|
1
|
Chiang MC, Nicol CJB, Yang YP, Chiang T, Yen C. The α-MG exhibits neuroprotective potential by reducing amyloid beta peptide-induced inflammation, oxidative stress, and tau aggregation in human neural stem cells. Brain Res 2025; 1852:149506. [PMID: 39954799 DOI: 10.1016/j.brainres.2025.149506] [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: 06/27/2024] [Revised: 12/29/2024] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Alzheimer's disease (AD) is the primary cause of dementia in older adults. Amyloid-beta (Aβ) and tau protein neurofibrillary tangles accumulate in the brain, leading to a progressive decline in memory, thinking, and behavior. Neuroinflammation and oxidative stress play a significant role in the development and progression of AD. Research has suggested that α-mangostin (α-MG), a compound found in mangosteen peels, may have anti-inflammatory, antioxidant, and neuroprotective properties, which could be beneficial in the context of AD. Further research is required to fully comprehend the therapeutic mechanisms of α-MG on AD and determine its potential as a treatment option. α-MG treatment significantly improves the viability of hNSCs exposed to Aβ and reduces caspase activity. Furthermore, this treatment is associated with a notable decrease in the expression of TNF-α and IL-1β. The treatment effectively restores alterations in the expression of IKK and NF-κB (p65) induced by Aβ, which are critical factors in the inflammatory response. Moreover, α-MG effectively reduces iNOS and COX-2 levels in Aβ-treated hNSCs, showcasing its potential therapeutic benefits. Treatment with α-MG protects hNSCs against Aβ-induced oxidative stress and effectively prevents the decrease in Nrf2 levels caused by Aβ. The treatment significantly enhances the activity and mRNA expression of Nrf2 downstream antioxidant target genes, including SOD-1, SOD-2, Gpx1, GSH, catalase, and HO-1, compared to Aβ-treated controls. α-MG significantly reduces tau and ubiquitin (Ub) aggregates, enhances proteasome activity, and increases the mRNA expression of HSF1, HSP27, HSP70, and HSP90 in Tau-GFP-expressed hNSCs. This study significantly improves our comprehension of the anti-inflammatory, antioxidative stress, and anti-aggregated effects of α-MG. These findings have potential therapeutic implications for developing treatments that could delay AD progression and promote healthy aging.
Collapse
Affiliation(s)
- Ming-Chang Chiang
- Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan.
| | - Christopher J B Nicol
- Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Cancer Biology and Genetics Division, Sinclair Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Yu-Ping Yang
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Tairui Chiang
- New Taipei Municipal Jinhe High School, New Taipei City 235, Taiwan; Ames Middle School, Ames, IA 50014, USA
| | - Chiahui Yen
- Department of International Business, Ming Chuan University, Taipei 111, Taiwan
| |
Collapse
|
|
2
|
Shen Y, Zhang G, Wei C, Zhao P, Wang Y, Li M, Sun L. Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer's disease. Neural Regen Res 2025; 20:613-631. [PMID: 38886929 PMCID: PMC11433915 DOI: 10.4103/nrr.nrr-d-23-01343] [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: 08/11/2023] [Revised: 11/27/2023] [Accepted: 12/21/2023] [Indexed: 06/20/2024] Open
Abstract
Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.
Collapse
Affiliation(s)
- Yanxin Shen
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Guimei Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Chunxiao Wei
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Panpan Zhao
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Yongchun Wang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Mingxi Li
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| | - Li Sun
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
- Cognitive Impairment Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
3
|
Yang L, Hou H, Lu L, Sun Y, Chen R, Deng Q, Chen H. Effects of natural source polysaccharides on neurological diseases: A review. Int J Biol Macromol 2025; 296:139697. [PMID: 39805435 DOI: 10.1016/j.ijbiomac.2025.139697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 01/16/2025]
Abstract
With the aging of society and changes in lifestyle, the incidence of neurological diseases (NDs) has been increasing year by year, bringing a heavy burden to patients and society. Although the efficacy of chemical drugs in the treatment of NDs is remarkable, there are problems such as high side effects and high costs. Therefore, finding mild and efficient drugs for NDs treatment has become an urgent clinical need. Natural source polysaccharides (NSPs) are macromolecules with unique bioactivity and low toxicity characteristics, which have great potential to become novel therapeutic agents for NDs. In the present study, the pharmacological activities and potential molecular mechanisms of NSPs to alleviate NDs are systematically reviewed from the perspectives of inflammation, oxidative stress, apoptosis, neuronal cell autophagy, neurotoxicity, and sedation-hypnosis. In addition, the limitations of the existing studies were analyzed and discussed, and the future research direction was suggested. This study may provide scientific basis for the research and development of therapeutic agents for NDs based on NSPs.
Collapse
Affiliation(s)
- Luyuan Yang
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control & Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Hailu Hou
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control & Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Liping Lu
- Guizhou Dalong Pharmaceutical Co., Ltd., Guiyang 550001, China
| | - Yu Sun
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control & Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Ruhai Chen
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control & Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Qingfang Deng
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control & Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China
| | - Huaguo Chen
- Key Laboratory for Information System of Mountainous Areas and Protection of Ecological Environment, Guizhou Normal University, Guiyang 550001, China; Guizhou Engineering Laboratory for Quality Control & Evaluation Technology of Medicine, Guizhou Normal University, Guiyang 550001, China.
| |
Collapse
|
|
4
|
Feng X, Zhao S. Untargeted urine metabolomics reveals dynamic metabolic differences and key biomarkers across different stages of Alzheimer's disease. Front Aging Neurosci 2025; 17:1530046. [PMID: 39931229 PMCID: PMC11807997 DOI: 10.3389/fnagi.2025.1530046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025] Open
Abstract
Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with mild cognitive impairment (MCI) often serving as its precursor stage. Early intervention at the MCI stage can significantly delay AD onset. Methods This study employed untargeted urine metabolomics, with data obtained from the MetaboLights database (MTBLS8662), combined with orthogonal partial least squares-discriminant analysis (OPLS-DA) to examine metabolic differences across different stages of AD progression. A decision tree approach was used to identify key metabolites within significantly enriched pathways. These key metabolites were then utilized to construct and validate an AD progression prediction model. Results The OPLS-DA model effectively distinguished the metabolic characteristics at different stages. Pathway enrichment analysis revealed that Drug metabolism was significantly enriched across all stages, while Retinol metabolism was particularly prominent during the transition stages. Key metabolites such as Theophylline, Vanillylmandelic Acid (VMA), and Adenosine showed significant differencesdifferencesin the early stages of the disease, whereas 1,7-Dimethyluric Acid, Cystathionine, and Indole exhibited strong predictive value during the MCI to AD transition. These metabolites play a crucial role in monitoring AD progression. Predictive models based on these metabolites demonstrated excellent classification and prediction capabilities. Conclusion This study systematically analyzed the dynamic metabolic differences during the progression of AD and identified key metabolites and pathways as potential biomarkers for early prediction and intervention. Utilizing urinary metabolomics, the findings provide a theoretical basis for monitoring AD progression and contribute to improving prevention and intervention strategies, thereby potentially delaying disease progression.
Collapse
Affiliation(s)
- Xiaoya Feng
- Department of Neurology, Shandong Provincial Third Hospital, Jinan, China
| | - Shenglan Zhao
- Department of Psychiatry and Psychology, Shandong Provincial Third Hospital, Jinan, China
| |
Collapse
|
|
5
|
Bandaru M, Sultana OF, Islam MA, Rainier A, Reddy PH. Rlip76 in ageing and Alzheimer's disease: Focus on oxidative stress and mitochondrial mechanisms. Ageing Res Rev 2025; 103:102600. [PMID: 39617058 DOI: 10.1016/j.arr.2024.102600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/12/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024]
Abstract
RLIP76 (Rlip), a stress-responsive protein, plays a multifaceted role in cellular function. This protein acts primarily as a glutathione-electrophile conjugate (GS-E) transporter, crucial for detoxifying hazardous compounds and converting them into mercapturic acids. RLIP76 also modulates cytoskeletal motility and membrane plasticity through its role in the Ral-signaling pathway, interacting with RalA and RalB, key small GTPases involved in growth and metastasis. Beyond its ATP-dependent transport functions in various tissues, RLIP76 also demonstrates GTPase Activating Protein (GAP) activity towards Rac1 and Cdc42, with a preference for Ral-GTP over Ral-GDP. Its functions span critical physiological processes including membrane dynamics, oxidative stress response, and mitochondrial dynamics. The protein's widespread expression and evolutionary conservation underscore its significance. Our lab discovered that Rlip interacts with Alzheimer's disease (AD) proteins, amyloid beta and phosphorylated and induce oxidative stress, mitochondrial dysfnction and synaptic damage in AD. Our in vitro studies revealed that overexpression of Rlip reduces mitochondrial abnormalities. Further, our in vivo studies (Rlip+/- mice) revealed that a partial reduction of Rlip in mice (Rlip+/-), leads to mitochondrial abnormalities, elevated oxidative stress, and cognitive deficits resembling late-onset AD, emphasizing the protein's crucial role in neuronal health and disease. Finally, we discuss the experimental cross-breedings of overexpression of mice Rlip TG/TG or Rlip + /- mice with Alzheimer's disease models - earlyonset 5XFAD, late-onset APPKI and Tau transgenic mice, providing new insights into RLIP76's role in AD progression and development. This review summarizes RLIP76's structure, function, and cellular pathways, highlighting its implications in AD and its potential as a therapeutic target.
