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Bhatia V, Vikram V, Chandel A, Rattan A. Interplay between PI3k/AKT signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications. Inflammopharmacology 2025:10.1007/s10787-025-01715-z. [PMID: 40088370 DOI: 10.1007/s10787-025-01715-z] [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: 02/11/2025] [Accepted: 02/21/2025] [Indexed: 03/17/2025]
Abstract
Alzheimer's disease, a neurodegenerative disorder, is characterized by cognitive impairment, neuronal loss, and synaptic dysfunction. The interplay between the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and the caspase-mediated apoptotic cascade plays a pivotal role in its progression. The signaling pathway responsible for neuronal survival also regulates synaptic plasticity and resistance to oxidative stress, whereas caspase activation accelerates neurodegeneration by triggering cell death and inflammation. Dysregulation of these pathways leads to amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and mitochondrial dysfunction, creating a negative feedback loop and accelerating disease progression. Emerging treatment methods that target PI3K/AKT activation and caspase inhibition have showed promise in preclinical models, preventing neuronal apoptosis while retaining cognitive function. This review investigates the molecular processes driving PI3K/AKT and caspase crosstalk, their significance in Alzheimer's disease, and prospective therapeutic strategies aiming at regulating these pathways to improve disease outcomes.
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Affiliation(s)
- Vandana Bhatia
- Department of Pharmacology, CT University Ludhiana, Ludhiana, Punjab, 142024, India.
| | - Vir Vikram
- Department of Pharmacology, CT University Ludhiana, Ludhiana, Punjab, 142024, India
| | - Anjali Chandel
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India
| | - Aditya Rattan
- Department of Pharmacology, Laureate Institute of Pharmacy Kathog, Kangra, 177101, India
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Alsfouk BA, Al-Kuraishy HM, Albuhadily AK, Al-Gareeb AI, Abdelaziz AM, Alexiou A, Papadakis M, Alruwaili M, Batiha GES. The potential therapeutic role of berberine in treating epilepsy focusing on temporal lobe epilepsy: State of art and ongoing perspective. Brain Res Bull 2025; 221:111189. [PMID: 39761924 DOI: 10.1016/j.brainresbull.2025.111189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/15/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Epilepsy is a neurological disease characterized by unprovoked recurrent epileptic seizures. Temporal lobe epilepsy (TLE) is the commonest type of focal epilepsy in adults that resist to the conventional anti-seizure medications (ASMs). Interestingly, ASMs do not affect the epileptogenesis and progression of disease. Therefore, repurposing of natural products with anti-inflammatory, anti-oxidant and anti-seizure effects such as berberine (BRB) may be logical in treating refractory epilepsy and TLE. However, the molecular mechanism of BRB against the development of epilepsy and progression of epileptic seizure mainly in TLE was not fully elucidated. Therefore, we attempt in this review to discuss the potential underlying molecular mechanism of BRB against the development and progression of epilepsy mainly the TLE.
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Affiliation(s)
- Bshra A Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad 14132, Iraq.
| | - Ali K Albuhadily
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad 14132, Iraq.
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad 14132, Iraq; Jabir ibn Hayyan Medical University, Al-Ameer Qu./Najaf-Iraq, PO. Box13, Kufa, Iraq.
| | - Ahmed M Abdelaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Arish Branch, Arish 45511, Egypt.
| | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh University, Mohali, India; Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, New South Wales, Australia; Department of Research & Development, Funogen, Athens, Greece.
| | - Marios Papadakis
- University Hospital Witten-Herdecke, University of Witten, Herdecke, Heusnerstrasse 40, Wuppertal 42283, Germany.
| | - Mubarak Alruwaili
- Department of Internal Medicine, College of Medicine, Jouf University, Sakaka, Saudi Arabia.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira 22511, Egypt.
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Almutary AG, Begum MY, Kyada AK, Gupta S, Jyothi SR, Chaudhary K, Sharma S, Sinha A, Abomughaid MM, Imran M, Lakhanpal S, Babalghith AO, Abu-Seer EA, Avinash D, Alzahrani HA, Alhindi AA, Iqbal D, Kumar S, Jha NK, Alghamdi S. Inflammatory signaling pathways in Alzheimer's disease: Mechanistic insights and possible therapeutic interventions. Ageing Res Rev 2025; 104:102548. [PMID: 39419399 DOI: 10.1016/j.arr.2024.102548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 10/09/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024]
Abstract
The complex pathophysiology of Alzheimer's disease (AD) poses challenges for the development of therapies. Recently, neuroinflammation has been identified as a key pathogenic mechanism underlying AD, while inflammation has emerged as a possible target for the management and prevention of AD. Several prior studies have demonstrated that medications modulating neuroinflammation might lessen AD symptoms, mostly by controlling neuroinflammatory signaling pathways such as the NF-κB, MAPK, NLRP3, etc, and their respective signaling cascade. Moreover, targeting these inflammatory modalities with inhibitors, natural products, and metabolites has been the subject of intensive research because of their anti-inflammatory characteristics, with many studies demonstrating noteworthy pharmacological capabilities and potential clinical applications. Therefore, targeting inflammation is considered a promising strategy for treating AD. This review comprehensively elucidates the neuroinflammatory mechanisms underlying AD progression and the beneficial effects of inhibitors, natural products, and metabolites in AD treatment.
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Affiliation(s)
- Abdulmajeed G Almutary
- Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, P.O. Box 59911, Abu Dhabi, United Arab Emirates
| | - M Yasmin Begum
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Ashish Kumar Kyada
- Marwadi University Research Center, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Marwadi University, Rajkot, Gujarat 360003, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India
| | - S Renuka Jyothi
- Department of Biotechnology and Genetics, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Swati Sharma
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjeri, Mohali, Punjab 140307, India
| | - Aashna Sinha
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand
| | - Mosleh Mohammad Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia; Center for Health Research, Northern Border University, Arar, Saudi Arabia
| | - Sorabh Lakhanpal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Ahmad O Babalghith
- Medical Genetics Department, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Eman Adnan Abu-Seer
- Department of Epidemiology and Medical Statistic, Faculty of Public Health and Health Informatics, Umm Al-Qura University, Makkah, Saudi Arabia
| | - D Avinash
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, India
| | - Hassan A Alzahrani
- Department of Respiratory Care, Medical Cities at the Minister of Interior, MCMOl, Riyadh, Saudi Arabia
| | | | - Danish Iqbal
- Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah 51418, Saudi Arabia
| | - Sandeep Kumar
- School of Pharmacy, Sharda University, Greater Noida, India; DST-FIST Laboratory, Sharda University, Greater Noida, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Biosciences and Technology (SBT), Galgotias University, Greater Noida, India; Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, India.
| | - Saad Alghamdi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
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Zhou Q, Guo X, Chen T, Liu Y, Ji H, Sun Y, Yang X, Ouyang C, Liu X, Lei M. The neuroprotective role of celastrol on hippocampus in diabetic rats by inflammation restraint, insulin signaling adjustment, Aβ reduction and synaptic plasticity alternation. Biomed Pharmacother 2024; 179:117397. [PMID: 39232386 DOI: 10.1016/j.biopha.2024.117397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/28/2024] [Accepted: 08/30/2024] [Indexed: 09/06/2024] Open
Abstract
Celastrol, the primary constituent of Tripterygium wilfordii, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.
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Affiliation(s)
- Qiaofeng Zhou
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Xiying Guo
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Tu Chen
- Xianning Public Inspection and Testing Center, Xianning 437100, China
| | - Yumin Liu
- Wuhan Huake Reproductive Specialist Hospital, Wuhan 430000, China
| | - Huimin Ji
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Yixuan Sun
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Xiaosong Yang
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Changhan Ouyang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
| | - Min Lei
- Hubei Key Laboratory of Diabetes And Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
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Li W, Gan C, Yu S, Xu J, Tang L, Cheng H. Wnt3a/GSK3β/β-catenin Signalling Modulates Doxorubicin-associated Memory Deficits in Breast Cancer. Mol Neurobiol 2024; 61:5441-5458. [PMID: 38198045 DOI: 10.1007/s12035-023-03910-x] [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: 11/03/2023] [Accepted: 12/25/2023] [Indexed: 01/11/2024]
Abstract
BACKGROUND Chemobrain is widespread in breast cancer patients receiving chemotherapy. However, the exact mechanism, especially the associated signalling pathway, is not currently clear. This study was to evaluate the behavioural changes in breast cancer mice after chemotherapy and to further explore the role of Wnt3a/glycogen synthase kinase (GSK3β)/β-catenin signalling in chemobrain. METHODS MMTV-PyMT(+) breast cancer mice were injected intraperitoneally with doxorubicin (4 mg/kg) once a week for three weeks to establish a chemobrain model. The Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and memory ability. Electron microscopy was used to observe the structural changes in the hippocampal CA1 region. The brain tissue of breast cancer mice after chemotherapy was taken out for mRNA-seq detection. Then, the expression levels and phosphorylation of key proteins in the Wnt3a/GSK3 β/β-catenin signalling pathway were evaluated through Western blotting (WB) and immunofluorescence. RESULTS Doxorubicin-induced spatial and short-term memory impairment was observed in breast cancer mice, and obvious neuronal damage could be seen in the hippocampal CA1 region. Immunofluorescence staining for GSK3β was increased. Wnt signalling pathway is highly enriched from mRNA-seq analysis, with GSK3β genes at important nodes. The relative protein levels of p-PI3K, p-AKT, p-GSK3 β, Wnt3a and TCF-1 were decreased significantly, while the p-β-catenin level was increased. After injection of the GSK3β inhibitor sb216763 (1 ng/0.5 µl/side), hippocampal neuronal injury was alleviated to some extent, and the changes in the expression of proteins upstream and downstream of this signalling pathway were reversed. CONCLUSION Wnt3a/GSK3 β/β-catenin signalling is likely involved in doxorubicin-induced memory impairment. This result provides basic evidence for the further study of chemobrain in breast cancer.
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Affiliation(s)
- Wen Li
- Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China
| | - Chen Gan
- Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China
| | - Sheng Yu
- Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China
| | - Jian Xu
- Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China
| | - LingXue Tang
- Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, 230601, China
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China
| | - Huaidong Cheng
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510500, China.
- Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China.
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Alkanad M, Hani U, V AH, Ghazwani M, Haider N, Osmani RAM, M D P, Hamsalakshmi, Bhat R. Bitter yet beneficial: The dual role of dietary alkaloids in managing diabetes and enhancing cognitive function. Biofactors 2024; 50:634-673. [PMID: 38169069 DOI: 10.1002/biof.2034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
With the rising prevalence of diabetes and its association with cognitive impairment, interest in the use of dietary alkaloids and other natural products has grown significantly. Understanding how these compounds manage diabetic cognitive dysfunction (DCD) is crucial. This comprehensive review explores the etiology of DCD and the effects of alkaloids in foods and dietary supplements that have been investigated as DCD therapies. Data on how dietary alkaloids like berberine, trigonelline, caffeine, capsaicin, 1-deoxynojirimycin, nuciferine, neferine, aegeline, tetramethylpyrazine, piperine, and others regulate cognition in diabetic disorders were collected from PubMed, Research Gate, Web of Science, Science Direct, and other relevant databases. Dietary alkaloids could improve memory in behavioral models and modulate the mechanisms underlying the cognitive benefits of these compounds, including their effects on glucose metabolism, gut microbiota, vasculopathy, neuroinflammation, and oxidative stress. Evidence suggests that dietary alkaloids hold promise for improving cognition in diabetic patients and could open exciting avenues for future research in diabetes management.
