|
1
|
Li T, Li S, Xiong Y, Li X, Ma C, Guan Z, Yang L. Binary Nano-inhalant Formulation of Icariin Enhances Cognitive Function in Vascular Dementia via BDNF/TrkB Signaling and Anti-inflammatory Effects. Neurochem Res 2024; 49:1720-1734. [PMID: 38520637 DOI: 10.1007/s11064-024-04129-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 02/12/2024] [Accepted: 02/14/2024] [Indexed: 03/25/2024]
Abstract
Vascular dementia (VaD) has a serious impact on the patients' quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood-brain barrier (BBB) permeability remain challenges. This research introduced a PEG-PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG-PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1β and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG-PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.
Collapse
Affiliation(s)
- Tieshu Li
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People's Republic of China
| | - Shuling Li
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People's Republic of China
| | - Yin Xiong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, People's Republic of China
| | - Xinxin Li
- Affiliated Hospital of Yangzhou University, Yangzhou University, 88 South Daxue Road, Yangzhou, 225009, People's Republic of China
| | - Chun Ma
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People's Republic of China
| | - Zhiying Guan
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People's Republic of China
| | - Lihua Yang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, 130117, People's Republic of China.
| |
Collapse
|
|
2
|
Basir HS, Mirazi N, Komaki A, Hosseini A. Cacao consumption improves passive avoidance memory impairment in a rat model of Alzheimer's disease: the role of hippocampal synaptic plasticity and oxidative stress. Front Pharmacol 2024; 15:1379264. [PMID: 38756381 PMCID: PMC11096498 DOI: 10.3389/fphar.2024.1379264] [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: 01/30/2024] [Accepted: 04/05/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction: Alzheimer's disease (AD) causes progressive loss of cognitive function and synaptic plasticity, which is the most common form of dementia. The present study was designed to scrutinize the effects of cacao on passive avoidance memory function and to identify the roles of hippocampal synaptic plasticity and oxidative stress in an AD rat model induced by unilateral intracerebroventricular (UICV) injection of amyloid-beta (Aβ). Methods: Oral administration of cacao (500 mg/kg/ day) was given for 2 consecutive months. A memory retention test was conducted 24 h after passive avoidance training was completed. Subsequently, the amplitude of population spike (PS) and slope of field excitatory postsynaptic potentials (fEPSPs) were assessed at hippocampal long-term potentiation (LTP) in perforant pathway-dentate gyrus (PP-DG) synapses. Moreover, total thiol group (TTG) and malondialdehyde (MDA) concentrations were evaluated in the plasma. Furthermore, compact Aβ plaques were detected in the hippocampal DG by performing Congo red staining. Results: As a result of AD induction, passive avoidance memory was impaired; also, reduced fEPSP slopes, PS amplitudes, and content of TTG, and increase in MDA levels in the rats were observed. In contrast, cacao treatment ameliorated passive avoidance memory impairment, improved hippocampal LTP impairment, modulated oxidative-antioxidative status, and delayed Aβ plaques production in AD rats. Disscussion: Conclusively, cacao alleviates Aβ-induced cognitive deficit, probably by the amelioration of hippocampal LTP impairment, modulation of oxidative-antioxidative status, and inhibition of Aβ plaque accumulation.
