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Sha S, Ren L, Xing X, Guo W, Wang Y, Li Y, Cao Y, Qu L. Recent advances in immunotherapy targeting amyloid-beta and tauopathies in Alzheimer's disease. Neural Regen Res 2026; 21:577-587. [PMID: 39885674 DOI: 10.4103/nrr.nrr-d-24-00846] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 12/28/2024] [Indexed: 02/01/2025] Open
Abstract
Alzheimer's disease, a devastating neurodegenerative disorder, is characterized by progressive cognitive decline, primarily due to amyloid-beta protein deposition and tau protein phosphorylation. Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer's disease. Conventional drugs, such as donepezil, can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline. Currently, active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer's disease and other transgenic animal models, attracting considerable attention. However, the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab. This review first discusses the advancements in the pathogenesis of Alzheimer's disease and active and passive immunotherapies targeting amyloid-beta and tau proteins. Furthermore, it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects. Although some antibodies have shown promise in patients with mild Alzheimer's disease, substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer's disease.
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Affiliation(s)
- Sha Sha
- Department of Geriatrics, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Lina Ren
- Department of Geriatrics, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Xiaona Xing
- Department of Neurology, Shenzhen Luohu People's Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China
| | - Wanshu Guo
- Department of Neurology, People's Hospital of Liaoning Province, Shenyang, Liaoning Province, China
| | - Yan Wang
- Department of Geriatrics, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ying Li
- Department of Geriatrics, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yunpeng Cao
- Department of Neurology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Le Qu
- Department of Dermatology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
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2
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Clasen F, Yildirim S, Arıkan M, Garcia-Guevara F, Hanoğlu L, Yılmaz NH, Şen A, Celik HK, Neslihan AA, Demir TK, Temel Z, Mardinoglu A, Moyes DL, Uhlen M, Shoaie S. Microbiome signatures of virulence in the oral-gut-brain axis influence Parkinson's disease and cognitive decline pathophysiology. Gut Microbes 2025; 17:2506843. [PMID: 40420833 PMCID: PMC12118390 DOI: 10.1080/19490976.2025.2506843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 03/25/2025] [Accepted: 05/07/2025] [Indexed: 05/28/2025] Open
Abstract
The human microbiome is increasingly recognized for its crucial role in the development and progression of neurodegenerative diseases. While the gut-brain axis has been extensively studied, the contribution of the oral microbiome and gut-oral tropism in neurodegeneration has been largely overlooked. Cognitive impairment (CI) is common in neurodegenerative diseases and develops on a spectrum. In Parkinson's Disease (PD) patients, CI is one of the most common non-motor symptoms but its mechanistic development across the spectrum remains unclear, complicating early diagnosis of at-risk individuals. Here, we generated 228 shotgun metagenomics samples of the gut and oral microbiomes across PD patients with mild cognitive impairment (PD-MCI) or dementia (PDD), and a healthy cohort, to study the role of gut and oral microbiomes on CI in PD. In addition to revealing compositional and functional signatures, the role of pathobionts, and dysregulated metabolic pathways of the oral and gut microbiome in PD-MCI and PDD, we also revealed the importance of oral-gut translocation in increasing abundance of virulence factors in PD and CI. The oral-gut virulence was further integrated with saliva metaproteomics and demonstrated their potential role in dysfunction of host immunity and brain endothelial cells. Our findings highlight the significance of the oral-gut-brain axis and underscore its potential for discovering novel biomarkers for PD and CI.
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Affiliation(s)
- Frederick Clasen
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
| | - Suleyman Yildirim
- Department of Medical Microbiology, Istanbul Medipol University International School of Medicine, Istanbul, Türkiye
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Tűrkiye
| | - Muzaffer Arıkan
- Department of Medical Microbiology, Istanbul Medipol University International School of Medicine, Istanbul, Türkiye
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Tűrkiye
| | - Fernando Garcia-Guevara
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
| | - Lűtfű Hanoğlu
- Neuroscience Graduate Program and Department of Neurology, Istanbul Medipol University School of Medicine, Istanbul, Tűrkiye
| | - Nesrin H. Yılmaz
- Department of Neurology, Istanbul Medipol University School of Medicine, Istanbul, Tűrkiye
| | - Aysu Şen
- Department of Neurology, Bakırkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Istanbul, Tűrkiye
| | - Handan Kaya Celik
- Department of Neurology, Kocaeli University Faculty of Medicine, Kocaeli, Türkiye
| | | | - Tuǧçe Kahraman Demir
- Department of Electroneurophysiology, Vocational School, Biruni University, Istanbul, Tűrkiye
| | - Zeynep Temel
- Department of Psychology, Faculty of Humanities and Social Sciences, Fatih Sultan Mehmet Vakif University, Istanbul, Tűrkiye
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - David L. Moyes
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
| | - Mathias Uhlen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, UK
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3
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Deng L, Guan G, Cannon RD, Mei L. Age-related oral microbiota dysbiosis and systemic diseases. Microb Pathog 2025; 205:107717. [PMID: 40403989 DOI: 10.1016/j.micpath.2025.107717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 05/08/2025] [Accepted: 05/17/2025] [Indexed: 05/24/2025]
Abstract
The oral microbiota is an essential microbial community within the human body, playing a vital role in maintaining health. In older adults, age-related changes in the oral microbiota are linked to both systemic and oral health impairments. The use of various medications for systemic diseases in the elderly can also contribute to the development of oral diseases. Oral microbiota dysbiosis refers to an imbalance in the composition of oral microbial communities. This imbalance, along with disruptions in the host immune response and prolonged inflammation, is closely associated with the onset and progression of several diseases. It contributes to oral conditions such as dental caries, periodontal disease, and halitosis. It is also linked to systemic diseases, including Alzheimer's disease, type 2 diabetes mellitus, rheumatoid arthritis, atherosclerotic cardiovascular disease, and aspiration pneumonia. This review aims to explore how oral microbiota influences specific health outcomes in older individuals, focusing on Alzheimer's disease, type 2 diabetes mellitus, rheumatoid arthritis, atherosclerotic cardiovascular disease, and aspiration pneumonia. The oral microbiota holds promise as a diagnostic tool, therapeutic target, and prognostic biomarker for managing cardiovascular disease, metabolic diseases, infectious diseases and autoimmune diseases. Emphasizing proper oral health care and instilling an understanding of how drugs prescribed for systemic disease impact the oral microbiome, is anticipated to emerge as a key strategy for promoting the general health of older adults.
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Affiliation(s)
- Ling Deng
- Department of Oral Pathology, The Affiliated Stomatological Hospital of Guizhou Medical University, Guiyang, PR China
| | - Guangzhao Guan
- Department of Oral Diagnostic and Surgical Sciences, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.
| | - Richard D Cannon
- Department of Oral Sciences, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Li Mei
- Department of Oral Sciences, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.
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4
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Liu K, Ma X, Zhang Y, Zhao L, Shi Y. Precision delivery of pretreated macrophage-membrane-coated Pt nanoclusters for improving Alzheimer's disease-like cognitive dysfunction induced by Porphyromonas gingivalis. Biomaterials 2025; 319:123211. [PMID: 40020501 DOI: 10.1016/j.biomaterials.2025.123211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/19/2025] [Accepted: 02/23/2025] [Indexed: 03/03/2025]
Abstract
Oral infection with Porphyromonas gingivalis (P. gingivalis), a kind of pathogenic bacteria causing periodontitis, can increase the risk of Alzheimer's disease (AD) and cause cognitive decline. Therefore, precise intracerebral antimicrobial therapy to reduce the load of P. gingivalis in brain may serve as a potential therapeutic approach to improve AD-like cognitive impairment. A kind of nano-delivery system precisely targets bacteria in the brain through coating P. gingivalis stimulated macrophage membrane onto the surface of platinum nanoclusters (Pg-M-PtNCs). Approximate 50 nm spherical Pg-M-PtNCs demonstrate good biocompatibility and the pretreated macrophage membranes can inhibit macrophages phagocytosis and increase the adherence to bacteria. Pg-M-PtNCs can significantly inhibit the growth of P.gingivalis in vitro, and are effectively delivered and remain at the infection site in the mice brain to reduce the bacterial load and neuronal damage, and then improve the AD-like cognitive dysfunction in the chronic periodontitis mice. Platinum nanoclusters coated with P. gingivalis pretreated macrophage membrane play an important role in targeting bacteria in the brain, and effectively improve AD-like cognitive function disorder caused by P. gingivalis infection in the brain.
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Affiliation(s)
- Kang Liu
- School of Pharmacy, Jinzhou Medical University, Jinzhou, 121000, PR China.
| | - Xuejing Ma
- School of Basic Medicine, Jinzhou Medical University, Jinzhou, 121000, PR China.
| | - Yifei Zhang
- School of Pharmacy, Jinzhou Medical University, Jinzhou, 121000, PR China.
| | - Liang Zhao
- School of Pharmacy, Jinzhou Medical University, Jinzhou, 121000, PR China; Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou, 121000, PR China.
| | - Yijie Shi
- School of Pharmacy, Jinzhou Medical University, Jinzhou, 121000, PR China; Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou, 121000, PR China.
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5
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Ma Y, Dong T, Luan F, Yang J, Miao F, Wei P. Interaction of major facilitator superfamily domain containing 2A with the blood-brain barrier. Neural Regen Res 2025; 20:2133-2152. [PMID: 39248155 PMCID: PMC11759009 DOI: 10.4103/nrr.nrr-d-24-00191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 06/02/2024] [Accepted: 07/08/2024] [Indexed: 09/10/2024] Open
Abstract
The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment; however, the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood. The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function. It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier, in addition to the transport of lipids, such as docosahexaenoic acid, across the blood-brain barrier. Furthermore, an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases; however, little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier. This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier, including their basic structures and functions, cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier, and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability. This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date. This will not only help to elucidate the pathogenesis of neurological diseases, improve the accuracy of laboratory diagnosis, and optimize clinical treatment strategies, but it may also play an important role in prognostic monitoring. In addition, the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized. This review may contribute to the development of new approaches for the treatment of neurological diseases.
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Affiliation(s)
- Yilun Ma
- College of Pharmacy and First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China
| | - Taiwei Dong
- College of Pharmacy and First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China
| | - Fei Luan
- College of Pharmacy and First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China
| | - Juanjuan Yang
- National Drug Clinical Trial Agency, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine/Xixian New District Central Hospital, Xi′an, Shaanxi Province, China
| | - Feng Miao
- College of Pharmacy and First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, China
| | - Peifeng Wei
- National Drug Clinical Trial Agency, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine/Xixian New District Central Hospital, Xi′an, Shaanxi Province, China
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Antequera D, Sande L, Mato EG, Romualdi D, Carrero L, Municio C, Diz P, Carro E. Salivary lactoferrin levels in Down Syndrome: a case-control study. Brain Behav Immun Health 2025; 46:100999. [PMID: 40343107 PMCID: PMC12060471 DOI: 10.1016/j.bbih.2025.100999] [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: 12/04/2024] [Revised: 03/14/2025] [Accepted: 04/21/2025] [Indexed: 05/11/2025] Open
Abstract
Individuals with Down Syndrome (DS) have a high age-dependent risk of developing Alzheimer's disease (AD). In addition to genetic causes, this high risk involves dysregulated immune-inflammatory system. Low lactoferrin levels, one of the main antimicrobial proteins present in saliva, has been associated with AD. Here, we evaluated whether salivary lactoferrin levels change across the life span of individuals with DS. The study included 152 participants, 72 subjects with DS and 80 euploid individuals, and were divided into those under and over 45 years of age, accordingly with the age-dependent risk of AD. Median of salivary lactoferrin were higher among DS individual, in parallel to salivary total protein, but there were no differences in the ratio of lactoferrin to total protein in saliva between groups. Only DS individuals had higher median salivary lactoferrin levels in the age group under 45 years. Meanwhile non-significant differences were detected for the ratio salivary lactoferrin levels to total salivary protein between groups under 45 years, those levels were lower in DS subjects over 45 years old compared with the age-matched control group. Furthermore, the ratio of salivary lactoferrin levels to total protein in DS was associated with cognitive decline being lower in demented groups compared with mild and moderate cognitive impairment groups. In summary, this study indicates that salivary lactoferrin was dysregulated in DS, with significant lower ratio of salivary lactoferrin levels to total salivary proteins in individuals with DS over 45 years old, a population with a gradually increasing risk of AD.
