1
|
Liu Y, Gong H, Mouse M, Xu F, Zou X, Yang J, Xue Q, Huang M. The phonation test can distinguish the patient with Parkinson's disease via Bayes inference. Cogn Neurodyn 2025; 19:18. [PMID: 39801919 PMCID: PMC11717751 DOI: 10.1007/s11571-024-10194-x] [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: 09/02/2024] [Revised: 11/05/2024] [Accepted: 11/10/2024] [Indexed: 01/16/2025] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease with various clinical manifestations caused by multiple risk factors. However, the effect of different factors and relationships between different features related to PD and the extent of those factors leading to the incidence of PD remains unclear. we employed Bayesian network to construct a prediction model. The prediction system was trained on the data of 35 patients and 26 controls. The structure learning and parameter learning of Bayesian Network was completed through the tree-augmented network (TAN) and Netica software, respectively. We employed four Bayesian Networks in terms of the syllable, including monosyllables, disyllables, multisyllables and unsegmented syllables. The area under the curve (AUC) of monosyllabic, disyllabic, multisyllabic, and unsegmented-syllable models were 0.95, 0.83, 0.80 and 0.84, respectively. In the monosyllabic tests, the best predictor of PD was duration, the posterior probability of which was 92.70%. Meanwhile, minimum f0 (61.60%) predicted best in the disyllabic tests and the variables that predicted best in multisyllables and unsegmented syllables were end f0 (59.40%) and maximum f0 (58.40%). In the cross-sectional comparison, the prediction effect of each variable in the monosyllabic tests was generally higher than that of other test groups. The monosyllabic models had the highest predicted performance of PD. Among acoustic parameters, duration was the strongest feature in predicting the prevalence of PD in monosyllabic tests. We believe that this network methodology will be a useful tool for the clinical prediction of Parkinson's disease. Supplementary Information The online version contains supplementary material available at 10.1007/s11571-024-10194-x.
Collapse
Affiliation(s)
- Yifeng Liu
- Department of clinical Medicine, School of Clinic Medicine, Chengdu Medical College, Sichuan, 610500 China
| | - Hongjie Gong
- Department of clinical Medicine, School of Clinic Medicine, Chengdu Medical College, Sichuan, 610500 China
| | - Meimei Mouse
- Department of clinical Medicine, School of Clinic Medicine, Chengdu Medical College, Sichuan, 610500 China
| | - Fan Xu
- Department of Evidence-based Medicine and Social Medicine, School of Public Health, Chengdu Medical College, Sichuan, 610500 China
| | - Xianwei Zou
- Department of Neurology, First Affiliated Hospital of Chengdu Medical College, Sichuan, 610500 China
| | - Jingsheng Yang
- Department of Evidence-based Medicine and Social Medicine, School of Public Health, Chengdu Medical College, Sichuan, 610500 China
| | - Qingping Xue
- Department of Evidence-based Medicine and Social Medicine, School of Public Health, Chengdu Medical College, Sichuan, 610500 China
| | - Min Huang
- Department of Physiology, School of Basic Medical Sciences, Chengdu Medical College, Sichuan, 610500 China
| |
Collapse
|
2
|
Zhou Y, Song Y, Song X, He F, Xu M, Ming D. Review of directional leads, stimulation patterns and programming strategies for deep brain stimulation. Cogn Neurodyn 2025; 19:33. [PMID: 39866658 PMCID: PMC11757656 DOI: 10.1007/s11571-024-10210-0] [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: 06/11/2024] [Revised: 09/02/2024] [Accepted: 09/26/2024] [Indexed: 01/28/2025] Open
Abstract
Deep brain stimulation (DBS) is a well-established treatment for both neurological and psychiatric disorders. Directional DBS has the potential to minimize stimulation-induced side effects and maximize clinical benefits. Many new directional leads, stimulation patterns and programming strategies have been developed in recent years. Therefore, it is necessary to review new progress in directional DBS. This paper summarizes progress for directional DBS from the perspective of directional DBS leads, stimulation patterns, and programming strategies which are three key elements of DBS systems. Directional DBS leads are reviewed in electrode design and volume of tissue activated visualization strategies. Stimulation patterns are reviewed in stimulation parameters and advances in stimulation patterns. Programming strategies are reviewed in computational modeling, monopolar review, direction indicators and adaptive DBS. This review will provide a comprehensive overview of primary directional DBS leads, stimulation patterns and programming strategies, making it helpful for those who are developing DBS systems.
Collapse
Affiliation(s)
- Yijie Zhou
- School of Disaster and Emergency Medicine of Tianjin University, Tianjin, 300072 China
- Academy of Medical Engineering and Translational Medicine of Tianjin University, Tianjin, 300072 China
- Haihe Laboratory of Brain-computer Interaction and Human-machine Integration, Tianjin, 300392 China
| | - Yibo Song
- Academy of Medical Engineering and Translational Medicine of Tianjin University, Tianjin, 300072 China
| | - Xizi Song
- Academy of Medical Engineering and Translational Medicine of Tianjin University, Tianjin, 300072 China
- Haihe Laboratory of Brain-computer Interaction and Human-machine Integration, Tianjin, 300392 China
| | - Feng He
- Academy of Medical Engineering and Translational Medicine of Tianjin University, Tianjin, 300072 China
- Haihe Laboratory of Brain-computer Interaction and Human-machine Integration, Tianjin, 300392 China
| | - Minpeng Xu
- Academy of Medical Engineering and Translational Medicine of Tianjin University, Tianjin, 300072 China
- Haihe Laboratory of Brain-computer Interaction and Human-machine Integration, Tianjin, 300392 China
| | - Dong Ming
- Academy of Medical Engineering and Translational Medicine of Tianjin University, Tianjin, 300072 China
- Haihe Laboratory of Brain-computer Interaction and Human-machine Integration, Tianjin, 300392 China
| |
Collapse
|
3
|
Jiang Y, Qi Z, Zhu H, Shen K, Liu R, Fang C, Lou W, Jiang Y, Yuan W, Cao X, Chen L, Zhuang Q. Role of the globus pallidus in motor and non-motor symptoms of Parkinson's disease. Neural Regen Res 2025; 20:1628-1643. [PMID: 38845220 PMCID: PMC11688550 DOI: 10.4103/nrr.nrr-d-23-01660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/12/2024] [Accepted: 04/21/2024] [Indexed: 08/07/2024] Open
Abstract
The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson's disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson's disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson's disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore, bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico-striato-pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson's disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson's disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson's disease, particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremor-dominant and non-tremor-dominant Parkinson's disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia-thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity, and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson's disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.
Collapse
Affiliation(s)
- Yimiao Jiang
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Zengxin Qi
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Neurological Disorders, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, China
| | - Huixian Zhu
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Kangli Shen
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Ruiqi Liu
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Chenxin Fang
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Weiwei Lou
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Yifan Jiang
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Wangrui Yuan
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Xin Cao
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| | - Liang Chen
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Neurological Disorders, Shanghai, China
- Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, China
| | - Qianxing Zhuang
- Department of Physiology, School of Medicine, Nantong University, Nantong, Jiangsu Province, China
| |
Collapse
|
4
|
He Q, Wang Z, Wang Y, Zhu M, Liang Z, Zhang K, Xu Y, Chen G. Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/Ascl1/Dlx2. Neural Regen Res 2025; 20:1801-1815. [PMID: 39104117 PMCID: PMC11688565 DOI: 10.4103/nrr.nrr-d-23-01897] [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: 11/20/2023] [Revised: 02/04/2024] [Accepted: 03/25/2024] [Indexed: 08/07/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202506000-00030/figure1/v/2024-08-05T133530Z/r/image-tiff Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors--NeuroD1, Ascl1, and Dlx2--in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore, we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4 (astrocyte endfeet signal), CX43 (gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into pre-existing neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.
Collapse
Affiliation(s)
- Qing He
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Zhen Wang
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Yuchen Wang
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Mengjie Zhu
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Zhile Liang
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Kanghong Zhang
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Yuge Xu
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Gong Chen
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| |
Collapse
|
5
|
Locatelli M, Farina C. Role of copper in central nervous system physiology and pathology. Neural Regen Res 2025; 20:1058-1068. [PMID: 38989937 PMCID: PMC11438321 DOI: 10.4103/nrr.nrr-d-24-00110] [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: 01/26/2024] [Revised: 03/21/2024] [Accepted: 04/23/2024] [Indexed: 07/12/2024] Open
Abstract
Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.
Collapse
Affiliation(s)
- Martina Locatelli
- Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Cinthia Farina
- Institute of Experimental Neurology, Division of Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
6
|
Li J, Wang L, Pan Y, Huang P, Xu L, Zhang Y, De Ridder D, Voon V, Li D. Subthalamic nucleus oscillations during facial emotion processing and apathy in Parkinson's disease. J Affect Disord 2025; 373:314-324. [PMID: 39761756 DOI: 10.1016/j.jad.2025.01.005] [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: 09/30/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Parkinson's disease (PD) is primarily characterized by motor symptoms, but patients also experience a relatively high prevalence of non-motor symptoms, including emotional and cognitive impairments. While the subthalamic nucleus (STN) is a common target for deep brain stimulation to treat motor symptoms in PD, its role in emotion processing is still under investigation. This study examines the subthalamic neural oscillatory activities during facial emotion processing and its association with affective characteristics. METHODS Twenty PD patients who underwent subthalamic deep brain stimulation surgery performed a facial-expression-recognition task while STN local field potential (LFP) and frontal electroencephalography (EEG) were recorded. The facial-emotion-induced time-frequency decomposition of the STN-LFP and the frontal EEG, as well as the LFP-EEG coherence, were analyzed. Furthermore, the correlation between STN activities and affective characteristics was examined. RESULTS Facial expressions elicited increased delta-theta-band and decreased alpha-beta-band activities in STN-LFP. Reduced alpha-beta-band LFP desynchronization was correlated with the severity of apathy. Increased theta-band and decreased alpha-beta-band EEG activities responded to facial emotion. Notably, lower coherence between STN-LFP and frontal EEG in delta-theta-band activity and alpha-band activity correlated with the degree of anhedonia. CONCLUSION These results indicate that subthalamic activities during facial emotion processing are associated with apathy and anhedonia, emphasizing the cognitive-limbic function of STN and its role as a physiological target for apathy neuromodulation in PD.
Collapse
Affiliation(s)
- Jun Li
- Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; School of Information Science and Technology, ShanghaiTech University, Shanghai, China
| | - Linbin Wang
- Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Yixin Pan
- Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peng Huang
- Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Xu
- Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuyao Zhang
- School of Information Science and Technology, ShanghaiTech University, Shanghai, China
| | - Dirk De Ridder
- Unit of Neurosurgery, Department of Surgical Sciences, University of Otago, Dunedin, Otago, New Zealand
| | - Valerie Voon
- Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
| | - Dianyou Li
- Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
7
|
Zielinska Z, Oldak L, Gorodkiewicz E. Biosensing systems for the detection of biomarkers of neurodegenerative diseases: A review. Talanta 2025; 284:127247. [PMID: 39586209 DOI: 10.1016/j.talanta.2024.127247] [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: 02/20/2024] [Revised: 08/23/2024] [Accepted: 11/18/2024] [Indexed: 11/27/2024]
Abstract
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are pathologies associated with neuronal disorders and degradation. They are difficult to detect in their early stages, when it is crucial for appropriate treatment to be implemented. Currently, many biosensors are being developed to enable the determination of compounds characteristic of the aforementioned diseases. This review includes a de-scription of the structure of biosensors, as well as their applications in many areas of qualitative and quantitative analysis, with particular emphasis on diagnostics. The structures of biosensors that can potentially be used for the diagnosis of AD, PD and MS are discussed, as well as their characteristics, which depend on the technique used for the analysis and the type of recognition element capable of specifically binding a given biomarker. A description is also given of biosensors classified according to the type of sample used for quantitative determinations.
Collapse
Affiliation(s)
- Zuzanna Zielinska
- Doctoral School of Exact and Natural Science, Faculty of Chemistry, Bioanalysis Laboratory, University of Bialystok, Ciolkowskiego 1K, 15-245, Bialystok, Poland.
| | - Lukasz Oldak
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245, Bialystok, Poland.
| | - Ewa Gorodkiewicz
- Bioanalysis Laboratory, Faculty of Chemistry, University of Bialystok, Ciolkowskiego 1K, 15-245, Bialystok, Poland.
| |
Collapse
|
8
|
Martinazzo MS, Guimarães ACDA, Moratelli J, Gil PR. Is Mat pilates effective in lower limb strength and hand grip strength of people with Parkinson's? A randomized clinical trial with follow-up. J Bodyw Mov Ther 2025; 41:138-143. [PMID: 39663080 DOI: 10.1016/j.jbmt.2024.11.004] [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: 04/30/2024] [Revised: 08/23/2024] [Accepted: 11/02/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION Parkinson's disease can contribute to the loss of muscle strength, and physical exercise such as Mat Pilates can be effective in improving this, core stability, flexibility, and muscle control. OBJECTIVE To analyze the effects of a 12-week intervention with Mat Pilates in the short and long term, on lower limb and hand grip strength in people with Parkinson's. METHODS The study included 23 people (61.7 ± 7.5 years) of both sexes, diagnosed with Parkinson's disease who were selected according to inclusion criteria and divided into intervention and control groups. RESULTS The hand grip variable showed improvement in the intervention group intragroup only in the right hand (p = 0.003) in the post-intervention period. In the lower limb strength variable, there was significance in the extension of the left leg both in the intervention intragroup (p = 0.042), and in the control group (p = 0.001) the result in the flexion of the left leg in the intervention group (p = 0.032). The follow-up data showed significance in the strength of extension of the right leg in the intervention group (p = 0.049) and in the control group (p = 0.024) and in the extension of the left leg in the intervention group (p = 0.021). CONCLUSION Mat Pilates classes for people with Parkinson's with mild and moderate degrees proved to be effective in the short term in the hand grip strength of the right hand, and in the extension and flexion of the left legs, and positive effects in the long term in the strength of extension of the right also left legs.
