korea
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18
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Fukuyama Y, Kubo M, Harada K. Neurotrophic Natural Products. PROGRESS IN THE CHEMISTRY OF ORGANIC NATURAL PRODUCTS 2024; 123:1-473. [PMID: 38340248 DOI: 10.1007/978-3-031-42422-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/12/2024]
Abstract
Neurotrophins (NGF, BDNF, NT3, NT4) can decrease cell death, induce differentiation, as well as sustain the structure and function of neurons, which make them promising therapeutic agents for the treatment of neurodegenerative disorders. However, neurotrophins have not been very effective in clinical trials mostly because they cannot pass through the blood-brain barrier owing to being high-molecular-weight proteins. Thus, neurotrophin-mimic small molecules, which stimulate the synthesis of endogenous neurotrophins or enhance neurotrophic actions, may serve as promising alternatives to neurotrophins. Small-molecular-weight natural products, which have been used in dietary functional foods or in traditional medicines over the course of human history, have a great potential for the development of new therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. In this contribution, a variety of natural products possessing neurotrophic properties such as neurogenesis, neurite outgrowth promotion (neuritogenesis), and neuroprotection are described, and a focus is made on the chemistry and biology of several neurotrophic natural products.
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Affiliation(s)
- Yoshiyasu Fukuyama
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan.
| | - Miwa Kubo
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan
| | - Kenichi Harada
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan
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19
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Zagrebelsky M, Korte M. Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor? Neural Regen Res 2024; 19:29-34. [PMID: 37488840 PMCID: PMC10479861 DOI: 10.4103/1673-5374.374138] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/20/2023] [Accepted: 03/27/2023] [Indexed: 07/26/2023] Open
Abstract
Brain-derived neurotrophic factor signaling via its receptor tropomyosin receptor kinase B regulates several crucial physiological processes. It has been shown to act in the brain, promoting neuronal survival, growth, and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism. Due to its crucial and very pleiotropic activity, reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases. However, because of its poor bioavailability and pharmacological properties, brain-derived neurotrophic factor itself has a very low therapeutic value. Moreover, the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects. Therefore, developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research. Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules. In this review, we give a comprehensive description of the different tropomyosin receptor kinase B receptor agonist drugs developed so far and of the results of their application in animal models of several neurological diseases. Moreover, we discuss the main benefits of tropomyosin receptor kinase B receptor agonists, concentrating especially on the new tropomyosin receptor kinase B agonist antibodies. The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity. Moreover, tropomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor. Therefore, while, based on the current knowledge, the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reverse the disease pathology per se, promoting brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling still has a very high therapeutic relevance.
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Affiliation(s)
- Marta Zagrebelsky
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
| | - Martin Korte
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
- Helmholtz Centre for Infection Research, AG NIND, Braunschweig, Germany
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20
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Cook AA, Leung TCS, Rice M, Nachman M, Zadigue-Dube É, Watt AJ. Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6. eLife 2023; 12:RP90510. [PMID: 38084749 PMCID: PMC10715727 DOI: 10.7554/elife.90510] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2023] Open
Abstract
Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA-sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-dihydroxyflavone, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6 and a promising therapeutic target.
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Affiliation(s)
- Anna A Cook
- Biology Department, McGill UniversityMontrealCanada
| | | | - Max Rice
- Biology Department, McGill UniversityMontrealCanada
- Department of Biological Sciences, Columbia UniversityNew YorkUnited States
| | - Maya Nachman
- Biology Department, McGill UniversityMontrealCanada
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Shi J, Song S, Wu K, Liang G, Wang A, Xu X. Role of brain-derived neurotrophic factor in endotoxaemia-induced acute lung injury. Exp Physiol 2023; 108:1456-1465. [PMID: 37909847 PMCID: PMC10988478 DOI: 10.1113/ep091228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 10/16/2023] [Indexed: 11/03/2023]
Abstract
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which is a pulmonary manifestation of a systemic reactive inflammatory syndrome, is a serious disease with high mortality, and sepsis is an important risk factor in the development of ALI. Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family. It plays an essential role in the regulation of the modification of synaptic efficacy and brain metabolic activity and enhances neuronal survival. However, the role and underlying mechanism of BDNF in sepsis-induced ALI remain unclear. Here, we sought to observe the expression of BDNF in the lung tissues of mice. C57BL/6J mice were divided randomly into two groups: saline (n = 4) and lipopolysaccharide (LPS) (n = 4). We found that BDNF expression was elevated in the lung tissues of septic mice. Furthermore, we found that BDNF colocalized with aquaporin 5, a marker for type I alveolar epithelial cells, by immunofluorescence staining. In addition, we also found that tropomyosin-related kinase B, the specific receptor of BDNF, colocalized with surfactant protein C, a marker for type II alveolar epithelial cells, by immunofluorescence staining. Finally, the present study indicated that BDNF may alleviate excessive LPS-induced autophagy in alveolar epithelial cells. Overall, we hypothesize that BDNF expression increases in the lung tissues of septic mice as a compensatory mechanism to ameliorate sepsis-induced ALI by inhibiting excessive alveolar epithelial cell autophagy.
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Affiliation(s)
- Jinye Shi
- College of Fisheries and Life ScienceShanghai Ocean UniversityShanghaiChina
- Department of Anesthesiology, Affiliated Shanghai Sixth People's HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - Shuang Song
- Department of Respiratory Medicine, Affiliated Shanghai Sixth People's HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - Kaixuan Wu
- Department of Anesthesiology, Affiliated Shanghai Sixth People's HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - Gui Liang
- Department of Anesthesiology, Affiliated Shanghai Sixth People's HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - Aizhong Wang
- Department of Anesthesiology, Affiliated Shanghai Sixth People's HospitalShanghai Jiao Tong UniversityShanghaiChina
| | - Xiaotao Xu
- Department of Anesthesiology, Affiliated Shanghai Sixth People's HospitalShanghai Jiao Tong UniversityShanghaiChina
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22
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Zhou F, Peterson T, Fan Z, Wang S. The Commonly Used Stabilizers for Phytochemical-Based Nanoparticles: Stabilization Effects, Mechanisms, and Applications. Nutrients 2023; 15:3881. [PMID: 37764665 PMCID: PMC10534333 DOI: 10.3390/nu15183881] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Phytochemicals, such as resveratrol, curcumin, and quercetin, have many benefits for health, but most of them have a low bioavailability due to their poor water solubility and stability, quick metabolism, and clearance, which restricts the scope of their potential applications. To overcome these issues, different types of nanoparticles (NPs), especially biocompatible and biodegradable NPs, have been developed. NPs can carry phytochemicals and increase their solubility, stability, target specificity, and oral bioavailability. However, NPs are prone to irreversible aggregation, which leads to NP instability and loss of functions. To remedy this shortcoming, stabilizers like polymers and surfactants are incorporated on NPs. Stabilizers not only increase the stability of NPs, but also improve their characteristics. The current review focused on discussing the state of the art in research on synthesizing phytochemical-based NPs and their commonly employed stabilizers. Furthermore, stabilizers in these NPs were also discussed in terms of their applications, effects, and underlying mechanisms. This review aimed to provide more references for developing stabilizers and NPs for future research.