Collapse
Affiliation(s)
- Hamid Shokati Basir
- Department of Biology, Faculty of Basic Science, Bu-Ali Sina University, Hamedan, Iran
| | - Naser Mirazi
- Department of Biology, Faculty of Basic Science, Bu-Ali Sina University, Hamedan, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Abdolkarim Hosseini
- Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| |
Collapse
|
|
3
|
Wang D, Zheng J, Sun X, Xie L, Yang Y. Study on the Pharmacological Mechanism of Icariin for the Treatment of Alzheimer's Disease Based on Network Pharmacology and Molecular Docking Techniques. Metabolites 2023; 14:1. [PMID: 38276291 PMCID: PMC10820555 DOI: 10.3390/metabo14010001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024] Open
Abstract
The purpose of this study is to explore the pharmacological mechanism of icariin (ICA) in the treatment of Alzheimer's disease (AD) based on network pharmacology and network molecular docking technology. In order to investigate the regulatory effect of ICA on the expression level of AD pathological phosphorylation regulatory proteins, this study further explored the possible molecular mechanism of ICA regulating AD autophagy through network pharmacology. Macromolecular docking network was verified by Autodock Vina 1.1.2 software. The main active ingredients of ICA, the physicochemical properties, and pharmacokinetic information of ICA were predicted using online databases and relevant information. The results showed that the targets of MAPK3, AKT1, HSP90AA1, ESR1, and HSP90AA1 were more critical in the treatment of AD. Autophagy, apoptosis, senescence factors, phosphatidylinositide 3-kinase/protein kinase B (P13K/AKT) signaling pathway, MAKP, mTOR, and other pathways were significantly associated with AD. Docking of ICA with HIF-1, BNIP3, PINK1, and Parkin pathway molecules showed that the key targets of the signaling pathway were more stably bound to ICA, which may provide a better pathway for ICA to regulate autophagy by providing a better pathway. ICA can improve AD, and its mechanism may be related to the P13K/AKT, MAKP, and mTOR signaling pathways, thereby regulating autophagy-related proteins.
Collapse
Affiliation(s)
- Dongwei Wang
- College of Police Dog Technology, Criminal Investigation Police University of China, Shenyang 110854, China; (D.W.); (J.Z.); (X.S.); (L.X.)
| | - Jilong Zheng
- College of Police Dog Technology, Criminal Investigation Police University of China, Shenyang 110854, China; (D.W.); (J.Z.); (X.S.); (L.X.)
| | - Xingsheng Sun
- College of Police Dog Technology, Criminal Investigation Police University of China, Shenyang 110854, China; (D.W.); (J.Z.); (X.S.); (L.X.)
| | - Liuwei Xie
- College of Police Dog Technology, Criminal Investigation Police University of China, Shenyang 110854, China; (D.W.); (J.Z.); (X.S.); (L.X.)
- The Second Affiliated Hospital of Shenyang Medical College, Shenyang 110031, China
| | - Yang Yang
- The Second Affiliated Hospital of Shenyang Medical College, Shenyang 110031, China
| |
Collapse
|
|
4
|
Marei HE, Khan MUA, Hasan A. Potential use of iPSCs for disease modeling, drug screening, and cell-based therapy for Alzheimer's disease. Cell Mol Biol Lett 2023; 28:98. [PMID: 38031028 PMCID: PMC10687886 DOI: 10.1186/s11658-023-00504-2] [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: 08/26/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Alzheimer's disease (AD) is a chronic illness marked by increasing cognitive decline and nervous system deterioration. At this time, there is no known medication that will stop the course of Alzheimer's disease; instead, most symptoms are treated. Clinical trial failure rates for new drugs remain high, highlighting the urgent need for improved AD modeling for improving understanding of the underlying pathophysiology of disease and improving drug development. The development of induced pluripotent stem cells (iPSCs) has made it possible to model neurological diseases like AD, giving access to an infinite number of patient-derived cells capable of differentiating neuronal fates. This advance will accelerate Alzheimer's disease research and provide an opportunity to create more accurate patient-specific models of Alzheimer's disease to support pathophysiological research, drug development, and the potential application of stem cell-based therapeutics. This review article provides a complete summary of research done to date on the potential use of iPSCs from AD patients for disease modeling, drug discovery, and cell-based therapeutics. Current technological developments in AD research including 3D modeling, genome editing, gene therapy for AD, and research on familial (FAD) and sporadic (SAD) forms of the disease are discussed. Finally, we outline the issues that need to be elucidated and future directions for iPSC modeling in AD.
