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Du X, Qi Z, Li Y, Wu S, Zhang F, Li Z, Chen J. Guhong injection attenuates brain injury and promotes neuroprotection after acute ischemic stroke. J Neuroimmunol 2025; 399:578515. [PMID: 39693770 DOI: 10.1016/j.jneuroim.2024.578515] [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: 08/27/2024] [Revised: 10/24/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND AND OBJECTIVES Guhong injection (GHI) has multiple components and generates diverse effects, and is mainly used in the treatment of acute ischemic stroke (AIS). The purpose of this study is to explore the multiple effects of GHI in AIS models in mice and the mechanism how they work together to affect the stroke outcome. METHODS Middle cerebral artery occlusion (MCAO) and photothrombotic stroke models were established with GHI or vehicle. Neurological function assessment including the Modified Neurological Severity Score (mNSS) and rota-rod test, and relative cerebral blood flow were monitored at day 1 and day 3 after model establishment. Flow cytometry, 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining, histology and immunofluorescence, Western blotting (WB) assay were performed at day 3. RESULTS The mean mNSS score was lower and the latency to falling off the rota-rod was prolonged at day 3 in the GHI group. GHI reduced the relative infarct volume and increased the relative cerebral blood flow. The histopathological damage of ischemic core was significantly ameliorated in the GHI group. GHI decreased the Caspase-3+ cells and increased the MAP-2+ and Claudin-5+ cells. GHI increased the expression of Bcl-2 and the ratio of Bcl-2/Bax, and decreased the expression levels of Bax, Caspase-3 and Cleaved-Caspased-3. GHI reduced the microglia, decreased the IL-6 positive cells, TNF-α positive cells and increased TGF-β1 positive cells. CONCLUSIONS GHI alleviated brain injury and neurological deficits through improving cerebral blood circulation, attenuating neuronal apoptosis, reducing the disruption of blood-brain barrier (BBB) and decreasing neuroinflammation in MCAO and photothrombotic stroke models in mice. GHI has certain neuroprotective function to be applied to clinical use.
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Affiliation(s)
- Xiaoshan Du
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhihui Qi
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Yulin Li
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Siting Wu
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Fang Zhang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhiguo Li
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Jingshan Chen
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
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He C, Hu Q, Liu C, Chu Y, Jia J, Zhang X, Niu Q. Aluminum Induces Neurotoxicity through the MicroRNA-98-5p/Insulin-like Growth Factor 2 Axis. ACS Chem Neurosci 2025; 16:329-341. [PMID: 39804702 DOI: 10.1021/acschemneuro.4c00429] [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] [Indexed: 02/06/2025] Open
Abstract
Aluminum is a well-known and widely distributed environmental neurotoxin. This study aimed to investigate the effect of miR-98-5p targeting insulin-like growth factor 2 (IGF2) on aluminum neurotoxicity. Thirty-two Sprague-Dawley rats were randomly divided into four groups and administered 0, 10, 20, and 40 μmol/kg maltol aluminum [Al(mal)3], respectively. They were intraperitoneally injected every other day for three months. PC12 cells were divided into four dose groups: 0, 100, 200, and 400 μmol/L Al(mal)3, and four intervention groups: inhibitor NC, Al(mal)3 + inhibitor NC, miR-98-5p inhibitor, and Al(mal)3 + miR-98-5p inhibitor. The Morris water maze was used to test the learning and memory abilities of rats. Hematoxylin and eosin staining was used to observe the arrangement and quantity of neurons in the CA1 area of the rat hippocampus. Cell viability was detected using the Cell Counting Kit-8. Cell apoptosis was detected using flow cytometry and the 5-ethynyl-2'-deoxyuridine assay. Real-time polymerase chain reaction and Western blotting were used to detect the expression levels of miR-98-5p, IGF2 mRNA, IGF2/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway proteins, and apoptosis-related proteins caspase3 and cleaved caspase3. The dual-luciferase assay was used to determine the targeting relationship between miR-98-5p and IGF2 mRNA. As the dose of aluminum exposure increased, the escape latency of rats gradually prolonged, and the target quadrant residence time and the number of crossing platforms gradually decreased. The arrangement of neurons in the hippocampal CA1 area was significantly loose, and their number gradually decreased. The total and early apoptosis rates of PC12 cells gradually increased, and the cell proliferation rate slowed down. Both in vivo and in vitro experimental results showed that with the increase of aluminum exposure dose, the relative expression levels of miR-98-5p and caspase3 and cleaved caspase3 proteins gradually increased, while the relative expression levels of IGF2 mRNA and IGF2, p-JAK2 (Tyr1007/1008), and p-STAT3 (Tyr705) proteins gradually decreased. After inhibiting miR-98-5p in the aluminum exposure group, the cell apoptosis rate and expression of apoptosis-related proteins decreased, and the expression of IGF2 mRNA and IGF2/JAK2/STAT3 proteins increased. These results indicate that miR-98-5p plays a vital role in aluminum-induced neurotoxicity by targeting IGF2.
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Affiliation(s)
- Chanting He
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China
- Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, Taiyuan, Shanxi 030001, China
- MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China
- Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Qian Hu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Congying Liu
- Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Yafen Chu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Jingjing Jia
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Xiaoyan Zhang
- Anesthesiology College, Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Qiao Niu
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China
- Key Lab of Environmental Hazard and Health of Shanxi Province, Shanxi Medical University, Taiyuan, Shanxi 030001, China
- MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China
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Wen X, Hu J. Targeting STAT3 signaling pathway in the treatment of Alzheimer's disease with compounds from natural products. Int Immunopharmacol 2024; 141:112936. [PMID: 39163684 DOI: 10.1016/j.intimp.2024.112936] [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: 06/12/2024] [Revised: 08/12/2024] [Accepted: 08/12/2024] [Indexed: 08/22/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder that is difficult to cure and of global concern. Neuroinflammation is closely associated with the onset and progression of AD, making its treatment increasingly important. Compounds from natural products, with fewer side effects than synthetic drugs, are of high research interest. STAT3, a multifunctional transcription factor, is involved in various cellular processes including inflammation, cell growth, and apoptosis. Its activation and inhibition can have different effects under various pathological conditions. In AD, the STAT3 protein plays a crucial role in promoting neuroinflammation and contributing to disease progression. This occurs primarily through the JAK2-STAT3 signaling pathway, which impacts microglia, astrocytes, and hippocampal neurons. This paper reviews the STAT3 signaling pathway in AD and 25 compounds targeting STAT3 up to 2024. Notably, Rutin, Paeoniflorin, and Geniposide up-regulate STAT3 in hippocampal and cortex neurons, showing neuroprotective effects in various AD models. Other 23 compounds downregulate AD by suppressing neuroinflammation through inhibition of STAT3 activation in microglia and astrocytes. These findings highlight the potential of compounds from natural products in improving AD by targeting STAT3, offering insights into the prevention and management of AD.
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Affiliation(s)
- Xiyue Wen
- Department of Clinical Laboratory, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, China
| | - Jinyue Hu
- Medical Research Center, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, China.
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Yu L, Zhang C, Gu L, Chen H, Huo Y, Wang S, Tao J, Xu C, Zhang Q, Ma M, Zhang J. Hydroxysafflor Yellow A and Tenuigenin Exhibit Neuroprotection Effects Against Focal Cerebral Ischemia Via Differential Regulation of JAK2/STAT3 and SOCS3 Signaling Interaction. Mol Neurobiol 2024; 61:5584-5600. [PMID: 38214838 DOI: 10.1007/s12035-023-03896-6] [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: 08/10/2023] [Accepted: 12/19/2023] [Indexed: 01/13/2024]
Abstract
Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke.
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Affiliation(s)
- Lu Yu
- Comprehensive Department of Traditional Chinese Medicine, Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Cheng Zhang
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Lingling Gu
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China
| | - Hong Chen
- Department of Clinical Laboratory, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yan Huo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China
| | - Shuyan Wang
- Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China
| | - Jie Tao
- Comprehensive Department of Traditional Chinese Medicine, Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Chuan Xu
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Qiujuan Zhang
- Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Mingliang Ma
- Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China.
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
| | - Jun Zhang
- Department of Clinical Laboratory, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
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Liu J, Zhou J, You C, Xia H, Gao Y, Liu Y, Gong X. Research progress in the mechanism of acupuncture regulating microglia in the treatment of Alzheimer's disease. Front Neurosci 2024; 18:1435082. [PMID: 39145293 PMCID: PMC11321967 DOI: 10.3389/fnins.2024.1435082] [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: 05/19/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease in the central nervous system, characterized by memory and cognitive dysfunction. Acupuncture is an effective means to alleviate the symptoms of AD. Recent studies have shown that microglia play an important role in the occurrence and development of AD. Acupuncture can regulate the activity of microglia, inhibit neuroinflammation, regulate phagocytosis, and clear Aβ Pathological products such as plaque can protect nerve cells and improve cognitive function in AD patients. This article summarizes the relationship between microglia and AD, as well as the research progress in the mechanism of acupuncture regulating microglia in the treatment of AD. The mechanism of acupuncture regulating microglia in the treatment of AD is mainly reviewed from two aspects: inhibiting neuroinflammatory activity and regulating phagocytic function.
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Affiliation(s)
- Jia Liu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Dalian Medical University College of Integrated Traditional Chinese and Western Medicine, Dalian, China
| | - Jiaqi Zhou
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Chong You
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Dalian Medical University College of Integrated Traditional Chinese and Western Medicine, Dalian, China
| | - Haonan Xia
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Dalian Medical University College of Integrated Traditional Chinese and Western Medicine, Dalian, China
| | - Yuling Gao
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yong Liu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaoyang Gong
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Sun Z, Zhang X, So KF, Jiang W, Chiu K. Targeting Microglia in Alzheimer's Disease: Pathogenesis and Potential Therapeutic Strategies. Biomolecules 2024; 14:833. [PMID: 39062547 PMCID: PMC11274940 DOI: 10.3390/biom14070833] [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: 05/03/2024] [Revised: 07/01/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Microglia, as resident macrophages in the central nervous system, play a multifunctional role in the pathogenesis of Alzheimer's disease (AD). Their clustering around amyloid-β (Aβ) deposits is a core pathological feature of AD. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have revealed dynamic changes in microglial phenotypes over time and across different brain regions during aging and AD progression. As AD advances, microglia primarily exhibit impaired phagocytosis of Aβ and tau, along with the release of pro-inflammatory cytokines that damage synapses and neurons. Targeting microglia has emerged as a potential therapeutic approach for AD. Treatment strategies involving microglia can be broadly categorized into two aspects: (1) enhancing microglial function: This involves augmenting their phagocytic ability against Aβ and cellular debris and (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce the neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches for AD treatment have garnered attention. Additionally, natural products show promise in enhancing beneficial effects and suppressing inflammatory responses. Clarifying microglial dynamics, understanding their roles, and exploring novel therapeutic approaches will advance our fight against AD.
