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Yu Y, Wang T, Li Q, Zhao H, Li B, Lei D, Dong F, Xiao Y, Wang S, Ji Y. DL-3-n-butylphthalide inhibits astrocyte activation in the cortical penumbra of ischemia-reperfusion model rats via AKT signaling. Brain Res Bull 2025; 225:111332. [PMID: 40185418 DOI: 10.1016/j.brainresbull.2025.111332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/23/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
Ischemic stroke triggers rapid activation of astrocytes, which contributes to tissue damage. Dl-3-n-butylphthalide (NBP), an independently developed compound in China for the treatment of ischemic stroke, has unclear molecular mechanisms. In this study, we established a Sprague-Dawley rat model of middle cerebral artery occlusion (MCAO) by occluding the middle cerebral artery for 1.5 h followed by reperfusion for 72 h. We assessed neurological scores, infarct volume, neuronal injury, and the expression levels of GFAP, C3, S100A10, GLT-1, p-AKT/AKT, and p-mTOR/mTOR, as well as immunofluorescence double staining of C3/S100A10 with GFAP and GLT-1 respectively. NBP significantly improved neurological function in MCAO rats, reduced infarct area, alleviated neuronal injury, inhibited A1 astrocyte polarization, promoted A2 astrocyte polarization, and upregulated GLT-1 expression. However, the AKT inhibitor (TCN) weakened NBP's regulatory effects on astrocytes and GLT-1. Finally, immunofluorescence experiments showed that GLT-1 colocalized more effectively with A2 astrocytes than with A1 astrocytes. We demonstrated that NBP reduces astrocyte activation and upregulates GLT-1 expression via the AKT/mTOR pathway, providing new insights into therapeutic strategies for ischemic stroke and valuable clues for drug design.
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Affiliation(s)
- Yiwen Yu
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Tinghong Wang
- Department of Forensic Pathology, School of Basic Medical Science and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Qiuling Li
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hao Zhao
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Biao Li
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Dong Lei
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Fei Dong
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yu Xiao
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Shan Wang
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yifei Ji
- Department of Neurology, Nanchong Central Hospital Affiliated to North Sichuan Medical College, Nanchong, Sichuan, China.
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Berlind JE, Lai JD, Lie C, Vicente J, Lam K, Guo S, Chang J, Yu V, Ichida JK. KCTD20 suppression mitigates excitotoxicity in tauopathy patient organoids. Neuron 2025; 113:1169-1189.e7. [PMID: 40049159 PMCID: PMC12005969 DOI: 10.1016/j.neuron.2025.02.001] [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: 05/07/2024] [Revised: 12/13/2024] [Accepted: 02/04/2025] [Indexed: 04/19/2025]
Abstract
Excitotoxicity is a major pathologic mechanism in patients with tauopathy and other neurodegenerative diseases. However, the key neurotoxic drivers and the most effective strategies for mitigating these degenerative processes are unclear. Here, we show that glutamate treatment of induced pluripotent stem cell (iPSC)-derived cerebral organoids induces tau oligomerization and neurodegeneration and that these phenotypes are enhanced in organoids derived from tauopathy patients. Using a genome-wide CRISPR interference (CRISPRi) screen, we find that the suppression of KCTD20 potently ameliorates tau pathology and neurodegeneration in glutamate-treated organoids and mice, as well as in transgenic mice overexpressing mutant human tau. KCTD20 suppression reduces oligomeric tau and improves neuron survival by activating lysosomal exocytosis, which clears pathological tau. Our results show that glutamate signaling can induce neuronal tau pathology and identify KCTD20 suppression and lysosomal exocytosis as effective strategies for clearing neurotoxic tau species.
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Affiliation(s)
- Joshua E Berlind
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Jesse D Lai
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA; Department of Neuroscience, Amgen Inc., Cambridge, MA, USA; Neurological & Rare Diseases, Dewpoint Therapeutics, Boston, MA, USA.
| | - Cecilia Lie
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Jokabeth Vicente
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Kelsey Lam
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Sheron Guo
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Jonathan Chang
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA
| | - Violeta Yu
- Neurological & Rare Diseases, Dewpoint Therapeutics, Boston, MA, USA
| | - Justin K Ichida
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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Lin D, Howard A, Raihane AS, Di Napoli M, Cáceres E, Ortiz M, Davis J, Abdelrahman AN, Divani AA. Traumatic Brain Injury and Gut Microbiome: The Role of the Gut-Brain Axis in Neurodegenerative Processes. Curr Neurol Neurosci Rep 2025; 25:23. [PMID: 40087204 DOI: 10.1007/s11910-025-01410-0] [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] [Accepted: 02/20/2025] [Indexed: 03/17/2025]
Abstract
PURPOSE OF REVIEW A deeper understanding of the communication network between the gut microbiome and the central nervous system, termed the gut-brain axis (GBA), has revealed new potential targets for intervention to prevent the development of neurodegenerative disease associated with tramatic brain injury (TBI). This review aims to comprehensively examine the role of GBA post-traumatic brain injury (TBI). RECENT FINDINGS The GBA functions through neural, metabolic, immune, and endocrine systems, creating bidirectional signaling pathways that modulate brain and gastrointestinal (GI) tract physiology. TBI perturbs these signaling pathways, producing pathophysiological feedback loops in the GBA leading to dysbiosis (i.e., a perturbed gut microbiome, impaired brain-blood barrier, impaired intestinal epithelial barrier (i.e., "leaky gut"), and a maladaptive, systemic inflammatory response. Damage to the CNS associated with TBI leads to GI dysmotility, which promotes small intestinal bacterial overgrowth (SIBO). SIBO has been associated with the early stages of neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Many of the bacteria associated with this overgrowth promote inflammation and, in rodent models, have been shown to compromise the structural integrity of the intestinal mucosal barrier, causing malabsorption of essential nutrients and further exacerbating dysbiosis. TBI-induced pathophysiology is strongly associated with an increased risk of neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, which represents a significant public health burden and challenge for patients and their families. A healthy gut microbiome has been shown to promote improved recovery from TBI and prevent the development of neurodegenerative disease, as well as other chronic complications. The role of the gut microbiome in brain health post-TBI demonstrates the potential for microbiome-targeted interventions to mitigate TBI-associated comorbidities. Promising new evidence on prebiotics, probiotics, diet, and fecal microbiota transplantation may lead to new therapeutic options for improving the quality of life for patients with TBI. Still, many of these preliminary findings must be explored further in clinical settings. This review covers the current understanding of the GBA in the setting of TBI and how the gut microbiome may provide a novel therapeutic target for treatment in this patient population.
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Affiliation(s)
- Derek Lin
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Andrea Howard
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Ahmed S Raihane
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Mario Di Napoli
- Neurological Service, dell'Annunziata Hospital, Sulmona, L'Aquila, Italy
| | - Eder Cáceres
- Bioscience, School of Engineering, Universidad de La Sabana, Chía, Colombia
- Department of Critical Care, Clínica Universidad de La Sabana, Chía, Colombia
- Unisabana Center for Translational Science, School of Medicine, Universidad de La Sabana, Chía, Colombia
| | - Michael Ortiz
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Justin Davis
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Allae N Abdelrahman
- School of Medicine, University of New Mexico, Albuquerque, NM, USA
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA
| | - Afshin A Divani
- Department of Neurology, University of New Mexico, MSC10-5620, Albuquerque, NM, 87131, USA.
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Hu N, Cheng Zeng, Cao Y, Li X, Bai F, Wang J, Yang B, Li C. Therapeutic potential of Shilong Qingxue Granule and its extract against glutamate induced neural injury: Insights from in vivo and in vitro models. JOURNAL OF ETHNOPHARMACOLOGY 2025; 342:119396. [PMID: 39848417 DOI: 10.1016/j.jep.2025.119396] [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: 11/19/2024] [Revised: 01/02/2025] [Accepted: 01/21/2025] [Indexed: 01/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Shilong Qingxue Granule (SQG), a traditional Chinese medicine, effectively treats the secondary neurological damage and functional deficits caused by cerebral hemorrhage, though its exact mechanism remains unclear. AIM OF THE STUDY This study aimed to investigate the effects of SQG and its mechanisms. MATERIALS AND METHODS we evaluated the effects of SQG and its extracts on glutamate induced nerve damage using in vivo and in vitro models. Brain water content was measured and brain tissue was stained with hematoxylin and eosin (HE) to evaluate the brain protective effect of SQG in rats. HPLC and UPLC-Q-TOF-MS were used to identify the chemical components in SQG. The model of PC12 cells induced by glutamate was established to detect intracellular Ca2+ and mitochondrial membrane potential (MMP), the content of intracellular reactive oxygen species (ROS), acridine orange/ethidium bromide (AO/EB), and the possible mechanism of action in vivo was explored by Western blot and RNA sequencing. RESULTS SQG alleviates brain edema and neuronal damage in glutamate induced rats by modulating mitochondrial apoptotic and MAPK signaling pathways. The SQG extract was separated by silica gel chromatographic column to obtain 20 components, and the S-18 improves PC12 survival under glutamate induced conditions by MMP, reducing ROS and Ca2+ levels, and protecting against cell body and nucleus damage to against apoptosis. CONCLUSION SQG and its extract demonstrate protective effects against glutamate induced nerve injury in vivo and in vitro, suggesting potential therapeutic benefits for neurological disorders involving glutamate excitotoxicity.
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Affiliation(s)
- Nan Hu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China; College of Pharmacy, Shenzhen Technology University, Shenzhen, Guangdong, China
| | - Cheng Zeng
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Yi Cao
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Xuehao Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Fei Bai
- College of Pharmacy, Shenzhen Technology University, Shenzhen, Guangdong, China; Department of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Jinhui Wang
- Department of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Baofeng Yang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China; Department of Pharmacy, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Chunli Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China; College of Pharmacy, Shenzhen Technology University, Shenzhen, Guangdong, China.
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Luo Y, Jiang N, Zhang Y, Zhao Y, Chen F, Li X, Qiang M, Zeng G, He Q, Liu X, Shan C. Chronic unpredictable mild stress induces anxiety-like behavior in female C57BL/6N mice, accompanied by alterations in inflammation and the kynurenine pathway of tryptophan metabolism. Front Neurosci 2025; 19:1556744. [PMID: 40078708 PMCID: PMC11897007 DOI: 10.3389/fnins.2025.1556744] [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: 01/07/2025] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Chronic stress can impact brain function through various mechanisms, contributing to the development of anxiety disorders. Chronic unpredictable mild stress (CUMS) is a well-established model for studying the effects of chronic stress. This study assessed the impacts of different durations of CUMS on anxiety-like behavior, inflammation, and tryptophan metabolism in female C57BL/6N mice. The results revealed significant behavioral changes after 2-4 weeks of CUMS. Specifically, the open arms ratio and open arms time ratio in the elevated plus maze (EPM) decreased, the latency to feed in the novelty-suppressed feeding test (NSFT) was prolonged, and the number of transitions in the light/dark box (LDB) was decreased. After 1 week of CUMS, the levels of some pro-inflammatory cytokines (such as IL-1β and iNOS) and anti-inflammatory cytokines (including IL-10) began to rise. After 2 weeks of CUMS, most pro-inflammatory cytokines (IL-1β, IL-6, CD86, iNOS) and the anti-inflammatory cytokines TGF-β and CD11b showed an increase, while some anti-inflammatory cytokines (Arg-1, IL-10) began to decrease. After 3 weeks of stress, the pro-inflammatory cytokine TNF-α also significantly increased, while the anti-inflammatory cytokine TGF-β began to decline. By 4 weeks of CUMS, the anti-inflammatory cytokine CD11b also started to decrease. Regarding tryptophan metabolism, after 3-4 weeks of CUMS, serotonin (5-HT) levels in the hippocampus of the mice began to decrease. Additionally, the kynurenine pathway in tryptophan metabolism shifted more towards the KYN-QA branch, resulting in the reduction in the neuroprotective substance kynurenic acid (KYNA), while neurotoxic substances such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QA) accumulated. In summary, female C57BL/6N mice exhibit anxiety-like behavior after 2 weeks of CUMS, accompanied by inflammatory responses. After 3-4 weeks of CUMS, anxiety-like behavior persists, with exacerbated inflammatory responses and disturbances in tryptophan metabolism.