Collapse
Affiliation(s)
- Madhuri Bandaru
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Omme Fatema Sultana
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Md Ariful Islam
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Alvir Rainier
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, United States; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA 5. Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| |
Collapse
|
|
6
|
Dimopoulou M, Bargiota A, Barmpa E, Outskouni Z, Stagos D, Trachana V, Androutsos O, Gortzi O. Postprandial Glucose Response in Type 2 Diabetes Mellitus Patients and Possible Antioxidant Properties of a Plant-Based Snack Bar. Foods 2024; 13:4123. [PMID: 39767064 PMCID: PMC11675813 DOI: 10.3390/foods13244123] [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: 11/12/2024] [Revised: 11/30/2024] [Accepted: 12/13/2024] [Indexed: 01/03/2025] Open
Abstract
Daily, more and more people consume snack bars that may have an impact on blood glucose levels. The aim of the present study was to compare the acute effects of a common snack and a plant-based snack bar (PB) that was developed at the University of Thessaly as a functional diabetic snack on blood glucose and insulin in patients with type 2 diabetes mellitus (T2DM). Adults with T2DM (n = 10) treated with oral medications were studied in a randomized, crossover clinical trial. On each trial day, postprandial glucose and insulin levels were measured at 30, 60, 90, and 120 min, and a morning snack containing 25 g of carbohydrate was consumed. The procedure was carried out on 2 days, with one of the test meals being consumed on each day. Consumption of a PB snack bar resulted in a smaller and steeper increase in postprandial glucose and insulin levels compared with the usual snack, and there were significant differences 60 and 90 min after consumption of the two tested snacks. The PB snack bar is rich in protein, fiber, vitamins, and minerals and can therefore be suggested as a nutritious and convenient snack for patients with T2DM. In addition, the extract of the snack bar was tested for its bioactivity in human cell cultures.
Collapse
Affiliation(s)
- Maria Dimopoulou
- Department of Agriculture Crop Production and Rural Environment, School of Agriculture Sciences, University of Thessaly, 38446 Volos, Greece;
| | - Alexandra Bargiota
- Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, School of Health Sciences, University Hospital of Larissa, University of Thessaly, 41334 Larissa, Greece;
| | - Eleftheria Barmpa
- Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, School of Health Sciences, University Hospital of Larissa, University of Thessaly, 41334 Larissa, Greece;
| | - Zozo Outskouni
- Department of Biology, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece; (Z.O.); (V.T.)
| | - Dimitrios Stagos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Biopolis, 41500 Larissa, Greece;
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece; (Z.O.); (V.T.)
| | - Odysseas Androutsos
- Laboratory of Clinical Nutrition and Dietetics, Department of Nutrition and Dietetics, University of Thessaly, 42132 Trikala, Greece;
| | - Olga Gortzi
- Department of Agriculture Crop Production and Rural Environment, School of Agriculture Sciences, University of Thessaly, 38446 Volos, Greece;
| |
Collapse
|
|
7
|
Goutas A, Goutzourelas N, Kevrekidou A, Kevrekidis DP, Malea P, Virgiliou C, Assimopoulou AN, Trachana V, Kollatos N, Moustafa T, Liu M, Lin X, Komiotis D, Stagos D. Hypnea musciformis Seaweed Extract Protected Human Mesenchymal Stem Cells From Oxidative Stress Through NRF2 Activation. Food Sci Nutr 2024; 12:10816-10835. [PMID: 39723057 PMCID: PMC11666820 DOI: 10.1002/fsn3.4615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 10/06/2024] [Accepted: 11/02/2024] [Indexed: 12/28/2024] Open
Abstract
Previous studies have shown that Hypnea musciformis seaweed extracts (HMEs) possess antioxidant properties, but the molecular mechanisms accounting for this activity are not known. Thus, the present study investigated the molecular mechanisms through which HME exerted its antioxidant activity in human mesenchymal stem cells (WJ-MSCs). After the isolation of HME, its chemical composition was analyzed with gas chromatography mass spectrometry, indicating that it contained amino acids, organic acids, organic amides, sugar alcohols, saturated fatty acids, hydrogenated diterpene alcohols, and other organic compounds. Afterward, HME was shown in vitro to scavenge DPPH·, ABTS·+, ·OH, and O2 ·- radicals, possess reducing activity, and protect from ROO·-induced DNA strand breakage. Finally, the results showed that HME treatment of WJ-MSCs prevented H2O2-induced oxidative stress by decreasing lipid peroxidation, protein oxidation, reactive oxygen species levels, and DNA damage and by increasing glutathione levels. Moreover, our findings showed for the first time that HME's antioxidant activity in WJ-MSCs was mediated through the activation of NRF2, which upregulated the expression of the antioxidant proteins GCLC, GSR, HMOX1, SOD1, TXN, and GPX1. These results provide new insights into H. musciformis' antioxidant properties, which could help substantially its use as a food supplement or for developing biofunctional foods.
Collapse
Affiliation(s)
- Andreas Goutas
- Department of Biochemistry and Biotechnology, School of Health SciencesUniversity of ThessalyLarissaGreece
- Department of Biology, Faculty of MedicineUniversity of ThessalyLarissaGreece
| | - Nikolaos Goutzourelas
- Department of Biochemistry and Biotechnology, School of Health SciencesUniversity of ThessalyLarissaGreece
| | - Alkistis Kevrekidou
- Laboratory of Organic Chemistry, School of Chemical EngineeringAristotle University of ThessalonikiThessalonikiGreece
- Environmental Engineering Laboratory, Department of Chemical EngineeringAristotle University of ThessalonikiThessalonikiGreece
| | - Dimitrios Phaedon Kevrekidis
- Laboratory of Forensic Medicine and Toxicology, Department of MedicineAristotle University of ThessalonikiThessalonikiGreece
| | - Paraskevi Malea
- Department of Botany, School of BiologyAristotle University of ThessalonikiThessalonikiGreece
| | - Christina Virgiliou
- Laboratory of Analytical Chemistry, School of Chemical EngineeringAristotle University of ThessalonikiThessalonikiGreece
| | - Andreana N. Assimopoulou
- Laboratory of Organic Chemistry, School of Chemical EngineeringAristotle University of ThessalonikiThessalonikiGreece
| | - Varvara Trachana
- Department of Biology, Faculty of MedicineUniversity of ThessalyLarissaGreece
| | - Nikolaos Kollatos
- Department of Biochemistry and Biotechnology, School of Health SciencesUniversity of ThessalyLarissaGreece
| | - Tafa Moustafa
- Department of Biochemistry and Biotechnology, School of Health SciencesUniversity of ThessalyLarissaGreece
| | - Ming Liu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and PharmacyOcean University of ChinaQingdaoChina
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
| | - Xiukun Lin
- Department of Pharmacology, School of PharmacySouthwest Medical UniversityLuzhouChina
| | - Dimitrios Komiotis
- Department of Biochemistry and Biotechnology, School of Health SciencesUniversity of ThessalyLarissaGreece
| | - Dimitrios Stagos
- Department of Biochemistry and Biotechnology, School of Health SciencesUniversity of ThessalyLarissaGreece
| |
Collapse
|
|
8
|
Firdous SM, Khan SA, Maity A. Oxidative stress-mediated neuroinflammation in Alzheimer's disease. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8189-8209. [PMID: 38832985 DOI: 10.1007/s00210-024-03188-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/24/2024] [Indexed: 06/06/2024]
Abstract
Reactive oxygen species (ROS) are metabolic by-products that constitute an indispensable component of physiological processes, albeit their heightened presence may proffer substantial perils to biological entities. Such a proliferation gives rise to a gradual escalation of oxidative stress within the organism, thereby compromising mitochondrial functionality and inflicting harm upon various bodily systems, with a particular predilection for the central nervous system. In its nascent stages, it is plausible that inflammation has been a facilitator in the progression of the malady. The precise role of inflammation in Alzheimer's disease (AD) remains somewhat enigmatic, although it is conceivable that activated microglia and astrocytes might be implicated in the removal of amyloid-β (Aβ) deposits. Nonetheless, prolonged microglial activation is associated with Tau phosphorylation and Aβ aggregation. Research studies have indicated that AD brains upregulate complementary molecules, inflammatory cytokines, acute phase reacting agents, and other inflammatory mediators that may cause neurodegeneration. In this review, oxidative damage products will be discussed as potential peripheral biomarkers for AD and its early stages. The disordered excretion of pro-inflammatory cytokines, chemokines, oxygen, and nitrogen-reactive species, along with the stimulation of the complement system by glial cells, has the potential to disrupt the functionality of neuronal termini. This perturbation, in turn, culminates in compromised synaptic function, a phenomenon empirically linked to the manifestation of cognitive impairments. The management of neurodegenerative conditions in the context of dementia necessitates therapeutic interventions that specifically target the excessive production of inflammatory and oxidative agents. Furthermore, we shall deliberate upon the function of microglia and oxidative injury in the etiology of AD and the ensuing neurodegenerative processes.