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Affiliation(s)
- Maged Alkanad
- Department of Pharmacognosy, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, India
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Annegowda H V
- Department of Pharmacognosy, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, Mandya, India
| | - Mohammed Ghazwani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Riyaz Ali M Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, India
| | - Pandareesh M D
- Center for Research and Innovations, Adichunchanagiri University, BGSIT, Mandya, India
| | - Hamsalakshmi
- Department of Pharmacognosy, Cauvery College of Pharmacy, Cauvery Group of Institutions, Mysuru, India
| | - Rajeev Bhat
- ERA-Chair in Food By-Products Valorisation Technologies (VALORTECH), Estonian University of Life Sciences, Tartu, Estonia
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Saleh SR, Abd-Elmegied A, Aly Madhy S, Khattab SN, Sheta E, Elnozahy FY, Mehanna RA, Ghareeb DA, Abd-Elmonem NM. Brain-targeted Tet-1 peptide-PLGA nanoparticles for berberine delivery against STZ-induced Alzheimer's disease in a rat model: Alleviation of hippocampal synaptic dysfunction, Tau pathology, and amyloidogenesis. Int J Pharm 2024; 658:124218. [PMID: 38734273 DOI: 10.1016/j.ijpharm.2024.124218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/06/2024] [Accepted: 05/08/2024] [Indexed: 05/13/2024]
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disorder that causes severe dementia and memory loss. Surface functionalized poly(lactic-co-glycolic acid) nanoparticles have been reported for better transport through the blood-brain barrier for AD therapy. This study investigated the improved therapeutic potential of berberine-loaded poly(lactic-co-glycolic acid)/Tet-1 peptide nanoparticles (BBR/PLGA-Tet NPs) in a rat model of sporadic AD. BBR was loaded into the PLGA-Tet conjugate. BBR/PLGA-Tet NPs were physicochemically and morphologically characterized. AD was achieved by bilateral intracerebroventricular (ICV) injection of streptozotocin (STZ). Cognitively impaired rats were divided into STZ, STZ + BBR, STZ + BBR/PLGA-Tet NPs, and STZ + PLGA-Tet NPs groups. Cognitive improvement was assessed using the Morris Water Maze. Brain acetylcholinesterase and monoamine oxidase activities, amyloid β42 (Aβ42), and brain glycemic markers were estimated. Further, hippocampal neuroplasticity (BDNF, pCREB, and pERK/ERK), Tau pathogenesis (pGSK3β/GSK3β, Cdk5, and pTau), inflammatory, and apoptotic markers were evaluated. Finally, histopathological changes were monitored. ICV-STZ injection produces AD-like pathologies evidenced by Aβ42 deposition, Tau hyperphosphorylation, impaired insulin signaling and neuroplasticity, and neuroinflammation. BBR and BBR/PLGA-Tet NPs attenuated STZ-induced hippocampal damage, enhanced cognitive performance, and reduced Aβ42, Tau phosphorylation, and proinflammatory responses. BBR/PLGA-Tet NPs restored neuroplasticity, cholinergic, and monoaminergic function, which are critical for cognition and brain function. BBR/PLGA-Tet NPs may have superior therapeutic potential in alleviating sporadic AD than free BBR due to their bioavailability, absorption, and brain uptake.
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Affiliation(s)
- Samar R Saleh
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
| | - Aml Abd-Elmegied
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Somaya Aly Madhy
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
| | - Sherine N Khattab
- Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
| | - Eman Sheta
- Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Fatma Y Elnozahy
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Radwa A Mehanna
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt; Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Doaa A Ghareeb
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
| | - Nihad M Abd-Elmonem
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
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Lu YW, Xie LY, Qi MH, Ren S, Wang YQ, Hu JN, Wang Z, Tang S, Zhang JT, Li W. Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:12516-12528. [PMID: 38491972 DOI: 10.1021/acs.jafc.3c08490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/18/2024]
Abstract
Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.
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Affiliation(s)
- Ya-Wei Lu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Li-Ya Xie
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Meng-Han Qi
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Shen Ren
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Yue-Qi Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Jun-Nan Hu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Zi Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Shan Tang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Jing-Tian Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
- College of Life Sciences, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun 130118, China
- Jilin Provincial International Joint Research Center for the Development and Utilization of Authentic Medicinal Materials, Changchun 130118, China
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9
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Yang XY, Yang CJ, Wang XF, Zhang L, Shi ZY, Jiang DC, Li MZ. Berberine improves cognitive impairment by alleviating brain atrophy and promoting white matter reorganization in diabetic db/db mice: a magnetic resonance imaging-based study. Metab Brain Dis 2024; 39:941-952. [PMID: 38801506 DOI: 10.1007/s11011-024-01361-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Diabetic cognitive impairment is a common complication in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid that has been shown to have neuroprotective effects against diabetes. This study aimed to investigate the effect of BBR on the gray and white matter of the brain by using magnetic resonance imaging (MRI) and to explore the underlying mechanisms. The study used diabetic db/db mice and administered BBR (50 and 100 mg/kg) intragastrically for twelve weeks. Morris water maze was applied to examine cognitive function. T2-weighted imaging (T2WI) was performed to assess brain atrophy, and diffusion tensor imaging (DTI) combined with fiber tracking was conducted to monitor the structural integrity of the white matter, followed by histological immunostaining. Furthermore, the protein expressions of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3β (GSK-3β) were detected. The results revealed that BBR significantly improved the spatial learning and memory of the db/db mice. T2WI exhibited ameliorated brain atrophy in the BBR-treated db/db mice, as evidenced by reduced ventricular volume accompanied by increased hippocampal volumes. DTI combined with fiber tracking revealed that BBR increased FA, fiber density and length in the corpus callosum/external capsule of the db/db mice. These imaging findings were confirmed by histological immunostaining. Notably, BBR significantly enhanced the protein levels of phosphorylated AKT at Ser473 and GSK-3β at Ser9. Collectively, this study demonstrated that BBR significantly improved the cognitive function of the diabetic db/db mice through ameliorating brain atrophy and promoting white matter reorganization via AKT/GSK-3β pathway.
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Affiliation(s)
- Xin-Yu Yang
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China
| | - Chun-Jing Yang
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China
| | - Xiao-Fang Wang
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China
| | - Lei Zhang
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China
| | - Zheng-Yuan Shi
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China
| | - De-Chun Jiang
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China.
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China.
| | - Man-Zhong Li
- Department of pharmacy, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing, 100038, China.
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, 100038, China.
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10
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Guo X, Lei M, Ma G, Ouyang C, Yang X, Liu C, Chen Q, Liu X. Schisandrin A Alleviates Spatial Learning and Memory Impairment in Diabetic Rats by Inhibiting Inflammatory Response and Through Modulation of the PI3K/AKT Pathway. Mol Neurobiol 2024; 61:2514-2529. [PMID: 37910285 DOI: 10.1007/s12035-023-03725-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 10/19/2023] [Indexed: 11/03/2023]
Abstract
Clinical and epidemiological research shows that people with diabetes mellitus frequently experience diabetic cognitive impairment. Schisandrin A (SchA), one of the lignans found in the dried fruit of Schisandra chinensis, has a variety of pharmacological effects on immune system control, apoptosis suppression, anti-oxidation and anti-inflammation. The goal of the current investigation was to clarify the probable neuro-protective effects of SchA against streptozotocin-induced diabetes deficiencies of the spatial learning and memory in rats. The outcomes show that SchA therapy effectively improved impaired glucose tolerance, fasting blood glucose level and serum insulin level in diabetic rats. Additionally, in the Morris water maze test, diabetic rats showed deficits in spatial learning and memory that were ameliorated by SchA treatment. Moreover, giving diabetic rats SchA reduced damage to the hippocampus structure and increased the production of synaptic proteins. Further research revealed that SchA therapy reduced diabetic-induced hippocampus neuron damage and the generation of Aβ, as demonstrated by the upregulated phosphorylation levels of insulin signaling pathway connected proteins and by the decreased expression levels of inflammatory-related factors. Collectively, these results suggested that SchA could improve diabetes-related impairments in spatial learning and memory, presumably by reducing inflammatory responses and regulating the insulin signaling system.
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Affiliation(s)
- Xiying Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Guandi Ma
- Hubei Key Laboratory of Diabetes and Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Changhan Ouyang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Xiaosong Yang
- Hubei Key Laboratory of Diabetes and Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Chao Liu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China.
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China.
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Medical Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China.
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11
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Tian R, Liu X, Xiao Y, Jing L, Tao H, Yang L, Meng X. Huang-Lian-Jie-Du decoction drug-containing serum inhibits IL-1β secretion from D-glucose and PA induced BV2 cells via autophagy/NLRP3 signaling. JOURNAL OF ETHNOPHARMACOLOGY 2024; 323:117686. [PMID: 38160864 DOI: 10.1016/j.jep.2023.117686] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/16/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huang-Lian-Jie-Du decoction (HLJDD), a famous traditional Chinese medicine prescription with heat-clearing and detoxifying effects, has been widely used to treat diabetes, dementia, stroke, and other diseases. However, the detailed mechanisms of HLJDD against type 2 diabetes associated cognitive dysfunction (DACD) through inhibiting interleukin-1β (IL-1β) mediated neuroinflammation remain to be further elucidated. AIM OF THE STUDY The aim of this study was to investigate the effect and potential mechanism of HLJDD on IL-1β secretion in a DACD model of BV2 cells induced by D-glucose and palmitic acid (PA). MATERIALS AND METHOD sUltra-performance liquid chromatography-quadrupole/electrostatic field orbital well high-resolution mass spectrometry technology was used to analyze the compounds in HLJDD drug-containing serum. The cytotoxicity was detected by cell counting kit-8. Enzyme-linked immunosorbent assay was used to measure the secretion of IL-1β in BV2 cells. Reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde kits were used to detect the intracellular oxidative stress levels. The autophagy level was determined by autophagy staining kit and transmission electron microscope. The expression levels of autophagy-related 7 (Atg7), P62, LC3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3(NLRP3), Caspase1, and IL-1β were detected by real-time PCR, immunofluorescence, and western blotting. The Atg7siRNA was transfected into BV2 cells to produce autophagy inhibitory effect. Then the effect of HLJDD drug-containing serum on IL-1β secretion in D-glucose and PA induced BV2 cells and the potential mechanism of autophagy-NLRP3 inflammasome activation were further observed. RESULTS Eighty-eight compounds were preliminarily identified in HLJDD drug-containing serum, among which geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid were identified as the main prototype components of HLJDD into the blood. In this study, the DACD model of BV2 cells induced by high concentrations of glucose and PA was successfully constructed. HLJDD drug-containing serum significantly reduced the secretion of IL-1β and the activity of NLRP3 inflammasome with improving the oxidative stress level. Interestingly, the enhanced autophagy level was also found. After transfection of Atg7siRNA into BV2 cells, the effect of HLJDD drug-containing serum on autophagy promotion was reversed, but the inhibitory effects on IL-1β secretion, NLRP3 inflammasome activation, and oxidative stress were reduced. CONCLUSIONS These results indicated that the inhibition of HLJDD drug-containing serum on the IL-1β secretion in D-glucose and PA induced BV2 cells was related to autophagy promotion, the decreased NLRP3 inflammasome activation, and the improved oxidative stress. Moreover, the improvement of HLJDD drug-containing serum on IL-1β secretion, NLRP3 inflammasome activation, and oxidative stress were all closely associated with Atg7 mediated autophagy promotion. Geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid may be the potential active ingredients of HLJDD drug-containing serum.
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Affiliation(s)
- Ruimin Tian
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Department of Pharmacology, North Sichuan Medical College, Nanchong, 637000, China
| | - Xianfeng Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yang Xiao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lijia Jing
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Honglin Tao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Lu Yang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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12
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Khezri MR, Mohammadipanah S, Ghasemnejad-Berenji M. The pharmacological effects of Berberine and its therapeutic potential in different diseases: Role of the phosphatidylinositol 3-kinase/AKT signaling pathway. Phytother Res 2024; 38:349-367. [PMID: 37922566 DOI: 10.1002/ptr.8040] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/15/2023] [Accepted: 09/30/2023] [Indexed: 11/07/2023]
Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases.
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Affiliation(s)
- Mohammad Rafi Khezri
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Morteza Ghasemnejad-Berenji
- Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
- Research Center for Experimental and Applied Pharmaceutical Sciences, Urmia University of Medical Sciences, Urmia, Iran
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13
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Gui Z, Wang J, Zhang Y, Wan B, Ke Z, Ren Z, Yang X, Lei M, Guo X, Liu X, Ouyang C, Wu N, Chen Q. Dapagliflozin improves diabetic cognitive impairment via indirectly modulating the mitochondria homeostasis of hippocampus in diabetic mice. Biofactors 2024; 50:145-160. [PMID: 37596888 DOI: 10.1002/biof.1998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/05/2023] [Indexed: 08/21/2023]
Abstract
Cognitive impairment is increasingly recognized as an important comorbidity of diabetes progression; however, the underlying molecular mechanism is unclear. Dapagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), has shown promising effects against diabetes in rodent experiments and human clinical assays. This study aimed to determine the underlying mechanism and examine the effect of dapagliflozin on diabetic cognitive impairment. To create an in vivo model of diabetic cognitive impairment, streptozotocin (STZ)-induced diabetic mice were used. Dapagliflozin was administered to mice for 8 weeks. The context fear condition and Morris water maze test was used to evaluate mice's behavioral change. Western blotting was used to evaluate protein expression. Hematoxylin and eosin (HE) and Nissl staining were applied to monitor morphological and structural changes. Congo red staining was performed to identify the formation of senile plaques. Mitochondria morphology was examined using a transmission electron microscope, and blood flow in the mouse cerebral cortex was measured using a laser Doppler imaging assay. Comparison to the diabetes mellitus (DM) group, the dapagliflozin group had lower glucose levels. Behavioral studies have shown that dapagliflozin can restore memory deficits in diabetic mice. The murky cell membrane edges and Nissl bodies more difficult to identify in the DM group were revealed by HE and Nissl staining, which were both improved by dapagliflozin treatment. Dapagliflozin inhibited the progression of Aβ generation and the reduced cerebral blood flow in the DM group was rescued. After dapagliflozin treatment, damaged mitochondria and lack of SGLT2 in the hippocampus and cortex of diabetic mice were repaired. Diabetes-induced cognitive dysfunction was attenuated by dapagliflozin and the effect was indirect rather than direct.