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Affiliation(s)
- Fang Zhou
- College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA;
| | - Tiffany Peterson
- College of Integrative Sciences and Arts, Arizona State University, Phoenix, AZ 85004, USA;
| | - Zhaoyang Fan
- School of Electrical, Computer and Energy Engineering, Arizona State University, Tempe, AZ 85281, USA;
| | - Shu Wang
- College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA;
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23
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Guilarte TR. Invited Perspective: Challenging the Dogma of Lead Neurotoxicity. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:81306. [PMID: 37639478 PMCID: PMC10461787 DOI: 10.1289/ehp13184] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/21/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Affiliation(s)
- Tomás R. Guilarte
- Robert Stempel College of Public Health & Social Work, Florida International University, Miami, Florida, USA
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24
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Espíndola C. Some Nanocarrier's Properties and Chemical Interaction Mechanisms with Flavones. Molecules 2023; 28:molecules28062864. [PMID: 36985836 PMCID: PMC10051830 DOI: 10.3390/molecules28062864] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/14/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
Flavones such as 7,8-dihydroxyflavone (tropoflavin), 5,6,7-trihydroxyflavone (baicalein), 3',4',5,6-tetrahydroxyflavone (luteolin), 3,3',4',5,5',7-hexahydroxyflavone (myricetin), 4',5,7-trihydroxyflavone (apigenin), and 5,7-dihydroxyflavone (chrysin) are important both for their presence in natural products and for their pharmacological applications. However, due to their chemical characteristics and their metabolic processes, they have low solubility and low bioavailability. Knowledge about the physicochemical properties of nanocarriers and the possible mechanisms of covalent and non-covalent interaction between nanoparticles (NPs) and drugs is essential for the design of nanocarriers to improve the bioavailability of molecules with pharmacological potential, such as tropoflavin, baicalein, luteolin, myricetin, apigenin, and chrysin. The parameters of characterization of some NPs of these flavones, such as size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), and % release/time, utilized in biomedical applications and the covalent and non-covalent interactions existing between the polymeric NPs and the drug were analyzed. Similarly, the presence of functional groups in the functionalized carbon nanotubes (CNTs), as well as the effect of pH on the % adsorption of flavonoids on functionalized multi-walled carbon nanotubes (MWCNT-COOH), were analyzed. Non-covalent interaction mechanisms between polymeric NPs and flavones, and covalent interaction mechanisms that could exist between the NPs and the amino and hydroxyl functional groups, are proposed.
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Affiliation(s)
- Cecilia Espíndola
- Department of Physical Chemistry, University of Seville, C/Profesor García González 1, 41012 Seville, Spain
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25
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Rawlings-Mortimer F, Lazari A, Tisca C, Tachrount M, Martins-Bach AB, Miller KL, Lerch JP, Johansen-Berg H. 7,8-dihydroxyflavone enhances long-term spatial memory and alters brain volume in wildtype mice. Front Syst Neurosci 2023; 17:1134594. [PMID: 37008453 PMCID: PMC10057119 DOI: 10.3389/fnsys.2023.1134594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/21/2023] [Indexed: 03/17/2023] Open
Abstract
Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases.Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume.Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing.Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease.
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Neurotrophin mimetics and tropomyosin kinase receptors: a futuristic pharmacological tool for Parkinson's. Neurol Sci 2023:10.1007/s10072-023-06684-1. [PMID: 36870001 DOI: 10.1007/s10072-023-06684-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/11/2023] [Indexed: 03/05/2023]
Abstract
Parkinson's disease is a complex age-related progressive dopaminergic neurodegenerative disease consistently viewed as a disorder of movement and is characterized by its cardinal motor symptoms. While the motor symptoms and its clinical manifestations are attributed to the nigral dopaminergic neuronal death and basal ganglia dysfunction, studies have subsequently proven that the non-dopaminergic neurons in various brain regions are also additionally involved with the disease progression. Thus, it is now well accepted that the involvement of various neurotransmitters and other ligands accounts for the non-motor symptoms (NMS) associated with the Parkinson's disease. Consequently, this has demonstrated to possess remarkable clinical concerns to the patients in terms of various disability, such impaired to compromised quality of life and increased risk of morbidity and mortality. Currently, available pharmacological, non-pharmacological, and surgical therapeutic strategies neither prevent, arrest, nor reverse the nigral dopaminergic neurodegeneration. Thus, there is an imminent medical necessity to increase patient's quality of life and survival, which in turn decreases the incidence and prevalence of the NMS. The current research article reviews the potential direct involvement of neurotrophin and its mimetics to target and modulate neurotrophin-mediated signal transduction pathways to enlighten a new and novel therapeutic strategy along with the pre-existing treatments for Parkinson's disease and other neurological/neurodegenerative disorders which are associated with the downregulation of neurotrophins.
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27
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Yoon S, Iqbal H, Kim SM, Jin M. Phytochemicals That Act on Synaptic Plasticity as Potential Prophylaxis against Stress-Induced Depressive Disorder. Biomol Ther (Seoul) 2023; 31:148-160. [PMID: 36694423 PMCID: PMC9970837 DOI: 10.4062/biomolther.2022.116] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023] Open
Abstract
Depression is a neuropsychiatric disorder associated with persistent stress and disruption of neuronal function. Persistent stress causes neuronal atrophy, including loss of synapses and reduced size of the hippocampus and prefrontal cortex. These alterations are associated with neural dysfunction, including mood disturbances, cognitive impairment, and behavioral changes. Synaptic plasticity is the fundamental function of neural networks in response to various stimuli and acts by reorganizing neuronal structure, function, and connections from the molecular to the behavioral level. In this review, we describe the alterations in synaptic plasticity as underlying pathological mechanisms for depression in animal models and humans. We further elaborate on the significance of phytochemicals as bioactive agents that can positively modulate stress-induced, aberrant synaptic activity. Bioactive agents, including flavonoids, terpenes, saponins, and lignans, have been reported to upregulate brain-derived neurotrophic factor expression and release, suppress neuronal loss, and activate the relevant signaling pathways, including TrkB, ERK, Akt, and mTOR pathways, resulting in increased spine maturation and synaptic numbers in the neuronal cells and in the brains of stressed animals. In clinical trials, phytochemical usage is regarded as safe and well-tolerated for suppressing stress-related parameters in patients with depression. Thus, intake of phytochemicals with safe and active effects on synaptic plasticity may be a strategy for preventing neuronal damage and alleviating depression in a stressful life.