Collapse
Affiliation(s)
- Sayed Mohammed Firdous
- Department of Pharmacology, Calcutta Institute of Pharmaceutical Technology & AHS, Uluberia, Howrah, 711316, West Bengal, India.
| | - Sahabaj Ali Khan
- Department of Pharmacology, Calcutta Institute of Pharmaceutical Technology & AHS, Uluberia, Howrah, 711316, West Bengal, India
| | - Amritangshu Maity
- Department of Pharmacology, Calcutta Institute of Pharmaceutical Technology & AHS, Uluberia, Howrah, 711316, West Bengal, India
| |
Collapse
|
|
9
|
Xu T, Chen G. MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import. Int J Mol Sci 2024; 25:10832. [PMID: 39409161 PMCID: PMC11476822 DOI: 10.3390/ijms251910832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 09/30/2024] [Accepted: 09/30/2024] [Indexed: 10/20/2024] Open
Abstract
Ferroptosis is a recently identified iron-dependent programmed cell death with lipid peroxide accumulation and condensation and compaction of mitochondria. A recent study indicated that ferroptosis plays a pivotal role in ischemic cardiac injury with the mechanisms remain largely unknown. This study demonstrates that when an iron overload occurs in the ischemia/reperfusion cardiac tissues, which initiates myocardial ferroptosis, the expression levels of mitochondrial inner membrane protein MPV17 are reduced. Overexpression of MPV17 delivered via adenovirus significantly reduced ferroptosis in both cardiomyocytes with high levels of iron and cardiac I/R tissues. Mitochondrial glutathione (mtGSH), crucial for reactive oxygen species scavenging and mitochondrial homeostasis maintenance, is depleted in myocardial ferroptosis caused by iron overload. This mechanistic study shows that MPV17 can increase mitochondrial glutathione levels through maintaining the protein homeostasis of SLC25A10, which is a mitochondrial inner-membrane glutathione transporter. The absence of MPV17 in iron overload resulted in the ubiquitination-dependent degradation of SLC25A10, leading to impaired mitochondrial glutathione import. Moreover, we found that MPV17 was the targeted gene of Nrf2, which plays a pivotal role in preventing lipid peroxide accumulation and ferroptosis. The decreased expression levels of Nrf2 led to the inactivation of MPV17 in iron overload-induced myocardial ferroptosis. In summary, this study demonstrates the critical role of MPV17 in protecting cardiomyocytes from ferroptosis and elucidates the Nrf2-MPV17-SLC25A10/mitochondrial glutathione signaling pathway in the regulation of myocardial ferroptosis.
Collapse
Affiliation(s)
| | - Guilan Chen
- Instrumental Analysis Center, Qingdao Agricultural University, Qingdao 266109, China;
| |
Collapse
|
|
10
|
Villalonga A, López-López D, García-Díez E, Sánchez A, Villalonga R, Ojeda I. Electrochemical sensor for glutathione reductase based on screen-printed electrodes coated with 3,5-dinitrobenzoic acid-modified carbon nanotubes. Mikrochim Acta 2024; 191:642. [PMID: 39361220 DOI: 10.1007/s00604-024-06728-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
The preparation of a hybrid nanomaterial is reported by covalently attaching 3,5-dinitrobenzoic acid groups to the surface of oxidized multi-walled carbon nanotubes using 1,6-diaminohexane as cross-linking agent. This nanomaterial, modified with the redox mediator, was used as transduction element to construct an amperometric sensor for the efficient indirect determination of glutathione reductase at a low working potential of - 0.05 V, through the oxidation of unconsumed nicotinamide adenine dinucleotide phosphate (NADPH) in the enzymatic reaction. The sensor exhibited an excellent linear response in the range 1.6 to 174 µU/µL, with high reproducibility and selectivity. The developed device was successfully validated in real samples, accurately determining the active enzyme in diluted human serum, making it a promising alternative for the determination of glutathione reductase and other related NADPH-dependent enzymes with relevance in clinical analysis.
Collapse
Affiliation(s)
- Anabel Villalonga
- Nanosensors and Nanomachines Group, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040, Madrid, Spain
| | - David López-López
- Nanosensors and Nanomachines Group, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040, Madrid, Spain
| | - Esther García-Díez
- Nanosensors and Nanomachines Group, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040, Madrid, Spain
| | - Alfredo Sánchez
- Nanosensors and Nanomachines Group, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040, Madrid, Spain
| | - Reynaldo Villalonga
- Nanosensors and Nanomachines Group, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Irene Ojeda
- Nanosensors and Nanomachines Group, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, 28040, Madrid, Spain.
- Department of Chemistry in Pharmaceutical Sciences, Analytical Chemistry, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain.
| |
Collapse
|
|
11
|
Chen HJ, Zhao L, Wang L, Wang ZG, Pang DW, Liu SL. Simultaneous Mapping of the Nanoscale Organization and Redox State of Extracellular Space in Living Brain Tissue. ACS NANO 2024; 18:22245-22256. [PMID: 39116272 DOI: 10.1021/acsnano.4c06059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
The spatial organization characteristics and redox status of the extracellular space (ECS) are crucial in the development of brain diseases. However, it remains a challenge to simultaneously capture dynamic changes in microstructural features and redox states at the submicron level within the ECS. Here, we developed a reversible glutathione (GSH)-responsive nanoprobe (RGN) for mapping the spatial organization features and redox status of the ECS in brain tissues with nanoscale resolution. The RGN is composed of polymer nanoparticles modified with GSH-responsive molecules and amino-functionalized methoxypoly(ethylene glycol), which exhibit exceptional single-particle brightness and excellent free diffusion capability in the ECS of brain tissues. Tracking single RGNs in acute brain slices allowed us to dynamically map spatial organizational features and redox levels within the ECS of brain tissues in disease models. This provides a powerful super-resolution imaging method that offers a potential opportunity to study the dynamic changes in the ECS microenvironment and to understand the physiological and pathological roles of the ECS in vivo.
Collapse
Affiliation(s)
- Hua-Jie Chen
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, P. R. China
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, P. R. China
| | - Liang Zhao
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, P. R. China
| | - Lei Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, P. R. China
| | - Zhi-Gang Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, P. R. China
| | - Dai-Wen Pang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, P. R. China
| | - Shu-Lin Liu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, P. R. China
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, P. R. China
| |
Collapse
|
|
12
|
Peng L, Cai H, Tang Y, Zhou F, Liu Y, Xu Z, Chen Q, Chen X. Causal associations between chronic heart failure and the cerebral cortex: results from Mendelian randomization study and integrated bioinformatics analysis. Front Cardiovasc Med 2024; 11:1396311. [PMID: 39027007 PMCID: PMC11254706 DOI: 10.3389/fcvm.2024.1396311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 06/11/2024] [Indexed: 07/20/2024] Open
Abstract
Background Chronic heart failure (CHF) patients exhibit alterations in cerebral cortical structure and cognitive function. However, the mechanisms by which CHF affects cortical structure and functional regions remain unknown. This study aims to investigate potential causal relationship between CHF and cerebral cortical structure through Mendelian randomization (MR). Methods The research utilized genome-wide association studies (GWAS) to explore the causal association between CHF and cerebral cortical structure. The results were primarily analyzed using the inverse-variance weighted (IVW). The reliability of the data was verified through horizontal pleiotropy and heterogeneity analysis by MR-Egger intercept test and Cochran's Q-test, respectively. Replication analysis was conducted in the Integrative Epidemiology Unit (IEU) OpenGWAS project for further validation. In addition, we collected mediator genes that mediate causality to reveal potential mechanisms. Integrated bioinformatics analysis was conducted using the Open Target Genetics platform, the STRING database, and Cytoscape software. Results The IVW results did not reveal any significant causal association between genetically predicted CHF and the overall structure of the cerebral cortex or the surface area (SA) of the 34 functional regions of the cerebral cortex (P > 0.05). However, the results revealed that CHF increased the thickness (TH) of pars opercularis (IVW: β = 0.015, 95% CI: 0.005-0.025, P = 3.16E-03). Replication analysis supported the causal association between CHF and pars opercularis TH (IVW: β = 0.02, 95% CI: 0.010-0.033, P = 1.84E-04). We examined the degree centrality values of the top 10 mediator genes, namely CDKN1A, CELSR2, NME5, SURF4, PSMA5, TSC1, RPL7A, SURF6, PRDX3, and FTO. Conclusion Genetic evidence indicates a positive correlation between CHF and pars opercularis TH.