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Affiliation(s)
- Zichen Gui
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
- Hepatic Surgery Center; Hubei key laboratory of Hepato-Pancreato-Biliary Diseases; Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Jiawen Wang
- Xianning Central hospital, First Affiliated Hospital, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Yue Zhang
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Binbin Wan
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Zhiqiang Ke
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Zhanhong Ren
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Xiaosong Yang
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Xiying Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Changhan Ouyang
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Ninghua Wu
- School of Stomatology and Ophthalmology, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
- School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Medicine Research Institute, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
- School of Stomatology and Ophthalmology, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei, China
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14
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Zhang J, Song J, Li H, Li Z, Chen M, Ma S, Shen R, Lou X. Berberine protects against neomycin-induced ototoxicity by reducing ROS generation and activating the PI3K/AKT pathway. Neurosci Lett 2023; 817:137518. [PMID: 37844727 DOI: 10.1016/j.neulet.2023.137518] [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: 06/09/2023] [Revised: 10/09/2023] [Accepted: 10/11/2023] [Indexed: 10/18/2023]
Abstract
In mammals, aminoglycoside antibiotic-induced injury to hair cells (HCs) and associated spiral ganglion neurons (SGNs) is irreversible and eventually leads to permanent hearing loss. Efforts have been directed towards the advancement of efficacious therapeutic treatments to protect hearing loss, but the ideal substance for treating the damaged cochlear sensory epithelium has yet to be identified. Berberine (BBR), a quaternary ammonium hydroxide extracted from Coptis chinensis, has been found to display potential anti-oxidant and neuroprotective properties. However, its involvement in aminoglycoside antibiotic-induced ototoxicity has yet to be explored or assessed. In the present study, we explored the possible anti-oxidative properties of BBR in mitigating neomycin-triggered ototoxicity. An improved survival of HCs and SGN nerve fibers (NFs) in organ of Corti (OC) explants after neomycin with BBR co-treatment was observed, and BBR treatment attenuated reactive oxygen species (ROS) generation and reduced cleaved caspase-3 signaling by activating six phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling relative subtypes, and the addition of PI3K/AKT suppressor LY294002 resulted in a decrease in the protective effect. The protective effect of BBR against ototoxicity was also evident in a neomycin-injured animal model, as evidenced by the preservation of HC and SGN in mice administered subcutaneous BBR for 7 days. In summary, all results suggest that BBR has potential as a new and effective otoprotective agent, operating via the PI3K/AKT signaling pathway.
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Affiliation(s)
- Junming Zhang
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China
| | - Jianhao Song
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China
| | - Haobo Li
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China
| | - Zhaoxia Li
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China
| | - Mengyu Chen
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China
| | - Shutao Ma
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China
| | - Rong Shen
- Department of Geriatrics, Yueyang Hosptial of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Xiangxin Lou
- College of Biological Science and Medical Engineering, Donghua University, Shanghai, PR China.
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15
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Xiao Y, Li K, Bian J, Zhang Y, Li J, Liu H, Ye Y, Han L, Gong L, Wang M. Urolithin A Protects Neuronal Cells against Stress Damage and Apoptosis by Atp2a3 Inhibition. Mol Nutr Food Res 2023; 67:e2300146. [PMID: 37667442 DOI: 10.1002/mnfr.202300146] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/30/2023] [Indexed: 09/06/2023]
Abstract
SCOPE This study aims to investigate the effect and mechanism of Urolithin A (UA) on neuronal stress damage on cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high-fat diet (HFD) and streptozotocin (STZ). METHODS AND RESULTS T2DM mice fed with UA display an attenuated cognitive impairment along with suppressed endoplasmic reticulum (ER) stress and Tau hyperphosphorylation in brain. Similar restraint effect of UA on Tau hyperphosphorylation and ER stress is also observed in high glucose-treated primary hippocampal neurons. Moreover, UA ameliorates oxidative stress, ER stress, aberrant energy metabolism, and apoptosis in 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced HT22 cells. Atp2a3 is identified as a potential target gene of UA which is closely related to intracellular calcium homeostasis, ER stress, and apoptosis, so that UA significantly down-regulated Atp2a3 expression in DMNQ-induced cells. Furthermore, the protection effect of UA against ER stress and apoptosis is abolished by Atp2a3 over-expression in HT22 cells. Taken together, these data suggest that UA performs anti-stress effect by suppressing the expression of Atp2a3 in damaged neuronal cells and thus attenuates diabetes-associated cognitive impairment in T2DM mice. CONCLUSION The study implies UA as a potential novel pharmaceutic target for neurodegeneration and stress damage through regulating the expression of Atp2a3.
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Affiliation(s)
- Yao Xiao
- College of Food Science and Engineering, Northwest A & F University, Yangling, Shaanxi, 712100, P. R. China
- Department of Orthopaedics, Shanghai Jiao Tong University School of Medicine Affiliated Sixth People's Hospital, 600 Yishan Rd, Shanghai, 200233, P. R. China
| | - Kailin Li
- College of Food Science and Engineering, Northwest A & F University, Yangling, Shaanxi, 712100, P. R. China
| | - Ji Bian
- Kolling Institute, Sydney Medical School, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW, 2065, Australia
| | - Yao Zhang
- College of Food Science and Engineering, Northwest A & F University, Yangling, Shaanxi, 712100, P. R. China
| | - Jia Li
- College of Food Science and Engineering, Northwest A & F University, Yangling, Shaanxi, 712100, P. R. China
| | - Hang Liu
- Shanxi Institute for Functional Food, Shanxi Agricultural University, Taiyuan, Shanxi, 030031, P. R. China
| | - Yingzhi Ye
- Zhejiang Conba Pharmaceutical Co., Ltd, No. 1 Conba Avenue, Lanxi, Zhejiang, 321109, P. R. China
| | - Lin Han
- College of Food Science and Engineering, Northwest A & F University, Yangling, Shaanxi, 712100, P. R. China
| | - Lan Gong
- Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW 2052, Australia
| | - Min Wang
- College of Food Science and Engineering, Northwest A & F University, Yangling, Shaanxi, 712100, P. R. China
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16
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Feng JH, Chen K, Shen SY, Luo YF, Liu XH, Chen X, Gao W, Tong YR. The composition, pharmacological effects, related mechanisms and drug delivery of alkaloids from Corydalis yanhusuo. Biomed Pharmacother 2023; 167:115511. [PMID: 37729733 DOI: 10.1016/j.biopha.2023.115511] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/22/2023] Open
Abstract
Corydalis yanhusuo W. T. Wang, also known as yanhusuo, yuanhu, yanhu and xuanhu, is one of the herb components of many Chinese Traditional Medicine prescriptions such as Jin Ling Zi San and Yuanhu-Zhitong priscription. C. yanhusuo was traditionally used to relieve pain and motivate blood and Qi circulation. Now there has been growing interest in pharmacological effects of alkaloids, the main bioactive components of C. yanhusuo. Eighty-four alkaloids isolated from C. yanhusuo are its important bioactive components and can be characterized into protoberberine alkaloids, aporphine alkaloids, opiate alkaloids and others and proper extraction or co-administration methods modulate their contents and efficacy. Alkaloids from C. yanhusuo have various pharmacological effects on the nervous system, cardiovascular system, cancer and others through multiple molecular mechanisms such as modulating neurotransmitters, ion channels, gut microbiota, HPA axis and signaling pathways and are potential treatments for many diseases. Plenty of novel drug delivery methods such as autologous red blood cells, self-microemulsifying drug delivery systems, nanoparticles and others have also been investigated to better exert the effects of alkaloids from C. yanhusuo. This review summarized the alkaloid components of C. yanhusuo, their pharmacological effects and mechanisms, and methods of drug delivery to lay a foundation for future investigations.
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Affiliation(s)
- Jia-Hua Feng
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Kang Chen
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Si-Yu Shen
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Yun-Feng Luo
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Xi-Hong Liu
- School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xin Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Wei Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, China
| | - Yu-Ru Tong
- School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
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17
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Cukier HN, Duarte CL, Laverde-Paz MJ, Simon SA, Van Booven DJ, Miyares AT, Whitehead PL, Hamilton-Nelson KL, Adams LD, Carney RM, Cuccaro ML, Vance JM, Pericak-Vance MA, Griswold AJ, Dykxhoorn DM. An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons. Neurobiol Aging 2023; 131:182-195. [PMID: 37677864 PMCID: PMC10538380 DOI: 10.1016/j.neurobiolaging.2023.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/11/2023] [Indexed: 09/09/2023]
Abstract
A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with late-onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing, and the resulting isogenic pair of iPSC lines was differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3-dimensional morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant.
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Affiliation(s)
- Holly N Cukier
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Carolina L Duarte
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Mayra J Laverde-Paz
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Shaina A Simon
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Derek J Van Booven
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Amanda T Miyares
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; JJ Vance Memorial Summer Internship in Biological and Computational Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Patrice L Whitehead
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kara L Hamilton-Nelson
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Larry D Adams
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Regina M Carney
- Mental Health & Behavioral Science Service, Bruce W. Carter VA Medical Center, Miami, FL, USA
| | - Michael L Cuccaro
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jeffery M Vance
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Margaret A Pericak-Vance
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anthony J Griswold
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Derek M Dykxhoorn
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
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An JR, Wang QF, Sun GY, Su JN, Liu JT, Zhang C, Wang L, Teng D, Yang YF, Shi Y. The Role of Iron Overload in Diabetic Cognitive Impairment: A Review. Diabetes Metab Syndr Obes 2023; 16:3235-3247. [PMID: 37872972 PMCID: PMC10590583 DOI: 10.2147/dmso.s432858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/29/2023] [Indexed: 10/25/2023] Open
Abstract
It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.
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Affiliation(s)
- Ji-Ren An
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
- College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, People’s Republic of China
| | - Qing-Feng Wang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Gui-Yan Sun
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Jia-Nan Su
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Jun-Tong Liu
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Chi Zhang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Li Wang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Dan Teng
- He University, Shenyang, 110163, People’s Republic of China
| | - Yu-Feng Yang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Yan Shi
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
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Li LF, Gao Y, Xu Y, Su DJ, Yang Q, Liu A, Wang SY, Tang XL, Zhao J, Luo L, Yan T, Wu YM, Liu SB, Zhao MG, Yang L. Praeruptorin C alleviates cognitive impairment in type 2 diabetic mice through restoring PI3K/AKT/GSK3β pathway. Phytother Res 2023; 37:4838-4850. [PMID: 37458182 DOI: 10.1002/ptr.7949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 10/18/2023]
Abstract
Diabetic encephalopathy is a common consequence of diabetes mellitus that causes cognitive dysfunction and neuropsychiatric disorders. Praeruptorin C (Pra-C) from the traditional Chinese medicinal herb Peucedanum praeruptorum Dunn. is a potential antioxidant and neuroprotective agent. This study was conducted to investigate the molecular mechanisms underlying the effect of Pra-C on diabetic cognitive impairment. A novel object recognition test and the Morris water maze test were performed to assess the behavioral performance of mice. Electrophysiological recordings were made to monitor synaptic plasticity in the hippocampus. A protein-protein interaction network of putative Pra-C targets was constructed, and molecular docking simulations were performed to predict the potential mechanisms of the action of Pra-C. Protein expression levels were detected by western blotting. Pra-C administration significantly lowered body weight and fasting blood glucose levels and alleviated learning and memory deficits in type 2 diabetic mice. Network pharmacology and molecular docking results suggested that Pra-C affects the PI3K/AKT/GSK3β signaling pathway. Western blot analysis confirmed significant increases in phosphorylated PI3K, AKT, and GSK3β levels in vivo and in vitro upon Pra-C administration. Pra-C alleviated cognitive impairment in type 2 diabetic mice by activating PI3K/AKT/GSK3β pathway.
