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Lagoa R, Rajan L, Violante C, Babiaka SB, Marques-da-Silva D, Kapoor B, Reis F, Atanasov AG. Application of curcuminoids in inflammatory, neurodegenerative and aging conditions - Pharmacological potential and bioengineering approaches to improve efficiency. Biotechnol Adv 2025; 82:108568. [PMID: 40157560 DOI: 10.1016/j.biotechadv.2025.108568] [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: 12/11/2024] [Revised: 03/21/2025] [Accepted: 03/22/2025] [Indexed: 04/01/2025]
Abstract
Curcumin, a natural compound found in turmeric, has shown promise in treating brain-related diseases and conditions associated with aging. Curcumin has shown multiple anti-inflammatory and brain-protective effects, but its clinical use is limited by challenges like poor absorption, specificity and delivery to the right tissues. A range of contemporary approaches at the intersection with bioengineering and systems biology are being explored to address these challenges. Data from preclinical and human studies highlight various neuroprotective actions of curcumin, including the inhibition of neuroinflammation, modulation of critical cellular signaling pathways, promotion of neurogenesis, and regulation of dopamine levels. However, curcumin's multifaceted effects - such as its impact on microRNAs and senescence markers - suggest novel therapeutic targets in neurodegeneration. Tetrahydrocurcumin, a primary metabolite of curcumin, also shows potential due to its presence in circulation and its anti-inflammatory properties, although further research is needed to elucidate its neuroprotective mechanisms. Recent advancements in delivery systems, particularly brain-targeting nanocarriers like polymersomes, micelles, and liposomes, have shown promise in enhancing curcumin's bioavailability and therapeutic efficacy in animal models. Furthermore, the exploration of drug-laden scaffolds and dermal delivery may extend the pharmacological applications of curcumin. Studies reviewed here indicate that engineered dermal formulations and devices could serve as viable alternatives for neuroprotective treatments and to manage skin or musculoskeletal inflammation. This work highlights the need for carefully designed, long-term studies to better understand how curcumin and its bioactive metabolites work, their safety, and their effectiveness.
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Affiliation(s)
- Ricardo Lagoa
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal; Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials LSRE-LCM, Associate Laboratory in Chemical Engineering ALiCE, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal; Applied Molecular Biosciences Unit UCIBIO, Institute for Health and Bioeconomy i4HB, NOVA University of Lisbon, 2829-516 Caparica, Portugal.
| | - Logesh Rajan
- Department of Pharmacognosy, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India.
| | - Cristiana Violante
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal
| | - Smith B Babiaka
- Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon; Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany.
| | - Dorinda Marques-da-Silva
- School of Technology and Management, Polytechnic Institute of Leiria, Morro do Lena-Alto do Vieiro, 2411-901 Leiria, Portugal; Laboratory of Separation and Reaction Engineering-Laboratory of Catalysis and Materials LSRE-LCM, Associate Laboratory in Chemical Engineering ALiCE, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.
| | - Bhupinder Kapoor
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Flávio Reis
- Institute of Pharmacology and Experimental Therapeutics & Coimbra Institute for Clinical and Biomedical Research iCBR, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology CIBB, University of Coimbra, 3000-548 Coimbra, Portugal; Clinical Academic Center of Coimbra, 3004-531 Coimbra, Portugal.
| | - Atanas G Atanasov
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Magdalenka, Poland; Laboratory of Natural Products and Medicinal Chemistry LNPMC, Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences SIMATS, Thandalam, Chennai, India; Ludwig Boltzmann Institute Digital Health and Patient Safety, Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
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Niu C, Zou Y, Dong M, Niu Y. Plant-derived compounds as potential neuroprotective agents in Parkinson's disease. Nutrition 2025; 130:112610. [PMID: 39546872 DOI: 10.1016/j.nut.2024.112610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/12/2024] [Accepted: 10/17/2024] [Indexed: 11/17/2024]
Abstract
OBJECTIVES Current Parkinson's disease (PD) medications treat symptoms; none can slow down or arrest the disease progression. Disease-modifying therapies for PD remain an urgent unmet clinical need. This review was designed to summarize recent findings regarding to the efficacy of phytochemicals in the treatment of PD and their underlying mechanisms. METHODS A literature search was performed using PubMed databases from inception until January 2024. RESULTS We first review the role of oxidative stress in PD and phytochemical-based antioxidant therapy. We then summarize recent work on neuroinflammation in the pathogenesis of PD, as well as preclinical data supporting anti-inflammatory efficacy in treating or preventing the disease. We last evaluate evidence for brain mitochondrial dysfunction in PD, together with the phytochemicals that protect mitochondrial function in preclinical model of PD. Furthermore, we discussed possible reasons for failures of preclinical-to-clinical translation for neuroprotective therapeutics. CONCLUSIONS There is now extensive evidence from preclinical studies that neuroprotective phytochemicals as promising candidate drugs for PD are needed to translate from the laboratory to the clinic.
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Affiliation(s)
- Chengu Niu
- Internal Medicine Residency Program, Rochester General Hospital, Rochester, NY 14621, USA
| | - Yu Zou
- College of Pharmacy, Qiqihar Medical University, Qiqihar 161006, China
| | - Miaoxian Dong
- The Institute of Medicine, Qiqihar Medical University, Qiqihar 161006, China
| | - Yingcai Niu
- The Institute of Medicine, Qiqihar Medical University, Qiqihar 161006, China.
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Moldoveanu CA, Tomoaia-Cotisel M, Sevastre-Berghian A, Tomoaia G, Mocanu A, Pal-Racz C, Toma VA, Roman I, Ujica MA, Pop LC. A Review on Current Aspects of Curcumin-Based Effects in Relation to Neurodegenerative, Neuroinflammatory and Cerebrovascular Diseases. Molecules 2024; 30:43. [PMID: 39795101 PMCID: PMC11722367 DOI: 10.3390/molecules30010043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Curcumin is among the most well-studied natural substances, known for its biological actions within the central nervous system, its antioxidant and anti-inflammatory properties, and human health benefits. However, challenges persist in effectively utilising curcumin, addressing its metabolism and passage through the blood-brain barrier (BBB) in therapies targeting cerebrovascular diseases. Current challenges in curcumin's applications revolve around its effects within neoplastic tissues alongside the development of intelligent formulations to enhance its bioavailability. Formulations have been discovered including curcumin's complexes with brain-derived phospholipids and proteins, or its liposomal encapsulation. These novel strategies aim to improve curcumin's bioavailability and stability, and its capability to cross the BBB, thereby potentially enhancing its efficacy in treating cerebrovascular diseases. In summary, this review provides a comprehensive overview of molecular pathways involved in interactions of curcumin and its metabolites, and brain vascular homeostasis. This review explores cellular and molecular current aspects, of curcumin-based effects with an emphasis on curcumin's metabolism and its impact on pathological conditions, such as neurodegenerative diseases, schizophrenia, and cerebral angiopathy. It also highlights the limitations posed by curcumin's poor bioavailability and discusses ongoing efforts to surpass these impediments to harness the full therapeutic potential of curcumin in neurological disorders.
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Affiliation(s)
- Claudia-Andreea Moldoveanu
- Department of Molecular Biology and Biotechnology, Babeș-Bolyai University, Clinicilor St., RO-400371 Cluj-Napoca, Romania;
- Department of Experimental Biology and Biochemistry, Institute of Biological Research from Cluj-Napoca, a Branch of NIRDBS Bucharest, 48 Republicii St., RO-400015 Cluj-Napoca, Romania;
| | - Maria Tomoaia-Cotisel
- Research Center of Excellence in Physical Chemistry, Faculty of Chemistry and Chemical Engineering, “Babes-Bolyai University”, 11 Arany Janos St., RO-400028 Cluj-Napoca, Romania or (M.T.-C.); (A.M.); (C.P.-R.); (M.-A.U.)
- Academy of Romanian Scientists, 3 Ilfov St., RO-050044 Bucharest, Romania;
| | - Alexandra Sevastre-Berghian
- Department of Physiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 1 Clinicilor St., RO-400006 Cluj-Napoca, Romania;
| | - Gheorghe Tomoaia
- Academy of Romanian Scientists, 3 Ilfov St., RO-050044 Bucharest, Romania;
- Department of Orthopedics and Traumatology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 47 Gen. Traian Moșoiu St., RO-400132 Cluj-Napoca, Romania
| | - Aurora Mocanu
- Research Center of Excellence in Physical Chemistry, Faculty of Chemistry and Chemical Engineering, “Babes-Bolyai University”, 11 Arany Janos St., RO-400028 Cluj-Napoca, Romania or (M.T.-C.); (A.M.); (C.P.-R.); (M.-A.U.)
| | - Csaba Pal-Racz
- Research Center of Excellence in Physical Chemistry, Faculty of Chemistry and Chemical Engineering, “Babes-Bolyai University”, 11 Arany Janos St., RO-400028 Cluj-Napoca, Romania or (M.T.-C.); (A.M.); (C.P.-R.); (M.-A.U.)
| | - Vlad-Alexandru Toma
- Department of Molecular Biology and Biotechnology, Babeș-Bolyai University, Clinicilor St., RO-400371 Cluj-Napoca, Romania;
- Department of Experimental Biology and Biochemistry, Institute of Biological Research from Cluj-Napoca, a Branch of NIRDBS Bucharest, 48 Republicii St., RO-400015 Cluj-Napoca, Romania;
- Academy of Romanian Scientists, 3 Ilfov St., RO-050044 Bucharest, Romania;
- Centre for Systems Biology, Biodiversity and Bioresources “3B”, Babeș-Bolyai University, 44 Republicii St., RO-400347 Cluj-Napoca, Romania
| | - Ioana Roman
- Department of Experimental Biology and Biochemistry, Institute of Biological Research from Cluj-Napoca, a Branch of NIRDBS Bucharest, 48 Republicii St., RO-400015 Cluj-Napoca, Romania;
| | - Madalina-Anca Ujica
- Research Center of Excellence in Physical Chemistry, Faculty of Chemistry and Chemical Engineering, “Babes-Bolyai University”, 11 Arany Janos St., RO-400028 Cluj-Napoca, Romania or (M.T.-C.); (A.M.); (C.P.-R.); (M.-A.U.)
| | - Lucian-Cristian Pop
- Research Center of Excellence in Physical Chemistry, Faculty of Chemistry and Chemical Engineering, “Babes-Bolyai University”, 11 Arany Janos St., RO-400028 Cluj-Napoca, Romania or (M.T.-C.); (A.M.); (C.P.-R.); (M.-A.U.)
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Xu M, Li T, Liu X, Islam B, Xiang Y, Zou X, Wang J. Mechanism and Clinical Application Prospects of Mitochondrial DNA Single Nucleotide Polymorphism in Neurodegenerative Diseases. Neurochem Res 2024; 50:61. [PMID: 39673588 DOI: 10.1007/s11064-024-04311-9] [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: 10/02/2024] [Revised: 11/12/2024] [Accepted: 12/03/2024] [Indexed: 12/16/2024]
Abstract
Mitochondrial dysfunction is well recognized as a critical component of the complicated pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. This review investigates the influence of mitochondrial DNA single nucleotide polymorphisms on mitochondrial function, as well as their role in the onset and progression of these neurodegenerative diseases. Furthermore, the contemporary approaches to mitochondrial regulation in these disorders are discussed. Our objective is to uncover early diagnostic targets and formulate precision medicine strategies for neurodegenerative diseases, thereby offering new paths for preventing and treating these conditions.
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Affiliation(s)
- Mengying Xu
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Tianjiao Li
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Xuan Liu
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Binish Islam
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Yuyue Xiang
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Xiyan Zou
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Jianwu Wang
- Xiangya School of Public Health, Central South University, Changsha, 410078, China.
