|
1
|
Yu D, Zhang H, Du X, Ren J, Qu X. Hydrogen-Bonded Organic Framework-Based NIR-II Activated Hydrogen Production for Treatment of Alzheimer's Disease Model Mice. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2410063. [PMID: 39989154 DOI: 10.1002/smll.202410063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/06/2025] [Indexed: 02/25/2025]
Abstract
Oxidative stress is the crucial pathologic factor for causing neuron death and cognitive impairment in the progression of Alzheimer's disease (AD). As a special antioxidant, molecular hydrogen (H2) is responsible for alleviating oxidative stress and associated inflammatory symptoms. However, in vivo continuous and efficient hydrogen accumulation is rather difficult to realize, thus frequent dosing is required to ensure the desired therapeutic effect. Herein, hydrogen-bonded organic frameworks (HOFs) composites are rationally designed to achieve sustainable near-infrared II (NIR-II) photocatalytic hydrogen evolution reaction for relieving neuroinflammation in AD model mice. The HOFs composites mainly consist of three parts: building block porphyrin as the photocatalyst, DSM (NIR-II-absorbing pyridinium hemicyanine dye) as fluorescent emitter, and platinum nanoparticles as co-catalyst. Under NIR-II laser illumination, DSM acts as an energy transducer to activate porphyrin to produce reductive hydrogen in situ. Specially, porphyrin selectively binds with the accumulated Cu ions in Aβ plaques and boosts H2 evolution. KLVFFAED (KD8) is covalently grafted on the HOFs to improve the blood-brain barrier permeability in vivo. This designed system exhibits an admirable therapeutic effect for relieving inflammation and recovering cognitive disorder in AD model mice, thus providing a new way for exploring HOFs used for sustainable hydrogen therapy.
Collapse
Affiliation(s)
- Dongqin Yu
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Science, Changchun, Jilin, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Haochen Zhang
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Science, Changchun, Jilin, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Xiubo Du
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Science, Changchun, Jilin, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Jinsong Ren
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Science, Changchun, Jilin, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Xiaogang Qu
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Science, Changchun, Jilin, 130022, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| |
Collapse
|
|
2
|
Nakagawa K, Kodama K, Nagata W, Takahashi S, Satoh Y, Ishizuka T. Molecular hydrogen inhibits neuroinflammation and ameliorates depressive-like behaviors and short-term cognitive impairment in senescence-accelerated mouse prone 8 mice. Behav Brain Res 2025; 478:115330. [PMID: 39522774 DOI: 10.1016/j.bbr.2024.115330] [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: 06/04/2024] [Revised: 10/11/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND AND AIMS Neuroinflammation, a low-grade chronic inflammation of the central nervous system, is linked to age-related neuropsychiatric disorders such as senile depression and Alzheimer's disease. Recent studies have explored controlling neuroinflammation as a novel treatment strategy. Molecular hydrogen shows anti-inflammatory effects. However, its impacts on neuroinflammation and age-related neuropsychiatric disorders remain unelucidated. We investigated molecular hydrogen's effects on microglial activation, neuroinflammation, depressive-like behavior, and short-term cognitive decline in senescence-accelerated mouse-prone 8 (SAMP8) mice. METHODS Six-week-old SAMP8 or senescence-accelerated mouse-resistant 1 (SAMR1) mice received hydrogen-rich jelly (HRJ) or placebo jelly (PJ) from six weeks of age for 26-28 weeks. Depressive-like behavior was assessed using tail suspension and forced swimming tests, while cognitive function was evaluated using the Y-maze and object recognition tests. Brain tissues were used for immunohistochemical studies or to measure pro-inflammatory cytokine levels via enzyme-linked immunosorbent assay (ELISA). RESULTS HRJ intake reduced immobility time in both tail suspension and forced swimming tests and enhanced visual cognitive and spatial working memory in SAMP8 mice. Additionally, HRJ intake suppressed the 8-hydroxy-2'-deoxyguanosine (8-OHdG), Iba1, and cleaved caspase 3 expression levels in the medial prefrontal cortex and hippocampal dentate gyrus. Furthermore, HRJ intake significantly lowered IL-6 levels in brain tissues of SAMP8 mice. CONCLUSIONS These findings suggest that molecular hydrogen treatment may regulate neuroinflammation induced by activated microglia and improve depressive-like behavior and short-term cognitive impairment in SAMP8 mice.
Collapse
Affiliation(s)
- Keiichi Nakagawa
- Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan
| | - Kayoko Kodama
- Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan
| | - Wataru Nagata
- Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan
| | - Sayaka Takahashi
- Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan
| | - Yasushi Satoh
- Department of Biochemistry, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan
| | - Toshiaki Ishizuka
- Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama 359-0042, Japan.
| |
Collapse
|
|
3
|
Lin TK, Pai MS, Yeh KC, Hung CF, Wang SJ. Hydrogen inhalation exerts anti-seizure effects by preventing oxidative stress and inflammation in the hippocampus in a rat model of kainic acid-induced seizures. Neurochem Int 2025; 183:105925. [PMID: 39725210 DOI: 10.1016/j.neuint.2024.105925] [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: 10/15/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 12/28/2024]
Abstract
Hydrogen gas (H2) is an antioxidant with demonstrated neuroprotective efficacy. In this study, we administered H2 via inhalation to rats to evaluate its effects on seizures induced by kainic acid (KA) injection and the underlying mechanism. The animals were intraperitoneally injected with KA (15 mg/kg) to induce seizures. H2 was inhaled 2 h once a day for 5 days before KA administration. The seizure activity was evaluated using Racine's convulsion scale and electroencephalography (EEG). Neuronal cell loss, glial cell activation, and the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, CCL2, and CCL3), reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the hippocampus were assessed. The cerebral blood flow of the rats was also evaluated. The results revealed that KA-treated rats presented increased seizure intensity; increased neuronal loss and astrocyte activation; increased levels of ROS, TNF-α, IL-1β, IL-6, CCL2, and CCL3; and reduced Nrf2 phosphorylation levels. Pretreatment with H2 inhalation significantly attenuated seizure intensity; prevented neuronal loss; decreased microglial and astrocytic activation; decreased ROS, TNF-α, IL-1β, IL-6, CCL2 and CCL3 levels; and increased Nrf2 levels. Inhalation of H2 also prevented the KA-induced decrease in cerebral blood flow. These results suggest that pretreatment with H2 inhalation ameliorates KA-induced seizures and inhibits the inflammatory response and oxidative stress, which protects neurons.
Collapse
Affiliation(s)
- Tzu-Kang Lin
- School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; Department of Neurosurgery, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, 24205, Taiwan
| | - Ming-Shang Pai
- School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, 33303, Taiwan
| | - Kun-Chieh Yeh
- School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; Department of Neurosurgery, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Chi-Feng Hung
- School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
| | - Su-Jane Wang
- School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, 33303, Taiwan.
| |
Collapse
|
|
4
|
Wang C, Yan M, Li Y, Han L, Wang H, Jia S, Liu X, Liu Y, Wu F, Wang B. Hydrogen-oxygen mixture inhalation as an adjunctive treatment to home-based exercise in older patients with knee osteoarthritis: an open-label, blinded-endpoint, randomized controlled trial. Front Pharmacol 2025; 16:1505922. [PMID: 39950118 PMCID: PMC11821916 DOI: 10.3389/fphar.2025.1505922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 01/09/2025] [Indexed: 02/16/2025] Open
Abstract
Objective Knee osteoarthritis (KOA) is a degenerative joint condition, leading to disability and diminished quality of life. Molecular hydrogen has been proven to have antioxidant and anti-inflammatory properties, but few studies have investigated its effects on osteoarthritis. Our study aims to assess the therapeutic potential of hydrogen-oxygen mixture (H2-O2) inhalation for KOA. Methods In this randomized controlled trial, eligible elderly KOA patients were randomly assigned to either Group H or Group C. Both groups participated in a 12-week home-based exercise (HBE) program, which included knee-joint exercises and health education. Group H additionally received H2-O2 inhalation for 60 min per day over 2 weeks, while Group C did not. The primary outcome was measured using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included inflammation levels (hs-CRP, NLR, PLR, LMR), Chair Stand Test (CST), Timed Up and Go (TUG), 36-item short-form health survey (SF-36), Exercise Adherence Rating Scale (EARS), and adverse events. Results A total of 121 subjects were enrolled, with an average age of 81.2 years, and 80.2% were female. The between-group mean difference in the WOMAC total score was -5.2 (95% CI -12.1 to 1.7, P = 0.140) at week 12, with Group H showing an improvement of -22.9 (95% CI -26.3 to -19.6, P < 0.001) and Group C showing an improvement of -19.4 (95% CI -22.7 to -16.0, P < 0.001) compared to baseline, revealing a significant group × time interaction (F (3, 356.034) = 14.425, P < 0.001). No significant differences were observed between both groups at week 12 in CST, TUG, SF-36 scores, EARS scores, or the incidence of adverse events. Conclusion Although clinical significance was not achieved, H2-O2 inhalation alleviated KOA symptoms and enhanced functional activity in elderly patients undergoing the HBE program during the initial 2 weeks. However, its sustained effects on improving KOA symptoms were not observed.
Collapse
Affiliation(s)
- Chenhui Wang
- Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Mengwei Yan
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Yuru Li
- Infirmary, Taikang Yanyuan Continuing Care Retirement Community, Beijing, China
| | - Lei Han
- Infirmary, Taikang Yanyuan Continuing Care Retirement Community, Beijing, China
| | - Hongqian Wang
- Infirmary, Taikang Yanyuan Continuing Care Retirement Community, Beijing, China
| | - Shufeng Jia
- Infirmary, Taikang Yanyuan Continuing Care Retirement Community, Beijing, China
| | - Xingchen Liu
- School of Nursing, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yang Liu
- Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Fan Wu
- Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Baoguo Wang
- Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
5
|
Xu M, Wu G, You Q, Chen X. The Landscape of Smart Biomaterial-Based Hydrogen Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401310. [PMID: 39166484 PMCID: PMC11497043 DOI: 10.1002/advs.202401310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 05/19/2024] [Indexed: 08/23/2024]
Abstract
Hydrogen (H2) therapy is an emerging, novel, and safe therapeutic modality that uses molecular hydrogen for effective treatment. However, the impact of H2 therapy is limited because hydrogen molecules predominantly depend on the systemic administration of H2 gas, which cannot accumulate at the lesion site with high concentration, thus leading to limited targeting and utilization. Biomaterials are developed to specifically deliver H2 and control its release. In this review, the development process, stimuli-responsive release strategies, and potential therapeutic mechanisms of biomaterial-based H2 therapy are summarized. H2 therapy. Specifically, the produced H2 from biomaterials not only can scavenge free radicals, such as reactive oxygen species (ROS) and lipid peroxidation (LPO), but also can inhibit the danger factors of initiating diseases, including pro-inflammatory cytokines, adenosine triphosphate (ATP), and heat shock protein (HSP). In addition, the released H2 can further act as signal molecules to regulate key pathways for disease treatment. The current opportunities and challenges of H2-based therapy are discussed, and the future research directions of biomaterial-based H2 therapy for clinical applications are emphasized.