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Affiliation(s)
- Yanqin Luo
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang, China
- Sino-Pakistan Center on Traditional Chinese Medicine, Hunan University of Medicine, Huaihua, China
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Jiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiwen Zhang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongzhi Zhao
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang, China
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Chen
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xueyan Li
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang, China
| | - Meng Qiang
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guirong Zeng
- Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qinghu He
- Sino-Pakistan Center on Traditional Chinese Medicine, Hunan University of Medicine, Huaihua, China
| | - Xinmin Liu
- Sino-Pakistan Center on Traditional Chinese Medicine, Hunan University of Medicine, Huaihua, China
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Chunhui Shan
- Engineering Research Center of Storage and Processing of Xinjiang Characteristic Fruits and Vegetables, Ministry of Education, School of Food Science, Shihezi University, Shihezi, Xinjiang, China
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Kuznetsov NV, Statsenko Y, Ljubisavljevic M. An Update on Neuroaging on Earth and in Spaceflight. Int J Mol Sci 2025; 26:1738. [PMID: 40004201 PMCID: PMC11855577 DOI: 10.3390/ijms26041738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was recognized by the 2024 Nobel Prize in Physiology or Medicine. Aging is not a gradual process that can be easily modeled and described. Instead, multiple temporal processes occur during aging, and they can lead to mosaic changes that are not uniform in pace. The rate of change depends on a combination of external and internal factors and can be boosted in accelerated aging. The rate can decrease in decelerated aging due to individual structural and functional reserves created by cognitive, physical training, or pharmacological interventions. Neuroaging can be caused by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle, and environmental factors, which are especially noticeable in space environments where adaptive changes can trigger aging-like processes. Numerous candidate molecular biomarkers specific to neuroaging need to be validated to develop diagnostics and countermeasures.
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Affiliation(s)
- Nik V. Kuznetsov
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
| | - Yauhen Statsenko
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Milos Ljubisavljevic
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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Yan HX, Zhang YZ, Niu YQ, Wang YW, Liu LH, Tang YP, Huang JM, Leung ELH. Investigating the interaction between calcium signaling and ferroptosis for novel cancer treatment. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 137:156377. [PMID: 39798340 DOI: 10.1016/j.phymed.2025.156377] [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: 08/22/2024] [Revised: 12/02/2024] [Accepted: 01/05/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Drug resistance in cancer is steadily rising, making the development of new therapeutic targets increasingly critical for improving treatment outcomes. PURPOSE The mutual regulation of ions is essential for cell growth. Based on this concept, ion interference strategies offer a highly effective approach for cancer treatment. Calcium ions (Ca2+), as major second messengers, are closely associated with ion exchange and homeostasis. Disruptions in this balance can lead to cell death. However, while iron ions are also crucial, the connection between Ca2+and iron-induced cell death (ferroptosis) has not been well established. Therefore, this study suggests that Ca2+ may play a role in the induction of ferroptosis, presenting a novel and efficient target for cancer therapy. STUDY DESIGN PubMed, Google Scholar, and Web of Science databases were systematically searched for articles published in the past 15 years on the mechanisms of calcium ion-induced ferroptosis in cancer and related drugs. RESULTS The analysis highlights how Ca2+regulate ferroptosis. The mechanisms by which Ca2+influence ferroptosis are summarized based on existing literature, and relevant drugs that act on Ca2+/ferroptosis axis are outlined. CONCLUSION Ca2+ regulate ferroptosis primarily through the modulation of reactive oxygen species (ROS) and glutathione (GSH) levels, a mechanism that applies to a wide range of cancer cells as well as paracancerous and normal cells in cancer treatment. Furthermore, plant-derived active compounds exhibit potent anticancer properties and often act on the Ca2+/ferroptosis axis. These natural compounds could play a significant role in the development of new cancer treatment strategies.
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Affiliation(s)
- Hao-Xin Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics of Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), PR China
| | - Yi-Zhong Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Dr. Neher's Biophysics of Innovative Drug Discovery, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), PR China
| | - Yu-Qing Niu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China. MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), PR China
| | - Yu-Wei Wang
- Key Laboratory of Shanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shanxi University of Chinese Medicine, Xianyang 712046, Shanxi Province, PR China
| | - Li-Hua Liu
- Economics and Management Yanbian University, Yanji, PR China
| | - Yu-Ping Tang
- Key Laboratory of Shanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shanxi University of Chinese Medicine, Xianyang 712046, Shanxi Province, PR China.
| | - Ju-Min Huang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China. MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), PR China.
| | - Elaine Lai-Han Leung
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau (SAR), China. MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau (SAR), PR China.
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Krasner AE, Martinez ME, Field CL, Fire SE. The Toxic Effects of Environmental Domoic Acid Exposure on Humans and Marine Wildlife. Mar Drugs 2025; 23:61. [PMID: 39997185 PMCID: PMC11857359 DOI: 10.3390/md23020061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/17/2025] [Accepted: 01/25/2025] [Indexed: 02/26/2025] Open
Abstract
Biotoxins produced by harmful algal blooms (HABs) are a substantial global threat to ocean and human health. Domoic acid (DA) is one such biotoxin whose negative impacts are forecasted to increase with climate change and coastal development. This manuscript serves as a review of DA toxicosis after environmental exposure in humans and wildlife, including an introduction to HAB toxins, the history of DA toxicosis, DA production, toxicokinetic properties of DA, susceptibility, clinical signs, DA detection methods and other diagnostic tests, time course of toxicosis, treatment, prognostics, and recommendations for future research. Additionally, we highlight the utility of California sea lions (CSLs; Zalophus californianus) as a model and sentinel of environmental DA exposure.
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Affiliation(s)
- Ami E. Krasner
- Florida Institute of Technology, Department of Ocean Engineering and Marine Sciences, Melbourne, FL 32901, USA;
| | | | | | - Spencer E. Fire
- Florida Institute of Technology, Department of Ocean Engineering and Marine Sciences, Melbourne, FL 32901, USA;
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9
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Li MR, Zhou GR, Wang ZY, Li BY, Men SH, Yan ZG. TDCPP promotes apoptosis and inhibits the calcium signaling pathway in human neural stem cells. THE SCIENCE OF THE TOTAL ENVIRONMENT 2025; 961:178429. [PMID: 39798459 DOI: 10.1016/j.scitotenv.2025.178429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 01/06/2025] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
Tris (1, 3-dichloro-2-propyl) phosphate (TDCPP) is an extensively used organophosphorus flame retardant (OFR). Previous studies have suggested that it has neurotoxic effects, but the neurotoxicity mechanism is still unclear. Neural stem cells are an important in vitro model for studying the neurotoxicity mechanism of pollutants. In this study, we investigated the neurotoxic effects and molecular mechanisms of TDCPP by using human induced pluripotent stem cells (hiPSCs)-derived neural stem cells. We found that TDCPP inhibited the viability of human neural stem cells (hNSCs), stimulated the generation of ROS, arrested the cell cycle in the S phase, and promoted apoptosis. A total of 387 differentially expressed genes were screened out by transcriptome sequencing analysis, and KEGG enrichment analysis showed that the "calcium signaling pathway" was the most significantly enriched. Further studies on the calcium signaling pathway showed that TDCPP disrupted intracellular calcium homeostasis and inhibited the activation of the Ca2+/CALM/CaN/CAMK signaling pathway and the expression levels of NFATC2 and GSK3β. In conclusion, TDCPP has significant toxicity on the calcium signaling pathway of human neural stem cells, which may affect the development process of the human nervous system.
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Affiliation(s)
- Ming-Rui Li
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Guo-Rui Zhou
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Zi-Ye Wang
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Bo-Yang Li
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Shu-Hui Men
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Zhen-Guang Yan
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China.
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10
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Zhang C, Deng D, Wu Y, Song L, Geng J, Feng H, Jiang S, Zhang K, Cheng Y, Yin S. New insights into the neurophysiological effects of heat stress on the Chinese mitten crab (Eriocheir sinensis). J Therm Biol 2025; 127:104055. [PMID: 39818005 DOI: 10.1016/j.jtherbio.2025.104055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/18/2025]
Abstract
Climate warming and frequent incidents of extreme high temperatures are serious global concerns. Heat stress induced by high temperature has many adverse effects on animal physiology, especially in aquatic poikilotherms. Chinese mitten crab (Eriocheir sinensis) is sensitive to high temperatures, this study evaluated the harmful effects of heat stress on the neurotoxicity, intestinal health, microbial diversity, and metabolite profiles. The results showed that heat stress caused histopathological damages and altered the ultrastructure of lesions in the cranial ganglia. Heat stress significantly upregulated the mRNA expression of apoptosis-related genes, and significantly altered the expression of neurotransmitter receptors. In addition, heat stress induced significant intestinal damages that mainly manifested as a significant increase in the activity of diamine oxidase in the serum and contents of histamine in the intestine. The diversity and abundance of intestinal microbiota altered abnormally in E. sinensis exposed to heat stress, and the bacteria that exhibited significant variations in abundance were closely related to the production of neurotransmitters and neuromodulators. Heat stress caused significant changes in the intestinal metabolite profiles, which mainly involved the amino acid and lipid metabolism pathways. Analysis of the correlation showed that the abnormal changes in metabolites were closely related to differences in the abundance of intestinal microbiota. Therefore, this study showed that heat stress could cause neurophysiological toxic effects, which may be related to intestinal ecological imbalance.
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Affiliation(s)
- Cong Zhang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China.
| | - Dunqian Deng
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Yi Wu
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Lexue Song
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Jiayin Geng
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Huixia Feng
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Su Jiang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Kai Zhang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Yongxu Cheng
- Key Laboratory of Integrated Rice-Fish Farming Ecosystem, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, PR China
| | - Shaowu Yin
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China.
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11
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Hayden MR, Tyagi N. Sodium Thiosulfate: An Innovative Multi-Target Repurposed Treatment Strategy for Late-Onset Alzheimer's Disease. Pharmaceuticals (Basel) 2024; 17:1741. [PMID: 39770582 PMCID: PMC11676759 DOI: 10.3390/ph17121741] [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: 12/06/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Late-onset Alzheimer's disease (LOAD) is a chronic, multifactorial, and progressive neurodegenerative disease that associates with aging and is highly prevalent in our older population (≥65 years of age). This hypothesis generating this narrative review will examine the important role for the use of sodium thiosulfate (STS) as a possible multi-targeting treatment option for LOAD. Sulfur is widely available in our environment and is responsible for forming organosulfur compounds that are known to be associated with a wide range of biological activities in the brain. STS is known to have (i) antioxidant and (ii) anti-inflammatory properties; (iii) chelation properties for calcium and the pro-oxidative cation metals such as iron and copper; (iv) donor properties for hydrogen sulfide production; (v) possible restorative properties for brain endothelial-cell-derived bioavailable nitric oxide. Thus, it becomes apparent that STS has the potential for neuroprotection and neuromodulation and may allow for an attenuation of the progressive nature of neurodegeneration and impaired cognition in LOAD. STS has been successfully used to prevent cisplatin oxidative-stress-induced ototoxicity in the treatment of head and neck and solid cancers, cyanide and arsenic poisoning, and fungal skin diseases. Most recently, intravenous STS has become part of the treatment plan for calciphylaxis globally due to vascular calcification and ischemia-induced skin necrosis and ulceration. Side effects have been minimal with reports of metabolic acidosis and increased anion gap; as with any drug treatment, there is also the possibility of allergic reactions, possible long-term osteoporosis from animal studies to date, and minor side-effects of nausea, headache, and rhinorrhea if infused too rapidly. While STS poorly penetrates the intact blood-brain barrier(s) (BBBs), it could readily penetrate BBBs that are dysfunctional and disrupted to deliver its neuroprotective and neuromodulating effects in addition to its ability to penetrate the blood-cerebrospinal fluid barrier of the choroid plexus. Novel strategies such as the future use of nano-technology may be helpful in allowing an increased entry of STS into the brain.
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Affiliation(s)
- Melvin R. Hayden
- Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65211, USA
| | - Neetu Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
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12
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Oyovwi MO, Atere AD, Chimwuba P, Joseph UG. Implication of Pyrethroid Neurotoxicity for Human Health: A Lesson from Animal Models. Neurotox Res 2024; 43:1. [PMID: 39680194 DOI: 10.1007/s12640-024-00723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 11/19/2024] [Accepted: 12/01/2024] [Indexed: 12/17/2024]
Abstract
Pyrethroids, synthetic insecticides used in pest management, pose health risks, particularly neurotoxic effects, with studies linking exposure to a neurodegenerative disorder. This review examines the neurotoxic mechanisms of pyrethroids analyzing literature from animal model studies. It identifies critical targets for neurotoxicity, including ion channels, oxidative stress, inflammation, neuronal cell loss, and mitochondrial dysfunction. The review also discusses key therapeutic targets and signaling pathways relevant to Pyrethroids neurotoxicity management, including calcium, Wnt/β-catenin, mTOR, MAPK/Erk, PI3K/Akt, Nrf2, Nurr1, and PPARγ. Our findings demonstrate that pyrethroid exposure triggers multiple neurotoxic pathways that bear resemblance to the mechanisms underlying neurotoxicity. Oxidative stress and inflammation emerge as prominent factors that contribute to neuronal degeneration, alongside disrupted mitochondrial function. The investigation highlights the significance of ion channels as primary neurodegeneration targets while acknowledging the potential involvement of various other receptors and enzymes that may exacerbate neurological damage. Additionally, we elucidate how pyrethroids may interfere with therapeutic targets associated with neuronal dysfunction, potentially impairing treatment efficacy.Also, exposure to these chemicals can alter DNA methylation patterns and histone modifications, ultimately leading to changes in gene expression that may enhance susceptibility to neurological disorders. Pyrethroid neurotoxicity poses a significant public health risk, necessitating future research for protective strategies against pesticide-induced neurological disorders and understanding the interplay between neurodegenerative diseases, potentially leading to innovative therapeutic interventions.