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Guo F, Qin X, Mao J, Xu Y, Xie J. Potential Protective Effects of Pungent Flavor Components in Neurodegenerative Diseases. Molecules 2024; 29:5700. [PMID: 39683859 PMCID: PMC11643850 DOI: 10.3390/molecules29235700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/25/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) have become a major global health burden, but the detailed pathogeneses of neurodegenerative diseases are still unknown, and current treatments are mainly aimed at controlling symptoms; there are no curative treatments for neurodegenerative diseases or treatments for the progressive cognitive, behavioral, and functional impairments that they cause. Studies have shown that some plant extracts with pungent flavor components have a certain neuroprotective effect in neurodegenerative diseases, and their mechanisms mainly involve inhibiting neuronal apoptosis, promoting neuronal regeneration, reducing mitochondrial degeneration, and reducing the production of oxides such as reactive oxygen species in cells, which are of great significance for exploring the treatment of neurodegenerative diseases. In this review, we searched the PubMed database for relevant literature collected in the past 15 years. Finally, we summarized the protective effects of pungent flavor components such as capsaicin, piperine, curcumin, cannabinoids, allicin, and nicotine on the nervous system, focusing on the molecular mechanisms and signaling pathways that they activate. In addition, we also compiled and summarized the laboratory experiments, preclinical experiments, and effects of various pungent flavor components in neurodegenerative diseases. The goal is to further explore their potential as effective drugs for the treatment of neurodegenerative diseases and provide new ideas for further research on the specific protective mechanisms of these substances for the treatment of neurodegenerative diseases and the targets of drug action in the future.
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Affiliation(s)
- Fangxin Guo
- Beijing Life Science Academy (BLSA), Beijing 102209, China
- School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Xudi Qin
- Beijing Life Science Academy (BLSA), Beijing 102209, China
- School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Jian Mao
- Beijing Life Science Academy (BLSA), Beijing 102209, China
- Flavour Science Research Center, College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
| | - Yan Xu
- Beijing Life Science Academy (BLSA), Beijing 102209, China
- School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou 450001, China
| | - Jianping Xie
- Beijing Life Science Academy (BLSA), Beijing 102209, China
- Flavour Science Research Center, College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
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Qiao L, Yang G, Wang P, Xu C. The potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health. Pharmacol Res 2024; 209:107434. [PMID: 39332752 DOI: 10.1016/j.phrs.2024.107434] [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: 07/04/2024] [Revised: 09/02/2024] [Accepted: 09/23/2024] [Indexed: 09/29/2024]
Abstract
Mitochondria are crucial organelles that regulate cellular energy metabolism, calcium homeostasis, and oxidative stress responses, playing pivotal roles in brain development and neurodegeneration. Concurrently, the gut microbiota has emerged as a key modulator of brain physiology and pathology through the microbiota-gut-brain axis. Recent evidence suggests an intricate crosstalk between the gut microbiota and mitochondrial function, mediated by microbial metabolites that can influence mitochondrial activities in the brain. This review aims to provide a comprehensive overview of the emerging role of mitochondria as critical mediators in the microbiota-gut-brain axis, shaping brain health and neurological disease pathogenesis. We discuss how gut microbial metabolites such as short-chain fatty acids, secondary bile acids, tryptophan metabolites, and trimethylamine N-oxide can traverse the blood-brain barrier and modulate mitochondrial processes including energy production, calcium regulation, mitophagy, and oxidative stress in neurons and glial cells. Additionally, we proposed targeting the mitochondria through diet, prebiotics, probiotics, or microbial metabolites as a promising potential therapeutic approach to maintain brain health by optimizing mitochondrial fitness. Overall, further investigations into how the gut microbiota and its metabolites regulate mitochondrial bioenergetics, dynamics, and stress responses will provide valuable insights into the microbiota-gut-brain axis in both health and disease states.
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Affiliation(s)
- Lei Qiao
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Ge Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Peng Wang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China; Department of Psychiatry, The Affiliated Xi'an Central Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710000, China
| | - Chunlan Xu
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China.
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Atoum MF, Padma KR, Don KR. Curcumin is a potential therapeutic agent that ameliorates diabetes among non-alcoholic fatty liver disease coexist with type 2 diabetes. NUTRITION AND HEALTHY AGING 2024; 9:77-90. [DOI: 10.3233/nha-231504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) harmonize and act synergistically in clinical practices. About 70–80% of diabetic patients develop NAFLD. At the same time, NAFLD existence increases T2DM development. Meanwhile, the presence of T2DM increases the progression to liver disease such as NAFLD, and to non-alcoholic steatohepatitis (NASH). The most prevalent chronic liver disease worldwide is a NAFLD. NAFLD and (T2DM) have a two-way pathophysiologic relationship, with the latter driving the development of the former into NASH. Nonetheless, NASH enhances the threat of cirrhosis as well as hepatocellular carcinoma (HCC), both cases in turn need transplantation of the liver. The only treatment for NAFLD is still lifestyle management because there are no FDA-approved drugs for the condition. In the current study, we review how curcumin (a naturally occurring phytopolyphenol pigment) treats NAFLD. Also we showed broad insights on curcumin-based therapy, by severe reduction of hepatic inflammation. Thus, our review showed that curcumin ingestion considerably decreased glycemic parameters (fasting blood glucose, glycosylated hemoglobin, insulin resistance index (HOMA-IR), and free fatty acids) and adipocyte-fatty acid binding protein (A-FABP), and adipokine released from adipocytes. Clinical trials are needed to evaluate the effects of curcumin and its specific dosage on liver enzymes, glycemic consequences, among NAFLD coexist with T2DM patients.
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Affiliation(s)
- Manar Fayiz Atoum
- Department of Medical Laboratory Sciences, Faculty of Applied Health Sciences, The Hashemite University, Zarqa, Jordan
| | - Kanchi Ravi Padma
- Department of Biotechnology, Sri Padmavati Mahila Visvavidyalayam (Women’s) University, Tirupati, AP, India
| | - Kanchi Ravi Don
- Department of Oral Pathology and Microbiology, Sree Balaji Dental College and Hospital, Bharath Institute of Higher Education and Research (BIHER) Bharath University, Chennai, Tamil Nadu, India
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Cai B, Wang Q, Zhong L, Liu F, Wang X, Chen T. Integrating Network Pharmacology, Transcriptomics to Reveal Neuroprotective of Curcumin Activate PI3K / AKT Pathway in Parkinson's Disease. Drug Des Devel Ther 2024; 18:2869-2881. [PMID: 39006191 PMCID: PMC11246089 DOI: 10.2147/dddt.s462333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 07/01/2024] [Indexed: 07/16/2024] Open
Abstract
Background Parkinson's disease (PD) is the most prevalent movement disorder. Curcumin, a polyphenol with hydrophobic properties, has been proved against Parkinson. Our previous study suggested that curcumin's effectiveness in treating Parkinson's disease may be linked to the gut-brain axis, although the specific mechanism by which curcumin exerts neuroprotective effects in the brain remains unknown. Methods The therapeutic efficacy of curcumin was evaluated using behavioral tests, immunofluorescence of tyrosine hydroxylase (TH). Network pharmacology and transcriptomics predicted the mechanisms of curcumin in PD. Activation of the phosphatidylinositol 3-kinase PI3K/AKT pathway was confirmed by quantitative polymerase chain reaction (qPCR) and immunofluorescence. Results Curcumin restored the dyskinesia and dopaminergic neurons damage of MPTP-induced mice. Curcumin against Parkinson's disease by regulating inflammation, oxidative stress, and aging. The mechanisms of these were associated with activation of PI3K / AKT pathway. Conclusion In conclusion, the neuroprotective mechanisms of curcumin activate PI3K / AKT pathway in Parkinson's disease was revealed by our study.
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Affiliation(s)
- Benchi Cai
- Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China
| | - Qitong Wang
- Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China
| | - Lifan Zhong
- Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China
| | - Fang Liu
- Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China
| | - Xinyu Wang
- Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China
| | - Tao Chen
- Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China
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Goyani S, Shinde A, Shukla S, Saranga MV, Currim F, Mane M, Singh J, Roy M, Gohel D, Chandak N, Vasiyani H, Singh R. Enhanced translocation of TRIM32 to mitochondria sensitizes dopaminergic neuronal cells to apoptosis during stress conditions in Parkinson's disease. FEBS J 2024; 291:2636-2655. [PMID: 38317520 DOI: 10.1111/febs.17065] [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: 06/21/2023] [Revised: 11/29/2023] [Accepted: 01/16/2024] [Indexed: 02/07/2024]
Abstract
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by progressive loss of dopamine-producing neurons from the substantia nigra region of the brain. Mitochondrial dysfunction is one of the major causes of oxidative stress and neuronal cell death in PD. E3 ubiquitin ligases such as Parkin (PRKN) modulate mitochondrial quality control in PD; however, the role of other E3 ligases associated with mitochondria in the regulation of neuronal cell death in PD has not been explored. The current study investigated the role of TRIM32, RING E3 ligase, in sensitization to oxidative stress-induced neuronal apoptosis. The expression of TRIM32 sensitizes SH-SY5Y dopaminergic cells to rotenone and 6-OHDA-induced neuronal death, whereas the knockdown increased cell viability under PD stress conditions. The turnover of TRIM32 is enhanced under PD stress conditions and is mediated by autophagy. TRIM32 translocation to mitochondria is enhanced under PD stress conditions and localizes on the outer mitochondrial membrane. TRIM32 decreases complex-I assembly and activity as well as mitochondrial reactive oxygen species (ROS) and ATP levels under PD stress. Deletion of the RING domain of TRIM32 enhanced complex I activity and rescued ROS levels and neuronal viability under PD stress conditions. TRIM32 decreases the level of XIAP, and co-expression of XIAP with TRIM32 rescued the PD stress-induced cell death and mitochondrial ROS level. In conclusion, turnover of TRIM32 increases during stress conditions and translocation to mitochondria is enhanced, regulating mitochondrial functions and neuronal apoptosis by modulating the level of XIAP in PD.
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Affiliation(s)
- Shanikumar Goyani
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Anjali Shinde
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Shatakshi Shukla
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - M V Saranga
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Fatema Currim
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Minal Mane
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Jyoti Singh
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Milton Roy
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dhruv Gohel
- Department of Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Nisha Chandak
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Hitesh Vasiyani
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
| | - Rajesh Singh
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, India
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Pandey M, Karmakar V, Majie A, Dwivedi M, Md S, Gorain B. The SH-SY5Y cell line: a valuable tool for Parkinson's disease drug discovery. Expert Opin Drug Discov 2024; 19:303-316. [PMID: 38112196 DOI: 10.1080/17460441.2023.2293158] [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: 09/27/2023] [Accepted: 12/06/2023] [Indexed: 12/21/2023]
Abstract
INTRODUCTION Owing to limited efficient treatment strategies for highly prevalent and distressing Parkinson's disease (PD), an impending need emerged for deciphering new modes and mechanisms for effective management. SH-SY5Y-based in vitro neuronal models have emerged as a new possibility for the elucidation of cellular and molecular processes in the pathogenesis of PD. SH-SY5Y cells are of human origin, adhered to catecholaminergic neuronal attributes, which consequences in imparting wide acceptance and significance to this model over conventional in vitro PD models for high-throughput screening of therapeutics. AREAS COVERED Herein, the authors review the SH-SY5Y cell line and its value to PD research. The authors also provide the reader with their expert perspectives on how these developments can lead to the development of new impactful therapeutics. EXPERT OPINION Encouraged by recent research on SH-SY5Y cell lines, it was envisaged that this in vitro model can serve as a primary model for assessing efficacy and toxicity of new therapeutics as well as for nanocarriers' capacity in delivering therapeutic agents across BBB. Considering the proximity with human neuronal environment as in pathogenic PD conditions, SH-SY5Y cell lines vindicated consistency and reproducibility in experimental results. Accordingly, exploitation of this standardized SH-SY5Y cell line can fast-track the drug discovery and development path for novel therapeutics.
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Affiliation(s)
- Manisha Pandey
- Department of Pharmaceutical Sciences, Central University of Haryana, Mahendergarh, India
| | - Varnita Karmakar
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
| | - Ankit Majie
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
| | - Monika Dwivedi
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India
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11
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Bandiwadekar A, Khot KB, Gopan G, Jose J. Microneedles: A Versatile Drug Delivery Carrier for Phytobioactive Compounds as a Therapeutic Modulator for Targeting Mitochondrial Dysfunction in the Management of Neurodegenerative Diseases. Curr Neuropharmacol 2024; 22:1110-1128. [PMID: 36237157 PMCID: PMC10964109 DOI: 10.2174/1570159x20666221012142247] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/29/2022] [Accepted: 10/06/2022] [Indexed: 11/22/2022] Open
Abstract
Neurodegenerative disease (ND) is the fourth leading cause of death worldwide, with limited symptomatic therapies. Mitochondrial dysfunction is a major risk factor in the progression of ND, and it-increases the generation of reactive oxygen species (ROS). Overexposure to these ROS induces apoptotic changes leading to neuronal cell death. Many studies have shown the prominent effect of phytobioactive compounds in managing mitochondrial dysfunctions associated with ND, mainly due to their antioxidant properties. The drug delivery to the brain is limited due to the presence of the blood-brain barrier (BBB), but effective drug concentration needs to reach the brain for the therapeutic action. Therefore, developing safe and effective strategies to enhance drug entry in the brain is required to establish ND's treatment. The microneedle-based drug delivery system is one of the effective non-invasive techniques for drug delivery through the transdermal route. Microneedles are micronsized drug delivery needles that are self-administrable. It can penetrate through the stratum corneum skin layer without hitting pain receptors, allowing the phytobioactive compounds to be released directly into systemic circulation in a controlled manner. With all of the principles mentioned above, this review discusses microneedles as a versatile drug delivery carrier for the phytoactive compounds as a therapeutic potentiating agent for targeting mitochondrial dysfunction for the management of ND.