Collapse
Affiliation(s)
- Min Xu
- College of Biomedical EngineeringTaiyuan University of TechnologyTaiyuan030024China
| | - Gege Wu
- Departments of Diagnostic Radiology, SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and College of Design and EngineeringNational University of SingaporeSingapore119074Singapore
- Nanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117597Singapore
- Theranostics Center of Excellence (TCE)Yong Loo Lin School of MedicineNational University of Singapore11 Biopolis Way, HeliosSingapore138667Singapore
- Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117599Singapore
| | - Qing You
- Departments of Diagnostic Radiology, SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and College of Design and EngineeringNational University of SingaporeSingapore119074Singapore
- Nanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117597Singapore
- Theranostics Center of Excellence (TCE)Yong Loo Lin School of MedicineNational University of Singapore11 Biopolis Way, HeliosSingapore138667Singapore
- Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117599Singapore
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and College of Design and EngineeringNational University of SingaporeSingapore119074Singapore
- Nanomedicine Translational Research ProgramNUS Center for NanomedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117597Singapore
- Theranostics Center of Excellence (TCE)Yong Loo Lin School of MedicineNational University of Singapore11 Biopolis Way, HeliosSingapore138667Singapore
- Clinical Imaging Research CentreCentre for Translational MedicineYong Loo Lin School of MedicineNational University of SingaporeSingapore117599Singapore
| |
Collapse
|
|
6
|
Jiang ZH, Wang JS, Wang JL, Zheng JF, Li XL, Yang ZC, Xu MQ, Zhang YL, Wang Y. Hydrogen attenuates ischaemia-reperfusion injury in skeletal muscles post-limb replantation by activating the NRF2/HO-1 signalling pathway to reduce BAX expression. Heliyon 2024; 10:e37018. [PMID: 39309900 PMCID: PMC11414507 DOI: 10.1016/j.heliyon.2024.e37018] [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: 04/24/2024] [Revised: 07/18/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024] Open
Abstract
Background Ischaemia-reperfusion injury (IRI) is a critical complication post-limb replantation. The oxidative stress and cellular apoptosis due to IRI considerably hinder the healing process. This study aimed to investigate the modulatory effects of pre-perfusion with hydrogen-rich heparin sodium on the nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 (HO-1) pathway and its potential mechanisms in mitigating skeletal muscle IRI post-limb replantation. Methods Forty healthy Sprague-Dawley rats (250-300 g) were classified into five groups (n = 8 each): normal control, IRI + heparin sodium pre-perfusion (heparin group), IRI + hydrogen-rich heparin sodium pre-perfusion (hydrogen-rich heparin group), IRI + hydrogen-rich heparin sodium pre-perfusion + NRF2 inhibitor (hydrogen-rich heparin + all-trans retinoic acid [ATRA] group), and IRI + heparin sodium pre-perfusion + NRF2 inhibitor (heparin + ATRA group). The activation of the NRF2/HO-1 pathway in skeletal muscle IRI was evaluated based on HO-1 expression using western blotting and immunofluorescence. Furthermore, haematoxylin and eosin staining and transmission electron microscopy were employed to determine the histopathological characteristics. Additionally, superoxide dismutase and malondialdehyde levels in skeletal muscle tissue were measured to assess antioxidant capacity and the degree of oxidative stress damage. Tissue hypoxia was assessed based on hypoxia-inducible factor 1-alpha expression, whereas apoptosis markers BCL-2-associated X protein (BAX) and Caspase-3 in skeletal muscle tissues were analysed using western blotting with terminal deoxynucleotidyl transferase dUTP nick end labelling staining to quantify cell apoptosis. Results Compared with the control group, the heparin group exhibited significant pathological changes, including inflammatory infiltration and cellular hypertrophy, with increased apoptosis and oxidative stress. Notably, NRF2 suppression aggravated these effects. However, hydrogen-rich heparin sodium prominently activated the NRF2/HO-1 pathway, enhancing antioxidant defence and reducing BAX/Caspase-3-mediated apoptosis, thereby mitigating IRI-induced damage. The use of an NRF2 inhibitor to inhibit NRF2 excitation by hydrogen-rich heparin sodium notably weakened NRF2 activation and the antioxidant response, resulting in a substantial increase in cellular apoptosis. Conclusion Pre-perfusion with hydrogen-rich heparin sodium markedly diminishes the BAX/Caspase-3-mediated apoptotic pathway in skeletal muscle tissues with IRI through the excitation of the NRF2/HO-1 pathway.
Collapse
Affiliation(s)
- zi-hao Jiang
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - jun-sheng Wang
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - jin-ling Wang
- Department of Emergency and Critical Care Center, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - jiang-fan Zheng
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - xiao-ling Li
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - zhi-cheng Yang
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - meng-qiu Xu
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - yong-li Zhang
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - yu Wang
- Department of Emergency, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| |
Collapse
|
|
7
|
Gao X, Niu S, Li L, Zhang X, Cao X, Zhang X, Pan W, Sun M, Zhao G, Zheng X, Song G, Zhang Y. Hydrogen therapy promotes macrophage polarization to the M2 subtype in radiation lung injury by inhibiting the NF-κB signalling pathway. Heliyon 2024; 10:e30902. [PMID: 38826750 PMCID: PMC11141264 DOI: 10.1016/j.heliyon.2024.e30902] [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: 01/14/2024] [Revised: 05/04/2024] [Accepted: 05/07/2024] [Indexed: 06/04/2024] Open
Abstract
Background Radiotherapy has become a standard treatment for chest tumors, but a common complication of radiotherapy is radiation lung injury. Currently, there is still a lack of effective treatment for radiation lung injury. Methods A mouse model of radioactive lung injury (RILI) was constructed and then treated with different cycles of hydrogen inhalation. Lung function tests were performed to detect changes in lung function.HE staining was used to detect pathological changes in lung tissue. Immunofluorescence staining was used to detect the polarization of macrophages in lung tissue. Immunohistochemistry was used to detect changes in cytokine expression in lung tissues. Western Blot was used to detect the expression of proteins related to the NF-κB signalling pathway. Results Lung function test results showed that lung function decreased in the model group and improved in the treatment group.HE staining showed that inflammatory response was evident in the model group and decreased in the treatment group. Immunohistochemistry results showed that the expression of pro-inflammatory factors was significantly higher in the model group, and the expression of pro-inflammatory factors was significantly higher in the treatment group. The expression of pro-inflammatory factors in the treatment group was significantly lower than that in the model group, and the expression of anti-inflammatory factors in the treatment group was higher than that in the model group. Immunofluorescence showed that the expression of M1 subtype macrophages was up-regulated in the model group and down-regulated in the treatment group. The expression of M2 subtype macrophages was up-regulated in the treatment group relative to the model group. Western Blot showed that P-NF-κB p65/NF-κB p65 was significantly increased in the model group, and P-NF-κB p65/NF-κB p65 was decreased in the treatment group. Conclusion Hydrogen therapy promotes macrophage polarization from M1 to M2 subtypes by inhibiting the NF-κB signalling pathway, thereby attenuating the inflammatory response to radiation lung injury.
Collapse
Affiliation(s)
- Xue Gao
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University, China
| | - Shiying Niu
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
- Department of Pathology, Linfen Central Hospital, China
| | - Lulu Li
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
| | - Xiaoyue Zhang
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University, China
| | - Xuetao Cao
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
| | - Xinhui Zhang
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University, China
| | - Wentao Pan
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
| | - Meili Sun
- Department of Pathology, Linfen Central Hospital, China
- Department of Oncology, Affiliated Central Hospital of Shandong First Medical University, China
| | - Guoli Zhao
- Department of Pathology, Liaocheng Infectious Disease Hospital, China
| | - Xuezhen Zheng
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University, China
| | - Guohua Song
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
| | - Yueying Zhang
- Department of Pathophysiology, School of Clinical and Basic Medicine, Shandong First Medical University, China
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University, China
| |
Collapse
|
|
8
|
Hu Q, Li Y, Lin Z, Zhang H, Chen H, Chao C, Zhao C. The Molecular Biological Mechanism of Hydrogen Therapy and Its Application in Spinal Cord Injury. Drug Des Devel Ther 2024; 18:1399-1414. [PMID: 38707612 PMCID: PMC11068043 DOI: 10.2147/dddt.s463177] [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: 02/15/2024] [Accepted: 04/23/2024] [Indexed: 05/07/2024] Open
Abstract
Hydrogen, which is a novel biomedical molecule, is currently the subject of extensive research involving animal experiments and in vitro cell experiments, and it is gradually being applied in clinical settings. Hydrogen has been proven to possess anti-inflammatory, selective antioxidant, and antiapoptotic effects, thus exhibiting considerable protective effects in various diseases. In recent years, several studies have provided preliminary evidence for the protective effects of hydrogen on spinal cord injury (SCI). This paper provides a comprehensive review of the potential molecular biology mechanisms of hydrogen therapy and its application in treating SCI, with an aim to better explore the medical value of hydrogen and provide new avenues for the adjuvant treatment of SCI.
Collapse
Affiliation(s)
- Quan Hu
- Department of Neurosurgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| | - Yingxiao Li
- Department of Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| | - Zhaochen Lin
- Hydrogen Medical Research Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| | - Hao Zhang
- Department of Rehabilitation Medical Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| | - Haoyue Chen
- Department of Rehabilitation Medical Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| | - Cui Chao
- Hydrogen Medical Research Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| | - Chuanliang Zhao
- Department of Orthopedics, the Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China
| |
Collapse
|
|
9
|
Perveen I, Bukhari B, Najeeb M, Nazir S, Faridi TA, Farooq M, Ahmad QUA, Abusalah MAHA, ALjaraedah TY, Alraei WY, Rabaan AA, Singh KKB, Abusalah MAHA. Hydrogen Therapy and Its Future Prospects for Ameliorating COVID-19: Clinical Applications, Efficacy, and Modality. Biomedicines 2023; 11:1892. [PMID: 37509530 PMCID: PMC10377251 DOI: 10.3390/biomedicines11071892] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 07/30/2023] Open
Abstract
Molecular hydrogen is renowned as an odorless and colorless gas. The recommendations developed by China suggest that the inhalation of hydrogen molecules is currently advised in COVID-19 pneumonia treatment. The therapeutic effects of molecular hydrogens have been confirmed after numerous clinical trials and animal-model-based experiments, which have expounded that the low molecular weight of hydrogen enables it to easily diffuse and permeate through the cell membranes to produce a variety of biological impacts. A wide range of both chronic and acute inflammatory diseases, which may include sepsis, pancreatitis, respiratory disorders, autoimmune diseases, ischemia-reperfusion damages, etc. may be treated and prevented by using it. H2 can primarily be inoculated through inhalation, by drinking water (which already contains H2), or by administrating the injection of saline H2 in the body. It may play a pivotal role as an antioxidant, in regulating the immune system, in anti-inflammatory activities (mitochondrial energy metabolism), and cell death (apoptosis, pyroptosis, and autophagy) by reducing the formation of excessive reactive O2 species and modifying the transcription factors in the nuclei of the cells. However, the fundamental process of molecular hydrogen is still not entirely understood. Molecular hydrogen H2 has a promising future in therapeutics based on its safety and possible usefulness. The current review emphasizes the antioxidative, anti-apoptotic, and anti-inflammatory effects of hydrogen molecules along with the underlying principle and fundamental mechanism involved, with a prime focus on the coronavirus disease of 2019 (COVID-19). This review will also provide strategies and recommendations for the therapeutic and medicinal applications of the hydrogen molecule.
Collapse
Affiliation(s)
- Ishrat Perveen
- Food and Biotechnology Research Centre, Pakistan Council of Scientific and Industrial Research Centre, Lahore 54590, Pakistan
| | - Bakhtawar Bukhari
- Food and Biotechnology Research Centre, Pakistan Council of Scientific and Industrial Research Centre, Lahore 54590, Pakistan
| | - Mahwish Najeeb
- University Institute of Public Health, The University of Lahore, Lahore 54590, Pakistan
| | - Sumbal Nazir
- School of Zoology, Minhaj University Lahore, Lahore 54770, Pakistan
| | - Tallat Anwar Faridi
- University Institute of Public Health, The University of Lahore, Lahore 54590, Pakistan
| | - Muhammad Farooq
- Food and Biotechnology Research Centre, Pakistan Council of Scientific and Industrial Research Centre, Lahore 54590, Pakistan
| | - Qurat-Ul-Ain Ahmad
- Division of Science and Technology, University of Education, Township Lahore, Lahore 54770, Pakistan
| | - Manal Abdel Haleem A Abusalah
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Thana' Y ALjaraedah
- Department of Diet Therapy Technology & Dietetics, Faculty of Allied Medical Sciences, Zarqa University, Al-Zarqa 13132, Jordan
| | - Wesal Yousef Alraei
- Department of Diet Therapy Technology & Dietetics, Faculty of Allied Medical Sciences, Zarqa University, Al-Zarqa 13132, Jordan
| | - Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
| | - Kirnpal Kaur Banga Singh
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Mai Abdel Haleem A Abusalah
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Zarqa University, Al-Zarqa 13132, Jordan
| |
Collapse
|
|
10
|
Rahman MH, Jeong ES, You HS, Kim CS, Lee KJ. Redox-Mechanisms of Molecular Hydrogen Promote Healthful Longevity. Antioxidants (Basel) 2023; 12:988. [PMID: 37237854 PMCID: PMC10215238 DOI: 10.3390/antiox12050988] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/07/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Age-related diseases represent the largest threat to public health. Aging is a degenerative, systemic, multifactorial and progressive process, coupled with progressive loss of function and eventually leading to high mortality rates. Excessive levels of both pro- and anti-oxidant species qualify as oxidative stress (OS) and result in damage to molecules and cells. OS plays a crucial role in the development of age-related diseases. In fact, damage due to oxidation depends strongly on the inherited or acquired defects of the redox-mediated enzymes. Molecular hydrogen (H2) has recently been reported to function as an anti-oxidant and anti-inflammatory agent for the treatment of several oxidative stress and aging-related diseases, including Alzheimer's, Parkinson's, cancer and osteoporosis. Additionally, H2 promotes healthy aging, increases the number of good germs in the intestine that produce more intestinal hydrogen and reduces oxidative stress through its anti-oxidant and anti-inflammatory activities. This review focuses on the therapeutic role of H2 in the treatment of neurological diseases. This review manuscript would be useful in knowing the role of H2 in the redox mechanisms for promoting healthful longevity.