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Affiliation(s)
- Soojung Yoon
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
| | - Hamid Iqbal
- Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sun Mi Kim
- Department of Psychiatry, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea,Department of Psychiatry, Chung-Ang University Hospital, Seoul 06973, Republic of Korea
| | - Mirim Jin
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea,Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea,Corresponding Author E-mail: , Tel: +82-32-899-6080, Fax: +82-32-899-6029
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Banerjee M, Shenoy RR. Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory. J Basic Clin Physiol Pharmacol 2023; 34:125-136. [PMID: 34751526 DOI: 10.1515/jbcpp-2021-0182] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is a crucial neurotrophic factor adding to neurons' development and endurance. The amount of BDNF present in the brain determines susceptibility to various neurodegenerative diseases. In Alzheimer's disease (AD), often it is seen that low levels of BDNF are present, which primarily contributes to cognition deficit by regulating long-term potentiation (LTP) and synaptic plasticity. Molecular mechanisms underlying the synthesis, storage and release of BDNF are widely studied. New molecules are found, which contribute to the signal transduction pathway. Two important receptors of BDNF are TrkB and p75NTR. When BDNF binds to the TrkB receptor, it activates three main signalling pathways-phospholipase C, MAPK/ERK, PI3/AKT. BDNF holds an imperative part in LTP and dendritic development, which are essential for memory formation. BDNF supports synaptic integrity by influencing LTP and LTD. This action is conducted by modulating the glutamate receptors; AMPA and NMDA. This review paper discusses the aforesaid points along with inducers of BDNF. Drugs and herbals promote neuroprotection by increasing the hippocampus' BDNF level in various disease-induced animal models for neurodegeneration. Advancement in finding pertinent molecules contributing to the BDNF signalling pathway has been discussed, along with the areas that require further research and study.
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Affiliation(s)
- Madhuparna Banerjee
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Udupi District, Karnataka, India
| | - Rekha R Shenoy
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Udupi District, Karnataka, India
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Gentile MT, Camerino I, Ciarmiello L, Woodrow P, Muscariello L, De Chiara I, Pacifico S. Neuro-Nutraceutical Polyphenols: How Far Are We? Antioxidants (Basel) 2023; 12:antiox12030539. [PMID: 36978787 PMCID: PMC10044769 DOI: 10.3390/antiox12030539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
The brain, composed of billions of neurons, is a complex network of interacting dynamical systems controlling all body functions. Neurons are the building blocks of the nervous system and their impairment of their functions could result in neurodegenerative disorders. Accumulating evidence shows an increase of brain-affecting disorders, still today characterized by poor therapeutic options. There is a strong urgency to find new alternative strategies to prevent progressive neuronal loss. Polyphenols, a wide family of plant compounds with an equally wide range of biological activities, are suitable candidates to counteract chronic degenerative disease in the central nervous system. Herein, we will review their role in human healthcare and highlight their: antioxidant activities in reactive oxygen species-producing neurodegenerative pathologies; putative role as anti-acetylcholinesterase inhibitors; and protective activity in Alzheimer’s disease by preventing Aβ aggregation and tau hyperphosphorylation. Moreover, the pathology of these multifactorial diseases is also characterized by metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), most important for cellular function. In this scenario, polyphenols’ action as natural chelators is also discussed. Furthermore, the critical importance of the role exerted by polyphenols on microbiota is assumed, since there is a growing body of evidence for the role of the intestinal microbiota in the gut–brain axis, giving new opportunities to study molecular mechanisms and to find novel strategies in neurological diseases.
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30
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Sharma V, Singh TG, Kaur A, Mannan A, Dhiman S. Brain-Derived Neurotrophic Factor: A Novel Dynamically Regulated Therapeutic Modulator in Neurological Disorders. Neurochem Res 2023; 48:317-339. [PMID: 36308619 DOI: 10.1007/s11064-022-03755-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 09/02/2022] [Accepted: 09/03/2022] [Indexed: 02/04/2023]
Abstract
The growth factor brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin-related kinase receptor type B (TrkB) play an active role in numerous areas of the adult brain, where they regulate the neuronal activity, function, and survival. Upregulation and downregulation of BDNF expression are critical for the physiology of neuronal circuits and functioning in the brain. Loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric disorders. This article reviews the BDNF gene structure, transport, secretion, expression and functions in the brain. This article also implicates BDNF in several brain-related disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, major depressive disorder, schizophrenia, epilepsy and bipolar disorder.
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Affiliation(s)
- Veerta Sharma
- Chitkara College of Pharmacy, Chitkara University, 140401, Rajpura, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, 140401, Rajpura, Punjab, India.
| | - Amarjot Kaur
- Chitkara College of Pharmacy, Chitkara University, 140401, Rajpura, Punjab, India
| | - Ashi Mannan
- Chitkara College of Pharmacy, Chitkara University, 140401, Rajpura, Punjab, India
| | - Sonia Dhiman
- Chitkara College of Pharmacy, Chitkara University, 140401, Rajpura, Punjab, India
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31
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Kaneko M, Stryker MP. Production of brain-derived neurotrophic factor gates plasticity in developing visual cortex. Proc Natl Acad Sci U S A 2023; 120:e2214833120. [PMID: 36634145 PMCID: PMC9934058 DOI: 10.1073/pnas.2214833120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 12/06/2022] [Indexed: 01/13/2023] Open
Abstract
We have previously shown that recovery of visual responses to a deprived eye during the critical period in mouse primary visual cortex requires phosphorylation of the TrkB receptor for BDNF [M. Kaneko, J. L. Hanover, P. M. England, M. P. Stryker, Nat. Neurosci. 11, 497-504 (2008)]. We have now studied the temporal relationship between the production of mature BDNF and the recovery of visual responses under several different conditions. Visual cortical responses to an eye whose vision has been occluded for several days during the critical period and is then re-opened recover rapidly during binocular vision or much more slowly following reverse occlusion, when the previously intact fellow eye is occluded in a model of "patch therapy" for amblyopia. The time to recovery of visual responses differed by more than 18 h between these two procedures, but in each, the production of mature BDNF preceded the physiological recovery. These findings suggest that a spurt of BDNF production is permissive for the growth of connections serving the deprived eye to restore visual responses. Attenuation of recovery of deprived-eye responses by interference with TrkB receptor activation or reduction of BDNF production by interference with homeostatic synaptic scaling had effects consistent with this suggestion.