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Affiliation(s)
- Akshay Bandiwadekar
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed-to-be University), Mangalore, 575018, India
| | - Kartik Bhairu Khot
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed-to-be University), Mangalore, 575018, India
| | - Gopika Gopan
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed-to-be University), Mangalore, 575018, India
| | - Jobin Jose
- Department of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE (Deemed-to-be University), Mangalore, 575018, India
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12
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Yang C, Luo P, Yang YT, Fu XL, Li BX, Shen X, Xu DN, Huang YM, Tian YB, Liu WJ. Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury. Poult Sci 2024; 103:103247. [PMID: 37980731 PMCID: PMC10685035 DOI: 10.1016/j.psj.2023.103247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 10/23/2023] [Accepted: 10/24/2023] [Indexed: 11/21/2023] Open
Abstract
The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.
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Affiliation(s)
- Chen Yang
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Pei Luo
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | | | - Xin-Liang Fu
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Bing-Xin Li
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Xu Shen
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Dan-Ning Xu
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Yun-Mao Huang
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Yun-Bo Tian
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China
| | - Wen-Jun Liu
- Zhongkai University of Agriculture and Engineering, Guangdong, Guangzhou 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangdong, Guangzhou 510225, China.
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13
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Mei L, Chen X, Wei F, Huang X, Liu L, Yao J, Chen J, Luo X, Wang Z, Yang A. Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria. Autophagy 2023; 19:2997-3013. [PMID: 37424101 PMCID: PMC10549199 DOI: 10.1080/15548627.2023.2234797] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 06/23/2023] [Accepted: 07/05/2023] [Indexed: 07/11/2023] Open
Abstract
Proteolysis-targeting chimeras (PROTACs) based on the ubiquitin-proteasome system have made great progress in the field of drug discovery. There is mounting evidence that the accumulation of aggregation-prone proteins or malfunctioning organelles is associated with the occurrence of various age-related neurodegenerative disorders and cancers. However, PROTACs are inefficient for the degradation of such large targets due to the narrow entrance channel of the proteasome. Macroautophagy (hereafter referred to as autophagy) is known as a self-degradative process involved in the degradation of bulk cytoplasmic components or specific cargoes that are sequestered into autophagosomes. In the present study, we report the development of a generalizable strategy for the targeted degradation of large targets. Our results suggested that tethering large target models to phagophore-associated ATG16L1 or LC3 induced targeted autophagic degradation of the large target models. Furthermore, we successfully applied this autophagy-targeting degradation strategy to the targeted degradation of HTT65Q aggregates and mitochondria. Specifically, chimeras consisting of polyQ-binding peptide 1 (QBP) and ATG16L1-binding peptide (ABP) or LC3-interacting region (LIR) induced targeted autophagic degradation of pathogenic HTT65Q aggregates; and the chimeras consisting of mitochondria-targeting sequence (MTS) and ABP or LIR promoted targeted autophagic degradation of dysfunctional mitochondria, hence ameliorating mitochondrial dysfunction in a Parkinson disease cell model and protecting cells from apoptosis induced by the mitochondrial stress agent FCCP. Therefore, this study provides a new strategy for the selective proteolysis of large targets and enrich the toolkit for autophagy-targeting degradation.Abbreviations: ABP: ATG16L1-binding peptide; ATG16L1: autophagy related 16 like 1; ATTEC: autophagy-tethering compound; AUTAC: autophagy-targeting chimera; AUTOTAC: autophagy-targeting chimera; Baf A1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CPP: cell-penetrating peptide; CQ: chloroquine phosphate; DAPI: 4',6-diamidino-2-phenylindole; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; FITC: fluorescein-5-isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK293: human embryonic kidney 293; HEK293T: human embryonic kidney 293T; HPLC: high-performance liquid chromatography; HRP: horseradish peroxidase; HTT: huntingtin; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFF: mitochondrial fission factor; MTS: mitochondria-targeting sequence; NBR1: NBR1 autophagy cargo receptor; NLRX1: NLR family member X1; OPTN: optineurin; P2A: self-cleaving 2A peptide; PB1: Phox and Bem1p; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; PROTACs: proteolysis-targeting chimeras; QBP: polyQ-binding peptide 1; SBP: streptavidin-binding peptide; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SPATA33: spermatogenesis associated 33; TIMM23: translocase of inner mitochondrial membrane 23; TMEM59: transmembrane protein 59; TOMM20: translocase of outer mitochondrial membrane 20; UBA: ubiquitin-associated; WT: wild type.
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Affiliation(s)
- Ligang Mei
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Xiaorong Chen
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Fujing Wei
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Xue Huang
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Lu Liu
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Jia Yao
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Jing Chen
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Xunguang Luo
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Zhuolin Wang
- School of Life Sciences, Chongqing University, Chongqing, China
| | - Aimin Yang
- School of Life Sciences, Chongqing University, Chongqing, China
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Mao Z, Hui H, Zhao X, Xu L, Qi Y, Yin L, Qu L, Han L, Peng J. Protective effects of dioscin against Parkinson's disease via regulating bile acid metabolism through remodeling gut microbiome/GLP-1 signaling. J Pharm Anal 2023; 13:1153-1167. [PMID: 38024855 PMCID: PMC10657977 DOI: 10.1016/j.jpha.2023.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/30/2023] [Accepted: 06/13/2023] [Indexed: 12/01/2023] Open
Abstract
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16 S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes-to-Bacteroidetes ratio and the abundances of Enterococcus, Streptococcus, Bacteroides and Lactobacillus genera, which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and β-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
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Affiliation(s)
- Zhang Mao
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
| | - Haochen Hui
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
| | - Xuerong Zhao
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
| | - Lina Xu
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
| | - Yan Qi
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
| | - Lianhong Yin
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
| | - Liping Qu
- Innovation Materials Research and Development Center, Botanee Research Institute, Yunnan Botanee Bio-technology Group Co., Ltd., Kunming, 650106, China
| | - Lan Han
- Department of Traditional Chinese Medicine Pharmacology, School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Jinyong Peng
- Department of Pharmaceutical Analysis, College of Pharmacy, Dalian Medical University, Dalian, Shenyang, 116044, China
- Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, 261053, China
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15
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Kaur S, Sharma N, Kumar V, Sharma D, Devi B, Kapil L, Singh C, Singh A. The Role of Mitophagy in Various Neurological Diseases as a Therapeutic Approach. Cell Mol Neurobiol 2023; 43:1849-1865. [PMID: 36326951 PMCID: PMC11412177 DOI: 10.1007/s10571-022-01302-8] [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: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/05/2022]
Abstract
Mitochondria are critical to multiple cellular processes, from the production of adenosine triphosphate (ATP), maintenance of calcium homeostasis, synthesis of key metabolites, and production of reactive oxygen species (ROS) to maintain necrosis, apoptosis, and autophagy. Therefore, proper clearance and regulation are essential to maintain various physiological processes carried out by the cellular mechanism, including mitophagy and autophagy, by breaking down the damaged intracellular connections under the influence of various genes and proteins and protecting against various neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), and Huntington disease (HD). In this review, we will discuss the role of autophagy, selective macroautophagy, or mitophagy, and its role in neurodegenerative diseases along with normal physiology. In addition, this review will provide a better understanding of the pathways involved in neuron autophagy and mitophagy and how mutations affect these pathways in the various genes involved in neurodegenerative diseases. Various new findings indicate that the pathways that remove dysfunctional mitochondria are impaired in these diseases, leading to the deposition of damaged mitochondria. Apart from that, we have also discussed the therapeutic strategies targeting autophagy and mitophagy in neurodegenerative diseases. The mitophagy cycle results in the degradation of damaged mitochondria and the biogenesis of new healthy mitochondria, also highlighting different stages at which a particular neurodegenerative disease could occur.
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Affiliation(s)
- Simranjit Kaur
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Neelam Sharma
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Vishal Kumar
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Deepali Sharma
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Bhawna Devi
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Lakshay Kapil
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Charan Singh
- Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, 142001, India
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India
| | - Arti Singh
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
- IK Gujral Punjab Technical University, Jalandhar, Punjab, India.
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Cai B, Zhong L, Wang Q, Xu W, Li X, Chen T. Curcumin alleviates 1-methyl- 4-phenyl- 1,2,3,6-tetrahydropyridine- induced Parkinson's disease in mice via modulating gut microbiota and short-chain fatty acids. Front Pharmacol 2023; 14:1198335. [PMID: 37388445 PMCID: PMC10303117 DOI: 10.3389/fphar.2023.1198335] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/06/2023] [Indexed: 07/01/2023] Open
Abstract
Background: The microbiota-gut-brain axis has been proposed as a potential therapeutic target of PD. The effects of curcumin against Parkinson's disease have been demonstrated; however, its neuroprotective mechanisms remain unknown. Our study investigated the potential mechanisms through which curcumin ameliorates Parkinson's disease via the microbiota-gut-brain axis. Methods: Mice were randomly divided into four groups: control, Curcumin, MPTP, and MPTP + Curcumin. Motor deficits and gastrointestinal dysfunction were assessed using behavioral test, intestinal motility test, and fecal parameter measurement. The loss of dopaminergic neurons and intestinal barrier function was measured using Western blot and immunofluorescence. Shotgun metagenomic sequencing and LC-MS were parallelly performed on mice feces to investigate alterations in microbiota and metabolites. Results: Curcumin alleviated motor deficits and the loss of dopaminergic neurons in MPTP-induced mice. Curcumin ameliorated gastrointestinal and intestinal barrier dysfunctions in MPTP-induced mice. Curcumin reduced gut microbial dysbiosis and modulated carbohydrate metabolism in MPTP-induced mice. Curcumin restored short-chain fatty acid (SCFA) profiles in MPTP-induced mice. Conclusion: Concurrently, these results indicate that curcumin inhibits Parkinson's disease by regulating the gut microbiota and short-chain fatty acids.
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Yu Q, Zhang R, Li T, Yang L, Zhou Z, Hou L, Wu W, Zhao R, Chen X, Yao Y, Huang S, Chen L. Mitochondrial Hydrogen Peroxide Activates PTEN and Inactivates Akt Leading to Autophagy Inhibition-Dependent Cell Death in Neuronal Models of Parkinson's Disease. Mol Neurobiol 2023; 60:3345-3364. [PMID: 36853430 PMCID: PMC10924433 DOI: 10.1007/s12035-023-03286-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 02/03/2023] [Indexed: 03/01/2023]
Abstract
Defective autophagy relates to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. Our recent study has demonstrated that PD toxins (6-OHDA, MPP+, or rotenone) induce neuronal apoptosis by impeding the AMPK/Akt-mTOR signaling. Here, we show that treatment with 6-OHDA, MPP+, or rotenone triggered decreases of ATG5/LC3-II and autophagosome formation with a concomitant increase of p62 in PC12, SH-SY5Y cells, and primary neurons, suggesting inhibition of autophagy. Interestingly, overexpression of wild-type ATG5 attenuated the inhibitory effect of PD toxins on autophagy, reducing neuronal apoptosis. The effects of PD toxins on autophagy and apoptosis were found to be associated with activation of PTEN and inactivation of Akt. Overexpression of dominant negative PTEN, constitutively active Akt and/or pretreatment with rapamycin rescued the cells from PD toxins-induced downregulation of ATG5/LC3-II and upregulation of p62, as well as consequential autophagosome diminishment and apoptosis in the cells. The effects of PD toxins on autophagy and apoptosis linked to excessive intracellular and mitochondrial hydrogen peroxide (H2O2) production, as evidenced by using a H2O2-scavenging enzyme catalase, a mitochondrial superoxide indicator MitoSOX and a mitochondria-selective superoxide scavenger Mito-TEMPO. Furthermore, we observed that treatment with PD toxins reduced the protein level of Parkin in the cells. Knockdown of Parkin alleviated the effects of PD toxins on H2O2 production, PTEN/Akt activity, autophagy, and apoptosis in the cells, whereas overexpression of wild-type Parkin exacerbated these effects of PD toxins, implying the involvement of Parkin in the PD toxins-induced oxidative stress. Taken together, the results indicate that PD toxins can elicit mitochondrial H2O2, which can activate PTEN and inactivate Akt leading to autophagy inhibition-dependent neuronal apoptosis, and Parkin plays a critical role in this process. Our findings suggest that co-manipulation of the PTEN/Akt/autophagy signaling by antioxidants may be exploited for the prevention of neuronal loss in PD.