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Affiliation(s)
- Zhongqing Sun
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Department of Ophthalmology, School of Clinical Medicine, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Lab of Brain and Cognitive Sciences, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Xin Zhang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Kwok-Fai So
- State Key Lab of Brain and Cognitive Sciences, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Key Laboratory of CNS Regeneration (Ministry of Education), Jinan University, Guangzhou 510632, China
- Department of Psychology, The University of Hong Kong, Hong Kong SAR, China
| | - Wen Jiang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Kin Chiu
- Department of Ophthalmology, School of Clinical Medicine, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Lab of Brain and Cognitive Sciences, Li Kai Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Psychology, The University of Hong Kong, Hong Kong SAR, China
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Kumar Nelson V, Jha NK, Nuli MV, Gupta S, Kanna S, Gahtani RM, Hani U, Singh AK, Abomughaid MM, Abomughayedh AM, Almutary AG, Iqbal D, Al Othaim A, Begum SS, Ahmad F, Mishra PC, Jha SK, Ojha S. Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications. Ageing Res Rev 2024; 98:102224. [PMID: 38346505 DOI: 10.1016/j.arr.2024.102224] [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: 08/29/2023] [Revised: 02/01/2024] [Accepted: 02/03/2024] [Indexed: 05/12/2024]
Abstract
Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD.
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Affiliation(s)
- Vinod Kumar Nelson
- Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India.
| | - Niraj Kumar Jha
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Centre of Research Impact and Outcome, Chitkara University, Rajpura 140401, Punjab, India; School of Bioengineering & Biosciences, Lovely Professional University, Phagwara 144411, India; Department of Biotechnology Engineering and Food Technology, Chandigarh University, Mohali, India.
| | - Mohana Vamsi Nuli
- Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India
| | - Sandeep Kanna
- Department of pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences, Chalapathi Nagar, Guntur 522034, India
| | - Reem M Gahtani
- Departement of Clinical Laboratory Sciences, King Khalid University, Abha, Saudi Arabia
| | - Umme Hani
- Department of pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Arun Kumar Singh
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology BHU, Varanasi, Uttar Pradesh, India
| | - Mosleh Mohammad Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ali M Abomughayedh
- Pharmacy Department, Aseer Central Hospital, Ministry of Health, Saudi Arabia
| | - Abdulmajeed G Almutary
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, P.O. Box 59911, United Arab Emirates
| | - Danish Iqbal
- Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia
| | - Ayoub Al Othaim
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
| | - S Sabarunisha Begum
- Department of Biotechnology, P.S.R. Engineering College, Sivakasi 626140, India
| | - Fuzail Ahmad
- Respiratory Care Department, College of Applied Sciences, Almaarefa University, Diriya, Riyadh, 13713, Saudi Arabia
| | - Prabhu Chandra Mishra
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Saurabh Kumar Jha
- Department of Zoology, Kalindi College, University of Delhi, 110008, India.
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, P.O. Box 15551, United Arab Emirates
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Zhu M, Liu Y, Chen C, Chen H, Ni W, Song Y, Lv B, Hua F, Cui G, Zhang Z. TLR4/Rac1/NLRP3 Pathway Mediates Amyloid-β-Induced Neuroinflammation in Alzheimer's Disease. J Alzheimers Dis 2024; 99:911-925. [PMID: 38728187 DOI: 10.3233/jad-240012] [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] [Indexed: 05/12/2024]
Abstract
Background Neuroinflammation plays a crucial part in the initial onset and progression of Alzheimer's disease (AD). NLRP3 inflammasome was demonstrated to get involved in amyloid-β (Aβ)-induced neuroinflammation. However, the mechanism of Aβ-triggered activation of NLRP3 inflammasome remains poorly understood. Objective Based on our previous data, the study aimed to identify the downstream signals that bridge the activation of TLR4 and NLRP3 inflammasome associated with Aβ. Methods BV-2 cells were transfected with TLR4siRNA or pretreated with a CLI-095 or NSC23766, followed by Aβ1-42 treatment. APP/PS1 mice were injected intraperitoneally with CLI-095 or NSC23766. NLRP3 inflammasome and microglia activation was detected with immunostaining and western blot. G-LISA and Rac1 pull-down activation test were performed to investigate the activation of Rac1. Real-time PCR and ELISA were used to detect the inflammatory cytokines. Aβ plaques were assessed by western blotting and immunofluorescence staining. Morris water maze test was conducted to determine the spatial memory in mice. Results Rac1 and NLRP3 inflammasome were activated by Aβ in both in vitro and in vivo experiments. Inhibition of TLR4 reduced the activity of Rac1 and NLRP3 inflammasome induced by Aβ1-42. Furthermore, inhibition of Rac1 blocked NLRP3 inflammasome activation mediated by TLR4. Blocking the pathway by CLI095 or NSC23766 suppressed Aβ1-42-triggered activation of microglia, reduced the expression of pro-inflammatory mediators and ameliorated the cognition deficits in APP/PS1 mice. Conclusions Our study demonstrated that TLR4/Rac1/NLRP3 pathway mediated Aβ-induced neuroinflammation, which unveiled a novel pathway and key contributors underlying the pathogenic mechanism of Aβ.
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Affiliation(s)
- Mengxin Zhu
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yang Liu
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, Xi'an People's hospital, Xi'an, China
| | - Chen Chen
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hao Chen
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wanyan Ni
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yuanjian Song
- Department of Genetics, Xuzhou Medical University, Xuzhou, China
| | - Bingchen Lv
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Fang Hua
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Guiyun Cui
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Zuohui Zhang
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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Hu E, Li T, Li Z, Su H, Yan Q, Wang L, Li H, Zhang W, Tang T, Wang Y. Metabolomics reveals the effects of hydroxysafflor yellow A on neurogenesis and axon regeneration after experimental traumatic brain injury. PHARMACEUTICAL BIOLOGY 2023; 61:1054-1064. [PMID: 37416997 PMCID: PMC10332220 DOI: 10.1080/13880209.2023.2229379] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 05/21/2023] [Indexed: 07/08/2023]
Abstract
CONTEXT Hydroxysafflor yellow A (HSYA) is the main bioactive ingredient of safflower (Carthamus tinctorius L., [Asteraceae]) for traumatic brain injury (TBI) treatment. OBJECTIVE To explore the therapeutic effects and underlying mechanisms of HSYA on post-TBI neurogenesis and axon regeneration. MATERIALS AND METHODS Male Sprague-Dawley rats were randomly assigned into Sham, controlled cortex impact (CCI), and HSYA groups. Firstly, the modified Neurologic Severity Score (mNSS), foot fault test, hematoxylin-eosin staining, Nissl's staining, and immunofluorescence of Tau1 and doublecortin (DCX) were used to evaluate the effects of HSYA on TBI at the 14th day. Next, the effectors of HSYA on post-TBI neurogenesis and axon regeneration were screened out by pathology-specialized network pharmacology and untargeted metabolomics. Then, the core effectors were validated by immunofluorescence. RESULTS HSYA alleviated mNSS, foot fault rate, inflammatory cell infiltration, and Nissl's body loss. Moreover, HSYA increased not only hippocampal DCX but also cortical Tau1 and DCX following TBI. Metabolomics demonstrated that HSYA significantly regulated hippocampal and cortical metabolites enriched in 'arginine metabolism' and 'phenylalanine, tyrosine and tryptophan metabolism' including l-phenylalanine, ornithine, l-(+)-citrulline and argininosuccinic acid. Network pharmacology suggested that neurotrophic factor (BDNF) and signal transducer and activator of transcription 3 (STAT3) were the core nodes in the HSYA-TBI-neurogenesis and axon regeneration network. In addition, BDNF and growth-associated protein 43 (GAP43) were significantly elevated following HSYA treatment in the cortex and hippocampus. DISCUSSION AND CONCLUSIONS HSYA may promote TBI recovery by facilitating neurogenesis and axon regeneration through regulating cortical and hippocampal metabolism, BDNF and STAT3/GAP43 axis.
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Affiliation(s)
- En Hu
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China
| | - Teng Li
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China
| | - Zhilin Li
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China
| | - Hong Su
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China
| | - Qiuju Yan
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China
| | - Lei Wang
- Department of Respiratory Diseases, Xiangxiang People’s Hospital, Xiangxiang, PR China
| | - Haigang Li
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, PR China
| | - Wei Zhang
- The College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, PR China
| | - Tao Tang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, PR China
| | - Yang Wang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, PR China
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10
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Zheng Y, Zhang X, Zhang R, Wang Z, Gan J, Gao Q, Yang L, Xu P, Jiang X. Inflammatory signaling pathways in the treatment of Alzheimer's disease with inhibitors, natural products and metabolites (Review). Int J Mol Med 2023; 52:111. [PMID: 37800614 PMCID: PMC10558228 DOI: 10.3892/ijmm.2023.5314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/11/2023] [Indexed: 10/07/2023] Open
Abstract
The intricate nature of Alzheimer's disease (AD) pathogenesis poses a persistent obstacle to drug development. In recent times, neuroinflammation has emerged as a crucial pathogenic mechanism of AD, and the targeting of inflammation has become a viable approach for the prevention and management of AD. The present study conducted a comprehensive review of the literature between October 2012 and October 2022, identifying a total of 96 references, encompassing 91 distinct pharmaceuticals that have been investigated for their potential impact on AD by inhibiting neuroinflammation. Research has shown that pharmaceuticals have the potential to ameliorate AD by reducing neuroinflammation mainly through regulating inflammatory signaling pathways such as NF‑κB, MAPK, NLRP3, PPARs, STAT3, CREB, PI3K/Akt, Nrf2 and their respective signaling pathways. Among them, tanshinone IIA has been extensively studied for its anti‑inflammatory effects, which have shown significant pharmacological properties and can be applied clinically. Thus, it may hold promise as an effective drug for the treatment of AD. The present review elucidated the inflammatory signaling pathways of pharmaceuticals that have been investigated for their therapeutic efficacy in AD and elucidates their underlying mechanisms. This underscores the auspicious potential of pharmaceuticals in ameliorating AD by impeding neuroinflammation.
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Affiliation(s)
| | | | - Ruifeng Zhang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Ziyu Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Jiali Gan
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Qing Gao
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Lin Yang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Pengjuan Xu
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
| | - Xijuan Jiang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P.R. China
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Liu J, Li T, Zhong G, Pan Y, Gao M, Su S, Liang Y, Ma C, Liu Y, Wang Q, Shi Q. Exploring the therapeutic potential of natural compounds for Alzheimer's disease: Mechanisms of action and pharmacological properties. Biomed Pharmacother 2023; 166:115406. [PMID: 37659206 DOI: 10.1016/j.biopha.2023.115406] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/04/2023] Open
Abstract
Alzheimer's Disease (AD) is a global public health priority characterized by high mortality rates in adults and an increasing prevalence in aging populations worldwide. Despite significant advancements in comprehending the pathogenesis of AD since its initial report in 1907, there remains a lack of effective curative or preventive measures for the disease. In recent years, natural compounds sourced from diverse origins have garnered considerable attention as potential therapeutic agents for AD, owing to their anti-inflammatory, antioxidant, and neuroprotective properties. This review aims to consolidate the therapeutic effects of natural compounds on AD, specifically targeting the reduction of β-amyloid (Aβ) overproduction, anti-apoptosis, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Notably, the identified compounds exhibiting these effects predominantly originate from plants. This review provides valuable insights into the potential of natural compounds as a reservoir of novel therapeutic agents for AD, thereby stimulating further research and contributing to the development of efficacious treatments for this devastating disease.
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Affiliation(s)
- Jinman Liu
- Affiliated Jiangmen TCM Hospital of Ji'nan University, Jiangmen 529099, China
| | - Tianyao Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Guangcheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yaru Pan
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Minghuang Gao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Shijie Su
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yong Liang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Cuiru Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yuanyue Liu
- Department of Neurology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210017, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Qing Shi
- Affiliated Jiangmen TCM Hospital of Ji'nan University, Jiangmen 529099, China.