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Affiliation(s)
- Desireé Antequera
- Neurobiology of Alzheimer's Disease Unit, Functional Unit for Research Into Chronic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Spain
| | - Lucía Sande
- Grupo de Investigación en Odontología Médico-Quirúrgica (OMEQUI), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain
| | - Eliane García Mato
- Grupo de Investigación en Odontología Médico-Quirúrgica (OMEQUI), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain
| | - Deborah Romualdi
- Neurobiology of Alzheimer's Disease Unit, Functional Unit for Research Into Chronic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Spain
- Programa de Doctorado en Ciencias Biomédicas y Salud Pública, IMIENS, Universidad Nacional de Educación a Distancia (UNED), Spain
| | - Laura Carrero
- Neurobiology of Alzheimer's Disease Unit, Functional Unit for Research Into Chronic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Spain
| | - Cristina Municio
- Neurobiology of Alzheimer's Disease Unit, Functional Unit for Research Into Chronic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Spain
| | - Pedro Diz
- Grupo de Investigación en Odontología Médico-Quirúrgica (OMEQUI), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain
| | - Eva Carro
- Neurobiology of Alzheimer's Disease Unit, Functional Unit for Research Into Chronic Diseases, Instituto de Salud Carlos III, Madrid, Spain
- Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Spain
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Hu Q, Wang S, Zhang W, Qu J, Liu GH. Unraveling brain aging through the lens of oral microbiota. Neural Regen Res 2025; 20:1930-1943. [PMID: 38993126 PMCID: PMC11691463 DOI: 10.4103/nrr.nrr-d-23-01761] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/22/2023] [Accepted: 05/31/2024] [Indexed: 07/13/2024] Open
Abstract
The oral cavity is a complex physiological community encompassing a wide range of microorganisms. Dysbiosis of oral microbiota can lead to various oral infectious diseases, such as periodontitis and tooth decay, and even affect systemic health, including brain aging and neurodegenerative diseases. Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration, indicating potential avenues for intervention strategies. In this review, we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases, and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration. We also highlight advances in therapeutic development grounded in the realm of oral microbes, with the goal of advancing brain health and promoting healthy aging.
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Affiliation(s)
- Qinchao Hu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
| | - Jing Qu
- University of Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
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8
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Zheng Z, Xu M, Xiao K, Yu K. Association between oral microbiome and depression: A population-based study. J Affect Disord 2025; 379:441-447. [PMID: 40049533 DOI: 10.1016/j.jad.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/05/2025] [Accepted: 03/03/2025] [Indexed: 03/18/2025]
Abstract
OBJECTIVE Depression is a global mental health issue, particularly affecting adolescents and young adults. While the role of gut microbiota in depression has been extensively studied, the influence of the oral microbiome remains underexplored. Recent studies suggest that the oral microbiome may affect systemic and brain health through the oral-brain axis. This study aimed to investigate the relationship between oral microbiome diversity and depression using data from 6212 participants in the National Health and Nutrition Examination Survey (NHANES) 2009-2012. METHODS Oral microbiome diversity was assessed through oral rinse samples using 16S rRNA sequencing, focusing on α-diversity metrics (observed ASVs and Faith's phylogenetic diversity) and β-diversity measures. Depressive symptoms were evaluated with the Patient Health Questionnaire (PHQ-9). Weighted logistic regression models were employed to assess associations between α-diversity and depression, while linear regression was used to examine the relationship between α-diversity and PHQ-9 scores. β-diversity differences were analyzed via permutational analysis of variance (PERMANOVA). RESULTS 10.03% of the participants were diagnosed with depression. Higher α-diversity in the oral microbiome was negatively correlated with depression: observed ASVs (OR: 0.713 [CI: 0.508-0.999], P = 0.050) and Faith's phylogenetic diversity (OR: 0.584 [CI: 0.367-0.931], P = 0.025). Linear regression indicated that greater α-diversity was associated with lower PHQ-9 scores, reflecting fewer depressive symptoms. Furthermore, β-diversity analysis revealed significant differences in the microbiome composition between depressed and non-depressed individuals. CONCLUSION Reduced oral microbiome diversity is associated with an increased risk and severity of depression. The study underscores the importance of exploring the oral-brain axis and highlights the need for further research into the mechanisms and therapeutic strategies targeting this relationship.
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Affiliation(s)
- Ziyang Zheng
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Luzhou 646000, China; Institute of Stomatology, Southwest Medical University, Luzhou 646000, China
| | - Mingzhang Xu
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Luzhou 646000, China; Institute of Stomatology, Southwest Medical University, Luzhou 646000, China
| | - Keming Xiao
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Luzhou 646000, China; Institute of Stomatology, Southwest Medical University, Luzhou 646000, China
| | - Ke Yu
- Department of Oral Implantology, The Affiliated Stomatological Hospital, Southwest Medical University, Luzhou 646000, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Luzhou 646000, China; Institute of Stomatology, Southwest Medical University, Luzhou 646000, China.
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9
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Lei Z, Ma Q, Zhou X, Li Y. The Secretion and Maturation Journey of Gingipains. Mol Oral Microbiol 2025. [PMID: 40490843 DOI: 10.1111/omi.12497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 05/11/2025] [Accepted: 05/22/2025] [Indexed: 06/11/2025]
Abstract
Multifunctional gingipains are trypsin-like enzymes secreted extracellularly by Porphyromonas gingivalis, which require delicate transit and processing to be activated in different mature forms. This review manages to reconstruct each processing step including the specific cleavage sites and relative proteins or helpers. Errors in any steps can lead to the accumulation of immature gingipains and weaken the virulence of P. gingivalis. Of special note, we emphasize the contribution of new studies to the refinement of the gingipain maturation process and factors that influence their pathogenicity. For example, it is proposed that glutamine cyclase, which is responsible for cyclizing exposed glutamine to pyroglutamic acid after the N-terminal signal peptide is removed, may be able to serve as a potential target for periodontitis treatment, as normal cyclization is key to maintaining the stability of gingipains. Further structural and functional unraveling of the type IX secretion system components, such as the identification of the structure of the PorV-associated shuttle complex, the determination of PorZ's role as the A-LPS deliverer, and the confirmation of the specific mechanism by which PorU promotes CTD removal and catalyzes the transpeptide reaction, has also contributed to a better understanding of gingipain processing. Meanwhile, as the successful activation of gingipains serves to fulfill their functions, this work also concentrates on gingipain pathogenicity, with a particular focus on how gingipains can induce or stimulate the development of systemic diseases, such as causing cardiovascular disorder through vascular damage or exacerbating inflammation in the brain in Alzheimer's disease after crossing the blood-brain barrier.
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Affiliation(s)
- Zixue Lei
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qizhao Ma
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xuedong Zhou
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuqing Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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10
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Xie L, Chen Q, Xu H, Li C, Lu J, Zhu Y. The research progress on periodontitis by the National Natural Science Foundation of China. Int J Oral Sci 2025; 17:44. [PMID: 40461458 PMCID: PMC12134109 DOI: 10.1038/s41368-025-00371-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 04/09/2025] [Accepted: 04/15/2025] [Indexed: 06/11/2025] Open
Abstract
Periodontitis has emerged as one of the most critical oral diseases, and research on this condition holds great importance for the advancement of stomatology. As the most authoritative national scientific research funding institution in China, the National Natural Science Foundation of China (NSFC) has played a pivotal role in driving the progress of periodontal science by supporting research on periodontitis. This article provides a comprehensive review of the research and development progress related to periodontitis in China from 2014 to 2023, highlighting the significant contributions of the NSFC to this field. We have summarized the detailed funding information from the NSFC, including the number of applicant codes, funded programs and the distribution of funded scholars. These data illustrate the efforts of the NSFC in cultivating young scientists and building research groups to address key challenges in national scientific research. This study offers an overview of the current hot topics, recent breakthroughs and future research prospects related to periodontitis in China.
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Affiliation(s)
- Liang Xie
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences & West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China
| | - Qian Chen
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Hao Xu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Research Unit of Oral Carcinogenesis and Management & Chinese Academy of Medical Sciences & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Cui Li
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China
| | - Jiayu Lu
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China.
| | - Yuangui Zhu
- Department of Health Sciences, National Natural Science Foundation of China, Beijing, China.
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11
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Kordi R, Andrews TJ, Hicar MD. Infections, genetics, and Alzheimer's disease: Exploring the pathogenic factors for innovative therapies. Virology 2025; 607:110523. [PMID: 40174330 DOI: 10.1016/j.virol.2025.110523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative condition that creates a significant global health challenge and profoundly affects patients and their families. Recent research has highlighted the critical role of microorganisms, particularly viral infections, in the pathogenesis of AD. The involvement of viral infections in AD pathogenesis is predominantly attributed to their ability to induce neuroinflammation and amyloid beta (Aβ) deposition in the brain. The extant research exploring the relationship between viruses and AD has focused largely on Herpesviridae family. Traces of Herpesviruses, such as Herpes Simplex Virus-1 and Epstein Barr Virus, have been found in the brains of patients with AD. These viruses are thought to contribute to the disease progression by triggering chronic inflammatory responses in the brain. They can remain dormant in the brain, and become reactivated due to stress, a secondary viral infection, or immune-senescence in older adults. This review focuses on the association between Herpesviridae and bacterial infections with AD. We explore the genetic factors that might regulate viral illness and discuss clinical trials investigating antiviral and anti-inflammatory agents as possible therapeutic strategies to mitigate cognitive decline in patients with AD. In summary, understanding the interplay between infections, genetic factors, and AD pathogenesis may pave the way for novel therapeutic approaches, facilitating better management and possibly even prevent this debilitating disease.
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Affiliation(s)
- Ramesh Kordi
- Department of Pediatrics, Division of Infectious Diseases, State University of New York at Buffalo, Buffalo, NY, 14203, USA
| | - Ted J Andrews
- Department of Pediatrics, Division of Developmental Pediatrics and Rehabilitation, State University of New York at Buffalo, Buffalo, NY, 14203, USA
| | - Mark D Hicar
- Department of Pediatrics, Division of Infectious Diseases, State University of New York at Buffalo, Buffalo, NY, 14203, USA.
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12
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Foroughi M, Torabinejad M, Angelov N, Ojcius DM, Parang K, Ravnan M, Lam J. Bridging oral and systemic health: exploring pathogenesis, biomarkers, and diagnostic innovations in periodontal disease. Infection 2025:10.1007/s15010-025-02568-y. [PMID: 40418274 DOI: 10.1007/s15010-025-02568-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Accepted: 05/16/2025] [Indexed: 05/27/2025]
Abstract
PURPOSE This narrative review explores the multifaceted links between periodontal diseases (gingivitis and periodontitis) and systemic health conditions, including cardiovascular disease, diabetes, adverse pregnancy outcomes, Alzheimer's disease, cancers, rheumatoid arthritis, and respiratory infections. It aims to synthesize evidence on how local oral infections exert systemic effects and evaluate the potential of diagnostic technologies to monitor these interactions. METHODS This narrative review synthesizes current scientific literature on periodontal disease pathogenesis, focusing on key pathogens (e.g., Porphyromonas gingivalis, Fusobacterium nucleatum) and their roles in driving local and systemic inflammation via virulence factors and microbial dysbiosis. It examines biomarker-based diagnostic approaches (e.g., IL-1β, TNF-α, microbial DNA) in saliva, blood, and gingival crevicular fluid (GCF) and evaluates current and emerging diagnostic tools (e.g., ELISA, PCR, lateral flow assays, biosensors, microfluidics). RESULTS The review highlights that periodontal pathogens contribute to systemic disease through complex mechanisms including persistent inflammation (driven by cytokines like IL-1β, TNF-α), endotoxemia (via LPS, noting pathogen-specific structural variations impacting immune response), molecular mimicry, and immune modulation. Current diagnostic methods provide valuable information but often face limitations in speed, portability, and multiplexing capability needed for comprehensive point-of-care assessment. Emerging technologies, particularly multiplex platforms integrating biosensors or microfluidics, demonstrate significant potential for rapid, user-friendly analysis of multiple biomarkers, facilitating earlier detection and personalized risk stratification, especially in high-risk populations. CONCLUSION Periodontal diseases significantly impact systemic health via intricate microbial and inflammatory pathways. The complexity of these interactions necessitates moving beyond conventional diagnostics towards integrated, advanced technologies. Implementing rapid, multiplex biomarker detection platforms within a multidisciplinary healthcare framework holds the potential to revolutionize early detection of linked conditions, improve personalized management strategies, and ultimately reduce the systemic burden of periodontal disease.