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Affiliation(s)
- Megumi Kaneko
- Department of Physiology and Kavli Institute for Fundamental Neuroscience, University of California, San Francisco94143
| | - Michael P. Stryker
- Department of Physiology and Kavli Institute for Fundamental Neuroscience, University of California, San Francisco94143
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32
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Tan X, Zhao L, Tang Y. The Function of BDNF and Its Receptor in the Male Genitourinary System and Its Potential Clinical Application. Curr Issues Mol Biol 2022; 45:110-121. [PMID: 36661494 PMCID: PMC9856797 DOI: 10.3390/cimb45010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/04/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Background: Brain-derived neurotrophic factor (BDNF), as a member of the nerve growth factor family, has been mentioned more and more frequently in recent literature reports. Among them, content about the male genitourinary system is also increasing. Objective and Rationale: BDNF plays an important role in the male genitourinary system. At the same time, the literature in this field is constantly increasing. Therefore, we systematically summarized the literature in order to more intuitively show the function of BDNF and its receptor in the male genitourinary system and its potential clinical application. Search Methods: An electronic search of, e.g., PubMed, scholar.google and Scopus, for articles relating to BDNF and its receptor in the male genitourinary system. Outcomes: In the male genitourinary system, BDNF and its receptors TrkB and p75 participate in a series of normal physiological activities, such as the maturation and morphogenesis of testes and epididymis and maintenance of isolated sperm motility. Similarly, an imbalance of the circulating concentration of BDNF also mediates the pathophysiological process of many diseases, such as prostate cancer, benign prostatic hyperplasia, male infertility, diabetes erectile dysfunction, penile sclerosis, and bladder fibrosis. As a consequence, we conclude that BDNF and its receptor are key regulatory proteins in the male genitourinary system, which can be used as potential therapeutic targets and markers for disease diagnosis.
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Affiliation(s)
- Xiaoli Tan
- Department of Urology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 510275, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 510275, China
| | - Liangyu Zhao
- Department of Urology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 510275, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 510275, China
| | - Yuxin Tang
- Department of Urology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 510275, China
- Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai 510275, China
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Lim SY, Cengiz P. Opioid tolerance and opioid-induced hyperalgesia: Is TrkB modulation a potential pharmacological solution? Neuropharmacology 2022; 220:109260. [PMID: 36165856 DOI: 10.1016/j.neuropharm.2022.109260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/23/2022] [Accepted: 09/15/2022] [Indexed: 11/29/2022]
Abstract
Opioids are widely prescribed for moderate to severe pain in patients with acute illness, cancer pain, and chronic noncancer pain. However, long-term opioid use can cause opioid tolerance and opioid-induced hyperalgesia (OIH), contributing to the opioid misuse and addiction crisis. Strategies to mitigate opioid tolerance and OIH are needed to reduce opioid use and its sequelae. Currently, there are few effective pharmacological strategies that reduce opioid tolerance and OIH. The intrinsic tyrosine kinase receptor B (TrkB) ligand, brain-derived neurotrophic factor (BDNF), has been shown to modulate pain. The BDNF-TrkB signaling plays a role in initiating and sustaining elevated pain sensitivity; however, increasing evidence has shown that BDNF and 7,8-dihydroxyflavone (7,8-DHF), a potent blood-brain barrier-permeable ligand to TrkB, exert neuroprotective, anti-inflammatory, and antioxidant effects that may protect against opioid tolerance and OIH. As such, TrkB signaling may be an important therapeutic avenue in opioid tolerance and OIH. Here, we review 1) the mechanisms of pain, opioid analgesia, opioid tolerance, and OIH; 2) the role of BDNF-TrkB in pain modulation; and 3) the neuroprotective effects of 7,8-DHF and their implications for opioid tolerance and OIH.
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Affiliation(s)
- Sin Yin Lim
- Pharmacy Practice and Translational Research Division, University of Wisconsin-Madison School of Pharmacy, Madison, WI, United States.
| | - Pelin Cengiz
- Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States; Waisman Center, University of Wisconsin-Madison, United States.
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Small-molecule 7,8-dihydroxyflavone counteracts compensated and decompensated cardiac hypertrophy via AMPK activation. J Geriatr Cardiol 2022; 19:853-866. [PMID: 36561053 PMCID: PMC9748273 DOI: 10.11909/j.issn.1671-5411.2022.11.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pathological cardiac hypertrophy is a compensated response to various stimuli and is considered a key risk factor for heart failure. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid derivative that acts as a small-molecule brain-derived neurotrophic factor mimetic. The present study aimed to explore the potential role of 7,8-DHF in cardiac hypertrophy. METHODS Kunming mice and H9c2 cells were exposed to transverse aortic constriction or isoproterenol (ISO) with or without 7,8-DHF, respectively. F-actin staining was performed to calculate the cell area. Transcriptional levels of hypertrophic markers, including ANP, BNP, and β-MHC, were detected. Echocardiography, hematoxylin-eosin staining, and transmission electron microscopy were used to examine the cardiac function, histology, and ultrastructure of ventricles. Protein levels of mitochondria-related factors, such as adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), were detected. RESULTS 7,8-DHF inhibited compensated and decompensated cardiac hypertrophy, diminished the cross-sectional area, and alleviated the mitochondrial disorders of cardiomyocytes. Meanwhile, 7,8-DHF reduced the cell size and repressed the mRNA levels of the hypertrophic markers of ISO-treated cardiomyocytes. In addition, 7,8-DHF activated AMPK and PGC-1α signals without affecting the protein levels of mitochondrial dynamics-related molecules. The effects of 7,8-DHF were eliminanted by Compound C, an AMPK inhibitor. CONCLUSIONS These findings suggest that 7,8-DHF inhibited cardiac hypertrophy and mitochondrial dysfunction by activating AMPK signaling, providing a potential agent for the treatment of pathological cardiac hypertrophy.