Collapse
Affiliation(s)
- Md. Habibur Rahman
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea (C.-S.K.)
| | - Eun-Sook Jeong
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea (C.-S.K.)
| | - Hae Sun You
- Department of Anesthesiology & Pain Medicine, Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Cheol-Su Kim
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea (C.-S.K.)
| | - Kyu-Jae Lee
- Department of Convergence Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Republic of Korea (C.-S.K.)
| |
Collapse
|
|
11
|
Wu C, Zou P, Feng S, Zhu L, Li F, Liu TCY, Duan R, Yang L. Molecular Hydrogen: an Emerging Therapeutic Medical Gas for Brain Disorders. Mol Neurobiol 2023; 60:1749-1765. [PMID: 36567361 DOI: 10.1007/s12035-022-03175-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/14/2022] [Indexed: 12/27/2022]
Abstract
Oxidative stress and neuroinflammation are the main physiopathological changes involved in the initiation and progression of various neurodegenerative disorders or brain injuries. Since the landmark finding reported in 2007 found that hydrogen reduced the levels of peroxynitrite anions and hydroxyl free radicals in ischemic stroke, molecular hydrogen's antioxidative and anti-inflammatory effects have aroused widespread interest. Due to its excellent antioxidant and anti-inflammatory properties, hydrogen therapy via different routes of administration exhibits great therapeutic potential for a wide range of brain disorders, including Alzheimer's disease, neonatal hypoxic-ischemic encephalopathy, depression, anxiety, traumatic brain injury, ischemic stroke, Parkinson's disease, and multiple sclerosis. This paper reviews the routes for hydrogen administration, the effects of hydrogen on the previously mentioned brain disorders, and the primary mechanism underlying hydrogen's neuroprotection. Finally, we discuss hydrogen therapy's remaining issues and challenges in brain disorders. We conclude that understanding the exact molecular target, finding novel routes, and determining the optimal dosage for hydrogen administration is critical for future studies and applications.
Collapse
Affiliation(s)
- Chongyun Wu
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China
| | - Peibin Zou
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China
| | - Shu Feng
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China
| | - Ling Zhu
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China
| | - Fanghui Li
- School of Sports Science, Nanjing Normal University, Nanjing, 210046, China
| | - Timon Cheng-Yi Liu
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China
| | - Rui Duan
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China
| | - Luodan Yang
- Laboratory of Exercise and Neurobiology, School of Physical Education and Sports Science, South China Normal University, Guangzhou, 510006, China.
| |
Collapse
|
|
12
|
Wang Z, Gao C, Zhang L, Sui R. Hesperidin methylchalcone (HMC) hinders amyloid-β induced Alzheimer's disease by attenuating cholinesterase activity, macromolecular damages, oxidative stress and apoptosis via regulating NF-κB and Nrf2/HO-1 pathways. Int J Biol Macromol 2023; 233:123169. [PMID: 36623626 DOI: 10.1016/j.ijbiomac.2023.123169] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 11/04/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023]
Abstract
Phytocompounds therapy has recently emerged as an effective strategy to treat Alzheimer's disease. Herein, the protective effect of hesperidin methylchalcone (HMC) was evaluated through Alzheimer's disease models of Neuro-2a cells and Wistar rats. The in vitro results showed that HMC possesses significant ability to inhibit the acetylcholinesterase enzyme and exhibiting anti-aggregation and disaggregation properties. Furthermore, HMC could protect the Neuro-2a cells against Aβ-induced neurotoxicity. Simultaneously, HMC treatment significantly improved the cognitive deficits caused by Aβ-peptide on spatial memory in Wistar rats. HMC significantly enhanced the cholinergic effects by inhibiting AChE, BuChE, β-secretase activity, caspase-3 activity, and attenuating macromolecular damages and apoptosis. Notably, HMC reduced the Aβ-induced oxidative stress by activating the antioxidative defence enzymes. In addition, the HMC treatment suppressed the expression of immunocytokines such as p-NF-κB p65, p-IκBα, induced by Aβ; whereas upregulating Nrf2, HO-1 in brain homogenate. These results suggest that HMC could attenuate Aβ-induced neuroinflammation in brain via suppressing NF-κB signalling pathway and activating the Nrf2/HO-1 pathway, thereby improving memory and cognitive impairments in Wistar rats. Overall, the present study reports that HMC can act as a potent candidate with multi-faceted neuroprotective potential against Aβ-induced memory dysfunction in Wistar rats for the treatment of Alzheimer's disease.
Collapse
Affiliation(s)
- Zhuo Wang
- School of Nursing, Jinzhou Medical University, Jinzhou 121099, China
| | - Chao Gao
- School of Nursing, Jinzhou Medical University, Jinzhou 121099, China
| | - Lei Zhang
- School of Nursing, Jinzhou Medical University, Jinzhou 121099, China
| | - Rubo Sui
- Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121099, China.
| |
Collapse
|
|
13
|
Hydrogen Gas Treatment Improves Postoperative Delirium and Cognitive Dysfunction in Elderly Noncardiac Patients. J Pers Med 2022; 13:jpm13010067. [PMID: 36675728 PMCID: PMC9867387 DOI: 10.3390/jpm13010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/03/2022] [Accepted: 12/08/2022] [Indexed: 12/29/2022] Open
Abstract
Purpose: Postoperative delirium is a state of acute brain dysfunction characterized by fluctuating mental status that affects millions of patients each year. We used prophylactic inhalation of hydrogen gas in elderly patients undergoing elective surgery to compare their occurrence of postoperative delirium with that of controls. Methods: A total of 184 patients aged ≥ 65 years were enrolled and randomized into either a control group or a hydrogen inhalation group. The quality of sleep was assessed 1 day before and 1, 3, and 7 days after surgery at 8 A.M. The Confusion Assessment Method (CAM) was used as a screening tool for delirium and assessed the patients’ state of consciousness 1−7 days after surgery. Results: Postoperative delirium occurred in 17 (24%) of 70 patients without hydrogen inhalation and in 10 (12%) of 83 patients after hydrogen inhalation. The incidence of delirium was decreased in the hydrogen group. No significant differences were found between length of stay in hospital after surgery and sleep quality at 1, 3, and 7 days postoperatively between the two groups. The numerical rating scale (NRS) pain scores were higher in the hydrogen group (4.08 ± 1.77) than the control group (3.54 ± 1.77) on day 1 (p < 0.05); however, the mean difference between the two groups was small (1 to 1.6). There were no significant differences on day 3 and 7. The postoperative C-reactive protein level was significantly lower in the hydrogen group than the control group. Conclusions: This study suggests that hydrogen inhalation can prevent postoperative delirium in elderly noncardiac patients by reducing the inflammatory response.
Collapse
|
|
14
|
Role of Molecular Hydrogen in Ageing and Ageing-Related Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2249749. [PMID: 35340218 PMCID: PMC8956398 DOI: 10.1155/2022/2249749] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 02/10/2022] [Accepted: 03/03/2022] [Indexed: 12/17/2022]
Abstract
Ageing is a physiological process of progressive decline in the organism function over time. It affects every organ in the body and is a significant risk for chronic diseases. Molecular hydrogen has therapeutic and preventive effects on various organs. It has antioxidative properties as it directly neutralizes hydroxyl radicals and reduces peroxynitrite level. It also activates Nrf2 and HO-1, which regulate many antioxidant enzymes and proteasomes. Through its antioxidative effect, hydrogen maintains genomic stability, mitigates cellular senescence, and takes part in histone modification, telomere maintenance, and proteostasis. In addition, hydrogen may prevent inflammation and regulate the nutrient-sensing mTOR system, autophagy, apoptosis, and mitochondria, which are all factors related to ageing. Hydrogen can also be used for prevention and treatment of various ageing-related diseases, such as neurodegenerative disorders, cardiovascular disease, pulmonary disease, diabetes, and cancer. This paper reviews the basic research and recent application of hydrogen in order to support hydrogen use in medicine for ageing prevention and ageing-related disease therapy.
Collapse
|
|
15
|
Abstract
Molecular hydrogen exerts biological effects on nearly all organs. It has anti-oxidative, anti-inflammatory, and anti-aging effects and contributes to the regulation of autophagy and cell death. As the primary organ for gas exchange, the lungs are constantly exposed to various harmful environmental irritants. Short- or long-term exposure to these harmful substances often results in lung injury, causing respiratory and lung diseases. Acute and chronic respiratory diseases have high rates of morbidity and mortality and have become a major public health concern worldwide. For example, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. An increasing number of studies have revealed that hydrogen may protect the lungs from diverse diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary arterial hypertension, and pulmonary fibrosis. In this review, we highlight the multiple functions of hydrogen and the mechanisms underlying its protective effects in various lung diseases, with a focus on its roles in disease pathogenesis and clinical significance.
Collapse
Affiliation(s)
- Zhiling Fu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Jin Zhang
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| |
Collapse
|
|
16
|
Huang Y, Xiao FM, Tang WJ, Qiao J, Wei HF, Xie YY, Wei YZ. Hydrogen inhalation promotes recovery of a patient in persistent vegetative state from intracerebral hemorrhage: A case report and literature review. World J Clin Cases 2022; 10:1311-1319. [PMID: 35211564 PMCID: PMC8855194 DOI: 10.12998/wjcc.v10.i4.1311] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/05/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Persistent vegetative state (PVS) is a devastating and long-lasting clinical condition with high morbidity and mortality; currently, there are no available effective interventions.
CASE SUMMARY We report the case of an 11-year-old boy with PVS caused by severe intracerebral bleeding in the left hemisphere following anticoagulation treatment. The patient’s PVS severity showed no notable improvement after 2-mo neuroprotective treatment and rehabilitation, including nerve growth factor and baclofen, hyperbaric oxygen, and comprehensive bedside rehabilitation therapies. Daily inhalation treatment (4-6 h) of high-concentration hydrogen (H2) gas (66.6% H2 + 33.3% O2) was provided. Surprisingly, the patient’s orientation, consciousness, ability to speak, facial expressions, and locomotor function were significantly restored, along with improvements in essential general health status, after H2 gas inhalation treatment, which was consistent with stabilized neuropathology in the left hemisphere and increased Hounsfield unit values of computed tomography in the right hemisphere. The patient finally recovered to a near normal conscious state with a Coma Recovery Scale-Revised Score of 22 from his previous score of 3.
CONCLUSION Phase 1 clinical trials are needed to explore the safety and efficacy of H2 gas inhalation in patients with PVS.