Collapse
Affiliation(s)
- Mainaluá Santana Martinazzo
- Santa Catarina State University, College of Health and Sport Science - Cefid Leisure and Physical Activity Research Laboratory, Brazil.
| | | | - Jessica Moratelli
- Santa Catarina State University, College of Health and Sport Science - Cefid Leisure and Physical Activity Research Laboratory, Brazil
| | - Priscila Rodrigues Gil
- Santa Catarina State University, College of Health and Sport Science - Cefid Leisure and Physical Activity Research Laboratory, Brazil
| |
Collapse
|
9
|
Yao YM, Shao XY, Sha LL, Qian LL. Effect of extended nursing based on self-efficacy theory on the anxiety of patients with intertrochanteric fracture. World J Psychiatry 2025; 15:100570. [DOI: 10.5498/wjp.v15.i2.100570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/08/2024] [Accepted: 12/16/2024] [Indexed: 01/14/2025] Open
Abstract
BACKGROUND Extended care based on self-efficacy theory to elderly patients with intertrochanteric fractures will provide data reference to optimize the care plan of these patients, reduce patients’ concurrent mental diseases, and improve prognosis.
AIM To analyze the value of extended nursing based on the self-efficacy theory in older patients with intertrochanteric fractures.
METHODS Older patients with intertrochanteric fractures (n = 88) admitted to our hospital between January 2021 and December 2024 were randomly divided into two groups - the control group (n = 44, routine nursing) and the observation group (n = 44, extended nursing) - via balloting and treated for 12 weeks. The mental state, pain severity, limb function, and self-nursing ability of all patients before and after nursing were analyzed.
RESULTS After nursing, the Hamilton Anxiety Scale and General Self-Efficacy Scale scores of patients in the two groups improved. Notably, Hamilton Anxiety Scale and General Self-Efficacy Scale scores in the observation group were lower and higher, respectively, than those in the control group (P < 0.05). The pain severity in the observation group (2.64 ± 0.22) was lower than that in the control group (2.85 ± 0.41) (P < 0.05). The recovery rate of limb function was higher in the observation group than in the control group (P < 0.05). In addition, the self-nursing ability scores of the patients in both groups increased, with a significantly higher score in the observation group (P < 0.05).
CONCLUSION Extended nursing based on the self-efficacy theory can significantly improve mental state, relieve pain, and promote the recovery of limb function and self-nursing ability in older patients with intertrochanteric fractures.
Collapse
Affiliation(s)
- You-Mei Yao
- Department of Trauma Orthopedics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Xue-Yun Shao
- Department of Trauma Orthopedics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Lin-Li Sha
- Department of Trauma Orthopedics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Lin-Lin Qian
- Department of Trauma Orthopedics, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| |
Collapse
|
10
|
Thakur J, Godad A. Deciphering the role of neuropeptides as biomarkers for early diagnosis of Parkinson's disease. Life Sci 2025; 363:123376. [PMID: 39793854 DOI: 10.1016/j.lfs.2025.123376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 01/04/2025] [Accepted: 01/04/2025] [Indexed: 01/13/2025]
Abstract
Parkinson's disease (PD) is a neurological condition and is characterized by both motor and non-motor symptoms. Early diagnosis is essential for effective therapy and management; nevertheless, present diagnostic methods are frequently insufficient and primarily rely on clinical symptoms that appear later in the disease. Neuropeptides, such as alpha-synuclein (α-syn), Substance P (SP), neurotensin (Nts), Neuropeptide Y (NPY), and somatostatin (SST), exhibit significant potential as biomarkers for the early identification of Parkinson's disease (PD). The pathophysiology of Parkinson's disease is closely associated with the dysregulation of these neuropeptides, which are essential in many neurophysiological processes. Advancements in detection technologies, including the Enzyme-Linked Immunosorbent Assay (ELISA), have rendered it possible to precisely and sensitively quantify neuropeptides in a variety of bodily fluids, including blood, saliva, tears, urine, and cerebrospinal fluid (CSF). Studies show that PD patients have different amounts of neuropeptides in their biological fluids. These differences are correlated with the severity of the disease and help to distinguish PD patients apart from individuals with other neurodegenerative conditions. Despite being less investigated, Nts and SST are also involved in neuroprotection and dopaminergic transmission, they too hold significant characteristics as diagnostic biomarkers. This article highlights the possible use of neuropeptides as PD diagnostic biomarkers. Integrating neuropeptide biomarkers into normal diagnostic processes can substantially enhance early diagnosis. This enables early therapeutic interventions and improves outcomes for individuals with PD.
Collapse
Affiliation(s)
- Jhanvi Thakur
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India
| | - Angel Godad
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V. M. Road, Vile Parle (W), Mumbai, India.
| |
Collapse
|
11
|
Hou X, Liang X, Zhao X, Shi Y, Zhuo F, Tong X, Yang X, Zhai Q, Wang J, Guo Q, Tu P, Zeng K, Zhang Q. Uncaria rhynchophylla alkaloid extract exerts neuroprotective activity against Parkinson's disease via activating mitophagy with the involvement of UCHL1. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119009. [PMID: 39471877 DOI: 10.1016/j.jep.2024.119009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/25/2024] [Accepted: 10/26/2024] [Indexed: 11/01/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Uncaria rhynchophylla (Miq.) Miq. ex Havil. (UR), a traditional Chinese medicinal plant, plays an active role in neuroprotection. Clinical medication and modern pharmacological studies have proved the efficacy of UR against Parkinson's disease (PD), with alkaloids being recognized as the main bioactive components. But the therapeutic effect and mechanism of U. rhynchophylla alkaloid extract (URA) against PD need further exploration. AIM OF STUDY The study aimed to investigate the therapeutic effect and potential mechanism of URA on PD. MATERIALS AND METHODS LC-MS methodology was used to evaluate the chemical constituents of URA. The anti-PD activity of URA in vivo was measured on the mouse and rat models of PD. Neuroprotective effect of URA on PC12 cells was measured by MTT assay. Dopamine (DA) and its metabolites were detected by LC-MS for probing the protection ability on dopaminergic neurons. The differentially expressed proteins between model group and URA administrated group were analyzed by proteomics, suggesting oxidative phosphorylation as possible pathway of URA. Considering the critical role of mitochondria in oxidative phosphorylation, JC-1 staining, MitoSOX staining, transmission electron microscopy (TEM) observation and adenosine triphosphate (ATP) levels detection were used to analyze the effects of URA on mitochondrial morphology and function. Biolayer interferometry (BLI) was used to search for the possible UCHL1-bonding compounds in URA. RESULTS URA significantly mitigated the behavioural defects by improving coordination, shortening the time to climb down the whole pole (T-LA) and increasing the forelimbs' muscle strength of MPTP-induced PD mice and 6-OHDA-induced PD rats. In addition, URA improved tyrosine hydroxylase expression in dopaminergic neurons by immunohistochemistry (IHC) staining, and thus increased the neurotransmitter levels of DA and relevant metabolites. Furthermore, URA promoted mitophagy as reflected by a significant decrease in reactive oxygen species (ROS) generation, an increase in ATP levels and clearance of damaged mitochondria. Subsequently, Ubiquitin C-terminal hydrolase 1 (UCHL1), which is associated with the mitochondrial dysfunction in PD, is suggested to be a promising target based on the proteomics result, and proved by the blocked protective effects of URA by UCHL1 inhibitor. Furthermore, hirsuteine (HTE) was identified as a potential active compound of URA binding to UCHL1 by BLI, and the binding capacity and site were verified by surface plasmon resonance (SPR) and molecular docking. CONCLUSION This work demonstrates that URA exerts effective neuroprotective activity against PD via activation of mitophagy with the involvement of UCHL1, and HTE may be a potential active compound of URA.
Collapse
Affiliation(s)
- Xingzi Hou
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Xiaomin Liang
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Xin Zhao
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Yanyan Shi
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, PR China.
| | - Fangfang Zhuo
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Xinnuo Tong
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Xunfang Yang
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Qi Zhai
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Jie Wang
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Qiang Guo
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, PR China.
| | - Pengfei Tu
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Kewu Zeng
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| | - Qingying Zhang
- State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, PR China.
| |
Collapse
|
12
|
Qin W, Su R, Chen X, Liang Z, Huang L, Qian X, Yang Y, Qi S, Luo X. Synergistic Anti-Ferroptosis with a Minimalistic, Peroxide-Triggered Carbon Monoxide Donor for Parkinson's Disease. J Med Chem 2025. [PMID: 39895106 DOI: 10.1021/acs.jmedchem.4c02691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Parkinson's disease (PD) is a debilitating neurodegenerative disease, with current treatments primarily focusing on improving dopaminergic activity, providing symptomatic relief but failing to halt disease progression. Ferroptosis drives PD pathogenesis and is a potential therapeutic target. Herein, we introduce a novel peroxide-activated carbon monoxide (CO) donor, PCOD, featuring a streamlined structure designed to potentially enhance blood-brain barrier (BBB) penetration and optimize therapeutic outcomes. PCOD releases CO upon activation by nucleophilic peroxides, e.g., ONOO- and H2O2. This mechanism provides a potent strategy against ferroptosis: first, scavenging peroxides that generate oxidative radicals involved in ferroptosis, and second, CO is proposed to inhibit Fenton chemistry through coordination to Fe2+. In MPTP-treated mice, PCOD prevents dopaminergic neuron loss in the substantia nigra and alleviates PD symptoms. This peroxide-triggered CO release offers a promising and innovative strategy to combat ferroptosis and neurodegeneration in PD.
Collapse
Affiliation(s)
- Wenjie Qin
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
| | - Ruiqi Su
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Tongshan Road 209, Xuzhou 221004, China
| | - Xiaodie Chen
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
| | - Zhiyan Liang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Tongshan Road 209, Xuzhou 221004, China
| | - Linyan Huang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Tongshan Road 209, Xuzhou 221004, China
| | - Xuhong Qian
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
| | - Youjun Yang
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
| | - Suhua Qi
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Tongshan Road 209, Xuzhou 221004, China
| | - Xiao Luo
- Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| |
Collapse
|
13
|
Zhang F, Liu YX, Zhu YY, Yu QY, Msigwa SS, Zeng ZH, Zhang X, Wu HM, Zhu JH. The epidemiological risk and prevention and interventions in Parkinson's disease: from a nutrition-based perspective. J Nutr 2025:S0022-3166(25)00035-5. [PMID: 39900185 DOI: 10.1016/j.tjnut.2025.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/21/2025] [Accepted: 01/29/2025] [Indexed: 02/05/2025] Open
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder associated with aging. Current treatments for PD primarily focus on alleviating symptoms rather than altering the progression of the disease. The sporadic form of PD, which accounts for most cases, is thought to arise from a complex interaction between genetic predispositions and environmental factors. This review examined epidemiological evidence regarding nutrition-related exposure factors and their associations with the risk of developing PD. We proposed a tentative conclusion for each factor based on the available evidence. These associations may vary by gender and depend on dietary intake patterns and adherence. We also reviewed clinical trials on nutrition-related interventions for PD symptoms and progression. Future clinical trials may benefit from combining nutrition factors in intervention and testing within single-gender cohorts or subgroups defined by epidemiological outcomes.
Collapse
Affiliation(s)
- Fan Zhang
- Department of Neurology and Institute of Geriatric Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; Institute of Nutrition and Diseases and Center for Research
| | - Yu-Xian Liu
- Department of Neurology and Institute of Geriatric Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yun-Yue Zhu
- Institute of Nutrition and Diseases and Center for Research
| | - Qiu-Yan Yu
- Department of Epidemiology and Statistics, School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Samwel Sylvester Msigwa
- Department of Neurology and Institute of Geriatric Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhi-Hai Zeng
- Institute of Nutrition and Diseases and Center for Research
| | - Xiong Zhang
- Department of Neurology and Institute of Geriatric Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hong-Mei Wu
- Institute of Nutrition and Diseases and Center for Research.
| | - Jian-Hong Zhu
- Institute of Nutrition and Diseases and Center for Research; Department of Neurology and Institute of Geriatric Neurology, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| |
Collapse
|
14
|
Salvadè M, DiLuca M, Gardoni F. An update on drug repurposing in Parkinson's disease: Preclinical and clinical considerations. Biomed Pharmacother 2025; 183:117862. [PMID: 39842271 DOI: 10.1016/j.biopha.2025.117862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/13/2025] [Accepted: 01/18/2025] [Indexed: 01/24/2025] Open
Abstract
The strategy of drug repositioning has historically played a significant role in the identification of new treatments for Parkinson's disease. Still today, numerous clinical and preclinical studies are investigating drug classes, already marketed for the treatment of metabolic disorders, for their potential use in Parkinson's disease patients. While drug repurposing offers a promising, fast, and cost-effective path to new treatments, these drugs still require thorough preclinical evaluation to assess their efficacy, addressing the specific neurodegenerative mechanisms of the disease. This review explores the state-of-the-art approaches to drug repurposing for Parkinson's disease, highlighting particularly relevant aspects. Preclinical studies still predominantly rely on traditional neurotoxin-based animal models, which fail to effectively replicate disease progression and are characterized by significant variability in model severity and timing of drug treatment. Importantly, for almost all the drugs analyzed here, there is insufficient data regarding the mechanism of action responsible for the therapeutic effect. Regarding drug efficacy, these factors may obviously render results less reliable or comparable. Accordingly, future preclinical drug repurposing studies in the Parkinson's disease field should be carried out using next-generation animal models like α-synuclein-based models that, unfortunately, have to date been used mostly for studies of disease pathogenesis and only rarely in pharmacological studies.