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Affiliation(s)
- Max Foroughi
- Department of Preventive and Restorative Dentistry, Arthur A. Dugoni School of Dentistry, University of the Pacific, 155 Fifth Street, San Francisco, CA, 94103, USA.
| | - Mahmoud Torabinejad
- Department of Endodontics, School of Dentistry, Loma Linda University School of Dentistry, Loma Linda, CA, USA
| | - Nikola Angelov
- Department of Periodontics and Dental Hygiene, The University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, USA
| | - David M Ojcius
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, CA, USA
| | - Keykavous Parang
- Department of Biomedical and Pharmaceutical Sciences, Center for Targeted Drug Delivery, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA, USA
| | - Marcus Ravnan
- Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA
| | - Jerika Lam
- Department of Pharmacy Practice, School of Pharmacy, Chapman University, Irvine, CA, USA
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13
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Pandey JP, Kimball C, Nietert PJ. Epistatic effects of immunoglobulin KM (κ marker) allotypes and APOE ε4 allele on the risk of Alzheimer's disease. J Alzheimers Dis 2025:13872877251343315. [PMID: 40400343 DOI: 10.1177/13872877251343315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
We investigated whether immunoglobulin KM (κ marker) allotypes were associated with Alzheimer's disease (AD) individually and/or epistatically with APOE ε4, the strongest known genetic susceptibility factor for the disease. Results showed a significant (p = 0.01) interaction between KM and APOE ε4. In KM 3/3 homozygotes, APOE ε4 was strongly associated with AD (OR = 8.3); however, in non-KM 3/3 subjects, the association between APOE ε4 and AD was markedly lower (OR = 0.9) and non-significant. If confirmed, these results may identify a subgroup of the population with a markedly higher risk of developing AD, who might require a different preventive/treatment strategy.
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Affiliation(s)
- Janardan P Pandey
- Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Christine Kimball
- Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Paul J Nietert
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
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14
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Hiregange DG, Samiya S, Mizgalska D, Ben-Zeev E, Waghalter M, Rivalta A, Rajan K, Halfon Y, Breiner-Goldstein E, Kaczmarczyk I, Sroka A, Taoka M, Nobe Y, Isobe T, Paukner S, Zimmerman E, Bashan A, Potempa J, Yonath A. Structural studies of ribosome from an anaerobic Bacteroidetes human pathogen Porphyromonas gingivalis. Nucleic Acids Res 2025; 53:gkaf458. [PMID: 40444637 PMCID: PMC12123416 DOI: 10.1093/nar/gkaf458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 03/27/2025] [Accepted: 05/19/2025] [Indexed: 06/02/2025] Open
Abstract
Porphyromonas gingivalis, an anaerobic pathogen in chronic periodontitis, belongs to the Bacteroidota phylum and is associated with various virulence factors. Its antibiotic-resistant strains and its propensity to form biofilms pose a challenge to effective treatment. To explore therapeutic avenues, we studied the high-resolution cryogenic electron microscope structures of ribosomes from the wild-type P. gingivalis W83 and the macrolide-resistant mutant strain ermΔporN. The structural analysis revealed unique features primarily at the ribosome periphery. Together with the distinctive distribution of ribosomal RNA modifications, these findings offer insights into the therapeutical potential, such as creation of novel therapeutic compounds inhibiting the specific cellular functions of the P. gingivalis ribosomes. Moreover, the high-resolution structure of the ermΔporN ribosome in its complex with the approved antibiotic lefamulin suggests its repurposing against P. gingivalis. Furthermore, we provide a foundation for additional effective strategies to treat periodontitis and associated systemic diseases.
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Affiliation(s)
- Disha-Gajanan Hiregange
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Sarit Samiya
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Danuta Mizgalska
- Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow 30-387, Poland
| | - Efrat Ben-Zeev
- Nancy and Stephen Grand Israel National Center for Personalized Medicine, Mantoux Institute for Bioinformatics, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Miriam Waghalter
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Andre Rivalta
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - K Shanmugha Rajan
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Yehuda Halfon
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Elinor Breiner-Goldstein
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Igor Kaczmarczyk
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow 30-387, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow 30-387, Poland
| | - Aneta Sroka
- Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow 30-387, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow 30-387, Poland
| | - Masato Taoka
- Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa 1-1, Hachioji-shi, Tokyo 192-0397, Japan
| | - Yuko Nobe
- Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa 1-1, Hachioji-shi, Tokyo 192-0397, Japan
| | - Toshiaki Isobe
- Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa 1-1, Hachioji-shi, Tokyo 192-0397, Japan
| | | | - Ella Zimmerman
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Anat Bashan
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow 30-387, Poland
- Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY 40292, United States
| | - Ada Yonath
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
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15
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Chen Y, Wang T, Zheng Z, Ai Z, Jiang J, Li S. Investigating the role of necroptosis in the immunological microenvironment of periodontitis. Mol Biol Rep 2025; 52:491. [PMID: 40402323 DOI: 10.1007/s11033-025-10589-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 05/09/2025] [Indexed: 05/23/2025]
Abstract
BACKGROUND Extensive research has delved into the nexus between necroptosis and immunity, yet its impact on the immunological microenvironment of periodontitis remains elusive. Therefore, the study aims to elucidate the role of necroptosis in shaping this particular microenvironment. RESULTS We examined the differential expression of necroptosis genes in healthy and periodontitis samples, analyzing their correlations with infiltrating immunocytes, immune responses, and the human leukocyte antigen (HLA) gene. Distinct necroptosis-mediated expression patterns were identified, along with genes associated with the necroptosis phenotype. Notably, 37 necroptosis genes were dysregulated, leading to the development of a seven-necroptosis classifier that accurately distinguished periodontitis from healthy samples. The findings reveal a profound association between necroptosis and the immunological microenvironment, evidenced by the positive correlation between ZBP1 and MLKL expression with plasma cells, the negative correlation between TNFRSF1B and ZBP1 with resting dendritic cells, and the modulation of BCR signaling and TGF family receptor activity by ZBP1 and MLKL. Furthermore, we uncovered a positive correlation between ZBP1 and HLA-C expression and a negative correlation between HSPA4 and HLA-A expression. The analysis identified two distinct necroptosis expression patterns, each characterized by unique immune features. Among the 5272 genes associated with the necroptosis phenotype, 339 genes were linked to immunity, their biological functions centering on immunocyte regulation. CONCLUSION This study underscores the significant role of necroptosis in shaping the immunological microenvironment of periodontitis, offering novel insights into the pathogenesis of this condition and paving the way for potential therapeutic strategies for periodontitis and its systemic comorbidities.
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Affiliation(s)
- Yuanwei Chen
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji Research Institute of Stomatology, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, 399 Middle Yanchang Road, Shanghai, 200072, China
| | - Tairan Wang
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji Research Institute of Stomatology, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, 399 Middle Yanchang Road, Shanghai, 200072, China
| | - Zhanglong Zheng
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji Research Institute of Stomatology, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, 399 Middle Yanchang Road, Shanghai, 200072, China
| | - Zexin Ai
- Shanghai Xuhui District Dental Center, Shanghai, China
| | - Jirui Jiang
- Shanghai Xuhui District Dental Center, Shanghai, China
| | - Shengjiao Li
- Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji Research Institute of Stomatology, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, 399 Middle Yanchang Road, Shanghai, 200072, China.
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16
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Clark R, Lira-Junior R, Jansson L, Eriksdotter M, Schultzberg M, Pussinen P, Buhlin K, Boström EA. Elevated levels of salivary interleukin-34 in patients suffering from Alzheimer's disease. Clin Oral Investig 2025; 29:303. [PMID: 40389754 PMCID: PMC12089168 DOI: 10.1007/s00784-025-06376-4] [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: 02/18/2025] [Accepted: 05/05/2025] [Indexed: 05/21/2025]
Abstract
OBJECTIVES To investigate interleukin (IL)-34 and colony-stimulating factor (CSF)-1 levels in saliva, cerebrospinal fluid, and plasma in different stages of cognitive impairment. The study also examines the relationship between these biomarkers and periodontal status across different stages of cognitive impairment. MATERIAL AND METHODS A total of 230 individuals diagnosed with Alzheimer's disease (AD, n = 52), mild cognitive impairment (MCI, n = 51), subjective cognitive impairment (SCI, n = 51), and controls (n = 76) were enrolled. Participants underwent clinical and radiological oral examinations. Cerebrospinal fluid samples were collected from all groups except controls. Stimulated saliva and blood were collected during oral examination. IL-34 and CSF-1 levels were assessed using enzyme-linked immunosorbent assays. RESULTS Salivary IL-34 levels were increased in AD compared to SCI (p = 0.010) and controls (p < 0.001), and in MCI compared to controls (p < 0.001). Elevated salivary CSF-1 levels were observed in AD compared to SCI (p = 0.003). Salivary IL-34 was inversely associated with Mini-Mental State Examination (MMSE) scores (p < 0.010) and body mass index (p = 0.040), while CSF-1 was associated with age (p = 0.015). IL-34 and CSF-1 levels did not differ in cerebrospinal fluid between groups, and periodontal status did not affect the levels in any biofluid measured. CONCLUSION Salivary IL-34 is increased in AD patients and is associated with MMSE scores. CLINICAL RELEVANCE Identifying reliable biomarkers for AD is crucial for early detection and intervention. This study suggests that salivary IL-34 could serve as a potential biomarker for AD.
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Affiliation(s)
- Reuben Clark
- Division of Oral diagnostics and surgery, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
| | - Ronaldo Lira-Junior
- Division of Oral diagnostics and surgery, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Leif Jansson
- Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Maria Eriksdotter
- Center for Alzheimer Research, Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
| | - Marianne Schultzberg
- Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Pirkko Pussinen
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
- Institute of Dentistry, University of Eastern Finland, Kuopio, Finland
| | - Kåre Buhlin
- Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
| | - Elisabeth A Boström
- Division of Oral diagnostics and surgery, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
- Department of Orofacial Medicine, Folktandvården Stockholms Län AB, Stockholm, Sweden
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17
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Niu RZ, Feng WQ, Chen L, Bao TH. Single-Cell Transcriptomic Profiling Reveals Regional Differences in the Prefrontal and Entorhinal Cortex of Alzheimer's Disease Brain. Int J Mol Sci 2025; 26:4841. [PMID: 40429980 PMCID: PMC12112128 DOI: 10.3390/ijms26104841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/02/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Previous studies have largely overlooked cellular differential alterations across differentially affected brain regions in both disease mechanisms and therapeutic development of Alzheimer's disease (AD). This study aimed to compare the differential cellular and transcriptional changes in the prefrontal cortex (PFC) and entorhinal cortex (EC) of AD patients through an integrated single-cell transcriptomic analysis. We integrated three single-cell RNA sequencing (scRNA-seq) datasets comprising PFC and EC samples from AD patients and age-matched healthy controls. A total of 124,658 nuclei and 31 cell clusters were obtained and classified into eight major cell types, with EC exhibiting much more pronounced transcriptional alterations than PFC. Through network analysis, we pinpointed hub regulatory genes that form interconnected networks driving AD pathogenesis, findings validated by RT-qPCR showing more pronounced expression changes in EC versus PFC of AD mice. Moreover, dysregulation of the LINC01099-associated regulatory networks in the PFC and EC, showing correlation with AD progression, may present new therapeutic targets for AD. Together, these results suggest that effective AD biomarkers and therapeutic strategies may require simultaneous, precise targeting of specific cell populations across multiple brain regions.
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Affiliation(s)
- Rui-Ze Niu
- Mental Health Center, Kunming Medical University, No. 733, Chuanjin Road, Panlong District, Kunming 650034, China; (L.C.); (T.-H.B.)
| | - Wan-Qing Feng
- Laboratory Zoology Department, Kunming Medical University, Kunming 650034, China;
| | - Li Chen
- Mental Health Center, Kunming Medical University, No. 733, Chuanjin Road, Panlong District, Kunming 650034, China; (L.C.); (T.-H.B.)
| | - Tian-Hao Bao
- Mental Health Center, Kunming Medical University, No. 733, Chuanjin Road, Panlong District, Kunming 650034, China; (L.C.); (T.-H.B.)
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18
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Li Q, Zhang H, Xiao N, Liang G, Lin Y, Yang X, Yang J, Qian Z, Fu Y, Zhang C, Liu A. Aging and Lifestyle Modifications for Preventing Aging-Related Diseases. FASEB J 2025; 39:e70575. [PMID: 40293686 DOI: 10.1096/fj.202402797rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 04/13/2025] [Accepted: 04/18/2025] [Indexed: 04/30/2025]
Abstract
The pathogenesis of various chronic diseases is closely associated with aging. Aging of the cardiovascular system promotes the development of severe cardiovascular diseases with high mortality, including atherosclerosis, coronary heart disease, and myocardial infarction. Similarly, aging of the nervous system promotes the development of neurodegenerative diseases, such as Alzheimer's disease, which seriously impairs cognitive function. Aging of the musculoskeletal system is characterized by decreased function and mobility. The molecular basis of organ aging is cellular senescence, which involves multiple cellular and molecular mechanisms, such as impaired autophagy, metabolic imbalance, oxidative stress, and persistent inflammation. Given the ongoing demographic shift toward an aging society, strategies to delay or reduce the effects of aging have gained significance. Lifestyle modifications, such as exercise and calorie restriction, are now recognized for their anti-aging effects, their capacity to reduce modification, their potential to prolong lifespan, and their capacity to lower the risk of cardiovascular disease. This review elucidates the molecular mechanisms and application significance of various anti-aging approaches at the molecular level, based on research progress in aging. It aims to provide a reference for the prevention and treatment of age-related diseases in progressively aging societies.