Collapse
Affiliation(s)
- Liqi Peng
- The First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Huzhi Cai
- International Medical Department, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yanping Tang
- College of Integrative Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Fang Zhou
- Health Management Department, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Yuemei Liu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Zelin Xu
- Preventive Treatment Center, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Qingyang Chen
- Intensive Care Unit, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xinyu Chen
- Preventive Treatment Center, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| |
Collapse
|
|
13
|
Zhang N, Nao J, Zhang S, Dong X. Novel insights into the activating transcription factor 4 in Alzheimer's disease and associated aging-related diseases: Mechanisms and therapeutic implications. Front Neuroendocrinol 2024; 74:101144. [PMID: 38797197 DOI: 10.1016/j.yfrne.2024.101144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/29/2024]
Abstract
Ageing is inherent to all human beings, most mechanistic explanations of ageing results from the combined effects of various physiological and pathological processes. Additionally, aging pivotally contributes to several chronic diseases. Activating transcription factor 4 (ATF4), a member of the ATF/cAMP response element-binding protein family, has recently emerged as a pivotal player owing to its indispensable role in the pathophysiological processes of Alzheimer's disease and aging-related diseases. Moreover, ATF4 is integral to numerous biological processes. Therefore, this article aims to comprehensively review relevant research on the role of ATF4 in the onset and progression of aging-related diseases, elucidating its potential mechanisms and therapeutic approaches. Our objective is to furnish scientific evidence for the early identification of risk factors in aging-related diseases and pave the way for new research directions for their treatment. By elucidating the signaling pathway network of ATF4 in aging-related diseases, we aspire to gain a profound understanding of the molecular and cellular mechanisms, offering novel strategies for addressing aging and developing related therapeutics.
Collapse
Affiliation(s)
- Nan Zhang
- Department of Neurology, the Seventh Clinical College of China Medical University, No. 24 Central Street, Xinfu District, Fushun 113000, Liaoning, China.
| | - Jianfei Nao
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang 110000, Liaoning, China.
| | - Shun Zhang
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang 110000, Liaoning, China.
| | - Xiaoyu Dong
- Department of Neurology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang 110000, Liaoning, China.
| |
Collapse
|
|
14
|
Gong Y, Wang Y, Li Y, Weng F, Chen T, He L. Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis. Phytother Res 2024; 38:2462-2481. [PMID: 38444049 DOI: 10.1002/ptr.8152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 01/16/2024] [Accepted: 01/21/2024] [Indexed: 03/07/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aβ1-42, p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.
Collapse
Affiliation(s)
- Yuhang Gong
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Yanan Wang
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Yanfeng Li
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Fanglin Weng
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Tong Chen
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Ling He
- Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
15
|
Ho K, Bodi NE, Sharma TP. Normal-Tension Glaucoma and Potential Clinical Links to Alzheimer's Disease. J Clin Med 2024; 13:1948. [PMID: 38610712 PMCID: PMC11012506 DOI: 10.3390/jcm13071948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Glaucoma is a group of optic neuropathies and the world's leading cause of irreversible blindness. Normal-tension glaucoma (NTG) is a subtype of glaucoma that is characterized by a typical pattern of peripheral retinal loss, in which the patient's intraocular pressure (IOP) is considered within the normal range (<21 mmHg). Currently, the only targetable risk factor for glaucoma is lowering IOP, and patients with NTG continue to experience visual field loss after IOP-lowering treatments. This demonstrates the need for a better understanding of the pathogenesis of NTG and underlying mechanisms leading to neurodegeneration. Recent studies have found significant connections between NTG and cerebral manifestations, suggesting NTG as a neurodegenerative disease beyond the eye. Gaining a better understanding of NTG can potentially provide new Alzheimer's Disease diagnostics capabilities. This review identifies the epidemiology, current biomarkers, altered fluid dynamics, and cerebral and ocular manifestations to examine connections and discrepancies between the mechanisms of NTG and Alzheimer's Disease.
Collapse
Affiliation(s)
- Kathleen Ho
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Nicole E. Bodi
- Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Tasneem P. Sharma
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Stark Neurosciences Research Institute, Indianapolis, IN 46202, USA
| |
Collapse
|
|
16
|
Song Y, Hupfeld KE, Davies-Jenkins CW, Zöllner HJ, Murali-Manohar S, Mumuni AN, Crocetti D, Yedavalli V, Oeltzschner G, Alessi N, Batschelett MA, Puts NA, Mostofsky SH, Edden RA. Brain glutathione and GABA+ levels in autistic children. Autism Res 2024; 17:512-528. [PMID: 38279628 PMCID: PMC10963146 DOI: 10.1002/aur.3097] [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: 09/29/2023] [Accepted: 12/28/2023] [Indexed: 01/28/2024]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a cohort of children aged 8-12 years with ASD (n = 52) and typically developing children (TDC, n = 49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.
Collapse
Affiliation(s)
- Yulu Song
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Kathleen E. Hupfeld
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Christopher W. Davies-Jenkins
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Helge J. Zöllner
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Saipavitra Murali-Manohar
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | | | - Deana Crocetti
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Vivek Yedavalli
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Georg Oeltzschner
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Natalie Alessi
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Mitchell A. Batschelett
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Nicolaas A.J. Puts
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
- MRC Center for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
| | - Stewart H. Mostofsky
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Richard A.E. Edden
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| |
Collapse
|
|
17
|
Bou Ghanem A, Hussayni Y, Kadbey R, Ratel Y, Yehya S, Khouzami L, Ghadieh HE, Kanaan A, Azar S, Harb F. Exploring the complexities of 1C metabolism: implications in aging and neurodegenerative diseases. Front Aging Neurosci 2024; 15:1322419. [PMID: 38239489 PMCID: PMC10794399 DOI: 10.3389/fnagi.2023.1322419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/11/2023] [Indexed: 01/22/2024] Open
Abstract
The intricate interplay of one-carbon metabolism (OCM) with various cellular processes has garnered substantial attention due to its fundamental implications in several biological processes. OCM serves as a pivotal hub for methyl group donation in vital biochemical reactions, influencing DNA methylation, protein synthesis, and redox balance. In the context of aging, OCM dysregulation can contribute to epigenetic modifications and aberrant redox states, accentuating cellular senescence and age-associated pathologies. Furthermore, OCM's intricate involvement in cancer progression is evident through its capacity to provide essential one-carbon units crucial for nucleotide synthesis and DNA methylation, thereby fueling uncontrolled cell proliferation and tumor development. In neurodegenerative disorders like Alzheimer's and Parkinson's, perturbations in OCM pathways are implicated in the dysregulation of neurotransmitter synthesis and mitochondrial dysfunction, contributing to disease pathophysiology. This review underscores the profound impact of OCM in diverse disease contexts, reinforcing the need for a comprehensive understanding of its molecular complexities to pave the way for targeted therapeutic interventions across inflammation, aging and neurodegenerative disorders.
Collapse
Affiliation(s)
- Ayman Bou Ghanem
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Yaman Hussayni
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Raghid Kadbey
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Yara Ratel
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Shereen Yehya
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Lara Khouzami
- College of Natural and Health Sciences, Zayed University, Dubai, United Arab Emirates
| | - Hilda E. Ghadieh
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
- AUB Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Amjad Kanaan
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Sami Azar
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Frederic Harb
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
- AUB Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| |
Collapse
|
|
18
|
Jannat K, Balakrishnan R, Han JH, Yu YJ, Kim GW, Choi DK. The Neuropharmacological Evaluation of Seaweed: A Potential Therapeutic Source. Cells 2023; 12:2652. [PMID: 37998387 PMCID: PMC10670678 DOI: 10.3390/cells12222652] [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: 10/13/2023] [Revised: 11/11/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
The most common neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), are the seventh leading cause of mortality and morbidity in developed countries. Clinical observations of NDD patients are characterized by a progressive loss of neurons in the brain along with memory decline. The common pathological hallmarks of NDDs include oxidative stress, the dysregulation of calcium, protein aggregation, a defective protein clearance system, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and damage to cholinergic neurons. Therefore, managing this pathology requires screening drugs with different pathological targets, and suitable drugs for slowing the progression or prevention of NDDs remain to be discovered. Among the pharmacological strategies used to manage NDDs, natural drugs represent a promising therapeutic strategy. This review discusses the neuroprotective potential of seaweed and its bioactive compounds, and safety issues, which may provide several beneficial insights that warrant further investigation.