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Yang G, Tong Y, Wang X, Zhao C, Ba Z, Ahelijiang R, Liu X, Gao W, Zhao Y, Gu Y, Yang J, Xu Y. Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice. Front Immunol 2023; 14:1185570. [PMID: 37465679 PMCID: PMC10350565 DOI: 10.3389/fimmu.2023.1185570] [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: 03/13/2023] [Accepted: 06/09/2023] [Indexed: 07/20/2023] Open
Abstract
Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer's disease (AD), which is associated with the regulation of microglial activation. Preventing microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. Here, the presenilin1/2 conditional double knockout (PS cDKO) mice, a well-established mouse model of AD, were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of lipopolysaccharide (LPS) (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL's anti-inflammatory potential was closely associated with Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL could inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL prevented LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Taken together, GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.
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Affiliation(s)
- Guang Yang
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuting Tong
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xingyu Wang
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chenyi Zhao
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zongtao Ba
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Reaila Ahelijiang
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinjuan Liu
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Waimao Gao
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Zhao
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yining Gu
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Yangzhi Rehabilitation Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianmei Yang
- Department of Traditional Chinese Medicine, Shanghai Xuhui District Central Hospital, Shanghai, China
| | - Ying Xu
- Department of Physiology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Zhao H, Wang L, Zhang L, Zhao H. Phytochemicals targeting lncRNAs: A novel direction for neuroprotection in neurological disorders. Biomed Pharmacother 2023; 162:114692. [PMID: 37058817 DOI: 10.1016/j.biopha.2023.114692] [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: 03/12/2023] [Revised: 04/06/2023] [Accepted: 04/10/2023] [Indexed: 04/16/2023] Open
Abstract
Neurological disorders with various etiologies impacting the nervous system are prevalent in clinical practice. Long non-coding RNA (lncRNA) molecules are functional RNA molecules exceeding 200 nucleotides in length that do not encode proteins, but participate in essential activities. Research indicates that lncRNAs may contribute to the pathogenesis of neurological disorders, and may be potential targets for their treatment. Phytochemicals in traditional Chinese herbal medicine (CHM) have been found to exert neuroprotective effects by targeting lncRNAs and regulating gene expression and various signaling pathways. We aim to establish the development status and neuroprotective mechanism of phytochemicals that target lncRNAs through a thorough literature review. A total of 369 articles were retrieved through manual and electronic searches of PubMed, Web of Science, Scopus and CNKI databases from inception to September 2022. The search utilized combinations of natural products, lncRNAs, neurological disorders, and neuroprotective effects as keywords. The included studies, a total of 31 preclinical trials, were critically reviewed to present the current situation and the progress in phytochemical-targeted lncRNAs in neuroprotection. Phytochemicals have demonstrated neuroprotective effects in preclinical studies of various neurological disorders by regulating lncRNAs. These disorders include arteriosclerotic ischemia-reperfusion injury, ischemic/hemorrhagic stroke, Alzheimer's disease, Parkinson's disease, glioma, peripheral nerve injury, post-stroke depression, and depression. Several phytochemicals exert neuroprotective roles through mechanisms such as anti-inflammatory, antioxidant, anti-apoptosis, autophagy regulation, and antagonism of Aβ-induced neurotoxicity. Some phytochemicals targeted lncRNAs and served a neuroprotective role by regulating microRNA and mRNA expression. The emergence of lncRNAs as pathological regulators provides a novel direction for the study of phytochemicals in CHM. Elucidating the mechanism of phytochemicals regulating lncRNAs will help to identify new therapeutic targets and promote their application in precision medicine.
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Affiliation(s)
- Hang Zhao
- Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Lin Wang
- Department of Emergency medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Lijuan Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
| | - Hongyu Zhao
- Department of Emergency medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
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Ma HH, Wen JR, Fang H, Su S, Wan C, Zhang C, Lu FM, Fan LL, Wu GL, Zhou ZY, Qiao LJ, Zhang SJ, Cai YF. Hydroxysafflor Yellow A Exerts Neuroprotective Effect by Reducing Aβ Toxicity Through Inhibiting Endoplasmic Reticulum Stress in Oxygen-Glucose Deprivation/Reperfusion Cell Model. Rejuvenation Res 2023; 26:57-67. [PMID: 36734410 DOI: 10.1089/rej.2022.0054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 μM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-β peptides (Aβ) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aβ toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress.
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Affiliation(s)
- Hui-Han Ma
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Jun-Ru Wen
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Hao Fang
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Shan Su
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Can Wan
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Chao Zhang
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Fang-Mei Lu
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Department of Neurology, Henan University of Chinese Medicine, Zhengzhou, China
| | - Ling-Ling Fan
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guang-Liang Wu
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Zi-Yi Zhou
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Li-Jun Qiao
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Shi-Jie Zhang
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Ye-Feng Cai
- Department of Neurology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
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15
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Wang C, Ye H, Zheng Y, Qi Y, Zhang M, Long Y, Hu Y. Phenylethanoid Glycosides of Cistanche Improve Learning and Memory Disorders in APP/PS1 Mice by Regulating Glial Cell Activation and Inhibiting TLR4/NF-κB Signaling Pathway. Neuromolecular Med 2023; 25:75-93. [PMID: 35781783 DOI: 10.1007/s12017-022-08717-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 06/06/2022] [Indexed: 11/25/2022]
Abstract
Phenylethanoid Glycosides of Cistanche (PhGs) have a certain curative effect on AD animal model, Echinacea (ECH) and verbascoside (ACT), as the quality control standard of Cistanche deserticola Y. C. Ma and the main representative compounds of PhGs have been proved to have neuroprotective effects, but the specific mechanism needs to be further explored. This study explored the mechanisms of PhGs, ECH, and ACT in the treatment of Alzheimer's disease (AD) from the perspectives of glial cell activation, TLR4/NF-κB signaling pathway, and synaptic protein expression. We used APP/PS1 mice as AD models. After treatment with PhGs, ECH, and ACT, the learning and memory abilities of APP/PS1 mice were enhanced, and the pathological changes in brain tissue were alleviated. The expression of pro-inflammatory M1 microglia markers (CD11b, iNOS, and IL-1β) was decreased; the expression of M2 microglia markers (Arg-1 and TGF-β1) was increased, which promoted the transformation of microglia from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. In addition, PhGs, ECH, and ACT could down-regulate the expression of proteins related to the TLR4/NF-κB signaling pathway and up-regulate the expression of synaptic proteins. The results indicated that PhGs, ECH, and ACT played a neuroprotective role by regulating the activation of glial cells and inhibiting the TLR4/NF-κB inflammatory pathway, and improving the expression levels of synapse-related proteins.
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Affiliation(s)
- Chunhui Wang
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China
| | - Hongxia Ye
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China
| | - Yanjie Zheng
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China
| | - Yanqiang Qi
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China
| | - Mengyu Zhang
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China
| | - Yan Long
- Central Laboratory, Shenzhen Sami Medical Center, Shenzhen, China
| | - Yanli Hu
- Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, Department of Pharmacology, Shihezi University, Shihezi, 832000, Xinjiang, People's Republic of China.
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Moini Jazani A, Arabzadeh A, Haghi-Aminjan H, Nasimi Doost Azgomi R. The role of ginseng derivatives against chemotherapy-induced cardiotoxicity: A systematic review of non-clinical studies. Front Cardiovasc Med 2023; 10:1022360. [PMID: 36844721 PMCID: PMC9946988 DOI: 10.3389/fcvm.2023.1022360] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 01/12/2023] [Indexed: 02/11/2023] Open
Abstract
Aims Although chemotherapy agents are used to treating cancers, they have serious side effects, like their harmful effects on the cardiovascular system, limiting the clinical use of these chemotherapy agents. This study aimed to systematically investigate the potential role of ginseng derivatives in the prevention of chemotherapy-induced cardiac toxicity. Methods This systematic review was performed according to PRISMA guidelines strategy in databases till August 2022. First, identify studies related to using search terms in titles and abstracts. After studying and screening 209 articles, 16 articles were selected in this study according to our inclusion and exclusion criteria. Results According to the findings of this study, ginseng derivatives showed significant changes in biochemical, histological, and heart weight loss, as well as a reduction in mortality, which occurred in the groups treated with chemotherapy agents compared to the control groups. Co-administration of ginseng derivatives with chemotherapy agents inhibited or reversed these changes to near-moderate levels. The protective effects of ginseng derivatives can be due to their anti-inflammatory, anti-oxidant, and anti-apoptotic action. Conclusion This systematic review shows evidence that concomitant administration of ginseng derivatives improves chemotherapy-induced cardiac toxicity. However, for better conclusions about the practical mechanisms of ginseng derivatives in reducing the cardiac toxic effects of chemotherapy agents and evaluating the efficacy and safety of the compound simultaneously, it is necessary to design comprehensive studies.
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Affiliation(s)
- Arezoo Moini Jazani
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - AmirAhmad Arabzadeh
- Department of Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran,*Correspondence: Hamed Haghi-Aminjan,✉
| | - Ramin Nasimi Doost Azgomi
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran,Ramin Nasimi Doost Azgomi,✉
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Integrating Network Pharmacology and Transcriptomic Strategies to Explore the Pharmacological Mechanism of Hydroxysafflor Yellow A in Delaying Liver Aging. Int J Mol Sci 2022; 23:ijms232214281. [PMID: 36430769 PMCID: PMC9697017 DOI: 10.3390/ijms232214281] [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: 09/16/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Aging affects the structure and function of the liver. Hydroxysafflor yellow A (HSYA) effectively improves liver aging (LA) in mice, but the potential mechanisms require further exploration. In this study, an integrated approach combining network pharmacology and transcriptomics was used to elucidate the potential mechanisms of HSYA delay of LA. The targets of HSYA were predicted using the PharmMapper, SwissTargetPrediction, and CTD databases, and the targets of LA were collected from the GeneCards database. An ontology (GO) analysis and a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation of genes related to HSYA delay of LA were performed using the DAVID database, and Cytoscape software was used to construct an HSYA target pathway network. The BMKCloud platform was used to sequence mRNA from mouse liver tissue, screen differentially expressed genes (DEGs) that were altered by HSYA, and enrich their biological functions and signaling pathways through the OmicShare database. The results of the network pharmacology and transcriptomic analyses were combined. Then, quantitative real-time PCR (qRT-PCR) and Western blot experiments were used to further verify the prediction results. Finally, the interactions between HSYA and key targets were assessed by molecular docking. The results showed that 199 potentially targeted genes according to network pharmacology and 480 DEGs according to transcriptomics were involved in the effects of HSYA against LA. An integrated analysis revealed that four key targets, including HSP90AA1, ATP2A1, NOS1 and CRAT, as well as their three related pathways (the calcium signaling pathway, estrogen signaling pathway and cGMP-PKG signaling pathway), were closely related to the therapeutic effects of HSYA. A gene and protein expression analysis revealed that HSYA significantly inhibited the expressions of HSP90AA1, ATP2A1 and NOS1 in the liver tissue of aging mice. The molecular docking results showed that HSYA had high affinities with the HSP90AA1, ATP2A1 and NOS1 targets. Our data demonstrate that HSYA may delay LA in mice by inhibiting the expressions of HSP90AA1, ATP2A1 and NOS1 and regulating the calcium signaling pathway, the estrogen signaling pathway, and the cGMP-PKG signaling pathway.