Collapse
Affiliation(s)
- Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35116, Egypt.
| | - Muhammad Umar Aslam Khan
- Biomedical Research Center, Qatar University, 2713, Doha, Qatar
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
| |
Collapse
|
|
5
|
Zhao ZL, Hu SH, Wan ZS, Bu WZ, Chen SQ, Han TH, Lu YQ. Effect of icariin on the transformation efficiency of induced pluripotent stem cells into sperm cells in vitro. Rev Int Androl 2023; 21:100373. [PMID: 37399730 DOI: 10.1016/j.androl.2023.100373] [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: 03/17/2022] [Revised: 07/16/2022] [Accepted: 03/18/2023] [Indexed: 07/05/2023]
Abstract
OBJECTIVE To investigate the effect of icariin on the transformation efficiency of germ cell-like cells from mouse induced pluripotent stem cells into sperm cells in vitro. METHODS Firstly, mouse induced pluripotent stem cells were induced and cultured to transform into germ cell-like cells, and the primordial germ cell-like cells were identified by Western blot and RT-PCR. Then, different concentrations of icariin (0.1μg/mL, 1μg/mL, 10μg/mL and 100μg/mL) were added into the culture medium, and the obtained primitive germ cell-like cells were cultured, Western blot and RT-PCR were used to identify the obtained sperm cells, the transformation efficiency was compared. RESULTS The primordium germ cell-like cells obtained from mouse induced pluripotent stem cells in vitro specially expressed Oct-4 protein, C-kit protein, Mvh mRNA, Fragilis mRNA and Stella mRNA. The sperm cells were specially expressed VASA, SCP3 and γH2AX proteins. RT-PCR showed that the sperm cells were specially expressed Ddx4, Tp2 and Prm1 mRNA. Compared with the control group, the expression level of VASA protein (1.744±0.283, 2.882±0.373, 6.489±0.460), SCP3 protein (2.250±0.306, 7.058±0.521, 8.654±0.804), γH2AX protein (4.304±0.433, 5.713±0.339, 9.268±0.545), Ddx4 mRNA (1.374±0.145, 2.846±0.194, 4.021±0.154), Tp2 mRNA (1.358±0.130, 3.623±0.326, 5.811±0.390) and Prm1 mRNA (1.326±0.162, 3.487±0.237, 4.666±0.307) in 0.1μg/mL, 1μg/mL, 10μg/mL icariin experimental groups were all lower than that of VASA protein (10.560±0.413), SCP3 protein (13.804±0.642), γH2AX protein (11.874±0.464), Ddx4 mRNA (6.4005±0.361), Tp2 mRNA (7.314±0.256) and Prm1 mRNA (7.334±0.390) in 100μg/mL icariin experimental group. CONCLUSIONS Icariin can promote the transformation of mouse induced pluripotent stem cells into sperm cells in vitro, and it is concentration-dependent manner in a certain concentration range.
Collapse
Affiliation(s)
- Zhen-Li Zhao
- Department of Urology, Hainan Women and Children's Medical Center, Haikou 570206, Hainan, China.