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Affiliation(s)
- Qianyun Yu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
- Department of Biological Sciences, College of Science and Technology, Xinyang University, Xinyang, 464000, People's Republic of China
| | - Ruijie Zhang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
- College of Life Sciences, Anhui Medical University, Anhui, 230032, People's Republic of China
| | - Tianjing Li
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Liu Yang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Zhihan Zhou
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Long Hou
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Wen Wu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Rui Zhao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Xiaoling Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Yajie Yao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA.
- Department of Hematology and Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
| | - Long Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, People's Republic of China.
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18
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He T, Lin X, Su A, Zhang Y, Xing Z, Mi L, Wei T, Li Z, Wu W. Mitochondrial dysfunction-targeting therapeutics of natural products in Parkinson's disease. Front Pharmacol 2023; 14:1117337. [PMID: 37234707 PMCID: PMC10206024 DOI: 10.3389/fphar.2023.1117337] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Parkinson's disease (PD), the second most common neurodegenerative disease worldwide, often occurs in middle-aged and elderly individuals. The pathogenesis of PD is complex and includes mitochondrial dysfunction, and oxidative stress. Recently, natural products with multiple structures and their bioactive components have become one of the most important resources for small molecule PD drug research targeting mitochondrial dysfunction. Multiple lines of studies have proven that natural products display ameliorative benefits in PD treatment by regulating mitochondrial dysfunction. Therefore, a comprehensive search of recent published articles between 2012 and 2022 in PubMed, Web of Science, Elesvier, Wliey and Springer was carried out, focusing on original publications related to natural products against PD by restoring mitochondrial dysfunction. This paper presented the mechanisms of various kinds of natural products on PD-related mitochondrial dysfunction regulation and provided evidence that natural products are promising to be developed as drugs for PD therapeutics.
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Abrishamdar M, Jalali MS, Farbood Y. Targeting Mitochondria as a Therapeutic Approach for Parkinson's Disease. Cell Mol Neurobiol 2023; 43:1499-1518. [PMID: 35951210 PMCID: PMC11412433 DOI: 10.1007/s10571-022-01265-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/21/2022] [Indexed: 11/03/2022]
Abstract
Neurodegeneration is among the most critical challenges that involve modern societies and annually influences millions of patients worldwide. While the pathophysiology of Parkinson's disease (PD) is complicated, the role of mitochondrial is demonstrated. The in vitro and in vivo models and genome-wide association studies in human cases proved that specific genes, including PINK1, Parkin, DJ-1, SNCA, and LRRK2, linked mitochondrial dysfunction with PD. Also, mitochondrial DNA (mtDNA) plays an essential role in the pathophysiology of PD. Targeting mitochondria as a therapeutic approach to inhibit or slow down PD formation and progression seems to be an exciting issue. The current review summarized known mutations associated with both mitochondrial dysfunction and PD. The significance of mtDNA in Parkinson's disease pathogenesis and potential PD therapeutic approaches targeting mitochondrial dysfunction was then discussed.
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Affiliation(s)
- Maryam Abrishamdar
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Sadat Jalali
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Yaghoob Farbood
- Department of Physiology, Medicine Faculty, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson's Disease. Antioxidants (Basel) 2023; 12:antiox12010130. [PMID: 36670992 PMCID: PMC9855117 DOI: 10.3390/antiox12010130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson’s disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD.
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21
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Asthana J, Shravage BV. Exploring therapeutic potential of mitophagy modulators using Drosophila models of Parkinson’s disease. Front Aging Neurosci 2022; 14:986849. [PMID: 36337696 PMCID: PMC9632658 DOI: 10.3389/fnagi.2022.986849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Parkinson’s disease (PD) is the second most popular age-associated neurodegenerative disorder after Alzheimer’s disease. The degeneration of dopaminergic neurons, aggregation of α-synuclein (α-syn), and locomotor defects are the main characteristic features of PD. The main cause of a familial form of PD is associated with a mutation in genes such as SNCA, PINK1, Parkin, DJ-1, LRKK2, and others. Recent advances have uncovered the different underlying mechanisms of PD but the treatment of PD is still unknown due to the unavailability of effective therapies and preventive medicines in the current scenario. The pathophysiology and genetics of PD have been strongly associated with mitochondria in disease etiology. Several studies have investigated a complex molecular mechanism governing the identification and clearance of dysfunctional mitochondria from the cell, a mitochondrial quality control mechanism called mitophagy. Reduced mitophagy and mitochondrial impairment are found in both sporadic and familial PD. Pharmacologically modulating mitophagy and accelerating the removal of defective mitochondria are of common interest in developing a therapy for PD. However, despite the extensive understanding of the mitochondrial quality control pathway and its underlying mechanism, the therapeutic potential of targeting mitophagy modulation and its role in PD remains to be explored. Thus, targeting mitophagy using chemical agents and naturally occurring phytochemicals could be an emerging therapeutic strategy in PD prevention and treatment. We discuss the current research on understanding the role of mitophagy modulators in PD using Drosophila melanogaster as a model. We further explore the contribution of Drosophila in the pathophysiology of PD, and discuss comprehensive genetic analysis in flies and pharmacological drug screening to develop potential therapeutic molecules for PD.
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Affiliation(s)
- Jyotsna Asthana
- Developmental Biology Group, MACS-Agharkar Research Institute, Pune, India
| | - Bhupendra V. Shravage
- Developmental Biology Group, MACS-Agharkar Research Institute, Pune, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, India
- Department of Zoology, Savitribai Phule Pune University, Pune, India
- *Correspondence: Bhupendra V. Shravage,
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22
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Khursheed R, Singh SK, Wadhwa S, Gulati M, Jha NK, Gupta G, Devkota HP, Prasher P, Chellappan DK, Dua K. A sojourn into therapeutic and nutraceutical potential of curcumin and its novel drug delivery system: Current achievements and future perspectives. SOUTH AFRICAN JOURNAL OF BOTANY 2022; 149:944-962. [DOI: 10.1016/j.sajb.2022.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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23
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Cui C, Han Y, Li H, Yu H, Zhang B, Li G. Curcumin-driven reprogramming of the gut microbiota and metabolome ameliorates motor deficits and neuroinflammation in a mouse model of Parkinson's disease. Front Cell Infect Microbiol 2022; 12:887407. [PMID: 36034698 PMCID: PMC9400544 DOI: 10.3389/fcimb.2022.887407] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 07/06/2022] [Indexed: 12/28/2022] Open
Abstract
Background Parkinson's disease (PD) is a common neurodegenerative disorder, accompanied by motor deficits as well as gastrointestinal dysfunctions. Recent studies have proved that the disturbance of gut microbiota and metabolism contributes to the pathogenesis of PD; however, the mechanisms underlying these effects have yet to be elucidated. Curcumin (CUR) has been reported to provide neuroprotective effects on neurological disorders and modulate the gut flora in intestinal-related diseases. Therefore, it is of significant interest to investigate whether CUR could exert a protective effect on PD and whether the effect of CUR is dependent on the intestinal flora and subsequent changes in metabolites. Methods In this study, we investigated the neuroprotective effects of CUR on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rRNA sequencing was performed to explore the profile of the gut microbiota among controls, MPTP-treated mice and CUR-treated mice. Then, antibiotic treatment (ABX) and fecal microbiota transplantation (FMT) experiments were conducted to examine the role of intestinal microbes on the protective effects of CUR in PD mice. Furthermore, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics analysis was used to identify the landscape of the CUR-driven serum metabolome. Finally, Pearson's analysis was conducted to investigate correlations between the gut flora-metabolite axis and CUR-driven neuroprotection in PD. Results Our results showed that CUR intervention effectively improved motor deficits, glial cell activation, and the aggregation of α-synuclein (α-syn) in MPTP-treated mice. 16S rRNA sequencing showed elevated abundances of Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae but depleted abundances of Aerococcaceae and Staphylococcaceae in CUR-treated mice when compared with MPTP mice. ABX and FMT experiments further confirmed that the gut microbiota was required for CUR-induced protection in PD mice. Serum metabolomics analysis showed that CUR notably upregulated the levels of tyrosine, methionine, sarcosine and creatine. Importantly, strong correlations were identified among crucial taxa (Aerococcaceae, Staphylococcaceae, Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae), pivotal metabolites (tyrosine, methionine, sarcosine and creatine) and the motor function and pathological results of mice. CUR treatment led to a rapid increase in the brain levels of tyrosine and levodopa (dopa) these changes were related to the abundances of Lactobacillaceae and Aerococcaceae. Conclusions CUR exerts a protective effect on the progression of PD by modulating the gut microbiota-metabolite axis. Lactobacillaceae and Aerococcaceae, along with key metabolites such as tyrosine and dopa play a dominant role in CUR-associated neuroprotection in PD mice. Our findings offer unique insights into the pathogenesis and potential treatment of PD.
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Affiliation(s)
- Can Cui
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yingying Han
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hongxia Li
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hongxiang Yu
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bei Zhang
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Gang Li
- Department of Neurology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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24
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Handl J, Nyvltova P, Capek J, Cesla P, Hovsepyan A, Avetisyan S, Micankova P, Bruckova L, Stankova P, Knotkova K, Petrosyan T, Rousar T. The comparison of biological effects of bacterial and synthetic melanins in neuroblastoma cells. Food Chem Toxicol 2022; 168:113355. [PMID: 35952821 DOI: 10.1016/j.fct.2022.113355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/28/2022] [Accepted: 08/03/2022] [Indexed: 11/26/2022]
Abstract
Melanins belong to a group of pigments of different structure and origin. They can be produced synthetically or isolated from living organisms. A number of studies have reported testing of various melanins in neurological studies providing different outcomes. Because the structure of melanins can have an effect on obtained results in cell toxicity studies, we present here our original study which aimed to compare the biological effects of bacterial melanin (biotechnologically obtained from B. thuringiensis) with that of synthetic melanin in neuroblastoma cells. Both melanins were structurally characterized in detail. After melanin treatment (0-200 μg/mL), cell viability, glutathione levels, cell morphology and respiration were assessed in SH-SY5Y cells. The structural analysis showed that bacterial melanin is more hydrophilic according to the presence of larger number of -OH moieties. After melanin treatment, we found that synthetic melanin at similar dosage caused always larger cell impairment compared to bacterial melanin. In addition, more severe toxic effect of synthetic melanin was found in mitochondria. In general, we conclude that more hydrophilic, bacterial melanin induced lower toxicity in neuroblastoma cells in comparison to synthetic melanin. Our findings can be useable for neuroscientific studies estimating the potential use for study of neuroprotection, neuromodulation or neurotoxicity.
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Affiliation(s)
- Jiri Handl
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Pavlina Nyvltova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Jan Capek
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Petr Cesla
- Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Anichka Hovsepyan
- Scientific and Production Center "Armbiotechnology" SNPO NAS RA, 14 Gyurjyan St., Yerevan, Armenia
| | - Sona Avetisyan
- Scientific and Production Center "Armbiotechnology" SNPO NAS RA, 14 Gyurjyan St., Yerevan, Armenia
| | - Petra Micankova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Lenka Bruckova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Pavla Stankova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Katerina Knotkova
- Department of Physical Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic
| | - Tigran Petrosyan
- Department of Physiology and Pathophysiology, Medical Institute, Yerevan Haybusak University, 6 Abelyan St., Yerevan, Armenia
| | - Tomas Rousar
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10, Pardubice, Czech Republic.