Collapse
Affiliation(s)
- Michela Salvadè
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan, Italy; School of Advanced Studies, Center for Neuroscience, University of Camerino, Camerino, Italy
| | - Monica DiLuca
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan, Italy
| | - Fabrizio Gardoni
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan, Italy.
| |
Collapse
|
15
|
Rojas-Pirela M, Andrade-Alviárez D, Rojas V, Marcos M, Salete-Granado D, Chacón-Arnaude M, Pérez-Nieto MÁ, Kemmerling U, Concepción JL, Michels PAM, Quiñones W. Exploring glycolytic enzymes in disease: potential biomarkers and therapeutic targets in neurodegeneration, cancer and parasitic infections. Open Biol 2025; 15:240239. [PMID: 39904372 PMCID: PMC11793985 DOI: 10.1098/rsob.240239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 12/11/2024] [Accepted: 12/16/2024] [Indexed: 02/06/2025] Open
Abstract
Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it is responsible for generating ATP in the cell through the conversion of glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed into the electron chain in the mitochondria to produce additional ATP by oxidative phosphorylation), as well as for producing intermediates that can serve as substrates for other metabolic processes. Glycolysis takes place through 10 consecutive chemical reactions, each of which is catalysed by a specific enzyme. Although energy transduction by glucose metabolism is the main function of this pathway, involvement in virulence, growth, pathogen-host interactions, immunomodulation and adaptation to environmental conditions are other functions attributed to this metabolic pathway. In humans, where glycolysis occurs mainly in the cytosol, the mislocalization of some glycolytic enzymes in various other subcellular locations, as well as alterations in their expression and regulation, has been associated with the development and progression of various diseases. In this review, we describe the role of glycolytic enzymes in the pathogenesis of diseases of clinical interest. In addition, the potential role of these enzymes as targets for drug development and their potential for use as diagnostic and prognostic markers of some pathologies are also discussed.
Collapse
Affiliation(s)
- Maura Rojas-Pirela
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca37007, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
- Servicio de Medicina Interna, Hospital Universitario de Salamanca, Salamanca37007, Spain
| | - Diego Andrade-Alviárez
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| | - Verónica Rojas
- Instituto de Biología, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso2373223, Chile
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca37007, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
- Servicio de Medicina Interna, Hospital Universitario de Salamanca, Salamanca37007, Spain
| | - Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca37007, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
| | - Marirene Chacón-Arnaude
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| | - María Á. Pérez-Nieto
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, Salamanca37007, Spain
- Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León, Soria42002, Spain
| | - Ulrike Kemmerling
- Instituto de Ciencias Biomédicas, Universidad de Chile, Facultad de Medicina, Santiago de Chile8380453, Chile
| | - Juan Luis Concepción
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| | - Paul A. M. Michels
- School of Biological Sciences, University of Edinburgh, The King’s Buildings, EdinburghEH9 3FL, UK
| | - Wilfredo Quiñones
- Laboratorio de Enzimología de Parásitos, Departamento de Biología, Facultad de Ciencias, Universidad de Los Andes, Mérida5101, Venezuela
| |
Collapse
|
16
|
Zhang J, Fu Z, Wen F, Lyu P, Huang S, Cai X, Zhang Z, Zhang Y, Fan C, Man W, Sun X, Huang Y. Electroacupuncture ameliorated locomotor symptoms in MPTP-induced mice model of Parkinson's disease by regulating autophagy via Nrf2 signaling. J Neurophysiol 2025; 133:490-501. [PMID: 39745671 DOI: 10.1152/jn.00497.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 01/25/2025] Open
Abstract
Parkinson's disease (PD) is a prevalent and challenging neurodegenerative disorder, and may involve impaired autophagy. Nuclear factor erythroid-2-related factor 2 (Nrf2) is crucial for regulating autophagy-related genes and maintaining cellular homeostasis. Electroacupuncture (EA), a complementary and alternative therapy for PD, has gained widespread clinical application. In this study, we investigate whether EA at Baihui (GV20) and Taichong (LR3) acupoints modulates autophagy through the Nrf2 pathway, providing neuroprotection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Using wild-type and Nrf2 knockout (KO) mice, we examined EA's effects on dopaminergic neuron survival, α-synuclein expression, motor function and the underlying mechanisms. Results showed that EA treatment significantly reduced dopaminergic neuron loss and α-synuclein expression, and improved motor deficits while restoring autophagy, as evidenced by increased autophagy markers (Atg7, LC3II) and decreased p62 levels. Transmission electron microscopy confirmed a rise in autophagosomes and lysosomes in the MPTP + EA group. EA also enhanced nuclear Nrf2 expression and activated Nrf2 signaling. Importantly, Nrf2 KO mice did not exhibit neuroprotection or increased autophagy-related proteins following EA treatment. In conclusion, our research demonstrated that EA ameliorated defective autophagy and activated the Nrf2 signaling pathway, which collectively contribute to its neuroprotective effects against MPTP-induced neurotoxicity.NEW & NOTEWORTHY In this study, we explored the potential mechanism of electroacupuncture (EA) therapy at the GV20 and LR3 acupoints of Parkinson's disease (PD). We demonstrated EA therapy's neuroprotective effect on PD, through ameliorating defective autophagy and activating the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway whereas the regulation of EA on autophagy was absent in Nrf2 knockout (KO) mice. Our study not only provides new insights into the therapeutic mechanisms of EA but also suggests a promising strategy for PD treatment.
Collapse
Affiliation(s)
- Jiping Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
- Zhujiang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhiyi Fu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Feng Wen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Peilin Lyu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Shengtao Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Xiaowen Cai
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhinan Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Ying Zhang
- Department of Ultrasonic Diagnosis, General Hospital of Southern Theater Command of PLA, Guangzhou, People's Republic of China
| | - Chun Fan
- League Committee, Guangzhou University of Chinese Medicine, Guangzhou, People's Republic of China
| | - Weitao Man
- Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People's Republic of China
| | - Xiaomin Sun
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Yong Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People's Republic of China
- Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| |
Collapse
|
17
|
Wang Y, Liu J, Hui Y, Wu Z, Wu X, Bai Y, Li J, Zhang L, Liu K, Zhang Q, Li L. Acute Intermittent Theta-Burst Stimulation Produces Antidepressant-Like Effects by Modulating Neuronal Oscillations and Serotonin Levels of the Medial Prefrontal Cortex in Experimental Parkinson's Disease. J Neurosci Res 2025; 103:e70022. [PMID: 39902890 DOI: 10.1002/jnr.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 11/18/2024] [Accepted: 01/05/2025] [Indexed: 02/06/2025]
Abstract
Parkinson's disease (PD)-related depression is associated with aberrant neuronal oscillations and 5-hydroxytryptamine (5-HT) neurotransmission in the medial prefrontal cortex (mPFC). Intermittent theta-burst stimulation (iTBS), an updated pattern of high-frequency repetitive transcranial magnetic stimulation, has possible efficacy in PD-related depression. However, whether iTBS alleviates PD-related depression through modulating neuronal oscillations and 5-HT levels in the mPFC has not been determined. In this study, male Sprague-Dawley rats were used to establish a unilateral 6-hydroxydopamine-induced PD model. Then, acute iTBS was applied to the parkinsonian rats, and behavioral, neurochemical, and electrophysiological experiments were performed. We found that the parkinsonian rats exhibited increased immobility time and decreased sucrose preference accompanied by an increase of δ power and a decrease of θ power in the mPFC compared to sham-operated rats. One block of iTBS (1 block-iTBS, 300 stimuli) alleviated depressive-like behaviors in parkinsonian rats and elevated 5-HT levels in the mPFC compared to sham-iTBS. Additionally, it altered neuronal oscillations in the mPFC in the opposite fashion by suppressing the δ rhythm and enhancing the θ and β rhythms compared to sham-iTBS, suggesting that acute iTBS induces hyperactivity in the mPFC. With this iTBS paradigm, we also observed decreased parvalbumin expression in the mPFC, reflecting reduced cortical inhibition. Finally, correlation analyses showed strong correlation between immobility time and θ power after 1 block-iTBS. These findings suggest that the application of acute iTBS in parkinsonian rats produces antidepressant-like effects, which may be associated with elevated 5-HT levels and normalized neuronal oscillations in the mPFC.
Collapse
Affiliation(s)
- Yixuan Wang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jian Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Yanping Hui
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Zhongheng Wu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Xiang Wu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yihua Bai
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jing Li
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Lei Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Kuncheng Liu
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiaojun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Libo Li
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| |
Collapse
|
18
|
Elkamhawy A, Oh JM, Kim M, El-Halaby LO, Abdellattif MH, Al-Karmalawy AA, Kim H, Lee K. Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase. Mol Divers 2025; 29:179-193. [PMID: 38727994 DOI: 10.1007/s11030-024-10841-9] [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: 12/29/2023] [Accepted: 03/07/2024] [Indexed: 02/02/2025]
Abstract
Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC50 value of 0.294 μM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC50 value of 0.519 μM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.
Collapse
Affiliation(s)
- Ahmed Elkamhawy
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Jong Min Oh
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea
| | - Minkyoung Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
| | - Lamiaa O El-Halaby
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Magda H Abdellattif
- Chemistry Department, College of Sciences, University College of Taraba, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, 12566, Giza, Egypt
| | - Hoon Kim
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.
| | - Kyeong Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
| |
Collapse
|
19
|
Ji W, Fu Y, Zheng H, Li Y. Multi-label speech feature selection for Parkinson's Disease subtype recognition using graph model. Comput Biol Med 2025; 185:109566. [PMID: 39719792 DOI: 10.1016/j.compbiomed.2024.109566] [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: 12/09/2023] [Revised: 06/10/2024] [Accepted: 12/09/2024] [Indexed: 12/26/2024]
Abstract
Parkinson's Disease (PD) is the second-most common neurodegenerative disorder. There is a certain pathological connection between PD and dysphonia. Speech signals have been successfully used to identify PD and predict its severity. Moreover, PD has several subtypes, such as tremor, freezing of gait and dysphagia. The recognition of subtypes is of great significance for the diagnosis and treatment of PD. In this paper, we consider PD subtype recognition as a multi-label learning task and try to simultaneously recognize these subtypes using speech signals. In the proposed recognition framework, multiple types of speech data are collected, such as/a/,/pa-ka-la/, etc., and different speech features are extracted from different types of speech data. The features are concatenated as the representation of speech data. Especially, a multi-label speech feature selection algorithm based on graph structure is proposed to choose the key features and followed by a multi-label classifier for PD subtype recognition. The speech samples of 70 PD patients are collected as speech corpus. Experimental results show that the proposed multi-label feature selection method can obtain higher recognition performance than other classical ones in most cases.
Collapse
Affiliation(s)
- Wei Ji
- School of Communications and Information Engineering, Nanjing University of Posts and Telecommunications, Nanjing, Jiangsu 210003, China.
| | - Yuchen Fu
- School of Communications and Information Engineering, Nanjing University of Posts and Telecommunications, Nanjing, Jiangsu 210003, China
| | - Huifen Zheng
- Affiliated Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Yun Li
- School of Computer Science, Nanjing University of Posts and Telecommunications, Nanjing, Jiangsu 210023, China.
| |
Collapse
|
20
|
Pham KY, Khanal S, Bohara G, Rimal N, Song SH, Nguyen TTK, Hong IS, Cho J, Kang JS, Lee S, Choi DY, Yook S. HDAC6 inhibitor-loaded brain-targeted nanocarrier-mediated neuroprotection in methamphetamine-driven Parkinson's disease. Redox Biol 2025; 79:103457. [PMID: 39700694 PMCID: PMC11722933 DOI: 10.1016/j.redox.2024.103457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/24/2024] [Accepted: 12/03/2024] [Indexed: 12/21/2024] Open
Abstract
The dynamic equilibrium between acetylation and deacetylation is vital for cellular homeostasis. Parkinson's disease (PD), a neurodegenerative disorder marked by α-synuclein (α-syn) accumulation and dopaminergic neuron loss in the substantia nigra, is associated with a disruption of this balance. Therefore, correcting this imbalance with histone deacetylase (HDAC) inhibitors represents a promising treatment strategy for PD. CAY10603 (CAY) is a potent and selective HDAC6 inhibitor. However, because of its poor water solubility and short biological half-life, it faces clinical limitations. Herein, we engineered lactoferrin-decorated CAY-loaded poly(lactic-co-glycolic acid) nanoparticles (denoted as PLGA@CAY@Lf NPs) to effectively counter methamphetamine (Meth)-induced PD. PLGA@CAY@Lf NPs showed enhanced blood-brain barrier crossing and significant brain accumulation. Notably, CAY released from PLGA@CAY@Lf NPs restored the disrupted acetylation balance in PD, resulting in neuroprotection by reversing mitochondrial dysfunction, suppressing reactive oxygen species, and inhibiting α-syn accumulation. Additionally, PLGA@CAY@Lf NPs treatment normalized dopamine and tyrosine hydroxylase levels, reduced neuroinflammation, and improved behavioral impairments. These findings underscore the potential of PLGA@CAY@Lf NPs in treating Meth-induced PD and suggest that an innovative HDAC6-inhibitor-based strategy can be used to treat PD.