| | - Shao-Hua Hu
- Department of Urology, Hainan Women and Children's Medical Center, Haikou 570206, Hainan, China
| | - Zhi-Sheng Wan
- Department of Urology, Hainan Women and Children's Medical Center, Haikou 570206, Hainan, China
| | - Wei-Zhen Bu
- Department of Urology, Hainan Women and Children's Medical Center, Haikou 570206, Hainan, China
| | - Song-Qiang Chen
- Department of Urology, Hainan Women and Children's Medical Center, Haikou 570206, Hainan, China
| | - Tian-Hong Han
- Department of Endoscopy Center, Hainan Women and Children's Medical Center, Haikou 570206, Hainan, China
| | - Yi-Qun Lu
- Department of Urology, Children's Hospital of Fudan University, Shanghai 201102, China
| |
Collapse
|
|
6
|
Gao D, Zheng CC, Hao JP, Yang CC, Hu CY. Icariin ameliorates behavioral deficits and neuropathology in a mouse model of multiple sclerosis. Brain Res 2023; 1804:148267. [PMID: 36731819 DOI: 10.1016/j.brainres.2023.148267] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/18/2023] [Accepted: 01/27/2023] [Indexed: 02/01/2023]
Abstract
Multiple sclerosis (MS) is a systemic inflammatory illness of the central nervous system that involves demyelinating lesions in the myelin-rich white matter and pathology in the grey matter. Despite significant advancements in drug research for MS, the disease's complex pathophysiology makes it difficult to treat the progressive forms of the disease. In this study, we identified a natural flavonoid compound icariin (ICA) as a potent effective agent for MS in ameliorating the deterioration of symptoms including the neurological deficit score and the body weight in a murine experimental autoimmune encephalomyelitis (EAE) model. These improvements were associated with decreased demyelination in the corpus callosum and neuron loss in the hippocampus and cortex confirmed by immunohistochemistry analysis. Meanwhile, it was observed that the activation of microglia in cerebral cortex and hippocampus were inhibited followed by the neuroinflammatory cytokines downregulation such as IL-1β, IL-6 and TNF-α after ICA treatment, which was probably attributable to the suppression of microglial NLRP3 inflammasome activation. Additionally, molecular docking also revealed the binding force of ICA to NLRP3 inflammasome protein complexes in vitro. Taken together, our findings have demonstrated that ICA, as pleiotropic agent, prevents EAE-induced MS by improving demyelination and neuron loss, which interferes with the neuroinflammation via microglial NLRP3 inflammasome activation.
Collapse
Affiliation(s)
- Dan Gao
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Engineering Research Center for Nervous System Drugs, Beijing 100053, China
| | - Ceng-Ceng Zheng
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Engineering Research Center for Nervous System Drugs, Beijing 100053, China
| | - Jin-Ping Hao
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Engineering Research Center for Nervous System Drugs, Beijing 100053, China
| | - Cui-Cui Yang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Engineering Research Center for Nervous System Drugs, Beijing 100053, China.
| | - Chao-Ying Hu
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Engineering Research Center for Nervous System Drugs, Beijing 100053, China; Phase I Clinical Trial Unit, Beijing Ditan Hospital Capital Medical University, Beijing 100015, China.
| |
Collapse
|
|
7
|
Ning K, Gao R. Icariin protects cerebral neural cells from ischemia‑reperfusion injury in an in vitro model by lowering ROS production and intracellular calcium concentration. Exp Ther Med 2023; 25:151. [PMID: 36911386 PMCID: PMC9995791 DOI: 10.3892/etm.2023.11849] [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: 10/12/2022] [Accepted: 01/26/2023] [Indexed: 02/18/2023] Open
Abstract
Ischemia is one of the major causes of stroke. The present study investigated the protection of cultured neural cells by icariin (ICA) against ischemia-reperfusion (I/R) injury and possible mechanisms underlying the protection. Neural cells were isolated from neonatal rats and cultured in vitro. The cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD-R) as an I/R mimic to generate I/R injury, and were post-OGD-R treated with ICA. Following the treatments, cell viability, apoptosis, reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and Ca2+ concentration were assessed using Cell Counting Kit-8 assay, flow cytometry, CyQUANT™ LDH Cytotoxicity Assay, H2DCFDA and SOD colorimetric activity kit. After OGD-R, considerable I/R injury was observed in the neural cells, as indicated by reduced cell viability, increased apoptosis and increased production of ROS and LDH (P<0.05). Cellular Ca2+ concentration was also increased, while SOD activity remained unchanged. Post-OGD-R ICA treatments increased cell viability up to 87.1% (P<0.05) and reduced apoptosis as low as 6.6% (P<0.05) in a concentration-dependent manner. The treatments also resulted in fewer ROS (P<0.05), lower extracellular LDH content (440.5 vs. 230.3 U/l; P<0.05) and reduced Ca2+ increase (P<0.05). These data suggest that ICA protects the neural cells from I/R injury in an in vitro model through antioxidation activity and maintaining cellular Ca2+ homeostasis. This function may be explored as a potential therapeutic strategy for ischemia-related diseases after further in vivo studies.