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Darbinyan LV, Simonyan KV, Hambardzumyan LE, Manukyan LP, Badalyan SH, Sarkisian VH. Protective effect of curcumin against rotenone-induced substantia nigra pars compacta neuronal dysfunction. Metab Brain Dis 2022; 37:1111-1118. [PMID: 35239141 DOI: 10.1007/s11011-022-00941-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/21/2022] [Indexed: 01/07/2023]
Abstract
Rotenone is involved in the degeneration of dopaminergic neurons, and curcumin may prevent or effectively slow the progression of Parkinson's disease (PD). Previous research has shown that the naturally occurring phenolic compound curcumin can reduce inflammation and oxidation, making it a potential therapeutic agent for neurodegenerative diseases. The present study involves investigation of rotenone-induced histological changes in the brain area, hippocampus using Nissl staining after 35 day of subcutaneous injection of rotenone in adult male rats. We sought to determine whether curcumin could protect against rotenone-induced dopaminergic neurotoxicity in a rat model by in vivo electrical recording from Substantia nigra pars compacta (SNc). Curcumin treatment significantly improved electrical activity of neurons in the SNc of rotenone-induced PD model rats. The pattern of histological alterations corresponds with electrophysiological manifestations.
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Affiliation(s)
- L V Darbinyan
- Sensorimotor Integration Laboratory, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - K V Simonyan
- Neuroendocrine Relationships Laboratory, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia.
| | - L E Hambardzumyan
- Sensorimotor Integration Laboratory, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - L P Manukyan
- Sensorimotor Integration Laboratory, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - S H Badalyan
- Sensorimotor Integration Laboratory, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - V H Sarkisian
- Sensorimotor Integration Laboratory, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
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26
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Goyal A, Gopika S, Kumar A, Garabadu D. A Comprehensive Review on Preclinical Evidence Based Neuroprotective Potential of Bacopa Monnieri Against Parkinson's Disease. Curr Drug Targets 2022; 23:889-901. [PMID: 35297345 DOI: 10.2174/1389450123666220316091734] [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: 08/21/2021] [Revised: 11/03/2021] [Accepted: 12/30/2021] [Indexed: 11/22/2022]
Abstract
Parkinson's diseaseis a chronic and gradually progressive neurodegenerative disorder triggered due to the loss of dopamine-releasing neurons in the region of substantianigra pars compacta characterized by the motor symptoms such as tremor, bradykinesia, akinesia, and postural instability. Proteinopathies, mitochondrial dysfunction induced dopaminergic neuronal deterioration, and gene mutations arethe hallmarks of Parkinson's disease. The bioactive components of Brahmi such as Bacoside A, Bacoside B, and Bacosaponins, belong to various chemical families. Brahmi's neuroprotective role includes reducing neuronal oxidative stress, dopaminergic neuronal degeneration, mitochondrial dysfunction, inflammation, aggregation inhibition of α-synuclein, and improvement of cognitive and learning behaviour. Researchers found that Bacopa monnieri significantly increased brain levels of glutathione, vitamin C, vitamin E, and vitamin A in rats exposed to cigarette smoke. Brahmi has a potent antioxidant property and neuroprotective effects against PD that help reduce oxidative stress, neuroinflammation and enhance the dopamine level. The review collates all the preclinical studies that prove the beneficial neuroprotective effect of Brahmi for treating PD.
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Affiliation(s)
- Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University 17-Km. stone, NH-2 Mathura-Delhi Highway, P.O. Chaumuhan, Mathura-281406 (U.P.), India
| | - S Gopika
- Institute of Pharmaceutical Research, GLA University 17-Km. stone, NH-2 Mathura-Delhi Highway, P.O. Chaumuhan, Mathura-281406 (U.P.), India
| | - Abhishek Kumar
- Institute of Pharmaceutical Research, GLA University 17-Km. stone, NH-2 Mathura-Delhi Highway, P.O. Chaumuhan, Mathura-281406 (U.P.), India
| | - Debapriya Garabadu
- Department of Pharmacology, School of Health Sciences, Central University of Punjab, Bathinda- 151001, Punjab, India
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27
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Hao M, Chu Y, Lei J, Yao Z, Wang P, Chen Z, Wang K, Sang X, Han X, Wang L, Cao G. Pharmacological Mechanisms and Clinical Applications of Curcumin: Update. Aging Dis 2022; 14:716-749. [PMID: 37191432 DOI: 10.14336/ad.2022.1101] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Curcumin, a well-known hydrophobic polyphenol extracted from the rhizomes of turmeric (Curcuma longa L.), has attracted great interest in the last ten years due to its multiple pharmacological activities. A growing body of evidence has manifested that curcumin has extensive pharmacological activities including anti-inflammatory, anti-oxygenation, lipid regulation, antiviral, and anticancer with hypotoxicity and minor adverse reactions. However, the disadvantages of low bioavailability, short half-life in plasma, low drug concentration in blood, and poor oral absorption severely limited the clinical application of curcumin. Pharmaceutical researchers have carried out plenty of dosage form transformations to improve the druggability of curcumin and have achieved remarkable results. Therefore, the objective of this review summarizes the pharmacological research progress, problems in clinical application and the improvement methods of curcumin's druggability. By reviewing the latest research progress of curcumin, we believe that curcumin has a broad clinical application prospect for its wide range of pharmacological activities with few side effects. The deficiencies of lower bioavailability of curcumin could be improved by dosage form transformation. However, curcumin in the clinical application still requires further study regarding the underlying mechanism and clinical trial verification.
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28
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Costas C, Faro LR. Do Naturally Occurring Antioxidants Protect Against Neurodegeneration of the Dopaminergic System? A Systematic Revision in Animal Models of Parkinson's Disease. Curr Neuropharmacol 2022; 20:432-459. [PMID: 33882808 PMCID: PMC9413795 DOI: 10.2174/1570159x19666210421092725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/18/2021] [Accepted: 04/16/2021] [Indexed: 11/22/2022] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by a significant decrease in dopamine levels, caused by progressive degeneration of the dopaminergic neurons in the nigrostriatal pathway. Multiple mechanisms have been implicated in its pathogenesis, including oxidative stress, neuroinflammation, protein aggregation, mitochondrial dysfunction, insufficient support for neurotrophic factors and cell apoptosis. The absence of treatments capable of slowing or stopping the progression of PD has increased the interest in the natural antioxidant substances present in the diet, since they have multiple beneficial properties and it is possible that they can influence the mechanisms responsible for the dysfunction and death of dopaminergic neurons. Thus, the purpose of this systematic review is to analyze the results obtained in a set of studies carried out in the last years, which describe the neuroprotective, antioxidant and regenerative functions of some naturally occurring antioxidants in experimental models of PD. The results show that the exogenous no enzymatic antioxidants can significantly modify the biochemical and behavioral mechanisms that contribute to the pathophysiology of Parkinsonism in experimental animals. Therefore, it is possible that they may contribute to effective neuroprotection by providing a significant improvement in neuropathological markers. In conclusion, the results of this review suggest that exogenous antioxidants can be promising therapeutic candidates for the prevention and treatment of PD.
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Affiliation(s)
- Carmen Costas
- Department of Functional Biology and Health Sciences, Faculty of Biology, University of Vigo, Campus Lagoas-Marcosende, 36310, Vigo, Spain
| | - Lilian R.F. Faro
- Department of Functional Biology and Health Sciences, Faculty of Biology, University of Vigo, Campus Lagoas-Marcosende, 36310, Vigo, Spain
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Benameur T, Giacomucci G, Panaro MA, Ruggiero M, Trotta T, Monda V, Pizzolorusso I, Lofrumento DD, Porro C, Messina G. New Promising Therapeutic Avenues of Curcumin in Brain Diseases. Molecules 2021; 27:236. [PMID: 35011468 PMCID: PMC8746812 DOI: 10.3390/molecules27010236] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/28/2021] [Accepted: 12/29/2021] [Indexed: 01/02/2023] Open
Abstract
Curcumin, the dietary polyphenol isolated from Curcuma longa (turmeric), is commonly used as an herb and spice worldwide. Because of its bio-pharmacological effects curcumin is also called "spice of life", in fact it is recognized that curcumin possesses important proprieties such as anti-oxidant, anti-inflammatory, anti-microbial, antiproliferative, anti-tumoral, and anti-aging. Neurodegenerative diseases such as Alzheimer's Diseases, Parkinson's Diseases, and Multiple Sclerosis are a group of diseases characterized by a progressive loss of brain structure and function due to neuronal death; at present there is no effective treatment to cure these diseases. The protective effect of curcumin against some neurodegenerative diseases has been proven by in vivo and in vitro studies. The current review highlights the latest findings on the neuroprotective effects of curcumin, its bioavailability, its mechanism of action and its possible application for the prevention or treatment of neurodegenerative disorders.
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Affiliation(s)
- Tarek Benameur
- Department of Biomedical Sciences, College of Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Giulia Giacomucci
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, 50134 Florence, Italy;
| | - Maria Antonietta Panaro
- Biotechnologies and Biopharmaceutics, Department of Biosciences, University of Bari, 70125 Bari, Italy; (M.A.P.); (M.R.)
| | - Melania Ruggiero
- Biotechnologies and Biopharmaceutics, Department of Biosciences, University of Bari, 70125 Bari, Italy; (M.A.P.); (M.R.)
| | - Teresa Trotta
- Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy; (T.T.); (V.M.); (G.M.)
| | - Vincenzo Monda
- Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy; (T.T.); (V.M.); (G.M.)
- Unit of Dietetic and Sport Medicine, Section of Human Physiology, Department of Experimental Medicine, Luigi Vanvitelli University of Campania, 81100 Naples, Italy
| | - Ilaria Pizzolorusso
- Child and Adolescent Neuropsychiatry Unit, Department of Mental Health, ASL Foggia, 71121 Foggia, Italy;
| | - Dario Domenico Lofrumento
- Department of Biological and Environmental Sciences and Technologies, Section of Human Anatomy, University of Salento, 73100 Lecce, Italy;
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy; (T.T.); (V.M.); (G.M.)
| | - Giovanni Messina
- Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy; (T.T.); (V.M.); (G.M.)
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30
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Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases. Int J Mol Sci 2021; 22:ijms222111444. [PMID: 34768878 PMCID: PMC8583882 DOI: 10.3390/ijms222111444] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023] Open
Abstract
Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species and are vulnerable targets for oxidative stress-induced damage. The brain is very susceptible to oxidative damage due to its high metabolic demand and low antioxidant defence systems, therefore minimal imbalances in the redox state can result in an oxidative environment that favours tissue damage and activates neuroinflammatory processes. Mitochondrial-associated molecular pathways are often compromised in the pathophysiology of neurodegeneration, including the parkin/PINK1, Nrf2, PGC1α, and PPARγ pathways. Impairments to these signalling pathways consequently effect the removal of dysfunctional mitochondria, which has been suggested as contributing to the development of neurodegeneration. Mitochondrial dysfunction prevention has become an attractive therapeutic target, and there are several molecular pathways that can be pharmacologically targeted to remove damaged mitochondria by inducing mitochondrial biogenesis or mitophagy, as well as increasing the antioxidant capacity of the brain, in order to alleviate mitochondrial dysfunction and prevent the development and progression of neurodegeneration in these disorders. Compounds such as natural polyphenolic compounds, bioactive quinones, and Nrf2 activators have been reported in the literature as novel therapeutic candidates capable of targeting defective mitochondrial pathways in order to improve mitochondrial function and reduce the severity of neurodegeneration in these disorders.
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31
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Nebrisi EE. Neuroprotective Activities of Curcumin in Parkinson's Disease: A Review of the Literature. Int J Mol Sci 2021; 22:11248. [PMID: 34681908 PMCID: PMC8537234 DOI: 10.3390/ijms222011248] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 08/30/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Parkinson's disease (PD) is a slowly progressive multisystem disorder affecting dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is characterized by a decrease of dopamine (DA) in their striatal terminals. Treatment of PD with levodopa or DA receptor agonists replaces the function of depleted DA in the striatum. Prolonged treatment with these agents often has variable therapeutic effects and leads to the development of undesirable dyskinesia. Consequently, a crucial unmet demand in the management of Parkinson's disease is the discovery of new approaches that could slow down, stop, or reverse the process of neurodegeneration. Novel potential treatments involving natural substances with neuroprotective activities are being developed. Curcumin is a polyphenolic compound isolated from the rhizomes of Curcuma longa (turmeric). It has been demonstrated to have potent anti-inflammatory, antioxidant, free radical scavenging, mitochondrial protecting, and iron-chelating effects, and is considered a promising therapeutic and nutraceutical agent for the treatment of PD. However, molecular and cellular mechanisms that mediate the pharmacological actions of curcumin remain largely unknown. Stimulation of nicotinic receptors and, more precisely, selective α7 nicotinic acetylcholine receptors (α7-nAChR), have been found to play a major modulatory role in the immune system via the "cholinergic anti-inflammatory pathway". Recently, α7-nAChR has been proposed to be a potential therapeutic approach in PD. In this review, the detailed mechanisms of the neuroprotective activities of curcumin as a potential therapeutic agent to help Parkinson's patients are being discussed and elaborated on in detail.