Collapse
Affiliation(s)
- Khang-Yen Pham
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Shristi Khanal
- College of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of Korea
| | - Ganesh Bohara
- College of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of Korea
| | - Nikesh Rimal
- College of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of Korea
| | - Sang-Hoon Song
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea
| | - Thoa Thi Kim Nguyen
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - In-Sun Hong
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 21565, Republic of Korea
| | - Jinkyung Cho
- College of Sport Science, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Jong-Sun Kang
- Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Sooyeun Lee
- College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea.
| | - Dong-Young Choi
- College of Pharmacy, Yeungnam University, Gyeongbuk, 38541, Republic of Korea.
| | - Simmyung Yook
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| |
Collapse
|
21
|
Soto C, Mollenhauer B, Hansson O, Kang UJ, Alcalay RN, Standaert D, Trenkwalder C, Marek K, Galasko D, Poston K. Toward a biological definition of neuronal and glial synucleinopathies. Nat Med 2025:10.1038/s41591-024-03469-7. [PMID: 39885358 DOI: 10.1038/s41591-024-03469-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 12/12/2024] [Indexed: 02/01/2025]
Abstract
Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living patients and to differentiate between neuronal or glial αSyn pathology. We anticipate that a biological definition of synucleinopathies, if well-integrated with the current clinical classifications, will enable further understanding of the disease pathogenesis and contribute to the development of effective, disease-modifying therapies.
Collapse
Affiliation(s)
- Claudio Soto
- Department of Neurology, Mitchell Center for Alzheimer's disease and related brain disorders, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.
| | - Brit Mollenhauer
- University Medical Center Göttingen, Department of Neurology, Göttingen, Germany
- Paracelsus-Elena-Klinik, Kassel, Germany
- Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Oskar Hansson
- Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
- Memory Clinic, Skåne University Hospital, Malmö, Sweden
| | - Un Jung Kang
- Departments of Neurology and Neuroscience & Physiology, Neuroscience Institute, Fresco Institute for Parkinson's Disease and Movement Disorders, Parekh Center for Interdisciplinary Neurology, Grossman School of Medicine, New York University, New York, NY, USA
| | - Roy N Alcalay
- Columbia University Irving Medical Center, New York, NY, USA
- Tel Aviv Sourasky Medical Center, Tel Aviv University School of Medicine, Tel Aviv, Israel
| | - David Standaert
- Department of Neurology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Claudia Trenkwalder
- University Medical Center Göttingen, Department of Neurology, Göttingen, Germany
- Paracelsus-Elena-Klinik, Kassel, Germany
| | - Kenneth Marek
- Institute for Neurodegerative Disorders, New Haven, CT, USA
| | - Douglas Galasko
- Department of Neurosciences and Shiley-Marcos Alzheimer's Disease Research Center, UC San Diego, La Jolla, CA, USA
| | - Kathleen Poston
- Department of Neurology & Neurological Sciences, Stanford Movement Disorders Center, Stanford University, Stanford, CA, USA
| |
Collapse
|
22
|
Shi X, He W, Gupta A, To K, Clark L, Mirle N, Wynn T, Wang D, Ganesh A, Zeng HM, Wang H. Extracellular vesicles as drug and gene delivery vehicles in central nervous system diseases. Biomater Sci 2025. [PMID: 39871579 PMCID: PMC11773327 DOI: 10.1039/d4bm01394h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 01/08/2025] [Indexed: 01/29/2025]
Abstract
Extracellular vesicles (EVs) are secreted by almost all cell types and contain DNA, RNA, proteins, lipids and other metabolites. EVs were initially believed to be cellular waste but now recognized for their role in cell-to-cell communication. Later, EVs from immune cells were discovered to function similarly to their parent cells, paving the way for their use as gene and drug carriers. EVs from different cell types or biological fluids carry distinct cargo depending on their origin, and they perform diverse functions. For instance, EVs derived from stem cells possess pluripotent properties, reflecting the cargo from their parent cells. Over the past two decades, substantial preclinical and clinical research has explored EVs-mediated drug and gene delivery to various organs, including the brain. Natural or intrinsic EVs may be effective for certain applications, but as drug or gene carriers, they demonstrate broader and more efficient potential across various diseases. Here, we review research on using EVs to treat central nervous system (CNS) diseases, such as Alzheimer's Disease, Parkinson diseases, depression, anxiety, dementia, and acute ischemic strokes. We first reviewed the naïve EVs, especially mesenchymal stem cell (MSC) derived EVs in CNS diseases and summarized the clinical trials of EVs in treating CNS diseases and highlighted the reports of two complete trials. Then, we overviewed the preclinical research of EVs as drug and gene delivery vehicles in CNS disease models, including the most recent two years' progress and discussed the mechanisms and new methods of engineered EVs for targeting CNS. Finally, we discussed challenges and future directions and of EVs as personalized medicine for CNS diseases.
Collapse
Affiliation(s)
- Xi Shi
- Department of Molecular Bioscience, The University of Texas at Austin, Austin, Texas 78712, USA.
| | - Weilong He
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Ashwin Gupta
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Kyran To
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Leonardo Clark
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Nitya Mirle
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Thomas Wynn
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Daniel Wang
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Akash Ganesh
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Helena M Zeng
- Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA
| | - Huiliang Wang
- Department of Molecular Bioscience, The University of Texas at Austin, Austin, Texas 78712, USA.
- Biomedical Engineering Cockrell School of Engineering, The University of Texas at Austin, Austin, Texas 78712, USA
| |
Collapse
|
23
|
Huang Y, Fu Q, Liu DF. Assessment of stigma among patients living with Parkinson's disease: an exploratory study. Acta Neurol Belg 2025:10.1007/s13760-025-02728-9. [PMID: 39865165 DOI: 10.1007/s13760-025-02728-9] [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: 09/15/2024] [Accepted: 01/12/2025] [Indexed: 01/28/2025]
Abstract
OBJECTIVE This cross-sectional study aims to assess the levels of stigma among patients with Parkinson's disease (PD) and identify the demographic and clinical factors influencing both internal and external stigma. MATERIALS AND METHODS A total of 200 patients diagnosed with PD were recruited from Beijing Tiantan Hospital between June 2023 and June 2024 using convenience sampling. Data were collected through face-to-face interviews, including demographic information, disease severity assessed via the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and stigma levels measured using the 24-item Stigma Scale for Chronic Illness (SSCI). Statistical analyses included t-tests, ANOVA, correlation analysis, and multivariate linear regression. RESULTS The average SSCI score among PD patients was 58.74 ± 13.73, with significant variation based on age, gender, educational level, marital status, disease duration, and motor subtype. Patients aged under 60, male, with lower educational attainment, divorced or widowed, and with longer disease duration had higher SSCI scores. MDS-UPDRS Part I-III scores were positively correlated with both internal and external stigma (r = 0.4, 0.5, and 0.5, respectively, p < 0.001). Multivariate linear regression analysis identified MDS-UPDRS scores, age, self-care ability, marital status, disease duration, and motor subtype as independent predictors of stigma. CONCLUSION Stigma in PD is influenced by a combination of demographic and disease-related factors, particularly disease severity. Targeted interventions focusing on reducing motor and non-motor symptoms, as well as addressing social determinants, may help alleviate the stigma experienced by PD patients. These findings underscore the need for comprehensive management strategies that incorporate both clinical treatment and psychosocial support.
Collapse
Affiliation(s)
- Yue Huang
- Department of Operating room, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
- Beijing Tiantan Hospital, 119 South 4th Ring West Rd, Fengtai District, Beijing, 100050, China.
| | - Qing Fu
- Department of Operating room, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - De-Feng Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| |
Collapse
|
24
|
Palm D, Swarowsky A, Kelly M, Grugel S, Stiers C, Wolden M. Effect of group exercise on quality of life for Parkinson disease: systematic review and meta-analysis. Disabil Rehabil 2025:1-13. [PMID: 39865595 DOI: 10.1080/09638288.2025.2453636] [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: 07/24/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/28/2025]
Abstract
PURPOSE Motor and non-motor symptoms can negatively affect quality of life (QoL) for people with Parkinson Disease (PD). Our purpose was to investigate the effects of group exercise (GE) compared to individual exercise (IE) and usual care (UC) on QoL for people with PD. A systematic review and meta-analysis were performed with randomized controlled trials that studied the effects of GE compared to IE and UC on QoL for people with PD. MATERIALS AND METHODS The systematic search was performed in EBSCO, PubMed, and Science Direct databases. Quality of methodology was assessed using the Cochrane GRADE approach. Thirteen studies met all inclusion criteria and were included in the analysis. RESULTS No significant difference was found on QoL between GE and IE; however, QoL was significantly improved with GE compared to UC. Results were based on low to moderate quality of evidence. CONCLUSIONS Based on low to moderate quality of evidence, GE has a similar effect on QoL when compared to IE and has a small and statistically significant effect when compared to UC, regardless of the patient reported outcome measure used or the total volume of exercise prescribed. GE may be an appropriate option for people with PD to improve their QoL.
Collapse
Affiliation(s)
- Diana Palm
- Physical Therapy Program, University of Jamestown, Fargo, ND, USA
| | | | | | - Samuel Grugel
- Physical Therapy Program, University of Jamestown, Fargo, ND, USA
| | - Connor Stiers
- Physical Therapy Program, University of Jamestown, Fargo, ND, USA
| | - Mitch Wolden
- Physical Therapy Program, University of Jamestown, Fargo, ND, USA
| |
Collapse
|
25
|
Cong H, Hu J, Wang J, Chang B, Li R, Cui X, Zhang C, Ji H, Lin C, Tang J, Liu J. Bromocriptine mesylate-loaded nanoparticles co-modified with low molecular weight protamine and lactoferrin for enhanced nose-to-brain delivery in Parkinson's disease treatment. Int J Pharm 2025; 669:125054. [PMID: 39667592 DOI: 10.1016/j.ijpharm.2024.125054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/01/2024] [Accepted: 12/05/2024] [Indexed: 12/14/2024]
Abstract
Parkinson's disease confronts challenges in drug delivery due to the blood-brain barrier. Intranasal delivery bypasses the blood-brain barrier for improved drug bioavailability, yet narrow nasal space and brief retention time hinder clinical applicability. We conducted a Bromocriptine Mesylate-loaded PLGA nanoparticles co-modified with low molecular weight protamine (LMWP) and lactoferrin (Lf) (LMWP/Lf-BCM-NPs) for nose-to-brain delivery. The resulting LMWP/Lf-BCM-NPs were uniform spheres with an average size of 248.53 ± 16.25 nm and zeta potential of -2.63 ± 0.74 mV. Fourier transform infrared spectroscopy confirmed LMWP and Lf attachment. The co-modified nanoparticles showed improving cellular transport and good viability. The LMWP/Lf-BCM-NPs showed increased brain targeting efficiency in mice. In haloperidol-induced Parkinson mouse models, the LMWP/Lf-BCM-NPs showed increased brain targeting efficiency, enhanced behavioral regulatory effects, enhanced antioxidant effects and neuroprotection effects. This study paves the way for a novel, non-invasive brain-targeted therapy, offering a promising avenue for Parkinson's disease clinical treatment.
Collapse
Affiliation(s)
- Huijing Cong
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jing Hu
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jing Wang
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Baiyu Chang
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Rongtao Li
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Xinran Cui
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Chenghao Zhang
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Hongyu Ji
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Congcong Lin
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China
| | - Jingling Tang
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China.
| | - Jiaxin Liu
- Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China.
| |
Collapse
|
26
|
Jana RD, Nguyen HD, Yan G, Chen TY, Do LH. Reversing Signs of Parkinsonism in a Cell Model Using Mitochondria-Targeted Organoiridium Catalysis. J Med Chem 2025; 68:1970-1983. [PMID: 39749732 PMCID: PMC11757046 DOI: 10.1021/acs.jmedchem.4c02741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
We report the application of organoiridium complexes as catalytic agents for the detoxification of biogenic reactive aldehyde species (RASP), which are implicated in the pathogenesis of neurodegenerative disorders. We show that Ir complexes functionalized with phosphonium cations localize selectively in the mitochondria and have better cellular retention compared to that of their parent Ir species. In a cell model for Parkinsonism, the mitochondria-targeted iridium catalysts exhibited superior cell protecting abilities and longer-lasting effects (up to 6 d) than conventional RASP scavengers, which failed to be effective beyond 24 h. Our biological assays indicate that treatment with the Ir compounds led to reduction in reactive oxygen species and aldehyde levels while partially preserving the native mitochondrial membrane potential and NAD+/NADH ratio in 1-methyl-4-phenylpyridinium-inhibited cells. Our work is the first to demonstrate catalytic nonenzymatic detoxification of RASP in living systems.