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Affiliation(s)
- Long-Fei Li
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Ying Gao
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Yuan Xu
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Dan-Jie Su
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Qi Yang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - An Liu
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Sai-Ying Wang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Xiu-Ling Tang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Jun Zhao
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Li Luo
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Tao Yan
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Yu-Mei Wu
- Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, China
| | - Shui-Bing Liu
- Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi'an, China
| | - Ming-Gao Zhao
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
| | - Le Yang
- Precision Pharmacy & Drug Development Center, Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China
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Hu Y, Xu J, Wang J, Zhu L, Wang J, Zhang Q. DPP-4 Inhibitors Suppress Tau Phosphorylation and Promote Neuron Autophagy through the AMPK/mTOR Pathway to Ameliorate Cognitive Dysfunction in Diabetic Mellitus. ACS Chem Neurosci 2023; 14:3335-3346. [PMID: 37655714 DOI: 10.1021/acschemneuro.2c00733] [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] [Indexed: 09/02/2023] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been considered as incretin-based agents that signal through GLP-1R. Our high-throughput RNA sequencing (RNA-seq) and bioinformatics methods indicated that GLP-1R, downregulated in diabetes mellitus (DM), was a potential target of DPP-4 inhibitors, which was further confirmed in DM rats. Thus, this study illuminated the alleviatory mechanism of DPP-4 on cognitive dysfunction in diabetes mellitus (DM), which may be associated with GLP-1R signaling. DM rats were administered with DPP-4 inhibitors, Chloroquine (an autophagy inhibitor), Exendin 9-39 (a GLP-1R antagonist), or Compound C (a specific inhibitor of AMPK). An in vitro model of DM was induced in rat hippocampal neuronal cell line H19-7 by exposure to high glucose (HG) and high fat (HF), followed by treatment with the above inhibitors and antagonists. It was found that cognitive dysfunction was promoted, and LC3 expression was lowered in DM rats by an autophagy inhibitor. The DPP-4 inhibitors decreased cognitive dysfunction, repressed Tau phosphorylation, and enhanced GLP-1R protein level, LC3 expression, and AMPK and mTOR phosphorylation in DM rats, while GLP-1R antagonist, an autophagy inhibitor, or AMPK inhibitor counteracted these effects. Such effects were also observed in HG/HF-induced neurons. In conclusion, our data elucidated the alleviatory mechanism of DPP-4 inhibitors in the cognitive dysfunction of DM rats via the AMPK/mTOR pathway.
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Affiliation(s)
- Ying Hu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
| | - Jiancheng Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
| | - Lingyan Zhu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
| | - Jiao Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang 330006, Jiangxi Province, P. R. China
| | - Qin Zhang
- Department of Anesthesiology and Operative Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, P. R. China
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Cao DM, Liang QF, Zhang ZT, He WJ, Tang D. Combination of UHPLC-Q Exactive-Orbitrap MS, Bioinformatics and Molecular Docking to Reveal the Mechanism of Huan-Lian-Jie-Du Decoction in the Treatment of Diabetic Encephalopathy. Chem Biodivers 2023; 20:e202300434. [PMID: 37486314 DOI: 10.1002/cbdv.202300434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 07/25/2023]
Abstract
Diabetic encephalopathy (DE) is a serious complication of diabetes, which affects patients' quality of life. We aimed to explore HLJDD in the treatment of DE by LC/MS and bioinformatics. UPLC-Q Exactive-Orbitrap MS was employed to clarify the compounds. The modules and hub targets of DE were gained from WGCNA. Subsequently, an Herb-Compound-Target network was constructed and enrichment analysis was used. In addition, a protein-protein interaction (PPI) network was constructed and molecular docking was used to verify the above analysis. As result, 138 compounds and 10 prototypes in brain were identified. In network pharmacology, 8 modules and 5692 hub targets were obtained from WGCNA. An Herb-Compound-Target network was constructed by 4 herbs, 10 compounds and 56 targets. The enrichment analysis showed that the treatment of DE with HLJDD involve oxidative stress and neuroprotection. Beside, SRC, JUN, STAT3, MAPK1 and PIK3R1 were identified and as hub targets of HLJDD in treating DE. Moreover, Molecular docking showed that five hub targets had strong affinity with the corresponding alkaloids. Therefore, we explored the underlying mechanisms of HLJDD in the treatment of DE and to provide the theoretical and scientific basis for subsequent experimental studies and clinical applications.
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Affiliation(s)
- Dong-Min Cao
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering and Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangdong, 510006, China
- Translational Medicine Research Institute, First People's Hospital of, Foshan, Guangdong, 528000, China
| | - Qing-Feng Liang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering and Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangdong, 510006, China
| | - Zhi-Tong Zhang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering and Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangdong, 510006, China
| | - Wen-Jiao He
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering and Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangdong, 510006, China
| | - Dan Tang
- Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM and Engineering and Technology Research Center for Chinese Materia Medica Quality of Guangdong Province, Guangdong Pharmaceutical University, Guangdong, 510006, China
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Wang XH, Zuo ZF, Meng L, Yang Q, Lv P, Zhao LP, Wang XB, Wang YF, Huang Y, Fu C, Liu WQ, Liu XZ, Zheng DY. Neuroprotective effect of salidroside on hippocampal neurons in diabetic mice via PI3K/Akt/GSK-3β signaling pathway. Psychopharmacology (Berl) 2023; 240:1865-1876. [PMID: 37490132 DOI: 10.1007/s00213-023-06373-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 12/08/2022] [Indexed: 07/26/2023]
Abstract
BACKGROUND Diabetic encephalopathy is manifested by cognitive dysfunction. Salidroside, a nature compound isolated from Rhodiola rosea L, has the effects of anti-inflammatory and antioxidant, hypoglycemic and lipid-lowering, improving insulin resistance, inhibiting cell apoptosis, and protecting neurons. However, the mechanism by which salidroside alleviates neuronal degeneration and improves learning and memory impairment in diabetic mice remains unclear. OBJECTIVE To investigate the effects and mechanisms of salidroside on hippocampal neurons in streptozotocin-induced diabetic mice. MATERIALS AND METHODS C57BL/6 mice were randomly divided into 4 groups to receive either sham (control group (CON)), diabetes mellitus (diabetes group (DM)), diabetes mellitus + salidroside (salidroside group (DM + SAL)), and diabetes mellitus + salidroside + phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (diabetes mellitus + salidroside + LY294002 group (DM + SAL + LY294002)). After 12 weeks of diabetes onset, the cognitive behaviors were tested using Morris water maze. The number of hippocampal neurons was detected by Nissl staining. The expressions of PI3K, p-PI3K, Akt, p-Akt, GSK-3β, p-GSK-3β, cleaved caspase-3, caspase-3, Bax, Bcl-2, MAP2, and SYN in the hippocampus were detected by Western blot. Moreover, the expression of MAP2 and SYN in the hippocampus was further confirmed by immunofluorescence staining. RESULTS Salidroside increased the time of diabetic mice in the platform quadrant and reduced the escape latency of diabetic mice. Salidroside also increased the expression of p-PI3K, p-Akt, p-GSK-3β, MAP2, SYN, Bcl-2, while suppressed the expression of cleaved caspase-3, caspase3, and Bax in the DM + SAL group compared with the DM group (P < 0.05). The Nissl staining showed that the number of hippocampus neurons in the DM + SAL group was increased with the intact, compact, and regular arrangement, compared with the DM groups (P < 0.05). Interestingly, the protective effects of salidroside on diabetic cognitive dysfunction, hippocampal morphological alterations, and protein expressions were abolished by inhibition of PI3K with LY294002. CONCLUSIONS Salidroside exerts neuroprotective properties in diabetic cognitive dysfunction partly via activating the PI3K/Akt/GSK-3β signaling pathway.
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Affiliation(s)
- Xue-Hua Wang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Zhong-Fu Zuo
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- Department of Anatomy, Histology and Embryology, Postdoctoral Research Station, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lu Meng
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Qi Yang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Pan Lv
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Li-Pan Zhao
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Xiao-Bai Wang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Yu-Fei Wang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Ying Huang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Cong Fu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Wen-Qiang Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Xue-Zheng Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
| | - De-Yu Zheng
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
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Guo X, Lei M, Zhao J, Wu M, Ren Z, Yang X, Ouyang C, Liu X, Liu C, Chen Q. Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats. Front Pharmacol 2023; 14:1146960. [PMID: 37701028 PMCID: PMC10493299 DOI: 10.3389/fphar.2023.1146960] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 08/14/2023] [Indexed: 09/14/2023] Open
Abstract
Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes's impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.
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Affiliation(s)
- Xiying Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Min Lei
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Jiangyan Zhao
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Min Wu
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Zhanhong Ren
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Xiaosong Yang
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Changhan Ouyang
- Pharmacy College, Xianning Medical College, Hubei University of Science and Technology, Xianning, China
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Xianning Medical College, Medical Research Institute, Hubei University of Science and Technology, Xianning, China
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Cukier HN, Duarte CL, Laverde-Paz MJ, Simon SA, Van Booven DJ, Miyares AT, Whitehead PL, Hamilton-Nelson KL, Adams LD, Carney RM, Cuccaro ML, Vance JM, Pericak-Vance MA, Griswold AJ, Dykxhoorn DM. An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.25.542316. [PMID: 37292815 PMCID: PMC10246004 DOI: 10.1101/2023.05.25.542316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
A missense variant in the tetratricopeptide repeat domain 3 ( TTC3 ) gene (rs377155188, p.S1038C, NM_003316.4:c.3113C>G) was found to segregate with disease in a multigenerational family with late onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing and the resulting isogenic pair of iPSC lines were differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3D morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant. Highlights The AD risk variant TTC3 p.S1038C reduces the expression levels of TTC3 The variant modifies the expression of AD specific genes BACE1 , INPP5F , and UNC5C Neurons with the variant are enriched for genes in the PI3K-Akt pathwayiPSC-derived neurons with the alteration have increased neurite length and branchingThe variant interferes with actin cytoskeleton and is ameliorated by Cytochalasin D.
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Huang R, Wang B, He J, Zhang Z, Xie R, Li S, Li Q, Tian C, Tuo Y, Zheng R, Chen W, Xiang M. Lian-Qu formula treats metabolic syndrome via reducing fat synthesis, insulin resistance and inflammation. JOURNAL OF ETHNOPHARMACOLOGY 2023; 306:116060. [PMID: 36535333 DOI: 10.1016/j.jep.2022.116060] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/08/2022] [Accepted: 12/14/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Metabolic syndrome (MetS) is a pathological condition characterized by obesity, hyperglycemia, hypertension and hyperlipidemia that increases the risk of cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease. The traditional Chinese medicine Lian-Qu formula (LQF) is modified from Xiaoxianxiong decoction, which has been used for coronary heart disease or metabolic disease in clinical for a long time. However, the pharmacological mechanism of LQF on MetS is unclear. AIM OF THE STUDY Here, we explored the actions of LQF on MetS via network pharmacology and validated the mechanism in the MetS mice. MATERIALS AND METHODS The chemical components of LQF were searched in the traditional Chinese medicine systems pharmacology database and the natural product activity & species source database. The related targets of MetS disease were gathered from genes cluster with literature profiles database. The protein-protein interaction network was constructed to obtain the key target genes. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment of the key targets were performed to predict the potential mechanisms of LQF action on MetS. And then, the high-fat diet-induced MetS mice were used to validate its therapeutic effect and molecular targets. Insulin tolerance test and oral glucose tolerance test were used to assess insulin sensitivity. Body weight and visceral fat index were measured to assess obesity. Liver metabolism was detected by H&E section, oil red O staining and untargeted lipid metabolomics experiments. Finally, the key targets of LQF action on MetS were verified by PCR and ELISA kits. RESULTS A total of 466 components in LQF were obtained, among which 71 were active. These components correspond to 74 targets associated with MetS. The predicted targets of LQF worked on MetS were AKT1, INSR, PPARs, FASN, LDLR, TNF, CRP, IL-6, IL-1β and so on. Furthermore, these targets were related to pathways in cellular response to lipid, inflammatory response, glucose transmembrane transport and insulin resistance. Finally, the animal experiments validated that LQF inhibited lipids accumulation by inhibiting the gene expression of FASN and increasing ADPN, and it relieved insulin resistance by increasing GLUT-4 expression. Moreover, LQF alleviated inflammation by reducing IL-6 and CRP levels. CONCLUSION LQF exerted anti-MetS effects through improving insulin sensitivity, ameliorating hyperlipidemia and obesity, reducing liver injury, and inhibiting inflammatory response.