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Affiliation(s)
- Mega Obukohwo Oyovwi
- Department of Physiology, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria.
| | - Adedeji David Atere
- Department of Medical Laboratory Science, College of Health Sciences, Osun State University, Osogbo, Nigeria
- Neurotoxicology Laboratory, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa
| | - Paul Chimwuba
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - Uchechukwu Gregory Joseph
- Department of Medical Laboratory Science, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria
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13
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Moreira ET, Lourenço MP, Cunha-Fernandes T, Silva TI, Siqueira LD, Castro-Faria-Neto HC, Reis PA. Minocycline inhibits microglial activation in the CA1 hippocampal region and prevents long-term cognitive sequel after experimental cerebral malaria. J Neuroimmunol 2024; 397:578480. [PMID: 39504755 DOI: 10.1016/j.jneuroim.2024.578480] [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: 06/24/2024] [Revised: 10/24/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024]
Abstract
Cerebral malaria is the worst complication of malaria infection, has a high mortality rate, and may cause different neurodysfunctions, including cognitive decline. Neuroinflammation is an important cause of cognitive damage in neurodegenerative diseases, and microglial cells can be activated in a disease-associated profile leading to tissue damage and neuronal death. Here, we demonstrated that treatment with minocycline reduced blood-brain barrier breakdown and modulated ICAM1 mRNA expression; reduced proinflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, and IL-6; and prevented long-term cognitive decline in contextual and aversive memory tasks. Taken together, our data suggest that microglial cells are activated during experimental cerebral malaria, leading to neuroinflammatory events that end up in cognitive damage. In addition, pharmacological modulation of microglial activation, by drugs such as minocycline may be an important therapeutic strategy in the prevention of long-term memory impairment.
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Affiliation(s)
- E T Moreira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Universidade Cruzeiro do Sul, Brazil; Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - M P Lourenço
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - T Cunha-Fernandes
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - T I Silva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - L D Siqueira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - H C Castro-Faria-Neto
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - P A Reis
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil
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14
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Anyachor CP, Orish CN, Ezejiofor AN, Cirovic A, Cirovic A, Dooka BD, Ezealisiji KM, Noundou XS, Orisakwe OE. Silica Nanoparticles from Melon Seed Husk Abrogated Binary Metal(loid) Mediated Cerebellar Dysfunction by Attenuation of Oxido-inflammatory Response and Upregulation of Neurotrophic Factors in Male Albino Rats. CEREBELLUM (LONDON, ENGLAND) 2024; 23:2426-2445. [PMID: 39331240 DOI: 10.1007/s12311-024-01747-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/22/2024] [Indexed: 09/28/2024]
Abstract
Silica nanoparticles (SiNPs) have been touted for their role in the management of non-communicable diseases. Their neuroprotective benefits against heavy metal-induced neurotoxicity remain largely unexplored. This is a comparative evaluation of the oxido-inflammatory and neurotrophic effects of Ni, Al, and Ni/Al mixture on the cerebellum of male albino rats with or without treatment with SiNPs generated from melon seed husk. The study complied with the ARRIVE guidelines for reporting in vivo experiments. A total of 91, 7-9 week-old weight-matched male Sprague rats (to avoid sex bias) were randomly divided into 13 different dosing groups where Group 1 served as the control. Other groups received 0.2 mg/kg Ni, 1 mg/kg Al, and 0.2 mg/kg Ni + 1 mg/kg Al mixture with or without different doses of SiNP for 90 days. Rotarod performance was carried out. Oxidative stress markers, Ni, Al, Ca, Fe, Mg, neurotrophic factors, amyloid beta (Aβ-42), cyclooxygenase-2 (COX-2), and acetylcholinesterase (AChE) were determined in the cerebellum. SiNPs from melon seed husk caused a significant decrease in Aβ-42 level and activities of AChE and COX-2 and a significant increase in brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mediated by Ni, Al, and Ni/Al mixture exposure in rats. Neurotoxicity of the Ni/Al mixture is via heightened neuronal lipoperoxidative damage, decreased Mg, and increased Fe, and co-administration of SiNPs from melon seed husk with the Ni/Al mixture attenuated some of these biochemical changes in the cerebellum.
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Affiliation(s)
- Chidinma P Anyachor
- African Centre of Excellence for Public Health and Toxicological Research (ACE‑PUTOR), University of Port Harcourt, PMB, Port Harcourt, Choba, 5323, Nigeria
| | - Chinna N Orish
- Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, PMB, Choba, Port Harcourt, 5323, Nigeria.
| | - Anthonet N Ezejiofor
- African Centre of Excellence for Public Health and Toxicological Research (ACE‑PUTOR), University of Port Harcourt, PMB, Port Harcourt, Choba, 5323, Nigeria
| | - Ana Cirovic
- Faculty of Medicine, Institute of Anatomy, University of Belgrade, Belgrade, Serbia
| | - Aleksandar Cirovic
- Faculty of Medicine, Institute of Anatomy, University of Belgrade, Belgrade, Serbia
| | - Baridoo Donatus Dooka
- African Centre of Excellence for Public Health and Toxicological Research (ACE‑PUTOR), University of Port Harcourt, PMB, Port Harcourt, Choba, 5323, Nigeria
| | - Kenneth M Ezealisiji
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Port Harcourt, PMB, Choba, Port Harcourt, 5323, Nigeria
| | - Xavier Siwe Noundou
- Department of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Sciences University, MEDUNSA, Box 218, 0204, Pretoria, South Africa
| | - Orish E Orisakwe
- African Centre of Excellence for Public Health and Toxicological Research (ACE‑PUTOR), University of Port Harcourt, PMB, Port Harcourt, Choba, 5323, Nigeria.
- Advanced Research Centre, European University of Lefke, Lefke, Mersin, TR-10, Northern Cyprus, Turkey.
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15
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Sharma V, Sharma P, Singh TG. Leukotriene signaling in neurodegeneration: implications for treatment strategies. Inflammopharmacology 2024; 32:3571-3584. [PMID: 39167313 DOI: 10.1007/s10787-024-01557-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 08/11/2024] [Indexed: 08/23/2024]
Abstract
Leukotrienes (LTs) are a group of substances that cause inflammation. They are produced by the enzyme 5-lipoxygenase (5-LOX) from arachidonic acid. Cysteinyl LTs are a group of lipid molecules that have a prominent role in inflammatory signaling in the allergic diseases. Although they are traditionally known for their role in allergic disease, current advancements in bio-medical research have shed light on the involvement of these inflammatory mediators in diseases such as in the inflammation related to central nervous system (CNS) disorders. Among the CNS diseases, LTs, along with 5-LOX and their receptors, have been shown to be associated with multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD). Through a comprehensive review of current research and experimentation, this investigation provides an insight on the biosynthesis, receptors, and biological effects of LTs in the body. Furthermore, implications of leukotriene signaling in CNS and its intricate role in neurodegeneration are also studied. Through the revelation of these insights, our aim is to establish a foundation for the development of enhanced and focused therapeutic approaches in the continuous endeavor to combat neurodegeneration. Furthermore, the pharmacological inhibition of leukotriene signaling with selective inhibitors offers promising prospects for future interventions and treatments for neurodegenerative diseases.
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Affiliation(s)
- Veerta Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Prateek Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India.
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16
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Gupta V, Singh S, Singh TG. Pervasive expostulation of p53 gene promoting the precipitation of neurogenic convulsions: A journey in therapeutic advancements. Eur J Pharmacol 2024; 983:176990. [PMID: 39251181 DOI: 10.1016/j.ejphar.2024.176990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/17/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024]
Abstract
Epilepsy, a neurological disorder characterized by prolonged and excessive seizures, has been linked to elevated levels of the tumor suppressor gene p53, which contributes to neuronal dysfunction. This review explores the molecular mechanisms of p53 in epilepsy and discusses potential future therapeutic strategies. Research indicates that changes in p53 expression during neuronal apoptosis, neuroinflammation, and oxidative stress play a significant role in the pathogenesis of epilepsy. Elevated p53 disrupts glutamatergic neurotransmission and hyperactivates NMDA and AMPA receptors, leading to increased neuronal calcium influx, mitochondrial oxidative stress, and activation of apoptotic pathways mediated neuronal dysfunction, exacerbating epileptogenesis. The involvement of p53 in epilepsy suggests that targeting this protein could be beneficial in mitigating neuronal damage and preventing seizure recurrence. Pharmacological agents like pifithrin-α have shown promise in reducing p53-mediated apoptosis and seizure severity. Gene therapy approaches, such as viral vector-mediated delivery of wild-type p53 or RNA interference targeting mutant p53, have also been effective in restoring normal p53 function and reducing seizure susceptibility. Despite these advances, the heterogeneous nature of epilepsy and potential long-term side effects of p53 modulation present challenges. Future research should focus on elucidating the precise molecular mechanisms of p53 and developing personalized therapeutic strategies. Modulating p53 activity holds promise for reducing seizure susceptibility and improving the quality of life for individuals with epilepsy. The current review provides the understanding the intricate role of p53 in neuroinflammatory pathways, including JAK-STAT, JNK, NF-κB, Sonic Hedgehog, and Wnt, is crucial for developing targeted therapies.
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Affiliation(s)
- Vrinda Gupta
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Shareen Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India; School of Public Health, Faculty of Health, University of Technology Sydney, PO Box 123, Broadway, NSW, 2007, Australia.
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17
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Jiang H, Zhang C, Lin M, Yin Y, Deng S, Liu W, Zhuo B, Tian G, Du Y, Meng Z. Deciphering the mechanistic impact of acupuncture on the neurovascular unit in acute ischemic stroke: Insights from basic research in a narrative review. Ageing Res Rev 2024; 101:102536. [PMID: 39384155 DOI: 10.1016/j.arr.2024.102536] [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: 08/18/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024]
Abstract
Ischemic stroke(IS), a severe acute cerebrovascular disease, not only imposes a heavy economic burden on society but also presents numerous challenges in treatment. During the acute phase, while thrombolysis and thrombectomy serve as primary treatments, these approaches are restricted by a narrow therapeutic window. During rehabilitation, commonly used neuroprotective agents struggle with their low drug delivery efficiency and inadequate preclinical testing, and the long-term pharmacological and toxicity effects of nanomedicines remain undefined. Meanwhile, acupuncture as a therapeutic approach is widely acknowledged for its effectiveness in treating IS and has been recommended by the World Health Organization (WHO) as an alternative and complementary therapy, even though its exact mechanisms remain unclear. This review aims to summarize the known mechanisms of acupuncture and electroacupuncture (EA) in the treatment of IS. Research shows that acupuncture treatment mainly protects the neurovascular unit through five mechanisms: 1) reducing neuronal apoptosis and promoting neuronal repair and proliferation; 2) maintaining the integrity of the blood-brain barrier (BBB); 3) inhibiting the overactivation and polarization imbalance of microglia; 4) regulating the movement of vascular smooth muscle (VSM) cells; 5) promoting the proliferation of oligodendrocyte precursors. Through an in-depth analysis, this review reveals the multi-level, multi-dimensional impact of acupuncture treatment on the neurovascular unit (NVU) following IS, providing stronger evidence and a theoretical basis for its clinical application.