Collapse
Affiliation(s)
- Ke Ning
- Department of International Medicine, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Rong Gao
- Surgical Intensive Care Unit, Affiliated Zhongshan Hospital, Dalian University, Dalian, Liaoning 116001, P.R. China
| |
Collapse
|
|
8
|
Zhang C, Xue P, Zhang H, Tan C, Zhao S, Li X, Sun L, Zheng H, Wang J, Zhang B, Lang W. Gut brain interaction theory reveals gut microbiota mediated neurogenesis and traditional Chinese medicine research strategies. Front Cell Infect Microbiol 2022; 12:1072341. [PMID: 36569198 PMCID: PMC9772886 DOI: 10.3389/fcimb.2022.1072341] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/07/2022] [Indexed: 12/13/2022] Open
Abstract
Adult neurogenesis is the process of differentiation of neural stem cells (NSCs) into neurons and glial cells in certain areas of the adult brain. Defects in neurogenesis can lead to neurodegenerative diseases, mental disorders, and other maladies. This process is directionally regulated by transcription factors, the Wnt and Notch pathway, the extracellular matrix, and various growth factors. External factors like stress, physical exercise, diet, medications, etc., affect neurogenesis and the gut microbiota. The gut microbiota may affect NSCs through vagal, immune and chemical pathways, and other pathways. Traditional Chinese medicine (TCM) has been proven to affect NSCs proliferation and differentiation and can regulate the abundance and metabolites produced by intestinal microorganisms. However, the underlying mechanisms by which these factors regulate neurogenesis through the gut microbiota are not fully understood. In this review, we describe the recent evidence on the role of the gut microbiota in neurogenesis. Moreover, we hypothesize on the characteristics of the microbiota-gut-brain axis based on bacterial phyla, including microbiota's metabolites, and neuronal and immune pathways while providing an outlook on TCM's potential effects on adult neurogenesis by regulating gut microbiota.
Collapse
Affiliation(s)
- Chenxi Zhang
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Peng Xue
- Medical School of Nantong University, Nantong University, Nantong, China
| | - Haiyan Zhang
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Chenxi Tan
- Department of Infection Control, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Shiyao Zhao
- Department of Nuclear Medicine, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Xudong Li
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lihui Sun
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Huihui Zheng
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China
| | - Jun Wang
- The Academic Affairs Office, Qiqihar Medical University, Qiqihar, China
| | - Baoling Zhang
- Department of Operating Room, Qiqihar First Hospital, Qiqihar, China
| | - Weiya Lang
- Basic Medical Science College, Qiqihar Medical University, Qiqihar, China,*Correspondence: Weiya Lang,
| |
Collapse
|
|
9
|
You M, Yuan P, Li L, Xu H. HIF-1 signalling pathway was identified as a potential new pathway for Icariin's treatment against Alzheimer's disease based on preclinical evidence and bioinformatics. Front Pharmacol 2022; 13:1066819. [PMID: 36532735 PMCID: PMC9751333 DOI: 10.3389/fphar.2022.1066819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/18/2022] [Indexed: 10/05/2023] Open
Abstract
Aim: Alzheimer's disease (AD) is a neurodegenerative condition that is characterized by the gradual loss of memory and cognitive function. Icariin, which is a natural chemical isolated from Epimedii herba, has been shown to protect against AD. This research examined the potential mechanisms of Icariin's treatment against AD via a comprehensive review of relevant preclinical studies coupled with network pharmacology. Methods: The PubMed, Web of Science, CNKI, WANFANG, and VIP databases were used to identify the relevant studies. The pharmacological characteristics of Icariin were determined using the SwissADME and TCMSP databases. The overlapping targets of Icariin and AD were then utilized to conduct disease oncology (DO) analysis to identify possible hub targets of Icariin in the treatment of AD. The hub targets were then used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and the interactions of the targets and Icariin were assessed via molecular docking and molecular dynamics simulation (MDS). Results: According to the literature review, Icariin alleviates cognitive impairment by regulating the expression of Aβ1-42, Aβ1-40, BACE1, tau, hyperphosphorylated tau, and inflammatory mediators. DO analysis revealed 35 AD-related hub targets, and the HIF-1 signalling pathway was ranked first according to the KEGG pathway analysis. Icariin effectively docked with the 35 hub targets and HIF-1α, and the dynamic binding of the HIF-1-Icariin complex within 100 ns indicated that Icariin contributed to the stability of HIF-1α. Conclusion: In conclusion, our research used a literature review and network pharmacology methods to identify the HIF-1 signalling pathway as a potential pathway for Icariin's treatment against AD.