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Affiliation(s)
- Rongrong Huang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Pharmacy, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baotian Wang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jialuo He
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zijun Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Xie
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Senlin Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Tian
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yali Tuo
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Clinical Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Zheng
- National Engineering Research Center for Big Data Technology and System Services Computing Technology and System Lab, Cluster and Grid Computing Lab, School of Computer Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
| | - Weihong Chen
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ming Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Zhang RL, Lei BX, Wu GY, Wang YY, Huang QH. Protective effects of berberine against β-amyloid-induced neurotoxicity in HT22 cells via the Nrf2/HO-1 pathway. Bioorg Chem 2023; 133:106210. [PMID: 36724611 DOI: 10.1016/j.bioorg.2022.106210] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 09/21/2022] [Accepted: 10/11/2022] [Indexed: 02/03/2023]
Abstract
Neuronal apoptosis has been found to have a pivotal role in the course of Alzheimer's disease (AD). Berberine (BBR), a potent antioxidant, occurs in plants such as Berberis, Phellodendron chinense, and Hydrastis canadensis. In this study, a neuronal apoptotic model was established in vitro using HT22 cells induced by Aβ25-35 to explore whether BBR contributes to protecting neurons against Aβ25-35-induced neurotoxicity, as well as its potential mechanisms. BBR was applied to HT22 cells for 1 h prior to exposing the cells to Aβ25-35 for 24 h. A CCK-8 assay was utilized to assess cell viability, and Annexin V - fluorescein isothiocyanate (FITC)/propidium iodide and Hoechst 33342 fluorescence staining were used to measure the rate of cell apoptosis. Existing scientific literature was also reviewed to further determine the effects of BBR on ROS production and mitochondrial function in HT22 cells. Furthermore, the expressions of proteins, including cytochrome C, cleaved caspase-3, p-p65, p65, and Nrf2/HO-1 antioxidant axis were assessed by Western blotting. The data indicated that BBR markedly improved cell viability, inhibited apoptosis and intracellular ROS levels, improved mitochondrial membrane potentials, decreased the rate of p-p65/p65, cytochrome C, and cleaved caspase-3, and intensified the activity of Nrf2/HO-1 antioxidants in HT22 cells. Overall, the findings indicated that BBR provides a certain level of neuroprotectiveness in HT22 cells exposed to Aβ25-35 via relieving oxidative stress, as well as by restraining the mitochondrial pathway of cellular apoptosis. In addition, the restraint of NF-κB activity and sensitization of the Nrf2/HO-1 antioxidant axis, which together are intimately involved in the neuroprotection of BBR, may be possible mechanisms accounting for its effectiveness against Aβ25-35in vitro.
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Affiliation(s)
- Ru-Lan Zhang
- Department of Chinese Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, China
| | - Bing-Xi Lei
- Department of Neurosurgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China
| | - Guo-Yong Wu
- Department of Thoracic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, China
| | - Yuan-Yuan Wang
- Department of Chinese Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, China
| | - Qi-Hui Huang
- Department of Chinese Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China.
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Huang J, Huang N, Mao Q, Shi J, Qiu Y. Natural bioactive compounds in Alzheimer's disease: From the perspective of type 3 diabetes mellitus. Front Aging Neurosci 2023; 15:1130253. [PMID: 37009462 PMCID: PMC10062602 DOI: 10.3389/fnagi.2023.1130253] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/20/2023] [Indexed: 03/18/2023] Open
Abstract
There is a close relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the link between the two is often referred to as type 3 diabetes mellitus (T3DM). Many natural bioactive compounds have shown the potential to treat AD and diabetes. We mainly review the polyphenols represented by resveratrol (RES) and proanthocyanidins (PCs) and alkaloids represented by berberine (BBR) and Dendrobium nobile Lindl. alkaloids (DNLA) from the perspective of T3DM to review the neuroprotective effects and molecular mechanisms of natural compounds in AD.
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Affiliation(s)
- Juan Huang
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
- School of Public Health, Zunyi Medical University, Zunyi, Guizhou, China
| | - Nanqu Huang
- National Drug Clinical Trial Institution, Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, Guizhou, China
| | - Qianhua Mao
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jingshan Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
- Jingshan Shi
| | - Yu Qiu
- Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Yu Qiu
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Yao J, Wei W, Wen J, Cao Y, Li H. The efficacy and mechanism of berberine in improving aging-related cognitive dysfunction: A study based on network pharmacology. Front Neurosci 2023; 17:1093180. [PMID: 36743801 PMCID: PMC9895386 DOI: 10.3389/fnins.2023.1093180] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/06/2023] [Indexed: 01/21/2023] Open
Abstract
Objective To analyze the effects and mechanisms of berberine in the treatment of aging-related cognitive dysfunction based on network pharmacology methods, molecular docking techniques, and animal experiments. Methods A mouse model of cognitive dysfunction was constructed by subcutaneous injection of D-galactose (D-gal) for 10 weeks, and the neuroprotective effects of berberine on aging-related cognitive dysfunction mice were evaluated by the Morris water maze (MWM) and immunofluorescence staining. The targets of berberine were obtained by SwissTargetPrediction, GeneCards, and PharmMapper. Putative targets of cognitive dysfunction were obtained by GeneCards, TTD, and DrugBank database. The STRING database and Cytoscape software were applied for protein-protein interaction (PPI) analysis and further screening of core targets. The DAVID database was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis to clarify the biological processes and pathways involved in the intersection targets, and AutoDockTools was adopted for molecular docking verification of core targets. Finally, the core genes were validated using real-time quantitative PCR. Results The MWM results showed that treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal. Immunofluorescence staining indicated that berberine modified the levels of aging-related markers in the brain. A total of 386 berberine putative targets associated with cognitive dysfunction were identified based on the public database. The core targets of berberine for improving cognitive function, include Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1. GO enrichment and KEGG pathway enrichment analyses indicated that the mechanism of berberine in the treatment of aging-related cognitive dysfunction is attributed to pathways such as PI3K-AKT and MAPK pathways. In vivo experiments further confirmed that Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine. Conclusion This study reveals the multi-target and multi-pathway effects of berberine on regulating aging-related cognitive dysfunction, which provides preclinical evidence and may promote new drug development in mitigating cognitive dysfunction.
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Affiliation(s)
- Jiuxiu Yao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wei Wei
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiayu Wen
- Graduate College, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Cao
- Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,*Correspondence: Yu Cao,
| | - Hao Li
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China,Hao Li,
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Malik J, Mandal SC, Choudhary S, Parihar S, Rahamathulla M. Herbal Medicines for Management of Alzheimer’s Disease. ROLE OF HERBAL MEDICINES 2023:231-250. [DOI: 10.1007/978-981-99-7703-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Deng C, Chen H, Meng Z, Meng S. Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment. Front Endocrinol (Lausanne) 2022; 13:955618. [PMID: 36213283 PMCID: PMC9533021 DOI: 10.3389/fendo.2022.955618] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/01/2022] [Indexed: 11/20/2022] Open
Abstract
The incidence of sporadic Alzheimer's disease (AD) is increasing in recent years. Studies have shown that in addition to some genetic abnormalities, the majority of AD patients has a history of long-term exposure to risk factors. Neuroendocrine related risk factors have been proved to be strongly associated with AD. Long-term hormone disorder can have a direct detrimental effect on the brain by producing an AD-like pathology and result in cognitive decline by impairing neuronal metabolism, plasticity and survival. Traditional Chinese Medicine(TCM) may regulate the complex process of endocrine disorders, and improve metabolic abnormalities, as well as the resulting neuroinflammation and oxidative damage through a variety of pathways. TCM has unique therapeutic advantages in treating early intervention of AD-related neuroendocrine disorders and preventing cognitive decline. This paper reviewed the relationship between neuroendocrine and AD as well as the related TCM treatment and its mechanism. The advantages of TCM intervention on endocrine disorders and some pending problems was also discussed, and new insights for TCM treatment of dementia in the future was provided.
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Affiliation(s)
- Chujun Deng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Huize Chen
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Zeyu Meng
- The Second Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shengxi Meng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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Feng H, Xue M, Deng H, Cheng S, Hu Y, Zhou C. Ginsenoside and Its Therapeutic Potential for Cognitive Impairment. Biomolecules 2022; 12:1310. [PMID: 36139149 PMCID: PMC9496100 DOI: 10.3390/biom12091310] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Cognitive impairment (CI) is one of the major clinical features of many neurodegenerative diseases. It can be aging-related or even appear in non-central nerve system (CNS) diseases. CI has a wide spectrum that ranges from the cognitive complaint with normal screening tests to mild CI and, at its end, dementia. Ginsenosides, agents extracted from a key Chinese herbal medicine (ginseng), show great promise as a new therapeutic option for treating CI. This review covered both clinical trials and preclinical studies to summarize the possible mechanisms of how ginsenosides affect CI in different diseases. It shows that ginsenosides can modulate signaling pathways associated with oxidative stress, apoptosis, inflammation, synaptic plasticity, and neurogenesis. The involved signaling pathways mainly include the PI3K/Akt, CREB/BDNF, Keap1/Nrf2 signaling, and NF-κB/NLRP3 inflammasome pathways. We hope to provide a theoretical basis for the treatment of CI for related diseases by ginsenosides.
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Affiliation(s)
- Hui Feng
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
| | - Mei Xue
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
| | - Hao Deng
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300073, China
| | - Shiqi Cheng
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang 330008, China
| | - Yue Hu
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
| | - Chunxiang Zhou
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210024, China
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Jingxuan L, Litian M, Yanyang T, Jianfang F. Knockdown of CLC-3 may improve cognitive impairment caused by diabetic encephalopathy. Diabetes Res Clin Pract 2022; 190:109970. [PMID: 35792204 DOI: 10.1016/j.diabres.2022.109970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 06/05/2022] [Accepted: 06/16/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Diabetic encephalopathy(DE) is a neurological complication of diabetes, and its pathogenesis is unclear. Current studies indicate that insulin receptors and downstream signaling pathways play a key role in the occurrence and development of DE. Additionally, CLC-3, a member of the CLC family of anion channels and transporters, is closely related to the secretion and processing of insulin. Here, we investigated the changes and putative roles of CLC-3 in diabetic encephalopathy. RESULTS To this aim, we combined lentivirus and adeno-associated virus gene transfer to change the expression level of CLC-3 in the HT-22 hippocampal cell line and hippocampal CA1. We studied the role of CLC-3 in DE through the Morris water maze test.CLC-3 expression increased significantly in HT-22 cells cultured with high glucose and STZ-induced DE model hippocampus. Moreover, Insulin receptor(IR) and downstream PI3K/AKT/GSK3β signaling pathways were also dysfunctional. After knocking down CLC-3, impaired cell proliferation, apoptosis, IR and the downstream PI3K/AKT/GSK3β signaling pathways were significantly improved. However, when CLC-3 was overexpressed, the neurotoxicity induced by high glucose was further aggravated. Rescue experiments found that through the use of inhibitors such as GSK3β, the PI3K/AKT/GSK3β signaling pathways pathway changes with the use of inhibition, and the expression of related downstream signaling molecules such as Tau and p-Tau also changes accordingly. Using adeno-associated virus gene transfer to knock down CLC-3 in the hippocampal CA1 of the DE model, the IR caused by DE and the dysfunction of the downstream PI3K/AKT/GSK3β signaling pathway were significantly improved. In addition, the impaired spatial recognition of DE was partially restored. CONCLUSION Our study proposes that CLC-3, as a key molecule, may regulate insulin receptor signaling and downstream PI3K/AKT/GSK3β signaling pathways and affect the pathogenesis of diabetic encephalopathy.
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Affiliation(s)
- Lian Jingxuan
- Department of Endocrinology, Xijing Hospital, The Air Force Medical University, Xi'an 710032, China
| | - Ma Litian
- Department of Gastroenterology, Tangdu Hospital, The Air Force Medical University, Xi'an 710038, China
| | - Tu Yanyang
- The Air Force Medical University, Xi'an 710032, China.
| | - Fu Jianfang
- Department of Endocrinology, Xijing Hospital, The Air Force Medical University, Xi'an 710032, China.
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PINK1 overexpression prevents forskolin-induced tau hyperphosphorylation and oxidative stress in a rat model of Alzheimer's disease. Acta Pharmacol Sin 2022; 43:1916-1927. [PMID: 34893682 PMCID: PMC9343460 DOI: 10.1038/s41401-021-00810-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/18/2022]
Abstract
PTEN-induced putative kinase 1 (PINK1)/parkin pathway mediates mitophagy, which is a specialized form of autophagy. Evidence shows that PINK1 can exert protective effects against stress-induced neuronal cell death. In the present study we investigated the effects of PINK1 overexpression on tau hyperphosphorylation, mitochondrial dysfunction and oxidative stress in a specific rat model of tau hyperphosphorylation. We showed that intracerebroventricular (ICV) microinjection of forskolin (FSK, 80 μmol) induced tau hyperphosphorylation in the rat brain and resulted in significant spatial working memory impairments in Y-maze test, accompanied by synaptic dysfunction (reduced expression of synaptic proteins synaptophysin and postsynaptic density protein 95), and neuronal loss in the hippocampus. Adeno-associated virus (AAV)-mediated overexpression of PINK1 prevented ICV-FSK-induced cognition defect and pathological alterations in the hippocampus, whereas PINK1-knockout significantly exacerbated ICV-FSK-induced deteriorated effects. Furthermore, we revealed that AAV-PINK1-mediated overexpression of PINK1 alleviated ICV-FSK-induced tau hyperphosphorylation by restoring the activity of PI3K/Akt/GSK3β signaling. PINK1 overexpression reversed the abnormal changes in mitochondrial dynamics, defective mitophagy, and decreased ATP levels in the hippocampus. Moreover, PINK1 overexpression activated Nrf2 signaling, thereby increasing the expression of antioxidant proteins and reducing oxidative damage. These results suggest that PINK1 deficiency exacerbates FSK-induced tau pathology, synaptic damage, mitochondrial dysfunction, and antioxidant system defects, which were reversed by PINK1 overexpression. Our data support a critical role of PINK1-mediated mitophagy in controlling mitochondrial quality, tau hyperphosphorylation, and oxidative stress in a rat model of Alzheimer's disease.