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Hang PZ, Liu J, Wang JP, Li FF, Li PF, Kong QN, Shi J, Ji HY, Du ZM, Zhao J. 7,8-Dihydroxyflavone alleviates cardiac fibrosis by restoring circadian signals via downregulating Bmal1/Akt pathway. Eur J Pharmacol 2022; 938:175420. [PMID: 36427535 DOI: 10.1016/j.ejphar.2022.175420] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/09/2022] [Accepted: 11/22/2022] [Indexed: 11/24/2022]
Abstract
Brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway is a therapeutic target in cardiac diseases. A BDNF mimetic, 7,8-dihydroxyflavone (7,8-DHF), is emerging as a protective agent in cardiomyocytes; however, its potential role in cardiac fibroblasts (CFs) and fibrosis remains unknown. Thus, we aimed to explore the effects of 7,8-DHF on cardiac fibrosis and the possible mechanisms. Myocardial ischemia (MI) and transforming growth factor-β1 (TGF-β1) were used to establish models of cardiac fibrosis. Hematoxylin & eosin and Masson's trichrome stains were used for histological analysis and determination of collagen content in mouse myocardium. Cell viability kit, EdU (5-ethynyl-2'-deoxyuridine) assay and immunofluorescent stain were employed to examine the effects of 7,8-DHF on the proliferation and collagen production of CFs. The levels of collagen I, α-smooth muscle actin (α-SMA), TGF-β1, Smad2/3, and Akt as well as circadian rhythm-related signals including brain and muscle Arnt-like protein 1 (Bmal1), period 2 (Per2), and cryptochrome 2 (Cry2) were analyzed. Treatment with 7,8-DHF markedly alleviated cardiac fibrosis in MI mice. It inhibited the activity of CFs accompanied by decreasing number of EdU-positive cells and downregulation of collagen I, α-SMA, TGF-β1, and phosphorylation of Smad2/3. 7,8-DHF significantly restored the dysregulation of Bmal1, Per2, and Cry2, but inhibited the overactive Akt. Further, inhibition of Bmal1 by SR9009 effectively attenuated CFs proliferation and collagen production of CFs. In summary, these findings indicate that 7,8-DHF attenuates cardiac fibrosis and regulates circadian rhythmic signals, at least partly, by inhibiting Bmal1/Akt pathway, which may provide new insights into therapeutic cardiac remodeling.
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Affiliation(s)
- Peng-Zhou Hang
- Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China; Department of Pharmacy, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Jie Liu
- Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China
| | - Jia-Pan Wang
- Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China
| | - Feng-Feng Li
- Department of Pharmacology, Harbin Medical University, Harbin, 150081, China
| | - Pei-Feng Li
- Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China
| | - Qing-Nan Kong
- Department of Pharmacology, Harbin Medical University, Harbin, 150081, China
| | - Jing Shi
- Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150001, China
| | - Hong-Yu Ji
- Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China
| | - Zhi-Min Du
- Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, China.
| | - Jing Zhao
- Department of Pharmacy, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225001, China; Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, 150001, China.
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Chen X, Zhao Y, You S, Xia Q, Mo X, Yuan F. 7,8-Dihydroxyflavone Simultaneously Provides Neuroprotection of Retinal Explants and Proangiogenesis of Human Umbilical Vein Endothelial Cells via the Tropomyosin-Related Kinase Receptor B Signaling Pathway In Vitro. J Ocul Pharmacol Ther 2022; 38:635-644. [PMID: 36260383 DOI: 10.1089/jop.2022.0064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose: This study aimed to investigate the simultaneous neuroprotective and proangiogenic effects of 7,8-dihydroxyflavone (7,8-DHF) and explore the potential underlying molecular mechanisms. Methods: A coculture system of rat retinal explants and human umbilical vein endothelial cells (HUVECs) was established to determine the optimal concentration of 7,8-DHF, promoting neurite regeneration and HUVEC proliferation. Subsequently, the neuroprotective effect, proangiogenesis properties, and action mechanism of 7,8-DHF at an optimal concentration were investigated. Results: The cell proliferation, survival, migration, tube formation and p-tropomyosin-related kinase receptor B (TrkB)/TrkB levels in HUVECs were significantly promoted by 5 μM 7,8-DHF. The ganglion cell layer neuron survival, neurite regeneration, and p-TrkB/TrkB levels in retinal explants were also significantly promoted by 5 μM 7,8-DHF. All of these pharmacological actions of 7,8-DHF were blocked by N-[2-[(2-oxoazepan-3-yl)carbamoyl]phenyl]-1-benzothiophene-2-carboxamide. Conclusions: 7,8-DHF yields neuroprotection of retinal explants and proangiogenesis of HUVECs through the TrkB signaling pathway in vitro.
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Affiliation(s)
- Xiangwu Chen
- Department of Ophthalmology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yingxi Zhao
- Department of Ophthalmology, Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shuqi You
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Qing Xia
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Xiaofen Mo
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Fei Yuan
- Department of Ophthalmology, Zhongshan Hospital of Fudan University, Shanghai, China
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Chiu YJ, Lin TH, Chang KH, Lin W, Hsieh-Li HM, Su MT, Chen CM, Sun YC, Lee-Chen GJ. Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity. Aging (Albany NY) 2022; 14:7568-7586. [PMID: 36170028 PMCID: PMC9550238 DOI: 10.18632/aging.204306] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 09/17/2022] [Indexed: 11/28/2022]
Abstract
Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer’s disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood–brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD.
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Affiliation(s)
- Ya-Jen Chiu
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Te-Hsien Lin
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Kuo-Hsuan Chang
- Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan
| | - Wenwei Lin
- Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Hsiu Mei Hsieh-Li
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Ming-Tsan Su
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Chiung-Mei Chen
- Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan
| | - Ying-Chieh Sun
- Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
| | - Guey-Jen Lee-Chen
- Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
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Cook AA, Jayabal S, Sheng J, Fields E, Leung TCS, Quilez S, McNicholas E, Lau L, Huang S, Watt AJ. Activation of TrkB-Akt signaling rescues deficits in a mouse model of SCA6. SCIENCE ADVANCES 2022; 8:eabh3260. [PMID: 36112675 PMCID: PMC9481119 DOI: 10.1126/sciadv.abh3260] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/29/2022] [Indexed: 06/01/2023]
Abstract
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in postmortem tissue from SCA6 patients. Here, we show that levels of cerebellar BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of exercise elevated cerebellar BDNF expression and improved ataxia and cerebellar Purkinje cell firing rate deficits. A TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), likewise improved motor coordination and Purkinje cell firing rate and elevated downstream Akt signaling. Prolonged 7,8-DHF administration persistently improved ataxia when treatment commenced near disease onset but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.