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Liang Y, Wang L. Carthamus tinctorius L.: A natural neuroprotective source for anti-Alzheimer's disease drugs. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115656. [PMID: 36041691 DOI: 10.1016/j.jep.2022.115656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 07/24/2022] [Accepted: 08/16/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alzheimer's disease (AD) is a multicausal neurodegenerative disease clinically characterized by generalized dementia. The pathogenic process of AD not only is progressive and complex but also involves multiple factors and mechanisms, including β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. As the first-line treatment for AD, cholinesterase inhibitors can, to a certain extent, relieve AD symptoms and delay AD progression. Nonetheless, the current treatment strategies for AD are far from meeting clinical expectations, and more options for AD treatment should be applied in clinical practice. AIM OF THE REVIEW The aim of this review was to investigate published reports of C. tinctorius L. and its active constituents in AD treatment through a literature review. MATERIALS AND METHODS Information was retrieved from scientific databases including Web of Science, ScienceDirect, Scopus, Google Scholar, Chemical Abstracts Services and books, PubMed, dissertations and technical reports. Keywords used for the search engines were "Honghua" or "Carthamus tinctorius L." or "safflower" in conjunction with "(native weeds OR alien invasive)"AND "Chinese herbal medicine". RESULTS A total of 47 literatures about C. tinctorius L. and its active constituents in AD treatment through signaling pathways, immune cells, and disease-related mediators and systematically elucidates potential mechanisms from the point of anti-Aβ aggregation, suppressing tau protein hyperphosphorylation, increasing cholinergic neurotransmitters levels, inhibiting oxidative stress, anti-neuroinflammation, ameliorating synaptic plasticity, and anti-apoptosis. CONCLUSIONS Chinese herbal medicine (CHM) is a treasure endowed by nature to mankind. Emerging studies have confirmed that CHM and its active constituents play a positive role in AD treatment. Carthamus tinctorius L., the most commonly used CHM, can be used with medicine and food, with the effect of activating blood circulation and eliminating blood stasis. In the paper, we have concluded that the existing therapeutic mechanisms of C. tinctorius L. and summarized the potential mechanisms of C. tinctorius L. and its active constituents in AD treatment through a literature review.
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Affiliation(s)
- Yuanyuan Liang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
| | - Lin Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, PR China.
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19
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Comprehensive review of two groups of flavonoids in Carthamus tinctorius L. Biomed Pharmacother 2022; 153:113462. [DOI: 10.1016/j.biopha.2022.113462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/11/2022] [Accepted: 07/21/2022] [Indexed: 11/22/2022] Open
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The effect of electroacupuncture on the expression of Sirt1 and STAT3 in hippocampus and amygdala of vascular dementia rats. Neuroreport 2022; 33:534-542. [PMID: 35882013 DOI: 10.1097/wnr.0000000000001814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Inflammation has long been considered a key factor in learning and memory impairment in patients with vascular dementia (VaD). Studies have confirmed that electroacupuncture can improve the learning and memory impairment of patients with VaD by reducing inflammation, but the specific mechanism of this effect is still unclear. The aim of this study was to explore the underlying mechanism of electroacupuncture in the treatment of VaD. METHODS The vascular dementia animal model was established by bilateral occlusion of common carotid arteries, and electroacupuncture treatment was given at Baihui (DU20) and Zusanli (ST36). The morris water maze (MWM) was used to test the spatial learning and memory ability of rats in each group. To evaluate the expression of Sirtuin1 (Sirt1), Signal transducer and activator of transcription 3 (STAT3) and inflammatory cytokine (IL-17) in the hippocampus and amygdala, immunohistochemistry and western blot were performed. RESULTS The MWM test and Nissl staining results show that electroacupuncture can significantly improve the learning and memory impairment of VaD rats, and can repair damaged neurons. Immunohistochemistry and western blot results showed that electroacupuncture could enhance the expression of sirt1 in VaD rats, on the contrary, the expression of STAT3 and IL-17 was reduced due to electroacupuncture. CONCLUSIONS The result suggests that electroacupuncture can suppress inflammation through the Sirt1/STAT3 pathway and improve spatial learning and memory in VaD rats.
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Cai S, Yang F, Wang X, Wu S, Huang L. Structural brain characteristics and gene co-expression analysis: A study with outcome label from normal cognition to mild cognitive impairment. Neurobiol Learn Mem 2022; 191:107620. [DOI: 10.1016/j.nlm.2022.107620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/15/2022] [Accepted: 04/04/2022] [Indexed: 10/18/2022]
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Abubakar MB, Sanusi KO, Ugusman A, Mohamed W, Kamal H, Ibrahim NH, Khoo CS, Kumar J. Alzheimer's Disease: An Update and Insights Into Pathophysiology. Front Aging Neurosci 2022; 14:742408. [PMID: 35431894 PMCID: PMC9006951 DOI: 10.3389/fnagi.2022.742408] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 02/25/2022] [Indexed: 12/17/2022] Open
Abstract
Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD.
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Affiliation(s)
- Murtala Bello Abubakar
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Kamaldeen Olalekan Sanusi
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Azizah Ugusman
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Wael Mohamed
- Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University Malaysia, Kuantan, Malaysia
- Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
| | - Haziq Kamal
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Nurul Husna Ibrahim
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Ching Soong Khoo
- Neurology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Jaya Kumar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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Pharmacological Actions, Molecular Mechanisms, Pharmacokinetic Progressions, and Clinical Applications of Hydroxysafflor Yellow A in Antidiabetic Research. J Immunol Res 2021; 2021:4560012. [PMID: 34938814 PMCID: PMC8687819 DOI: 10.1155/2021/4560012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/01/2021] [Accepted: 11/16/2021] [Indexed: 11/23/2022] Open
Abstract
Hydroxysafflor yellow A (HSYA), a nutraceutical compound derived from safflower (Carthamus tinctorius), has been shown as an effective therapeutic agent in cardiovascular diseases, cancer, and diabetes. Our previous study showed that the effect of HSYA on high-glucose-induced podocyte injury is related to its anti-inflammatory activities via macrophage polarization. Based on the information provided on PubMed, Scopus and Wanfang database, we currently aim to provide an updated overview of the role of HSYA in antidiabetic research from the following points: pharmacological actions, molecular mechanisms, pharmacokinetic progressions, and clinical applications. The pharmacokinetic research of HSYA has laid foundations for the clinical applications of HSYA injection in diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. The application of HSYA as an antidiabetic oral medicament has been investigated based on its recent oral delivery system research. In vivo and in vitro pharmacological research indicated that the antidiabetic activities of HSYA were based mainly on its antioxidant and anti-inflammatory mechanisms via JNK/c-jun pathway, NOX4 pathway, and macrophage differentiation. Further anti-inflammatory exploration related to NF-κB signaling, MAPK pathway, and PI3K/Akt/mTOR pathway might deserve attention in the future. The anti-inflammatory activities of HSYA related to diabetes and diabetic complications will be a highlight in our following research.
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Long QH, Wu YG, He LL, Ding L, Tan AH, Shi HY, Wang P. Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice. Chin Med 2021; 16:14. [PMID: 33478552 PMCID: PMC7818567 DOI: 10.1186/s13020-021-00425-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/08/2021] [Indexed: 01/23/2023] Open
Abstract
Background Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD’s improvement in cognitive function remain unclear. In this study, we examined SZRD’s effect on APP/PS1 transgenic mice and mechanisms associated with SZRD’s action in alleviating neuroinflammation and improving synaptic plasticity. Methods
The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aβ1−40 and Aβ1−42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aβ1−42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1β, IL-6 and TNF-α through ELISA. Results Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P < 0.05 or 0.01). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum and hippocampal concentrations of IL-6, IL-1β and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (P < 0.05 or 0.01). Conclusions The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through inhibiting Aβ accumulation and neuroinflammation via the JAK2/STAT3 pathway.
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Affiliation(s)
- Qing-Hua Long
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China
| | - Yong-Gui Wu
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China
| | - Li-Ling He
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China
| | - Li Ding
- School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China
| | - Ai-Hua Tan
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China
| | - He-Yuan Shi
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China.
| | - Ping Wang
- School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, Hubei, China.
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Uddin MS, Hasana S, Ahmad J, Hossain MF, Rahman MM, Behl T, Rauf A, Ahmad A, Hafeez A, Perveen A, Ashraf GM. Anti-Neuroinflammatory Potential of Polyphenols by Inhibiting NF-κB to Halt Alzheimer's Disease. Curr Pharm Des 2021; 27:402-414. [PMID: 33213314 DOI: 10.2174/1381612826666201118092422] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 10/01/2020] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD) is an irrevocable chronic brain disorder featured by neuronal loss, microglial accumulation, and progressive cognitive impairment. The proper pathophysiology of this life-threatening disorder is not completely understood and no exact remedies have been found yet. Over the last few decades, research on AD has mainly highlighted pathomechanisms linked to a couple of the major pathological hallmarks, including extracellular senile plaques made of amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs) made of tau proteins. Aβ can induce apoptosis, trigger an inflammatory response, and inhibit the synaptic plasticity of the hippocampus, which ultimately contributes to reducing cognitive functions and memory impairment. Recently, a third disease hallmark, the neuroinflammatory reaction that is mediated by cerebral innate immune cells, has become a spotlight in the current research area, assured by pre-clinical, clinical, and genetic investigations. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a cytokine producer, is significantly associated with physiological inflammatory proceedings and thus shows a promising candidate for inflammation- based AD therapy. Recent data reveal that phytochemicals, mainly polyphenol compounds, exhibit potential neuroprotective functions and these may be considered as a vital resource for discovering several drug candidates against AD. Interestingly, phytochemicals can easily interfere with the signaling pathway of NF-κB. This review represents the anti-neuroinflammatory potential of polyphenols as inhibitors of NF-κB to combat AD pathogenesis.
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Affiliation(s)
- Md Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
| | - Sharifa Hasana
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
| | - Jamil Ahmad
- Department of Human Nutrition, The University of Agriculture Peshawar, Khyber Pakhtunkhwa, Pakistan
| | | | | | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Anbar, Khyber Pakhtunkhwa, Pakistan
| | - Ausaf Ahmad
- Amity Institute of Biotechnology, Amity University Uttar Pradesh Lucknow Campus, Uttar Pradesh, India
| | - Abdul Hafeez
- Glocal School of Pharmacy, Glocal University, Saharanpur, India
| | - Asma Perveen
- Glocal School of Life Sciences, Glocal University, Saharanpur, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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26
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Ali A, Shah SA, Zaman N, Uddin MN, Khan W, Ali A, Riaz M, Kamil A. Vitamin D exerts neuroprotection via SIRT1/nrf-2/ NF-kB signaling pathways against D-galactose-induced memory impairment in adult mice. Neurochem Int 2020; 142:104893. [PMID: 33159979 DOI: 10.1016/j.neuint.2020.104893] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022]
Abstract
Vitamin D (Vt. D) is one of the vital hormone having multiple functions in various tissues, including brain. Several evidences reported that Vt. D plays a significant part in memory and cognition as its inadequate amount may accelerate cognitive impairment. This study shows for the first time the antioxidant potential of Vt. D against D-Galactose (D-gal) induced oxidative stress mediated Alzheimer disease (AD) pathology in male adult albino mice. The result reveals that the mice exposed to D-gal (120 mg/kg) for eight weeks have pre-and post-synaptic dysfunction and impaired memory investigated through Morris water maze and Y-maze tests. This is followed by the suppressed Nuclear factor erythroid 2-related factor 2 (NRF2), Heme Oxygenase-1 (HO-1) and elevated expressions of Nuclear Factor kappa B (NF-kB), Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β) proteins in the brain homogenates evaluated through western blotting technique. On the other hand Vt. D (100 μg/kg) administration (three times a week for 4 weeks) activated Silent mating type information regulation 2 homolog 1 (SIRT1) and significantly improved both the neuronal synapse and memory, reduced oxidative stress by upregulating NRF-2 and HO-1 and downregulating NF-kB, TNF-α and IL-1β proteins expression. Most importantly, Vt. D significantly abrogate the amyloidogenic pathway of amyloid beta (Aβ) production against D-gal in the brains of adult male albino mice. These results reveal that Vt. D being an antioxidant agent plays a vital role in reducing the AD pathophysiology in D-gal induced animal model of aging, therefore act as a potential drug candidate in neurodegenerative diseases.