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Affiliation(s)
- Hailun Jiang
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Chao Zhang
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Mengxuan Lin
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Yu Yin
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shizhe Deng
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Wei Liu
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Bifang Zhuo
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Guang Tian
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Yuzheng Du
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| | - Zhihong Meng
- Department of Acupuncture, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Acupuncture, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
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18
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Zhang G, Liang Z, Wang Y, Zhang Z, Hoi PM. Tetramethylpyrazine Analogue T-006 Protects Neuronal and Endothelial Cells Against Oxidative Stress via PI3K/AKT/mTOR and Nrf2 Signaling. Antioxidants (Basel) 2024; 13:1272. [PMID: 39456524 PMCID: PMC11505549 DOI: 10.3390/antiox13101272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/13/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND T-006, a novel neuroprotective derivative of tetramethylpyrazine (TMP), exhibits multifunctional neuroprotective properties. T-006 has been shown to improve neurological and behavioral functions in animal models of ischemic stroke and neurodegenerative diseases. The present study aims to further elucidate the mechanisms underlying the protective effects of T-006 against oxidative injuries induced by glutamate or hypoxia. METHODS Mouse hippocampal HT22 cells were used to evaluate the neuroprotective effects of T-006 against glutamate-induced injuries, while mouse brain endothelial bEnd.3 cells were used to evaluate the cerebrovascular protective effects of T-006 against oxygen-glucose deprivation followed by reperfusion (OGD/R)-induced injuries. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to measure cell viability and oxidative stress. Western blot and immunofluorescence analyses of protein expression were used to study cell signaling pathways. RESULTS T-006 exhibited significant protective effects in both oxidative injury models. In HT22 cells, T-006 reduced cell death and enhanced antioxidant capacity by upregulating mTOR and nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling. Similarly, in bEnd.3 cells, T-006 reduced oxidative injuries and preserved tight junction integrity through Nrf2/HO-1 upregulation. These effects were inhibited by LY294002, a Phosphoinositide 3-kinase (PI3K) inhibitor. CONCLUSIONS T-006 may exert its neuroprotective and cerebrovascular protective effects via the regulation of PI3K/AKT-mediated pathways, which facilitate downstream mTOR and Nrf2 signaling, leading to improved cell survival and antioxidant defenses.
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Affiliation(s)
- Guiliang Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China; (G.Z.); (Z.L.)
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Zirong Liang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China; (G.Z.); (Z.L.)
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Yuqiang Wang
- Institute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Guangzhou 510632, China; (Y.W.); (Z.Z.)
- Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University College of Pharmacy, Guangzhou 510632, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University College of Pharmacy, Guangzhou 510632, China
| | - Zaijun Zhang
- Institute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Guangzhou 510632, China; (Y.W.); (Z.Z.)
- Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University College of Pharmacy, Guangzhou 510632, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University College of Pharmacy, Guangzhou 510632, China
| | - Pui-Man Hoi
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China; (G.Z.); (Z.L.)
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, China
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19
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Coluk Y, Peker EGG, Yildirmak S, Keskin A, Yildirim G. Exploring the protective role of green tea extract against cardiovascular alterations induced by chronic REM sleep deprivation via modulation of inflammation and oxidative stress. BMC Complement Med Ther 2024; 24:351. [PMID: 39363261 PMCID: PMC11448275 DOI: 10.1186/s12906-024-04643-7] [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: 09/12/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND Chronic Rapid eye movement (REM) sleep deprivation has been associated with various cardiovascular alterations, including disruptions in antioxidant defense mechanisms, lipid metabolism, and inflammatory responses. This study investigates the therapeutic potential of green tea extract (GTE) in mitigating these adverse effects. METHODS A total of 24 male Wistar albino rats were used in this study and divided into the control group (n = 8), Chronic-REM Sleep Deprivation (CRSD) Group (n = 8) and Chronic-REM SD + Green Tea 200 (CRSD + GTE200) Group (n = 8). After 21 days, a comprehensive analysis of paraoxonase (PON1), arylesterase (ARE), malondialdehyde (MDA), glutathione (GSH), nitric oxide (NOx), proinflammatory cytokines, and lipid profiles in aortic tissue, heart tissue, and serum was conducted in a sleep-deprived rat model. RESULTS Chronic REM sleep deprivation led to a significant reduction in PON1 and ARE levels in aortic (p = 0.046, p = 0.035 respectively) and heart tissues (p = 0.020, p = 0.019 respectively), indicative of compromised antioxidant defenses. MDA levels increased, and NOx levels decreased, suggesting oxidative stress and impaired vascular function. Lipid profile alterations, including increased triglycerides and total cholesterol, were observed in serum. Elevated levels of inflammatory cytokines (IL-6 and TNF-alpha) further indicated an inflammatory response (p = 0.007, p = 0.018 respectively). GTE administration demonstrated a protective role, restoring antioxidant enzyme levels, suppressing lipid peroxidation, and improving NOx levels. CONCLUSION These findings suggest the therapeutic potential of GTE in alleviating the cardiovascular impairments of chronic REM sleep deprivation, emphasizing its candidacy for further clinical exploration as a natural intervention in sleep-related disorders and associated cardiovascular risks.
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Affiliation(s)
- Yonca Coluk
- Department of Otorhinolaryngology, Faculty of Medicine, Giresun University, Giresun, 28200, Turkey.
| | - Emine Gulceri Gulec Peker
- Department of Natural and Mathematical Sciences, Faculty of Engineering, Giresun University, Giresun, 28200, Turkey
| | - Sembol Yildirmak
- Department of Biochemistry, Faculty of Medicine, Mersin University, Mersin, 33010, Turkey
| | - Arif Keskin
- Department of Anatomy, Faculty of Medicine, Giresun University, Giresun, 28200, Turkey
| | - Guven Yildirim
- Private Practice, Otorhinolaryngology, İstanbul, 34360, Turkey
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20
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Yang L, Guttman L, Dawson VL, Dawson TM. Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke. Biochem Pharmacol 2024; 228:116174. [PMID: 38552851 PMCID: PMC11410548 DOI: 10.1016/j.bcp.2024.116174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/16/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024]
Abstract
Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition.
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Affiliation(s)
- Liu Yang
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lauren Guttman
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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21
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Sanaeifar F, Pourranjbar S, Pourranjbar M, Ramezani S, Mehr SR, Wadan AHS, Khazeifard F. Beneficial effects of physical exercise on cognitive-behavioral impairments and brain-derived neurotrophic factor alteration in the limbic system induced by neurodegeneration. Exp Gerontol 2024; 195:112539. [PMID: 39116955 DOI: 10.1016/j.exger.2024.112539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Neurodegenerative diseases (NDDs) are a class of neurological disorders marked by the progressive loss of neurons that afflict millions of people worldwide. These illnesses affect brain connection, impairing memory, cognition, behavior, sensory perception, and motor function. Alzheimer's, Parkinson's, and Huntington's diseases are examples of common NDDs, which frequently include the buildup of misfolded proteins. Cognitive-behavioral impairments are early markers of neurodevelopmental disorders, emphasizing the importance of early detection and intervention. Neurotrophins such as brain-derived neurotrophic factor (BDNF) are critical for neuron survival and synaptic plasticity, which is required for learning and memory. NDDs have been associated with decreased BDNF levels. Physical exercise, a non-pharmacological intervention, benefits brain health by increasing BDNF levels, lowering cognitive deficits, and slowing brain degradation. Exercise advantages include increased well-being, reduced depression, improved cognitive skills, and neuroprotection by lowering amyloid accumulation, oxidative stress, and neuroinflammation. This study examines the effects of physical exercise on cognitive-behavioral deficits and BDNF levels in the limbic system impacted by neurodegeneration. The findings highlight the necessity of including exercise into NDD treatment to improve brain structure, function, and total BDNF levels. As research advances, exercise is becoming increasingly acknowledged as an important technique for treating cognitive decline and neurodegenerative disorders.
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Affiliation(s)
- Farhad Sanaeifar
- Department of Behavioral and Cognitive Sciences in Sport, Faculty of Sport Sciences andHealth, University of Tehran, Tehran, Iran
| | - Sina Pourranjbar
- Doctor of Medicine, Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Pourranjbar
- Department of Physical Education, Faculty of Medicine and Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Sana Ramezani
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Samira Rostami Mehr
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Farnaz Khazeifard
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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22
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Unno K, Taguchi K, Matsuda T, Nakamura Y. Stress-Relieving Effects of Green Tea Depend on the Ratio of Its Special Ingredients and the Infusion Conditions. Molecules 2024; 29:4553. [PMID: 39407485 PMCID: PMC11477503 DOI: 10.3390/molecules29194553] [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: 08/07/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Theanine, an amino acid unique to tea leaves, has been reported to exhibit stress-relieving effects. However, the stress-relieving effects of theanine (T) are greatly inhibited by caffeine (C) and epigallocatechin gallate (E), the main components of green tea, while being enhanced by arginine (A). Animal and clinical studies using matcha tea have shown that it can alleviate stress if the molar ratio of C and E against T and A (CE/TA) is less than 2. In general, the CE/TA ratio in tea leaves is reflected by the CE/TA ratio in the infused solution; however, it is not clear what infusion conditions would be expected to ensure a stress-relieving effect. In this study, to examine the stress-relieving effect of green-tea-infused solutions, the CE/TA ratio was measured under different infusion conditions. Furthermore, a study using a model solution consisting of C, E, T, and A revealed that a CE/TA ratio of at least less than 2 and a T content greater than 0.23 mM were required for stress reduction. Based on these results, we identified tea leaves and their infusion conditions that can be expected to reduce stress.
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Affiliation(s)
- Keiko Unno
- Tea Science Center, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan; (K.T.); (Y.N.)
| | - Kyoko Taguchi
- Tea Science Center, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan; (K.T.); (Y.N.)
| | - Tomoko Matsuda
- Mie Prefecture Agricultural Research Institute Green Tea Industry Flower and Planting Laboratory, 992-2 Tsubakise-cho, Kameyama City 519-0104, Japan;
| | - Yoriyuki Nakamura
- Tea Science Center, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan; (K.T.); (Y.N.)
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23
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Sood R, Anoopkumar-Dukie S, Rudrawar S, Hall S. Neuromodulatory effects of leukotriene receptor antagonists: A comprehensive review. Eur J Pharmacol 2024; 978:176755. [PMID: 38909933 DOI: 10.1016/j.ejphar.2024.176755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/09/2024] [Accepted: 06/16/2024] [Indexed: 06/25/2024]
Abstract
Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT1 and CysLT2 subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
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Affiliation(s)
- Radhika Sood
- School of Pharmacy and Medical Sciences, Griffith University, Queensland, 4222, Australia
| | | | - Santosh Rudrawar
- School of Pharmacy and Medical Sciences, Griffith University, Queensland, 4222, Australia; Institute for Glycomics, Griffith University, Queensland, 4222, Australia
| | - Susan Hall
- School of Pharmacy and Medical Sciences, Griffith University, Queensland, 4222, Australia.
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24
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Jiang A, You L, Handley RR, Hawkins V, Reid SJ, Jacobsen JC, Patassini S, Rudiger SR, Mclaughlan CJ, Kelly JM, Verma PJ, Bawden CS, Gusella JF, MacDonald ME, Waldvogel HJ, Faull RLM, Lehnert K, Snell RG. Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model. Hum Mol Genet 2024; 33:1524-1539. [PMID: 38776957 PMCID: PMC11336116 DOI: 10.1093/hmg/ddae087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/11/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.
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Affiliation(s)
- Andrew Jiang
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Linya You
- Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, 131 Dong'an Road, Shanghai 200032, China
- Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, 130 Dong'an Road, Shanghai 200032, China
| | - Renee R Handley
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Victoria Hawkins
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Suzanne J Reid
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Jessie C Jacobsen
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Stefano Patassini
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Skye R Rudiger
- Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia
| | - Clive J Mclaughlan
- Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia
| | - Jennifer M Kelly
- Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia
| | - Paul J Verma
- Aquatic and Livestock Sciences, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia
| | - C Simon Bawden
- Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia
| | - James F Gusella
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States
- Department of Genetics, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, United States
| | - Marcy E MacDonald
- Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States
- Department of Neurology, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, United States
| | - Henry J Waldvogel
- Department of Anatomy and Medical Imaging, Centre for Brain Research, Faculty of Medical and Health Science, The University of Auckland, 85 Park Road, Auckland 1023, New Zealand
| | - Richard L M Faull
- Department of Anatomy and Medical Imaging, Centre for Brain Research, Faculty of Medical and Health Science, The University of Auckland, 85 Park Road, Auckland 1023, New Zealand
| | - Klaus Lehnert
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
| | - Russell G Snell
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand
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25
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Khan S, Bano N, Ahamad S, John U, Dar NJ, Bhat SA. Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms. Aging Dis 2024:AD.2024.0125-1. [PMID: 39122453 DOI: 10.14336/ad.2024.0125-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.