Collapse
Affiliation(s)
- Khoshnur Jannat
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju 27478, Republic of Korea; (K.J.); (J.-H.H.); (Y.-J.Y.); (G.-W.K.)
| | - Rengasamy Balakrishnan
- Department of Biotechnology, Research Institute of Inflammatory Disease (RID), College of Biomedical and Health Science, Konkuk University, Chungju 27478, Republic of Korea;
| | - Jun-Hyuk Han
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju 27478, Republic of Korea; (K.J.); (J.-H.H.); (Y.-J.Y.); (G.-W.K.)
| | - Ye-Ji Yu
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju 27478, Republic of Korea; (K.J.); (J.-H.H.); (Y.-J.Y.); (G.-W.K.)
| | - Ga-Won Kim
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju 27478, Republic of Korea; (K.J.); (J.-H.H.); (Y.-J.Y.); (G.-W.K.)
| | - Dong-Kug Choi
- Department of Applied Life Sciences, Graduate School, Konkuk University, Chungju 27478, Republic of Korea; (K.J.); (J.-H.H.); (Y.-J.Y.); (G.-W.K.)
- Department of Biotechnology, Research Institute of Inflammatory Disease (RID), College of Biomedical and Health Science, Konkuk University, Chungju 27478, Republic of Korea;
| |
Collapse
|
|
19
|
Ramírez-Cruz A, Gómez-González B, Baiza-Gutman LA, Manuel-Apolinar L, Ángeles-Mejía S, López-Cervantes SP, Ortega-Camarillo C, Cruz-López M, Gómez-Olivares JL, Díaz-Flores M. Nicotinamide, an acetylcholinesterase uncompetitive inhibitor, protects the blood‒brain barrier and improves cognitive function in rats fed a hypercaloric diet. Eur J Pharmacol 2023; 959:176068. [PMID: 37775016 DOI: 10.1016/j.ejphar.2023.176068] [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: 06/29/2023] [Accepted: 09/19/2023] [Indexed: 10/01/2023]
Abstract
Oxidative stress and inflammation induced by abundant consumption of high-energy foods and caloric overload are implicated in the dysfunction of the blood‒brain barrier (BBB), cognitive impairment, and overactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These enzymes hydrolyse acetylcholine, affecting anti-inflammatory cholinergic signalling. Our aim was to evaluate whether nicotinamide (NAM) attenuates the impairment of the BBB and cognitive function, improving cholinergic signalling. Forty male rats were distributed into five groups: one group was fed a standard diet, and the remaining groups were fed a high-fat diet and a beverage with 40% sucrose (HFS; high-fat sucrose). In three of the HFS groups, the carbohydrate was replaced by drinking water containing different concentrations of NAM for 5 h every morning for 12 weeks. The biochemical profile, levels of stress and inflammation markers, cholinesterase activities, BBB permeability, and cognitive capacity were evaluated. The results showed that the HFS diet disturbed the metabolism of carbohydrates and lipids, causing insulin resistance. Simultaneously, AChE and BChE activities, levels of proinflammatory cytokines, oxidation of proteins and lipoperoxidation increased along with decreased antioxidant capacity in serum. In the hippocampus, increased activity of cholinesterases, protein carbonylation and lipoperoxidation were associated with decreased antioxidant capacity. Systemic and hippocampal changes were reflected in increased BBB permeability and cognitive impairment. In contrast, NAM attenuated the above changes by reducing oxidative stress and inflammation through decreasing cholinesterase activities, especially by uncompetitive inhibition. NAM may be a potential systemic and neuroprotective agent to mitigate cognitive damage due to hypercaloric diets.
Collapse
Affiliation(s)
- A Ramírez-Cruz
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Ciudad de México, Mexico; Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda Gutiérrez" Centro Médico Nacional Siglo XXI, Instituto Mexicano Del Seguro Social, Ciudad de México, Mexico.
| | - B Gómez-González
- Departamento de Biología de La Reproducción, División de Ciencias Biológicas y de La Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Ciudad de México, Mexico.
| | - L A Baiza-Gutman
- Laboratorio de Biología Del Desarrollo, Unidad de Morfología y Función, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Estado de México, Mexico.
| | - L Manuel-Apolinar
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades "Bernardo Sepúlveda Gutiérrez" Centro Médico Nacional Siglo XXI, Instituto Mexicano Del Seguro Social, Ciudad de México, Mexico.
| | - S Ángeles-Mejía
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda Gutiérrez" Centro Médico Nacional Siglo XXI, Instituto Mexicano Del Seguro Social, Ciudad de México, Mexico.
| | - S P López-Cervantes
- Posgrado en Biología Experimental, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Ciudad de México, Mexico.
| | - C Ortega-Camarillo
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda Gutiérrez" Centro Médico Nacional Siglo XXI, Instituto Mexicano Del Seguro Social, Ciudad de México, Mexico.
| | - M Cruz-López
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda Gutiérrez" Centro Médico Nacional Siglo XXI, Instituto Mexicano Del Seguro Social, Ciudad de México, Mexico.
| | - J L Gómez-Olivares
- Laboratorio de Biomembranas, División de Ciencias Biológicas y de La Salud, Universidad Autónoma Metropolitana, Unidad Iztapalapa, Ciudad de México, Mexico.
| | - M Díaz-Flores
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades "Bernardo Sepúlveda Gutiérrez" Centro Médico Nacional Siglo XXI, Instituto Mexicano Del Seguro Social, Ciudad de México, Mexico.
| |
Collapse
|
|
20
|
Moore JM, Crom AB, Feldblyum JI, Genna DT. Disulfide-Driven Pore Functionalization of Metal-Organic Frameworks. Chemistry 2023; 29:e202302144. [PMID: 37486291 DOI: 10.1002/chem.202302144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 07/25/2023]
Abstract
Post-synthetic modification (PSM) imparts additional functionality to metal-organic frameworks (MOFs) that is often difficult to access using solvothermal synthesis. As such, expanding the repertory of PSM reactions available to the practitioner is of increased importance for the generation of materials tailored for desired applications. Herein, a method is described for the protecting group-free installation of diverse functional groups within the pores of a MIL-53(Al) analogue via disulfide bond formation. The majority of the reactions proceed with thiol-to-disulfide conversions ranging from high to nearly quantitative. The disulfide bonds are stable in various solvents and can be cleaved in the presence of a reducing agent.
Collapse
Affiliation(s)
- Jennifer M Moore
- Department of Chemical and Biological Sciences, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
| | - Audrey B Crom
- Department of Chemistry, The University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY, 12222, USA
| | - Jeremy I Feldblyum
- Department of Chemistry, The University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY, 12222, USA
| | - Douglas T Genna
- Department of Chemical and Biological Sciences, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
| |
Collapse
|
|
21
|
Song Y, Hupfeld KE, Davies-Jenkins CW, Zöllner HJ, Murali-Manohar S, Mumuni AN, Crocetti D, Yedavalli V, Oeltzschner G, Alessi N, Batschelett MA, Puts NAJ, Mostofsky SH, Edden RAE. Brain Glutathione and GABA+ levels in autistic children. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.28.559718. [PMID: 37808813 PMCID: PMC10557661 DOI: 10.1101/2023.09.28.559718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a large cohort of children aged 8-12 years with ASD (n=52) and typically developing children (TDC, n=49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.