Collapse
Affiliation(s)
- Yan Huang
- Department of Rehabilitation, Qilu Children’s Hospital of Shandong University, Jinan 250022, Shandong Province, China
| | - Feng-Ming Xiao
- Department of Rehabilitation, Qilu Children’s Hospital of Shandong University, Jinan 250022, Shandong Province, China
| | - Wen-Jie Tang
- Research Center for Translational Medicine & Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, Shanghai Province, China
| | - Jing Qiao
- Department of Pediatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, Shanghai Province, China
| | - Hai-Feng Wei
- Department of Clinical Imaging, The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250022, Shandong Province, China
| | - Yuan-Yun Xie
- National Clinic and Medicine Research Institute for Geriatric Diseases, Gannan Health Promotion and Translational Laboratory, The First Affiliated Hospital, Gannan University of Medical Sciences, Ganzhou 341000, Jiangxi Province, China
| | - You-Zhen Wei
- Research Center for Translational Medicine & Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, Shanghai Province, China
| |
Collapse
|
|
17
|
Tian Y, Zhang Y, Wang Y, Chen Y, Fan W, Zhou J, Qiao J, Wei Y. Hydrogen, a Novel Therapeutic Molecule, Regulates Oxidative Stress, Inflammation, and Apoptosis. Front Physiol 2022; 12:789507. [PMID: 34987419 PMCID: PMC8721893 DOI: 10.3389/fphys.2021.789507] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/22/2021] [Indexed: 12/21/2022] Open
Abstract
Molecular hydrogen (H2) is a colorless and odorless gas. Studies have shown that H2 inhalation has the therapeutic effects in many animal studies and clinical trials, and its application is recommended in the novel coronavirus pneumonia treatment guidelines in China recently. H2 has a relatively small molecular mass, which helps it quickly spread and penetrate cell membranes to exert a wide range of biological effects. It may play a role in the treatment and prevention of a variety of acute and chronic inflammatory diseases, such as acute pancreatitis, sepsis, respiratory disease, ischemia reperfusion injury diseases, autoimmunity diseases, etc.. H2 is primarily administered via inhalation, drinking H2-rich water, or injection of H2 saline. It may participate in the anti-inflammatory and antioxidant activity (mitochondrial energy metabolism), immune system regulation, and cell death (apoptosis, autophagy, and pyroptosis) through annihilating excess reactive oxygen species production and modulating nuclear transcription factor. However, the underlying mechanism of H2 has not yet been fully revealed. Owing to its safety and potential efficacy, H2 has a promising potential for clinical use against many diseases. This review will demonstrate the role of H2 in antioxidative, anti-inflammatory, and antiapoptotic effects and its underlying mechanism, particularly in coronavirus disease-2019 (COVID-19), providing strategies for the medical application of H2 for various diseases.
Collapse
Affiliation(s)
- Yan Tian
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China
| | - Yafang Zhang
- Department of Pediatrics, Taian City Central Hospital, Taian, China
| | - Yu Wang
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China.,Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China
| | - Yunxi Chen
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China
| | - Weiping Fan
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, China
| | - Jianjun Zhou
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China
| | - Jing Qiao
- Department of Pediatrics, Tongji University Affiliated East Hospital, Shanghai, China
| | - Youzhen Wei
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China
| |
Collapse
|
|
18
|
Jeong ES, Bajgai J, You IS, Rahman MH, Fadriquela A, Sharma S, Kwon HU, Lee SY, Kim CS, Lee KJ. Therapeutic Effects of Hydrogen Gas Inhalation on Trimethyltin-Induced Neurotoxicity and Cognitive Impairment in the C57BL/6 Mice Model. Int J Mol Sci 2021; 22:ijms222413313. [PMID: 34948107 PMCID: PMC8703468 DOI: 10.3390/ijms222413313] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 12/04/2022] Open
Abstract
Oxidative stress (OS) is one of the causative factors in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s disease (AD) and cognitive dysfunction. In the present study, we investigated the effects of hydrogen (H2) gas inhalation in trimethyltin (TMT)-induced neurotoxicity and cognitive dysfunction in the C57BL/6 mice. First, mice were divided into the following groups: mice without TMT injection (NC), TMT-only injection group (TMT only), TMT injection + lithium chloride-treated group as a positive control (PC), and TMT injection + 2% H2 inhalation-treated group (H2). The TMT injection groups were administered a single dosage of intraperitoneal TMT injection (2.6 mg/kg body weight) and the H2 group was treated with 2% H2 for 30 min once a day for four weeks. Additionally, a behavioral test was performed with Y-maze to test the cognitive abilities of the mice. Furthermore, multiple OS- and AD-related biomarkers such as reactive oxygen species (ROS), nitric oxide (NO), calcium (Ca2+), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase, inflammatory cytokines, apolipoprotein E (Apo-E), amyloid β (Aβ)-40, phospho-tau (p-tau), Bcl-2, and Bcl-2- associated X (Bax) were investigated in the blood and brain. Our results demonstrated that TMT exposure alters seizure and spatial recognition memory. However, after H2 treatment, memory deficits were ameliorated. H2 treatment also decreased AD-related biomarkers, such as Apo-E, Aβ-40, p-tau, and Bax and OS markers such as ROS, NO, Ca2+, and MDA in both serum and brain. In contrast, catalase and GPx activities were significantly increased in the TMT-only group and decreased after H2 gas treatment in serum and brain. In addition, inflammatory cytokines such as granulocyte colony-stimulating factors (G-CSF), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) were found to be significantly decreased after H2 treatment in both serum and brain lysates. In contrast, Bcl-2 and vascular endothelial growth factor (VEGF) expression levels were found to be enhanced after H2 treatment. Taken together, our results demonstrated that 2% H2 gas inhalation in TMT-treated mice exhibits memory enhancing activity and decreases the AD, OS, and inflammatory-related markers. Therefore, H2 might be a candidate for repairing neurodegenerative diseases with cognitive dysfunction. However, further mechanistic studies are needed to fully clarify the effects of H2 inhalation on TMT-induced neurotoxicity and cognitive dysfunction.
Collapse
Affiliation(s)
- Eun-Sook Jeong
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (E.-S.J.); (J.B.); (M.H.R.); (S.S.); (C.-S.K.)
| | - Johny Bajgai
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (E.-S.J.); (J.B.); (M.H.R.); (S.S.); (C.-S.K.)
| | - In-Soo You
- GOOTZ Co., Ltd., 79-6, Yuljeong-ro 247 beon-gil, Yangju-si, Suwon 11457, Korea; (I.-S.Y.); (H.-U.K.); (S.-Y.L.)
| | - Md. Habibur Rahman
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (E.-S.J.); (J.B.); (M.H.R.); (S.S.); (C.-S.K.)
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
| | - Ailyn Fadriquela
- Department of Laboratory Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea;
| | - Subham Sharma
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (E.-S.J.); (J.B.); (M.H.R.); (S.S.); (C.-S.K.)
- Department of Global Medical Science, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea
| | - Hwang-Un Kwon
- GOOTZ Co., Ltd., 79-6, Yuljeong-ro 247 beon-gil, Yangju-si, Suwon 11457, Korea; (I.-S.Y.); (H.-U.K.); (S.-Y.L.)
| | - So-Yeon Lee
- GOOTZ Co., Ltd., 79-6, Yuljeong-ro 247 beon-gil, Yangju-si, Suwon 11457, Korea; (I.-S.Y.); (H.-U.K.); (S.-Y.L.)
| | - Cheol-Su Kim
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (E.-S.J.); (J.B.); (M.H.R.); (S.S.); (C.-S.K.)
| | - Kyu-Jae Lee
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju 26426, Korea; (E.-S.J.); (J.B.); (M.H.R.); (S.S.); (C.-S.K.)
- Correspondence: ; Tel.: +82-(033)-741-331
| |
Collapse
|
|
19
|
Walia V, Kaushik D, Mittal V, Kumar K, Verma R, Parashar J, Akter R, Rahman MH, Bhatia S, Al-Harrasi A, Karthika C, Bhattacharya T, Chopra H, Ashraf GM. Delineation of Neuroprotective Effects and Possible Benefits of AntioxidantsTherapy for the Treatment of Alzheimer's Diseases by Targeting Mitochondrial-Derived Reactive Oxygen Species: Bench to Bedside. Mol Neurobiol 2021; 59:657-680. [PMID: 34751889 DOI: 10.1007/s12035-021-02617-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/19/2021] [Indexed: 12/25/2022]
Abstract
Alzheimer's disease (AD) is considered the sixth leading cause of death in elderly patients and is characterized by progressive neuronal degeneration and impairment in memory, language, etc. AD is characterized by the deposition of senile plaque, accumulation of fibrils, and neurofibrillary tangles (NFTs) which are responsible for neuronal degeneration. Amyloid-β (Aβ) plays a key role in the process of neuronal degeneration in the case of AD. It has been reported that Aβ is responsible for the production of reactive oxygen species (ROS), depletion of endogenous antioxidants, increase in intracellular Ca2+ which further increases mitochondria dysfunctions, oxidative stress, release of pro-apoptotic factors, neuronal apoptosis, etc. Thus, oxidative stress plays a key role in the pathogenesis of AD. Antioxidants are compounds that have the ability to counteract the oxidative damage conferred by ROS. Therefore, the antioxidant therapy may provide benefits and halt the progress of AD to advance stages by counteracting neuronal degeneration. However, despite the beneficial effects imposed by the antioxidants, the findings from the clinical studies suggested inconsistent results which might be due to poor study design, selection of the wrong antioxidant, inability of the molecule to cross the blood-brain barrier (BBB), treatment in the advanced state of disease, etc. The present review insights into the neuroprotective effects and limitations of the antioxidant therapy for the treatment of AD by targeting mitochondrial-derived ROS. This particular article will certainly help the researchers to search new avenues for the treatment of AD by utilizing mitochondrial-derived ROS-targeted antioxidant therapies.
Collapse
Affiliation(s)
- Vaibhav Walia
- SGT College of Pharmacy, SGT University, Gurugram, Haryana, India
| | - Deepak Kaushik
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India
| | - Vineet Mittal
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India
| | - Kuldeep Kumar
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
- University Institute of Pharmaceutical Sciences (UIPS), Chandigarh University, Gharuan, Mohali, Punjab, India
| | - Ravinder Verma
- Department of Pharmacy, School of Medical and Allied Sciences, G.D. Goenka University, Gurugram, 122103, India
| | - Jatin Parashar
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India
| | - Rokeya Akter
- Department of Pharmacy, Jagannath University, Sadarghat, Dhaka, 1100, Bangladesh
| | - Md Habibur Rahman
- Department of Pharmacy, Southeast University, Banani, Dhaka, 1213, Bangladesh.
| | - Saurabh Bhatia
- School of Health Science University of Petroleum and Energy Studies, Dehrandun, Uttarkhand, 248007, India
- Natural & Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mouz, P.O. Box 33, Nizwa, Oman
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mouz, P.O. Box 33, Nizwa, Oman
| | - Chenmala Karthika
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, The Nilgiris, Ooty, 643001, Tamil Nadu, India
| | - Tanima Bhattacharya
- College of Chemistry & Chemical Engineering, Hubei University, Wuhan, 430062, China
| | - Hitesh Chopra
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Ghulam Md Ashraf
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
|
20
|
Zolkiffly SZI, Stanslas J, Abdul Hamid H, Mehat MZ. Ficus deltoidea: Potential inhibitor of pro-inflammatory mediators in lipopolysaccharide-induced activation of microglial cells. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114309. [PMID: 34119609 DOI: 10.1016/j.jep.2021.114309] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/29/2021] [Accepted: 06/02/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ficus deltoidea Jack (FD) is widely consumed in traditional medicine as a treatment for various diseases in Malaysia. Each part of the plant such as its leave, stem, fruit and root are used traditionally to treat different types of diseases. Vitexin and isovitexin are bioactive compounds abundantly found in the leaves of FD that possessed many pharmacological properties including neuroprotection. Nonetheless, its effects on key events in neuroinflammation are unknown. AIM OF THE STUDY To determine the inhibitory properties of FD aqueous extract on pro-inflammatory mediators involved in lipopolysaccharide (LPS)-induced microglial cells. METHODS Vitexin and isovitexin in the extract were quantified via high performance liquid chromatography (HPLC). The extract was evaluated for its cytotoxicity activity via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Pre-treatment with the extract on LPS-induced microglial cells was done to determine its antioxidant and anti-neuroinflammatory properties by measuring the level of reactive oxygen species (ROS), nitric oxide (NO), tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) via 2'-7'-dichlorofluorescin diacetate (DCFDA) assay, Griess assay and Western blot respectively. RESULTS The extract at all tested concentrations (0.1 μg/mL, 1 μg/mL, 10 μg/mL, 100 μg/mL) were not cytotoxic as the percentage viability of microglial cells were all above ~80%. At the highest concentration (100 μg/mL), the extract significantly reduced the formation of ROS, NO, TNF-α, IL-1β and IL-6 in microglial cells induced by LPS. CONCLUSION The extract showed neuroprotective effects by attenuating the levels of pro-inflammatory and cytotoxic factors in LPS-induced microglial cells, possibly by mediating the nuclear factor-kappa B (NF-κB) signalling pathway.