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Affiliation(s)
- Qiao Li
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Zhang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nanyin Xiao
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangyu Liang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Lin
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiankun Yang
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zonghao Qian
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yangguang Fu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cuntai Zhang
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Anding Liu
- Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Lv C, Shi K, Guo Y, Guo Z, Luo P, Wang L, Wu Z, Yu P. Emerging Roles of Periodontal Pathogen-Derived Outer Membrane Vesicles in NAFLD. Int Dent J 2025; 75:100825. [PMID: 40378508 PMCID: PMC12145673 DOI: 10.1016/j.identj.2025.03.029] [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: 02/28/2025] [Revised: 03/27/2025] [Accepted: 03/31/2025] [Indexed: 05/19/2025] Open
Abstract
The rising incidence of nonalcoholic fatty liver disease (NAFLD) poses a great socioeconomic burden worldwide. Also, periodontitis is the most common chronic inflammatory disease caused by a group of oral pathogens, affecting both oral health and systemic conditions, especially liver disease. Although accumulating evidence has elucidated an association between periodontal pathogens and NAFLD, the role of periodontal pathogen-derived outer membrane vesicles (OMVs) has not yet been clarified. In this comprehensive review, we aim to address this gap by summarising the progression and pathogenesis of NAFLD and revealing the relationship between periodontal disease and NAFLD multidimensionally. Additionally, this review sheds light on the multifunctional roles of periodontal pathogens OMVs and emphasises that periodontal pathogen-derived OMVs promote the development of NAFLD by stimulating Kupffer cells to produce inflammatory factors and inducing the activation of Hepatic stellate cells. However, it is still controversial whether periodontal pathogen-derived OMVs can be transferred to the liver through the bloodstream route or the oral-gut-liver axis. This highlights the pressing need for continued research efforts to develop new and optimised research schemes to observe the formation of the systemic distribution pathway of periodontal pathogen-derived OMVs. Finally, it is notable that there are currently no relevant clinical treatment guidelines to make specific provisions on controlling the level of periodontal pathogen-derived OMVs in patients with NAFLD. Guidelines developed based on our findings may contribute to the standardisation of practices. It can also provide effective strategies and potential therapeutic targets for NAFLD patients with periodontitis to alleviate the development of NAFLD diseases by inhibiting periodontal pathogens OMVs.
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Affiliation(s)
- Congcong Lv
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China
| | - Kaikai Shi
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China
| | - Yadong Guo
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China
| | - Zixin Guo
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China
| | - Pingchan Luo
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China
| | - Lijing Wang
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China
| | - Zhe Wu
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China.
| | - Pei Yu
- Department of Prosthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, China.
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20
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Eid F, Boushehri M, Boucher C, Rajkanth N, Sa AF, Alhoutan T, Vavetsi K, Dibart S, Ma Y. Chronic Lipopolysaccharide Exposure Causes AD-Like Pathology in Male Mice With Intact Blood-Brain Barrier. FASEB J 2025; 39:e70601. [PMID: 40317532 DOI: 10.1096/fj.202403117rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 04/08/2025] [Accepted: 04/24/2025] [Indexed: 05/07/2025]
Abstract
Chronic inflammatory conditions like periodontitis and inflammatory bowel disease (IBD) are reported to contribute to the pathogenesis of late-onset Alzheimer's disease (AD). Gram-negative bacteria are the main bacterial species causing oral and gut mucosal infections. Lipopolysaccharide (LPS) is a major inflammation-inducing molecule in Gram-negative bacteria. LPS derived from the oral bacterium Porphyromonas gingivalis exhibits heterogeneous tetra-acylated and penta-acylated lipid A, while LPS from Escherichia coli exhibits the classical hexa-acylated lipid A. Whether P. gingivalis-LPS and E. coli-LPS play a similar role in the progression of late-onset AD is unknown. Using adult, wild-type C57BL/6J mice to mimic the adult population without genetically determined predisposition to AD, we showed that chronic inflammation induced by a 28-day, subcutaneous infusion of P. gingivalis-LPS or E. coli-LPS can lead to neuroinflammation and AD-like cognitive decline and pathology in male mice. At this relatively early stage (4 weeks) of chronic inflammation when the blood-brain barrier is intact, both P. gingivalis-LPS and E. coli-LPS cause neuroinflammation through Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2) expressed at microglia in the brain. Notably, only E. coli-LPS induces significant inflammatory responses systemically. In short, our results suggest that chronic P. gingivalis-LPS release (occurring in chronic periodontitis) or E. coli-LPS release (occurring in IBD) could harm the brain before the blood-brain barrier is disrupted; continuous local P. gingivalis-LPS release might do harm to the brain before exhibiting adverse effects systemically.
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Affiliation(s)
- Fady Eid
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Mohammad Boushehri
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Chloé Boucher
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Nischwethaa Rajkanth
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Ana Flor Sa
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Thamir Alhoutan
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Konstantina Vavetsi
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Serge Dibart
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
| | - Yun Ma
- Department of Periodontology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
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21
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Ana DP, O SJ, Flavia T, Zhang Y, Jorge FL. Longitudinal host-microbiome dynamics of metatranscription identify hallmarks of progression in periodontitis. MICROBIOME 2025; 13:119. [PMID: 40369640 PMCID: PMC12077055 DOI: 10.1186/s40168-025-02108-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 04/08/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND In periodontitis, the interplay between the host and microbiome generates a self-perpetuating cycle of inflammation of tooth-supporting tissues, potentially leading to tooth loss. Despite increasing knowledge of the phylogenetic compositional changes of the periodontal microbiome, the current understanding of in situ activities of the oral microbiome and the interactions among community members and with the host is still limited. Prior studies on the subgingival plaque metatranscriptome have been cross-sectional, allowing for only a snapshot of a highly variable microbiome, and do not include the transcriptome profiles from the host, a critical element in the progression of the disease. RESULTS To identify the host-microbiome interactions in the subgingival milieu that lead to periodontitis progression, we conducted a longitudinal analysis of the host-microbiome metatranscriptome from clinically stable and progressing sites in 15 participants over 1 year. Our research uncovered a distinct timeline of activities of microbial and host responses linked to disease progression, revealing a significant clinical and metabolic change point (the moment in time when the statistical properties of a time series change) at the 6-month mark of the study, with 1722 genes differentially expressed (DE) in the host and 111,705 in the subgingival microbiome. Genes associated with immune response, especially antigen presentation genes, were highly up-regulated in stable sites before the 6-month change point but not in the progressing sites. Activation of cobalamin, porphyrin, and motility in the microbiome contribute to the progression of the disease. Conversely, inhibition of lipopolysaccharide and glycosphingolipid biosynthesis in stable sites coincided with increased immune response. Correlation delay analysis revealed that the positive feedback loop of activities leading to progression consists of immune regulation and response activation in the host that leads to an increase in potassium ion transport and cobalamin biosynthesis in the microbiome, which in turn induces the immune response. Causality analysis identified two clusters of microbiome genes whose progression can accurately predict the outcomes at specific sites with high confidence (AUC = 0.98095 and 0.97619). CONCLUSIONS A specific timeline of host-microbiome activities characterizes the progression of the disease. The metabolic activities of the dysbiotic microbiome and the host are responsible for the positive feedback loop of reciprocally reinforced interactions leading to progression and tissue destruction. Video Abstract.
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Affiliation(s)
- Duran-Pinedo Ana
- Department of Oral Biology, University of Florida, College of Dentistry, 1395 Center Drive Gainesville, Gainesville, FL, 32610 - 0424, USA
| | - Solbiati Jose O
- Department of Oral Biology, University of Florida, College of Dentistry, 1395 Center Drive Gainesville, Gainesville, FL, 32610 - 0424, USA
| | - Teles Flavia
- Department of Basic & Translational Sciences, University of Pennsylvania, School of Dental Medicine, 240 South 40 Street, Philadelphia, PA, 19104 - 6030, USA
- Center for Innovation and Precision Dentistry (CiPD), University of Pennsylvania, School of Dental Medicine, 240 South 40 Street, Philadelphia, PA, 19104 - 6030, USA
| | - Yanping Zhang
- Gene Expression & Genotyping Core, Interdisciplinary Center for Biotechnology Research, University of Florida, 178 B CGRC, 2033 Mowry Road, Gainesville, FL, 32610, USA
| | - Frias-Lopez Jorge
- Department of Oral Biology, University of Florida, College of Dentistry, 1395 Center Drive Gainesville, Gainesville, FL, 32610 - 0424, USA.
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22
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Chen TL, Zhang TL, Lu HJ, Yue AX, Wang YE, Zhou YJ, Hou J. Comment on "Oral Microbiome and Serological Analyses on Association of Alzheimer's Disease and Periodontitis". Oral Dis 2025. [PMID: 40364449 DOI: 10.1111/odi.15379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 02/19/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025]
Affiliation(s)
- Tie-Lou Chen
- Department of Periodontology, Stomatology Center, The First Affiliated Hospital of Naval Medical University, National Specialty Alliance Unit of Periodontology, Shanghai, China
| | - Ting-Lin Zhang
- Clinical Research Center, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hui-Jie Lu
- Department of Aerospace Medicine, Air Force Medical University, Xi'an, China
| | - An-Xin Yue
- Department of Stomatology, Medical College and Hospital Affiliated to Dalian University, Dalian, China
| | - Yan-En Wang
- Department of Periodontology, Stomatology Center, The First Affiliated Hospital of Naval Medical University, National Specialty Alliance Unit of Periodontology, Shanghai, China
| | - Yi-Jun Zhou
- Department of Periodontology, School of Stomatology, Fourth Military Medical University, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, State Key Laboratory of Military Stomatology, Xi'an, China
| | - Jin Hou
- National Key Laboratory of Immunity and Inflammation, Institute of Immunology, Naval Medical University, Shanghai, China
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23
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Li Y, Liu Y, Yin T, He M, Fang C, Tang X, Peng S, Liu Y. Association of periodontitis, tooth loss, and self-rated oral health with circadian syndrome in US adults: a cross-sectional population study. BMC Oral Health 2025; 25:713. [PMID: 40361086 PMCID: PMC12070748 DOI: 10.1186/s12903-025-06078-z] [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: 11/04/2024] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND This study was to investigate associations of periodontitis, tooth loss and self-rated oral health with circadian syndrome. METHODS Data regarding periodontitis, dentition, oral health questionnaire and circadian syndrome of 30-85 years old participants from US National Health and Nutrition Examination Survey 2005-2020 were analyzed. Periodontitis questions for periodontitis and dentition status were validated. Weighted multivariable logistic regression analyses were used. RESULTS Weighted prevalence of circadian syndrome and stage II-IV periodontitis was 33.29% and 88.87%, respectively. When compared with stage I periodontitis, stage II periodontitis was significantly associated with greater circadian syndrome prevalence after adjustment (odds ratio (OR) and 95% confidence interval (CI): Stage II: 1.35 (1.03, 1.76), P = 0.032; Stage III: 1.30 (0.97, 1.73), P = 0.069; Stage IV: 1.17 (0.82, 1.65), P = 0300). Stage II periodontitis was significantly associated with greater prevalence of lower high-density lipoprotein cholesterol (HDL) and elevated triglycerides and stage III and stage IV periodontitis were significantly associated with greater hypertension prevalence. A 1 tooth increase in the number of missing teeth was associated with a 1% increase in circadian syndrome and its components of obesity, elevated fasting plasma glucose (FPG) and short sleep. Poor or fair self-rated oral health showed a specificity of > 70% for periodontitis and lack of functional dentition. Meanwhile, poor or fair self-rated oral health had relatively higher levels of sensitivity for stage II-IV periodontitis (35%), stage III-IV periodontitis (46%), stage IV periodontitis (60%) and lacking functional dentition (56%). When compared to excellent self-rated oral health, good, fair and poor self-rated oral health were significantly associated with higher circadian syndrome prevalence (OR and 95% CI: Very good: 1.13 (0.97, 1.32), P = 0.120; Good: 1.34 (1.14, 1.57), P < 0.001; Fair: 1.41 (1.16, 1.71), P = 0.001; Poor: 1.63 (1.32, 2.03), P < 0.001). Additionally, participants with worse self-rated oral health had significantly higher prevalence of elevated FPG, hypertension, low HDL, elevated triglycerides, short sleep and depression. CONCLUSIONS Periodontitis, tooth loss and worse self-rated oral health were associated with circadian syndrome in US adults. Self-rated oral health may be a simple question to indicate oral and systemic health.