Collapse
Affiliation(s)
- Rahul D. Jana
- Department of Chemistry, University of Houston, 4800 Calhoun Rd., Houston, Texas, 77204, United States
| | - Hieu D. Nguyen
- Department of Chemistry, University of Houston, 4800 Calhoun Rd., Houston, Texas, 77204, United States
| | - Guangjie Yan
- Department of Chemistry, University of Houston, 4800 Calhoun Rd., Houston, Texas, 77204, United States
| | - Tai-Yen Chen
- Department of Chemistry, University of Houston, 4800 Calhoun Rd., Houston, Texas, 77204, United States
| | - Loi H. Do
- Department of Chemistry, University of Houston, 4800 Calhoun Rd., Houston, Texas, 77204, United States
| |
Collapse
|
27
|
Dou L, Xu Z, Xu J, Zang C, Su C, Pieper AA, Leverenz JB, Wang F, Zhu X, Cummings J, Cheng F. A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson's disease. NPJ Parkinsons Dis 2025; 11:22. [PMID: 39837893 PMCID: PMC11751448 DOI: 10.1038/s41531-025-00870-y] [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: 08/06/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments only manage symptoms and lack the ability to slow or prevent disease progression. We utilized a systems genetics approach to identify potential risk genes and repurposable drugs for PD. First, we leveraged non-coding genome-wide association studies (GWAS) loci effects on five types of brain-specific quantitative trait loci (xQTLs, including expression, protein, splicing, methylation and histone acetylation) under the protein-protein interactome (PPI) network. We then prioritized 175 PD likely risk genes (pdRGs), such as SNCA, CTSB, LRRK2, DGKQ, and CD44, which are enriched in druggable targets and differentially expressed genes across multiple human brain-specific cell types. Integrating network proximity-based drug repurposing and patient electronic health record (EHR) data observations, we identified Simvastatin as being significantly associated with reduced incidence of PD (hazard ratio (HR) = 0.91 for fall outcome, 95% confidence interval (CI): 0.87-0.94; HR = 0.88 for dementia outcome, 95% CI: 0.86-0.89) after adjusting for 267 covariates. In summary, our network-based systems genetics framework identifies potential risk genes and repurposable drugs for PD and other neurodegenerative diseases if broadly applied.
Collapse
Affiliation(s)
- Lijun Dou
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Zhenxing Xu
- Department of Population Health Sciences, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
| | - Jielin Xu
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Chengxi Zang
- Department of Population Health Sciences, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
| | - Chang Su
- Department of Population Health Sciences, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
| | - Andrew A Pieper
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA
- Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, 44106, USA
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
- Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA
| | - James B Leverenz
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
- Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Fei Wang
- Department of Population Health Sciences, Weill Cornell Medical College, Cornell University, New York, NY, 10065, USA
| | - Xiongwei Zhu
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA
| | - Jeffrey Cummings
- Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, Kirk Kerkorian School of Medicine, UNLV, Las Vegas, NV, 89154, USA
| | - Feixiong Cheng
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
| |
Collapse
|
28
|
Lai Y, Reina-Gonzalez P, Maor G, Miller GW, Sarkar S. Biotin mitigates the development of manganese-induced, Parkinson's disease-related neurotoxicity in Drosophila and human neurons. Sci Signal 2025; 18:eadn9868. [PMID: 39836750 DOI: 10.1126/scisignal.adn9868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 08/16/2024] [Accepted: 12/18/2024] [Indexed: 01/30/2025]
Abstract
Chronic exposure to manganese (Mn) induces manganism and has been widely implicated as a contributing environmental factor to Parkinson's disease (PD), featuring notable overlaps between the two in motor symptoms and clinical hallmarks. Here, we developed an adult Drosophila model of Mn toxicity that recapitulated key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosomes and mitochondria. Metabolomics analysis of the brain and body tissues of these flies at an early stage of toxicity identified systemic changes in the metabolism of biotin (also known as vitamin B7) in Mn-treated groups. Biotinidase-deficient flies showed exacerbated Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction. Supplementing the diet of wild-type flies with biotin ameliorated the pathological phenotypes of concurrent exposure to Mn. Biotin supplementation also ameliorated the pathological phenotypes of three standard fly models of PD. Furthermore, supplementing the culture media of human induced stem cells (iPSCs) differentiated midbrain dopaminergic neurons with biotin protected against Mn-induced mitochondrial dysregulation, cytotoxicity, and neuronal loss. Last, analysis of the expression of genes encoding biotin-related proteins in patients with PD revealed increased amounts of biotin transporters in the substantia nigra compared with healthy controls, suggesting a potential role of altered biotin metabolism in PD. Together, our findings identified changes in biotin metabolism as underlying Mn neurotoxicity and parkinsonian pathology in flies, for which dietary biotin supplementation was preventative.
Collapse
Affiliation(s)
- Yunjia Lai
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Pablo Reina-Gonzalez
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
| | - Gali Maor
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Gary W Miller
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - Souvarish Sarkar
- Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| |
Collapse
|
29
|
Wang C, Wang YL, Xu QH. Integrating network pharmacology with molecular docking and dynamics to uncover therapeutic targets and signaling mechanisms of vitamin D3 in Parkinson's disease. Mol Divers 2025:10.1007/s11030-024-11090-6. [PMID: 39821175 DOI: 10.1007/s11030-024-11090-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 12/19/2024] [Indexed: 01/19/2025]
Abstract
Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD's hub targets and related pathways. We identified 24 VD's anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD's anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson's disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson's disease treatment.
Collapse
Affiliation(s)
- Cheng Wang
- School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, People's Republic of China
| | - Yi-Ling Wang
- School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, People's Republic of China
| | - Qiu-Han Xu
- School of Medicine, Zhejiang University, Hangzhou, 310000, Zhejiang, People's Republic of China.
| |
Collapse
|
30
|
Wang J, Yuan Y, Xie T, Zhang L, Xu H, Lin SC, Yang Y, Zhu D, Zhuang J. Optimal dose and type of exercise to improve motor symptoms in adults with Parkinson's disease: A network meta-analysis. J Sci Med Sport 2025:S1440-2440(25)00003-9. [PMID: 39880702 DOI: 10.1016/j.jsams.2025.01.003] [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: 05/09/2024] [Revised: 12/05/2024] [Accepted: 01/08/2025] [Indexed: 01/31/2025]
Abstract
OBJECTIVES This study aimed to evaluate the dose-response relationship between different exercise types and the alleviation of motor symptoms in Parkinson's Disease patients. DESIGN A systematic review and network meta-analysis were conducted to compare the effects of 12 exercise types on motor symptoms in Parkinson's Disease patients using randomized controlled trials. METHODS A systematic search was conducted across PubMed, Medline, Embase, PsycINFO, Cochrane Library, and Web of Science until September 10, 2024. A total of 81 trials involving 4596 patients were included. Mean differences with 95 % credible intervals were calculated, and evidence quality was assessed using Confidence in Network Meta-Analysis. The Minimum Clinically Important Difference was used to assess clinical efficacy. RESULTS The optimal exercise dose for overall motor symptom improvement was 1300 MET-min/week (mean difference: -6.07, 95 % credible intervals: -8.10 to -4.01). Dance at 850 MET-min/week provided the greatest improvement (mean difference: -11.18, 95 % credible intervals: -16.01 to -6.22). Significant improvements were seen with doses as low as 60-100 MET-min/week for body weight support training, dance, resistance training, and sensory exercise. The Minimum Clinically Important Difference was achieved with doses exceeding 670 MET-min/week for overall exercise, and at lower doses for specific types: aerobic exercise (1100 MET-min/week), body weight support (420 MET-min/week), and dance (230 MET-min/week). CONCLUSIONS The optimal exercise dose for alleviating motor symptoms in Parkinson's Disease patients is 1300 MET-min/week, with dance being most effective at 850 MET-min/week. These findings provide evidence-based recommendations for Parkinson's Disease management.
Collapse
Affiliation(s)
- Junyu Wang
- Hunan University of Medicine, China; School of Exercise and Health, Shanghai University of Sport, China
| | - Yuan Yuan
- School of Physical Education, Kunsan National University, Republic of Korea
| | - Ting Xie
- Chengdu Xinqiao Primary School, China
| | - Ligong Zhang
- China Wushu School, Beijing Sport University, China
| | - Hong Xu
- Exercise Rehabilitation Research Institute, Sangmyung University, 03016, Republic of Korea
| | - Shu-Cheng Lin
- Department of Sport, Leisure and Health Management, Tainan University of Technology, Taiwan
| | - Yong Yang
- Laboratory of Kinesiology and Rehabilitation, School of Physical Education and Sport, Chaohu University, China.
| | - Dong Zhu
- Hunan University of Medicine, China.
| | - Jie Zhuang
- School of Exercise and Health, Shanghai University of Sport, China.
| |
Collapse
|
31
|
Sobral J, Empadinhas N, Esteves AR, Cardoso SM. Impact of Nutrition on the Gut Microbiota: Implications for Parkinson's Disease. Nutr Rev 2025:nuae208. [PMID: 39812804 DOI: 10.1093/nutrit/nuae208] [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] [Indexed: 01/16/2025] Open
Abstract
Parkinson's disease (PD) is a multifactorial neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and by the anomalous accumulation of α-synuclein aggregates into Lewy bodies and Lewy neurites. Research suggests 2 distinct subtypes of PD: the brain-first subtype if the pathology arises from the brain and then spreads to the peripheral nervous system (PNS) and the body-first subtype, where the pathological process begins in the PNS and then spreads to the central nervous system. This review primarily focuses on the body-first subtype. The influence of the gut microbiota on the development of PD has been the subject of growing interest among researchers. It has been suggested that gut inflammation may be closely associated with pathogenesis in PD, therefore leading to the hypothesis that gut microbiota modulation could play a significant role in this process. Nutrition can influence gut health and alter the risk and progression of PD by altering inflammatory markers. This review provides an overview of recent research that correlates variations in gut microbiota composition between patients with PD and healthy individuals with the impact of certain nutrients and dietary patterns, including the Mediterranean diet, the Western diet, and the ketogenic diet. It explores how these diets influence gut microbiota composition and, consequently, the risk of PD. Last, it examines fecal transplantation and the use of prebiotics, probiotics, or synbiotics as potential therapeutic strategies to balance the gut microbiome, aiming to reduce the risk or delay the progression of PD.
Collapse
Affiliation(s)
- Joana Sobral
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra 3004-504, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra 3004-504, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal
| | - Nuno Empadinhas
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra 3004-504, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra 3004-504, Portugal
| | - Ana Raquel Esteves
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra 3004-504, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra 3004-504, Portugal
| | - Sandra Morais Cardoso
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra 3004-504, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra 3004-504, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal
| |
Collapse
|
32
|
Li CH, Hsueh SJ, Tsai LK, Chang WH, Cheng SY, Cheng HM, Yeh CF, Lin YH, Tsai HH. Blood pressure targets, medication considerations and special concerns in elderly hypertension III: Focus on stroke and neurodegenerative disorders. J Formos Med Assoc 2025:S0929-6646(25)00008-7. [PMID: 39818464 DOI: 10.1016/j.jfma.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 12/01/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025] Open
Abstract
Controlling hypertension has become an important issue in the elderly population in whom neurological comorbidities are highly prevalent. Most of the large-scale trials focusing on hypertension management in older populations have excluded patients with comorbid neurological disorders. However, this population requires special considerations, as the benefits of antihypertensive agents are mostly uncertain and there is a higher risk of adverse events. In this review article, we discuss current evidence regarding the management of elderly patients with hypertension and common neurological disorders, including stroke and neurodegenerative diseases. In elderly patient with a history of stroke, the blood pressure management strategy is generally similar to that for young patients, however the benefits of stroke prevention from blood pressure control are less significant. For patients with neurodegenerative disorders such as cognitive dysfunction and Parkinson's disease, achieving adequate blood pressure control may be beneficial in reducing cardiovascular risks, although the higher risk of adverse events from antihypertensive treatment may offset some of these benefits. Special considerations for factors such as orthostatic hypotension, risk of falls, polypharmacy, and significant drug-drug interactions are required but frequently neglected in clinical practice. More efforts are warranted to determine the optimal treatment strategy for elderly populations with neurological disorders.
Collapse
Affiliation(s)
- Cheng-Hsuan Li
- Department of Neurology, National Taiwan University Hospital Hsinchu Branch, Hsin-Chu, Taiwan; Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Sung-Ju Hsueh
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan; Department of Neurology, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
| | - Li-Kai Tsai
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Hung Chang
- Department of Psychiatry, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Shao-Yi Cheng
- Department of Family Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Hao-Min Cheng
- Ph.D. Program of Interdisciplinary Medicine (PIM), National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Division of Faculty Development, Taipei Veterans General Hospital, Taiwan; Center for Evidence-based Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Public Health, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan; Institute of Health and Welfare Policy, National Yang Ming Chiao Tung University College of Medicine, Taipei, Taiwan
| | - Chih-Fan Yeh
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hung Lin
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-Hsi Tsai
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
33
|
Gao W, Wu X, Wang Y, Lu F, Liu F. Brazilin-Rich Extract from Caesalpinia sappan L. Attenuated the Motor Deficits and Neurodegeneration in MPTP/p-Induced Parkinson's Disease Mice by Regulating Gut Microbiota and Inhibiting Inflammatory Responses. ACS Chem Neurosci 2025; 16:181-194. [PMID: 39711007 DOI: 10.1021/acschemneuro.4c00679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024] Open
Abstract
Parkinson's disease (PD) is a complicated neurological disease with an unclear pathogenesis. However, dysregulation of gut microbiota and inflammation response play crucial roles in the progression of PD. Caesalpinia sappan L., a traditional medicinal plant containing brazilin as its primary active compound, is known for its anti-inflammatory and neuroprotective properties. However, the impact of C. sappan L. extract (SE) on PD through the regulation of the microbiota-gut-brain axis remains unclear. This study investigated the effects and mechanisms of a 91.23% brazilin-enriched SE on MPTP/p-induced PD mice. Results showed that SE significantly ameliorated motor deficits and protected dopaminergic neurons in PD mice. Additionally, SE reduced oxidative stress and inflammation in the brain. SE also restored gut microbiota by increasing Firmicutes and decreasing Bacteroidetes, alongside enhancing the production of short-chain fatty acids (SCFAs) like butyric acid. Furthermore, SE mitigated intestinal barrier damage by enhancing the expression of ZO-1 and occludin, thereby decreasing lipopolysaccharide leakage and inflammatory factor release. Molecular simulations suggested that butyric acid may maintain intestinal integrity by stabilizing ZO-I and occludin conformations. In conclusion, SE exhibited a protective effect on motor deficits and neurodegeneration in PD by regulating gut microbiota and SCFAs, repairing the intestinal barrier, and mitigating inflammatory responses.