Collapse
Affiliation(s)
- Siti Zaidathul Iman Zolkiffly
- Department of Human Anatomy, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Johnson Stanslas
- Department of Medicine, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Hafizah Abdul Hamid
- Department of Human Anatomy, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Muhammad Zulfadli Mehat
- Department of Human Anatomy, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
| |
Collapse
|
|
21
|
Influence of Cs Promoter on Ethanol Steam-Reforming Selectivity of Pt/m-ZrO2 Catalysts at Low Temperature. Catalysts 2021. [DOI: 10.3390/catal11091104] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The decarboxylation pathway in ethanol steam reforming ultimately favors higher selectivity to hydrogen over the decarbonylation mechanism. The addition of an optimized amount of Cs to Pt/m-ZrO2 catalysts increases the basicity and promotes the decarboxylation route, converting ethanol to mainly H2, CO2, and CH4 at low temperature with virtually no decarbonylation being detected. This offers the potential to feed the product stream into a conventional methane steam reformer for the production of hydrogen with higher selectivity. DRIFTS and the temperature-programmed reaction of ethanol steam reforming, as well as fixed bed catalyst testing, revealed that the addition of just 2.9% Cs was able to stave off decarbonylation almost completely by attenuating the metallic function. This occurs with a decrease in ethanol conversion of just 16% relative to the undoped catalyst. In comparison with our previous work with Na, this amount is—on an equivalent atomic basis—just 28% of the amount of Na that is required to achieve the same effect. Thus, Cs is a much more efficient promoter than Na in facilitating decarboxylation.
Collapse
|
|
22
|
Yamamoto H, Ichikawa Y, Hirano SI, Sato B, Takefuji Y, Satoh F. Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases. Int J Mol Sci 2021; 22:7211. [PMID: 34281264 PMCID: PMC8268741 DOI: 10.3390/ijms22137211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/17/2022] Open
Abstract
Mibyou, or pre-symptomatic diseases, refers to state of health in which a disease is slowly developing within the body yet the symptoms are not apparent. Common examples of mibyou in modern medicine include inflammatory diseases that are caused by chronic inflammation. It is known that chronic inflammation is triggered by the uncontrolled release of proinflammatory cytokines by neutrophils and macrophages in the innate immune system. In a recent study, it was shown that molecular hydrogen (H2) has the ability to treat chronic inflammation by eliminating hydroxyl radicals (·OH), a mitochondrial reactive oxygen species (ROS). In doing so, H2 suppresses oxidative stress, which is implicated in several mechanisms at the root of chronic inflammation, including the activation of NLRP3 inflammasomes. This review explains these mechanisms by which H2 can suppress chronic inflammation and studies its applications as a protective agent against different inflammatory diseases in their pre-symptomatic state. While mibyou cannot be detected nor treated by modern medicine, H2 is able to suppress the pathogenesis of pre-symptomatic diseases, and thus exhibits prospects as a novel protective agent.
Collapse
Affiliation(s)
- Haru Yamamoto
- Department of Molecular & Cell Biology, University of California, Berkeley, 3060 Valley Life Sciences Bldg #3140, Berkeley, CA 94720-3140, USA
- MiZ Inc., 39899 Balentine Drive Suite 200, Newark, CA 94560, USA;
| | - Yusuke Ichikawa
- MiZ Inc., 39899 Balentine Drive Suite 200, Newark, CA 94560, USA;
| | - Shin-ichi Hirano
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan; (S.-i.H.); (B.S.); (F.S.)
| | - Bunpei Sato
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan; (S.-i.H.); (B.S.); (F.S.)
| | - Yoshiyasu Takefuji
- Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa 252-0882, Japan;
- Faculty of Data Science, Musashino University, 3-3-3 Ariake, Koto-Ku, Tokyo 134-8181, Japan
| | - Fumitake Satoh
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan; (S.-i.H.); (B.S.); (F.S.)
| |
Collapse
|
|
23
|
Tofighi N, Asle-Rousta M, Rahnema M, Amini R. Protective effect of alpha-linoleic acid on Aβ-induced oxidative stress, neuroinflammation, and memory impairment by alteration of α7 nAChR and NMDAR gene expression in the hippocampus of rats. Neurotoxicology 2021; 85:245-253. [PMID: 34111468 DOI: 10.1016/j.neuro.2021.06.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/23/2021] [Accepted: 06/04/2021] [Indexed: 01/06/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects many older people around the world. Numerous studies are underway to evaluate the protective effects of natural products in AD. Alpha-linoleic acid (ALA) is an essential unsaturated fatty acid that exhibits neuroprotective outcomes in rat models of ischemic stroke and Parkinson's disease. This research aimed to investigate the effect of ALA on oxidative stress, neuroinflammation, neuronal death, and memory deficit induced by amyloid-beta (Aβ) peptide. After intrahippocampal injection of Aβ1-42, rats received ALA (150 μg/kg, subcutaneously) for 14 consecutive days. ALA decreased the levels of malondialdehyde and nitric oxide, enhanced glutathione content, and increased the activity of catalase in the hippocampus of the rat model of AD. It also reduced the expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, nuclear factor-kappa B, and N-methyl-d-aspartate receptor subunits NR2A and NR2B mRNAs in the hippocampus, prevented the neuronal loss in the CA1 region, and enhanced the expression of α7 nicotinic acetylcholine receptor. In addition, ALA allowed Aβ1-42-injected rats to spend less time and distance to reach the hidden platform in the Morris water maze test and to swim longer in the target quadrant. We concluded that ALA reduces the biochemical, molecular, histological, and behavioral changes caused by Aβ1-42 and it may be an effective option for treating AD.
Collapse
Affiliation(s)
- Nahaleh Tofighi
- Department of Physiology, Zanjan Branch, Islamic Azad University, Zanjan, Iran
| | | | - Mehdi Rahnema
- Department of Physiology, Zanjan Branch, Islamic Azad University, Zanjan, Iran
| | - Rahim Amini
- Department of Biology, Zanjan Branch, Islamic Azad University, Zanjan, Iran
| |
Collapse
|
|
24
|
Chen JB, Kong XF, Mu F, Lu TY, Lu YY, Xu KC. Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer. Med Gas Res 2021; 10:75-80. [PMID: 32541132 PMCID: PMC7885710 DOI: 10.4103/2045-9912.285560] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Chemotherapy, targeted therapy, and immunotherapy are used against advanced non-small cell lung cancer. A clinically efficacious method for relieving the adverse events associated of such therapies is lacking. Fifty-eight adult patients were enrolled in our trial to relieve pulmonary symptoms or the adverse events of drugs. Twenty patients who refused drug treatment were assigned equally and randomly to a hydrogen (H2)-only group and a control group. According to the results of tumor-gene mutations and drug-sensitivity tests, 10, 18, and 10 patients were enrolled into chemotherapy, targeted therapy, and immunotherapy groups in which these therapies were combined with H2-therapy, respectively. Patients underwent H2 inhalation for 4–5 hours per day for 5 months or stopped when cancer recurrence. Before study initiation, the demographics (except for tumor-mutation genes) and pulmonary symptoms (except for moderate cough) of the five groups showed no significant difference. During the first 5 months of treatment, the prevalence of symptoms of the control group increased gradually, whereas that of the four treatment groups decreased gradually. After 16 months of follow-up, progression-free survival of the control group was lower than that of the H2-only group, and significantly lower than that of H2 + chemotherapy, H2 + targeted therapy, and H2 + immunotherapy groups. In the combined-therapy groups, most drug-associated adverse events decreased gradually or even disappeared. H2 inhalation was first discovered in the clinic that can be used to control tumor progression and alleviate the adverse events of medications for patients with advanced non-small cell lung cancer. This study was approved by the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval No. Fuda20181207), and was registered at ClinicalTrials.gov (Identifier: NCT03818347) on January 28, 2019.
Collapse
Affiliation(s)
- Ji-Bing Chen
- Fuda Cancer Hospital of Jinan University, Guangzhou; Fuda Cancer Institute, Guangzhou, Guangdong Province, China
| | - Xiao-Feng Kong
- Fuda Cancer Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Feng Mu
- Fuda Cancer Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Tian-Yu Lu
- Fuda Cancer Hospital of Jinan University, Guangzhou; Fuda Cancer Institute, Guangzhou, Guangdong Province, China
| | - You-Yong Lu
- Central Lab, Beijing Cancer Hospital, Beijing, China
| | - Ke-Cheng Xu
- Fuda Cancer Hospital of Jinan University, Guangzhou; Fuda Cancer Institute, Guangzhou, Guangdong Province, China
| |
Collapse
|
|
25
|
Bajgai J, Lee KJ, Rahman MH, Fadriquela A, Kim CS. Role of Molecular Hydrogen in Skin Diseases and its Impact in Beauty. Curr Pharm Des 2021; 27:737-746. [PMID: 32981497 DOI: 10.2174/1381612826666200925124235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/16/2020] [Indexed: 11/22/2022]
Abstract
In today's society, healthy skin and a beautiful appearance are considered the foundation of general well-being. The skin is the largest organ of the body and plays an important role in protecting it against various hazards such as environmental, physical, chemical, and biological hazards. These factors include mediators that lead to oxidation reactions that produce reactive oxygen/nitrogen species and additional oxidants in the skin cells. An increase in oxidants beyond the antioxidant capacity of its defense system causes oxidative stress and chronic inflammation in the body. This response can cause further disruption of collagen fibers and hinder the functioning of skin cells that may result in the development of various skin diseases including psoriasis, atopic dermatitis, and aging. In this review, we summarized the present information related to the role of oxidative stress in the pathogenesis of dermatological disorders, and its impact on physical beauty and the daily lives of patients. We also discussed how molecular hydrogen exhibits a therapeutic effect against skin diseases via its effects on oxidative stress. Furthermore, findings from this summary review indicate that molecular hydrogen might be an effective treatment modality for the prevention and treatment of skin-related illnesses.
Collapse
Affiliation(s)
- Johny Bajgai
- Department of Environmental Medical Biology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do26426, Korea
| | - Kyu-Jae Lee
- Department of Environmental Medical Biology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do26426, Korea
| | - Md Habibur Rahman
- Department of Environmental Medical Biology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do26426, Korea
| | - Ailyn Fadriquela
- Department of Environmental Medical Biology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do26426, Korea
| | - Cheol-Su Kim
- Department of Environmental Medical Biology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do26426, Korea
| |
Collapse
|
|
26
|
Noda M, Liu J, Long J. Neuroprotective and Preventative Effects of Molecular Hydrogen. Curr Pharm Des 2021; 27:585-591. [PMID: 33076798 DOI: 10.2174/1381612826666201019103020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 08/12/2020] [Indexed: 11/22/2022]
Abstract
One of the beneficial effects of molecular hydrogen (H2, hydrogen gas) is neuroprotection and prevention of neurological disorders. It is important and useful if taking H2 every day can prevent or ameliorate the progression of neurodegenerative disorders, such as Parkinson's disease or Alzheimer's disease, both lacking specific therapeutic drugs. There are several mechanisms of how H2 protects neuronal damage. Anti-oxidative, anti-inflammatory, and the regulation of the endocrine system via stomach-brain connection seem to play an important role. At the cellular and tissue level, H2 appears to prevent the production of reactive oxygen species (ROS), and not only hydroxy radical (•OH) but also superoxide. In Parkinson's disease model mice, chronic intake of H2 causes the release of ghrelin from the stomach. In Alzheimer's disease model mice, sex-different neuroprotection is observed by chronic intake of H2. In female mice, declines of estrogen and estrogen receptor-β (ERβ) are prevented by H2, upregulating brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB). The question of how drinking H2 upregulates the release of ghrelin or attenuates the decline of estrogen remains to be investigated and the mechanism of how H2 modulates endocrine systems and the fundamental question of what or where is the target of H2 needs to be elucidated for a better understanding of the effects of H2.