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Affiliation(s)
- Yibo Li
- Department of Orthodontics, Changsha Stomatological Hospital, Changsha, Hunan, 410004, P. R. China
- School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, P. R. China
| | - Yuhao Liu
- Changjun Bilingual School of Changsha, Changsha, Hunan, 410013, P. R. China
| | - Tao Yin
- Changsha Health Vocational College, Changsha, Hunan, 410605, P. R. China
| | - Mi He
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Changyun Fang
- Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Xiong Tang
- Department of General Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, P. R. China.
| | - Yundong Liu
- Health Management Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, P. R. China.
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24
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Zhang WL, Yu LP, Zhou W, Wang X, Du J. Exploring the oral bacteria-oral lichen planus connection: mechanisms, clinical implications and future directions. Arch Microbiol 2025; 207:143. [PMID: 40353891 DOI: 10.1007/s00203-025-04342-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/15/2025] [Accepted: 04/25/2025] [Indexed: 05/14/2025]
Abstract
Oral lichen planus (OLP) is a prevalent T-cell mediated inflammatory-immune disease with uncertain etiology. Recently, there is emerging evidence suggesting that oral bacteria may exert a prominent role in the onset and development of OLP. They might promote the initiation and progression of OLP by disrupting the oral epithelia, invading the lamina propria, stimulating pro-inflammatory cytokines production and inducing immune dysfunction. In this review, we will focus on the possible mechanisms of oral bacteria contributing to occurrence and development of OLP, and provide new insights into the bacteria-related diagnosis, prevention and treatment strategies for OLP.
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Affiliation(s)
- Wei-Long Zhang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- School of Stomatology, Shandong First Medical University, Jinan, China
| | - Lian-Pin Yu
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Wei Zhou
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xue Wang
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- School of Stomatology, Shandong First Medical University, Jinan, China
| | - Juan Du
- Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
- School of Stomatology, Shandong First Medical University, Jinan, China.
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25
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Ma Y, Ghosh S, Kong X, Kalimuthu S, Pudipeddi A, Okuro K, Ye Z, Dubey N, Neelakantan P. Nanoscale bismuth infused bioadhesive gelatin methacryloyl electrospun mats demonstrate excellent antibiofilm activity and biocompatibility. Int J Biol Macromol 2025; 312:144103. [PMID: 40350112 DOI: 10.1016/j.ijbiomac.2025.144103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 04/21/2025] [Accepted: 05/08/2025] [Indexed: 05/14/2025]
Abstract
Periodontal diseases affect a large portion of the global population, imposing significant health and economic burdens. Traditional treatments, including antibiotics, face challenges like antibiotic resistance and rapid clearance from target sites. The study addresses these issues using nanoscale antimicrobial bismuth nanoparticles (BiNPs) delivered through electrospun gelatin methacryloyl (GelMA) nanofibrous mats. BiNPs were synthesized via a rapid chemical reduction process, yielding particles with an average size of 30 nm and a stable surface charge of -18 mV. These nanoparticles were incorporated into GelMA fibers through electrospinning and characterized using techniques such as scanning electron microscopy and Fourier transform infrared spectroscopy. The GelMA fibers exhibited a uniform morphology with a diameter of 414 nm, controlled degradation, and sustained BiNPs release. Adhesion to soft tissue was measured at ∼3 N, and the fibers maintained their mechanical strength after BiNPs incorporation. The BiNPs-loaded mats demonstrated potent antimicrobial activity, killing 100 % of Porphyromonas gingivalis, a key periodontal pathogen. Biocompatibility tests with periodontal ligament stem cells confirmed no significant cytotoxicity. This study highlights BiNPs-infused GelMA nanofibrous mats as a promising localized treatment for periodontal diseases, offering sustained antimicrobial activity, and biocompatibility.
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Affiliation(s)
- Yuqi Ma
- Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong
| | - Soumen Ghosh
- Department of Chemistry, Faculty of Science, The University of Hong Kong, Hong Kong; State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong
| | - Xinzi Kong
- Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong
| | - Shanthini Kalimuthu
- Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong
| | - Akhila Pudipeddi
- Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong
| | - Kou Okuro
- Department of Chemistry, Faculty of Science, The University of Hong Kong, Hong Kong; State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong
| | - Zhou Ye
- Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong.
| | - Nileshkumar Dubey
- Faculty of Dentistry, National University of Singapore, Singapore; Division of Cariology and Operative Dentistry, Department of Comprehensive Dentistry, University of Maryland School of Dentistry, Baltimore, MD, United States.
| | - Prasanna Neelakantan
- Mike Petryk School of Dentistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada; Medical Microbiology and Immunology; Li Ka Shing Institute of Virology; Women & Children's Health Research Institute, University of Alberta.
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26
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Britos M, Hernández M, Fernández A, Pellegrini E, Chaparro L, Chaparro A, Suárez LJ, Hoare A, Hernández-Ríos P. Bacterial translocation signatures and subgingival microbiome in individuals with periodontitis. Clin Oral Investig 2025; 29:288. [PMID: 40329006 DOI: 10.1007/s00784-025-06363-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 04/27/2025] [Indexed: 05/08/2025]
Abstract
OBJECTIVES To determine bacterial blood translocation signatures and their association with the subgingival microbiota in individuals with and without periodontitis. MATERIALS AND METHODS Cross-sectional study. DNA was extracted from blood and subgingival samples of individuals with periodontitis (n = 21) and control volunteers (n = 24). Subgingival microbiota was explored by 16 S rRNA gene sequencing. Detection frequency and loads of total bacteria, Porphyromonas gingivalis (Pg), Porphyromonas endodontalis (Pe) and Fusobacterium nucleatum (Fn) were determined in all samples using quantitative polymerase chain reaction (qPCR). The statistical analysis was performed using STATA 16. RESULTS Subgingival samples from individuals with periodontitis presented higher relative abundance of Prevotella intermedia, F. nucleatum subsp. vincentii, Treponema sp. HMT 237, Alloprevotella tannerae, Filifactor alocis, Pg, Treponema denticola and Pe, and higher loads of total bacteria, Pg, Pe and Fn, compared to the control group (p < 0.001). While Pg and Fn were not detected in blood, Pe was detected in 95% of individuals with periodontitis and 83% of the control ones (p = 0.205), with higher loads in blood samples from periodontitis (p = 0.034). No significant correlation was found between subgingival bacterial loads and blood loads of Pe in periodontitis and control groups (p > 0.05). CONCLUSIONS Individuals with periodontitis presented higher relative abundance and loads of periodontal bacteria in subgingival samples and higher Pe loads in blood samples, although further research is needed to understand the correlation between subgingival and blood bacterial loads. CLINICAL RELEVANCE The present study showed higher loads of Pe in the blood of individuals with periodontitis, suggesting potential extraoral dissemination and a linking mechanism with several systemic diseases.
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Affiliation(s)
- Marcelo Britos
- Laboratory of Periodontal Biology, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile
| | - Marcela Hernández
- Laboratory of Periodontal Biology, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile
- Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile
| | - Alejandra Fernández
- Faculty of Dentistry, Universidad Andres Bello, Región Metropolitana, Santiago, 8370133, Chile
| | - Elizabeth Pellegrini
- Laboratory of Periodontal Biology, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile
| | - Laura Chaparro
- Department of Pathology and Oral Medicine, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile
| | - Alejandra Chaparro
- Department of Pathology and Conservative Dentistry, Faculty of Dentistry, Universidad de Los Andes, Av. Plaza 2501, Las Condes, Santiago, 7620157, Chile
| | - Lina J Suárez
- Centro de Investigaciones Odontológicas, Facultad de Odontología, Pontificia Universidad Javeriana, Cra. 7 #40-62, Bogotá, Colombia
- Departamento de Ciencias Básicas y Medicina Oral, Facultad de Odontología, Universidad Nacional de Colombia, Carrera 45 No. 26-85, Bogotá, Colombia
| | - Anilei Hoare
- Oral Microbiology and Immunology Laboratory, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile.
- Laboratory of Oral Microbiota Ecology, Faculty of Dentistry, Universidad Andrés Bello, Echaurren 277, Santiago, 8370133, Chile.
| | - Patricia Hernández-Ríos
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Olivos 943, Independencia, Santiago, 8380544, Chile.
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27
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Jeitner TM, Singh PK, Azcona J, Euler CW, Kelly JM. Identifying transglutaminase substrate glutaminyls using dansylcadaverine. Anal Biochem 2025; 704:115888. [PMID: 40345315 DOI: 10.1016/j.ab.2025.115888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 04/29/2025] [Accepted: 04/30/2025] [Indexed: 05/11/2025]
Abstract
Dansylcadaverine is often used at a final concentration of 1 mM to identify transglutaminase substrate glutaminyl residues. At this concentration, dansylcadaverine only labels a fraction of the possible substrates. Therefore, we developed a 500 mM stock dansylcadaverine solution in dimethyl sulfoxide:acetic acid (19:1) that allows the identification of all transglutaminase substrate glutaminyl residues. This solution was used to identify these substrate residues: Gln 283, Gln 325, and Gln 677 in a fragment of arginine-specific gingipain A.
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Affiliation(s)
- Thomas M Jeitner
- Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
| | | | - Juan Azcona
- Department of Radiology, Weill Cornell Medicine, New York, NY, USA
| | - Chad W Euler
- Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, NY, USA; Department of Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
| | - James M Kelly
- Department of Radiology, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, USA
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28
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Zhang Y, Liu K, Sun Q, Qi Y, Li F, Su X, Song M, Lv R, Sui H, Shi Y, Zhao L. Collagenase Degradable Biomimetic Nanocages Attenuate Porphyromonas gingivalis Mediated Neurocognitive Dysfunction via Targeted Intracerebral Antimicrobial Photothermal and Gas Therapy. ACS NANO 2025; 19:16448-16468. [PMID: 40285729 DOI: 10.1021/acsnano.4c17748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Porphyromonas gingivalis (P.g.), a pathogen linked to periodontitis, is reported to be associated with severe neurocognitive dysfunction. However, there are few reports focusing on improving neurological function in the brain by eliminating P.g.. Therefore, we developed a core-shell nanocomposite for targeted intracerebral P.g. clearance and ameliorating neurocognitive impairments, Pt-Au@C-P.g.-MM, consisting of platinum nanoparticles (Pt NPs) encapsulated within Au nanocages (Pt-Au) as the core and a shell made of collagen and macrophage membranes from macrophage pretreated with P.g. (C-P.g.-MM). This design enhanced the nanocomposite's ability to cross the blood-brain barrier (BBB) and specifically target intracerebral P.g. through coating of P.g.-MM. Pt-Au@C-P.g.-MM depended on collagen to neutralize excessive collagenase from P.g., promoting its directed migration toward P.g.. Au nanocages exhibited excellent photothermal effects under near-infrared (NIR) laser irradiation, while Pt NPs also provided an efficient antibacterial gas therapy by generating oxygen to expose anaerobic P.g.. As a result, Pt-Au@C-P.g.-MM contributed to a synergistic antibacterial therapy and significantly reduced P.g. mediated neurocognitive dysfunction in periodontitis mice induced by oral P.g. infection. Based on the insights provided by the transcriptome sequencing analysis, anti-P.g. activity of Pt-Au@C-P.g.-MM facilitated the transition of microglia from the M1 to M2 phenotype by stimulating the PI3K-Akt pathway and reducing neuronal damage through the Wnt/β-catenin pathway.
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Affiliation(s)
- Yifei Zhang
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Kang Liu
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Qing Sun
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Yao Qi
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Fang Li
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Xiangchen Su
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Mingzhu Song
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Ruizhen Lv
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Haijuan Sui
- Department of Pharmacology, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Yijie Shi
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
- Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou 121000, P. R. China
| | - Liang Zhao
- School of Pharmacy, Jinzhou Medical University, Jinzhou 121000, P. R. China
- Collaborative Innovation Center for Age-related Disease, Jinzhou Medical University, Jinzhou 121000, P. R. China
- Key Laboratory of Neurodegenerative Diseases of Liaoning Province, Jinzhou Medical University, Jinzhou 121000, P. R. China
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Heneka MT, van der Flier WM, Jessen F, Hoozemanns J, Thal DR, Boche D, Brosseron F, Teunissen C, Zetterberg H, Jacobs AH, Edison P, Ramirez A, Cruchaga C, Lambert JC, Laza AR, Sanchez-Mut JV, Fischer A, Castro-Gomez S, Stein TD, Kleineidam L, Wagner M, Neher JJ, Cunningham C, Singhrao SK, Prinz M, Glass CK, Schlachetzki JCM, Butovsky O, Kleemann K, De Jaeger PL, Scheiblich H, Brown GC, Landreth G, Moutinho M, Grutzendler J, Gomez-Nicola D, McManus RM, Andreasson K, Ising C, Karabag D, Baker DJ, Liddelow SA, Verkhratsky A, Tansey M, Monsonego A, Aigner L, Dorothée G, Nave KA, Simons M, Constantin G, Rosenzweig N, Pascual A, Petzold GC, Kipnis J, Venegas C, Colonna M, Walter J, Tenner AJ, O'Banion MK, Steinert JR, Feinstein DL, Sastre M, Bhaskar K, Hong S, Schafer DP, Golde T, Ransohoff RM, Morgan D, Breitner J, Mancuso R, Riechers SP. Neuroinflammation in Alzheimer disease. Nat Rev Immunol 2025; 25:321-352. [PMID: 39653749 DOI: 10.1038/s41577-024-01104-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2024] [Indexed: 02/20/2025]
Abstract
Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.