Collapse
Affiliation(s)
- Wen Gao
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Xinni Wu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Yang Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Fuping Lu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| | - Fufeng Liu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, P. R. China
- Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, P. R. China
- College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, P. R. China
| |
Collapse
|
34
|
Chen J, Wu J, Zhou C, Wu H, Guo T, Bai X, Wu C, Wen J, Qin J, Duanmu X, Tan S, Yuan W, Zheng Q, Zhang B, Guan X, Xu X, Zhang M. Microstructural Degeneration of the Corpus Callosum in Parkinson's Disease with Unilateral Onset: A Free-Water Imaging Study. ACS Chem Neurosci 2025; 16:161-170. [PMID: 39723476 DOI: 10.1021/acschemneuro.4c00598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Background: Motor symptom laterality is an important clinical feature of PD that not only manifests as lateral limb dysfunction but also affects the nonmotor symptoms and the prognosis in PD patients. Previous studies suggested that the compensatory mechanisms in the dominant hemisphere of the brain may be an underlying explanation. The corpus callosum (CC) is the largest fiber connecting the two hemispheres of the brain. Considering the CC as the pointcut may help elucidate the mechanisms underlying how motor symptom laterality affects nonmotor symptoms and prognosis in PD patients. Purpose: To explore microstructural degeneration of the CC in PD patients with unilateral motor symptom onset and evaluate its relationship with motor and nonmotor performance. Methods: In this study, 201 right-handed PD patients with unilateral motor symptom onset (91 patients with left-onset [LPD] and 110 with right-onset [RPD]) and 100 right-handed healthy controls (HC) were included. A bitensor model of diffusion tensor imaging was applied to analyze free water (FW) as well as fractional anisotropy (FAT) and mean diffusivity (MDT) of the tissue compartment after correcting FW. These provide noninvasive in vivo measures of white matter integrity and pathological processes including atrophy, edema, and neuroinflammation. The CC was divided into halves along the median sagittal line, and each half was manually divided into five functional segments. A total of 10 subregions were obtained and numbered in sequence. The laterality index was calculated to quantify the asymmetry of the CC and its segments. A general linear model was used to compare among groups, and partial correlation analysis was performed to explore the relationships between the diffusion parameters of CC subregions and clinical manifestations. Results: Compared with HC, FW and FAT of the bilateral CC were decreased in the LPD group, whereas MDT in the right hemisphere was increased. In the LPD group, FAT of all CC subregions except for subregions 1, 3, and 6 was significantly lower than HC, and MDT in the anterior and posterior segments of the CC (CC subregions 1, 5-7, and 10) was significantly higher than HC. In the RPD group, FAT of subregion 7 was significantly decreased and MDT was increased than HC. Laterality index analysis of the CC indicated significant interhemispheric FAT asymmetry in the anterior and middle in the RPD group, with a more significant reduction in the right CC. Moreover, degeneration of the CC and its subregions was related to motor and nonmotor symptoms in PD. Conclusions: More extensive CC damage was observed in the LPD group than in the RPD group. Additional, asymmetrical damage was observed in the anterior and middle segments of the CC in the RPD group, suggesting that differences in callosal degeneration patterns may be a potential mechanism underlying how asymmetrical motor symptoms affect the nonmotor symptoms and prognosis in PD.
Collapse
Affiliation(s)
- Jingwen Chen
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Jingjing Wu
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Cheng Zhou
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Haoting Wu
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Tao Guo
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Xueqin Bai
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Chenqing Wu
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Jiaqi Wen
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Jianmei Qin
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Xiaojie Duanmu
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Sijia Tan
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Weijin Yuan
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Qianshi Zheng
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Baorong Zhang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Xiaojun Guan
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Xiaojun Xu
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| | - Minming Zhang
- Department of Radiology, The Second Affiliated Hospital, Zhejiang University of Medicine, Hangzhou 310009, China
| |
Collapse
|
35
|
Jiang Z, Huang H, Chen Y, Xie H, Lu Y, Ge Y, Yao R, Wang L, Wu Z, Bu Y, Chen G, Yang D. The role of the immune system in Parkinson's disease pathogenesis: A focus on Th17 cells - A systematic review and meta-analysis. J Neuroimmunol 2025; 398:578484. [PMID: 39577101 DOI: 10.1016/j.jneuroim.2024.578484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 07/16/2024] [Accepted: 11/07/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND Parkinson's disease (PD) has been linked to T helper 17 (Th17) cells in prior investigations, but the evidence remains inconclusive. To gain a deeper understanding of this potential connection, we conducted a systematic review and meta-analysis. METHODS A comprehensive search for relevant studies published up to July 8, 2023, was performed across PubMed, EMBASE, and Cochrane Library databases. A random-effect model was employed to synthesize effect sizes and their corresponding 95 % confidence intervals (CIs). Leave-one-out sensitivity analysis and funnel plots with trim-and-fill were utilized to assess the combined results' robustness. RESULTS Thirteen studies were ultimately included in the meta-analysis. Pooled effect sizes indicated a significantly higher percentage of Th17 cells in PD patients (Standardized Mean Difference [SMD] = 1.00, 95 % CI 0.30-1.71). Notably, Th17 cell levels were more elevated in Asian PD patients (SMD = 1.33, 95 % CI 0.31-2.35). Additionally, the percentage of Th17 cells positively correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale-III (UPDRS-III) scores (r = 0.22, 95 % CI 0.01-0.41), indicating a link to motor dysfunction. Conversely, a negative correlation was observed with Cognitive function scale scores (r = - 0.27, 95 % CI -0.47--0.04), suggesting a potential association with cognitive decline. CONCLUSIONS This study revealed a positive association between Th17 cells and PD, with PD patients exhibiting elevated Th17 levels. Furthermore, the percentage of Th17 cells correlated with motor and cognitive impairments in PD patients.
Collapse
Affiliation(s)
- Zihan Jiang
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Honghao Huang
- Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiqun Chen
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Haobo Xie
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Yangguang Lu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Yaoyin Ge
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Ruotong Yao
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Lingsheng Wang
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Zihao Wu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Yiran Bu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Guangyong Chen
- Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Dehao Yang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| |
Collapse
|
36
|
Li M, Xiong F, Wu S, Wei W, Wang H, Qiao Y, Guo D. Pharmacodynamic Mechanisms of Cicadae Periostracum in Parkinson's Disease: A Metabolomics-Based Study. Int J Mol Sci 2025; 26:544. [PMID: 39859260 PMCID: PMC11764672 DOI: 10.3390/ijms26020544] [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: 12/11/2024] [Revised: 12/31/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Cicadae Periostracum (CP) is a traditional Chinese animal-derived medicine with the potential to treat Parkinson's disease (PD). This study aims to explore the pharmacodynamic mechanisms of CP against PD-based on metabolomics technology and provide a theoretical basis for developing new anti-PD medicine. First, MPP+-induced SH-SY5Y cells were used to evaluate the anti-PD activity of CP. In the animal study, an MPTP-induced PD mouse model was employed to assess CP's therapeutic effects. Immunofluorescence (IF) staining and Western blotting (WB) were used to evaluate its neuroprotective activity on neurons. A Serum metabolomics analysis was conducted to examine CP's regulatory effects on metabolites and to identify vital metabolic pathways. Finally, cellular experiments were performed to validate the critical pathways. Cellular activity experiments demonstrated that CP mitigates MPP+-induced SH-SY5Y cytotoxicity, inhibits apoptosis, and restores mitochondrial homeostasis. Animal experiments revealed that CP significantly alleviates dyskinesia in PD mice, enhances motor performance, and restores neuronal integrity while reducing α-synuclein (α-syn) aggregation in the striatum (STR), showing its strong anti-PD effect. Metabolomic analysis revealed that CP can significantly improve the metabolic disorders of ten biomarkers that are mainly involved in amino acid metabolism and fatty acid β-oxidation and are closely related to oxidative stress pathways. Finally, pathway verification was performed, and the results show that CP exerted neuroprotective effects against PD through the dual signaling pathways of Bcl-2/Bax/Caspase-3 and Nrf2/HO-1. This study provides a comprehensive strategy for elucidating the mechanisms by which CP exerts its therapeutic effects against PD, highlighting its potential in developing anti-PD drugs.
Collapse
Affiliation(s)
- Mengmeng Li
- College of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, China; (M.L.); (F.X.); (H.W.)
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| | - Fuyu Xiong
- College of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, China; (M.L.); (F.X.); (H.W.)
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| | - Shifei Wu
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| | - Wenlong Wei
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| | - Hanze Wang
- College of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, China; (M.L.); (F.X.); (H.W.)
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| | - Yajun Qiao
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| | - Dean Guo
- College of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, China; (M.L.); (F.X.); (H.W.)
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Research Center of TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (S.W.); (W.W.); (Y.Q.)
| |
Collapse
|
37
|
Szablewski L. Associations Between Diabetes Mellitus and Neurodegenerative Diseases. Int J Mol Sci 2025; 26:542. [PMID: 39859258 PMCID: PMC11765393 DOI: 10.3390/ijms26020542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.
Collapse
Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland
| |
Collapse
|
38
|
Evers LJW, Raykov YP, Heskes TM, Krijthe JH, Bloem BR, Little MA. Passive Monitoring of Parkinson Tremor in Daily Life: A Prototypical Network Approach. SENSORS (BASEL, SWITZERLAND) 2025; 25:366. [PMID: 39860736 PMCID: PMC11768787 DOI: 10.3390/s25020366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/17/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025]
Abstract
Objective and continuous monitoring of Parkinson's disease (PD) tremor in free-living conditions could benefit both individual patient care and clinical trials, by overcoming the snapshot nature of clinical assessments. To enable robust detection of tremor in the context of limited amounts of labeled training data, we propose to use prototypical networks, which can embed domain expertise about the heterogeneous tremor and non-tremor sub-classes. We evaluated our approach using data from the Parkinson@Home Validation study, including 8 PD patients with tremor, 16 PD patients without tremor, and 24 age-matched controls. We used wrist accelerometer data and synchronous expert video annotations for the presence of tremor, captured during unscripted daily life activities in and around the participants' own homes. Based on leave-one-subject-out cross-validation, we demonstrate the ability of prototypical networks to capture free-living tremor episodes. Specifically, we demonstrate that prototypical networks can be used to enforce robust performance across domain-informed sub-classes, including different tremor phenotypes and daily life activities.
Collapse
Affiliation(s)
- Luc J. W. Evers
- Center of Expertise for Parkinson and Movement Disorders, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Institute for Computing and Information Sciences, Radboud University, 6525 EC Nijmegen, The Netherlands;
| | - Yordan P. Raykov
- School of Mathematical Sciences, University of Nottingham, Nottingham NG9 2SE, UK
| | - Tom M. Heskes
- Institute for Computing and Information Sciences, Radboud University, 6525 EC Nijmegen, The Netherlands;
| | - Jesse H. Krijthe
- Pattern Recognition & Bioinformatics Group, Delft University of Technology, 2628 XE Delft, The Netherlands
| | - Bastiaan R. Bloem
- Center of Expertise for Parkinson and Movement Disorders, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Max A. Little
- School of Computer Science, University of Birmingham, Birmingham B15 2TT, UK
| |
Collapse
|
39
|
Chan H, Tang A, Li O, Orprecio AJ, Abrams SW, Wiley E, MacDonald K, Ma J, Namasivayam-MacDonald A. The Effects of Whole-Body Exercise on Swallowing Function in Older Adults With Parkinson's Disease: A Proof-of-Principle Study. AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY 2025; 34:314-332. [PMID: 39656994 DOI: 10.1044/2024_ajslp-24-00137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
PURPOSE Rodent models suggest that when respiratory demands increase during an exercise program, tongue and thyroarytenoid muscles engage to maintain a patent airway, leading to increased muscle strength. This suggests that nonspecific exercises that increase respiratory rate may improve swallowing. As such, the purpose of this proof-of-principle study was to determine the potential for whole-body exercise to improve tongue strength, cough strength, and self-reported swallowing function in older adults with Parkinson's disease (PD). METHOD Nine community-dwelling adults with PD (six men, three women; M ± SD age = 73 ± 7 years) were enrolled in a 10-week (30 min/session, three sessions/week, for a total of 30 sessions) virtual, whole-body exercise program, designed to increase respiratory rate. Demographic, frailty (Strength, Assistance in walking, Rise from a chair, Climb stairs, and Falls [SARC-F]), mobility (Schwab & England Activities of Daily Living Scale), and swallowing (tongue strength, cough strength, Eating Assessment Tool 10 [EAT-10]) measures were collected. Data were analyzed using descriptive statistics and linear mixed models. RESULTS Baseline frailty and mobility severity scores indicated mild PD severity. Post-exercise, four of nine participants demonstrated improvement in either anterior or posterior tongue strength, as well as cough strength. Three participants with higher exercise heart rate or rating of perceived exertion scores reported a decrease in EAT-10 scores to a level of below clinical concern (< 3). Results from linear mixed models demonstrated no statistically significant effects on any measures of swallowing function. CONCLUSIONS Findings from this pilot study suggest potential signal for a higher intensity whole-body exercise program to improve self-reported swallowing function, given that heart rate and/or exertion intensity that met or exceeded the target was associated with positive changes in self-reported swallowing function, but not tongue or cough strength. Future research including a larger sample size and intervention controls is needed to further elucidate a relationship between whole-body exercise and swallowing.