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Affiliation(s)
- Ammar Ali
- Department of Biotechnology, Abdul Wali Khan University, Mardan, Pakistan
| | - Shahid Ali Shah
- Department of Chemistry, Sarhad University of Information and Technology, Peshawar, Pakistan; Neuro Molecular Medicine Research Center (NMMRC), Ring Road, Peshawar, Pakistan
| | - Nasib Zaman
- Center for Biotechnology and Microbiology, University of Swat, Pakistan
| | | | - Wajid Khan
- Center for Biotechnology and Microbiology, University of Swat, Pakistan
| | - Abid Ali
- Department of Zoology, Abdul Wali Khan University, Mardan, Pakistan
| | - Muhammad Riaz
- Department of Biochemistry, Abdul Wali Khan University, Mardan, Pakistan
| | - Atif Kamil
- Department of Biotechnology, Abdul Wali Khan University, Mardan, Pakistan.
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Zou JJ, Zhou XT, Chen YK, Liu JL, Wang C, Ma YR, Wang L. A review on the efficacy and mechanism of action of Shenkang injection against chronic kidney disease. Biomed Pharmacother 2020; 132:110833. [PMID: 33035831 DOI: 10.1016/j.biopha.2020.110833] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/15/2020] [Accepted: 09/28/2020] [Indexed: 02/07/2023] Open
Abstract
Chronic kidney disease (CKD) is one of the most common conditions which significantly increases the risk for serious health outcomes. Epidemiological investigations have shown that CKD has become a serious global health problem. At present, there are no treatments for CKD, thus the need for an effective and safe treatment for this condition. Shenkang Injection (SKI), which is an herbal medication in Chinese Medicine, has been used in the management and treatment of CKD and has achieved favorable therapeutic effects. The purpose of this paper is to review the clinical efficacy, mechanism of action, and safety profile of SKI when used in CKD, and to provide comprehensive potential evidence for its clinical application.
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Affiliation(s)
- Jun-Ju Zou
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xiao-Tao Zhou
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yan-Kun Chen
- Hunan University of Chinese Medicine, Changsha, 410200, China
| | - Jia-Lu Liu
- School of Educational Science, Hunan Normal University, Changsha, 410006, China
| | - Cheng Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yue-Rong Ma
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Hunan University of Chinese Medicine, Changsha, 410200, China.
| | - Li Wang
- Department of Pathology, Affiliated Hospital of Chengdu University of Chinese Medicine, Chengdu, 611137, China.
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Qin X, Chen J, Zhang G, Li C, Zhu J, Xue H, Li J, Guan T, Zheng H, Liu Y, Cai H. Hydroxysafflor Yellow A Exerts Anti-Inflammatory Effects Mediated by SIRT1 in Lipopolysaccharide-Induced Microglia Activation. Front Pharmacol 2020; 11:1315. [PMID: 33041785 PMCID: PMC7517830 DOI: 10.3389/fphar.2020.01315] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022] Open
Abstract
Abnormal microglia activation causes sever neuroinflammation, contributing to the development of many diseases, yet the mechanism remains incompletely unknown. In current study, we identified that Hydroxysafflor yellow A (HYA), a chalcone glycoside derived from Carthamus tinctorius L effectively attenuates LPS-induced inflammation response in primary microglia via regulating the expression of inflammatory genes and remodeling the polarization of microglia. We also reported the effects of HYA on improving lipopolysaccharide (LPS)-stimulated mitochondrial dysfunction and oxidative stress for the first time. Interestingly, we found that HYA could serves as an effective SIRT1 activator. Deficiency of SIRT1 abrogates the protective effects of HYA against LPS-induced response. Overall, our data suggest HYA, a novel SIRT1 activator, could serve as an effective approach to treat LPS-induced neurodegenerative diseases.
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Affiliation(s)
- Xiude Qin
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Juanjuan Chen
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Guowei Zhang
- Department of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Hebei University, Baoding, China
| | - Chuanpeng Li
- The 1st Clinical Medical College, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jinqiang Zhu
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hong Xue
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Jinfang Li
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Tianxiang Guan
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Haotao Zheng
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yu Liu
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Haobin Cai
- Encephalopathy Department, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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Liu Y, Dai Y, Li Q, Chen C, Chen H, Song Y, Hua F, Zhang Z. Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia. Neurosci Lett 2020; 736:135279. [PMID: 32726591 DOI: 10.1016/j.neulet.2020.135279] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 07/15/2020] [Accepted: 07/23/2020] [Indexed: 12/26/2022]
Abstract
Beta-amyloid(Aβ)-induced inflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD). Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) inflammasome is involved in the Aβ-induced inflammation. However, the mechanisms by which extracellular Aβ activates cytoplasmic NLRP3 inflammasome are poorly understood. Toll-like receptor 4(TLR4) acts as a sensor of Aβ and performs a key role in neuroinflammation. TLR4 is involved in activating the NLRP3 inflammasome in several diseases. In this study, the interaction between TLR4 and NLRP3 inflammasome in Aβ1-42-induced neuroinflammation was investigated. BV-2 microglia and primary microglia were primed with lipopolysaccharide (LPS) and then pretreated with TLR4 inhibitor CLI-095, followed by stimulation with Aβ1-42. The protein expression of NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 p 10 was detected by western blotting and immunostaining. The mRNA expression of inflammatory factors was measured by real-time PCR. The protein level of pro IL-1β and IL-1β was examined by ELISA. Activated microglia were examined by immunofluorescence staining for ionized calcium-binding adapter molecule-1 (Iba-1). Conditioned medium of BV-2 cells was collected to challenge HT-22 neurons. Cell viability was assessed with MTT assay. Assessment of HT-22 cell apoptosis was performed by Annexin V/PI staining and western blotting to detect the protein level of cleaved caspase 3. The results showed that Aβ1-42 activated and up-regulated the expression of NLRP3 inflammasome in BV-2 microglia, as indicated by increased activation of caspase-1 and secretion of IL-1β. Pharmacological inhibition of TLR4 by CLI-095 abolished Aβ1-42-induced NLRP3 inflammasome activation, which curbed the development of inflammation and exerted protective effect on HT-22 neurons. Furthermore, the inhibitory effects of CLI-095 on Aβ1-42-induced inflammation were reversed by NLRP3 activator ATP. Overall, our findings suggested TLR4 mediated Aβ1-42-induced NLRP3 inflammasome activation in mouse microglia. TLR4/NLRP3 pathway plays a critical role in Aβ1-42-induced neuroinflammation.
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Affiliation(s)
- Yang Liu
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
| | - Yue Dai
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
| | - Qing Li
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
| | - Chen Chen
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Hao Chen
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
| | - Yuanjian Song
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, China; Department of Genetics, Research Center for Neurobiology, Xuzhou Medical University, Xuzhou, China
| | - Fang Hua
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
| | - Zuohui Zhang
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China.
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Yang J, Wang R, Cheng X, Qu H, Qi J, Li D, Xing Y, Bai Y, Zheng X. The vascular dilatation induced by Hydroxysafflor yellow A (HSYA) on rat mesenteric artery through TRPV4-dependent calcium influx in endothelial cells. JOURNAL OF ETHNOPHARMACOLOGY 2020; 256:112790. [PMID: 32234595 DOI: 10.1016/j.jep.2020.112790] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/20/2020] [Accepted: 03/21/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hydroxysafflor yellow A (HSYA) is the principal constituent of the flowers of Carthamus tinctorius L., a traditional Chinese herbal medicine, which has been used for the treatment of cerebrovascular and cardiovascular diseases due to its property of promoting blood circulation and removing blood stasis. It is dominated in the water extract of Carthamus tinctorius L., which has been used in the clinical treatment for cardiovascular diseases. HSYA exerts a variety of pharmacological efficacy upon the vascular system. However, the underlying mechanisms remain unclear. AIM OF THE STUDY To investigate the vascular dilatation effect of HSYA on rat mesenteric artery (MA) and its potential mechanism. MATERIALS AND METHODS Adult male Wistar rats were applied to the study. Tension studies were conducted to determine the dilatation activity of HSYA against pre-contracted mesenteric arterial (MA) rings by U 46619 and Phenylephrine (PE). The vascular activities were measured with or without incubation with some selective inhibitors, including L-N(ω)-nitro-L-arginine methyl ester (L-NAME, a nitro oxide synthase inhibitor), HC-067047 (a selective TRPV4 antagonist), BaCl2 (a Kir channel blocker), and Indomethacin (Indo, a nonselective cyclooxygenase inhibitor), respectively. Immunocytochemistry, Calcium Imaging, NO Production detection, and Western Blot were also employed to further study the underlying mechanism. RESULTS HSYA reversed the constriction of MAs induced by U 46619 in a manner of concentration dependency, and the dilatation capability was reversed by L-NAME. This effect was significantly dependent on the intactness of MA endothelium, accompanying an increment of NO production in mesenteric arterial endothelium cells. The increment of NO production was reversed by inhibiting the PKA. Also, the expression of p-eNOS was activated by HSYA shown in Western Blot assays. The cells imaging revealed a significant increase and drop of the influx of Ca2+ before and after treatment with HC-067047. CONCLUSIONS These findings suggest that HSYA exerts vessel dilation effect on MAs via a TRPV4-dependent influx of Ca2+ in endothelium cells, PKA-dependent eNOS phosphorylation and NO production mechanism. The present study indicates that HSYA has the potential to be a future candidate for the treatment of hypertension.
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Affiliation(s)
- Jianfeng Yang
- College of Pharmacy, Harbin Medical University - Daqing, Daqing, 163319, China.
| | - Rui Wang
- College of Pharmacy, Harbin Medical University - Daqing, Daqing, 163319, China.
| | - Xiaohan Cheng
- College of Pharmacy, Harbin Medical University - Daqing, Daqing, 163319, China.
| | - HuiChong Qu
- College of Pharmacy, Harbin Medical University - Daqing, Daqing, 163319, China.
| | - Jing Qi
- College of Basic Medicine, Harbin Medical University - Daqing, Daqing, Heilongjiang, 163319, PR China.
| | - Dan Li
- College of Pharmacy, Harbin Medical University - Daqing, Daqing, 163319, China.
| | - Yan Xing
- College of Basic Medicine, Harbin Medical University - Daqing, Daqing, Heilongjiang, 163319, PR China.
| | - Yuhua Bai
- College of Pharmacy, Harbin Medical University - Daqing, Daqing, 163319, China.
| | - Xiaodong Zheng
- College of Basic Medicine, Harbin Medical University - Daqing, Daqing, Heilongjiang, 163319, PR China.