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Affiliation(s)
- Michael T Heneka
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg.
| | - Wiesje M van der Flier
- Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Frank Jessen
- Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
| | - Jeroen Hoozemanns
- Department of Pathology, Amsterdam Neuroscience, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Dietmar Rudolf Thal
- Department of Pathology, University Hospitals Leuven, Leuven, Belgium
- Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
- Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), Leuven, Belgium
| | - Delphine Boche
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Charlotte Teunissen
- Department of Laboratory Medicine, VUMC Amsterdam, Amsterdam, The Netherlands
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Andreas H Jacobs
- European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Paul Edison
- Division of Neurology, Department of Brain Sciences, Imperial College London, London, UK
| | - Alfredo Ramirez
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
- Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Carlos Cruchaga
- Department of Psychiatry, Washington School of Medicine in St. Louis, St. Louis, MO, USA
| | - Jean-Charles Lambert
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France
| | - Agustin Ruiz Laza
- ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain
| | - Jose Vicente Sanchez-Mut
- Instituto de Neurociencias, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas (UMH-CSIC), Alicante, Spain
| | - Andre Fischer
- Clinic for Psychiatry and Psychotherapy, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany
- Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative Disease (DZNE), Göttingen, Germany
| | - Sergio Castro-Gomez
- Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Physiology II, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Thor D Stein
- Boston University Alzheimer's Disease Research Center and CTE Center, Department of Pathology & Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Luca Kleineidam
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Michael Wagner
- Department of Neurodegenerative Disease and Geriatric Psychiatry, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Jonas J Neher
- Biomedical Center Munich, Biochemistry, Medical Faculty, LMU Munich, Munich, Germany
- Neuroimmunology and Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Colm Cunningham
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
- Trinity College Institute of Neuroscience (TCIN), Trinity College Dublin, Dublin, Ireland
| | - Sim K Singhrao
- Brain and Behaviour Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK
| | - Marco Prinz
- Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany
- Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Christopher K Glass
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Johannes C M Schlachetzki
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
| | - Oleg Butovsky
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kilian Kleemann
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Philip L De Jaeger
- Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Hannah Scheiblich
- Center for Neurology, Clinic of Parkinson, Sleep and Movement Disorders, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Guy C Brown
- Deparment of Biochemistry, University of Cambridge, Cambridge, UK
| | - Gary Landreth
- School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Miguel Moutinho
- School of Medicine, Indiana University, Indianapolis, IN, USA
| | - Jaime Grutzendler
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA
| | - Diego Gomez-Nicola
- School of Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Róisín M McManus
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Katrin Andreasson
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Christina Ising
- Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Deniz Karabag
- Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Darren J Baker
- Department of Paediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Shane A Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York City, NY, USA
- Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York City, NY, USA
- Department of Ophthalmology, NYU Grossman School of Medicine, New York City, NY, USA
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Malu Tansey
- College of Medicine, University of Florida, Gainsville, FL, USA
| | - Alon Monsonego
- Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ludwig Aigner
- Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Guillaume Dorothée
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Hôpital Saint-Antoine, Paris, France
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Mikael Simons
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
| | - Gabriela Constantin
- Section of General Pathology, Department of Medicine, University of Verona, Verona, Italy
| | - Neta Rosenzweig
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alberto Pascual
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
| | - Gabor C Petzold
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Vascular Neurology, University of Bonn, Bonn, Germany
| | - Jonathan Kipnis
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, USA
| | - Carmen Venegas
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg
- Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
- Instituto Biosanitario de Granada (ibs.Granada), Granada, Spain
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Jochen Walter
- Center of Neurology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Andrea J Tenner
- Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA, USA
- Department of Neurobiology and Behaviour, University of California Irvine, Irvine, CA, USA
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - M Kerry O'Banion
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
- Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA
| | - Joern R Steinert
- Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Douglas L Feinstein
- Department of NeuroAnesthesia, University of Illinois at Chicago, Chicago, IL, USA
| | - Magdalena Sastre
- Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
| | - Kiran Bhaskar
- Department of Molecular Genetics & Microbiology and Neurology, University of New Mexico, Albuquerque, NM, USA
| | - Soyon Hong
- UK Dementia Research Institute, Institute of Neurology, University College London, London, UK
| | - Dorothy P Schafer
- Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Todd Golde
- Department of Pharmacology and Chemical Biology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA
- Department of Neurology, Emory Center for Neurodegenerative Disease, Emory University, Atlanta, GA, USA
| | | | - David Morgan
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - John Breitner
- Department of Psychiatry, McGill University Faculty of Medicine, Montreal, Québec, Canada
| | - Renzo Mancuso
- Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Sean-Patrick Riechers
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette/Belvaux, Luxembourg
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Kalkman HO, Smigielski L. Ceramides may Play a Central Role in the Pathogenesis of Alzheimer's Disease: a Review of Evidence and Horizons for Discovery. Mol Neurobiol 2025:10.1007/s12035-025-04989-0. [PMID: 40295359 DOI: 10.1007/s12035-025-04989-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/19/2025] [Indexed: 04/30/2025]
Abstract
While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none have been entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders and psychological stress, contribute to this debilitating disease. Multiple lines of evidence indicate that ceramides may be central to the pathogenesis of Alzheimer's disease. Tumor necrosis factor-α, saturated fatty acids and cortisol elevate the brain levels of ceramides, while genetic risk factors, such as mutations in APP, presenilin, TREM2 and APOE ε4, also elevate ceramide synthesis. Importantly, ceramides displace sphingomyelin and cholesterol from lipid raft-like membrane patches that connect the endoplasmic reticulum and mitochondria, disturbing mitochondrial oxidative phosphorylation and energy production. As a consequence, the flattening of lipid rafts alters the function of γ-secretase, leading to increased production of Aβ42. Moreover, ceramides inhibit the insulin-signaling cascade via at least three mechanisms, resulting in the activation of glycogen synthase kinase-3 β. Activation of this kinase has multiple consequences, as it further deteriorates insulin resistance, promotes the transcription of BACE1, causes hyperphosphorylation of tau and inhibits the transcription factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity and improves blood-brain barrier function. Thus, various seemingly unrelated Alzheimer's disease risk factors converge on ceramide production, whereas the elevated levels of ceramides give rise to the well-known pathological features of Alzheimer's disease. Understanding and targeting these mechanisms may provide a promising foundation for the development of novel preventive and therapeutic strategies.
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Affiliation(s)
- Hans O Kalkman
- Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland.
| | - Lukasz Smigielski
- Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland
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31
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Krishnan D, Ghosh P, Lakshman N, Justin A, Ramasamy S. Oro-pharyngeal mucosal microbiome alternations causing immune system dysregulation in schizophrenia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2025; 180:125-156. [PMID: 40414631 DOI: 10.1016/bs.irn.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Schizophrenia is a chronic and thoughtful psychological disorder that affects a person's thinking, feelings, and behaviours. Multi-factorial genetic, environmental, and neurological variables cause it. Recently, more research focused on the human microbiome, which alters the immune system and develops adverse health effects on the human body. The study discusses a possible relationship between the oropharyngeal microbiome and schizophrenia. According to recent studies, the oropharyngeal microbiome may alter the immune system in the human body and cause various psychiatric disorders, including schizophrenia. The oropharyngeal microbiome can cause schizophrenia either by affecting the genes, chromosomes, and immune system in the human body. Additionally, it examines the combined mechanism of how the oropharyngeal microbiome's alterations lead to genetic abnormalities and immune dysregulation in schizophrenia. By combining the various approaches, this chapter offers a comprehensive view of the oropharyngeal microbiome's role in schizophrenia and suggests that microbial alterations could serve as biomarkers or therapeutic targets for the disorder.
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Affiliation(s)
- Deena Krishnan
- Molecular Genetics and Cancer Biology Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Puja Ghosh
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
| | - Nathish Lakshman
- Molecular Genetics and Cancer Biology Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Antony Justin
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
| | - Sivasamy Ramasamy
- Molecular Genetics and Cancer Biology Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India.
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Kurek-Górecka A, Kłósek M, Balwierz R, Pietsz G, Czuba ZP. The Immunomodulatory Effects of Apigenin and Quercetin on Cytokine Secretion by the Human Gingival Fibroblast Cell Line and Their Potential Link to Alzheimer's Disease. Pharmaceuticals (Basel) 2025; 18:628. [PMID: 40430449 PMCID: PMC12114632 DOI: 10.3390/ph18050628] [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: 02/27/2025] [Revised: 04/22/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025] Open
Abstract
Background: The link between periodontal pathogens, inflammation, and neurodegenerative processes, including Alzheimer's disease (AD), is evident. Porphyromonas gingivalis and Treponema denticola release lipopolysaccharide (LPS), constituting a virulence factor that takes part in the brain inflammatory process. Human gingival fibroblasts (HGF-1) are a source of pro-inflammatory cytokines released during periodontal diseases. Propolis is a rich source of quercetin and apigenin, which exhibit anti-inflammatory and immunomodulatory activities, influencing the concentration of pro-inflammatory cytokines. Considering this aspect, models with stimulated HGF-1, followed by LPS and/or interferon-α (IFN-α), were used. Aim: This study was designed to evaluate the concentrations of selected cytokines produced by HGF-1, which may influence brain inflammation. The immunomodulatory effects of apigenin and quercetin were investigated by measuring the concentration of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), and tumour necrosis factor (TNF-α). This study's novelty is based on insights into the immunomodulatory effects of selected flavonoids by correlating the secretion of pro-inflammatory cytokines by gingival fibroblasts during periodontal disease with inflammatory processes in the brain. The cytotoxicity of apigenin and quercetin was estimated using the MTT assay. Fibroblasts were stimulated with LPS at 200 ng/mL and/or IFN-α at 100 U/mL concentration, followed by incubation with apigenin (25-50 µg/mL) and quercetin (25-50 µg/mL). Cytokine concentrations were measured using the xMAP technology. Results: The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and IL-15, was observed for quercetin in both concentrations (25 µg/mL and 50 µg/mL), especially following LPS stimulation. Apigenin in both analysed concentrations also significantly decreased the level of IL-6. These results suggest that quercetin and apigenin may indirectly act as potential immunomodulators in preventing brain inflammation by inhibiting the inflammatory process in periodontitis; however, this should be confirmed in further studies.
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Affiliation(s)
- Anna Kurek-Górecka
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (M.K.); (G.P.); (Z.P.C.)
| | - Małgorzata Kłósek
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (M.K.); (G.P.); (Z.P.C.)
| | - Radosław Balwierz
- Institute of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland;
| | - Grażyna Pietsz
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (M.K.); (G.P.); (Z.P.C.)
| | - Zenon P. Czuba
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (M.K.); (G.P.); (Z.P.C.)
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Sarmiento-Ordóñez JM, Brito-Samaniego DR, Vásquez-Palacios AC, Pacheco-Quito EM. Association Between Porphyromonas gingivalis and Alzheimer's Disease: A Comprehensive Review. Infect Drug Resist 2025; 18:2119-2136. [PMID: 40308631 PMCID: PMC12043021 DOI: 10.2147/idr.s491628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 03/13/2025] [Indexed: 05/02/2025] Open
Abstract
Background Periodontitis has long been linked to various inflammatory, chronic, and immunological diseases, such as heart disease or diabetes. Recently, there has been increasing scientific interest in the bidirectional relationship that may exist between periodontitis and the presence and progression of Alzheimer's disease (AD), where it is hypothesized that the infiltration of oral microorganisms (mainly Porphyromonas gingivalis) into the bloodstream, which subsequently reaches the brain, causes inflammatory and neurodegenerative processes related to AD. Purpose The purpose of this review is to determine the association between Porphyromonas gingivalis and Alzheimer's disease in older adults. Patients and Methods It was carried out using different databases such as PubMed, Web of Science, among others, of no more than 10 years old focused on older adult patients who have presented periodontitis and Alzheimer's disease. MESH-indexed terms were used, getting 307 articles. After removing 206 duplicates and applying inclusion criteria (language, relevance, and contribution to the study's objectives), 24 articles were selected for analysis. Conclusion Evidence has been found that gingipains produced by P. gingivalis may contribute to the formation of amyloid plaques in the brain and nerve cell damage characteristic of Alzheimer's disease. It has also been observed that P. gingivalis can enter the brain and stimulate a local immune response. Although the association is promising, more research is needed to confirm it and to develop effective treatments. These findings may have significant implications for clinical practice, potentially leading to preventive or therapeutic strategies targeting oral health as a modifiable risk factor for AD. Further research could focus on exploring these pathways and developing targeted interventions.