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Yang M, Wang J. Berberine Ameliorates Cognitive Disorder via GSK3β/PGC-1α Signaling in APP/PS1 Mice. J Nutr Sci Vitaminol (Tokyo) 2022; 68:228-235. [PMID: 35768254 DOI: 10.3177/jnsv.68.228] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Previous studies have revealed that Berberine (BBR) had therapeutic effects on Alzheimer's disease (AD). However, the underlying mechanism of BBR in the treatment of AD is unclear. The study was to investigate whether berberine ameliorates cognitive disorder in AD by regulating on GSK3β/PGC-1α signaling pathway. APP/PS1 mice were treated with BBR (50 mg/kg and 100 mg/kg) for 4 mo, and the cognitive function of mice was tested by Morris water maze. The levels of inflammatory cytokines IL-1β, TNF-α, and IL-6 in hippocampus of mice were detected by ELISA kits. The damage of neuronal in hippocampal CA1 was detected by Nissl staining. The tau and GSK3β protein were detected by western blot. The results showed that BBR treatment obviously improved spatial cognitive function of APP/PS1 mice. Meanwhile, the pro-inflammatory cytokines were decreased in hippocampus by the administration of BBR. Additionally, BBR significantly alleviated neuronal damage and reduced the levels of hyperphosphorylated tau at sites of Thr205 and Thr231 in hippocampus. Importantly, BBR inhibited the activity of GSK3β and increased the expression of PGC-1α. Consequently, our results demonstrates that BBR could improve the cognitive function by inhibiting the tau hyperphosphorylation and neuroinflammation. These beneficial effects of BBR may be attributed to the regulation of GSK3β/PGC-1α signaling pathway in APP/PS1 mice. These findings reveal a vital role for GSK3β/PGC-1α signaling pathway in retarding cognitive disorder, indicating that PGC-1α might be a potential target for the treatment of AD.
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Affiliation(s)
- Meng Yang
- College of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College
| | - Jing Wang
- College of Pharmaceutical Engineering, Jiangsu Food & Pharmaceutical Science College
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Ye XW, Wang HL, Cheng SQ, Xia LJ, Xu XF, Li XR. Network Pharmacology-Based Strategy to Investigate the Pharmacologic Mechanisms of Coptidis Rhizoma for the Treatment of Alzheimer's Disease. Front Aging Neurosci 2022; 14:890046. [PMID: 35795239 PMCID: PMC9252849 DOI: 10.3389/fnagi.2022.890046] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022] Open
Abstract
BackgroundAlzheimer's disease (AD) is becoming a more prevalent public health issue in today's culture. The experimental study of Coptidis Rhizoma (CR) and its chemical components in AD treatment has been widely reported, but the principle of multi-level and multi-mechanism treatment of AD urgently needs to be clarified.ObjectiveThis study focuses on network pharmacology to clarify the mechanism of CR's multi-target impact on Alzheimer's disease.MethodsThe Phytochemical-compounds of CR have been accessed from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) and Symmap database or HPLC determination. The values of Oral Bioavailability (OB) ≥ 30% and Drug Like (DL) ≥ 0.18 or blood ingredient were used to screen the active components of CR; the interactive network of targets and compounds were constructed by STRING and Cytoscape platform, and the network was analyzed by Molecular Complex Detection (MCODE); Gene Ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) and metabolic pathway enrichment of targets were carried out with Metascape, the Database for Annotation, Visualization and Integrated Discovery (DAVID) and MetaboAnalyst platform; Based on CytoHubba, the potential efficient targets were screened by Maximal Clique Centrality (MCC) and Degree, the correlation between potential efficient targets and amyloid β-protein (Aβ), Tau pathology was analyzed by Alzdata database, and the genes related to aging were analyzed by Aging Altas database, and finally, the core targets were obtained; the binding ability between ingredients and core targets evaluated by molecular docking, and the clinical significance of core targets was assessed with Gene Expression Omnibus (GEO) database.Results19 active components correspond to 267 therapeutic targets for AD, of which 69 is potentially effective; in module analysis, RELA, TRAF2, STAT3, and so on are the critical targets of each module; among the six core targets, RELA, MAPK8, STAT3, and TGFB1 have clinical therapeutic significance; GO function, including 3050 biological processes (BP), 257 molecular functions (MF), 184 cellular components (CC), whose functions are mainly related to antioxidation, regulation of apoptosis and cell composition; the HIF-1 signaling pathway, glutathione metabolism is the most significant result of 134 KEGG signal pathways and four metabolic pathways, respectively; most of the active components have an excellent affinity in docking with critical targets.ConclusionThe pharmacological target prediction of CR based on molecular network pharmacology paves the way for a multi-level networking strategy. The study of CR in AD treatment shows a bright prospect for curing neurodegenerative diseases.
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Affiliation(s)
- Xian-wen Ye
- Centre of TCM Processing Research, Beijing University of Chinese Medicine, Beijing, China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Hai-li Wang
- Centre of TCM Processing Research, Beijing University of Chinese Medicine, Beijing, China
| | - Shui-qing Cheng
- Centre of TCM Processing Research, Beijing University of Chinese Medicine, Beijing, China
| | - Liang-jing Xia
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xin-fang Xu
- Centre of TCM Processing Research, Beijing University of Chinese Medicine, Beijing, China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- Xin-fang Xu
| | - Xiang-ri Li
- Centre of TCM Processing Research, Beijing University of Chinese Medicine, Beijing, China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Xiang-ri Li
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Hao Y, Li J, Yue S, Wang S, Hu S, Li B. Neuroprotective Effect and Possible Mechanisms of Berberine in Diabetes-Related Cognitive Impairment: A Systematic Review and Meta-Analysis of Animal Studies. Front Pharmacol 2022; 13:917375. [PMID: 35734409 PMCID: PMC9208278 DOI: 10.3389/fphar.2022.917375] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/02/2022] [Indexed: 12/09/2022] Open
Abstract
Berberine, the main bioactive component of Coptis chinensis Franch., is widely used in the treatment of diabetes. Previous studies have reported that berberine supplementation may play a multitarget therapeutic role in diabetes-related cognitive impairment (DCI). This systematic review and meta-analysis evaluated the effect and possible mechanisms of berberine in animal models of DCI. Relevant studies were searched through PubMed, Web of Science, Embase, and three Chinese databases (CNKI, Wanfang, and VIP) until March 2022. Twenty studies involving 442 animals were included, and SYRCLE’s risk of bias tool was used to assess methodological quality. The statistical analysis was performed using STATA 15.0 to calculate the weighted standard mean difference (SMD) with a 95% confidence interval (CI). The fasting blood glucose (FBG) and Morris water maze test (MWM) were the main outcomes to be analyzed. The overall results showed that berberine could significantly improve FBG, escape latency, the times of crossing the platform, the time spent in the target quadrant, serum insulin, 2hBG of oral glucose tolerance test (OGTT), amyloid β (Aβ), acetylcholinesterase (AChE), oxidative stress, and inflammation levels. The present meta-analysis demonstrated that berberine could not only lower blood glucose levels but also improve learning and memory in DCI animal models, which might involve regulating glucose and lipid metabolism, improving insulin resistance, anti-oxidation, anti-neuroinflammation, inhibiting endoplasmic reticulum (ER) stress; and improving the cholinergic system. However, additional attention should be paid to these outcomes due to the significant heterogeneity.
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Affiliation(s)
- Yanwei Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiaxin Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shengnan Yue
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shaofeng Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuangyuan Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bin Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Bin Li,
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Ma Z, Zhu L, Wang S, Guo X, Sun B, Wang Q, Chen L. Berberine protects diabetic nephropathy by suppressing epithelial-to-mesenchymal transition involving the inactivation of the NLRP3 inflammasome. Ren Fail 2022; 44:923-932. [PMID: 35618411 PMCID: PMC9154812 DOI: 10.1080/0886022x.2022.2079525] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Accumulating evidence has implicated that berberine (BBR) has a beneficial effect on diabetic kidney disease (DKD), but its mechanism is not clear. The aim of this study was to assess whether berberine could alleviate tubulointerstitial fibrosis and attenuate epithelial-to-mesenchymal transition (EMT) and its possible molecular mechanism. High-fat diet (HFD) followed by injection of STZ was used to induce diabetic rats in vivo. After the onset of diabetes, rats were treated with either BBR or saline for 12 weeks. In vitro, the human renal proximal tubular epithelial cell line (HK-2) was exposed to high glucose, with or without BBR. The influence of berberine on renal tubulointerstitial histological changes, markers of epithelial-to-mesenchymal transition (EMT) and (NOD-like receptor pyrin domain-containing protein 3) NLRP3 inflammasome expression were examined. Results showed that in vivo, BBR could significantly ameliorate microalbumin and renal pathologic changes in diabetic rats. Immunofluorescence showed that BBR could inhibit EMT. Furthermore, BBR could down-regulate the level of the NLRP3 inflammasome in diabetic rats. Consistently, in vitro, BBR suppressed high glucose-induced EMT and activation of NLRP3 inflammasome in HK-2. Our study demonstrated that BBR could inhibit high glucose-induced EMT and renal interstitial fibrosis by suppressing the NLRP3 inflammasome. BBR might be used as a novel drug to ameliorate tubulointerstitial fibrosis in DKD.
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Affiliation(s)
- Zejun Ma
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin
| | - Lili Zhu
- Tianjin Medical Devices Quality Supervision and Testing Center, Tianjin, China
| | - Shangshang Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin
| | - Xin Guo
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin
| | - Qilong Wang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Liming Chen
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin
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Pak ME, Park YJ, Yang HJ, Hwang YH, Li W, Go Y. Samhwangsasim-tang attenuates neuronal apoptosis and cognitive decline through BDNF-mediated activation of tyrosin kinase B and p75-neurotrophin receptors. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 99:153997. [PMID: 35279612 DOI: 10.1016/j.phymed.2022.153997] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 02/04/2022] [Accepted: 02/15/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Samhwangsasim-tang (SST) is a traditional medicine used to treat hypertension and arteriosclerosis. Additionally, due to the effects of its constituent herbs, SST is considered effective for memory-related disorders. PURPOSE We investigated the effects of SST on neuronal survival and memory in glutamate-induced hippocampal cells and in a mouse model of scopolamine-induced memory impairment. METHODS SST components were identified using 3D-ultra performance liquid chromatography (3D-UPLC). In vitro, we induced glutamate-induced excitotoxicity in HT22 cells after SST pretreatment. We used a cell counting kit-8 and cell cytotoxicity assay, flow cytometry, and western blotting to test the protective effects of SST on neuronal death. In vivo, C57BL/6J mice were administered with 150 and 300 mg/kg SST once daily for 7 days and then intraperitoneally injected with 1 mg/kg scopolamine for 7 days to induce cognitive impairment. We then measured cognitive behavior using a novel object recognition test (NORT) and passive avoidance test (PAT) and analyzed the histological and protein changes. RESULTS Our results showed that treatment with 50 and 100 μg/ml SST provided significant protection against glutamate-induced cell death. Flow cytometry and western blotting results suggested that 100 μg/ml SST treatment reduced oxidative stress and mitochondrial dysfunction. SST treatment also increased brain-derived neurotrophic factor (BDNF), its receptor, TrkB receptor, and cAMP-response element binding protein (CREB) activation while reducing the P75NTR and JNK signaling activation. Our in vivo results showed that SST administration improved cognitive impairment, similar to donepezil treatment (as a positive control), in NORT and PAT. SST and donepezil decreased neuronal cell death and apoptosis, and acetylcholine levels were increased in the scopolamine-treated hippocampus. Additionally, SST promoted CREB phosphorylation and BDNF maturation while reducing JNK and P75NTR activation; in contrast, donepezil did not alter levels of these proteins in the scopolamine-treated mouse hippocampus. CONCLUSION Our results suggest that SST has neuroprotective effects to attenuate neuronal cell death and oxidative stress through CREB/JNK signaling via BDNF activation. SST may regulate endogenous survival factors in the hippocampus, which may be a safe and potential clinical treatment for cognitive impairment in AD.