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Safflower Yellow Improves the Synaptic Structural Plasticity by Ameliorating the Disorder of Glutamate Circulation in Aβ 1-42-induced AD Model Rats. Neurochem Res 2020; 45:1870-1887. [PMID: 32410043 DOI: 10.1007/s11064-020-03051-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 05/02/2020] [Accepted: 05/06/2020] [Indexed: 01/05/2023]
Abstract
Safflower yellow (SY) is the main effective component of Carthamus tinctorius L., and Hydroxysafflor yellow A (HSYA) is the single active component with the highest content in SY. SY and HSYA have been shown to have neuroprotective effects in several AD models. In this study, we aimed to clarify whether the effects of SY and HSYA on the learning and memory abilities of Aβ1-42-induced AD model rats are related to the enhancement of synaptic structural plasticity in brain tissues and the amelioration of disorder of glutamate circulation. We used rats injected with Aβ1-42 into the bilateral hippocampus as a model of AD. After treatment with SY and HSYA, the learning and memory abilities of the Aβ1-42-induced AD model rats were enhanced, Aβ deposition in the AD model rats was decreased, structural damage to dendritic spines and the loss of synaptic-associated proteins were alleviated, and the disorder of glutamate circulation was ameliorated. The results indicated that SY and HSYA improve synaptic structural plasticity by ameliorating the disorder of glutamate circulation in Aβ1-42-induced AD model rats.
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Ganoderic acid A alleviates myocardial ischemia-reperfusion injury in rats by regulating JAK2/STAT3/NF-κB pathway. Int Immunopharmacol 2020; 84:106543. [PMID: 32353688 DOI: 10.1016/j.intimp.2020.106543] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/21/2020] [Accepted: 04/23/2020] [Indexed: 12/28/2022]
Abstract
This study aimed to investigate the protective effect of GanodericacidA (GA) on myocardial ischemia-reperfusion (MIR) injury. The myocardial injury model in rats was established by ligating left anterior descending coronary artery. We measured cardiac hemodynamic, antioxidant enzyme activity, and various biochemical indexes of myocardial tissue, and evaluated myocardial infarction and damage. Further, the expression of JAK2/STAT3/NF-κB signaling pathway-related proteins in myocardial tissue was measured by western blot. The results showed that the myocardial infarction extention was obviously reduced upon GA treatment. Compared with the control group, ischemia-reperfusion rats showed significant increase in lactate dehydrogenase (LDH) and creatine Kinase (CK), which were significantly decreased in GA group. Besides, GA pretreatment effectively decreased the levels of inflammatory cytokines in serum. The phosphorylation of Janus Kinase 2 (JAK2), signal transducer and activator of transcription (STAT3)and Nuclear factor-κB (NF-κB) in reperfusion group were significantly higher than that in control group, which were reversed upon GA treatment. In conclusion, GA may reduce myocardial injury by regulating JAK2/STAT3/NF-κB pathway.
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Chen SY, Gao Y, Sun JY, Meng XL, Yang D, Fan LH, Xiang L, Wang P. Traditional Chinese Medicine: Role in Reducing β-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer's Disease. Front Pharmacol 2020; 11:497. [PMID: 32390843 PMCID: PMC7188934 DOI: 10.3389/fphar.2020.00497] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/30/2020] [Indexed: 12/19/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The major characteristics of AD are amyloid β plaques, apoptosis, autophagy dysfunction, neuroinflammation, oxidative stress, and mitochondrial dysfunction. These are mostly used as the significant indicators for selecting the effects of potential drugs. It is imperative to explain AD pathogenesis and realize productive treatments. Although the currently used chemical drugs for clinical applications of AD are effective in managing the symptoms, they are inadequate to achieve anticipated preventive or therapeutic outcomes. There are new strategies for treating AD. Traditional Chinese Medicine (TCM) has accumulated thousands of years of experience in treating dementia. Nowadays, numerous modern pharmacological studies have verified the efficacy of many bioactive ingredients isolated from TCM for AD treatment. In this review, representative TCM for the treatment of AD are discussed, and among these herbal medicines, the Lamiaceae family accounts for the highest proportion. It is concluded that monomers and extracts from TCM have potential therapeutic effect for AD treatment.
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Affiliation(s)
- Shi-Yu Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yue Gao
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia-Yi Sun
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xian-Li Meng
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dong Yang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lin-Hong Fan
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Xiang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ping Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Lei Z, Lu Y, Bai X, Jiang Z, Yu Q. Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ 1–42-Induced Object Memory Impairment in Mice. Biol Pharm Bull 2020; 43:272-283. [DOI: 10.1248/bpb.b19-00510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- ZeLin Lei
- Key Laboratory of Biotherapy and Regenerative Medicine, the First Hospital of Lanzhou University
| | - YaQin Lu
- Department of Neurology, the First Hospital of Lanzhou University
| | - Xue Bai
- Key Laboratory of Biotherapy and Regenerative Medicine, the First Hospital of Lanzhou University
| | - ZhenXiu Jiang
- Department of Neurology, the First Hospital of Lanzhou University
| | - Qin Yu
- Key Laboratory of Biotherapy and Regenerative Medicine, the First Hospital of Lanzhou University
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Human Gastrointestinal Organoid Models for Studying Microbial Disease and Cancer. Curr Top Microbiol Immunol 2020; 430:55-75. [PMID: 32889597 DOI: 10.1007/82_2020_223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
One of the major discoveries in stem cell research in the past decade embraces the development of "organs in a dish," also known as "organoids." Organoids are three-dimensional cellular structures derived from primary stem cells of different organ-specific cell types which are capable of self-renewal and maintenance of the parental lineages. Researchers have developed in vitro organoid models to mimic in vivo host-microbial interactions and disease. In this review, we focus on the use of gastrointestinal organoids as models of microbial disease and cancer.
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Correlation between angiotensin 1-7-mediated Mas receptor expression with motor improvement, activated STAT3/SOCS3 cascade, and suppressed HMGB-1/RAGE/NF-κB signaling in 6-hydroxydopamine hemiparkinsonian rats. Biochem Pharmacol 2019; 171:113681. [PMID: 31669235 DOI: 10.1016/j.bcp.2019.113681] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 10/23/2019] [Indexed: 12/21/2022]
Abstract
In the current investigation, a Parkinson's disease (PD) model was established by a single direct right intrastriatal injection of the 6-hydroxydopamine (OHDA) in male Wistar rats followed by 7 daily unilateral injection of angiotensin (Ang) 1-7 in the striatum. To confirm the putative role of Mas receptor (MasR), the selective antagonist A779 was also injected intrastriatally prior to Ang 1-7 injections and a correlation analysis was performed between MasR expression and the assessed parameters. Ang 1-7 upregulated MasR expression to correlate strongly with the improved rotarod (r = 0.95, p = 0.003) and spontaneous activity task (r = 0.99, p < 0.0001). This correlation extends to involve other effects of Ang 1-7, such as the increased striatal dopamine content (r = 0.98, p = 0.0005), substantia nigra pars compacta tyrosine hydroxylase immune-reactivity (r = 0.97, p = 0.001), active pY705-STAT3 (r = 0.99, p < 0.0001) and SOCS3 (r = 0.99, p < 0.0001). Conversely, Ang 1-7 inhibited inflammatory markers to correlate negatively with NF-κBp65 (r = -0.99, p < 0.0003) and its downstream targets, high mobility group box-1 (HMGB-1; r = -0.97, p = 0.002), receptor for advanced glycation end products (RAGE; r = -0.98, p = 0.0004), and TNF-α (r = -0.99, p < 0.0003), besides poly-ADP-ribose polymerase-1 (r = -0.99, p = 0.0002). In confirmation, the pre-administration of the selective MasR antagonist, A779, partially attenuated Ang 1-7-induced alterations towards 6-OHDA neurodegeneration. Collectively, our findings support a novel role for the anti-inflammatory capacity of the MasR axis to prove potential therapeutic relevance in PD via the upregulation/activation of MasR-dependent STAT3/SOCS3 cascade to negatively control the HMGB-1/RAGE/NF-κB axis hindering PD associated neuro-inflammation along with DA depletion and motor deficits.
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HuoXueTongFu Formula Alleviates Intraperitoneal Adhesion by Regulating Macrophage Polarization and the SOCS/JAK2/STAT/PPAR- γ Signalling Pathway. Mediators Inflamm 2019; 2019:1769374. [PMID: 31772499 PMCID: PMC6854253 DOI: 10.1155/2019/1769374] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/08/2019] [Indexed: 12/17/2022] Open
Abstract
Intraperitoneal adhesion is a common complication after abdominal surgery, which seriously affects the quality of life of patients. HuoXueTongFu Formula (HXTF) plays an important role in the prevention and treatment of intraperitoneal adhesions. However, the molecular-related mechanisms are still not fully known. In this study, the model of Intrapetitoneal adhesion was established by cecum abrasion and treated with HXTF for one week. RAW264.7 cells were given LPS, IFN-γ, IL-4, HXTF-medicated serum, and PPAR-γ agonist/antagonist, respectively. Histopathology, flow cytometry, ELISA, real-time PCR, and Western blotting were used to further detect the related protein, M1/M2 polarization tendency, and PPAR-γ nuclear translocation. The deposition of collagen fibres reduced in the local area of rats after the operation with HXTF treatment. Similar to IL-4, HXTF induced a tendency for macrophages to polarize toward M2 and promoted peroxisome proliferator-activated receptor-gamma (PPAR-γ) nuclear translocation. Furthermore, the use of HXTF and PPAR-γ agonists downregulated macrophage M1 polarization-related factors IL-1, IL-6, and TNF-alpha and upregulated M2 polarization-related factors IL-4, IL-10, and TGF-beta 1. Meanwhile, the use of HXTF and PPAR-γ agonists downregulated the SOCS3/JAK2/STAT1 pathway and activated the SOCS1/STAT6/PPAR-γ pathway. These results show that HXTF may reduce intraperitoneal adhesion by inducing macrophage M2 polarization and regulating the SOCS/JAK2/STAT/PPAR-γ pathway.