Collapse
Affiliation(s)
- Yulu Song
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Kathleen E Hupfeld
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Christopher W Davies-Jenkins
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Helge J Zöllner
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Saipavitra Murali-Manohar
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | | | - Deana Crocetti
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Vivek Yedavalli
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Georg Oeltzschner
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Natalie Alessi
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Mitchell A Batschelett
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Nicolaas A J Puts
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom
- MRC Center for Neurodevelopmental Disorders, King's College London, London, United Kingdom
| | - Stewart H Mostofsky
- Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, United States
- Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Richard A E Edden
- The Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States
| |
Collapse
|
|
22
|
Aleksandrova Y, Neganova M. Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases. Int J Mol Sci 2023; 24:14766. [PMID: 37834214 PMCID: PMC10573395 DOI: 10.3390/ijms241914766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
The relationship between oncological pathologies and neurodegenerative disorders is extremely complex and is a topic of concern among a growing number of researchers around the world. In recent years, convincing scientific evidence has accumulated that indicates the contribution of a number of etiological factors and pathophysiological processes to the pathogenesis of these two fundamentally different diseases, thus demonstrating an intriguing relationship between oncology and neurodegeneration. In this review, we establish the general links between three intersecting aspects of oncological pathologies and neurodegenerative disorders, i.e., oxidative stress, epigenetic dysregulation, and metabolic dysfunction, examining each process in detail to establish an unusual epidemiological relationship. We also focus on reviewing the current trends in the research and the clinical application of the most promising chemical structures and therapeutic platforms that have a modulating effect on the above processes. Thus, our comprehensive analysis of the set of molecular determinants that have obvious cross-functional pathways in the pathogenesis of oncological and neurodegenerative diseases can help in the creation of advanced diagnostic tools and in the development of innovative pharmacological strategies.
Collapse
Affiliation(s)
- Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Margarita Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 420088 Kazan, Russia
| |
Collapse
|
|
23
|
Roy R, Mandal PK, Maroon JC. Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer's Disease: Role of Glutathione and Metal Ions. ACS Chem Neurosci 2023; 14:2944-2954. [PMID: 37561556 PMCID: PMC10485904 DOI: 10.1021/acschemneuro.3c00486] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023] Open
Abstract
Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aβ) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aβ in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aβ deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.
Collapse
Affiliation(s)
- Rimil
Guha Roy
- Neuroimaging
and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre, Gurgaon 122052, India
| | - Pravat K Mandal
- Neuroimaging
and Neurospectroscopy (NINS) Laboratory, National Brain Research Centre, Gurgaon 122052, India
- Florey
Institute of Neuroscience and Mental Health, Melbourne School of Medicine Campus, Melbourne, 3052 VIC, Australia
| | - Joseph C. Maroon
- Department
of Neurosurgery, University of Pittsburgh
Medical School, Pittsburgh, Pennsylvania 15213, United States
| |
Collapse
|
|
24
|
Fujii J, Osaki T, Soma Y, Matsuda Y. Critical Roles of the Cysteine-Glutathione Axis in the Production of γ-Glutamyl Peptides in the Nervous System. Int J Mol Sci 2023; 24:ijms24098044. [PMID: 37175751 PMCID: PMC10179188 DOI: 10.3390/ijms24098044] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
γ-Glutamyl moiety that is attached to the cysteine (Cys) residue in glutathione (GSH) protects it from peptidase-mediated degradation. The sulfhydryl group of the Cys residue represents most of the functions of GSH, which include electron donation to peroxidases, protection of reactive sulfhydryl in proteins via glutaredoxin, and glutathione conjugation of xenobiotics, whereas Cys-derived sulfur is also a pivotal component of some redox-responsive molecules. The amount of Cys that is available tends to restrict the capacity of GSH synthesis. In in vitro systems, cystine is the major form in the extracellular milieu, and a specific cystine transporter, xCT, is essential for survival in most lines of cells and in many primary cultivated cells as well. A reduction in the supply of Cys causes GPX4 to be inhibited due to insufficient GSH synthesis, which leads to iron-dependent necrotic cell death, ferroptosis. Cells generally cannot take up GSH without the removal of γ-glutamyl moiety by γ-glutamyl transferase (GGT) on the cell surface. Meanwhile, the Cys-GSH axis is essentially common to certain types of cells; primarily, neuronal cells that contain a unique metabolic system for intercellular communication concerning γ-glutamyl peptides. After a general description of metabolic processes concerning the Cys-GSH axis, we provide an overview and discuss the significance of GSH-related compounds in the nervous system.
Collapse
Affiliation(s)
- Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
| | - Tsukasa Osaki
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
| | - Yuya Soma
- Graduate School of Nursing, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
| | - Yumi Matsuda
- Graduate School of Nursing, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
| |
Collapse
|
|
25
|
Rey F, Berardo C, Maghraby E, Mauri A, Messa L, Esposito L, Casili G, Ottolenghi S, Bonaventura E, Cuzzocrea S, Zuccotti G, Tonduti D, Esposito E, Paterniti I, Cereda C, Carelli S. Redox Imbalance in Neurological Disorders in Adults and Children. Antioxidants (Basel) 2023; 12:antiox12040965. [PMID: 37107340 PMCID: PMC10135575 DOI: 10.3390/antiox12040965] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/03/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus-Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.
Collapse
Affiliation(s)
- Federica Rey
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Clarissa Berardo
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Erika Maghraby
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy
| | - Alessia Mauri
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Letizia Messa
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
- Department of Electronics, Information and Bioengineering (DEIB), Politecnico di Milano, 20133 Milano, Italy
| | - Letizia Esposito
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Sara Ottolenghi
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy
| | - Eleonora Bonaventura
- Child Neurology Unit, Buzzi Children's Hospital, 20154 Milano, Italy
- Center for Diagnosis and Treatment of Leukodystrophies and Genetic Leukoencephalopathies (COALA), Buzzi Children's Hospital, 20154 Milano, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Davide Tonduti
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Child Neurology Unit, Buzzi Children's Hospital, 20154 Milano, Italy
- Center for Diagnosis and Treatment of Leukodystrophies and Genetic Leukoencephalopathies (COALA), Buzzi Children's Hospital, 20154 Milano, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Cristina Cereda
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| | - Stephana Carelli
- Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Sciences, University of Milano, 20157 Milano, Italy
- Center of Functional Genomics and Rare diseases, Department of Pediatrics, Buzzi Children's Hospital, 20154 Milano, Italy
| |
Collapse
|
|
26
|
Zhao J, Guo F, Hou L, Zhao Y, Sun P. Electron transfer-based antioxidant nanozymes: Emerging therapeutics for inflammatory diseases. J Control Release 2023; 355:273-291. [PMID: 36731800 DOI: 10.1016/j.jconrel.2023.01.068] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/27/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023]
Abstract
Inflammatory diseases are usually featured with relatively high level of reactive oxygen species (ROS). The excess ROS facilitate the polarization of microphages into proinflammatory M1 phenotype, and cause DNA damage, protein carbonylation, and lipid peroxidation, resulting in further deterioration of inflammatory diseases. Therefore, alleviating oxidative stress by ROS scavenging has been an effective strategy for reversing inflammation. Inspired by the natural antioxidant enzymes, electron transfer-based artificial antioxidant nanozymes have been emerging therapeutics for the treatment of inflammatory diseases. The present review starts with the basic knowledge of ROS and diseases, followed by summarizing the possible active centers for the preparation of antioxidant nanozymes. The strategies for the design of antioxidant nanozymes on the purpose of higher catalytic activity are provided, and the applications of the developed antioxidant nanozymes on the therapy of inflammatory diseases are discussed. A perspective is included for the design and applications of artificial antioxidant nanozymes in biomedicine as well.
Collapse
Affiliation(s)
- Jingnan Zhao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Fanfan Guo
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China
| | - Lin Hou
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China
| | - Yongxing Zhao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, PR China
| | - Pengchao Sun
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, Zhengzhou University, Zhengzhou 450001, PR China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, Zhengzhou 450001, PR China.
| |
Collapse
|
|
27
|
Kolonas A, Vareltzis P, Kiroglou S, Goutzourelas N, Stagos D, Trachana V, Tsadila C, Mossialos D, Mourtakos S, Gortzi O. Antioxidant and Antibacterial Properties of a Functional Sports Beverage Formulation. Int J Mol Sci 2023; 24:ijms24043558. [PMID: 36834967 PMCID: PMC9959907 DOI: 10.3390/ijms24043558] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/04/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Athletes often consume functional beverages in order to improve performance and reduce oxidative stress caused by high-intensity exercise. The present study aimed to evaluate the antioxidant and antibacterial properties of a functional sports beverage formulation. The beverage's antioxidant effects were assessed on human mesenchymal stem cells (MSCs) by determining thiobarbituric acid reactive substances (TBARS; TBARS levels decreased significantly by 52.67% at 2.0 mg/mL), total antioxidant capacity (TAC; TAC levels increased significantly by 80.82% at 2.0 mg/mL) and reduced glutathione (GSH; GSH levels increased significantly by 24.13% at 2.0 mg/mL) levels. Furthermore, the beverage underwent simulated digestion following the INFOGEST protocol to assess its oxidative stability. The analysis of the total phenolic content (TPC) using the Folin-Ciocalteu assay revealed that the beverage contained a TPC of 7.58 ± 0.066 mg GAE/mL, while the phenolics identified by HPLC were catechin (2.149 mg/mL), epicatechin (0.024 mg/mL), protocatechuic acid (0.012 mg/mL), luteolin 7-glucoside (0.001 mg/mL), and kaempferol-3-O-β-rutinoside (0.001 mg/mL). The beverage's TPC was strongly correlated with TAC (R2 = 896). Moreover, the beverage showcased inhibitory and bacteriostatic effects against Staphylococcus aureus and Pseudomonas aeruginosa. Lastly, the sensory acceptance test demonstrated that the functional sports beverage was well accepted by the assessors.