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Affiliation(s)
- Sameera Khan
- Department of Zoology, Aligarh Muslim University, Aligarh-202002, India
| | - Nargis Bano
- Department of Zoology, Aligarh Muslim University, Aligarh-202002, India
| | - Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh-202002, India
| | - Urmilla John
- School of Studies in Neuroscience, Jiwaji University, Gwalior, India; School of Studies in Zoology, Jiwaji University, Gwalior, India
| | - Nawab John Dar
- CNB, SALK Institute of Biological Sciences, La Jolla, CA 92037, USA
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26
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Afridi R, Kim JH, Bhusal A, Lee WH, Suk K. Lipocalin-2 as a mediator of neuroimmune communication. J Leukoc Biol 2024; 116:357-368. [PMID: 38149462 DOI: 10.1093/jleuko/qiad157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 12/28/2023] Open
Abstract
Lipocalin-2, a neutrophil gelatinase-associated lipocalin, is a 25-kDa secreted protein implicated in a broad range of inflammatory diseases affecting the brain and periphery. It is a pleotropic protein expressed by various immune and nonimmune cells throughout the body. Importantly, the surge in lipocalin-2 levels in disease states has been associated with a myriad of undesirable effects, further exacerbating the ongoing pathological processes. In the brain, glial cells are the principal source of lipocalin-2, which plays a definitive role in determining their functional phenotypes. In different central nervous system pathologies, an increased expression of glial lipocalin-2 has been linked to neurotoxicity. Lipocalin-2 mediates a crosstalk between central and peripheral immune cells under neuroinflammatory conditions. One intriguing aspect is that elevated lipocalin-2 levels in peripheral disorders, such as cancer, metabolic conditions, and liver diseases, potentially incite an inflammatory activation of glial cells while disrupting neuronal functions. This review comprehensively summarizes the influence of lipocalin-2 on the exacerbation of neuroinflammation by regulating various cellular processes. Additionally, this review explores lipocalin-2 as a mediator of neuroimmune crosstalk in various central nervous system pathologies and highlights the role of lipocalin-2 in carrying inflammatory signals along the neuroimmune axis.
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Affiliation(s)
- Ruqayya Afridi
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
| | - Jae-Hong Kim
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
| | - Anup Bhusal
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
| | - Won-Ha Lee
- School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea
- Brain Science and Engineering Institute, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
| | - Kyoungho Suk
- Department of Pharmacology, School of Medicine, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
- Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41940, Republic of Korea
- Brain Science and Engineering Institute, Kyungpook National University, 680 Gukchaebosang Street, Joong-gu, Daegu 41944, Republic of Korea
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27
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Xi Y, Bai S, Tian Y, Lv Y, Ji L, Li W, He G, Yang L. Golgi-targeted NIR fluorescent probe with large stokes shift for real-time monitoring of nitric oxide in depression model. Bioorg Chem 2024; 148:107476. [PMID: 38788368 DOI: 10.1016/j.bioorg.2024.107476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/09/2024] [Accepted: 05/18/2024] [Indexed: 05/26/2024]
Abstract
Depression is a debilitating mental illness that poses a serious threat to human health. Nitric Oxide (NO), as an important gasotransmitter, is closely associated with the pathogenesis of depressive disorders. Effective monitoring of NO fluctuation is beneficial for the diagnosis of depression and therapy assessment of antidepressants. Currently, there is a lack of effective methods for rapidly and sensitively identifying NO and elucidating its relationship with depression diseases. Herein, we developed a NIR dye TJ730-based fluorescent probe TJ730-Golgi-NO incorporating benzenesulfonamide as a Golgi-targeted moiety and the thiosemicarbazide group for NO detection. The probe exhibited turn-on fluorescence ability and a large Stokes shift of 158 nm, which shows high sensitivity, selectivity, and rapid response (<1 min) for NO detection. TJ730-Golgi-NO could detect exogenous and endogenous NO in cells stimulated by Glu and LPS, and target Golgi apparatus. Moreover, we disclose a significant increase of NO in the depression model and a weak fluorescence evidenced in the fluoxetine-treated depression mice. This study provides a competent tool for studying the function of NO and helping improve the effective treatment of depression diseases.
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Affiliation(s)
- Yanbei Xi
- Henan Key Laboratory of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Xinxiang Key Laboratory of Forensic Science Evidence, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
| | - Shiqiong Bai
- Xinxiang Key Laboratory of Forensic Science Evidence, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
| | - Yuan Tian
- Henan Key Laboratory of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
| | - Yanan Lv
- Xinxiang Key Laboratory of Forensic Science Evidence, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
| | - Liguo Ji
- Xinxiang Key Laboratory of Forensic Science Evidence, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China
| | - Wenqiang Li
- Henan Key Laboratory of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China.
| | - Guangjie He
- Henan Key Laboratory of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Xinxiang Key Laboratory of Forensic Science Evidence, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China.
| | - Linlin Yang
- Xinxiang Key Laboratory of Forensic Science Evidence, School of Forensic Medicine, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China.
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28
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Golmohammadi M, Meibodi SAA, Al-Hawary SIS, Gupta J, Sapaev IB, Najm MAA, Alwave M, Nazifi M, Rahmani M, Zamanian MY, Moriasi G. Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review. Animal Model Exp Med 2024; 7:195-207. [PMID: 38808561 PMCID: PMC11228121 DOI: 10.1002/ame2.12438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/22/2024] [Indexed: 05/30/2024] Open
Abstract
Glaucoma, an irreversible optic neuropathy, primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness. The damage to RGCs in glaucoma occurs by various mechanisms, including elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, the loss of RGCs leads to vision loss. Therefore, protecting RGCs from damage and promoting their survival are important goals in managing glaucoma. In this regard, resveratrol (RES), a polyphenolic phytoalexin, exerts antioxidant effects and slows down the evolution and progression of glaucoma. The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina. Additionally, RES plays protective roles in RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H2O2-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways. RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway. Therefore, RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.
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Affiliation(s)
- Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Ibrohim B Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers, Tashkent, Uzbekistan
- New Uzbekistan University, Tashkent, Uzbekistan
| | - Mazin A A Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Marim Alwave
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Mozhgan Nazifi
- Department of Neurology, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammadreza Rahmani
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Gervason Moriasi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Mount Kenya University, Thika, Kenya
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29
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Blaylock RL. Additive aluminum as a cause of induced immunoexcitoxicity resulting in neurodevelopmental and neurodegenerative disorders: A biochemical, pathophysiological, and pharmacological analysis. Surg Neurol Int 2024; 15:171. [PMID: 38840623 PMCID: PMC11152537 DOI: 10.25259/sni_296_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 06/07/2024] Open
Abstract
Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain's innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal's toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum's neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.
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Affiliation(s)
- Russell L. Blaylock
- Theoretical Neuroscience Research, LLC, Ridgeland, Mississippi, United States
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30
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Xiong W, Liu Y, Zhou H, Li J, Jing S, Jiang C, Li M, He Y, Ye Q. Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer's disease. Int J Oral Sci 2024; 16:40. [PMID: 38740746 PMCID: PMC11091120 DOI: 10.1038/s41368-024-00300-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 03/15/2024] [Accepted: 04/09/2024] [Indexed: 05/16/2024] Open
Abstract
Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer's disease.
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Affiliation(s)
- Wei Xiong
- Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ye Liu
- Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Heng Zhou
- Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Junyi Li
- Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shuili Jing
- Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Cailei Jiang
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Mei Li
- Department of Oral Science, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Yan He
- Institute of Regenerative and Translational Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China.
- Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
| | - Qingsong Ye
- Center of Regenerative Medicine, Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
- Department of Stomatology, Linhai Second People's Hospital, Linhai, Zhejiang, China.
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31
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Tang Y, Wu X, Li J, Li Y, Xu X, Li G, Zhang P, Qin C, Wu LJ, Tang Z, Tian DS. The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair. Aging Dis 2024; 15:1176-1203. [PMID: 38029392 PMCID: PMC11081154 DOI: 10.14336/ad.2023.1107] [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: 08/17/2023] [Accepted: 11/07/2023] [Indexed: 12/01/2023] Open
Abstract
In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.
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Affiliation(s)
- Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xuan Wu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jiarui Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yuanwei Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiaoxiao Xu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Gaigai Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Chuan Qin
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Long-Jun Wu
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Dai-Shi Tian
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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32
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Ding F, Sun Q, Long C, Rasmussen RN, Peng S, Xu Q, Kang N, Song W, Weikop P, Goldman SA, Nedergaard M. Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration. Brain 2024; 147:1726-1739. [PMID: 38462589 PMCID: PMC11068329 DOI: 10.1093/brain/awae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/15/2024] [Accepted: 02/18/2024] [Indexed: 03/12/2024] Open
Abstract
Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.
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Affiliation(s)
- Fengfei Ding
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Qian Sun
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Department of Pharmacology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Carter Long
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Rune Nguyen Rasmussen
- Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, Neurology Department, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Sisi Peng
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Qiwu Xu
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Ning Kang
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Wei Song
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Pia Weikop
- Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, Neurology Department, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Steven A Goldman
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, Neurology Department, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Maiken Nedergaard
- Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA
- Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, Neurology Department, University of Copenhagen, 2200 Copenhagen, Denmark
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Coronel‐Oliveros C, Gómez RG, Ranasinghe K, Sainz‐Ballesteros A, Legaz A, Fittipaldi S, Cruzat J, Herzog R, Yener G, Parra M, Aguillon D, Lopera F, Santamaria‐Garcia H, Moguilner S, Medel V, Orio P, Whelan R, Tagliazucchi E, Prado P, Ibañez A. Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole-brain modeling. Alzheimers Dement 2024; 20:3228-3250. [PMID: 38501336 PMCID: PMC11095480 DOI: 10.1002/alz.13788] [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: 06/16/2023] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 03/20/2024]
Abstract
INTRODUCTION Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) lack mechanistic biophysical modeling in diverse, underrepresented populations. Electroencephalography (EEG) is a high temporal resolution, cost-effective technique for studying dementia globally, but lacks mechanistic models and produces non-replicable results. METHODS We developed a generative whole-brain model that combines EEG source-level metaconnectivity, anatomical priors, and a perturbational approach. This model was applied to Global South participants (AD, bvFTD, and healthy controls). RESULTS Metaconnectivity outperformed pairwise connectivity and revealed more viscous dynamics in patients, with altered metaconnectivity patterns associated with multimodal disease presentation. The biophysical model showed that connectome disintegration and hypoexcitability triggered altered metaconnectivity dynamics and identified critical regions for brain stimulation. We replicated the main results in a second subset of participants for validation with unharmonized, heterogeneous recording settings. DISCUSSION The results provide a novel agenda for developing mechanistic model-inspired characterization and therapies in clinical, translational, and computational neuroscience settings.
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Affiliation(s)
- Carlos Coronel‐Oliveros
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Global Brain Health Institute (GBHI)University of California San Francisco (UCSFA)San FranciscoCaliforniaUSA
- Trinity College DublinDublinIreland
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV)Universidad de ValparaísoValparaísoChile
| | - Raúl Gónzalez Gómez
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Center for Social and Cognitive NeuroscienceSchool of Psychology, Universidad Adolfo IbáñezSantiagoChile
| | - Kamalini Ranasinghe
- Memory and Aging CenterDepartment of NeurologyUniversity of California, San FranciscoSan FranciscoCaliforniaUSA
| | | | - Agustina Legaz
- Cognitive Neuroscience Center (CNC), Universidad de San Andrés, Provincia de Buenos AiresVictoriaArgentina
| | - Sol Fittipaldi
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Global Brain Health Institute (GBHI)University of California San Francisco (UCSFA)San FranciscoCaliforniaUSA
- Trinity College DublinDublinIreland
- Cognitive Neuroscience Center (CNC), Universidad de San Andrés, Provincia de Buenos AiresVictoriaArgentina
| | - Josephine Cruzat
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
| | - Rubén Herzog
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
| | - Gorsev Yener
- Izmir University of Economics, Faculty of Medicine, Fevzi Çakmak, Balçova/İzmirSakaryaTurkey
- Dokuz Eylül University, Brain Dynamics Multidisciplinary Research Center, KonakAlsancakTurkey
| | - Mario Parra
- School of Psychological Sciences and HealthUniversity of StrathclydeGlasgowScotland
| | - David Aguillon
- Neuroscience Research Group, University of AntioquiaBogotáColombia
| | - Francisco Lopera
- Neuroscience Research Group, University of AntioquiaBogotáColombia
| | - Hernando Santamaria‐Garcia
- Pontificia Universidad Javeriana, PhD Program of NeuroscienceBogotáColombia
- Hospital Universitario San Ignacio, Center for Memory and Cognition IntellectusBogotáColombia
| | - Sebastián Moguilner
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Cognitive Neuroscience Center (CNC), Universidad de San Andrés, Provincia de Buenos AiresVictoriaArgentina
| | - Vicente Medel
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Brain and Mind Centre, The University of SydneySydneyNew South WalesAustralia
- Department of NeuroscienceUniversidad de Chile, IndependenciaSantiagoChile
| | - Patricio Orio
- Centro Interdisciplinario de Neurociencia de Valparaíso (CINV)Universidad de ValparaísoValparaísoChile
- Instituto de NeurocienciaFacultad de Ciencias, Universidad de Valparaíso, Playa AnchaValparaísoChile
| | - Robert Whelan
- Global Brain Health Institute (GBHI)University of California San Francisco (UCSFA)San FranciscoCaliforniaUSA
- Trinity College DublinDublinIreland
| | - Enzo Tagliazucchi
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Buenos Aires Physics Institute and Physics DepartmentUniversity of Buenos Aires, Intendente Güiraldes 2160 – Ciudad UniversitariaBuenos AiresArgentina
| | - Pavel Prado
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Escuela de Fonoaudiología, Facultad de Odontología y Ciencias de la RehabilitaciónUniversidad San Sebastián, Región MetropolitanaSantiagoChile
| | - Agustín Ibañez
- Latin American Brain Health Institute (BrainLat)Universidad Adolfo Ibáñez, PeñalolénSantiagoChile
- Global Brain Health Institute (GBHI)University of California San Francisco (UCSFA)San FranciscoCaliforniaUSA
- Trinity College DublinDublinIreland
- Cognitive Neuroscience Center (CNC), Universidad de San Andrés, Provincia de Buenos AiresVictoriaArgentina
- Trinity College Institute of NeuroscienceTrinity College DublinDublinIreland
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Fontana ACK, Poli AN, Gour J, Srikanth YV, Anastasi N, Ashok D, Khatiwada A, Reeb KL, Cheng MH, Bahar I, Rawls SM, Salvino JM. Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators. J Med Chem 2024; 67:6119-6143. [PMID: 38626917 PMCID: PMC11056993 DOI: 10.1021/acs.jmedchem.3c01909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 03/23/2024] [Accepted: 03/27/2024] [Indexed: 04/19/2024]
Abstract
Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric modulators (PAM) of EAAT2, the main CNS transporter, and have demonstrated their neuroprotective properties in vitro. Herein, we report on the structure-activity relationships (SAR) for the analogs identified from virtual screening and from our medicinal chemistry campaign. This work identified several selective EAAT2 positive allosteric modulators (PAMs) such as compounds 4 (DA-023) and 40 (NA-014) from a library of analogs inspired by GT949, an early generation compound. This series also provides nonselective EAAT PAMs, EAAT inhibitors, and inactive compounds that may be useful for elucidating the mechanism of EAAT allosteric modulation.