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Ham HJ, Han SB, Yun J, Yeo IJ, Ham YW, Kim SH, Park PH, Choi DY, Hong JT. Bee venom phospholipase A2 ameliorates amyloidogenesis and neuroinflammation through inhibition of signal transducer and activator of transcription-3 pathway in Tg2576 mice. Transl Neurodegener 2019; 8:26. [PMID: 31592103 PMCID: PMC6774221 DOI: 10.1186/s40035-019-0167-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 08/12/2019] [Indexed: 12/21/2022] Open
Abstract
Background Neuroinflammation and accumulation of β-amyloid (Aβ) play a significant role in the onset and progression of Alzheimer’s disease (AD). Our previous study demonstrated that signal transducer and activator of transcription-3 (STAT3) plays a major role in neuroinflammation and amyloidogenesis. Methods In the present study, we investigated the inhibitory effect of bee venom phospholipase A2 (bvPLA2) on memory deficiency in Tg2576 mice, which demonstrate genetic characteristics of AD and the mechanism of its action at the cellular and animal level. For in vivo study, we examined the effect of bvPLA2 on improving memory by conducting several behavioral tests with the administration of bvPLA2 (1 mg/kg) to Tg2576 mice. For in vitro study, we examined the effect of bvPLA2 on amyloidogenesis and neuroinflammation by treating bvPLA2 on LPS-activated BV2 cells. Results We found that bvPLA2 alleviated memory impairment in Tg2576 mice, as demonstrated in the behavioral tests assessing memory. In the bvPLA2-treated group, Aβ, amyloid precursor protein (APP), and β-secretase 1 (BACE1) levels and β-secretase activity were significantly decreased. Expression of pro-inflammatory cytokines and inflammation-related proteins decreased in the brain of bvPLA2-treated group, whereas anti-inflammatory cytokines increased. In addition, bvPLA2 reduced STAT3 phosphorylation in the brains of the bvPLA2-treated group. At the cellular level, bvPLA2 inhibits production of nitric oxide, pro-inflammatory cytokines, and inflammation-related proteins including p-STAT3. Additionally, bvPLA2 inhibits the production of Aβ in cultured BV-2 cells. Results from the docking experiment, pull-down assay, and the luciferase assay show that bvPLA2 directly binds STAT3 and, thus, regulates gene expression levels. Moreover, when the STAT3 inhibitor and bvPLA2 were administered together, the anti-amyloidogenic and anti-inflammatory effects were further enhanced than when they were administered alone. Conclusion These results suggest that bvPLA2 could restore memory by inhibiting the accumulation of Aβ and inflammatory responses via blockage of STAT3 activity. Electronic supplementary material The online version of this article (10.1186/s40035-019-0167-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hyeon Joo Ham
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - Sang-Bae Han
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - Jaesuk Yun
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - In Jun Yeo
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
| | - Young Wan Ham
- 2Department of Chemistry, Utah Valley University, 800 W University Pkwy, Orem, UT 84058 USA
| | - Se Hyun Kim
- INISTst Co., LTD, 767, Sinsu-ro, Suji-gu, Yongin-si, 16827 Gyeonggi-do Republic of Korea
| | - Pil-Hoon Park
- 4College of Pharmacy, Yeungnam University, 280 Daehak Road, Gyeonsan, Gyeongbuk, 38541 Republic of Korea
| | - Dong-Young Choi
- 4College of Pharmacy, Yeungnam University, 280 Daehak Road, Gyeonsan, Gyeongbuk, 38541 Republic of Korea
| | - Jin Tae Hong
- 1College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160 Republic of Korea
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Hongyan L, Mengjiao Z, Chunyan W, Yaruo H. Rhynchophyllin attenuates neuroinflammation in Tourette syndrome rats via JAK2/STAT3 and NF-κB pathways. ENVIRONMENTAL TOXICOLOGY 2019; 34:1114-1120. [PMID: 31231976 DOI: 10.1002/tox.22813] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 06/03/2019] [Accepted: 06/06/2019] [Indexed: 06/09/2023]
Abstract
The aim of this study was designed to investigate the effects of rhynchophyllin (RH) on neuroinflammation in Tourette syndrome (TS) rats. TS model was established in rats by the injection of selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Behavior in DOI-induced rats was tested. Inflammatory cytokines levels such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum and striatum were detected. The expression levels of janus kinase 2 (JAK2)/signal transducer and transcription activator 3 (STAT3) and nuclear factor (NF)-κB pathways in striatum were measured by Western blot. Data indicated that RH can significantly reduce the numbers of nodding experiment of TS rats. RH significantly decreased IL-6, IL-1β, and TNF-α in serum and striatum of TS rats, with altered expression of P-JAK2, P-STAT3, P-NF-κBp65, and P-IκBα in TS rats, as evidenced by Western blot analysis and immunohistochemistry, suggesting that the regulation of JAK2/STAT3 and NF-κB pathways might be involved in the mechanism of RH on TS.
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Affiliation(s)
- Long Hongyan
- Central Laboratory, Nanjing Hospital of Chinese Medicine, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | | | - Wang Chunyan
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Huang Yaruo
- Nanjing University of Chinese Medicine, Nanjing, China
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Xu M, Zhang X, Ren F, Yan T, Wu B, Bi K, Bi W, Jia Y. Essential oil of Schisandra chinensis ameliorates cognitive decline in mice by alleviating inflammation. Food Funct 2019; 10:5827-5842. [PMID: 31463498 DOI: 10.1039/c9fo00058e] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In this study, we aim to assess possible impacts of essential oil (SEO) from Schisandra chinensis (Turcz.) Baill. (S. chinensis) on mice with cognition impairment. Our data showed that SEO improved the cognitive ability of mice with Aβ1-42 or lipopolysaccharides (LPS)-induced Alzheimer's disease (AD) and suppressed the production of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in the hippocampus. Furthermore, SEO inhibited p38 activation, but had little effect on other signaling proteins in the MAPK family, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 (JNK). The SEO and BV-2 microglia co-culture was performed to further confirm the anti-inflammatory activity of SEO. The data showed that SEO decreased nitric oxide (NO) levels in LPS-stimulated BV-2 microglia and significantly blocked LPS-induced MAPKs activation. Taken together, these findings suggested that SEO produces anti-AD effects on AD mice partly by modulating neuroinflammation through the NF-κB/MAPK signaling pathway.
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Affiliation(s)
- Mengjie Xu
- Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Traditional Chinese MateriaMedica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Xiaoying Zhang
- Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Traditional Chinese MateriaMedica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Fangyi Ren
- Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Traditional Chinese MateriaMedica, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Tingxu Yan
- Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
| | - Bo Wu
- Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
| | - Kaishun Bi
- The Engineering Laboratory of National and Local Union of Quality Control for Traditional Chinese Medicine, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China
| | - Wenchuan Bi
- School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China
| | - Ying Jia
- Key Laboratory of Active Components of Chinese Medicine Screening and Evaluation, School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
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Khan M, Ullah R, Rehman SU, Shah SA, Saeed K, Muhammad T, Park HY, Jo MH, Choe K, Rutten BPF, Kim MO. 17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model. Cells 2019; 8:cells8080928. [PMID: 31430865 PMCID: PMC6721687 DOI: 10.3390/cells8080928] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/08/2019] [Accepted: 08/14/2019] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor α (ERα)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17β-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17β-estradiol, by stimulating ERα/SIRT1, halts d-gal-induced oxidative stress–mediated JNK/NF-ҡB overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17β-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17β-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17β-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17β-estradiol, in an ERα/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress–mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice.
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Affiliation(s)
- Mehtab Khan
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Rahat Ullah
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Shafiq Ur Rehman
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Shahid Ali Shah
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Kamran Saeed
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Tahir Muhammad
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Hyun Young Park
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Medical Center (MUMC+), Faculty of Health, Medicine and Life Sciences, Maastricht University, European Graduate School of Neuroscience (EURON), 6229ER Maastricht, The Netherlands
| | - Myeung Hoon Jo
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea
| | - Kyonghwan Choe
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Medical Center (MUMC+), Faculty of Health, Medicine and Life Sciences, Maastricht University, European Graduate School of Neuroscience (EURON), 6229ER Maastricht, The Netherlands
| | - Bart P F Rutten
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Medical Center (MUMC+), Faculty of Health, Medicine and Life Sciences, Maastricht University, European Graduate School of Neuroscience (EURON), 6229ER Maastricht, The Netherlands
| | - Myeong Ok Kim
- Division of Life sciences and Applied Life Science (BK 21plus), College of Natural Science, Gyeongsang National University, Jinju 52828, Korea.
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Li H, Liu Y, Wen M, Zhao F, Zhao Z, Liu Y, Lin X, Wang L. Hydroxysafflor yellow A (HSYA) alleviates apoptosis and autophagy of neural stem cells induced by heat stress via p38 MAPK/MK2/Hsp27-78 signaling pathway. Biomed Pharmacother 2019; 114:108815. [PMID: 30954890 DOI: 10.1016/j.biopha.2019.108815] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 01/01/2023] Open
Abstract
This study aimed to explore mechanisms of the effects of hydroxysafflor yellow A (HSYA) on neural stem cells (NSCs) after heat stress (HS). Rat NSCs cells were cultured at 42 °C to impose heat stress. Cell counting kit-8 and Edu assay were used to analyze NSC proliferation. Annexin V/PI apoptosis kit was used to detect NSC apoptosis. Expression and phosphorylation of autophagy and apoptosis-associated proteins were determined by western blotting. We showed that HSYA significantly promoted proliferation and attenuated apoptosis of NSCs after heat stress. HSYA also increased Bcl-2 expression but decreased the expression of Bax and cleaved caspase-3 in NSCs induced by heat stress. In addition, HSYA decreased p38 and Hsp27-78 phosphorylation and MK-2 expression after heat stress, which was consistent with NSCs treated with SB203850 treatment or p38 knockdown. Furthermore, we demonstrated that heat stress increased LC3-II expression and mTOR phosphorylation, and decreased the expression of p62 in NSCs, while HSYA, SB203850 treatment or p38 knockdown reversed these alterations. In conclusion, HSYA significantly reversed the apoptosis and autophagy of NSCs induced by heat stress (P < 0.05), via downregulating MK2 expression and p38 and Hsp27-78 phosphorylation.
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Affiliation(s)
- Hongbo Li
- Department of Intensive Care Unit, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Yanan Liu
- Department of Intensive Care Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Minyong Wen
- Department of Intensive Care Unit, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Fu Zhao
- Department of Intensive Care Unit, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Zhihui Zhao
- Department of Traditional Chinese Medicine Surgery, Jilin People's Hospital, Jilin, 132000, China
| | - Yunsong Liu
- Intensive Care Unit, Clifford Hospital, Guangzhou University of Chinese Medicine, No.3 Hongfu Road, Panyu District, Guangzhou 511495, PR China.
| | - Xinfeng Lin
- Department of Intensive Care Unit, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
| | - Lin Wang
- Department of Emergency, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16 Jichang Road, Baiyun District, Guangzhou, 510405, China.
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Astaxanthin Ameliorates Lipopolysaccharide-Induced Neuroinflammation, Oxidative Stress and Memory Dysfunction through Inactivation of the Signal Transducer and Activator of Transcription 3 Pathway. Mar Drugs 2019; 17:md17020123. [PMID: 30781690 PMCID: PMC6410230 DOI: 10.3390/md17020123] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 02/10/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022] Open
Abstract
Astaxanthin (AXT), a xanthophyll carotenoid compound, has potent antioxidant, anti-inflammatory and neuroprotective properties. Neuroinflammation and oxidative stress are significant in the pathogenesis and development of Alzheimer's disease (AD). Here, we studied whether AXT could alleviate neuroinflammation, oxidative stress and memory loss in lipopolysaccharide (LPS) administered mice model. Additionally, we investigated the anti-oxidant activity and the anti-neuroinflammatory response of AXT in LPS-treated BV-2 microglial cells. The AXT administration ameliorated LPS-induced memory loss. This effect was associated with the reduction of LPS-induced expression of inflammatory proteins, as well as the production of reactive oxygen species (ROS), nitric oxide (NO), cytokines and chemokines both in vivo and in vitro. AXT also reduced LPS-induced β-secretase and Aβ1⁻42 generation through the down-regulation of amyloidogenic proteins both in vivo and in vitro. Furthermore, AXT suppressed the DNA binding activities of the signal transducer and activator of transcription 3 (STAT3). We found that AXT directly bound to the DNA- binding domain (DBD) and linker domain (LD) domains of STAT3 using docking studies. The oxidative stress and inflammatory responses were not downregulated in BV-2 cells transfected with DBD-null STAT3 and LD-null STAT3. These results indicated AXT inhibits LPS-induced oxidant activity, neuroinflammatory response and amyloidogenesis via the blocking of STAT3 activity through direct binding.