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Affiliation(s)
- Eslam El Nebrisi
- Department of Pharmacology, Dubai Medical College, Dubai 20170, United Arab Emirates
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32
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Enogieru AB, Haylett W, Hiss D, Ekpo O. Inhibition of γH2AX, COX-2 and regulation of antioxidant enzymes in MPP +-exposed SH-SY5Y cells pre-treated with rutin. Metab Brain Dis 2021; 36:2119-2130. [PMID: 33978902 DOI: 10.1007/s11011-021-00746-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/27/2021] [Indexed: 12/16/2022]
Abstract
Many plant-derived bioactive compounds such as rutin are reportedly effective in attenuating neuronal death in most neurodegenerative disorders. Parkinson's disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra of the midbrain, and has previously been modelled in-vitro through the specific neurotoxic activity of 1-methyl-4-phenylpyridinium (MPP+) on dopaminergic neurons. Rutin is a bioflavonoid with multiple pharmacological effects, and this study investigated the neuroprotective effects of rutin in the human dopaminergic SH-SY5Y cell line using the neurotoxin MPP+. SH-SY5Y cells pretreated with rutin, were exposed to MPP+ and evaluated for cell viability, nitric oxide (NO), reactive oxygen species (ROS) and antioxidant enzymes activities. In addition, western blot techniques were used to determine the protein expression levels of γH2AX and COX-2. Rutin significantly attenuated MPP+-induced loss of cell viability, mitigated ROS and NO production and inhibited the disruption of antioxidant enzymes activity. It was also observed that rutin significantly reduced protein expression levels of γH2AX and COX-2 in SH-SY5Y cells treated with MPP+. Taken together, findings from this study tend to suggest that rutin is a promising neuroprotective compound for the treatment of PD through its effects on some of the mechanisms that characterize this neurodegenerative disease.
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Affiliation(s)
- Adaze Bijou Enogieru
- Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, South Africa.
- Department of Anatomy, School of Basic Medical Sciences, University of Benin, Edo State, Nigeria.
| | - William Haylett
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Donavon Hiss
- Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, South Africa
| | - Okobi Ekpo
- Department of Medical Biosciences, University of the Western Cape, Robert Sobukwe Road, Private Bag X17, Bellville, 7535, South Africa.
- Department of Anatomy and Cellular Biology College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, 127788, United Arab Emirates.
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Rezaei Kamelabad M, Jahanbin Sardroodi J, Rastkar Ebrahimzadeh A, Ajamgard M. Influence of curcumin and rosmarinic acid on disrupting the general properties of Alpha-Synuclein oligomer: Molecular dynamics simulation. J Mol Graph Model 2021; 107:107963. [PMID: 34147836 DOI: 10.1016/j.jmgm.2021.107963] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 01/25/2023]
Abstract
Alpha-Synuclein (αS) is a protein involved in Parkinson's disease (PD) and is probably the main cause of the pathology of the disease. During pathogenesis, αS monomers aggregate, leading to the formation of a variety of oligomeric species. Recent research studies suggest that the oligomeric toxic species may be one of the main processes for pathology and disease. Here, we studied influence of two natural polyphenolic compounds, Curcumin (CUR) and Rosmarinic acid (RA), on disrupting the general properties of αS oligomer by molecular dynamics (MD) simulation method. The hydrophobic central domain of αS (NAC), is the most essential district responsible for protein self-aggregation; so, in this study, our systems have been developed to form a quintuplet NAC region of αS called 5mer; they have 10 and 20 CUR and RA molecules and a 5mer with no ligand. The several important and efficient analyzes were performed to investigate the effect of ligands on the structural properties of αS oligomers. The results indicated that both ligands can be successful in disrupting the original structure of αS oligomers; therefore, they can be considered suitable candidates for designing Parkinson's drugs.
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Affiliation(s)
- Mahrokh Rezaei Kamelabad
- Molecular Simulation Laboratory (MSL), Azarbaijan Shahid Madani University, Tabriz, Iran; Department of Chemistry, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran; Molecular Sciences and Engineering Research Group (MSERG), Iran
| | - Jaber Jahanbin Sardroodi
- Molecular Simulation Laboratory (MSL), Azarbaijan Shahid Madani University, Tabriz, Iran; Department of Chemistry, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran; Molecular Sciences and Engineering Research Group (MSERG), Iran.
| | - Alireza Rastkar Ebrahimzadeh
- Molecular Simulation Laboratory (MSL), Azarbaijan Shahid Madani University, Tabriz, Iran; Department of Physics, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran; Molecular Sciences and Engineering Research Group (MSERG), Iran
| | - Marzieh Ajamgard
- Molecular Simulation Laboratory (MSL), Azarbaijan Shahid Madani University, Tabriz, Iran; Department of Chemistry, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran; Molecular Sciences and Engineering Research Group (MSERG), Iran
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Yao L, Wu J, Koc S, Lu G. Genetic Imaging of Neuroinflammation in Parkinson's Disease: Recent Advancements. Front Cell Dev Biol 2021; 9:655819. [PMID: 34336822 PMCID: PMC8320775 DOI: 10.3389/fcell.2021.655819] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 06/14/2021] [Indexed: 12/14/2022] Open
Abstract
Parkinson's disease (PD) is one of the most prevalent neurodegenerative aging disorders characterized by motor and non-motor symptoms due to the selective loss of midbrain dopaminergic (DA) neurons. The decreased viability of DA neurons slowly results in the appearance of motor symptoms such as rigidity, bradykinesia, resting tremor, and postural instability. These symptoms largely depend on DA nigrostriatal denervation. Pharmacological and surgical interventions are the main treatment for improving clinical symptoms, but it has not been possible to cure PD. Furthermore, the cause of neurodegeneration remains unclear. One of the possible neurodegeneration mechanisms is a chronic inflammation of the central nervous system, which is mediated by microglial cells. Impaired or dead DA neurons can directly lead to microglia activation, producing a large number of reactive oxygen species and pro-inflammatory cytokines. These cytotoxic factors contribute to the apoptosis and death of DA neurons, and the pathological process of neuroinflammation aggravates the primary morbid process and exacerbates ongoing neurodegeneration. Therefore, anti-inflammatory treatment exerts a robust neuroprotective effect in a mouse model of PD. Since discovering the first mutation in the α-synuclein gene (SNCA), which can cause disease-causing, PD has involved many genes and loci such as LRRK2, Parkin, SNCA, and PINK1. In this article, we summarize the critical descriptions of the genetic factors involved in PD's occurrence and development (such as LRRK2, SNCA, Parkin, PINK1, and inflammasome), and these factors play a crucial role in neuroinflammation. Regulation of these signaling pathways and molecular factors related to these genetic factors can vastly improve the neuroinflammation of PD.
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Affiliation(s)
- Longping Yao
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiayu Wu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Sumeyye Koc
- Department of Neuroscience, Institute of Health Sciences, Ondokuz Mayıs University, Samsun, Turkey
| | - Guohui Lu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Farkhondeh T, Samarghandian S, Roshanravan B, Peivasteh-Roudsari L. Impact of Curcumin on Traumatic Brain Injury and Involved Molecular Signaling Pathways. Recent Pat Food Nutr Agric 2021; 11:137-144. [PMID: 31288732 DOI: 10.2174/2212798410666190617161523] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 04/14/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023]
Abstract
Traumatic Brain Injury (TBI) is one of the main causes of mortality and morbidity worldwide with no suitable treatment. The present study was designed to review the present literature about the protective effects of curcumin and the underlying mechanism against TBI. All published English language papers from beginning to 2019 were selected in this study. The findings indicate that curcumin may be effective against TBI outcomes by modulating the molecular signaling pathways involved in oxidative stress, inflammation, apoptosis, and autophagy. However, more experimental studies should be done to identify all mechanisms involved in the pathogenesis of TBI. Patents for Curcumin and chronic inflammation and traumatic brain injury management (WO2017097805A1 and US9101580B2) were published. In conclusion, the present study confirmed the potential therapeutic impact of curcumin for treating TBI.
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Affiliation(s)
- Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Noncommunicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Babak Roshanravan
- Medical Student, Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Leila Peivasteh-Roudsari
- Devision of Food Safety and Hygiene, Department of Environmental Health, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Abrahams S, Miller HC, Lombard C, van der Westhuizen FH, Bardien S. Curcumin pre-treatment may protect against mitochondrial damage in LRRK2-mutant Parkinson's disease and healthy control fibroblasts. Biochem Biophys Rep 2021; 27:101035. [PMID: 34189277 PMCID: PMC8219994 DOI: 10.1016/j.bbrep.2021.101035] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 05/19/2021] [Accepted: 05/23/2021] [Indexed: 12/05/2022] Open
Abstract
Mitochondrial dysfunction has been proposed as one of the pathobiological underpinnings in Parkinson's disease. Environmental stressors, such as paraquat, induce mitochondrial dysfunction and promote reactive oxygen species production. Targeting oxidative stress pathways could prevent mitochondrial dysfunction and thereby halt the neurodegeneration in Parkinson's disease. Since curcumin is touted as an antioxidant and neuroprotective agent, the aim of this study was to investigate if curcumin is a suitable therapy to target mitochondrial dysfunction in Parkinson's disease using a paraquat-toxicity induced model in fibroblasts from LRRK2-mutation positive Parkinson's disease individuals and healthy controls. The fibroblasts were exposed to five treatment groups, (i) untreated, (ii) curcumin only, (iii) paraquat only, (iv) pre-curcumin group: with curcumin for 2hr followed by paraquat for 24hr and (v) post-curcumin group: with paraquat for 24hr followed by curcumin for 2hr. Mitochondrial function was determined by measuring three parameters of mitochondrial respiration (maximal respiration, ATP-associated respiration, and spare respiratory capacity) using the Seahorse XFe96 Extracellular Flux Analyzer. As expected, paraquat effectively disrupted mitochondrial function for all parameters. Pre-curcumin treatment improved maximal and ATP-associated respiration whereas, post-curcumin treatment had no effect. These findings indicate that curcumin may be most beneficial as a pre-treatment before toxin exposure, which has implications for its therapeutic use. These promising findings warrant future studies testing different curcumin dosages, exposure times and curcumin formulations in larger sample sizes of Parkinson's disease and control participants.
Paraquat reduced respiration in Parkinson's disease and control fibroblasts. Curcumin, an antioxidant, improved mitochondrial respiration, as a pre-treatment. Post-treatment with curcumin did not improve mitochondrial respiration.
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Key Words
- ATP, Adenosine Triphosphate
- DMEM, Dulbecco's Modified Eagle Medium
- DMSO, Dimethyl Sulfoxide
- FCCP, Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone
- LRRK2, Leucine Rich Repeat Kinase 2
- MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- Mitochondrial function
- OCR, oxygen consumption rate
- Oxidative stress
- PD, Parkinson's disease
- Paraquat
- Turmeric
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Affiliation(s)
- Shameemah Abrahams
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Hayley C Miller
- Human Metabolomics, Faculty of Natural Sciences, North West University, Potchefstroom, South Africa
| | - Carl Lombard
- Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.,Biostatistics Unit, South African Medical Research Council, Cape Town, South Africa
| | | | - Soraya Bardien
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Liang Z, Currais A, Soriano-Castell D, Schubert D, Maher P. Natural products targeting mitochondria: emerging therapeutics for age-associated neurological disorders. Pharmacol Ther 2021; 221:107749. [PMID: 33227325 PMCID: PMC8084865 DOI: 10.1016/j.pharmthera.2020.107749] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 12/17/2022]
Abstract
Mitochondria are the primary source of energy production in the brain thereby supporting most of its activity. However, mitochondria become inefficient and dysfunctional with age and to a greater extent in neurological disorders. Thus, mitochondria represent an emerging drug target for many age-associated neurological disorders. This review summarizes recent advances (covering from 2010 to May 2020) in the use of natural products from plant, animal, and microbial sources as potential neuroprotective agents to restore mitochondrial function. Natural products from diverse classes of chemical structures are discussed and organized according to their mechanism of action on mitochondria in terms of modulation of biogenesis, dynamics, bioenergetics, calcium homeostasis, and membrane potential, as well as inhibition of the oxytosis/ferroptosis pathway. This analysis emphasizes the significant value of natural products for mitochondrial pharmacology as well as the opportunities and challenges for the discovery and development of future neurotherapeutics.