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Affiliation(s)
- Malk Eun Pak
- Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Yeo Jin Park
- Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea; Korean Convergence Medicine, University of Science and Technology, Daejeon 34054, Republic of Korea
| | - Hye Jin Yang
- Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Youn-Hwan Hwang
- Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Wei Li
- Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea
| | - Younghoon Go
- Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
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Li LL, Peng Z, Hu Q, Xu LJ, Zou X, Huang DM, Yi P. Berberine retarded the growth of gastric cancer xenograft tumors by targeting hepatocyte nuclear factor 4α. World J Gastrointest Oncol 2022; 14:842-857. [PMID: 35582103 PMCID: PMC9048536 DOI: 10.4251/wjgo.v14.i4.842] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 10/15/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer is the third deadliest cancer in the world and ranks second in incidence and mortality of cancers in China. Despite advances in prevention, diagnosis, and therapy, the absolute number of cases is increasing every year due to aging and the growth of high-risk populations, and gastric cancer is still a leading cause of cancer-related death. Gastric cancer is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor-suppressing signaling pathways. Global efforts have been made to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers. Trastuzumab, a monoclonal antibody against the HER2 receptor, is approved in the first-line treatment of patients with HER2+ tumors, which accounts for 13%-23% of the gastric cancer population. Ramucirumab, a monoclonal antibody against VEGFR2, is currently recommended in patients progressing after first-line treatment. Several clinical trials have also tested novel agents for advanced gastric cancer but mostly with disappointing results, such as anti-EGFR and anti-MET monoclonal antibodies. Therefore, it is still of great significance to screen specific molecular targets for gastric cancer and drugs directed against the molecular targets.
AIM To investigate the effect and mechanism of berberine against tumor growth in gastric cancer xenograft models and to explore the role of hepatocyte nuclear factor 4α (HNF4α)-WNT5a/β-catenin pathways played in the antitumor effects of berberine.
METHODS MGC803 and SGC7901 subcutaneous xenograft models were established. The control group was intragastrically administrated with normal saline, and the berberine group was administrated intragastrically with 100 mg/kg/d berberine. The body weight of nude mice during the experiment was measured to assess whether berberine has any adverse reaction. The volume of subcutaneous tumors during this experiment was recorded to evaluate the inhibitory effect of berberine on the growth of MGC803 and SGC7901 subcutaneous transplantation tumors. Polymerase chain reaction assays were conducted to evaluate the alteration of transcriptional expression of HNF4α, WNT5a and β-catenin in tumor tissues and liver tissues from the MGC803 and SGC7901 xenograft models. Western blotting and IHC were performed to assess the protein expression of HNF4α, WNT5a and β-catenin in tumor tissues and liver tissues from the MGC803 and SGC7901 xenograft models.
RESULTS In the both MGC803 and SGC7901 xenograft tumor models, berberine significantly reduced tumor volume and weight and thus retarded the growth rate of tumors. In the SGC7901 and MGC803 subcutaneously transplanted tumor models, berberine down-regulated the expression of HNF4α, WNT5a and β-catenin in tumor tissues from both transcription and protein levels. Besides, berberine also suppressed the protein expression of HNF4α, WNT5a and β-catenin in liver tissues.
CONCLUSION Berberine retarded the growth of MGC803 and SGC7901 xenograft model tumors, and the mechanism behind these anti-growth effects might be the downregulation of the expression of HNF4α-WNT5a/β-catenin signaling pathways both in tumor tissues and liver tissues of the xenograft models.
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Affiliation(s)
- Ling-Li Li
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430045, Hubei Province, China
| | - Ze Peng
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430045, Hubei Province, China
| | - Qian Hu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Jun Xu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430045, Hubei Province, China
| | - Xin Zou
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430045, Hubei Province, China
| | - Dong-Mei Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430045, Hubei Province, China
| | - Ping Yi
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430045, Hubei Province, China
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Ding H, Liu C, Zhang S, Li B, Xu Q, Shi B, Li S, Dong S, Ma X, Zhang Y, Zhong M, Zhang G. Sleeve gastrectomy attenuated diabetes-related cognitive decline in diabetic rats. Front Endocrinol (Lausanne) 2022; 13:1015819. [PMID: 36407319 PMCID: PMC9669300 DOI: 10.3389/fendo.2022.1015819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE To investigate the effects of sleeve gastrectomy (SG) on diabetes-related cognitive decline (DCD) in rats with diabetic mellitus (DM). METHODS AND METHODS Forty Wistar rats were randomly divided into control (CON) group (n=10), diabetes mellitus (DM) group (n=10), sham operation (SHAM) group (n=10) and SG group (n=10). DM model was established by high-fat diet (HFD) combined with intraperitoneal injection of streptozocin (STZ). Behavioral evaluation was given using Morris water maze test and Y-maze. In addition, PET-CT, TUNEL assay, histological analysis, transmission electron microscopy (TEM), immunohistochemistry (IHC) and Western blot analysis were used to evaluate the alleviating effects and potential mechanisms of SG on DCD in DM rats. RESULTS Compared with the sham group, SG induced significant improvement in the metabolic indices such as blood glucose and body weight. Besides, it could attenuate the insulin resistance compared with SHAM group. In addition, SG could improve the cognitive function of DM rats, which were featured by significant decrease in the escape latency (P<0.05), and significant increase in the time in target quadrant and platform crossings (P<0.05) compared with the SHAM group. SG induced significant elevation in the spontaneous alternation compared with SHAM group (P<0.05). Moreover, SG could improve the arrangement and biosynthesis of hippocampus neuron. Moreover, SG triggered the inhibition of apoptosis of hippocampus neurons, and Western blot analysis showed SG induced significant increase in the ratios of Bcl-2/Bax and Caspase3/cleaved Caspase 3. TEM demonstrated SG could significantly improve the microstructure of hippocampus neurons compared with the SHAM group. Western blot and IHC confirmed the significant decrease in the phosphorylation of tau at Ser404 and Ser396 sites in the SG group. Furthermore, SG activated the PI3K signaling pathway by elevating the phosphorylation of PI3K and Akt and GSK3β compared with the SHAM group. CONCLUSION SG attenuated the DCD in DM rats, which may be related to the activation of PI3K signaling pathway.
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Affiliation(s)
- Huanxin Ding
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuxuan Liu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuo Zhang
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bingjun Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Qian Xu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Bowen Shi
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Songhan Li
- Department of Breast Disease, Peking University People’s Hospital, Beijing, China
| | - Shuohui Dong
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaomin Ma
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Yun Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Guangyong Zhang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Guangyong Zhang,
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Meng J, Zhu Y, Ma H, Wang X, Zhao Q. The role of traditional Chinese medicine in the treatment of cognitive dysfunction in type 2 diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2021; 280:114464. [PMID: 34329715 DOI: 10.1016/j.jep.2021.114464] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/04/2021] [Accepted: 07/24/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Diabetic cognitive dysfunction (DCD) is mainly one of the complications of type 2 diabetes mellitus (T2DM) with complex and obscure pathogenesis. Extensive evidence has demonstrated the effectiveness and safety of traditional Chinese medicine (TCM) for DCD management. AIM OF THE STUDY This review attempted to systematically summarize the possible pathogenesis of DCD and the current Chinese medicine on the treatment of DCD. MATERIALS AND METHODS We acquired information of TCM on DCD treatment from PubMed, Web of Science, Science Direct and CNKI databases. We then dissected the potential mechanisms of currently reported TCMs and their active ingredients for the treatment of DCD by discussing the deficiencies and giving further recommendations. RESULTS Most TCMs and their active ingredients could improve DCD through alleviating insulin resistance, microvascular dysfunction, abnormal gut microbiota composition, inflammation, and the damages of the blood-brain barrier, cerebrovascular and neurons under hyperglycemia conditions. CONCLUSIONS TCM is effective in the treatment of DCD with few adverse reactions. A large number of in vivo and in vitro, and clinical trials are still needed to further reveal the potential quality markers of TCM on DCD treatment.
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Affiliation(s)
- Jinni Meng
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Ningxia, China
| | - Yafei Zhu
- College of Basic Medicine, Ningxia Medical University, Ningxia, China
| | - Huixia Ma
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Ningxia, China
| | - Xiaobo Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Qipeng Zhao
- Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Ningxia, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Ningxia, China.
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Fu X, Liu Q, Sun X, Chang H, Liu Y, Han J. Research Advances in the Treatment of Alzheimer's Disease with Polysaccharides of Danggui-Shaoyao-San. J Alzheimers Dis 2021; 85:7-19. [PMID: 34776439 DOI: 10.3233/jad-210656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Alzheimer's disease (AD) is a common progressive neurodegenerative disease. In recent years, the research on the treatment of AD with Chinese medicine is increasing and the results are optimistic, which may provide some new options for the treatment of AD. Existing animal and clinical studies have found that Danggui Shaoyao San (DSS), which has been used in gynecological diseases, is effective in the treatment of AD. As the main component of DSS, macromolecular polysaccharide plays an indispensable role in the treatment of AD. In addition to anti-inflammatory, anti-neuronal injury, and immune regulation, polysaccharides extracted from Danggui Shaoyao San (p-DSS) also have good activities in hypoglycemia, and participate in the physiological regulation of ubiquitination, iron metabolism, intestinal flora, estrogen, and autophagy. Given that there is little systematic analysis of p-DSS, this paper reviews the possible mechanism of p-DSS in the treatment of AD, so as to provide reference for further research.
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Affiliation(s)
- Xin Fu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qiantong Liu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiaowei Sun
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Hui Chang
- Heilongjiang University of Chinese Medicine, Harbin, China.,First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Ying Liu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiatong Han
- Heilongjiang University of Chinese Medicine, Harbin, China
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Razani E, Pourbagheri-Sigaroodi A, Safaroghli-Azar A, Zoghi A, Shanaki-Bavarsad M, Bashash D. The PI3K/Akt signaling axis in Alzheimer's disease: a valuable target to stimulate or suppress? Cell Stress Chaperones 2021; 26:871-887. [PMID: 34386944 PMCID: PMC8578535 DOI: 10.1007/s12192-021-01231-3] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/23/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
Among the long list of age-related complications, Alzheimer's disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.
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Affiliation(s)
- Elham Razani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anahita Zoghi
- Department of Neurology, School of Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Shanaki-Bavarsad
- Institute of Neuroscience, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Durairajan SSK, Selvarasu K, Bera MR, Rajaram K, Iyaswamy A, Li M. Alzheimer's Disease and other Tauopathies: Exploring Efficacy of Medicinal Plant-Derived Compounds in Alleviating Tau-Mediated Neurodegeneration. Curr Mol Pharmacol 2021; 15:361-379. [PMID: 34488602 DOI: 10.2174/1874467214666210906125318] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/12/2020] [Accepted: 01/27/2021] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD), a major form of dementia, has been reported to affect more than 50 million people worldwide. It is characterized by the presence of amyloid-β (Aβ) plaques and hyperphosphorylated Tau-associated neurofibrillary tangles in the brain. Apart from AD, microtubule (MT)-associated protein Tau is also involved in other neurodegenerative diseases called tauopathies, including Pick's disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and corticobasal degeneration. The recently unsuccessful phase III clinical trials related to Aβ-targeted therapeutic drugs indicated that alternative targets, such as Tau, should be studied to discover more effective and safer drugs. Recent drug discovery approaches to reduce AD-related Tau pathologies are primarily based on blocking Tau aggregation, inhibiting Tau phosphorylation, compensating impaired Tau function with MT-stabilizing agents, and targeting the degradation pathways in neuronal cells to degrade Tau protein aggregates. Owing to several limitations of the currently-available Tau-directed drugs, further studies are required to generate further effective and safer Tau-based disease-modifying drugs. Here, we review the studies that focused on medicinal plant-derived compounds capable of modulating the Tau protein, which is significantly elevated and hyperphosphorylated in AD and other tauopathies. We mainly considered the studies that focused on Tau protein as a therapeutic target. We reviewed several pertinent papers retrieved from PubMed and ScienceDirect using relevant keywords, with a primary focus on the Tau-targeting compounds from medicinal plants. These compounds include indolines, phenolics, flavonoids, coumarins, alkaloids, and iridoids, which have been scientifically proven to be Tau-targeting candidates for the treatment of AD.