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Nguyen BT, Sharma N, Shin EJ, Jeong JH, Lee SH, Jang CG, Nah SY, Nabeshima T, Yoneda Y, Kim HC. Theanine attenuates memory impairments induced by klotho gene depletion in mice. Food Funct 2019; 10:325-332. [DOI: 10.1039/c8fo01577e] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Theanine (γ-glutamylethylamide), an amino acid in tea, is a putative neuroprotective and antioxidant compound capable of improving lifespan and cognitive function.
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45
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Zhao Y, Wang J, Du J, Li B, Gou X, Liu J, Hou L, Sang H, Deng B. TAT-Ngn2 Enhances Cognitive Function Recovery and Regulates Caspase-Dependent and Mitochondrial Apoptotic Pathways After Experimental Stroke. Front Cell Neurosci 2018; 12:475. [PMID: 30618628 PMCID: PMC6302814 DOI: 10.3389/fncel.2018.00475] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 11/21/2018] [Indexed: 12/20/2022] Open
Abstract
Neurogenin-2 (Ngn2) is a basic helix-loop-helix (bHLH) transcription factor that contributes to the identification and specification of neuronal fate during neurogenesis. In our previous study, we found that Ngn2 plays an important role in alleviating neuronal apoptosis, which may be viewed as an attractive candidate target for the treatment of cerebral ischemia. However, novel strategies require an understanding of the function and mechanism of Ngn2 in mature hippocampal neurons after global cerebral ischemic injury. Here, we found that the expression of Ngn2 decreased in the hippocampus after global cerebral ischemic injury in mice and in primary hippocampal neurons after oxygen glucose deprivation (OGD) injury. Then, transactivator of transcription (TAT)-Ngn2, which was constructed by fusing a TAT domain to Ngn2, was effectively transported and incorporated into hippocampal neurons after intraperitoneal (i.p.) injection and enhanced cognitive functional recovery in the acute stage after reperfusion. Furthermore, TAT-Ngn2 alleviated hippocampal neuronal damage and apoptosis, and inhibited the cytochrome C (CytC) leak from the mitochondria to the cytoplasm through regulating the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylation tropomyosin-related kinase B (pTrkB), Bcl-2, Bax and cleaved caspase-3 after reperfusion injury in vivo and in vitro. These findings suggest that the downregulation of Ngn2 expression may have an important role in triggering brain injury after ischemic stroke and that the neuroprotection of TAT-Ngn2 against stroke might involve the modulation of BDNF-TrkB signaling that regulates caspase-dependent and mitochondrial apoptotic pathways, which may be an attractive therapeutic strategy for cerebral ischemic injury.
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Affiliation(s)
- Yu Zhao
- Department of Hygienic Toxicology, Public Health College, Harbin Medical University, Harbin, China.,Department of Anesthesiology, Heilongjiang Provincial Hospital, Harbin, China
| | - Jinling Wang
- Department of Emergency, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Jiwei Du
- Department of Nursing, Xiang'an Hospital, Xiamen University, Xiamen, China
| | - Baixiang Li
- Department of Hygienic Toxicology, Public Health College, Harbin Medical University, Harbin, China
| | - Xingchun Gou
- Shaanxi Key Laboratory of Brain Disorders & Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China
| | - Jiannan Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China
| | - Lichao Hou
- Department of Anesthesiology, Xiang'an Hospital, Xiamen University, Xiamen, China
| | - Hanfei Sang
- Department of Anesthesiology, Xiang'an Hospital, Xiamen University, Xiamen, China
| | - Bin Deng
- Department of Anesthesiology, Xiang'an Hospital, Xiamen University, Xiamen, China
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Xu L, Botchway BOA, Zhang S, Zhou J, Liu X. Inhibition of NF-κB Signaling Pathway by Resveratrol Improves Spinal Cord Injury. Front Neurosci 2018; 12:690. [PMID: 30337851 PMCID: PMC6180204 DOI: 10.3389/fnins.2018.00690] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 09/14/2018] [Indexed: 12/13/2022] Open
Abstract
Spinal cord injury (SCI) can have a significant impact on an individual’s life. Herein, we discuss how resveratrol improves SCI by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Evidences show resveratrol suppresses NF-κB signaling pathway to exert its beneficial effects on various diseases. NF-κB signaling pathway plays a significant role in the pathophysiological mechanisms of SCI including increase in inflammation, augmentation of damage caused by free radicals and lipid peroxidation as well as facilitation of apoptosis and axonal demyelination. We also discuss mechanisms between resveratrol and NF-κB signaling pathway in the wake of SCI, which can be potential targets for resveratrol to treat SCI.
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Affiliation(s)
- Luyao Xu
- Department of Histology and Embryology, Medical College, Shaoxing University, Shaoxing, China
| | - Benson O A Botchway
- Institute of Neuroscience, Zhejiang University School of Medicine, Hangzhou, China
| | - Songou Zhang
- Department of Histology and Embryology, Medical College, Shaoxing University, Shaoxing, China
| | - Jingying Zhou
- Department of Histology and Embryology, Medical College, Shaoxing University, Shaoxing, China
| | - Xuehong Liu
- Department of Histology and Embryology, Medical College, Shaoxing University, Shaoxing, China
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Hydroxysafflor Yellow A: A Promising Therapeutic Agent for a Broad Spectrum of Diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:8259280. [PMID: 30356354 PMCID: PMC6176289 DOI: 10.1155/2018/8259280] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/12/2018] [Indexed: 01/13/2023]
Abstract
Hydroxysafflor yellow A (HSYA) is one of the major bioactive and water-soluble compounds isolated from Carthami Flos, the flower of safflower (Carthamus tinctorius L.). As a natural pigment with favorable medical use, HSYA has gained extensive attention due to broad and effective pharmacological activities since first isolation in 1993. In clinic, the safflor yellow injection which mainly contains about 80% HSYA was approved by the China State Food and Drug Administration and used to treat cardiac diseases such as angina pectoris. In basic pharmacology, HSYA has been proved to exhibit a broad spectrum of biological effects that include, but not limited to, cardiovascular effect, neuroprotection, liver and lung protection, antitumor activity, metabolism regulation, and endothelium cell protection. Although a great number of studies have been carried out to prove the pharmacological effects and corresponding mechanisms of HYSA, a systemic review of HYSA has not yet been seen. Here, we provide a comprehensive summarization of the pharmacological effects of HYSA. Together with special attention to mechanisms of actions, this review can serve as the basis for further researches and developments of this medicinal compound.
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Gu QF, Yu JZ, Wu H, Li YH, Liu CY, Feng L, Zhang GX, Xiao BG, Ma CG. Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of Alzheimer's disease. Exp Ther Med 2018; 16:3929-3938. [PMID: 30344671 PMCID: PMC6176147 DOI: 10.3892/etm.2018.6701] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 08/23/2018] [Indexed: 12/29/2022] Open
Abstract
Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer's disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of its action. The results showed that FSD-C10 effectively improved learning and memory impairment, accompanied by reduced expression of amyloid-β 1-42 (Aβ1-42), Tau protein phosphorylation (P-tau) and β-site APP-cleaving enzyme in the hippocampus and cortex area of brain. In addition, FSD-C10 administration boosted the expression of synapse-associated proteins, such as postynaptic density protein 95, synaptophsin, α-amino 3-hydroxy-5-methyl-4-isoxa-zolep-propionate receptor and neurotrophic factors, e,g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Taken together, our results demonstrate that FSD-C10 has therapeutic potential in the AD mouse model, possibly through inhibiting the formation of Aβ1-42 and P-tau, and promoting the generation of synapse-associated proteins and neurotrophic factors.
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Affiliation(s)
- Qing-Fang Gu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Jie-Zhong Yu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Hao Wu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Yan-Hua Li
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Chun-Yun Liu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Ling Feng
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Guang-Xian Zhang
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Bao-Guo Xiao
- Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, P.R. China
| | - Cun-Gen Ma
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China.,2011 Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi 030024, P.R. China
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Protective effect of hydroxysafflor yellow A against acute kidney injury via the TLR4/NF-κB signaling pathway. Sci Rep 2018; 8:9173. [PMID: 29907783 PMCID: PMC6003992 DOI: 10.1038/s41598-018-27217-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 05/24/2018] [Indexed: 12/20/2022] Open
Abstract
This study aimed to evaluate the protective effect of hydroxysafflor yellow A (HSYA) on ischemia/reperfusion (I/R)-induced acute kidney injury via the TLR4/NF-κB pathway, both in vitro and in vivo. Rats were subjected to removal of the right kidney and I/R injury to the left kidney. Rats subjected to renal I/R injury were treated with HSYA at 0.5 h prior to I/R injury. Renal function, histopathological analysis, and cells apoptosis were measured in vivo. In vitro, proximal renal tubular cells (HK-2) were subjected to hypoxia/reoxygenation (H/R). Apoptotic cell death and inflammatory cytokines, Toll-like receptor 4 (TLR4), and nuclear factor (NF)-κB expression were determined. Treatment of I/R rats with HSYA markedly reduced the levels of serum creatinine and blood urea nitrogen, attenuated renal cell apoptosis, alleviated changes in renal tissue morphology, and reduced IL-1β, TNF-α, and caspase-3 release. In vitro, HSYA effectively decreased NF-κB p65 and inflammatory cytokines, such as IL-1β, TNF-α, and IL-6. Thus, HSYA can protect renal function from I/R injury by ameliorating acute kidney injury and partly by promoting tubular cell survival via the TLR4/NF-κB pathway. These results suggest that HSYA can be used to prevent I/R-induced acute kidney injury.
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Protosappanin A exerts anti-neuroinflammatory effect by inhibiting JAK2-STAT3 pathway in lipopolysaccharide-induced BV2 microglia. Chin J Nat Med 2018; 15:674-679. [PMID: 28991528 DOI: 10.1016/s1875-5364(17)30096-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Indexed: 12/16/2022]
Abstract
Microglial activation and resultant neuroinflammatory response are implicated in various brain diseases including Alzheimer's disease and Parkinson's disease. Treatment with anti-neuroinflammatory agents could provide therapeutic benefits for such disorders. Protosappanin A (PTA) is a major bioactive ingredient isolated from Caesalpinia sappan L.. In this work, the anti-neuroinflammatory effects of PTA on LPS-stimulated BV2 cells were investigated and the underlying mechanisms were explored. Results showed that PTA significantly inhibited the production of TNF-α and IL-1β in LPS-activated BV2 microglia. Moreover, the mRNA expressions of IL-6, IL-1β, and MCP-1 were reduced by PTA in a dose-dependent manner. Furthermore, PTA suppressed JAK2/STAT3-dependent inflammation pathway through down-regulating the phosphorylation of JAK2 and STAT3, as well as STAT3 nuclear translocation against LPS treatment. These observations suggested a novel role for PTA in regulating LPS-induced neuroinflammatory injuries.
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