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Affiliation(s)
- Zhibin Liang
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States; The Paul F. Glenn Center for Biology of Aging Research, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States.
| | - Antonio Currais
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
| | - David Soriano-Castell
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
| | - David Schubert
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States; The Paul F. Glenn Center for Biology of Aging Research, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Pamela Maher
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States.
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Singla RK, Agarwal T, He X, Shen B. Herbal Resources to Combat a Progressive & Degenerative Nervous System Disorder- Parkinson's Disease. Curr Drug Targets 2021; 22:609-630. [PMID: 33050857 DOI: 10.2174/1389450121999201013155202] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/06/2020] [Accepted: 06/12/2020] [Indexed: 02/08/2023]
Abstract
Parkinson's disease is one of the most common adult-onset, a chronic disorder involving neurodegeneration, which progressively leads to deprivation of dopaminergic neurons in substantia nigra, causing a subsequent reduction of dopamine levels in the striatum resulting in tremor, myotonia, and dyskinesia. Genetics and environmental factors are believed to be responsible for the onset of Parkinson's disease. The exact pathogenesis of Parkinson's disease is quite complicated and the present anti-Parkinson's disease treatments appear to be clinically insufficient. Comprehensive researches have demonstrated the use of natural products such as ginseng, curcumin, ashwagandha, baicalein, etc. for the symptomatic treatment of this disease. The neuroprotective effects exhibited by these natural products are mainly due to their ability to increase dopamine levels in the striatum, manage oxidative stress, mitochondrial dysfunction, glutathione levels, clear the aggregation of α- synuclein, induce autophagy and decrease the pro-inflammatory cytokines and lipid peroxidation. This paper reviews various natural product studies conducted by scientists to establish the role of natural products (both metabolite extracts as well as pure metabolites) as adjunctive neuroprotective agents.
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Affiliation(s)
- Rajeev K Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Xinchuan Road 2222, Chengdu, Sichuan, China
| | - Tanya Agarwal
- School of Medical and Allied Sciences, K.R. Mangalam University, Sohna Road, Gurugram-122103, India
| | - Xuefei He
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Xinchuan Road 2222, Chengdu, Sichuan, China
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Xinchuan Road 2222, Chengdu, Sichuan, China
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Luthra R, Roy A. Role of medicinal plants against neurodegenerative diseases. Curr Pharm Biotechnol 2021; 23:123-139. [PMID: 33573549 DOI: 10.2174/1389201022666210211123539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/12/2020] [Accepted: 11/23/2020] [Indexed: 11/22/2022]
Abstract
Diseases with a significant loss of neurons, structurally and functionally are termed as neurodegenerative diseases. Due to the present therapeutic interventions and progressive nature of diseases, a variety of side effects have risen up, thus leading the patients to go for an alternative medication. The role of medicinal plants in such cases has been beneficial because of their exhibition via different cellular and molecular mechanisms. Alleviation in inflammatory responses, suppression of the functionary aspect of pro-inflammatory cytokines like a tumor, improvement in antioxidative properties is among few neuroprotective mechanisms of traditional plants. Variation in transcription and transduction pathways play a vital role in the preventive measures of plants in such diseases. Neurodegenerative diseases are generally caused by depletion of proteins, oxidative and inflammatory stress, environmental changes and so on, with aging being the most important cause. Natural compounds can be used in order to treat neurodegenerative diseases Medicinal plants such as Ginseng, Withania somnifera, Bacopa monnieri, Ginkgo biloba, etc. are some of the medicinal plants for prevention of neurological symptoms. This review deals with the use of different medicinal plants for the prevention of neurodegenerative diseases.
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Affiliation(s)
- Ritika Luthra
- Department of Biotechnology, Delhi Technological University, Delhi. India
| | - Arpita Roy
- Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida. India
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40
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Xing R, Liu X, Tian B, Cheng Y, Li L. Neuroprotective effect of Na + /H + exchangers isoform-1 inactivation against 6-hydroxydopamine-induced mitochondrial dysfunction and neuronal apoptosis in Parkinson's disease models. Drug Dev Res 2021; 82:969-979. [PMID: 33538000 DOI: 10.1002/ddr.21799] [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: 11/19/2020] [Revised: 01/05/2021] [Accepted: 01/21/2021] [Indexed: 11/09/2022]
Abstract
Parkinson's disease (PD) is a disabling neurodegenerative disease mainly caused by degeneration of mesencephalic dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neuroprotective role of Na+ /H+ exchangers isoform-1 (NHE1) inactivation in cerebral ischemic damage has been elucidated. The current study aimed to investigate the impacts of NHE1 in PD. In this study, 6-hydroxydopamine (6-OHDA)-induced PD rat models were established to attempt to illuminate the role and underlying mechanisms of NHE1 in SNpc neurons of PD. Meanwhile, nerve growth factor-stimulated PC12 cells followed by 6-OHDA treatment was used to mimic PD in vitro. Results showed that the protein levels of NHE1 were significantly increased in the SNpc neurons of rats and differentiated PC12 cells after 6-OHDA treatment. Inactivation of NHE1 with chemical inhibitor HOE642 suppressed SNpc neuronal loss and NHE1 expression in PD rats. The overlays of tyrosine hydroxylase and NHE1 displayed that NHE1 expression was not colocalized but closely associated with TH. Besides, treatment with HOE642 relieved the dyskinesia, mitochondrial dysfunction, and neuronal apoptosis. Further in vitro evidence confirmed that inhibition of NHE1 by genetic-knockdown prevented mitochondrial dysfunction and apoptosis. Our study represents the first experimental evidence of a potential role for NHE1 in the pathogenesis of PD.
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Affiliation(s)
- Ruixian Xing
- Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Xuewen Liu
- Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Buxian Tian
- Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Yan Cheng
- Department of Neurology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Longguang Li
- Department of Rehabilitation, Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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Lakey-Beitia J, Burillo AM, Penna GL, Hegde ML, Rao K. Polyphenols as Potential Metal Chelation Compounds Against Alzheimer's Disease. J Alzheimers Dis 2021; 82:S335-S357. [PMID: 32568200 PMCID: PMC7809605 DOI: 10.3233/jad-200185] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-β protein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.
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Affiliation(s)
- Johant Lakey-Beitia
- Centre for Biodiversity and Drug Discovery, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Clayton, City of Knowledge, Panama
| | - Andrea M. Burillo
- Centre for Biodiversity and Drug Discovery, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Clayton, City of Knowledge, Panama
| | - Giovanni La Penna
- National Research Council, Institute of Chemistry of Organometallic Compounds, Sesto Fiorentino (FI), Italy
| | - Muralidhar L. Hegde
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA
- Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
- Weill Medical College of Cornell University, New York, NY, USA
| | - K.S. Rao
- Centre for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Clayton, City of Knowledge, Panama
- Zhongke Jianlan Medical Institute, Hangzhou, Republic of China
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Bekker M, Abrahams S, Loos B, Bardien S. Can the interplay between autophagy and apoptosis be targeted as a novel therapy for Parkinson's disease? Neurobiol Aging 2020; 100:91-105. [PMID: 33516928 DOI: 10.1016/j.neurobiolaging.2020.12.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 10/24/2020] [Accepted: 12/11/2020] [Indexed: 01/01/2023]
Abstract
Development of efficacious treatments for Parkinson's disease (PD) demands an improved understanding of mechanisms underlying neurodegeneration. Two cellular death pathways postulated to play key roles in PD are autophagy and apoptosis. Molecular overlap between these pathways was investigated through identifying studies that used therapeutic compounds to alter expression of specific molecular components of the pathways. Bcl-2 was identified as an important protein with the ability to suppress autophagy and apoptosis through inhibiting Beclin-1 and Bax, respectively. Involvement of c-Jun N-terminal kinases (JNK) and p38, was evident in the activation of apoptosis through increasing the Bax/Bcl-2 ratio. JNK-mediated phosphorylation also suppresses the inhibiting functions of Bcl-2, indicating an ability to induce not only apoptosis but also autophagy. Additionally, a p38-mediated increase in heme oxygenase-1 expression inhibits apoptosis. Moreover, besides inhibiting mammalian target of rapamycin, Akt is associated with decreased Bax expression, thereby acting as both an autophagy inducer and apoptosis inhibitor. Ultimately, manipulation of molecular components involved in autophagy and apoptosis regulation could be targeted as possible therapies for PD.
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Affiliation(s)
- Minke Bekker
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Department of Psychiatry, South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Cape Town, South Africa
| | - Shameemah Abrahams
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Department of Psychiatry, South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Cape Town, South Africa
| | - Ben Loos
- Department of Physiological Sciences, Faculty of Natural Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Soraya Bardien
- Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Department of Psychiatry, South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Cape Town, South Africa.
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Uddin MJ, Zidorn C. Traditional Herbal Medicines Against CNS Disorders from Bangladesh. NATURAL PRODUCTS AND BIOPROSPECTING 2020; 10:377-410. [PMID: 33057963 PMCID: PMC7648845 DOI: 10.1007/s13659-020-00269-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 10/03/2020] [Indexed: 05/07/2023]
Abstract
The majority of the population in Bangladesh uses traditional plant-based medicines to manage various ailments, including central nervous system (CNS) disorders. This review presents ethnobotanical information and relevant scientific studies on plants used in traditional healthcare for the management of various CNS disorders in Bangladesh. The information on the medicinal plants of Bangladesh effective against CNS disorders published in scientific journals, books, and reports was compiled from different electronic databases using specific key words. The present article provides comprehensive information on a total of 224 medicinal plant species belonging to 81 families used for the treatment of CNS disorders by the various peoples of Bangladesh. In total, we reviewed more than 290 relevant papers. In this study, leaves were found as the most often used plant organ, followed by roots, fruits, whole plants, barks, seeds, stems, rhizomes, and flowers. The Fabaceae family contributes the highest number of used species, followed by Rubiaceae, Lamiaceae, Cucurbitaceae, Vitaceae, Euphorbiaceae, Malvaceae, and Zingiberaceae. The most frequently used species (in decreasing order) are Asparagus racemosus, Centella asiatica, Stephania japonica, Aegle marmelos, Coccinia grandis, Tabernaemontana divaricata, Bacopa monnieri, Abroma augusta, and Scoparia dulcis. This review may serve as a starting point for a rational search for neuroactive natural products against CNS disorders within the Flora of Bangladesh.
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Affiliation(s)
- Md. Josim Uddin
- Pharmazeutisches Institut, Abteilung Pharmazeutische Biologie, Christian-Albrechts-Universität zu Kiel, Gutenbergstraße 76, 24118 Kiel, Germany
- Department of Pharmacy, Faculty of Science and Engineering, International Islamic University Chittagong, Chittagong, 4318 Bangladesh
| | - Christian Zidorn
- Pharmazeutisches Institut, Abteilung Pharmazeutische Biologie, Christian-Albrechts-Universität zu Kiel, Gutenbergstraße 76, 24118 Kiel, Germany
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Crocetin Alleviates Inflammation in MPTP-Induced Parkinson's Disease Models through Improving Mitochondrial Functions. PARKINSON'S DISEASE 2020; 2020:9864370. [PMID: 33101635 PMCID: PMC7569465 DOI: 10.1155/2020/9864370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. Crocetin, derived from saffron, exerts multiple pharmacological properties, such as anti-inflammatory, antioxidant, antifatigue, and anticancer effects. However, the effect of crocetin on PD remains unclear. In this study, we designed experiments to investigate the effect of crocetin against MPTP-induced PD models and the underlying mechanisms. Our results showed that crocetin treatment attenuates MPTP-induced motor deficits and protects dopaminergic neurons. Both in vivo and in vitro experiments demonstrated that crocetin treatment decreased the expression of inflammatory associated genes and inflammatory cytokines. Furthermore, crocetin treatment protected mitochondrial functions against MPP+ induced damage by regulating the mPTP (mitochondrial permeability transition pore) viability in the interaction of ANT (adenine nucleotide translocase) and Cyp D (Cyclophilin D) dependent manner. Therefore, our results demonstrate that crocetin has therapeutic potential in Parkinson's disease.