Collapse
Affiliation(s)
| | | | | | - Hongbei Xu
- Department of Neurology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| |
Collapse
|
|
10
|
Tan W, Qi L, Hu X, Tan Z. Research progress in traditional Chinese medicine in the treatment of Alzheimer's disease and related dementias. Front Pharmacol 2022; 13:921794. [PMID: 36506569 PMCID: PMC9729772 DOI: 10.3389/fphar.2022.921794] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022] Open
Abstract
Alzheimer's disease (AD) is the world's leading cause of dementia and has become a huge economic burden on nations and families. However, the exact etiology of AD is still unknown, and there are no efficient medicines or methods to prevent the deterioration of cognition. Traditional Chinese medicine (TCM) has made important contributions in the battle against AD based on the characteristics of multiple targets of TCM. This study reviewed the treatment strategies and new discoveries of traditional Chinese medicine in current research, which may be beneficial to new drug researchers.
Collapse
Affiliation(s)
- Wanying Tan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lingjun Qi
- Sichuan Academy of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhenghuai Tan
- Sichuan Academy of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
11
|
Zhang SY, Zhao J, Ni JJ, Li H, Quan ZZ, Qing H. Application and prospects of high-throughput screening for in vitro neurogenesis. World J Stem Cells 2022; 14:393-419. [PMID: 35949394 PMCID: PMC9244953 DOI: 10.4252/wjsc.v14.i6.393] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/07/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Over the past few decades, high-throughput screening (HTS) has made great contributions to new drug discovery. HTS technology is equipped with higher throughput, minimized platforms, more automated and computerized operating systems, more efficient and sensitive detection devices, and rapid data processing systems. At the same time, in vitro neurogenesis is gradually becoming important in establishing models to investigate the mechanisms of neural disease or developmental processes. However, challenges remain in generating more mature and functional neurons with specific subtypes and in establishing robust and standardized three-dimensional (3D) in vitro models with neural cells cultured in 3D matrices or organoids representing specific brain regions. Here, we review the applications of HTS technologies on in vitro neurogenesis, especially aiming at identifying the essential genes, chemical small molecules and adaptive microenvironments that hold great prospects for generating functional neurons or more reproductive and homogeneous 3D organoids. We also discuss the developmental tendency of HTS technology, e.g., so-called next-generation screening, which utilizes 3D organoid-based screening combined with microfluidic devices to narrow the gap between in vitro models and in vivo situations both physiologically and pathologically.