Collapse
Affiliation(s)
- Alexandros Kolonas
- Department of Agriculture Crop Production and Rural Environment, School of Agricultural Sciences, University of Thessaly, 384 46 Volos, Greece
| | - Patroklos Vareltzis
- Laboratory of Food and Agricultural Industries Technologies, Chemical Engineering Department, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
| | - Smaro Kiroglou
- Laboratory of Food and Agricultural Industries Technologies, Chemical Engineering Department, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
| | - Nikolaos Goutzourelas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Biopolis, 415 00 Larissa, Greece
| | - Dimitrios Stagos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Biopolis, 415 00 Larissa, Greece
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, Biopolis, 415 00 Larissa, Greece
| | - Christina Tsadila
- Microbial Biotechnology-Molecular Bacteriology-Virology Laboratory, Department of Biochemistry & Biotechnology, University of Thessaly, 415 00 Larissa, Greece
| | - Dimitris Mossialos
- Microbial Biotechnology-Molecular Bacteriology-Virology Laboratory, Department of Biochemistry & Biotechnology, University of Thessaly, 415 00 Larissa, Greece
| | - Stamatis Mourtakos
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, 176 71 Athens, Greece
| | - Olga Gortzi
- Department of Agriculture Crop Production and Rural Environment, School of Agricultural Sciences, University of Thessaly, 384 46 Volos, Greece
- Correspondence:
| |
Collapse
|
|
28
|
Ma H, Dong Y, Chu Y, Guo Y, Li L. The mechanisms of ferroptosis and its role in alzheimer’s disease. Front Mol Biosci 2022; 9:965064. [PMID: 36090039 PMCID: PMC9459389 DOI: 10.3389/fmolb.2022.965064] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/25/2022] [Indexed: 12/06/2022] Open
Abstract
Alzheimer’s disease (AD) accounts for two-thirds of all dementia cases, affecting 50 million people worldwide. Only four of the more than 100 AD drugs developed thus far have successfully improved AD symptoms. Furthermore, these improvements are only temporary, as no treatment can stop or reverse AD progression. A growing number of recent studies have demonstrated that iron-dependent programmed cell death, known as ferroptosis, contributes to AD-mediated nerve cell death. The ferroptosis pathways within nerve cells include iron homeostasis regulation, cystine/glutamate (Glu) reverse transporter (system xc−), glutathione (GSH)/glutathione peroxidase 4 (GPX4), and lipid peroxidation. In the regulation pathway of AD iron homeostasis, abnormal iron uptake, excretion and storage in nerve cells lead to increased intracellular free iron and Fenton reactions. Furthermore, decreased Glu transporter expression leads to Glu accumulation outside nerve cells, resulting in the inhibition of the system xc− pathway. GSH depletion causes abnormalities in GPX4, leading to excessive accumulation of lipid peroxides. Alterations in these specific pathways and amino acid metabolism eventually lead to ferroptosis. This review explores the connection between AD and the ferroptosis signaling pathways and amino acid metabolism, potentially informing future AD diagnosis and treatment methodologies.
Collapse
Affiliation(s)
- Hongyue Ma
- Department of Neurology, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China
| | - Yan Dong
- Department of Neurology, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China
| | - Yanhui Chu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
| | - Yanqin Guo
- Department of Neurology, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
- *Correspondence: Yanqin Guo, ; Luxin Li,
| | - Luxin Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, China
- *Correspondence: Yanqin Guo, ; Luxin Li,
| |
Collapse
|
|
29
|
Wang H, Dai JY, He YZ, Xia ZW, Chen XF, Hong ZY, Chai YF. Therapeutic effect and mechanism of Anemarrhenae Rhizoma on Alzheimer’s disease based on multi-platform metabolomics analyses. Front Pharmacol 2022; 13:940555. [PMID: 35991874 PMCID: PMC9385998 DOI: 10.3389/fphar.2022.940555] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/04/2022] [Indexed: 12/04/2022] Open
Abstract
Anemarrhenae Rhizoma (AR) has multiple pharmacological activities to prevent and treat Alzheimer’s disease (AD). However, the effect and its molecular mechanism are not elucidated clear. This study aims to evaluate AR’s therapeutic effect and mechanism on AD model rats induced by D-galactose and AlCl3 with serum metabolomics. Behavior study, histopathological observations, and biochemical analyses were applied in the AD model assessment. Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-QTOF/MS) were combined with multivariate statistical analysis to identify potential biomarkers of AD and evaluate the therapeutic effect of AR on AD from the perspective of metabolomics. A total of 49 biomarkers associated with the AD model were identified by metabolomics, and pathway analysis was performed to obtain the metabolic pathways closely related to the model. With the pre-treatment of AR, 32 metabolites in the serum of AD model rats were significantly affected by AR compared with the AD model group. The regulated metabolites affected by AR were involved in the pathway of arginine biosynthesis, arginine and proline metabolism, ether lipid metabolism, glutathione metabolism, primary bile acid biosynthesis, and steroid biosynthesis. These multi-platform metabolomics analyses were in accord with the results of behavior study, histopathological observations, and biochemical analyses. This study explored the therapeutic mechanism of AR based on multi-platform metabolomics analyses and provided a scientific basis for the application of AR in the prevention and treatment of AD.
Collapse
Affiliation(s)
- Hui Wang
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Jian-Ying Dai
- College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Yu-Zhen He
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Zhe-Wei Xia
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Xiao-Fei Chen
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai, China
| | - Zhan-Ying Hong
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai, China
- *Correspondence: Zhan-Ying Hong,
| | - Yi-Feng Chai
- Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Naval Medical University, Shanghai, China
| |
Collapse
|
|
30
|
Genetic Disruption of the γ-Glutamylcysteine Ligase in PDAC Cells Induces Ferroptosis-Independent Cell Death In Vitro without Affecting In Vivo Tumor Growth. Cancers (Basel) 2022; 14:cancers14133154. [PMID: 35804926 PMCID: PMC9264981 DOI: 10.3390/cancers14133154] [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: 03/23/2022] [Revised: 05/29/2022] [Accepted: 06/02/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The newly described form of iron-dependent cell death, called ferroptosis, has emerged as a powerful strategy for eradicating cancer cells. This is of particular importance for pancreatic ductal adenocarcinoma (PDAC), which has been shown to be one of the most aggressive tumors, with a five-year overall survival of less than 8%. The aim of the present study is to identify the most potent and selective target for the induction of ferroptosis in PDAC cells. The results presented here are of great importance not only for the development of novel and more effective anti-cancer therapeutics, but also anticipate potential resistant mechanisms that cancer cells might deploy. This way, ferroptosis-based therapeutics may be a step ahead of highly adaptable cancer cells. Abstract The conceptualization of a novel type of cell death, called ferroptosis, opens new avenues for the development of more efficient anti-cancer therapeutics. In this context, a full understanding of the ferroptotic pathways, the players involved, their precise role, and dispensability is prerequisite. Here, we focused on the importance of glutathione (GSH) for ferroptosis prevention in pancreatic ductal adenocarcinoma (PDAC) cells. We genetically deleted a unique, rate-limiting enzyme for GSH biosynthesis, γ-glutamylcysteine ligase (GCL), which plays a key role in tumor cell proliferation and survival. Surprisingly, although glutathione peroxidase 4 (GPx4) has been described as a guardian of ferroptosis, depletion of its substrate (GSH) led preferentially to apoptotic cell death, while classical ferroptotic markers (lipid hydroperoxides) have not been observed. Furthermore, the sensitivity of PDAC cells to the pharmacological/genetic inhibition of GPx4 revealed GSH dispensability in this context. To the best of our knowledge, this is the first time that the complete dissection of the xCT-GSH-GPx4 axis in PDAC cells has been investigated in great detail. Collectively, our results revealed the necessary role of GSH in the overall redox homeostasis of PDAC cells, as well as the dispensability of this redox-active molecule for a specific, antioxidant branch dedicated to ferroptosis prevention.