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Affiliation(s)
- Anna A. Cook
- Biology Department, McGill University, Montreal, QC, Canada
| | - Sriram Jayabal
- Biology Department, McGill University, Montreal, QC, Canada
- Integrated Neuroscience Program, McGill University, Montreal, QC, Canada
- Department of Neurobiology, Stanford School of Medicine, Stanford, CA, USA
| | - Jacky Sheng
- Biology Department, McGill University, Montreal, QC, Canada
| | - Eviatar Fields
- Biology Department, McGill University, Montreal, QC, Canada
- Integrated Neuroscience Program, McGill University, Montreal, QC, Canada
| | | | - Sabrina Quilez
- Biology Department, McGill University, Montreal, QC, Canada
| | | | - Lois Lau
- Biology Department, McGill University, Montreal, QC, Canada
| | - Shixia Huang
- Department of Molecular and Cellular Biology, Department of Education, Innovation and Technology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Alanna J. Watt
- Biology Department, McGill University, Montreal, QC, Canada
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Bian N, Chen X, Ren X, Yu Z, Jin M, Chen X, Liu C, Luan Y, Wei L, Chen Y, Song W, Zhao Y, Wang B, Jiang T, Zhang C, Shu Z, Su X, Wang L. 7,8-Dihydroxyflavone attenuates the virulence of Staphylococcus aureus by inhibiting alpha-hemolysin. World J Microbiol Biotechnol 2022; 38:200. [PMID: 35995893 DOI: 10.1007/s11274-022-03378-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/05/2022] [Indexed: 11/29/2022]
Abstract
Staphylococcus aureus (S. aureus), a Gram-positive bacteria, is an incurable cause of hospital and community-acquired infections. Inhibition bacterial virulence is a viable strategy against S. aureus infections based on the multiple virulence factors secreted by S. aureus. Alpha-hemolysin (Hla) plays a crucial role in bacteria virulence without affecting bacterial viability. Here, we identified that 7,8-Dihydroxyflavone (7,8-DHF), a natural compound, was able to decrease the expression of and did not affect the in vitro growth of S. aureus USA300 at a concentration of 32 μg/mL. It was verified by western blot and RT-qPCR that the natural compound could inhibit the transcription and translation of Hla. Further mechanism studies revealed that 7,8-DHF has a negative effect on transcriptional regulator agrA and RNAIII, preventing the upregulation of virulence gene. Cytotoxicity assays showed that 7,8-DHF did not produce significant cytotoxicity to A549 cells. Animal experiments showed that the combination of 7,8-DHF and vancomycin had a more significant therapeutic effect on S. aureus infection, reflecting the synergistic effect of 7,8-DHF with antibiotics. In conclusion, 7,8-DHF was able to target Hla to protect host cells from hemolysis while limiting the development of bacterial resistance.
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Affiliation(s)
- Nan Bian
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Xiangqian Chen
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Xinran Ren
- School of Pharmaceutical Science, Jilin University, Changchun, 130021, China
| | - Zishu Yu
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Mengli Jin
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Xiaoyu Chen
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Chang Liu
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Yanhe Luan
- The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Lin Wei
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Ying Chen
- The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Wu Song
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Yicheng Zhao
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Bingmei Wang
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Tao Jiang
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Chi Zhang
- Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Zunhua Shu
- The Third Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130118, China.
| | - Xin Su
- Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Li Wang
- Changchun University of Chinese Medicine, Changchun, 130117, China.
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Sharma P, Silva C, Pfreundschuh S, Ye H, Sampath H. Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome. Front Nutr 2022; 9:987956. [PMID: 36061902 PMCID: PMC9428675 DOI: 10.3389/fnut.2022.987956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 07/29/2022] [Indexed: 11/18/2022] Open
Abstract
Background 7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in Godmania, Tridax, and Primula species that confers protection against high-fat diet (HFD) induced metabolic pathologies selectively in female mice. We have previously reported that this metabolic protection is associated with early and stable remodeling of the intestinal microbiome, evident in female but not male DHF-supplemented mice. Early changes in the gut microbiome in female DHF-fed mice were highly predictive of subsequent metabolic protection, suggesting a causative association between the gut microbiome and the metabolic effects of DHF. Objective To investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation. Materials and methods Age-matched male and female C57Bl6/J mice were given ad libitum access to HFD and drinking water containing vehicle or DHF for 12 weeks. For antibiotic (Abx) treatment, female mice were given drinking water containing a cocktail of antibiotics for 2 weeks prior to HFD feeding and throughout the feeding period. Metabolic phenotyping consisted of longitudinal assessments of body weights, body composition, food, and water intake, as well as measurement of energy expenditure, glucose tolerance, and plasma and hepatic lipids. Protein markers mediating the cellular effects of DHF were assessed in brown adipose tissue (BAT) and skeletal muscle. Results Metabolic protection conferred by DHF in female HFD-fed mice was only apparent in the presence of an intact gut microbiome. Abx-treated mice were not protected from HFD-induced obesity by DHF administration. Further, tissue activation of the tropomyosin-related kinase receptor B (TrkB) receptor, which has been attributed to the biological activity of DHF, was lost upon gut microbiome ablation, indicating a requirement for microbial “activation” of DHF for its systemic effects. In addition, we report for the first time that DHF supplementation significantly activates TrkB in BAT of female, but not male, mice uncovering a novel target tissue of DHF. DHF supplementation also increased uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) protein in BAT, consistent with protection from diet-induced obesity. Conclusion These results establish for the first time a requirement for the gut microbiome in mediating the metabolic effects of DHF in female mice and uncover a novel target tissue that may mediate these sexually-dimorphic protective effects.
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Affiliation(s)
- Priyanka Sharma
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States
- Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States
| | - Camila Silva
- Department of Biotechnology, Rutgers University, New Brunswick, NJ, United States
| | - Sarah Pfreundschuh
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States
| | - Hong Ye
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States
| | - Harini Sampath
- Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States
- Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States
- Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States
- *Correspondence: Harini Sampath,
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Xiong J, Liao J, Liu X, Zhang Z, Adams J, Pacifici R, Ye K. A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin. Nat Commun 2022; 13:4820. [PMID: 35973996 PMCID: PMC9381595 DOI: 10.1038/s41467-022-32435-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 07/26/2022] [Indexed: 11/12/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/− mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG. BDNS and TrkB are involved in bone fracture healing by inhibiting AEP. Here the authors show that a TrkB agonist prodrug can inhibit AEP and promote bone formation in osteoporotic mice.