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Affiliation(s)
- Jéssica María Sarmiento-Ordóñez
- Unidad Académica de Salud y Bienestar, Facultad de Odontología, Universidad Católica de Cuenca, Cuenca, Ecuador
- Grupo de Investigación Innovación y Desarrollo Farmacéutico en Odontología, Facultad de Odontología, Jefatura de Investigación e Innovación, Universidad Católica de Cuenca, Cuenca, Ecuador
| | | | | | - Edisson-Mauricio Pacheco-Quito
- Unidad Académica de Salud y Bienestar, Facultad de Odontología, Universidad Católica de Cuenca, Cuenca, Ecuador
- Grupo de Investigación Innovación y Desarrollo Farmacéutico en Odontología, Facultad de Odontología, Jefatura de Investigación e Innovación, Universidad Católica de Cuenca, Cuenca, Ecuador
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Li K, Song J, Lu Y, Zhang D, Wang Y, Wang X, Tang Y, Yu Y, Zhang X, Yang X, Cai Q. Biodegradable Piezoelectric Janus Membrane Enabling Dual Antibacterial and Osteogenic Functions for Periodontitis Therapy. ACS APPLIED MATERIALS & INTERFACES 2025; 17:23707-23721. [PMID: 40202058 DOI: 10.1021/acsami.5c02557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Guided tissue regeneration (GTR) using barrier membranes is a common clinical approach for treating periodontitis-induced alveolar bone loss. However, conventional GTR membranes lack antibacterial and osteoinductive properties, limiting their effectiveness. Piezoelectric materials, which generate electrical outputs under chewing forces, offer antibacterial and bone-regenerative potential due to their oppositely charged surfaces. Inspired by this, a piezoelectric Janus membrane was developed for dual-function GTR therapy. Biodegradable poly(l-lactide) (PLLA) and PLLA/gelatin membranes were electrospun, annealed, and polarized to create the A-P(+)/PG(-) piezoelectric Janus membrane. Notably, in this Janus membrane, the outer surface of the PLLA side (A-P(+)) carries positive charges and is positioned toward the gingival tissue to kill bacteria via charge interactions; the inner surface of the PG side (PG(-)) holds negative charges and faces the alveolar bone defect, promoting bone growth through immunomodulation and enhanced mineralization. In a mouse model of periodontitis, the Janus membrane A-P(+)/PG(-) demonstrated dual functionality, effectively reducing inflammation, inhibiting bone resorption. The bone mineral density of A-P(+)/PG(-) reached 1637 ± 37 mg/cm3 at 8 weeks after surgery, which was superior to commercial collagen membranes lacking antibacterial properties. Overall, this study introduces an innovative approach, leveraging biodegradable piezoelectric PLLA to construct a versatile Janus GTR membrane with enhanced antibacterial and osteogenic activity for periodontitis treatment.
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Affiliation(s)
- Ke Li
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
- SINOPEC (Beijing) Research Institute of Chemical Industry Co., Ltd., Beijing 100013, China
| | - Jia Song
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Yanhui Lu
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Daixing Zhang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Yuqing Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Xinyu Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Yujing Tang
- SINOPEC (Beijing) Research Institute of Chemical Industry Co., Ltd., Beijing 100013, China
| | - Yingjie Yu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Xuehui Zhang
- Department of Dental Materials & Dental Medical Devices Testing Center, Peking University School and Hospital of Stomatology, Beijing 100081, China
- Oral Translational Medicine Research Center, Joint Training Base for Shanxi Provincial Key Laboratory in Oral and Maxillofacial Repair, Reconstruction and Regeneration, The First People's Hospital of Jinzhong, Jinzhong, 030600, China
| | - Xiaoping Yang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
| | - Qing Cai
- State Key Laboratory of Organic-Inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China
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35
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Cho MY, Eom JH, Choi EM, Yang SJ, Lee D, Kim YY, Kim HS, Hwang I. Recent advances in therapeutic probiotics: insights from human trials. Clin Microbiol Rev 2025:e0024024. [PMID: 40261032 DOI: 10.1128/cmr.00240-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025] Open
Abstract
SUMMARYRecent advances in therapeutic probiotics have shown promising results across various health conditions, reflecting a growing understanding of the human microbiome's role in health and disease. However, comprehensive reviews integrating the diverse therapeutic effects of probiotics in human subjects have been limited. By analyzing randomized controlled trials (RCTs) and meta-analyses, this review provides a comprehensive overview of key developments in probiotic interventions targeting gut, liver, skin, vaginal, mental, and oral health. Emerging evidence supports the efficacy of specific probiotic strains and combinations in treating a wide range of disorders, from gastrointestinal (GI) and liver diseases to dermatological conditions, bacterial vaginosis, mental disorders, and oral diseases. We discuss the expanding understanding of microbiome-organ connections underlying probiotic mechanisms of action. While many clinical trials demonstrate significant benefits, we acknowledge areas requiring further large-scale studies to establish definitive efficacy and optimal treatment protocols. The review addresses challenges in standardizing probiotic research methodologies and emphasizes the importance of considering individual variations in microbiome composition and host genetics. Additionally, we explore emerging concepts such as the oral-gut-brain axis and future directions, including high-resolution microbiome profiling, host-microbe interaction studies, organoid models, and artificial intelligence applications in probiotic research. Overall, this review offers a comprehensive update on the current state of therapeutic probiotics across multiple domains of human health, providing insights into future directions and the potential for probiotics to revolutionize preventive and therapeutic medicine.
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Affiliation(s)
- Mu-Yeol Cho
- Apple Tree Institute of Biomedical Science, Apple Tree Medical Foundation, Goyang-si, South Korea
| | - Je-Hyun Eom
- Apple Tree Institute of Biomedical Science, Apple Tree Medical Foundation, Goyang-si, South Korea
| | - Eun-Mi Choi
- Apple Tree Institute of Biomedical Science, Apple Tree Medical Foundation, Goyang-si, South Korea
| | | | - Dahye Lee
- Department of Orthodontics, Apple Tree Dental Hospital, Goyang-si, South Korea
| | - Young Youn Kim
- Department of Oral and Maxillofacial Surgery, Apple Tree Dental Hospital, Goyang-si, South Korea
| | - Hye-Sung Kim
- Department of Oral and Maxillofacial Surgery, Apple Tree Dental Hospital, Goyang-si, South Korea
| | - Inseong Hwang
- Apple Tree Institute of Biomedical Science, Apple Tree Medical Foundation, Goyang-si, South Korea
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Adamowicz K, Lima Ribeiro AS, Golda A, Wadowska M, Potempa J, Schmaderer C, Anders HJ, Koziel J, Lech M. Bidirectional Interaction Between Chronic Kidney Disease and Porphyromonas gingivalis Infection Drives Inflammation and Immune Dysfunction. J Immunol Res 2025; 2025:8355738. [PMID: 40276114 PMCID: PMC12021489 DOI: 10.1155/jimr/8355738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 12/22/2024] [Accepted: 02/04/2025] [Indexed: 04/26/2025] Open
Abstract
Introduction: Chronic kidney disease (CKD) is characterized by a decline in renal function, increased mortality, and significant impairments in the immune system and function of immune cells. These alterations are often derived by uremic toxins, which, in turn, modify the immune system's response to infections. Our research investigates the progression of Porphyromonas gingivalis (P. gingivalis) infection during CKD and its subsequent impact on kidney failure. Methods: We utilized two infectious models, a chamber model representing short-term local inflammation and alveolar bone loss that mimic chronic infection of periodontium, both in conjunction with a CKD model. Additionally, our in vitro studies employed primary macrophages, osteoclasts, and lymphocytes to characterize the immune responses to P. gingivalis and pathogen-associated molecular patterns (PAMPs) in the presence of uremic toxins. Results and Conclusion: Our findings demonstrate that uremic toxins, such as indoxyl sulfate (IS), alter responses of macrophages and lymphocytes to P. gingivalis. In vivo, CKD significantly enhanced P. gingivalis survival and infection-induced alveolar bone loss. The increased distribution of pathogen within peripheral tissues was associated with altered inflammatory responses, indicating that CKD promotes infection. Moreover, P. gingivalis-infected mice exhibited a marked increase in renal inflammation, suggesting that the relationship between uremia and infection is bidirectional, with infection exacerbating kidney dysfunction. Furthermore, we observed that infected CKD mice exhibit decreased serum immunoglobulin G (IgG) levels compared to infected mice without CKD, implying that uremia is associated with immune dysfunction characterized by immunodepression and impaired B lymphocyte function.
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Affiliation(s)
- Karina Adamowicz
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Andrea Sofia Lima Ribeiro
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- TUM University Hospital, Technical University Munich (TUM), Munich, Germany
| | - Anna Golda
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Marta Wadowska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
- Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | | | - Hans-Joachim Anders
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Joanna Koziel
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland
| | - Maciej Lech
- Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
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Śmiga M, Roszkiewicz E, Ślęzak P, Tracz M, Olczak T. cAMP-independent Crp homolog adds to the multi-layer regulatory network in Porphyromonas gingivalis. Front Cell Infect Microbiol 2025; 15:1535009. [PMID: 40308968 PMCID: PMC12040651 DOI: 10.3389/fcimb.2025.1535009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/21/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction Porphyromonas gingivalis encodes three CRP/FNR superfamily proteins: HcpR, PgRsp, and CrpPg, with CrpPg similar to cAMP-sensing proteins but not classified into known families. This study investigates the role of CrpPg in regulating the expression of factors essential for P. gingivalis virulence in A7436 and ATCC 33277 strains. Methods The role of CrpPg protein in P. gingivalis was determined using the ΔcrpPg mutant strains to characterize their phenotype and to assess the impact of crpPg inactivation on gene expression using RNA-seq and RT-qPCR. Additionally, the CrpPg protein was purified and characterized. Results Key findings in the ΔcrpPg mutant strain include up-regulated mfa1-5 and rgpA genes and down-regulated trxA, soxR, and ustA genes. While crpPg inactivation does not affect growth in liquid culture media, it impairs biofilm formation and enhances adhesion to and invasion of gingival keratinocytes. CrpPg binds directly to its own and mfa promoters without interacting with cyclic nucleotides or di-nucleotides. Its three-dimensional structure, resembling E. coli Crp in complex with cAMP and DNA, suggests that CrpPg functions as a global regulator independently of cAMP binding. The highest crpPg expression in the early exponential growth phase declines as cell density and metabolic conditions change over time, suggesting a regulatory function depending on the CrpPg protein amount. Conclusions By controlling the shift from planktonic to biofilm lifestyle, CrpPg may play a role in pathogenicity. Regulating the expression of virulence factors required for host cell invasion and intracellular replication, CrpPg may help P. gingivalis evade immune responses.
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Affiliation(s)
- Michał Śmiga
- Laboratory of Medical Biology, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Ewa Roszkiewicz
- Laboratory of Medical Biology, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Paulina Ślęzak
- Laboratory of Medical Biology, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Michał Tracz
- Laboratory of Protein Mass Spectrometry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
| | - Teresa Olczak
- Laboratory of Medical Biology, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
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Ioannou P, Katsoulieris E, Afratis NA. Matrix Dynamics and Microbiome Crosstalk: Matrix Metalloproteinases as Key Players in Disease and Therapy. Int J Mol Sci 2025; 26:3621. [PMID: 40332093 PMCID: PMC12027064 DOI: 10.3390/ijms26083621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/02/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
Matrix metalloproteinases (MMPs) are key enzymes involved in extracellular matrix (ECM) remodeling, regulating a wide range of cellular and immune processes in both homeostatic and pathological conditions. Host-microbiota interactions play a critical role in maintaining ECM balance; however, during dysbiosis, this regulation is disrupted, leading to compromised barrier integrity, pathogen translocation into circulation, and the development of systemic diseases and cancer. This review highlights the bidirectional relationship between MMP expression/activity and microbiota dysbiosis, emphasizing tissue-specific alterations in MMP activity that contribute to disease progression. In addition, it integrates interdisciplinary evidence to illustrate the MMP-dependent mechanisms underlying various pathologies associated with oral and gut microbiome dysbiosis, including long-range effects through the gut-skin and gut-brain axes. Thus, this review introduces the emerging field of MatrixBiome, which explores the complex interactions between the ECM, microbiota, and host tissues. Finally, it also outlines therapeutic strategies to modulate MMP levels, either indirectly through microbiome-targeted approaches (e.g., prebiotics, probiotics, and postbiotics) or directly using MMP inhibitors, offering promising avenues for future clinical interventions.