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Affiliation(s)
- Andréia C. K. Fontana
- Department
of Pharmacology and Physiology, Drexel University
College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Adi N.R. Poli
- Medicinal
Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Jitendra Gour
- Medicinal
Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Yellamelli V.V. Srikanth
- Medicinal
Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Nicholas Anastasi
- Medicinal
Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Devipriya Ashok
- Medicinal
Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
| | - Apeksha Khatiwada
- Department
of Pharmacology and Physiology, Drexel University
College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Katelyn L. Reeb
- Department
of Pharmacology and Physiology, Drexel University
College of Medicine, Philadelphia, Pennsylvania 19102, United States
| | - Mary Hongying Cheng
- Laufer
Center for Physical & Quantitative Biology, Stony Brook University, Stony
Brook, New York 11794, United States
| | - Ivet Bahar
- Department
of Biochemistry and Cell Biology, College of Arts & Sciences and
School of Medicine, Stony Brook University, Stony Brook, New York 11794, United States
- Laufer
Center for Physical & Quantitative Biology, Stony Brook University, Stony
Brook, New York 11794, United States
| | - Scott M. Rawls
- Center
for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140United States
| | - Joseph M. Salvino
- Medicinal
Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, United States
- The
Wistar
Cancer Center Molecular Screening, The Wistar
Institute, Philadelphia, Pennsylvania 19104, United States
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35
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Pszczołowska M, Walczak K, Miśków W, Antosz K, Batko J, Kurpas D, Leszek J. Chronic Traumatic Encephalopathy as the Course of Alzheimer's Disease. Int J Mol Sci 2024; 25:4639. [PMID: 38731858 PMCID: PMC11083609 DOI: 10.3390/ijms25094639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/15/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
This editorial investigates chronic traumatic encephalopathy (CTE) as a course of Alzheimer's disease (AD). CTE is a debilitating neurodegenerative disease that is the result of repeated mild traumatic brain injury (TBI). Many epidemiological studies show that experiencing a TBI in early or middle life is associated with an increased risk of dementia later in life. Chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD) present a series of similar neuropathological features that were investigated in this work like recombinant tau into filaments or the accumulation and aggregation of Aβ protein. However, these two conditions differ from each other in brain-blood barrier damage. The purpose of this review was to evaluate information about CTE and AD from various articles, focusing especially on new therapeutic possibilities for the improvement in cognitive skills.
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Affiliation(s)
- Magdalena Pszczołowska
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Kamil Walczak
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Weronika Miśków
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Katarzyna Antosz
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Joanna Batko
- Faculty of Medicine, Wroclaw Medical University, Ludwika Pasteura 1, 50-367 Wrocław, Poland; (M.P.)
| | - Donata Kurpas
- Faculty of Health Sciences, Wroclaw Medical University, Ul. Kazimierza Bartla 5, 51-618 Wrocław, Poland
| | - Jerzy Leszek
- Clinic of Psychiatry, Department of Psychiatry, Wroclaw Medical University, Ludwika Pasteura 10, 50-367 Wrocław, Poland
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36
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Amin SN, Shaltout SA, El Gazzar WB, Abdel Latif NS, Al-Jussani GN, Alabdallat YJ, Albakri KA, Elberry DA. Impact of NMDA receptors block versus GABA-A receptors modulation on synaptic plasticity and brain electrical activity in metabolic syndrome. Adv Med Sci 2024; 69:176-189. [PMID: 38561071 DOI: 10.1016/j.advms.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 12/18/2023] [Accepted: 03/25/2024] [Indexed: 04/04/2024]
Abstract
PURPOSE Metabolic syndrome (MetS) is a common disorder associated with disturbed neurotransmitter homeostasis. Memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, was first used in Alzheimer's disease. Allopregnanolone (Allo), a potent positive allosteric modulator of the Gamma-Amino-Butyric Acid (GABA)-A receptors, decreases in neurodegenerative diseases. The study investigated the impact of Memantine versus Allo administration on the animal model of MetS to clarify whether the mechanism of abnormalities is related more to excitatory or inhibitory neurotransmitter dysfunction. MATERIALS AND METHODS Fifty-six male rats were allocated into 7 groups: 4 control groups, 1 MetS group, and 2 treated MetS groups. They underwent assessment of cognition-related behavior by open field and forced swimming tests, electroencephalogram (EEG) recording, serum markers confirming the establishment of MetS model and hippocampal Glial Fibrillary Acidic Protein (GFAP) and Brain-Derived Neurotrophic Factor (BDNF). RESULTS Allo improved anxiety-like behavior and decreased grooming frequency compared to Memantine. Both drugs increased GFAP and BDNF expression, improving synaptic plasticity and cognition-related behaviors. The therapeutic effect of Allo was more beneficial regarding lipid profile and anxiety. We reported progressive slowing of EEG waves in the MetS group with Memantine and Allo treatment with increased relative theta and decreased relative delta rhythms. CONCLUSIONS Both Allo and Memantine boosted the outcome parameters in the animal model of MetS. Allo markedly improved the anxiety-like behavior in the form of significantly decreased grooming frequency compared to the Memantine-treated groups. Both drugs were associated with increased hippocampal GFAP and BDNF expression, indicating an improvement in synaptic plasticity and so, cognition-related behaviors.
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Affiliation(s)
- Shaimaa Nasr Amin
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Sherif Ahmed Shaltout
- Department of Pharmacology, Public Health, and Clinical Skills, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; Department of Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Walaa Bayoumie El Gazzar
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan; Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Noha Samir Abdel Latif
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University Cairo, Egypt; Department of Medical Pharmacology, Armed Forces College of Medicine, Cairo, Egypt
| | - Ghadah Nazar Al-Jussani
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
| | | | | | - Dalia Azmy Elberry
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Yin S, Yang X, Li H, Li C, Li C, Chen C, Ye S, Zou L, Liang S, Liu S. P2Y 13 receptor involved in HIV-1 gp120 induced neuropathy in superior cervical ganglia through NLRP3 inflammasome activation. Neuropharmacology 2024; 245:109818. [PMID: 38142931 DOI: 10.1016/j.neuropharm.2023.109818] [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: 06/14/2023] [Revised: 10/06/2023] [Accepted: 12/16/2023] [Indexed: 12/26/2023]
Abstract
Cardiac autonomic neuropathy resulting from human immunodeficiency virus (HIV) infection is common; however, its mechanism remains unknown. The current work attempted to explore the function and mechanism of the P2Y13 receptor in HIV-glycoprotein 120 (gp120)-induced neuropathy in cervical sympathetic ganglion. The superior cervical ganglion (SCG) of the male SD rat was coated with HIV-gp120 to establish a model of autonomic neuropathy. In each group, we measured heart rate, blood pressure, heart rate variability, sympathetic nerve discharge and cardiac function. The expression of P2Y13 mRNA and protein in the SCG was tested by real-time polymerase chain reaction and western blotting. Additionally, this study focused on identifying the protein levels of NOD-like receptor family pyrin domain-containing 3 (NLRP3), Caspase-1, Gasdermin D (GSDMD), interleukin (IL)-1β and IL-18 in the SCG using western blotting and immunofluorescence. In gp120 rats, increased blood pressure, heart rate, cardiac sympathetic nerve activity, P2Y13 receptor levels and decreased cardiac function could be found. P2Y13 shRNA or MRS2211 inhibited the above mentioned changes induced by gp120, suggesting that the P2Y13 receptor may be engaged in gp120-induced sympathetic nerve injury. Moreover, the levels of NLRP3, Caspase-1, GSDMD, IL-1β and IL-18 in the gp120 group were increased, while significantly decreased by P2Y13 shRNA or MRS2211. Therefore, the P2Y13 receptor is involved in gp120-induced sympathetic neuropathy, and its molecular mechanism shows an association with the activation of the NLRP3 inflammasome, followed by GSDMD formation along with the release of inflammatory factors including IL-1β and IL-18. This article is part of the Special Issue on "Purinergic Signaling: 50 years".
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Affiliation(s)
- Sui Yin
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China; Jinan Center for Disease Control and Prevention, Jinan, China
| | - Xuexuan Yang
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China
| | - Honglei Li
- Department of Basic medicine, School of Basic medicine, Jiangxi Medical College, Nanchang University, China
| | - Chenxi Li
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China
| | - Changyi Li
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China
| | - Chengxu Chen
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China
| | - Shang Ye
- Department of Clinical Medicine, School of Marry Queen, Jiangxi Medical College, Nanchang University, China
| | - Lifang Zou
- Center of Hematology, the 1st affiliated Hospital, Jiangxi Medical College, Nanchang University, China; Institute of Hematology, Academy of Clinical Medicine of Jiangxi Province, Nanchang, China
| | - Shangdong Liang
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China
| | - Shuangmei Liu
- Department of Physiology, School of Basic medicine, Jiangxi Medical College, Nanchang University, China.
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Hammer M, Krzyzaniak C, Bahramnejad E, Smelser K, Hack J, Watkins J, Ronaldson P. Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy. Clin Sci (Lond) 2024; 138:205-223. [PMID: 38348743 PMCID: PMC10881277 DOI: 10.1042/cs20231572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 02/01/2024] [Accepted: 02/09/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models. METHODS We characterized sex differences in mice carrying a pathogenic knockin variant (p.N1768D) in the Scn8a gene that causes spontaneous tonic-clonic seizures (TCs) at ∼3 months of age and found that heterozygous females are more resilient than males in mortality and morbidity. To investigate the cellular mechanisms that underlie female resilience, we utilized blood-brain barrier (BBB) and hippocampal transcriptomic analyses in heterozygous mice before seizure onset (pre-TC) and in mice that experienced ∼20 TCs (post-TC). RESULTS In the pre-TC latent phase, both sexes exhibited leaky BBB; however, patterns of gene expression were sexually dimorphic. Females exhibited enhanced oxidative phosphorylation and protein biogenesis, while males activated gliosis and CREB signaling. After seizure onset (chronic phase), females exhibited a metabolic switch to lipid metabolism, while males exhibited increased gliosis and BBB dysfunction and a strong activation of neuroinflammatory pathways. CONCLUSION The results underscore the central role of oxidative stress and BBB permeability in the early stages of epileptogenesis, as well as sex dimorphism in response to increasing neuronal hyperexcitability. Our results also highlight the need to include both sexes in preclinical studies to effectively translate results of drug efficacy studies.
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Affiliation(s)
- Michael F. Hammer
- BIO5 Institute, University of Arizona, Tucson, Arizona, U.S.A
- Department of Neurology, University of Arizona, Tucson, Arizona, U.S.A
| | | | - Erfan Bahramnejad
- BIO5 Institute, University of Arizona, Tucson, Arizona, U.S.A
- Department of Pharmacology, University of Arizona, Tucson, Arizona, U.S.A
| | | | - Joshua B. Hack
- BIO5 Institute, University of Arizona, Tucson, Arizona, U.S.A
| | - Joseph C. Watkins
- Department of Mathematics, University of Arizona, Tucson, Arizona, U.S.A
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Egunlusi AO, Malan SF, Palchykov VA, Joubert J. Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration. Mini Rev Med Chem 2024; 24:1277-1292. [PMID: 38275027 DOI: 10.2174/0113895575273868231128104121] [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: 09/06/2023] [Revised: 10/09/2023] [Accepted: 10/23/2023] [Indexed: 01/27/2024]
Abstract
Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage- gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.