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Affiliation(s)
- Jing Xiong
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, PR China
| | - Jianming Liao
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, PR China
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, PR China
| | - Jonathan Adams
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Roberto Pacifici
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. .,Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology (SIAT) Shenzhen, Guangdong, PR China.
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Serotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes. Cells 2022; 11:cells11152384. [PMID: 35954229 PMCID: PMC9368268 DOI: 10.3390/cells11152384] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 02/04/2023] Open
Abstract
Serotonin receptor 5-HT2A and tropomyosin receptor kinase B (TrkB) strongly contribute to neuroplasticity regulation and are implicated in numerous neuronal disorders. Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation and biophysical and biochemical approaches. Heterodimerization decreased TrkB autophosphorylation, preventing its activation with agonist 7,8-DHF, even with low 5-HT2A receptor expression. A blockade of 5-HT2A receptor with the preferential antagonist ketanserin prevented the receptor-mediated downregulation of TrkB phosphorylation without restoring the TrkB response to its agonist 7,8-DHF in vitro. In adult mice, intraperitoneal ketanserin injection increased basal TrkB phosphorylation in the frontal cortex and hippocampus, which is in accordance with our findings demonstrating the prevalence of 5-HT2A–TrkB heteroreceptor complexes in these brain regions. An expression analysis revealed strong developmental regulation of 5-HT2A and TrkB expressions in the cortex, hippocampus, and especially the striatum, demonstrating that the balance between TrkB and 5-HT2A may shift in certain brain regions during postnatal development. Our data reveal the functional role of 5-HT2A–TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions during development and under pathophysiological conditions.
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Kang SS, Wu Z, Liu X, Edgington-Mitchell L, Ye K. Treating Parkinson's Disease via Activation of BDNF/TrkB Signaling Pathways and Inhibition of Delta-Secretase. Neurotherapeutics 2022; 19:1283-1297. [PMID: 35595958 PMCID: PMC9587159 DOI: 10.1007/s13311-022-01248-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2022] [Indexed: 10/18/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease with motor disorders as the key clinical features. BDNF/TrkB neurotrophic signalings are progressively reduced, whereas δ-secretase, a protease that cleaves α-synuclein (α-Syn) at N103 and promotes its aggregation and neurotoxicity, is gradually escalated in PD patient brains, associated with dopaminergic neuronal loss in the Substantia Nigra. Here, we show that stimulation of deficient BDNF/TrkB signalings with its small molecular agonist CF3CN displays the promising therapeutic effect, and blockade of δ-secretase with an optimal specific inhibitor #11A exhibits marked therapeutic effect, and combination of both demonstrates additive restorative efficacy in MPTP-induced human SNCA transgenic PD mice. Upon oral administration, CF3CN robustly activates TrkB-mediated neurotrophic pathway in the brains of SNCA mice and decreases α-Syn N103 cleavage by δ-secretase, and #11A strongly blocks δ-secretase and reduces α-Syn N103 fragmentation, increasing TH-positive dopaminergic neurons. The mixture of CF3CN and #11A shows the maximal TH and dopamine levels with demonstrable BDNF as compared to negligible BDNF in vehicle-treated MPTP/SNCA mice, leading to the climaxed motor functions. Notably, both compounds possess the appropriate in vivo PK profiles. Hence, our findings support that CF3CN and #11A are promising therapeutic pharmaceutical agents for treating PD.
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Affiliation(s)
- Seong Su Kang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Zhourui Wu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education of the People's Republic of China, Shanghai, 200072, China
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Laura Edgington-Mitchell
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, 3010, Australia
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Faculty of Life and Health Sciences, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
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Peregud D, Kvichansky A, Shirobokova N, Stepanichev M, Gulyaeva N. 7,8-DHF enhances SHH in the hippocampus and striatum during early abstinence but has minor effects on alcohol intake in IA2BC paradigm and abstinence-related anxiety-like behavior in rats. Neurosci Lett 2022; 781:136671. [DOI: 10.1016/j.neulet.2022.136671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 11/30/2022]
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45
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Tian Y, Pan L, Yuan X, Xiong M, Zhang Z, Meng L, Zheng Y, Bu L, Xu X, Zhang Z. 7,8-Dihydroxyflavone ameliorates mitochondrial impairment and motor dysfunction in the α-synuclein 1–103 transgenic mice. Neurobiol Dis 2022; 169:105736. [DOI: 10.1016/j.nbd.2022.105736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 04/06/2022] [Accepted: 04/14/2022] [Indexed: 10/18/2022] Open
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Chen Y, Gao X, Liu S, Cai Q, Wu L, Sun Y, Xia G, Wang Y. Establishment and Characterization of Stable Zein/Glycosylated Lactoferrin Nanoparticles to Enhance the Storage Stability and in vitro Bioaccessibility of 7,8-Dihydroxyflavone. Front Nutr 2022; 8:806623. [PMID: 35047548 PMCID: PMC8763018 DOI: 10.3389/fnut.2021.806623] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 11/29/2021] [Indexed: 12/21/2022] Open
Abstract
In this work, the lactoferrin (LF) was glycosylated by dextran (molecular weight 10, 40, and 70 kDa, LF 10K, LF 40K, and LF 70K) via Maillard reaction as a stabilizer to establish zein/glycosylated LF nanoparticles and encapsulate 7,8-dihydroxyflavone (7,8-DHF). Three zein/glycosylated LF nanoparticles (79.27–87.24 nm) with low turbidity (<0.220) and polydispersity index (PDI) (<0.230) were successfully established by hydrophobic interactions and hydrogen bonding. Compared with zein/LF nanoparticles, zein/glycosylated LF nanoparticles further increased stability to ionic strength (0–500 mM NaCl) at low pH conditions. Zein/glycosylated LF nanoparticles had nanoscale spherical shape and glycosylated LF changed surface morphology of zein nanoparticles. Besides, encapsulated 7,8-DHF exhibited an amorphous state inside zein/glycosylated LF nanoparticles. Most importantly, zein/glycosylated LF nanoparticles had good water redispersibility, high encapsulation efficiency (above 98.50%), favorable storage stability, and bioaccessibility for 7,8-DHF, particularly LF 40K. Collectively, the above research provides a theoretical reference for the application of zein-based delivery systems.