Collapse
Affiliation(s)
- Harmonie Chan
- School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
| | - Ada Tang
- School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
| | - Oliver Li
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - A J Orprecio
- School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
| | - Sophia Werden Abrams
- School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
| | - Elise Wiley
- School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
| | - Kyle MacDonald
- School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada
| | - Jinhui Ma
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | | |
Collapse
|
40
|
Carrazana E, Montalbán-Gutiérrez L, Chana-Cuevas P, Salvadores N. Advancing Parkinson's diagnosis: seed amplification assay for α-synuclein detection in minimally invasive samples. Mol Cell Biochem 2025:10.1007/s11010-024-05190-y. [PMID: 39760833 DOI: 10.1007/s11010-024-05190-y] [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: 09/09/2024] [Accepted: 12/07/2024] [Indexed: 01/07/2025]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity, and bradykinesia, beginning with early loss of dopaminergic neurons in the ventrolateral substantia nigra and advancing to broader neurodegeneration in the midbrain. The clinical heterogeneity of PD and the lack of specific diagnostic tests present significant challenges, highlighting the need for reliable biomarkers for early diagnosis. Alpha-synuclein (α-Syn), a protein aggregating into Lewy bodies and neurites in PD patients, has emerged as a key biomarker due to its central role in PD pathophysiology and potential to reflect pathological processes. Additionally, α-Syn allows earlier differentiation between PD and other neurodegenerative disorders with similar symptoms. Currently, detection of α-Syn pathology in post-mortem brain tissue remains the primary means of achieving a conclusive diagnosis, often revealing significant misdiagnoses. Seed amplification assay (SAA), initially developed for prion diseases, has been adapted to detect α-Syn aggregates in cerebrospinal fluid, showing promise for early diagnosis. Recent studies have demonstrated that SAA can also detect α-Syn aggregates in peripheral samples collected via minimally invasive procedures, such as skin, olfactory mucosa, saliva, and blood. However, the lack of standardized protocols limits clinical application. Standardizing protocols is essential to improve assay reliability and enable accurate patient identification for emerging therapies. This review examines studies on SAA for detecting α-Syn aggregates in minimally invasive samples, focusing on sample collection, processing, and reaction conditions.
Collapse
Affiliation(s)
- Elizabeth Carrazana
- Neurodegenerative Diseases Laboratory, Center for Biomedicine, Universidad Mayor, Avenida Alemania 0281, 4780000, Temuco, La Araucanía, Chile
| | - Leonardo Montalbán-Gutiérrez
- Neurodegenerative Diseases Laboratory, Center for Biomedicine, Universidad Mayor, Avenida Alemania 0281, 4780000, Temuco, La Araucanía, Chile
- Escuela de Medicina, Facultad de Medicina y Ciencias de La Salud, Universidad Mayor, Temuco, Chile
| | - Pedro Chana-Cuevas
- Centro de Trastornos del Movimiento (CETRAM), Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile
| | - Natalia Salvadores
- Neurodegenerative Diseases Laboratory, Center for Biomedicine, Universidad Mayor, Avenida Alemania 0281, 4780000, Temuco, La Araucanía, Chile.
- Escuela de Medicina, Facultad de Medicina y Ciencias de La Salud, Universidad Mayor, Temuco, Chile.
| |
Collapse
|
41
|
Ghaith WZ, Wadie W, El-Yamany MF. Crosstalk between SIRT1/Nrf2 signaling and NLRP3 inflammasome/pyroptosis as a mechanistic approach for the neuroprotective effect of linagliptin in Parkinson's disease. Int Immunopharmacol 2025; 145:113716. [PMID: 39642562 DOI: 10.1016/j.intimp.2024.113716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 11/24/2024] [Accepted: 11/24/2024] [Indexed: 12/09/2024]
Abstract
In recent years, special attention has been paid to highlighting the antiparkinsonian effect of linagliptin. However, the mechanism of its action has not yet been well investigated. The present study aimed to verify the neuroprotective effect of linagliptin in the rotenone model of Parkinson's disease (PD) and further explore its potential molecular mechanisms. Rats were intoxicated with rotenone (2 mg/kg/day; sc) and treated with linagliptin (10 mg/kg/day; po) for 14 consecutive days. The present finding showed that linagliptin ameliorated the histopathological changes of rotenone on substantia nigra and striata. Linagliptin decreased α-synuclein immunoreactivity along with an increase in tyrosine hydroxylase immunoreactivity and striatal dopamine content. This was reflected in the marked improvement of the behavior and motor deficits in rotenone-intoxicated rats. On the molecular level, linagliptin upregulated sirtuin 1 (SIRT1)/ nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, reduced ionized calcium-binding adaptor molecule 1 (Iba1) protein expression, restored glutathione (GSH) content, and elevated heme oxygenase-1 (HO-1) level in rats with rotenone intoxication. Moreover, linagliptin inhibited NOD-like receptor protein 3 (NLRP3)/caspase-1/interleukin-1β (IL-1β) cascade with subsequent reduction in gasdermin D (GSDMD) expression. Therefore, the present study reveals the ability of linagliptin, through the activation of SIRT1/Nrf2 signaling, to suppress NLRP3 inflammasome-mediated pyroptosis and protect against rotenone-induced parkinsonism.
Collapse
Affiliation(s)
| | - Walaa Wadie
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt
| | - Mohammed F El-Yamany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Egypt.
| |
Collapse
|
42
|
Panunggal B, Yeh TH, Tsao SP, Pan CH, Shih WT, Lin YT, Faradina A, Fang CL, Huang HY, Huang SY. Treadmill intervention attenuates motor deficit with 6-OHDA-induced Parkinson's disease rat via changes in lipid profiles in brain and muscle. Aging (Albany NY) 2025; 17:232-250. [PMID: 39754647 DOI: 10.18632/aging.206181] [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: 01/02/2024] [Accepted: 07/15/2024] [Indexed: 01/06/2025]
Abstract
One of the key hallmarks of Parkinson's disease is the disruption of lipid homeostasis in the brain, which plays a critical role in neuronal membrane integrity and function. Understanding how treadmill training impacts lipid restructuring and its subsequent influence on motor function could provide a basis for developing targeted non-pharmacological interventions for individuals living with early stage of PD. This study aims to investigate the effects of a treadmill training intervention on motor deficits induced by 6-OHDA in rats model of PD. PD was induced by injecting 6-hydroxy dopamine (6-OHDA) into the medial forebrain bundle (MFB). For 10 weeks, rats underwent treadmill training on a four-lane motorized treadmill. Motor function deficits were evaluated through behavioral tests. Lipidomic analysis was performed through ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS). Treadmill intervention significantly improved motor function and restored altered brain and muscle lipid profiles in PD rats. Among the lipid species identified in PD rats, brain abundance was highest for phosphatidylethanolamine (PE), correlating positively with the beam-walking scores; muscle abundance peaked with lysophosphatidylethanolamine (LysoPE), correlating positively with grip strength scores. In the brain, the levels of diacylglycerol (DG), triacylglycerol (TG), and lysophosphatidylcholine (PC) correlated positively with grip strength and rotarod scores, while only phosphatidylethanolamine (PE) linked to beam-walking scores. In the muscle, the levels of phosphatidylinositol (PI), lysophosphatidylethanolamine (PE), lysophosphatidic acid (PA), ceramide (Cer), and ganglioside were positively correlated with grip strength and rotarod scores. In conclusion, treadmill may protect the cortex, mitigating motor deficits via change lipid profiles in the brain and muscle.
Collapse
Affiliation(s)
- Binar Panunggal
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
- Department of Nutrition Science, Faculty of Medicine, Diponegoro University, Central Java, Indonesia
| | - Tu-Hsueh Yeh
- Department of Neurology, Taipei Medical University Hospital, Taipei 11031, Taiwan
- School of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Shu-Ping Tsao
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
| | - Chun-Hsu Pan
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Ting Shih
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Ya-Tin Lin
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Amelia Faradina
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Chia-Lang Fang
- Department of Pathology, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Hui-Yu Huang
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
- Department of Pathology, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Research Centre for Digestive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Neuroscience Research Centre, Taipei Medical University, Taipei 11031, Taiwan
| | - Shih-Yi Huang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| |
Collapse
|
43
|
Bai X, Zhu J, Chen Y, Sun H. The design and development of LRRK2 inhibitors as novel therapeutics for Parkinson's disease. Future Med Chem 2025; 17:221-236. [PMID: 39717965 PMCID: PMC11749465 DOI: 10.1080/17568919.2024.2444875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/03/2024] [Indexed: 12/25/2024] Open
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease affecting nearly 10 million people worldwide and placing a heavy medical burden on both society and families. However, due to the complexity of its pathological mechanisms, current treatments for PD can only alleviate patients' symptoms. Therefore, novel therapeutic strategies are urgently sought in clinical practice. Leucine-rich repeat kinase 2 (LRRK2) has emerged as a highly promising target for PD therapy. Missense mutations within the structural domain of LRRK2, the most common genetic risk factor for PD, lead to abnormally elevated kinase activity and increase the risk of developing PD. In this article, we provide a comprehensive overview of the structure, biological function, and pathogenic mutations of LRRK2, and examine recent advances in the development of LRRK2 inhibitors. We hope that this article will provide a reference for the design of novel LRRK2 inhibitors based on summarizing the facts and elucidating the viewpoints.
Collapse
Affiliation(s)
- Xiaoxue Bai
- School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China
| | - Jiawei Zhu
- School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China
| | - Yao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China
| | - Haopeng Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China
| |
Collapse
|
44
|
Yan YC, Su L, Zhao WB, Fan Y, Koprich JB, Xiao BG, Song B, Wang J, Yu WB. Bidirectional interaction between IL and 17A/IL-17RA pathway dysregulation and α-synuclein in the pathogenesis of Parkinson's disease. Brain Behav Immun 2025; 123:1114-1126. [PMID: 39461385 DOI: 10.1016/j.bbi.2024.10.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 10/08/2024] [Accepted: 10/20/2024] [Indexed: 10/29/2024] Open
Abstract
Parkinson's disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.
Collapse
Affiliation(s)
- Yu-Chen Yan
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Lu Su
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Wan-Bing Zhao
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yun Fan
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - James B Koprich
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Bao-Guo Xiao
- Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200040, China
| | - Bin Song
- Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Shanghai 200032, China; Fudan University, Shanghai 200032, China; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Jian Wang
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China.
| | - Wen-Bo Yu
- Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China.
| |
Collapse
|
45
|
Bi Y, Li M, Wang Y, Yao J, Wang Y, Wang S, Zhuang L, Liu S, Li Z, Hao Z, Guan W, Pan J, Jiang P, Zhang Y, Kuang H, Chen Q, Zhang L, Yang B, Liu Y. Saikosaponins from Bupleurum scorzonerifolium Willd. alleviates microglial pyroptosis in depression by binding and inhibiting P2X7 expression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156240. [PMID: 39637473 DOI: 10.1016/j.phymed.2024.156240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/27/2024] [Accepted: 11/07/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND The major depressive disorder (MDD) is a heterogeneous condition and characterized by a high recurrence rate, with neuroinflammation playing a significant role in its various potential pathologies. In recent years, neuronal pyroptosis induced by neuroinflammation has garnered increasing attention in depression research. Bupleurum scorzonerifolium Willd. is depression research in traditional Chinese medicine prescriptions to treat depression and exhibits notable anti-inflammatory properties. Saikosaponins (SSs) are the primary active components of Bupleurum scorzonerifolium Willd., although their mechanism of action in relation to anti-depressive effects remains unclear. PURPOSE The purpose is to evaluate the efficacy of Chinese herbal medicine in treating depression through the lens of modern pharmacology. Additionally, it aims to explore the potential value of new mechanisms in the treatment of depression. STUDY DESIGN AND METHODS An in vivo model of depression was established by intraperitoneal injection of LPS. HE staining, Nissl staining, and Golgi staining were used to evaluate the effectiveness of depression treatments in each group of mice. The activation of microglia was analyzed using immunofluorescence to evaluate the anti-inflammatory effects of drugs. In vitro models, N9 cells induced by LPS and ATP used CCK-8 assay, and lactate dehydrogenase assay were conducted to explore the therapeutic effect of the SSs. Western blot and immunohistochemical methods were employed to investigate the expression of P2X7 and apoptosis-related proteins. BzATP was introduced as a P2X7 agonist, and CETSA and CHX pulse-chase assay were utilized to verify the combined action and stability of the SSs with P2X7. RESULTS 57 triterpenoid saponin compounds were identified by Unifi in Bupleurum scorzonerifolium Willd. In both in vivo and in vitro models, the SSs has been shown to significantly improve depression-like behavior, reduce central inflammation, and significantly inhibit neuronal pyroptosis in mice. The SSs can significantly decrease the expression of P2X7 in the brains of depressed mice and enhance the stability of P2X7 protein in N9 cells. CONCLUSION SSs in Bupleurum scorzonerifolium Willd. bind and inhibit the P2X7 receptor to alleviate neuronal pyroptosis and improve symptoms of depression.