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Affiliation(s)
- Ayodeji O Egunlusi
- Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa
| | - Sarel F Malan
- Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa
| | - Vitalii A Palchykov
- Research Institute of Chemistry and Geology, Oles Honchar Dnipropetrovsk National University, 72 Gagarina Av., Dnipro 49010, Ukraine
| | - Jacques Joubert
- Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa
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Zanchi MM, Marafon F, Marins K, Bagatini MD, Zamoner A. Redox imbalance and inflammation: A link to depression risk in brazilian pesticide-exposed farmers. Toxicology 2024; 501:153706. [PMID: 38097130 DOI: 10.1016/j.tox.2023.153706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/23/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023]
Abstract
This study aims to elucidate the mechanisms linking occupational pesticide exposure to depression among rural workers from Maravilha, Brazil. We assessed the mental health, oxidative, and inflammatory profiles of farmers exposed to pesticides (N = 28) and compared them to an urban control group without occupational exposure to pesticides (N = 25). Data on sociodemographic, occupational history, and clinical records were collected. Emotional states were evaluated using the State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI). Biochemical, hematological, inflammatory, and redox parameters were examined in blood samples from both groups. Results showed educational disparities between groups and unveiled a concerning underutilization of personal protective equipment (PPEs) among farmers. Glyphosate was the predominant pesticide used by farmers. Farmers exhibited higher BDI scores, including more severe cases of depression. Additionally, elevated levels of creatinine, ALT, AST, and LDH were observed in farmers, suggesting potential renal and hepatic issues due to pesticide exposure. Oxidative stress markers, such as increased lipid peroxidation and superoxide dismutase (SOD) activity, along with decreased catalase (CAT) activity and ascorbic acid levels, were noted in the pesticide-exposed group compared to controls. Elevated levels of inflammatory cytokines, particularly IL-1β, IL-6 and TNF-α, were also observed in pesticide-exposed group. Our findings suggest that inflammation, oxidative distress and lower educational levels may be associated with depression in pesticide-exposed farmers. This study highlights the impact of occupational pesticide exposure on the mental health of rural workers. The underuse of PPEs and the link between depressive symptoms, inflammation, and oxidative stress underscore the urgent need for improved safety measures in agricultural practices. Addressing these issues will contribute to a deeper understanding of the intricate relationship between environmental exposures and mental health outcomes.
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Affiliation(s)
- Mariane Magalhães Zanchi
- Laboratory of Biochemistry and Cell Signaling, Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, 88037-000 SC, Brazil
| | - Filomena Marafon
- Laboratory of Cell Culture, Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó, 89815-899 SC, Brazil
| | - Katiuska Marins
- Laboratory of Biochemistry and Cell Signaling, Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, 88037-000 SC, Brazil
| | - Margarete Dulce Bagatini
- Laboratory of Biochemistry and Cell Signaling, Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, 88037-000 SC, Brazil
| | - Ariane Zamoner
- Laboratory of Biochemistry and Cell Signaling, Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, 88037-000 SC, Brazil.
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41
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Kusama-Eguchi K, Tokui Y, Minoura A, Yanai Y, Hirose D, Furukawa M, Kosuge Y, Miura M, Ohkoshi E, Makino M, Minagawa K, Matsuzaki K, Ogawa Y, Watanabe K, Ohsaki A. 2(3H)-Dihydrofranolactone metabolites from Pleosporales sp. NUH322 as anti-amyotrophic lateral sclerosis drugs. J Nat Med 2024; 78:146-159. [PMID: 37804412 DOI: 10.1007/s11418-023-01751-5] [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: 06/15/2023] [Accepted: 09/08/2023] [Indexed: 10/09/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3-7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001-0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor.
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Affiliation(s)
- Kuniko Kusama-Eguchi
- Department of Chemistry, College of Humanities and Science, Ninon University, Setagaya-Ku, Tokyo, 156-8550, Japan.
- Laboratory of Biochemistry, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan.
- Laboratory of Medical Microbiology, School of Pharmacy, Nihon University. Funabashi, Chiba, 274-8555, Japan.
| | - Yuki Tokui
- Department of Chemistry, College of Humanities and Science, Ninon University, Setagaya-Ku, Tokyo, 156-8550, Japan
| | - Ai Minoura
- Laboratory of Biochemistry, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Yuta Yanai
- Department of Chemistry, College of Humanities and Science, Ninon University, Setagaya-Ku, Tokyo, 156-8550, Japan
- Laboratory of Biochemistry, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Dai Hirose
- Laboratory of Medical Microbiology, School of Pharmacy, Nihon University. Funabashi, Chiba, 274-8555, Japan
| | - Megumi Furukawa
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Yasuhiro Kosuge
- Laboratory of Pharmacology, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Motofumi Miura
- Laboratory of Molecular Chemistry, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Emika Ohkoshi
- Department of Natural Products Chemistry, Faculty of Pharmaceutical Sciences, Aomori University, Aomori, Aomori, 030-0943, Japan
| | - Mitsuko Makino
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Kimino Minagawa
- Laboratory of Biochemistry, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan
| | - Keiichi Matsuzaki
- Laboratory of Pharmacognosy, School of Pharmacy, Nihon University, Funabashi, Chiba, 274-8555, Japan
| | - Yoshio Ogawa
- Laboratory of Medical Microbiology, School of Pharmacy, Nihon University. Funabashi, Chiba, 274-8555, Japan
| | - Kazuko Watanabe
- Laboratory of Medical Microbiology, School of Pharmacy, Nihon University. Funabashi, Chiba, 274-8555, Japan
| | - Ayumi Ohsaki
- Department of Chemistry, College of Humanities and Science, Ninon University, Setagaya-Ku, Tokyo, 156-8550, Japan.
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Abstract
Post-traumatic stress disorder (PTSD) develops after trauma exposure and involves symptoms of avoidance, intrusive re-experiencing, mood and cognitive dysfunction, and hypervigilance. PTSD is often comorbid with Gulf War Illness (GWI), a neurological condition involving widespread pain, cognitive dysfunction, digestive problems, and other symptoms, in Gulf War veterans. PTSD tends to be more severe when comorbid with GWI. Low cortisol and elevated homocysteine levels have been found in PTSD, making them potential PTSD biomarkers. The low-glutamate diet, which aims to reduce excitotoxicity by eliminating the consumption of free glutamate and aspartate, has been shown to significantly reduce GWI and PTSD symptoms. This study examined whether changes in serum cortisol and homocysteine are associated with reduced PTSD severity in veterans with GWI after one month on the low-glutamate diet, and whether reducing the consumption of dietary excitotoxins was associated changes in PTSD and serum biomarkers. Data were analyzed for 33 veterans. No serum biomarkers significantly changed post-diet; however, cortisol increased as dietary excitotoxin consumption decreased, which held in a multivariable linear regression after adjustment for sex. Reduced dietary excitotoxin consumption was also associated with reduced hyperarousal symptoms, which held in a multivariable linear regression after adjustment for sex. Cortisol increase was associated with reduced avoidance symptoms after adjustment for change in BMI, and was marginally associated with overall PTSD reduction. Change in homocysteine was not significantly related to dietary adherence nor change in PTSD. Results suggest that reducing the consumption of dietary excitotoxins may normalize cortisol levels, which has been associated with alleviating PTSD.
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Affiliation(s)
- Sidney L Murray
- Department of Neuroscience, American University, Washington, DC, USA
| | - Kathleen F Holton
- Department of Neuroscience, American University, Washington, DC, USA
- Department of Health Studies, American University, Washington, DC, USA
- Center for Neuroscience and Behaviour, American University, Washington, DC, USA
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43
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Keimasi M, Salehifard K, Mirshah Jafar Esfahani N, Esmaeili F, Farghadani A, Amirsadri M, Keimasi M, Noorbakhshnia M, Moradmand M, Mofid MR. The synergic effects of presynaptic calcium channel antagonists purified from spiders on memory elimination of glutamate-induced excitotoxicity in the rat hippocampus trisynaptic circuit. Front Mol Biosci 2023; 10:1243976. [PMID: 38099194 PMCID: PMC10720730 DOI: 10.3389/fmolb.2023.1243976] [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: 06/21/2023] [Accepted: 11/14/2023] [Indexed: 12/17/2023] Open
Abstract
The hippocampus is a complex area of the mammalian brain and is responsible for learning and memory. The trisynaptic circuit engages with explicit memory. Hippocampal neurons express two types of presynaptic voltage-gated calcium channels (VGCCs) comprising N and P/Q-types. These VGCCs play a vital role in the release of neurotransmitters from presynaptic neurons. The chief excitatory neurotransmitter at these synapses is glutamate. Glutamate has an essential function in learning and memory under normal conditions. The release of neurotransmitters depends on the activity of presynaptic VGCCs. Excessive glutamate activity, due to either excessive release or insufficient uptake from the synapse, leads to a condition called excitotoxicity. This pathological state is common among all neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Under these conditions, glutamate adversely affects the trisynaptic circuitry, leading to synaptic destruction and loss of memory and learning performance. This study attempts to clarify the role of presynaptic VGCCs in memory performance and reveals that modulating the activity of presynaptic calcium channels in the trisynaptic pathway can regulate the excitotoxic state and consequently prevent the elimination of neurons and synaptic degradation. All of these can lead to an improvement in learning and memory function. In the current study, two calcium channel blockers-omega-agatoxin-Aa2a and omega-Lsp-IA-were extracted, purified, and identified from spiders (Agelena orientalis and Hogna radiata) and used to modulate N and P/Q VGCCs. The effect of omega-agatoxin-Aa2a and omega-Lsp-IA on glutamate-induced excitotoxicity in rats was evaluated using the Morris water maze task as a behavioral test. The local expression of synaptophysin (SYN) was visualized for synaptic quantification using an immunofluorescence assay. The electrophysiological amplitudes of the field excitatory postsynaptic potentials (fEPSPs) in the input-output and LTP curves of the mossy fiber and Schaffer collateral circuits were recorded. The results of our study demonstrated that N and P/Q VGCC modulation in the hippocampus trisynaptic circuit of rats with glutamate-induced excitotoxicity dysfunction could prevent the destructive consequences of excitotoxicity in synapses and improve memory function and performance.
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Affiliation(s)
- Mohammad Keimasi
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Kowsar Salehifard
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Noushin Mirshah Jafar Esfahani
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Fariba Esmaeili
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Arman Farghadani
- Department of Biology, Faculty of Biological Sciences, University Duisburg-Essen, Essen, Germany
| | - Mohammadreza Amirsadri
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadjavad Keimasi
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Maryam Noorbakhshnia
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Majid Moradmand
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Mohammad Reza Mofid
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Han JH, Lee EJ, Park W, Ha KT, Chung HS. Natural compounds as lactate dehydrogenase inhibitors: potential therapeutics for lactate dehydrogenase inhibitors-related diseases. Front Pharmacol 2023; 14:1275000. [PMID: 37915411 PMCID: PMC10616500 DOI: 10.3389/fphar.2023.1275000] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 09/27/2023] [Indexed: 11/03/2023] Open
Abstract
Lactate dehydrogenase (LDH) is a crucial enzyme involved in energy metabolism and present in various cells throughout the body. Its diverse physiological functions encompass glycolysis, and its abnormal activity is associated with numerous diseases. Targeting LDH has emerged as a vital approach in drug discovery, leading to the identification of LDH inhibitors among natural compounds, such as polyphenols, alkaloids, and terpenoids. These compounds demonstrate therapeutic potential against LDH-related diseases, including anti-cancer effects. However, challenges concerning limited bioavailability, poor solubility, and potential toxicity must be addressed. Combining natural compounds with LDH inhibitors has led to promising outcomes in preclinical studies. This review highlights the promise of natural compounds as LDH inhibitors for treating cancer, cardiovascular, and neurodegenerative diseases.