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Xie S, Niu W, Xu F, Wang Y, Hu S, Niu C. Differential expression and significance of miRNAs in plasma extracellular vesicles of patients with Parkinson's disease. Int J Neurosci 2020; 132:673-688. [PMID: 33045885 DOI: 10.1080/00207454.2020.1835899] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To study the feasibility of plasma extracellular vesicles (EVs) miRNAs as diagnostic biomarkers for Parkinson's disease (PD). METHODS Plasma EVs were isolated from 30 PD patients and 30 age- and sex-matched healthy controls. Plasma EVs miRNAs were analysed by qRT-PCR. SH-SY5Y cells were induced by different concentrations of 1-Methyl-4-phenil-pyridinium (MPP+) to obtain PD cellular model. The levels of miRNAs and α-synuclein (α-syn) in PD cellular model were analysed by qRT-PCR and Western blot. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic usefulness of the miRNAs in plasma EVs for PD. The gene ontology (GO) and KEGG pathways of the target genes of miRNAs were analysed by softwares. RESULTS The level of hsa-miR-30c-2-3p in plasma EVs was significantly higher in PD patients than that in controls, and the levels of hsa-miR-15b-5p, hsa-miR-138-5p, hsa-miR-338-3p, hsa-miR-106b-3p and hsa-miR-431-5p in plasma EVs were lower in PD patients than that in controls. When compared with the control group, the area under the curve (AUC) values for hsa-miR-15b-5p, hsa-miR-30c-2-3p, hsa-miR-138-5p, hsa-miR-431-5p, hsa-miR-338-3p and hsa-miR-106b-3p were all greater than 0.6. The target genes of hsa-miR-15b-5p, hsa-miR-30c-2-3p, hsa-miR-138-5p and hsa-miR-338-3p were enriched in dopaminergic synapse and PD pathway. CONCLUSIONS The hsa-miR-15b-5p, hsa-miR-30c-2-3p, hsa-miR-138-5p, hsa-miR-106b-3p, hsa-miR-338-3p and hsa-miR-431-5p may be used as potential biomarkers for the diagnosis of PD, and the combined diagnostic accuracy of hsa-miR-15b-5p, hsa-miR-30c-2-3p, hsa-miR-138-5p and hsa-miR-106b-3p was better. The target genes of hsa-miR-15b-5p, hsa-miR-30c-2-3p, hsa-miR-138-5p and hsa-miR-338-3p may regulate the expression of dopamine by dopaminergic synapse and PD pathway.HighlightsIsolation and identification of plasma EVs.The miRNAs in plasma EVs may be used as potential biomarkers for the diagnosis of PD.When SH-SY5Y cells were induced by different concentrations of MPP+, the levels of miRNAs and α-syn changed gradually.The target genes of miRNAs were enriched in dopaminergic synapse and PD pathway.The target genes of miRNAs may regulate the expression of dopamine.
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Affiliation(s)
- Shishuai Xie
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.,Anhui Provincial Key Laboratory of Brain Function and Brain Disease, Hefei, PR China.,Department of Neurosurgery, Anhui Provincial Hospital, Anhui Medical University, Hefei, PR China
| | - Wanxiang Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.,Anhui Provincial Key Laboratory of Brain Function and Brain Disease, Hefei, PR China.,Department of Neurosurgery, Anhui Provincial Hospital, Anhui Medical University, Hefei, PR China
| | - Feng Xu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.,Anhui Provincial Key Laboratory of Brain Function and Brain Disease, Hefei, PR China.,Department of Neurosurgery, Anhui Provincial Hospital, Anhui Medical University, Hefei, PR China
| | - Yuping Wang
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.,Anhui Provincial Key Laboratory of Brain Function and Brain Disease, Hefei, PR China
| | - Shanshan Hu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.,Anhui Provincial Key Laboratory of Brain Function and Brain Disease, Hefei, PR China
| | - Chaoshi Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.,Anhui Provincial Key Laboratory of Brain Function and Brain Disease, Hefei, PR China.,Department of Neurosurgery, Anhui Provincial Hospital, Anhui Medical University, Hefei, PR China
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Eleftheriadou D, Kesidou D, Moura F, Felli E, Song W. Redox-Responsive Nanobiomaterials-Based Therapeutics for Neurodegenerative Diseases. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e1907308. [PMID: 32940007 DOI: 10.1002/smll.201907308] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 07/20/2020] [Indexed: 05/24/2023]
Abstract
Redox regulation has recently been proposed as a critical intracellular mechanism affecting cell survival, proliferation, and differentiation. Redox homeostasis has also been implicated in a variety of degenerative neurological disorders such as Parkinson's and Alzheimer's disease. In fact, it is hypothesized that markers of oxidative stress precede pathologic lesions in Alzheimer's disease and other neurodegenerative diseases. Several therapeutic approaches have been suggested so far to improve the endogenous defense against oxidative stress and its harmful effects. Among such approaches, the use of artificial antioxidant systems has gained increased popularity as an effective strategy. Nanoscale drug delivery systems loaded with enzymes, bioinspired catalytic nanoparticles and other nanomaterials have emerged as promising candidates. The development of degradable hydrogels scaffolds with antioxidant effects could also enable scientists to positively influence cell fate. This current review summarizes nanobiomaterial-based approaches for redox regulation and their potential applications as central nervous system neurodegenerative disease treatments.
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Affiliation(s)
- Despoina Eleftheriadou
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Division of Surgery and Interventional Science, Royal Free Campus, University College London, London, NW3 2PF, UK
- Department of Mechanical Engineering, University College London, London, WC1E 7JE, UK
- UCL Centre for Nerve Engineering, University College London, London, WC1E 6BT, UK
| | - Despoina Kesidou
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Division of Surgery and Interventional Science, Royal Free Campus, University College London, London, NW3 2PF, UK
| | - Francisco Moura
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Division of Surgery and Interventional Science, Royal Free Campus, University College London, London, NW3 2PF, UK
| | - Eric Felli
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Division of Surgery and Interventional Science, Royal Free Campus, University College London, London, NW3 2PF, UK
| | - Wenhui Song
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Division of Surgery and Interventional Science, Royal Free Campus, University College London, London, NW3 2PF, UK
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Soo SK, Rudich PD, Traa A, Harris-Gauthier N, Shields HJ, Van Raamsdonk JM. Compounds that extend longevity are protective in neurodegenerative diseases and provide a novel treatment strategy for these devastating disorders. Mech Ageing Dev 2020; 190:111297. [PMID: 32610099 PMCID: PMC7484136 DOI: 10.1016/j.mad.2020.111297] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022]
Abstract
While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. In the inherited forms of these diseases, the disease-causing mutation is present from birth but symptoms appear decades later. This indicates that these mutations are well tolerated in younger individuals but not in older adults. Based on this observation, we hypothesized that changes taking place during normal aging make the cells in the brain (and elsewhere) susceptible to the disease-causing mutations. If so, then delaying some of these age-related changes may be beneficial in the treatment of neurodegenerative disease. In this review, we examine the effects of five compounds that have been shown to extend longevity (metformin, rapamycin, resveratrol, N-acetyl-l-cysteine, curcumin) in four of the most common neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis). While not all investigations observe a beneficial effect of these compounds, there are multiple studies that show a protective effect of each of these lifespan-extending compounds in animal models of neurodegenerative disease. Combined with genetic studies, this suggests the possibility that targeting the aging process may be an effective strategy to treat neurodegenerative disease.
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Affiliation(s)
- Sonja K Soo
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
| | - Paige D Rudich
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
| | - Annika Traa
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
| | - Namasthée Harris-Gauthier
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
| | - Hazel J Shields
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada
| | - Jeremy M Van Raamsdonk
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, H4A 3J1, Canada; Metabolic Disorders and Complications Program, and Brain Repair and Integrative Neuroscience Program, Research Institute of the McGill University Health Centre, Montreal, QC, H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, H4A 3J1, Canada; Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
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Yan YQ, Fang Y, Zheng R, Pu JL, Zhang BR. NLRP3 Inflammasomes in Parkinson's disease and their Regulation by Parkin. Neuroscience 2020; 446:323-334. [PMID: 32795556 DOI: 10.1016/j.neuroscience.2020.08.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022]
Abstract
Chronic inflammation might correlate with the formation of α-synuclein oligomers, subsequently leading to dopaminergic (DA) neuronal death in Parkinson's disease (PD). As major components of chronic inflammation, NOD-like receptor protein 3 (NLRP3) inflammasomes play a crucial role in PD via caspase 1 activation, primarily induced by mitochondrial damage. NLRP3 binds to apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC), and forms inflammasomes in the brain. Inflammasomes act as a platform for caspase 1 to induce interleukin 1 Beta (IL1β) maturation, leading to neuronal pyroptosis. Furthermore, alpha-synuclein, whose abnormal aggregation is the main pathogenesis of PD, also activates NLRP3 inflammasomes. Mutations to PRKN (encoding Parkin) are the most common cause of autosomal recessive familial and sporadic early-onset PD. Evidence has confirmed a relationship between Parkin and NLRP3 inflammasomes. In this review, we summarize the current understanding of NLRP3 inflammasomes and their role in PD progression, and discuss their regulation by Parkin.
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Affiliation(s)
- Yi-Qun Yan
- Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Yi Fang
- Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Ran Zheng
- Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China
| | - Jia-Li Pu
- Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
| | - Bao-Rong Zhang
- Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China.
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Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson's disease increase cellular susceptibility to oxidative stress. Brain Behav Immun 2020; 88:920-924. [PMID: 32276028 PMCID: PMC9012133 DOI: 10.1016/j.bbi.2020.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/01/2020] [Accepted: 04/04/2020] [Indexed: 01/18/2023] Open
Abstract
The human genes for interleukin 13 (IL-13) and its receptor alpha 1 (IL-13Rα1) are in chromosomal regions associated with Parkinson's disease (PD). The interaction of IL-13 with its receptor increases the susceptibility of mouse dopaminergic neurons to oxidative stress. We identified two rare single SNPs in IL13 and IL13RA1 and measured their cytotoxic effects. rs148077750 is a missense leucine to proline substitution in IL13. It was found in individuals with early onset PD and no other known monogenic forms of the disease and is significantly linked with PD (Fisher's exact test: p-value = 0.01, odds ratio = 14.2). rs145868092 is a leucine to phenylalanine substitution in IL13RA1 affecting a residue critical for IL-13 binding. Both mutations increased the cytotoxic activity of IL-13 on human SH-SY5Y neurons exposed to sublethal doses of hydrogen peroxide, t-butyl hydroperoxide or RLS3, an inducer of ferroptosis. Our data show that both rs148077750 and rs145868092 conferred a gain-of-function that may increase the risk of developing PD.
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Park HA, Ellis AC. Dietary Antioxidants and Parkinson's Disease. Antioxidants (Basel) 2020; 9:antiox9070570. [PMID: 32630250 PMCID: PMC7402163 DOI: 10.3390/antiox9070570] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/14/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022] Open
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder caused by the depletion of dopaminergic neurons in the basal ganglia, the movement center of the brain. Approximately 60,000 people are diagnosed with PD in the United States each year. Although the direct cause of PD can vary, accumulation of oxidative stress-induced neuronal damage due to increased production of reactive oxygen species (ROS) or impaired intracellular antioxidant defenses invariably occurs at the cellular levels. Pharmaceuticals such as dopaminergic prodrugs and agonists can alleviate some of the symptoms of PD. Currently, however, there is no treatment to halt the progression of PD pathology. Due to the nature of PD, a long and progressive neurodegenerative process, strategies to prevent or delay PD pathology may be well suited to lifestyle changes like dietary modification with antioxidant-rich foods to improve intracellular redox homeostasis. In this review, we discuss cellular and genetic factors that increase oxidative stress in PD. We also discuss neuroprotective roles of dietary antioxidants including vitamin C, vitamin E, carotenoids, selenium, and polyphenols along with their potential mechanisms to alleviate PD pathology.
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