Collapse
Affiliation(s)
- Shu-Yuan Zhang
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Juan Zhao
- Aerospace Medical Center, Aerospace Center Hospital, Beijing 100049, China
| | - Jun-Jun Ni
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hui Li
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Zhen-Zhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy in the Ministry of Industry and Information Technology, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
| |
Collapse
|
|
12
|
Wang ZB, Wang ZT, Sun Y, Tan L, Yu JT. The future of stem cell therapies of Alzheimer's disease. Ageing Res Rev 2022; 80:101655. [PMID: 35660003 DOI: 10.1016/j.arr.2022.101655] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/04/2022] [Accepted: 05/27/2022] [Indexed: 11/26/2022]
Abstract
Alzheimer's disease (AD) places a heavy burden on the global economy. There is no effective disease-modifying treatment available at present. Since the advent of induced pluripotent stem cells (iPSCs) reprogrammed from human somatic cells, new approaches using iPSC-derived products provided novel insights into AD pathogenesis and drug candidates for the AD treatment. Multiple recent studies using animal models have increased the possibility of reducing pathology and improving cognitive function by cell replacement therapies. In this review, we summarized the advantages, limitations, and future directions of cell replacement therapy, discussed the safety and ethical concerns of this novel therapeutic approach and the possibility of translation to clinical practice.
Collapse
|
|
13
|
Wang J, Kong L, Guo RB, He SY, Liu XZ, Zhang L, Liu Y, Yu Y, Li XT, Cheng L. Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer's disease. Drug Deliv 2022; 29:1648-1662. [PMID: 35616263 PMCID: PMC9154764 DOI: 10.1080/10717544.2022.2072543] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The blood-brain barrier (BBB) is a protective barrier for brain safety, but it is also a major obstacle to the delivery of drugs to the cerebral parenchyma such as the hippocampus, hindering the treatment of central nervous system diseases such as Alzheimer's disease (AD). In this work, an anti-AD brain-targeted nanodrug delivery system by co-loading icariin (ICA) and tanshinone IIA (TSIIA) into Aniopep-2-modified long-circulating (Ang2-ICA/TSIIA) liposomes was developed. Low-density lipoprotein receptor-related protein-1 (LRP1) was a receptor overexpressed on the BBB. Angiopep-2, a specific ligand of LRP1, exhibited a high binding efficiency with LRP1. Additionally, ICA and TSIIA, drugs with neuroprotective effects are loaded into the liposomes, so that the liposomes not only have an effective BBB penetration effect, but also have a potential anti-AD effect. The prepared Ang2-ICA/TSIIA liposomes appeared narrow dispersity and good stability with a diameter of 110 nm, and a round morphology. Cell uptake observations, BBB models in vitro, and imaging analysis in vivo showed that Ang2-ICA/TSIIA liposomes not only penetrate the BBB through endocytosis, but also accumulate in N2a cells or brain tissue. The pharmacodynamic analysis in vivo demonstrated that Ang2-ICA/TSIIA liposomes could improve AD-like pathological features in APP/PS1 mice, including inhibiting neuroinflammation and oxidative stress, reducing apoptosis, protecting neurons, and improving cognitive function. Therefore, Ang2-ICA/TSIIA liposomes are considered a potentially effective therapeutic strategy for AD.
Collapse
Affiliation(s)
- Jiao Wang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China.,Shenyang Medical College, Shenyang, China
| | - Liang Kong
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China.,Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Rui-Bo Guo
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Si-Yu He
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Xin-Ze Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Lu Zhang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Yang Liu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Yang Yu
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Xue-Tao Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| | - Lan Cheng
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, China
| |
Collapse
|
|
14
|
Li LR, Sethi G, Zhang X, Liu CL, Huang Y, Liu Q, Ren BX, Tang FR. The neuroprotective effects of icariin on ageing, various neurological, neuropsychiatric disorders, and brain injury induced by radiation exposure. Aging (Albany NY) 2022; 14:1562-1588. [PMID: 35165207 PMCID: PMC8876913 DOI: 10.18632/aging.203893] [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: 10/18/2021] [Accepted: 02/08/2022] [Indexed: 11/25/2022]
Abstract
Epimedium brevicornum Maxim, a Traditional Chinese Medicine, has been used for the treatment of impotence, sinew and bone disorders, “painful impediment caused by wind-dampness,” numbness, spasms, hypertension, coronary heart disease, menopausal syndrome, bronchitis, and neurasthenia for many years in China. Recent animal experimental studies indicate that icariin, a major bioactive component of epimedium may effectively treat Alzheimer’s disease, cerebral ischemia, depression, Parkinson’s disease, multiple sclerosis, as well as delay ageing. Our recent study also suggested that epimedium extract could exhibit radio-neuro-protective effects and prevent ionizing radiation-induced impairment of neurogenesis. This paper reviewed the pharmacodynamics of icariin in treating different neurodegenerative and neuropsychiatric diseases, ageing, and radiation-induced brain damage. The relevant molecular mechanisms and its anti-neuroinflammatory, anti-apoptotic, anti-oxidant, as well as pro-neurogenesis roles were also discussed.