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Affiliation(s)
- Jung Ho Han
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
| | - Eun-Ji Lee
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
| | - Wonyoung Park
- Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), Daegu, Republic of Korea
| | - Ki-Tae Ha
- Korean Convergence Medical Science Major, KIOM Campus, University of Science and Technology (UST), Daegu, Republic of Korea
| | - Hwan-Suck Chung
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu, Republic of Korea
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Republic of Korea
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Statsenko Y, Kuznetsov NV, Morozova D, Liaonchyk K, Simiyu GL, Smetanina D, Kashapov A, Meribout S, Gorkom KNV, Hamoudi R, Ismail F, Ansari SA, Emerald BS, Ljubisavljevic M. Reappraisal of the Concept of Accelerated Aging in Neurodegeneration and Beyond. Cells 2023; 12:2451. [PMID: 37887295 PMCID: PMC10605227 DOI: 10.3390/cells12202451] [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: 08/04/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Genetic and epigenetic changes, oxidative stress and inflammation influence the rate of aging, which diseases, lifestyle and environmental factors can further accelerate. In accelerated aging (AA), the biological age exceeds the chronological age. OBJECTIVE The objective of this study is to reappraise the AA concept critically, considering its weaknesses and limitations. METHODS We reviewed more than 300 recent articles dealing with the physiology of brain aging and neurodegeneration pathophysiology. RESULTS (1) Application of the AA concept to individual organs outside the brain is challenging as organs of different systems age at different rates. (2) There is a need to consider the deceleration of aging due to the potential use of the individual structure-functional reserves. The latter can be restored by pharmacological and/or cognitive therapy, environment, etc. (3) The AA concept lacks both standardised terminology and methodology. (4) Changes in specific molecular biomarkers (MBM) reflect aging-related processes; however, numerous MBM candidates should be validated to consolidate the AA theory. (5) The exact nature of many potential causal factors, biological outcomes and interactions between the former and the latter remain largely unclear. CONCLUSIONS Although AA is commonly recognised as a perspective theory, it still suffers from a number of gaps and limitations that assume the necessity for an updated AA concept.
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Affiliation(s)
- Yauhen Statsenko
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Big Data Analytic Center, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Nik V. Kuznetsov
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Daria Morozova
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Katsiaryna Liaonchyk
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Gillian Lylian Simiyu
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Darya Smetanina
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Aidar Kashapov
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Sarah Meribout
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Klaus Neidl-Van Gorkom
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Rifat Hamoudi
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Fatima Ismail
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Suraiya Anjum Ansari
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bright Starling Emerald
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Milos Ljubisavljevic
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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Keimasi M, Salehifard K, Hoseini SJ, Esmaeili F, Esfahani NMJ, Amirsadri M, Keimasi M, Moradmand M, Mofid MR. Purified Native Protein Extracted from the Venom of Agelena orientalis Attenuates Memory Defects in the Rat Model of Glutamate-Induced Excitotoxicity. Protein J 2023; 42:586-595. [PMID: 37531037 DOI: 10.1007/s10930-023-10140-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2023] [Indexed: 08/03/2023]
Abstract
Spider venom contains various peptides and proteins, which can be used for pharmacological applications. Finding novel therapeutic strategies against neurodegenerative diseases with the use of purified peptides and proteins, extracted from spiders can be greatly precious. Neurodegenerative diseases are rapidly developing and expanding all over the world. Excitotoxicity is a frequent condition amongst neuro-degenerative disorders. This harmful process is usually induced through hyper-activation of N-Methyl-D-Aspartate (NMDA) receptor, and P/Q-type voltage-gated calcium channels (VGCCs). The omega-agatoxin-Aa4b is a selective and strong VGCCblocker. This study aimed to investigate the effects of this blocker on the NMDA-induced memory and learning defect in rats. For this purpose, nineteen spiders of the funnel-weaver Agelena orientalis species were collected. The extracted venom was lyophilized andpurified through gel-filtration chromatography, and capillary electrophoresis techniques. Subsequently, mass spectrometry (HPLC-ESI-MS) was used for identification of this bio-active small protein. Afterward, the effect of the omega-agatoxin-Aa4b (2 μg, intra-cornu ammonis-3 of the hippocampus) on the NMDA-induced learning and memory deficits in rats was evaluated. Learning and memory performances were evaluated by the use of passive avoidance test. For synaptic quantification and memory function the amount of calcium/calmodulin-dependent protein kinase ІІ (CaCdPKІІ) gene expression was measured using the Real-time PCR technique. To compare the experimental groups, hematoxylin and eosin (H&E) staining of hippocampus tissues was performed. Our results rendered that the omega-Agatoxin-Aa4b treatment can ameliorate and reverse the learning and memory impairment caused by NMDA-induced excitotoxicity in rat hippocampus.
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Affiliation(s)
- Mohammad Keimasi
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Kowsar Salehifard
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sayyed Jafar Hoseini
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Fariba Esmaeili
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Noushin Mirshah Jafar Esfahani
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Mohammadreza Amirsadri
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammadjavad Keimasi
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran
| | - Majid Moradmand
- Department of Plant and Animal Biology, Faculty of Biological Sciences and Technology, University of Isfahan, Isfahan, Iran.
| | - Mohammad Reza Mofid
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
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Mallan S, Singh S. Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen-activated protein kinase: Possible molecular approach. ENVIRONMENTAL TOXICOLOGY 2023; 38:2400-2415. [PMID: 37357844 DOI: 10.1002/tox.23876] [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: 12/06/2022] [Revised: 05/09/2023] [Accepted: 06/11/2023] [Indexed: 06/27/2023]
Abstract
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior followed by impairment in social, verbal, and non-verbal interaction and communication. Valproic acid (VPA) is a well-known anti-epileptic drug, but its prenatal exposure to animals causes social impairment, neurotransmitters imbalance, and neuroinflammation with ASD-like phenotypes. Syringic acid (SA) is a polyphenolic compound with anti-inflammatory, anti-apoptotic, antioxidant, and neuromodulator activity. The purpose of study was to investigate the protective effect of Syringic acid (SA) in prenatal VPA-treated rats through behavioral, neuroinflammation, oxidative stress, neurotransmitters, neuronal integrity, and apoptotic marker. Single dose of VPA was administered 600 mg/kg, i.p. on a gestational day (GD) 12th and SA was administrated from PnD 26th to 54th at the dose of 25, 50, and 100 mg/kg, p.o. On PnD 56th behavioral parameters (Pain sensitivity, open field test, narrow beam walks test and social impairment test) were performed and all animals were sacrificed, and brain tissue was isolated for oxidative stress (GSH, CAT, and LPO), neuroinflammation (TNF-α and IL-6) and neurotransmitters (GABA and Glutamate), histopathology (H&E, Nissl), immunohistochemistry (p38 MAPK) analysis. Rat treated with SA dose-dependently prevented behavioral alteration, restored antioxidant enzymes, neurotransmitters level, decreased neuroinflammatory markers, and improved neuronal integrity. Furthermore, immunohistochemistry confirmed the reduced p38 MAPK marker expression by SA in VPA induced autistic behavior.
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Affiliation(s)
- Sudhanshu Mallan
- Neuropharmacology division, Department of Pharmacology, ISF College of Pharmacy, Moga, India
| | - Shamsher Singh
- Neuropharmacology division, Department of Pharmacology, ISF College of Pharmacy, Moga, India
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Ghenaatgar-Kasbi M, Rezaei M, Moharreri P, Heidarian Miri H, Sazegar G, Haghir H. The effect of maternal diabetes on the expression of gamma-aminobutyric acid and metabotropic glutamate receptors in male newborn rats' inferior colliculi. J Perinat Med 2023; 51:940-949. [PMID: 37139647 DOI: 10.1515/jpm-2022-0553] [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: 11/14/2022] [Accepted: 02/28/2023] [Indexed: 05/05/2023]
Abstract
OBJECTIVES Few studies have examined the molecular alterations in the auditory pathway of infants of diabetic mothers, notwithstanding the fact that maternal diabetes may have an impact on the development of the neonatal peripheral and central nervous systems. Male newborn rats were studied to determine how maternal diabetes affected the expression of gamma-aminobutyric acid (GABAAα1 and GABAB1) and metabotropic glutamate (mGlu2) receptors in the inferior colliculus (IC) in this research. METHODS Female rats were given a single intraperitoneal injection of streptozotocin (STZ) at a 65 mg/kg dose to develop a model of diabetic mothers. The study population was split into sham, diabetes without treatment, and diabetes with insulin groups. Their male neonatal rats were anesthetized on P0, P7, and P14 after mating and delivery. The receptors' distribution pattern was studied using immunohistochemistry (IHC). RESULTS Pairwise comparison in the groups revealed that the GABA receptors (Aα1 and B1) were significantly downregulated in the diabetes without treatment group (p<0.001). Furthermore, pairwise comparison in the groups indicated significant mGlu2 upregulation in the diabetes without treatment group (p<0.001). Regarding the concentration of all receptors, there was no discernible distinction between the diabetes with insulin and sham groups. CONCLUSIONS This investigation showed that the concentration of GABAAα1 and GABAB1 receptors decreased significantly over time, whereas the concentration of mGlu2 receptors increased significantly over time in male neonatal rats born to streptozotocin-induced diabetic mothers.
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Affiliation(s)
- Maryam Ghenaatgar-Kasbi
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Rezaei
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Payam Moharreri
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Heidarian Miri
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ghasem Sazegar
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Haghir
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetic Research Center (MGRC), School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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49
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Pan X, Giustarini D, Lang F, Rossi R, Wieder T, Köberle M, Ghashghaeinia M. Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion. Cell Cycle 2023; 22:1827-1853. [PMID: 37522842 PMCID: PMC10599211 DOI: 10.1080/15384101.2023.2234177] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 08/01/2023] Open
Abstract
Background: Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET.Aims: To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms.Methods: Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH]i from high performance liquid chromatography.Results: Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca2+) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC.Conclusion: Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.
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Affiliation(s)
- Xia Pan
- Physiological Institute, Department of Vegetative and Clinical Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Daniela Giustarini
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Florian Lang
- Physiological Institute, Department of Vegetative and Clinical Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Ranieri Rossi
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Thomas Wieder
- Physiological Institute, Department of Vegetative and Clinical Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Martin Köberle
- Department of Dermatology and Allergology, School of Medicine, Technical University of Munich, München, Germany
| | - Mehrdad Ghashghaeinia
- Physiological Institute, Department of Vegetative and Clinical Physiology, Eberhard Karls University of Tübingen, Tübingen, Germany
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50
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Mannino G, Serio G, Gaglio R, Maffei ME, Settanni L, Di Stefano V, Gentile C. Biological Activity and Metabolomics of Griffonia simplicifolia Seeds Extracted with Different Methodologies. Antioxidants (Basel) 2023; 12:1709. [PMID: 37760012 PMCID: PMC10525635 DOI: 10.3390/antiox12091709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/26/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Griffonia simplicifolia, a tropical plant endemic to West Africa, is highly regarded for its significant pharmacological potential. The objective of this study was to evaluate the metabolomic profile and to explore the antioxidant properties, antiproliferative activity, and antimicrobial potential of G. simplicifolia seed extracts obtained through either maceration, microwave-assisted extraction (MAE), or Soxhlet extraction using water, acetone, methanol and ethanol as solvents. Overall, methanol possessed superior total extraction efficiency. HPLC analyses confirmed the efficacy of acetone and ethanol as optimal solvents for the extraction of flavonoids and flavan-3-ols, whereas MAE exhibited enhanced effectiveness in extracting N-containing compounds, including 5-hydroxytryptophan (5-HTP). HPLC-MS analyses identified forty-three compounds, including thirty-four phenolic compounds and nine N-containing molecules. Isomyricitrin, taxifolin and a flavonol glucuronide were the main polyphenols, whereas 5-HTP was the main N-containing compound. Hydroalcoholic G. simplicifolia extracts showed the highest radical scavenging and metal-reducing antioxidant power, suggesting that most of the contribution to antioxidant activity depends on the more polar bioactive compounds. G. simplicifolia extracts showed dose-dependent antiproliferative activity against three distinct cancer cell lines (HeLa, HepG2, and MCF-7), with notable variations observed among both the different extracts and cell lines and divergent GI50 values, emphasizing substantial discrepancies in cell sensitivity to the various extracts. Furthermore, G. simplicifolia extracts revealed antibiotic activity against Staphylococcus aureus. Our results highlight the potential of G. simplicifolia phytochemicals in the development of functional foods, nutraceuticals, and dietary supplements.
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Affiliation(s)
- Giuseppe Mannino
- Plant Physiology Unit, Department of Life Sciences and Systems Biology, University of Turin, Via Quarello 15/A, 10135 Turin, Italy;
| | - Graziella Serio
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.S.); (V.D.S.)
| | - Raimondo Gaglio
- Department of Agricultural, Food and Forest Sciences, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (R.G.); (L.S.)
| | - Massimo E. Maffei
- Plant Physiology Unit, Department of Life Sciences and Systems Biology, University of Turin, Via Quarello 15/A, 10135 Turin, Italy;
| | - Luca Settanni
- Department of Agricultural, Food and Forest Sciences, University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (R.G.); (L.S.)
| | - Vita Di Stefano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.S.); (V.D.S.)
| | - Carla Gentile
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy; (G.S.); (V.D.S.)
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