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Affiliation(s)
- Siva Sundara Kumar Durairajan
- Mycobiology and Neurodegenerative Disease Research Lab, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur. India
| | - Karthikeyan Selvarasu
- Mycobiology and Neurodegenerative Disease Research Lab, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur. India
| | - Minu Rani Bera
- Mycobiology and Neurodegenerative Disease Research Lab, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur. India
| | - Kaushik Rajaram
- Mycobiology and Neurodegenerative Disease Research Lab, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur. India
| | - Ashok Iyaswamy
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR. China
| | - Min Li
- Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR. China
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Shang Y, Ding S, Liu Q. The Effects and Regulative Mechanism of Scutellaria Baicalensis Georgi Stems and Leaves Flavonoids in Promoting Neurogenesis and Improving Memory Impairment Mediated by BDNF-ERK-CREB Signal Pathway in Rats. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:354-366. [PMID: 34455975 DOI: 10.2174/1871527320666210827112048] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/30/2021] [Accepted: 07/04/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND It is well known that Alzheimer's disease (AD) is a degenerative disease, and accompanied by memory impairment and main pathological changes of the extracellular senile plaque (SP) and intracellular neurofibrillary tangles (NFTs). However, there are many evidences showing that the disorders of neurogenesis are also regarded as a new opinion in AD. OBJECTIVE To investigate the effects and regulative mechanism of Scutellaria baicalensis Georgi stems and leaves flavonoids in promoting neurogenesis and improving memory impairment mediated by BDNF-ERK-CREB signal pathway in rats. METHODS Male Wistar rats were intracerebroventricularly injected with amyloid-beta protein 25-35 (Aβ25-35) in combination with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1 (RHTGF-β1) (composited Aβ), to establish an AD model. Morris water maze was used to screen AD model of rats and measure the rats' learning and memory ability. The expression of cell neurogenesis related molecule Ki67 protein in the hippocampal gyrus of rats was detected by the immunohistochemical method. The expression of mRNA and protein of Grb2, SOS1, Ras, ERK and BDNF in the BDNF-ERK-CREB signaling pathway, in the hippocampus and cerebral cortex were assayed by the Quantitative real-time PCR (qPCR) and Western blotting methods, respectively. RESULTS Intracerebroventricular injection of composited Aβ could produce the rats' memory impairment, decrease the protein expression of Ki67 in the hippocampal gyrus, and increase the mRNA and protein expression levels of Grb2, SOS1, Ras, ERK and BDNF in the hippocampus and cerebral cortex. However, SSF could significantly ameliorate the rats' memory impairment, lower the reduction of Ki67 protein expression in the hippocampal gyrus and regulate the mRNA and protein expression abnormal levels of Grb2, SOS1, Ras, ERK and BDNF in the hippocampus and cerebral cortex induced by composited Aβ. CONCLUSION Composited Aβ can result in memory impairment, decrease neurogenesis and regulate the mRNA and protein abnormal expression of Grb2, SOS1, Ras, ERK and BDNF in BDNF-ERK-CREB signaling pathway. The effects of SSF in promoting neurogenesis and improving memory impairment may be related to the regulation in Grb2, SOS1, Ras, ERK and BDNF molecules' expression of the BDNF-ERK-CREB signaling pathway.
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Affiliation(s)
- Yazhen Shang
- Institute of Traditional Chinese Medicine, Chengde Medical College / Hebei Province Key Research Office of Traditional Chinese Medicine Against Dementia / Hebei Province Key Laboratory of Traditional Chinese Medicine Research and Development / Hebei Key Laboratory of Nerve Injury and Repair, An Yuan Road, Chengde 067000. China
| | - Shengkai Ding
- Institute of Traditional Chinese Medicine, Chengde Medical College / Hebei Province Key Research Office of Traditional Chinese Medicine Against Dementia / Hebei Province Key Laboratory of Traditional Chinese Medicine Research and Development / Hebei Key Laboratory of Nerve Injury and Repair, An Yuan Road, Chengde 067000. China
| | - Qianqian Liu
- Institute of Traditional Chinese Medicine, Chengde Medical College / Hebei Province Key Research Office of Traditional Chinese Medicine Against Dementia / Hebei Province Key Laboratory of Traditional Chinese Medicine Research and Development / Hebei Key Laboratory of Nerve Injury and Repair, An Yuan Road, Chengde 067000. China
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Wu Y, Chen Q, Wen B, Wu N, He B, Chen J. Berberine Reduces Aβ 42 Deposition and Tau Hyperphosphorylation via Ameliorating Endoplasmic Reticulum Stress. Front Pharmacol 2021; 12:640758. [PMID: 34349640 PMCID: PMC8327086 DOI: 10.3389/fphar.2021.640758] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 04/29/2021] [Indexed: 12/15/2022] Open
Abstract
Alzheimer’s disease (AD) is tightly related to endoplasmic reticulum stress (ER stress), which aggravates two dominant pathological manifestations of AD: senile plaques and neurofibrillary tangles. Berberine is widely applied in the clinical treatment of many diseases and is reported to have anti-AD effects. In the present study, berberine was shown to ameliorate ER stress and cognitive impairment in APP/PS1 mice. We found ER stress plays a role as a central hub for signal transduction, which was evidenced by the hyperactivation of glycogen synthase kinase 3β (GSK3β) to phosphorylate tau and the activation of PRKR-like endoplasmic reticulum kinase (PERK) subsequently to phosphorylate eukaryotic translation initiation factor-2 α (eIF2α). Also, eIF2α has regulated the expression of beta-site APP cleaving enzyme-1 (BACE1), which cleaves APP into pro-oligomerized amyloid beta 42 (Aβ42), the main component of senile plaques, proven by using siRNA targeting at eIF2α. Mechanically, berberine can reduce GSK3β activity, contributing to the downregulation of tau phosphorylation. Berberine also suppressed Aβ42 production via inhibiting the PERK/eIF2α/BACE1 signaling pathway. Taken together, these findings indicated that berberine had the potential to ameliorate two major pathological manifestations of AD mainly by suppressing ER stress. Our work provided knowledge on the pharmacological intervention of AD and the possible targets for future drug development.
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Affiliation(s)
- Yue Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Bing Wen
- Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ninghua Wu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China.,Basic Medical College, Hubei University of Science and Technology, Xianning, China
| | - Benhong He
- Department of Cardiovascular Medicine, Lichuan People's Hospital, Lichuan, China
| | - Juan Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wu N, Liu W, Wang J, Han Y, Ye Y, Liu X, Yu Y, Chen Q, Bao Y, Liu C. Berberine ameliorates neuronal AD-like change via activating Pi3k/PGCε pathway. Biofactors 2021; 47:587-599. [PMID: 33740285 DOI: 10.1002/biof.1725] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/24/2021] [Indexed: 12/11/2022]
Abstract
IR (insulin resistance) in diabetic brain gave rise to the generation of toxic factor Aβ42 and axon collapse which were the marker of AD (Alzheimer's disease)-like lesions in the circumstance of diabetes mellitus. But the underling molecular mechanism was not clear. Chronic HGHI (high glucose and high insulin) exposure accelerates IR has been reported in type II diabetes models. Berberine has been shown to promising effect for IR in vitro and in vivo. This study demonstrates the protective effect and the underlying mechanism of berberine on HGHI-induced IR. HGHI-induced cells were used to mimic the hyperinsulinemia resulting in IR. Berberine was used to uncover the mechanisms for the treatment of hyperinsulinemia in IR model. Morris water maze (MWM), PET imaging, CCK8 assay, ELISA assay, glucose kits, microscopy, and western blot analysis were performed to evaluate the protective effects of berberine. Berberine-improved HGHI-induced IR was correlated with the increase of glucose application in neurons. Meanwhile, the expressions of Pi3K, as well as GLUT3, PKCε, and APP were downregulated in the model, while p-IRS Ser307 was upregulated compared with Normal group. Fortunately, these scenes were reversed by berberine administration. Furthermore, berberine decreased GSK3β Y216 expressions, inhibited the production of oligomer Aβ42 and extended neuronal axon. The monomeric berberine treatment improves IR that may be involved in glucose effective application, rectifying the related proteins of the aberrant insulin pathway. Additionally, it suppressed the generation of Aβ42 and ameliorated neuron axon damage. Finally, berberine improves DM (diabetes mellitus)-induced cognitive impairment.
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Affiliation(s)
- Ninghua Wu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
- Basic Medical College, Hubei University of Science and Technology, Xianning, China
| | - Wu Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Jiawen Wang
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Yanqi Han
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Yu Ye
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Xiufen Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Yuandong Yu
- Department of Oncology, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Yongfen Bao
- Basic Medical College, Hubei University of Science and Technology, Xianning, China
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
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The Use of Natural Compounds as a Strategy to Counteract Oxidative Stress in Animal Models of Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22137009. [PMID: 34209800 PMCID: PMC8268811 DOI: 10.3390/ijms22137009] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disease characterised by insulin deficiency, resulting in hyperglycaemia, a characteristic symptom of type 2 diabetes mellitus (DM2). DM substantially affects numerous metabolic pathways, resulting in β-cell dysfunction, insulin resistance, abnormal blood glucose levels, impaired lipid metabolism, inflammatory processes, and excessive oxidative stress. Oxidative stress can affect the body’s normal physiological function and cause numerous cellular and molecular changes, such as mitochondrial dysfunction. Animal models are useful for exploring the cellular and molecular mechanisms of DM and improving novel therapeutics for their safe use in human beings. Due to their health benefits, there is significant interest in a wide range of natural compounds that can act as naturally occurring anti-diabetic compounds. Due to rodent models’ relatively similar physiology to humans and ease of handling and housing, they are widely used as pre-clinical models for studying several metabolic disorders. In this review, we analyse the currently available rodent animal models of DM and their advantages and disadvantages and highlight the potential anti-oxidative effects of natural compounds and their mechanisms of action.
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Xu Y, Liu S, Zhu L, Dai L, Qian W, Zhang J, Li X, Pan W. Green tea protects against hippocampal neuronal apoptosis in diabetic encephalopathy by inhibiting JNK/MLCK signaling. Mol Med Rep 2021; 24:575. [PMID: 34132368 PMCID: PMC8223107 DOI: 10.3892/mmr.2021.12214] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/15/2021] [Indexed: 12/23/2022] Open
Abstract
Although diabetic encephalopathy (DE) is a major late complication of diabetes, the pathophysiology of postural instability in DE remains poorly understood. Prior studies have suggested that neuronal apoptosis is closely associated with cognitive function, but the mechanism remains to be elucidated. Green tea, which is a non-fermented tea, contains a number of tea polyphenols, alkaloids, amino acids, polysaccharides and other components. Some studies have found that drinking green tea can reduce the incidence of neurodegenerative diseases and improve cognitive dysfunction. We previously found that myosin light chain kinase (MLCK) regulates apoptosis in high glucose-induced hippocampal neurons. In neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, activation of the JNK signaling pathway promotes neuronal apoptosis. However, the relationship between JNK and MLCK remains to be elucidated. Green tea serum was obtained using seropharmacological methods and applied to hippocampal neurons. In addition, a type 1 diabetes rat model was established and green tea extract was administered, and the Morris water maze test, Cell Counting Kit-8 assays, flow cytometry, western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling assays were used to examine the effects of green tea on hippocampal neuronal apoptosis in diabetic rats. The results demonstrated that green tea can protect against hippocampal neuronal apoptosis by inhibiting the JNK/MLCK pathway and ultimately improves cognitive function in diabetic rats. The present study provided novel insights into the neuroprotective effects of green tea.
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Affiliation(s)
- Yongjie Xu
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Shengju Liu
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Liying Zhu
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Longguang Dai
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Wen Qian
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Jingzhi Zhang
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
| | - Xing Li
- Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550004, P.R. China
| | - Wei Pan
- Department of Medical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang Medical College, Guiyang, Guizhou 550004, P.R. China
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Yoon JH, Lee N, Youn K, Jo MR, Kim HR, Lee DS, Ho CT, Jun M. Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell. Mar Drugs 2021; 19:md19030152. [PMID: 33804171 PMCID: PMC8001366 DOI: 10.3390/md19030152] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/06/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
The proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase releases amyloid-β peptide (Aβ), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer’s disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aβ accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), β-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPβ, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3β at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3β. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3β activation and Aβ expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aβ production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3β, resulting in the reduction in Aβ levels.
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Affiliation(s)
- Jeong-Hyun Yoon
- Department of Health Sciences, The graduate School of Dong-A University, Busan 49315, Korea; (J.-H.Y.); (N.L.)
| | - Nayoung Lee
- Department of Health Sciences, The graduate School of Dong-A University, Busan 49315, Korea; (J.-H.Y.); (N.L.)
| | - Kumju Youn
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea;
| | - Mi Ra Jo
- Division of Food Safety and Processing Research, National Institute of Fisheries Science, Busan 46083, Korea;
| | - Hyeung-Rak Kim
- Department of Food Science and Nutrition, Pukyong National University, Busan 48513, Korea;
| | - Dong-Seok Lee
- School of Life Sciences & Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea;
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA;
| | - Mira Jun
- Department of Health Sciences, The graduate School of Dong-A University, Busan 49315, Korea; (J.-H.Y.); (N.L.)
- Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea;
- Correspondence: ; Tel.: +82-51-200-7323
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