Collapse
Affiliation(s)
- Yu Bi
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Mengmeng Li
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Yue Wang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Junhan Yao
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Yuxuan Wang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Siyi Wang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Leixin Zhuang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Shuang Liu
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Ziwei Li
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Zhichao Hao
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Wei Guan
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Juan Pan
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Peng Jiang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Yiqiang Zhang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Haixue Kuang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China
| | - Qingshan Chen
- College of Agriculture, Northeast Agricultural University, Harbin 150030, China
| | - Lili Zhang
- College of Agriculture, Northeast Agricultural University, Harbin 150030, China
| | - Bingyou Yang
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China.
| | - Yan Liu
- Heilongjiang University of Chinese Medicine, Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Traditional Chinese medicine (TCM) biological genetics (Heilongjiang province double first-class construction interdiscipline), Heilongjiang Touyan Innovation Team Program, 150040, China.
| |
Collapse
|
46
|
Xu J, Dai P, Zhang C, Dong N, Li C, Tang C, Jin Z, Lin S, Ye L, Sun T, Jin Y, Wu F, Luo L, Wu P, Li S, Li X, Hsu S, Jiang D, Wang Z. Injectable Hierarchical Bioactive Hydrogels with Fibroblast Growth Factor 21/Edaravone/Caffeic Acid Asynchronous Delivery for Treating Parkinson's Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412020. [PMID: 39630931 PMCID: PMC11775539 DOI: 10.1002/advs.202412020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/11/2024] [Indexed: 12/07/2024]
Abstract
Parkinson's disease (PD) is one of the most common long-term neurodegenerative disorders, with multiple comorbid psychiatric and behavioral abnormalities. The combination of clinical drugs targeting different symptoms with smart hydrogels to achieve asynchronous releases is highly translational and challenging. Here, a hierarchical bioactive hydrogel (OACDP) is designed with asynchronous release based on PD pathology. The hydrogel with caffeic acid-grafted polymer main chain is crosslinked using a micellar nanocrosslinker, with sufficient modulus (≈167 Pa), antioxidant activity (> 50%), injectability (30-gauge syringe needle), and shape-adaptability. Each of the three drugs (caffeic acid, fibroblast growth factor 21, and Edaravone) is separately engaged in different micro- or nanostructures of the hydrogel and released with asynchronous kinetics of first-order release, zero-order release, or matching Korsmeyer-Peppas model. The triple-loaded hydrogel is injected into the brains of PD rats, showing behavioral improvement. Histological analysis revealed that the triple-loaded OACDP hydrogels are effective in achieving immediate neuroprotection, i.e., reduction the loss of tyrosine hydroxylase in substantia nigra compacta and striatum (retained ≈10-fold versus control), decreasing oxidative stress, reducing astrocyte and microglia activation, and stimulating the AMPK/PGC-1α axis to regulate the mitochondrial function, providing a multi-dimensional PD therapy. The asynchronous release of OACDP hydrogel provides a new conception for PD treatment and other neurodegenerative diseases.
Collapse
Affiliation(s)
- Junpeng Xu
- Affiliated Cixi HospitalWenzhou Medical UniversityNingboZhejiang315300China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Peng Dai
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Chen Zhang
- School and Hospital of StomatologyWenzhou Medical UniversityWenzhouZhejiang324025China
| | - Na Dong
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Caiyan Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Chonghui Tang
- Affiliated Cixi HospitalWenzhou Medical UniversityNingboZhejiang315300China
| | - Zhihao Jin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Shih‐Ho Lin
- Institute of Polymer Science and EngineeringNational Taiwan UniversityTaipeiTaiwan106319Republic of China
| | - Luyang Ye
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Tianmiao Sun
- Affiliated Cixi HospitalWenzhou Medical UniversityNingboZhejiang315300China
| | - Yukai Jin
- Affiliated Cixi HospitalWenzhou Medical UniversityNingboZhejiang315300China
| | - Fenzan Wu
- Affiliated Cixi HospitalWenzhou Medical UniversityNingboZhejiang315300China
| | - Lihua Luo
- School and Hospital of StomatologyWenzhou Medical UniversityWenzhouZhejiang324025China
| | - Ping Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Shengcun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- Rehabilitation Medicine CenterThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Shan‐hui Hsu
- Institute of Polymer Science and EngineeringNational Taiwan UniversityTaipeiTaiwan106319Republic of China
- Institute of Cellular and System MedicineNational Health Research InstitutesMiaoliTaiwan350401Republic of China
| | - Dawei Jiang
- Affiliated Cixi HospitalWenzhou Medical UniversityNingboZhejiang315300China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| | - Zhouguang Wang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
- State Key Laboratory of Macromolecular Drugs and Large‐scale PreparationSchool of Pharmaceutical ScienceWenzhou Medical UniversityWenzhouZhejiang325000China
| |
Collapse
|
47
|
Akyuz E, Aslan FS, Hekimoglu A, Yilmaz BN. Insights Into Retinal Pathologies in Neurological Disorders: A Focus on Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and Alzheimer's Disease. J Neurosci Res 2025; 103:e70006. [PMID: 39737769 DOI: 10.1002/jnr.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 09/10/2024] [Accepted: 11/24/2024] [Indexed: 01/01/2025]
Abstract
Neurological diseases are central nervous system (CNS) disorders affecting the whole body. Early diagnosis of the diseases is difficult due to the lack of disease-specific tests. Adding new biomarkers external to the CNS facilitates the diagnosis of neurological diseases. In this respect, the retina has a common embryologic origin with the CNS. Retinal imaging technologies including optical coherence tomography (OCT) can be used in the understanding and processual monitoring of neurological diseases. Retinal imaging has been recently recognized as a potential source of biomarkers for neurological diseases, increasing the number of studies in this direction. In this review, the association of retinal abnormalities with Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD) is explained. Structural and functional abnormalities in retina as a predictive marker may facilitate early diagnosis of diseases. Although not all retinal abnormalities are predictive of neurologic diseases, changes in the retinal layers including retinal pigment epithelium and plexiform layers should suggest the risk of PD, MS, ALS, and AD.
Collapse
Affiliation(s)
- Enes Akyuz
- Department of Biophysics, International School of Medicine, University of Health Science, Istanbul, Turkey
| | | | | | - Beyza Nur Yilmaz
- International School of Medicine, University of Health Sciences, Istanbul, Turkey
| |
Collapse
|
48
|
Wang F, Liu X, Chen M, Xu X, Yang Y, Xu Q, Zhu H, Xu A, Pouladi MA, Xu X. Neuroprotective role of CHCHD2 in Parkinson's disease: Insights into the GPX4-related ferroptosis pathway. Free Radic Biol Med 2025; 226:348-363. [PMID: 39566750 DOI: 10.1016/j.freeradbiomed.2024.11.034] [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: 08/16/2024] [Revised: 10/29/2024] [Accepted: 11/18/2024] [Indexed: 11/22/2024]
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by pathogenesis involving mitochondrial dysfunction, oxidative stress, and ferroptosis. Unfortunately, there are currently no effective interventions to slow down the progression of PD. The mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), which is implicated in neurodegeneration and serves as a biomarker for PD, has been reported to have neuroprotective effects against oxidative stress, but the potential molecular mechanisms involved remain elusive. In this study, we uncovered a critical mechanism by which CHCHD2 protected neuronal cells against oxidative stress with the ferroptosis pathway playing a pivotal role, as determined through tandem mass tags (TMT)-based proteomic analysis. The overexpression of CHCHD2 was observed to enhance cell viability, reduce levels of lipid peroxidation and reactive oxygen species (ROS), and upregulate the expression of the ferroptosis negative regulatory protein Glutathione peroxidase 4 (GPX4) in PD cells. Conversely, CHCHD2 knockdown led to reduced cell viability, elevated lipid peroxidation, and a decreased expression of GPX4. Additionally, CHCHD2 overexpression ameliorated motor function impairment, reduced α-synuclein levels, and mitigated dopaminergic (DA) neuron loss in the substantia nigra and striatum of PD mice. Importantly, we show that the inhibitory effect of CHCHD2 on ferroptosis in PD is related to the GPX4 signaling pathway. In summary, our study elucidates the neuroprotective role of CHCHD2 in regulating the GPX4-related ferroptosis pathway in PD, providing new targets and ideas for future PD drug development and therapy.
Collapse
Affiliation(s)
- Fang Wang
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Xuanzhuo Liu
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Department of Neurology, Taihe Hospital of Shiyan, Affiliated Hospital of Hubei Medical University, Shiyan, 442000, China
| | - Mingyi Chen
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Xiaoxin Xu
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Ying Yang
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Qiuhong Xu
- Department of Plastic Surgery, The First Affiliated Hospital, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Huili Zhu
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Anding Xu
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China
| | - Mahmoud A Pouladi
- Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Djavad Mowafaghian Centre for Brain Health, Edwin S. H. Leong Centre for Healthy Aging, Faculty of Medicine, University of British Columbia, BritishColumbia Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Xiaohong Xu
- Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China; Clinical Neuroscience Institute, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong, 510632, China.
| |
Collapse
|
49
|
Larrañaga-SanMiguel A, Bengoa-Vergniory N, Flores-Romero H. Crosstalk between mitochondria-ER contact sites and the apoptotic machinery as a novel health meter. Trends Cell Biol 2025; 35:33-45. [PMID: 39379268 DOI: 10.1016/j.tcb.2024.08.007] [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: 02/26/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 10/10/2024]
Abstract
Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) function as transient signaling platforms that regulate essential cellular functions. MERCS are enriched in specific proteins and lipids that connect mitochondria and the ER together and modulate their activities. Dysregulation of MERCS is associated with several human pathologies including Alzheimer's disease (AD), Parkinson's disease (PD), and cancer. BCL-2 family proteins can locate at MERCS and control essential cellular functions such as calcium signaling and autophagy in addition to their role in mitochondrial apoptosis. Moreover, the BCL-2-mediated apoptotic machinery was recently found to trigger cGAS-STING pathway activation and a proinflammatory response, a recognized hallmark of these diseases that requires mitochondria-ER interplay. This review underscores the pivotal role of MERCS in regulating essential cellular functions, focusing on their crosstalk with BCL-2 family proteins, and discusses how their dysregulation is linked to disease.
Collapse
Affiliation(s)
| | - Nora Bengoa-Vergniory
- Achucarro Basque Center for Neuroscience, Leioa, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain; Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QU, UK; Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Hector Flores-Romero
- Achucarro Basque Center for Neuroscience, Leioa, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
| |
Collapse
|
50
|
Rundquist LD, Lyons SE, Moljo RJ, Blavo C. An Unusual Presentation of Respiratory Dysfunction in Parkinson's Disease: A Case Study. Cureus 2025; 17:e77101. [PMID: 39917160 PMCID: PMC11802192 DOI: 10.7759/cureus.77101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/09/2024] [Indexed: 02/09/2025] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting around 10 million people worldwide. It is primarily associated with the loss of dopaminergic neurons in the substantia nigra pars compacta, though the exact mechanism is unclear. PD is characterized by resting tremor, muscular rigidity, bradykinesia, and postural instability. These motor symptoms, resulting from impaired muscle function, can lead to dysphagia and respiratory dysfunction. It is suggested that the muscular rigidity and bradykinesia in PD may impair repetitive motor actions, negatively impacting respiration. While less studied, PD-related respiratory dysfunction could stem from obstructive, restrictive, or CNS disturbances. This case report discusses a 69-year-old male with PD and dementia presented at an assisted living facility in Palmar Sur, Costa Rica, with difficulty exhaling after deep inhalation. Physical examination revealed typical PD symptoms (resting tremor, muscular rigidity, bradykinesia, postural instability) along with hypotension, bradycardia, and bradypnea. Respiratory assessment showed he could inhale but had difficulty exhaling, suggesting a myotonic-like pathology. The cogwheel-like rigidity during exhalation is unique and points to a myotonic-like respiratory dysfunction related to his PD, a presentation not commonly observed in PD patients. Research suggests respiratory impairments in PD may result from issues with central ventilatory control, restrictive lung disease (reduced lung capacity), or obstructive lung disease (blocked airflow). Restrictive mechanisms might stem from thoracic rigidity and posture changes, while obstructive factors could be exacerbated by the patient's smoking history. Respiratory muscle fatigue may arise from the demands of repetitive ventilation. Additionally, degeneration in the brain's respiratory center, possibly linked to α-synuclein deposits, could affect respiratory regulation. Osteopathic Manipulation Treatment (OMT) may help alleviate these symptoms by improving thoracic flexibility and respiratory function. Overall, this case highlights the varied presentations of PD, focusing on the lens respiratory dysfunction, possibly due to respiratory muscle rigidity or central nervous system involvement. Recognizing these symptoms is crucial for early intervention and preventing complications like aspiration pneumonia, a major cause of morbidity and mortality in PD. Further research is needed to better understand the relationship between PD and respiratory dysfunction.
Collapse
Affiliation(s)
- Lily D Rundquist
- Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Davie, USA
| | - Sarah E Lyons
- Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Davie, USA
| | - Rosa J Moljo
- Family Medicine, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
| | - Cyril Blavo
- Public Health and Pediatrics, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
| |
Collapse
|