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Affiliation(s)
- Yufeng Chen
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China.,Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China
| | - Xiaojing Gao
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China
| | - Shucheng Liu
- Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, China
| | - Qiuxing Cai
- College of Food Engineering, Beibu Gulf University, Qinzhou, China
| | - Lijun Wu
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China
| | - Yi Sun
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China
| | - Guobin Xia
- Department of Pediatrics Section of Neonatology, Texas Children's Hospital, Houston, TX, United States
| | - Yueqi Wang
- College of Food Engineering, Beibu Gulf University, Qinzhou, China.,Key Lab of Aquatic Product Processing, Ministry of Agriculture and Rural Affairs of the People's Republic of China, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China
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Porter GA, O’Connor JC. Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime? World J Psychiatry 2022; 12:77-97. [PMID: 35111580 PMCID: PMC8783167 DOI: 10.5498/wjp.v12.i1.77] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/21/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.
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Affiliation(s)
- Grace A Porter
- Department of Pharmacology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Jason C O’Connor
- Department of Pharmacology, University of Texas Health San Antonio, San Antonio, TX 78229, United States
- Audie L. Murphy VA Hospital, South Texas Veterans Health System, San Antonio, TX 78229, United States
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Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell 2022; 185:62-76. [PMID: 34963057 PMCID: PMC8741740 DOI: 10.1016/j.cell.2021.12.003] [Citation(s) in RCA: 308] [Impact Index Per Article: 102.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/10/2021] [Accepted: 12/02/2021] [Indexed: 01/09/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.
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Affiliation(s)
- Camille S Wang
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA
| | - Ege T Kavalali
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA
| | - Lisa M Monteggia
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232-2050, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37240-7933, USA.
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Yu A, Wang S, Xing Y, Han M, Shao K. 7,8-Dihydroxyflavone alleviates apoptosis and inflammation induced by retinal ischemia-reperfusion injury via activating TrkB/Akt/NF-kB signaling pathway. Int J Med Sci 2022; 19:13-24. [PMID: 34975295 PMCID: PMC8692126 DOI: 10.7150/ijms.65733] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/26/2021] [Indexed: 12/31/2022] Open
Abstract
Retinal ischemia-reperfusion injury (RIRI) is of common occurrence in retinal and optic nerve diseases. The BDNF/TrkB signaling pathway has been examined to be neuroprotective in RIRI. In this study, we investigated the role of a potent selective TrkB agonist 7,8-dihydroxyfavone (DHF) in rat retinas with RIRI. Our results showed that RIRI inhibited the conversion of BDNF precursor (proBDNF) to mature BDNF (mBDNF) and increased the level of neuronal cell apoptosis. Compared with RIRI, DHF+RIRI reduced proBDNF level and at the same time increased mBDNF level. Moreover, DHF administration effectively activated TrkB signaling and and downstream Akt and Erk signaling pathways which increased nerve cell survival. The combined effects of mBDNF/proBDNF increase and TrkB signaling activation lead to reduction of apoptosis level and protection of retinas with RIRI. Moreover, it was also found that astrocytes labeled by GFAP were activated in RIRI and NF-kB mediated the increased expressions of inflammatory factors and these effects were partially reversed by DHF administration. Besides, we also used RNA sequencing to analyze the differently expressed genes (DEGs) and their enriched (Kyoto Encyclopedia of Genes and Genomes) KEGG pathways between Sham, RIRI, and DHF+RIRI. It was found that 1543 DEGs were differently expressed in RIRI and 619 DEGs were reversed in DHF+RIRI. The reversed DEGs were typically enriched in PI3K-Akt signaling pathway, Jak-STAT signaling pathway, NF-kB signaling pathway, and Apoptosis. To sum up, the DHF administration alleviated apoptosis and inflammation induced by RIRI via activating TrkB signaling pathway and may serve as a promising drug candidate for RIRI related ophthalmopathy.
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Affiliation(s)
- Aihua Yu
- Eye Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, Hubei Province, China
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan University,Wuhan 430071, Hubei Province, China
| | - Shun Wang
- Eye Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, Hubei Province, China
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan University,Wuhan 430071, Hubei Province, China
| | - Yiqiao Xing
- Eye Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, Hubei Province, China
| | - Mengyao Han
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan University,Wuhan 430071, Hubei Province, China
| | - Kun Shao
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan University,Wuhan 430071, Hubei Province, China
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50
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Chrysin restores memory deficit in hypothyroidism mice: Behavioral, neurochemical and computational approaches involving the neurotrophinergic system. J Psychiatr Res 2021; 144:225-233. [PMID: 34700210 DOI: 10.1016/j.jpsychires.2021.10.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 09/24/2021] [Accepted: 10/18/2021] [Indexed: 02/01/2023]
Abstract
Hypothyroidism is a condition that affects multiple systems, including the central nervous system, causing, for example, cognitive deficits closely related to Alzheimer's disease. The flavonoid chrysin is a natural compound associated with neuronal improvement in several experimental models. Here, we evaluated the effect of chrysin on cognitive impairment in hypothyroid female mice by exploring neuroplasticity. Hypothyroidism was induced by continuous exposure to 0.1% methimazole (MTZ) in drinking water for 31 days. On the 32nd day, the animals showed low plasma levels of thyroid hormones (hypothyroid mice) than the control group (euthyroid mice). Subsequently, mice were intragastrically administered with vehicle or chrysin (20 mg/kg) once a day for 28 consecutive days. At the end of the treatments, behavioral tests were performed: open-field test (OFT) and morris water maze (MWM). Then, the levels of neurotrophins (BDNF and NGF) in the hippocampus and prefrontal cortex were measured and tested the affinity of chrysin with neurotrophinergic receptors through molecular docking. Hypothyroid mice showed memory deficit in the MWM and reduced neurotrophins levels in the hippocampus and prefrontal cortex, meanwhile, the chrysin treatment was able to reversed the deficit of spatial memory function and increased the levels of BDNF in hipocamppus and NGF in both structures. Additionally, molecular docking analysis showed that chrysin potentially binds to the active site of the TrkA, TrkB, and p75NTR receptors. Together, these findings suggest that chrysin reversed behavioral and neurochemical alterations associated with memory deficit induced by hypothyroidism, possibly by modulating synaptic plasticity in the neurotrophinergic system.
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