Collapse
|
|
31
|
Delbreil P, Rabanel JM, Banquy X, Brambilla D. Therapeutic nanotechnologies for Alzheimer's disease: a critical analysis of recent trends and findings. Adv Drug Deliv Rev 2022; 187:114397. [PMID: 35738546 DOI: 10.1016/j.addr.2022.114397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 11/01/2022]
Abstract
Alzheimer's Disease (AD) is an irreversible neurodegenerative disease for which no disease modifying therapies are presently available. Besides the identification of pathological targets, AD presents numerous clinical and pharmacological challenges such as efficient active delivery to the central nervous system, cell targeting, and long-term dosing. Nanoparticles have been explored to overcome some of these challenges as drug delivery vehicles or drugs themselves. However, early promises have failed to materialize as no nanotechnology-based product has been able to reach the market and very few have moved past preclinical stages. In this review, we perform a critical analysis of the past decade's research on nanomedicine-based therapies for AD at the preclinical and clinical stages. The main obstacles to nanotechnology products and the most promising approaches were also identified, including renewed promise with gene editing, gene modulation, and vaccines.
Collapse
Affiliation(s)
- Philippe Delbreil
- Faculty of pharmacy, Université de Montréal, PO Box 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada
| | - Jean-Michel Rabanel
- Faculty of pharmacy, Université de Montréal, PO Box 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada
| | - Xavier Banquy
- Faculty of pharmacy, Université de Montréal, PO Box 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada
| | - Davide Brambilla
- Faculty of pharmacy, Université de Montréal, PO Box 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada.
| |
Collapse
|
|
32
|
D’Cunha NM, Sergi D, Lane MM, Naumovski N, Gamage E, Rajendran A, Kouvari M, Gauci S, Dissanayka T, Marx W, Travica N. The Effects of Dietary Advanced Glycation End-Products on Neurocognitive and Mental Disorders. Nutrients 2022; 14:nu14122421. [PMID: 35745150 PMCID: PMC9227209 DOI: 10.3390/nu14122421] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 02/04/2023] Open
Abstract
Advanced glycation end products (AGEs) are glycated proteins or lipids formed endogenously in the human body or consumed through diet. Ultra-processed foods and some culinary techniques, such as dry cooking methods, represent the main sources and drivers of dietary AGEs. Tissue accumulation of AGEs has been associated with cellular aging and implicated in various age-related diseases, including type-2 diabetes and cardiovascular disease. The current review summarizes the literature examining the associations between AGEs and neurocognitive and mental health disorders. Studies indicate that elevated circulating AGEs are cross-sectionally associated with poorer cognitive function and longitudinally increase the risk of developing dementia. Additionally, preliminary studies show that higher skin AGE accumulation may be associated with mental disorders, particularly depression and schizophrenia. Potential mechanisms underpinning the effects of AGEs include elevated oxidative stress and neuroinflammation, which are both key pathogenetic mechanisms underlying neurodegeneration and mental disorders. Decreasing dietary intake of AGEs may improve neurological and mental disorder outcomes. However, more sophisticated prospective studies and analytical approaches are required to verify directionality and the extent to which AGEs represent a mediator linking unhealthy dietary patterns with cognitive and mental disorders.
Collapse
Affiliation(s)
- Nathan M. D’Cunha
- Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Canberra, ACT 2601, Australia (N.N.); (M.K.)
- Functional Foods and Nutrition Research (FFNR) Laboratory, University of Canberra, Bruce, ACT 2617, Australia
| | - Domenico Sergi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy;
| | - Melissa M. Lane
- Food and Mood Centre, IMPACT—The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia; (M.M.L.); (E.G.); (A.R.); (T.D.); (W.M.)
| | - Nenad Naumovski
- Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Canberra, ACT 2601, Australia (N.N.); (M.K.)
- Functional Foods and Nutrition Research (FFNR) Laboratory, University of Canberra, Bruce, ACT 2617, Australia
- Department of Nutrition-Dietetics, Harokopio University, 17671 Athens, Greece
| | - Elizabeth Gamage
- Food and Mood Centre, IMPACT—The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia; (M.M.L.); (E.G.); (A.R.); (T.D.); (W.M.)
| | - Anushri Rajendran
- Food and Mood Centre, IMPACT—The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia; (M.M.L.); (E.G.); (A.R.); (T.D.); (W.M.)
- Institute for Intelligent Systems Research and Innovation (IISRI), Deakin University, Waurn Ponds, VIC 3216, Australia
| | - Matina Kouvari
- Discipline of Nutrition and Dietetics, Faculty of Health, University of Canberra, Canberra, ACT 2601, Australia (N.N.); (M.K.)
- Functional Foods and Nutrition Research (FFNR) Laboratory, University of Canberra, Bruce, ACT 2617, Australia
- Department of Nutrition-Dietetics, Harokopio University, 17671 Athens, Greece
| | - Sarah Gauci
- Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC 3122, Australia;
- Heart and Mind Research, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, School of Medicine, Deakin University, Geelong, VIC 3220, Australia
| | - Thusharika Dissanayka
- Food and Mood Centre, IMPACT—The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia; (M.M.L.); (E.G.); (A.R.); (T.D.); (W.M.)
| | - Wolfgang Marx
- Food and Mood Centre, IMPACT—The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia; (M.M.L.); (E.G.); (A.R.); (T.D.); (W.M.)
| | - Nikolaj Travica
- Food and Mood Centre, IMPACT—The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC 3220, Australia; (M.M.L.); (E.G.); (A.R.); (T.D.); (W.M.)
- Correspondence:
| |
Collapse
|
|
33
|
Voltammetric studies of glutathione transfer across arrays of liquid-liquid microinterfaces for sensing applications. Amino Acids 2022; 54:911-922. [PMID: 35583563 DOI: 10.1007/s00726-022-03166-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/20/2022] [Indexed: 11/01/2022]
Abstract
The simple and facilitated transfer of tripeptide glutathione across the water/2-nitrophenyl octhyl ether interface was studied via cyclic voltammetry at interface between two immiscible electrolyte solutions (ITIES). The micro-perforated membrane prepared with a laser with a femtosecond pulse was used for mechanical stabilization of the interface. The method of cyclic voltammetry was used to study the passive and facilitated interfacial transfer of glutathione and its complex with the crown ether dibenzo-18-crown-6 (DB18C6).The glutathione mass transfer mechanism was established and substantiated, the diffusion coefficients, thermodynamic characteristics of interphase transfer and the constant of complexation of the glutathione by DB18C6 were determined. Square wave voltammetry based on facilitated transfer was used for more accurate and sensitive determination of glutathione low detection limit (0.8 μM) with wide linear dynamic range (from 3.0 to 80 μM) was reached. The influence of various potentially interfering ions on the voltammetric determination of glutathione has also been investigated. The method developed was applied to determine glutathione in aqueous solutions and malt extract.
Collapse
|
|
34
|
Varesi A, Carrara A, Pires VG, Floris V, Pierella E, Savioli G, Prasad S, Esposito C, Ricevuti G, Chirumbolo S, Pascale A. Blood-Based Biomarkers for Alzheimer's Disease Diagnosis and Progression: An Overview. Cells 2022; 11:1367. [PMID: 35456047 PMCID: PMC9044750 DOI: 10.3390/cells11081367] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 01/10/2023] Open
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1-42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.
Collapse
Affiliation(s)
- Angelica Varesi
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
- Almo Collegio Borromeo, 27100 Pavia, Italy
| | - Adelaide Carrara
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Vitor Gomes Pires
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA;
| | - Valentina Floris
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Elisa Pierella
- School of Medicine, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK;
| | - Gabriele Savioli
- Emergency Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Sakshi Prasad
- Faculty of Medicine, National Pirogov Memorial Medical University, 21018 Vinnytsya, Ukraine;
| | - Ciro Esposito
- Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, 27100 Pavia, Italy;
| | - Giovanni Ricevuti
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy;
| | - Alessia Pascale
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy;
| |
Collapse
|
|
35
|
Buccellato FR, D’Anca M, Fenoglio C, Scarpini E, Galimberti D. Role of Oxidative Damage in Alzheimer's Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery. Antioxidants (Basel) 2021; 10:antiox10091353. [PMID: 34572985 PMCID: PMC8471953 DOI: 10.3390/antiox10091353] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/11/2021] [Accepted: 08/17/2021] [Indexed: 12/16/2022] Open
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.
Collapse
Affiliation(s)
- Francesca Romana Buccellato
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (E.S.); (D.G.)
- Correspondence: ; Tel.: +39-02 55033814
| | - Marianna D’Anca
- Fondazione IRCSS ca’ Granda, Ospedale Policlinico, 20122 Milano, Italy;
| | - Chiara Fenoglio
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy;
| | - Elio Scarpini
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (E.S.); (D.G.)
- Fondazione IRCSS ca’ Granda, Ospedale Policlinico, 20122 Milano, Italy;
| | - Daniela Galimberti
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; (E.S.); (D.G.)
- Fondazione IRCSS ca’ Granda, Ospedale Policlinico, 20122 Milano, Italy;
| |
Collapse
|