Collapse
Affiliation(s)
- Mami Noda
- Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine and Center for Translational Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine and Center for Translational Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China
| |
Collapse
|
|
27
|
Chen WT, Lin GB, Kuo YY, Hsieh CH, Lu CH, Sun YK, Chao CY. Effect of high-frequency low-intensity pulsed electric field on protecting SH-SY5Y cells against hydrogen peroxide and β-amyloid-induced cell injury via ERK pathway. PLoS One 2021; 16:e0250491. [PMID: 33901243 PMCID: PMC8075192 DOI: 10.1371/journal.pone.0250491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/08/2021] [Indexed: 11/21/2022] Open
Abstract
As the most common type of neurodegenerative diseases (NDDs), Alzheimer's disease (AD) is thought to be caused mainly by the excessive aggregation of β-amyloid protein (Aβ). However, a growing number of studies have found that reactive oxygen species (ROS) play a key role in the onset and progression of AD. The present study aimed to probe the neuroprotective effect of high-frequency low-intensity pulsed electric field (H-LIPEF) for SH-SY5Y cells against hydrogen peroxide (H2O2) and Aβ-induced cytotoxicity. By looking in a systematic way into the frequency- and amplitude-dependent neuroprotective effect of pulsed electric field (PEF), the study finds that H-LIPEF at 200 Hz produces the optimal protective effect for SH-SY5Y cells. The underlying mechanisms were confirmed to be due to the activation of extracellular signal-regulated kinase (ERK) pathway and the downstream prosurvival and antioxidant proteins. Because the electric field can be modified to focus on specific area in a non-contact manner, the study suggests that H-LIPEF holds great potential for treating NDDs, whose effect can be further augmented with the administering of drugs or natural compounds at the same time.
Collapse
Affiliation(s)
- Wei-Ting Chen
- Department of Physics, Lab for Medical Physics & Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Guan-Bo Lin
- Department of Physics, Lab for Medical Physics & Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Yi Kuo
- Department of Physics, Lab for Medical Physics & Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chih-Hsiung Hsieh
- Department of Physics, Lab for Medical Physics & Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chueh-Hsuan Lu
- Department of Physics, Lab for Medical Physics & Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Kun Sun
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chih-Yu Chao
- Department of Physics, Lab for Medical Physics & Biomedical Engineering, National Taiwan University, Taipei, Taiwan
- Biomedical & Molecular Imaging Center, National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Applied Physics, Biophysics Division, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
28
|
Slezak J, Kura B, LeBaron TW, Singal PK, Buday J, Barancik M. Oxidative Stress and Pathways of Molecular Hydrogen Effects in Medicine. Curr Pharm Des 2021; 27:610-625. [PMID: 32954996 DOI: 10.2174/1381612826666200821114016] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/02/2020] [Indexed: 11/22/2022]
Abstract
There are many situations of excessive production of reactive oxygen species (ROS) such as radiation, ischemia/reperfusion (I/R), and inflammation. ROS contribute to and arises from numerous cellular pathologies, diseases, and aging. ROS can cause direct deleterious effects by damaging proteins, lipids, and nucleic acids as well as exert detrimental effects on several cell signaling pathways. However, ROS are important in many cellular functions. The injurious effect of excessive ROS can hypothetically be mitigated by exogenous antioxidants, but clinically this intervention is often not favorable. In contrast, molecular hydrogen provides a variety of advantages for mitigating oxidative stress due to its unique physical and chemical properties. H2 may be superior to conventional antioxidants, since it can selectively reduce ●OH radicals while preserving important ROS that are otherwise used for normal cellular signaling. Additionally, H2 exerts many biological effects, including antioxidation, anti-inflammation, anti-apoptosis, and anti-shock. H2 accomplishes these effects by indirectly regulating signal transduction and gene expression, each of which involves multiple signaling pathways and crosstalk. The Keap1-Nrf2-ARE signaling pathway, which can be activated by H2, plays a critical role in regulating cellular redox balance, metabolism, and inducing adaptive responses against cellular stress. H2 also influences the crosstalk among the regulatory mechanisms of autophagy and apoptosis, which involve MAPKs, p53, Nrf2, NF-κB, p38 MAPK, mTOR, etc. The pleiotropic effects of molecular hydrogen on various proteins, molecules and signaling pathways can at least partly explain its almost universal pluripotent therapeutic potential.
Collapse
Affiliation(s)
- Jan Slezak
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
| | - Branislav Kura
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
| | - Tyler W LeBaron
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
| | - Pawan K Singal
- Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
| | - Jozef Buday
- Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, 121 08 Prague 2, Czech Republic
| | - Miroslav Barancik
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia
| |
Collapse
|
|
29
|
CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-κB/p53 axis. Biosci Rep 2021; 40:222486. [PMID: 32219332 PMCID: PMC7560515 DOI: 10.1042/bsr20200092] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/22/2020] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Severe acute pancreatitis (SAP) is a common and life-threatening clinical acute abdominal disease. C1q/tumor necrosis factor-related protein 3 (CTRP3), a novel paralog of adiponectin, has been identified as a crucial regulator in multiple types of inflammatory disorders. However, the biological role of CTRP3 in SAP remains poorly understood. The present study aimed to characterize the role of CTRP3 in SAP and illuminate the potential mechanisms involved. In the current study, SAP mouse models were induced by seven hourly intraperitoneal injection of cerulein (50 μg/kg) and an immediate intraperitoneal injection of lipopolysaccharide (10 mg/kg) after the last cerulein administration. Histological examination and serological analysis demonstrated that SAP mouse models were successfully established. Herein, we found that CTRP3 expression was significantly decreased in the pancreatic tissues of SAP mice compared with normal control mice. Furthermore, we explored the effects of CTRP3 rescue in SAP mice and discovered that CTRP3 overexpression attenuated pathological lesions, inhibited inflammatory mediator release and repressed acinar cell apoptosis. Notably, mechanistic studies revealed that CTRP3 overexpression suppressed NF-κB p65 phosphorylation and p53 acetylation to alleviate cerulein-induced SAP in mouse models through activation of silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase. Collectively, our data indicate that CTRP3 may exert its protective effects in SAP mice via regulation of SIRT1-mediated NF-κB and p53 signaling pathways, implying a promising therapeutic strategy against SAP.
Collapse
|
|
30
|
Qu Y, Wang W, Chen T, Yang Y, Zhang Y, Wang D. The neuroprotection of deproteinized calf blood extractives injection against Alzheimer's disease via regulation of Nrf-2 signaling. Aging (Albany NY) 2021; 13:11150-11169. [PMID: 33819182 PMCID: PMC8109110 DOI: 10.18632/aging.202776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 02/12/2021] [Indexed: 12/29/2022]
Abstract
Alzheimer’s disease (AD) is characterized by cognitive decline due to the accumulation of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles in the brain, which impair glutamate (Glu) metabolism. Deproteinized Calf Blood Extractive Injection (DCBEI) is a biopharmaceutical that contains 17 types of amino acids and 5 types of nucleotides. In this study, we found that DCBEI pretreatment reduced L-Glu-dependent neuroexcitation toxicity by maintaining normal mitochondrial function in HT22 cells. DCBEI treatment also reduced the expression of pro-apoptosis proteins and increased the expression of anti-apoptosis proteins. Furthermore, DCBEI attenuated AD-like behaviors (detected via the Morris water maze test) in B6C3-Tg (APPswePSEN1dE9)/Nju double transgenic (APP/PS1) mice; this effect was associated with a reduction in the amount of Aβ and neurofibrillary tangle deposition and the concomitant reduction of phospho-Tau in the hippocampus. Metabonomic profiling revealed that DCBEI regulated the level of neurotransmitters in the hippocampus of APP/PS1 mice. Label-free proteomics revealed that DCBEI regulated the expression of Nrf-2 and its downstream targets, as well as the levels of phospho-protein kinase B and mitogen-activated protein kinase. Together, these data show that DCBEI can ameliorate AD symptoms by upregulating Nrf2-mediated antioxidative pathways and thus preventing mitochondrial apoptosis.
Collapse
Affiliation(s)
- Yidi Qu
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Wenqi Wang
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Tianrui Chen
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Yumin Yang
- School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yizhi Zhang
- Department of Neurology, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun 130012, China
| |
Collapse
|
|
31
|
Ohta S. Direct Targets and Subsequent Pathways for Molecular Hydrogen to Exert Multiple Functions: Focusing on Interventions in Radical Reactions. Curr Pharm Des 2021; 27:595-609. [PMID: 32767925 DOI: 10.2174/1381612826666200806101137] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/27/2020] [Indexed: 01/10/2023]
Abstract
Molecular hydrogen (H2) was long regarded as non-functional in mammalian cells. We overturned the concept by demonstrating that H2 exhibits antioxidant effects and protects cells against oxidative stress. Subsequently, it has been revealed that H2 has multiple functions in addition to antioxidant effects, including antiinflammatory, anti-allergic functions, and as cell death and autophagy regulation. Additionally, H2 stimulates energy metabolism. As H2 does not readily react with most biomolecules without a catalyst, it is essential to identify the primary targets with which H2 reacts or interacts directly. As a first event, H2 may react directly with strong oxidants, such as hydroxyl radicals (•OH) in vivo. This review addresses the key issues related to this in vivo reaction. •OH may have a physiological role because it triggers a free radical chain reaction and may be involved in the regulation of Ca2+- or mitochondrial ATP-dependent K+-channeling. In the subsequent pathway, H2 suppressed a free radical chain reaction, leading to decreases in lipid peroxide and its end products. Derived from the peroxides, 4-hydroxy-2-nonenal functions as a mediator that up-regulates multiple functional PGC-1α. As the other direct target in vitro and in vivo, H2 intervenes in the free radical chain reaction to modify oxidized phospholipids, which may act as an antagonist of Ca2+-channels. The resulting suppression of Ca2+-signaling inactivates multiple functional NFAT and CREB transcription factors, which may explain H2 multi-functionality. This review also addresses the involvement of NFAT in the beneficial role of H2 in COVID-19, Alzheimer's disease and advanced cancer. We discuss some unsolved issues of H2 action on lipopolysaccharide signaling, MAPK and NF-κB pathways and the Nrf2 paradox. Finally, as a novel idea for the direct targeting of H2, this review introduces the possibility that H2 causes structural changes in proteins via hydrate water changes.
Collapse
Affiliation(s)
- Shigeo Ohta
- Department of Neurology Medicine, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan
| |
Collapse
|
|
32
|
Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress. Int J Mol Sci 2021; 22:ijms22052549. [PMID: 33806292 PMCID: PMC7961517 DOI: 10.3390/ijms22052549] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 01/10/2023] Open
Abstract
Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).
Collapse
|
|
33
|
Chen W, Zhang HT, Qin SC. Neuroprotective Effects of Molecular Hydrogen: A Critical Review. Neurosci Bull 2021; 37:389-404. [PMID: 33078374 PMCID: PMC7954968 DOI: 10.1007/s12264-020-00597-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/31/2020] [Indexed: 12/15/2022] Open
Abstract
Molecular hydrogen (H2) is a physiologically inert gas. However, during the last 10 years, increasing evidence has revealed its biological functions under pathological conditions. More specifically, H2 has protective effects against a variety of diseases, particularly nervous system disorders, which include ischemia/reperfusion injury, traumatic injury, subarachnoid hemorrhage, neuropathic pain, neurodegenerative diseases, cognitive dysfunction induced by surgery and anesthesia, anxiety, and depression. In addition, H2 plays protective roles mainly through anti-oxidation, anti-inflammation, anti-apoptosis, the regulation of autophagy, and preservation of mitochondrial function and the blood-brain barrier. Further, H2 is easy to use and has neuroprotective effects with no major side-effects, indicating that H2 administration is a potential therapeutic strategy in clinical settings. Here we summarize the H2 donors and their pharmacokinetics. Meanwhile, we review the effectiveness and safety of H2 in the treatment of various nervous system diseases based on preclinical and clinical studies, leading to the conclusion that H2 can be a simple and effective clinical therapy for CNS diseases such as ischemia-reperfusion brain injury, Parkinson's disease, and diseases characterized by cognitive dysfunction. The potential mechanisms involved in the neuroprotective effect of H2 are also analyzed.
Collapse
Affiliation(s)
- Wei Chen
- Taishan Institute for Hydrogen Biomedicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, 271000, China
- Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, 271000, China
| | - Han-Ting Zhang
- Departments of Neuroscience and Behavioral Medicine and Psychiatry, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
| | - Shu-Cun Qin
- Taishan Institute for Hydrogen Biomedicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, 271000, China.
- Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, 271000, China.
| |
Collapse
|
|
34
|
Yadav RK, Minz E, Mehan S. Understanding Abnormal c-JNK/p38MAPK Signaling in Amyotrophic Lateral Sclerosis: Potential Drug Targets and Influences on Neurological Disorders. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 20:417-429. [PMID: 33557726 DOI: 10.2174/1871527320666210126113848] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/29/2020] [Accepted: 10/07/2020] [Indexed: 11/22/2022]
Abstract
c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to regulate neuronal signals. The abnormal activation of these cellular signals can cause glutamate excitotoxicity, disrupted protein homeostasis, defective axonal transport, and synaptic dysfunction. Various pre-clinical and clinical findings indicate that the up-regulation of c-JNK and p38MAPK signaling is associated with neurological disorders. Exceptionally, a significant amount of experimental data has recently shown that dysregulated c-JNK and p38MAPK are implicated in the damage to the central nervous system, including amyotrophic lateral sclerosis. Furthermore, currently available information has shown that c- JNK/p38MAPK signaling inhibitors may be a promising therapeutic alternative for improving histopathological, functional, and demyelination defects related to motor neuron disabilities. Understanding the abnormal activation of c-JNK/p38MAPK signaling and the prediction of motor neuron loss may help identify important therapeutic interventions that could prevent neurocomplications. Based on the involvement of c-JNK/p38MAPK signaling in the brain, we have assumed that the downregulation of the c-JNK/p38MAPK signaling pathway could trigger neuroprotection and neurotrophic effects towards clinicopathological presentations of ALS and other brain diseases. Thus, this research-based review also outlines the inhibition of c-JNK and p38MAPK signal downregulation in the pursuit of disease-modifying therapies for ALS.
Collapse
Affiliation(s)
- Rajeshwar Kumar Yadav
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Elizabeth Minz
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| |
Collapse
|
|
35
|
Redox Effects of Molecular Hydrogen and Its Therapeutic Efficacy in the Treatment of Neurodegenerative Diseases. Processes (Basel) 2021. [DOI: 10.3390/pr9020308] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Oxidative stress (OS) and neuroinflammatory stress affect many neurological disorders. Despite the clinical significance of oxidative damage in neurological disorders, still, no effective and safe treatment methods for neuro diseases are available. With this, molecular hydrogen (H2) has been recently reported as an antioxidant and anti-inflammatory agent to treat several oxidative stress-related diseases. In animal and human clinical trials, the routes for H2 administration are mainly categorized into three types: H2 gas inhalation, H2 water dissolving, and H2-dissolved saline injection. This review explores some significant progress in research on H2 use in neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease, neonatal disorders of the brain, and other NDs (retinal ischemia and traumatic brain injury). Even though most neurological problems are not currently curable, these studies have shown the therapeutic potential for prevention, treatment, and mitigation of H2 administration. Several possible H2-effectors, including cell signaling molecules and hormones, which prevent OS and inflammation, will also be addressed. However, more clinical and other related studies are required to evaluate the direct H2 target molecule.
Collapse
|
|
36
|
Panina E, Ivanov A, Petrov D. The condition of the hairline of Chinchilla lanigera after the introduction of a hydrogen antioxidant into the diet. BIO WEB OF CONFERENCES 2021. [DOI: 10.1051/bioconf/20213606026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
It was found that the inclusion of water enriched with molecular hydrogen into the diet of a long-tailed chinchilla changed the fur quality indicators. In animals of the experimental group, the guard and downy hairs were thinner than in the control group. The length of downy hair in the experimental group was higher, the number of hairs in the follicle in the chinchillas of the experimental group was greater than in the control group, besides, the hair was stronger and softer. The animals of the experimental group showed less tendency to gnaw out fur. When considering the data on the chemical composition, it was found that in the dry matter of the hair of the animals of the experimental group, there were less organic substances, and there were more minerals in comparison with the animals of the control group.
Collapse
|
|
37
|
Panina E, Ivanov A, Petrov D, Panteleeva N. Influence of molecular hydrogen on behavioral adaptation of Сhinchilla lanigera taking into account gender factor in conditions of cage keeping. BIO WEB OF CONFERENCES 2021. [DOI: 10.1051/bioconf/20213607006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
It was found that the inclusion of water enriched with molecular hydrogen in the diet of animals increased the overall proportion of active behavior. According to the form of behavior "moving around the cage", it was found that males and females of the experimental group spent more time than animals of the control group. Males of the experimental group were 24% more active at night, and females were 60% more active than in the control group. In the daily dynamics, the period of activity of animals in the experimental group was from 19:00 to 8:00, and in the control group-from 22:00 to 8:00. In the daily balance according to the form of behavior "moving around the cage", chinchillas of the experimental group spent 5% more than in the control group.
Collapse
|
|
38
|
Bihaqi SW, Rao HV, Sen A, Grammas P. Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease. CEREBRAL CIRCULATION - COGNITION AND BEHAVIOR 2021; 2:100014. [PMID: 36324711 PMCID: PMC9616330 DOI: 10.1016/j.cccb.2021.100014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 11/30/2022]
Abstract
Thrombin treatment induced proteins linked to neuroinflammation in SH-SY5Y cells. Thrombin exposure elevated the expression/ levels of proteins of AD pathway. EMSA showed dabigatran reduced activation of NFκB in SH-SY5Y cells. Dabigatran reduced thrombin-driven neuroinflammation and downstream AD pathology. Background Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y. Methods SH-SY5Y cells exposed to thrombin concentrations (10–100 nM) +/- 250 nM dabigatran for 24 h were analyzed for protein and gene expression. Electrophoretic mobility shift assay (EMSA) was used to determine DNA binding of NFkB. Western blotting, qRT-PCR and ELISA were used to measure the protein, mRNA, and activity levels of known AD hallmarks and signaling molecules. Results Dabigatran treatment attenuated thrombin-induced increase in DNA binding of NFκB by 175% at 50 nM and by 77% at 100 nM thrombin concentration. Thrombin also augmented accumulation of Aβ protein expression and phosphorylation of p38 MAPK, a downstream molecule in the signaling cascade, expression of pro-apoptotic mediator caspase 3, APP, tTau and pTau. Additionally, thrombin increased BACE1 activity, GSK3β expression, and APP, BACE1, Tau and GSK3β mRNA levels. Co-incubation with dabigatran attenuated thrombin-induced increases in the protein, mRNA, and activities of the aforesaid molecules to various extents (between −31% and −283%). Conclusion Our data demonstrates that thrombin promotes AD-related pathological changes in neuronal cultures and suggests that use of direct oral anticoagulants may provide a therapeutic benefit against thrombin-driven neuroinflammation and downstream pathology in AD.
Collapse
Affiliation(s)
- Syed Waseem Bihaqi
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States
- Department of Pathology, Anatomy and Cell biology, Thomas Jefferson University, Philadelphia, PA 19107, United States
- Corresponding author at: Department of Pathology, Anatomy and Cell biology, 1020 Locust Street, Jefferson Alumni Hall, Thomas Jefferson University, Philadelphia, PA 19107, United States.
| | - Haripriya Vittal Rao
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States
- Wake Forest Alzheimer's Disease Research Center, Winston Salem, NC 27101, United States
| | - Abhik Sen
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States
- ICMR-Rajendra Memorial Research Institute of Medical Sciences, Patna, India
| | - Paula Grammas
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI 02881, United States
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States
| |
Collapse
|
|
39
|
Flores-Cuadra JA, Madrid A, Fernández PL, Pérez-Lao AR, Oviedo DC, Britton GB, Carreira MB. Critical Review of the Alzheimer's Disease Non-Transgenic Models: Can They Contribute to Disease Treatment? J Alzheimers Dis 2020; 82:S227-S250. [PMID: 33216029 DOI: 10.3233/jad-200870] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Alzheimer's disease (AD) is a growing neurodegenerative disease without effective treatments or therapies. Despite the use of different approaches and an extensive variety of genetic amyloid based models, therapeutic strategies remain elusive. AD is characterized by three main pathological hallmarks that include amyloid-β plaques, neurofibrillary tangles, and neuroinflammatory processes; however, many other pathological mechanisms have been described in the literature. Nonetheless, the study of the disease and the screening of potential therapies is heavily weighted toward the study of amyloid-β transgenic models. Non-transgenic models may aid in the study of complex pathological states and provide a suitable complementary alternative to evaluating therapeutic biomedical and intervention strategies. In this review, we evaluate the literature on non-transgenic alternatives, focusing on the use of these models for testing therapeutic strategies, and assess their contribution to understanding AD. This review aims to underscore the need for a shift in preclinical research on intervention strategies for AD from amyloid-based to alternative, complementary non-amyloid approaches.
Collapse
Affiliation(s)
- Julio A Flores-Cuadra
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá
| | - Alanna Madrid
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá
| | - Patricia L Fernández
- Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá
| | - Ambar R Pérez-Lao
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá
| | - Diana C Oviedo
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá.,Escuela de Psicología, Facultad de Ciencias Sociales, Universidad Católica Santa María La Antigua (USMA), Panamá
| | - Gabrielle B Britton
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá
| | - Maria B Carreira
- Centro de Neurociencias, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Panamá, República de Panamá
| |
Collapse
|
|
40
|
Li L, Li X, Zhang Z, Liu L, Zhou Y, Liu F. Protective Mechanism and Clinical Application of Hydrogen in Myocardial Ischemia-reperfusion Injury. Pak J Biol Sci 2020; 23:103-112. [PMID: 31944068 DOI: 10.3923/pjbs.2020.103.112] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Cardiovascular disease accounts for one-third of all deaths, with ischemic heart disease as the main cause of death. Under pathological conditions, ischemia-reperfusion injury (IRI) often occurs in tissues. Ischemic injury is mainly caused by anaerobic cell death and reperfusion which results in a wide range of inflammatory responses. These responses are able to increase tissue damage and even damage to the whole body. IRI can also aggravate the original cardiovascular disease during the treatment of cardiovascular disease. Therefore, it is particularly important to understand the mechanism of myocardial ischemia-reperfusion injury (MIRI) for clinical treatment and application. At the same time, it is necessary to find a safe, reliable and feasible method for treating MIRI to reduce the incidence of complications and mortality as well as improve the prognosis and quality of life of patients. As a selective antioxidant, hydrogen can neutralize excessive free radicals, has certain anti-apoptotic and anti-inflammatory effects and it has gradually become a focus and hotspot of preclinical and clinical research. Hydrogen has been shown to have a certain therapeutic effect on MIRI, which can provide a new therapeutic direction for the clinical treatment of myocardial ischemia-reperfusion injury. In this review, the protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury is discussed.
Collapse
|
|
41
|
Prospects of molecular hydrogen in perioperative neuroprotection from basic research to clinical application. Curr Opin Anaesthesiol 2020; 33:655-660. [PMID: 32826628 DOI: 10.1097/aco.0000000000000915] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The current systematic review summarizes recent, basic clinical achievements regarding the neuroprotective effects of molecular hydrogen in distinct central nervous system conditions. RECENT FINDINGS Perioperative neuroprotection remains a major topic of clinical anesthesia. Various gaseous molecules have previously been explored as a feasible therapeutic option in neurological disorders. Among them, molecular hydrogen, which has emerged as a novel and potential therapy for perioperative neuroprotection, has received much attention. SUMMARY Fundamental and clinical evidence supports the antioxidant, antiinflammation, antiapoptosis and mitochondrial protective effects of hydrogen in the pathophysiology of nervous system diseases. The clinically preventive and therapeutic effects of hydrogen on different neural diseases, however, remain uncertain, and the lack of support by large randomized controlled trials has delayed its clinical application.
Collapse
|
|
42
|
Hydrogen gas inhalation improves delayed brain injury by alleviating early brain injury after experimental subarachnoid hemorrhage. Sci Rep 2020; 10:12319. [PMID: 32704088 PMCID: PMC7378202 DOI: 10.1038/s41598-020-69028-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 07/03/2020] [Indexed: 01/10/2023] Open
Abstract
Molecular hydrogen (H2) protect neurons against reactive oxygen species and ameliorates early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effect of H2 on delayed brain injury (DBI) using the rat SAH + unilateral common carotid artery occlusion (UCCAO) model with the endovascular perforation method. 1.3% H2 gas (1.3% hydrogen premixed with 30% oxygen and balanced nitrogen) inhalation was performed on days 0 and 1, starting from anesthesia induction and continuing for 2 h on day 0, and starting from anesthesia induction and continuing for 30 min on day 1. EBI was assessed on the basis of brain edema, expression of S100 calcium-binding protein B (S100B), and phosphorylation of C-Jun N-terminal kinase on day 2, and neurological deficits on day 3. Reactive astrogliosis and severity of cerebral vasospasm (CV) were assessed on days 3 and 7. DBI was assessed on the basis of neurological deficits and neuronal cell death on day 7. EBI, reactive astrogliosis, and DBI were ameliorated in the H2 group compared with the control group. CV showed no significant improvement between the control and H2 groups. This study demonstrated that H2 gas inhalation ameliorated DBI by reducing EBI without improving CV in the rat SAH + UCCAO model.