Collapse
Affiliation(s)
- Ling Rui Li
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Xing Zhang
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Cui Liu Liu
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Yan Huang
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Qun Liu
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Bo Xu Ren
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, Hubei, China
| | - Feng Ru Tang
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore
| |
Collapse
|
|
15
|
Yang W, Han YH, Wang HC, Lu CT, Yu XC, Zhao YZ. Intradermal injection of icariin-HP-β-cyclodextrin improved traumatic brain injury via the trigeminal epineurium-brain dura pathway. J Drug Target 2022; 30:557-566. [PMID: 35023434 DOI: 10.1080/1061186x.2021.2023159] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The lower bioavailability after oral administration limited icariin applications in Central Nervous System. Icariin/HP-β-cyclodextrin (HP-β-CD) inclusion complex was prepared for acute severe opening traumatic brain injury (TBI) via facial intradermal(i.d.) in mystacial pad. After fluid percussion-induced TBI, icariin/HP-β-CD at 0.4 mg/kg i.d. preserved more neurons and oligodendrocytes than intranasal injection (i.n.) or intravenous injection via tail vein (i.v.) and decreased microglia and astrocyte activation. Icariin/HP-β-CD i.d. reduced apoptosis in cortical penumbra while i.n. and i.v. showed weak or no effects. Icariin/HP-β-CD i.d. reduced Evans blue leakage and altered CD34, ZO-1, Claudin-5 and beta-catenin expression after TBI. Moreover, icariin/HP-β-CD promoted human umbilical vein endothelial cells proliferation. Thus, Icariin/HP-β-CD i.d. improved TBI, including blood brain barrier opening. Fluorescein 5-isothiocyanate (FITC) and 3,3'-Dioctadecyloxacarbocyanine perchlorate (DiOC18(3)) mimic HP-β-CD and icariin respectively. FITC and DiOC18(3) were similarly delivered to trigeminal epineurium, perineurium and perivascular spaces or tissues, caudal dura mater and scattered in trigeminal fasciculus, indicating that icariin/HP-β-CD was delivered to brain via trigeminal nerve-dura mater-brain pathways. In sum, intradermal injection in mystacial pad might delivered icariin/HP-β-CD to brain and icariin/HP-β-CD improved acute severe opening TBI.
Collapse
Affiliation(s)
- Wei Yang
- School of pharmaceutics sciences, Wenzhou medical university, Wenzhou city, Zhejiang province, China
| | - Yong-Hui Han
- School of pharmaceutics sciences, Wenzhou medical university, Wenzhou city, Zhejiang province, China
| | - Heng-Cai Wang
- School of pharmaceutics sciences, Wenzhou medical university, Wenzhou city, Zhejiang province, China
| | - Cui-Tao Lu
- School of pharmaceutics sciences, Wenzhou medical university, Wenzhou city, Zhejiang province, China
| | - Xi-Chong Yu
- School of pharmaceutics sciences, Wenzhou medical university, Wenzhou city, Zhejiang province, China
| | - Ying-Zheng Zhao
- School of pharmaceutics sciences, Wenzhou medical university, Wenzhou city, Zhejiang province, China
| |
Collapse
|