Collapse
|
|
43
|
Jesus AA, Passaglia P, Santos BM, Rodrigues-Santos I, Flores RA, Batalhão ME, Stabile AM, Cárnio EC. Chronic molecular hydrogen inhalation mitigates short and long-term memory loss in polymicrobial sepsis. Brain Res 2020; 1739:146857. [PMID: 32348775 DOI: 10.1016/j.brainres.2020.146857] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 04/04/2020] [Accepted: 04/24/2020] [Indexed: 01/13/2023]
Abstract
The central nervous system (CNS) is one of the first physiological systems to be affected in sepsis. During the exacerbated systemic inflammatory response at the early stage of sepsis, circulatory inflammatory mediators are able to reach the CNS leading to neuroinflammation and, consequently, long-term impairment in learning and memory formation is observed. The acute treatment with molecular hydrogen (H2) exerts important antioxidative, antiapoptotic, and anti-inflammatory effects in sepsis, but little is known about the mechanism itself and the efficacy of chronic H2 inhalation in sepsis treatment. Thus, we tested two hypotheses. We first hypothesized that chronic H2 inhalation is also an effective therapy to treat memory impairment induced by sepsis. The second hypothesis is that H2 treatment decreases sepsis-induced neuroinflammation in the hippocampus and prefrontal cortex, important areas related to short and long-term memory processing. Our results indicate that (1) chronic exposure of hydrogen gas is a simple, safe and promising therapeutic strategy to prevent memory loss in patients with sepsis and (2) acute H2 inhalation decreases neuroinflammation in memory-related areas and increases total nuclear factor E2-related factor 2 (Nrf2), a transcription factorthat regulates a vast group of antioxidant and inflammatory agents expression in these areas of septic animals.
Collapse
Affiliation(s)
- Aline A Jesus
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Patrícia Passaglia
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Bruna M Santos
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Isabelle Rodrigues-Santos
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Rafael A Flores
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil
| | - Marcelo E Batalhão
- Department of General and Specialized Nursing, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil
| | - Angelita M Stabile
- Department of General and Specialized Nursing, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil
| | - Evelin C Cárnio
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900, Brazil; Department of General and Specialized Nursing, School of Nursing of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP 14049-900 Brazil.
| |
Collapse
|
|
44
|
Peng Y, Gao P, Shi L, Chen L, Liu J, Long J. Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer's Disease: Targeting Mitochondria for Diagnosis and Prevention. Antioxid Redox Signal 2020; 32:1188-1236. [PMID: 32050773 PMCID: PMC7196371 DOI: 10.1089/ars.2019.7763] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 02/09/2020] [Accepted: 02/10/2020] [Indexed: 12/20/2022]
Abstract
Significance: Epidemiological studies indicate that metabolic disorders are associated with an increased risk for Alzheimer's disease (AD). Metabolic remodeling occurs in the central nervous system (CNS) and periphery, even in the early stages of AD. Mitochondrial dysfunction has been widely accepted as a molecular mechanism underlying metabolic disorders. Therefore, focusing on early metabolic changes, especially from the perspective of mitochondria, could be of interest for early AD diagnosis and intervention. Recent Advances: We and others have identified that the levels of several metabolites are fluctuated in the periphery before their accumulation in the CNS, which plays an important role in the pathogenesis of AD. Mitochondrial remodeling is likely one of the earliest signs of AD, linking nutritional imbalance to cognitive deficits. Notably, by improving mitochondrial function, mitochondrial nutrients efficiently rescue cellular metabolic dysfunction in the CNS and periphery in individuals with AD. Critical Issues: Peripheral metabolic disorders should be intensively explored and evaluated for the early diagnosis of AD. The circulating metabolites derived from mitochondrial remodeling represent novel potential diagnostic biomarkers for AD that are more readily detected than CNS-oriented biomarkers. Moreover, mitochondrial nutrients provide a promising approach to preventing and delaying AD progression. Future Directions: Abnormal mitochondrial metabolism in the CNS and periphery is involved in AD pathogenesis. More clinical studies provide evidence for the suitability and reliability of circulating metabolites and cytokines for the early diagnosis of AD. Targeting mitochondria to rewire cellular metabolism is a promising approach to preventing AD and ameliorating AD-related metabolic disorders.
Collapse
Affiliation(s)
- Yunhua Peng
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Peipei Gao
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Le Shi
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Lei Chen
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiankang Liu
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiangang Long
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| |
Collapse
|
|
45
|
Abstract
Central nervous system injuries are a leading cause of death and disability worldwide. Although the exact pathophysiological mechanisms of various brain injuries vary, central nervous system injuries often result in an inflammatory response, and subsequently lead to brain damage. This suggests that neuroprotection may be necessany in the treatment of multiple disease models. The use of medical gases as neuroprotective agents has gained great attention in the medical field. Medical gases include common gases, such as oxygen, hydrogen and carbon dioxide; hydrogen sulphide and nitric oxide that have been considered toxic; volatile anesthetic gases, such as isoflurane and sevoflurane; and inert gases like helium, argon, and xenon. The neuroprotection from these medical gases has been investigated in experimental animal models of various types of brain injuries, such as traumatic brain injury, stroke, subarachnoid hemorrhage, cerebral ischemic/reperfusion injury, and neurodegenerative diseases. Nevertheless, the transition into the clinical practice is still lagging. This delay could be attributed to the contradictory paradigms and the conflicting results that have been obtained from experimental models, as well as the presence of inconsistent reports regarding their safety. In this review, we summarize the potential mechanisms underlying the neuroprotective effects of medical gases and discuss possible candidates that could improve the outcomes of brain injury.
Collapse
Affiliation(s)
- Yue-Zhen Wang
- Department of Anesthesiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Ting-Ting Li
- Department of Anesthesiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Hong-Ling Cao
- Department of Anesthesiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Wan-Chao Yang
- Department of Anesthesiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| |
Collapse
|
|
46
|
Zhang Y, Hou B, Li C, Li H. Overexpression of circARF3 mitigates TNF-α-induced inflammatory damage by up-regulating miR-125b. Cell Cycle 2020; 19:1253-1264. [PMID: 32329660 DOI: 10.1080/15384101.2020.1731652] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Encephalitis is the highest disability illness. We studied the function and mechanisms of circular RNA circARF3 (circARF3) in neurocyte cell inflammatory damage. CCK-8 assay and flow cytometry were, respectively, employed for examining the influences of tumor necrosis factor α (TNF-α), circARF3 and microRNA (miR)-125b on cell viability and apoptosis. The expression of circARF3 and miR-125b were changed by employing cell transfection and the results were determined by using qRT-PCR. Besides, the expression of Bcl-2, Bax, Cleaved-caspase-3, interleukin (IL)-1β, IL-6, IL-8 and cell pathways-related proteins were examined by using Western blot. The productions of IL-6, IL-8 and IL-1β were also tested by ELISA. The level of reactive oxygen species (ROS) was examined by ROS assay. We found that TNF-α caused inflammatory damage showing as suppressed cell viability, enhanced cell apoptosis, and increased cytokines production and ROS generation. Besides, TNF-α inducement also markedly reduced circARF3 expression. circARF3 overexpression mitigated TNF-α-induced cell inflammatory damage. Moreover, miR-125b was targeted and positively regulated by circARF3. Furthermore, miR-125b inhibition could reverse the influences of circARF3 overexpression. Besides, circARF3 restrained the JNK and NF-κB pathways by up-regulation of miR-125b. In conclusion, overexpression of circARF3 mitigated cell inflammatory damage via inactivation of JNK and NF-κB pathways and thereby up-regulation of miR-125b.
Collapse
Affiliation(s)
- Yingying Zhang
- Department of Neurology, The Affiliated Hospital of Qingdao University , Qingdao, 266000, Shandong, China
| | - Binghui Hou
- Department of Neurology, The Affiliated Hospital of Qingdao University , Qingdao, 266000, Shandong, China
| | - Chunxiao Li
- Department of Neurology, The Affiliated Hospital of Qingdao University , Qingdao, 266000, Shandong, China
| | - Hong Li
- Department of Neurology, The Affiliated Hospital of Qingdao University , Qingdao, 266000, Shandong, China
| |
Collapse
|
|
47
|
Nogueira JE, de Deus JL, Amorim MR, Batalhão ME, Leão RM, Carnio EC, Branco LG. Inhaled molecular hydrogen attenuates intense acute exercise-induced hippocampal inflammation in sedentary rats. Neurosci Lett 2020; 715:134577. [DOI: 10.1016/j.neulet.2019.134577] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/24/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022]
|
|
48
|
Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities. Pharmacol Res 2019; 148:104450. [PMID: 31509764 DOI: 10.1016/j.phrs.2019.104450] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/26/2019] [Accepted: 09/06/2019] [Indexed: 12/12/2022]
Abstract
Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus "Fukuda" criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.
Collapse
|
|
49
|
Li S, Fujino M, Takahara T, Li XK. Protective role of heme oxygenase-1 in fatty liver ischemia-reperfusion injury. Med Mol Morphol 2019; 52:61-72. [PMID: 30171344 PMCID: PMC6542780 DOI: 10.1007/s00795-018-0205-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 08/21/2018] [Indexed: 12/12/2022]
Abstract
Ischemia-reperfusion (IR) injury is a kind of injury resulting from the restoration of the blood supply after blood vessel closure during liver transplantation and is the main cause of graft failure. The pathophysiological mechanisms of hepatic IR include a variety of oxidative stress responses. Hepatic IR is characterized by ischemia and hypoxia inducing oxidative stress, immune response and apoptosis. Fat-denatured livers are also used as donors due to the lack of liver donors. Fatty liver is less tolerant to IR than normal liver. Heme oxygenase (HO) is an enzyme that breaks down hemoglobin to bilirubin, ferrous iron and carbon monoxide (CO). Inducible HO subtype HO-1 is an important protective molecule in mammalian cells used to improve acute and chronic liver injury owing to its characteristic anti-inflammatory and anti-apoptotic qualities. HO-1 degrades heme, and its reaction product CO has been shown to reduce hepatic IR injury and increase the survival rate of grafts. As an induced form of HO, HO-1 also exerts a protective effect against liver IR injury and may be useful as a new strategy of ameliorating this kind of damage. This review summarizes the protective effects of HO-1 in liver IR injury, especially in fatty liver.
Collapse
Affiliation(s)
- Shaowei Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Masayuki Fujino
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Terumi Takahara
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
| |
Collapse
|
|
50
|
Kura B, Bagchi AK, Singal PK, Barancik M, LeBaron TW, Valachova K, Šoltés L, Slezák J. Molecular hydrogen: potential in mitigating oxidative-stress-induced radiation injury. Can J Physiol Pharmacol 2019; 97:287-292. [DOI: 10.1139/cjpp-2018-0604] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Uncontrolled production of oxygen and nitrogen radicals results in oxidative and nitrosative stresses that impair cellular functions and have been regarded as causative common denominators of many pathological processes. In this review, we report on the beneficial effects of molecular hydrogen in scavenging radicals in an artificial system of•OH formation. As a proof of principle, we also demonstrate that in rat hearts in vivo, administration of molecular hydrogen led to a significant increase in superoxide dismutase as well as pAKT, a cell survival signaling molecule. Irradiation of the rats caused a significant increase in lipid peroxidation, which was mitigated by pre-treatment of the animals with molecular hydrogen. The nuclear factor erythroid 2-related factor 2 is regarded as an important regulator of oxyradical homeostasis, as well as it supports the functional integrity of cells, particularly under conditions of oxidative stress. We suggest that the beneficial effects of molecular hydrogen may be through the activation of nuclear factor erythroid 2-related factor 2 pathway that promotes innate antioxidants and reduction of apoptosis, as well as inflammation.
Collapse
Affiliation(s)
- Branislav Kura
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic
| | - Ashim K. Bagchi
- Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
| | - Pawan K. Singal
- Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
| | - Miroslav Barancik
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic
| | - Tyler W. LeBaron
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic
- Molecular Hydrogen Institute, Enoch, Utah 84721, USA
| | - Katarina Valachova
- Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovak Republic
| | - Ladislav Šoltés
- Centre of Experimental Medicine, Institute of Experimental Pharmacology and Toxicology, 841 04 Bratislava, Slovak Republic
| | - Ján Slezák
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic
| |
Collapse
|