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Affiliation(s)
- Paraskevi Ioannou
- Laboratory of Biotechnology and Molecular Analysis, Department of Agricultural Development, Agri-Food & Management of Natural Resources, National and Kapodistrian University of Athens, Evripos Campus, 34400 Psachna, Evia, Greece (E.K.)
| | - Elias Katsoulieris
- Laboratory of Biotechnology and Molecular Analysis, Department of Agricultural Development, Agri-Food & Management of Natural Resources, National and Kapodistrian University of Athens, Evripos Campus, 34400 Psachna, Evia, Greece (E.K.)
| | - Nikolaos A. Afratis
- Laboratory of Biotechnology and Molecular Analysis, Department of Agricultural Development, Agri-Food & Management of Natural Resources, National and Kapodistrian University of Athens, Evripos Campus, 34400 Psachna, Evia, Greece (E.K.)
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, 234 Herzl Street, Rehovot 7610001, Israel
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Popovici IA, Orasanu CI, Cozaru GC, Ionescu AC, Kajanto L, Cimpineanu B, Chisoi A, Mitroi AN, Poinareanu I, Voda RI, Ursica OA, Pundiche MB. An Overview of the Etiopathogenic Mechanisms Involved in the Expression of the Oral Microbiota. Clin Pract 2025; 15:80. [PMID: 40310312 PMCID: PMC12026067 DOI: 10.3390/clinpract15040080] [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: 02/13/2025] [Revised: 03/17/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025] Open
Abstract
Background/Objectives: The diversity of the oral microbiota exerts its effects in maintaining dental and overall health. The unique genetic profile of each individual influences the composition of the oral microbiota, determining susceptibility to certain diseases. The aim is to observe its role by highlighting the pathogenic mechanisms involved in oral dysbiosis and identify genetic determinism's influence in maintaining balance. Methods: This study was designed as a narrative review of the oral microbiota, utilizing some of the principles and guidelines of systematic review to increase methodological rigor. We examined 121 articles such as reviews, meta-analyses, editorials, and observational studies, which met the inclusion and exclusion criteria. The inclusion criteria for studies were as follows: (1) studies that evaluated the impact of the microbiota in oral or/and systemic diseases; (2) studies that observed pathogenic mechanisms in the oral microbiota; (3) studies that evaluated the interaction of the microbiota with the immune system (4); studies that evaluated genetic implications in the microbiota. Results: Host genes regulate inflammatory and immunological reactions that play a role in microbiological balance. This explains the increased resistance of some to diseases, including gingivitis or periodontitis. Also, the implications of oral dysbiosis are reflected not only locally, but also generally, being associated with various systemic conditions. Conclusions: Understanding the pathogenic mechanisms and genetic determinants involved in oral dysbiosis may help create individualized therapies for preventing and managing oral and systemic disorders. A healthy lifestyle and adequate oral hygiene can facilitate a diverse and balanced microbiome, crucial for overall health.
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Affiliation(s)
- Ion Alexandru Popovici
- Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 010221 Bucharest, Romania;
| | - Cristian Ionut Orasanu
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
| | - Georgeta-Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Anita-Cristina Ionescu
- Oncological Institute “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania; (A.-C.I.); (L.K.)
| | - Lidia Kajanto
- Oncological Institute “Prof. Dr. Alexandru Trestioreanu”, 022328 Bucharest, Romania; (A.-C.I.); (L.K.)
| | - Bogdan Cimpineanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Adrian Nelutu Mitroi
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- Railway Clinical Hospital, 900123 Constanta, Romania
| | - Ionut Poinareanu
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
| | - Raluca Ioana Voda
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology (CEDMOG), “Ovidius” University of Constanta, 900591 Constanta, Romania; (G.-C.C.); (A.C.); (R.I.V.)
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
| | - Oana Andreea Ursica
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
| | - Mihaela Butcaru Pundiche
- Faculty of Medicine, “Ovidius” University of Constanta, 900470 Constanta, Romania; (B.C.); (A.N.M.); (I.P.); (O.A.U.); (M.B.P.)
- “Sf. Apostol Andrei” County Emergency Clinical Hospital, 900591 Constanta, Romania
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Vosála O, Šmídová B, Novák J, Svoboda J, Petrásek T, Vojtěchová I, Macháček T. No evidence of Alzheimer's disease pathology in mice infected with Toxocara canis. Parasite 2025; 32:24. [PMID: 40214165 PMCID: PMC11987500 DOI: 10.1051/parasite/2025019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
The potential link between the infections and the development of Alzheimer's disease (AD) has led to speculations about the role of various pathogens in triggering amyloid-β (Aβ) overproduction, possibly leading to AD onset. The globally distributed dog roundworm Toxocara canis was suggested to be a suitable candidate due to neurotropism of the larvae and infection chronicity. This study investigated whether chronic T. canis infection induces AD-like pathology in mice and whether Aβ is toxic to T. canis. BALB/c and APP/PS1 transgenic mice, which overproduce Aβ, were infected with T. canis L3 larvae and monitored for larval burden, Aβ accumulation, and behavioral changes. In vitro tests of recombinant Aβ toxicity against the larvae were also performed. Despite the presence of T. canis larvae in the central nervous system 8 and 16 weeks post-infection, no significant increase in Aβ concentration or AD-related behavioral alterations were observed. Aβ was detected on the surface and within the intestines of T. canis larvae, but in vitro exposure to recombinant Aβ did not affect larval viability or morphology. Our findings suggest that T. canis infection does not trigger AD-like pathology in mice, and Aβ does not act as an antiparasitic agent. This challenges the emerging hypothesis that chronic neurotoxocarosis infections may contribute to AD development.
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Affiliation(s)
- Ondřej Vosála
- Department of Parasitology, Faculty of Science, Charles University Viničná 7 Prague 2 12844 Czechia
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University Akademika Heyrovského 1203 Hradec Králové 50005 Czechia
| | - Barbora Šmídová
- Department of Parasitology, Faculty of Science, Charles University Viničná 7 Prague 2 12844 Czechia
| | - Jan Novák
- Institute of Medical Microbiology, First Faculty of Medicine, Charles University and General University Hospital in Prague Studničkova 7 Prague 2 12800 Czechia
| | - Jan Svoboda
- Laboratory of Neurophysiology of Memory, Institute of Physiology, Czech Academy of Sciences Vídeňská 1083 Prague 4 14200 Czechia
| | - Tomáš Petrásek
- Sleep and Chronobiology Research Centre, National Institute of Mental Health Topolová 748 Klecany 25067 Czechia
| | - Iveta Vojtěchová
- Sleep and Chronobiology Research Centre, National Institute of Mental Health Topolová 748 Klecany 25067 Czechia
| | - Tomáš Macháček
- Department of Parasitology, Faculty of Science, Charles University Viničná 7 Prague 2 12844 Czechia
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Adil NA, Omo-Erigbe C, Yadav H, Jain S. The Oral-Gut Microbiome-Brain Axis in Cognition. Microorganisms 2025; 13:814. [PMID: 40284650 PMCID: PMC12029813 DOI: 10.3390/microorganisms13040814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/29/2025] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, affecting millions worldwide. Emerging evidence highlights the oral microbiome-a complex ecosystem of bacteria, fungi, viruses, and protozoa as a significant factor in cognitive health. Dysbiosis of the oral microbiome contributes to systemic inflammation, disrupts the blood-brain barrier, and promotes neuroinflammation, processes increasingly implicated in the pathogenesis of AD. This review examines the mechanisms linking oral microbiome dysbiosis to cognitive decline through the oral-brain and oral-gut-brain axis. These interconnected pathways enable bidirectional communication between the oral cavity, gut, and brain via neural, immune, and endocrine signaling. Oral pathogens, such as Porphyromonas gingivalis, along with virulence factors, including lipopolysaccharides (LPS) and gingipains, contribute to neuroinflammation, while metabolic byproducts, such as short-chain fatty acids (SCFAs) and peptidoglycans, further exacerbate systemic immune activation. Additionally, this review explores the influence of external factors, including diet, pH balance, medication use, smoking, alcohol consumption, and oral hygiene, on oral microbial diversity and stability, highlighting their role in shaping cognitive outcomes. The dynamic interplay between the oral and gut microbiomes reinforces the importance of microbial homeostasis in preserving systemic and neurological health. The interventions, including probiotics, prebiotics, and dietary modifications, offer promising strategies to support cognitive function and reduce the risk of neurodegenerative diseases, such as AD, by maintaining a diverse microbiome. Future longitudinal research is needed to identify the long-term impact of oral microbiome dysbiosis on cognition.
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Affiliation(s)
- Noorul Ain Adil
- USF Center for Microbiome Research, Microbiomes Institute, Tampa, FL 33612, USA; (N.A.A.); (C.O.-E.); (H.Y.)
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612, USA
| | - Christabel Omo-Erigbe
- USF Center for Microbiome Research, Microbiomes Institute, Tampa, FL 33612, USA; (N.A.A.); (C.O.-E.); (H.Y.)
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612, USA
| | - Hariom Yadav
- USF Center for Microbiome Research, Microbiomes Institute, Tampa, FL 33612, USA; (N.A.A.); (C.O.-E.); (H.Y.)
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612, USA
| | - Shalini Jain
- USF Center for Microbiome Research, Microbiomes Institute, Tampa, FL 33612, USA; (N.A.A.); (C.O.-E.); (H.Y.)
- Department of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612, USA
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Liao Y, Chen HW, Qiu C, Shen H, He ZY, Song ZC, Zhou W. Detection of Amyloid-β Peptides in Gingival Crevicular Fluid and Its Effect on Oral Pathogens. Mol Oral Microbiol 2025; 40:94-103. [PMID: 39668581 DOI: 10.1111/omi.12488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 07/04/2024] [Accepted: 07/14/2024] [Indexed: 12/14/2024]
Abstract
Periodontitis is the most common oral inflammatory disease, contributing to the onset and progression of Alzheimer's disease. However, a full investigation has not been performed on the expression level of amyloid-β (Aβ) peptides in gingival crevicular fluid (GCF) and its effects on oral pathogens. This study aimed to analyze the expression level of Aβ peptides in GCF of patients with periodontitis and the effects of Aβ peptides against common oral pathogens. GCF samples were collected from patients with periodontitis (n = 15) and periodontally healthy people (n = 10). The antimicrobial effects of Aβ peptides were evaluated on four common oral pathogenic strains using an MTT assay, crystal violet staining, fluorescence microscope, and transmission electron microscope. The protein levels of Aβ40 and Aβ42 were upregulated in the GCF of periodontitis group compared with the healthy group. Both Aβ40 and Aβ42 exhibited antimicrobial effects on Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Lactobacillus acidophilus in both planktonic and biofilm conditions. Further, only Aβ40 showed an antimicrobial effect on the Fusobacterium nucleatum. The results of this study demonstrate that Aβ peptides in GCF may be a relevant indicator of periodontitis status. Besides, the antimicrobial peptides derived from Aβ peptides have great potential in periodontal therapy.
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Affiliation(s)
- Yue Liao
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Hui-Wen Chen
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Che Qiu
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Hui Shen
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Zhi-Yan He
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhong-Chen Song
- Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
| | - Wei Zhou
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Xie M, Huang X, Tang Q, Yu S, Zhang K, Lu X, Zhang Y, Wang J, Zhang L, Chen L. Porphyromonas gingivalis Impairs Microglial Aβ Clearance in a Mouse Model. J Dent Res 2025; 104:408-418. [PMID: 39953680 DOI: 10.1177/00220345241294009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025] Open
Abstract
Porphyromonas gingivalis (Pg), a keystone pathogen in chronic periodontitis, has been identified as an emerging risk factor for Alzheimer's disease (AD). Pg can promote the accumulation of amyloid β protein (Aβ), a characteristic feature of AD pathology. However, the underlying mechanism, particularly in Aβ clearance, remains poorly understood. Here, by using 3 different strains of Pg, ATCC33277, W50, and W83, we discovered that APP/PS1 mice infected with all 3 Pg strains showed decreased microglial Aβ internalization, increased Aβ deposition in the brain, and impaired cognitive function. Using in vitro experiments, we further demonstrated that all 3 Pg strains inhibited microglial Aβ clearance, where gingipains, a group of toxic proteases derived from Pg, were involved. Gingipains were shown to hydrolyze CD14, subsequently impeding the CD14-mediated Vav-Rac/Cdc42 signaling cascade, which ultimately suppressed phagocytosis. Gingipain inhibitor could effectively restore microglial Aβ clearance and diminish Aβ deposition, leading to improved cognitive function in Pg-infected APP/PS1 mice. These findings may provide new insights into the mechanism through which Pg impairs microglial Aβ clearance to aggravate AD phenotypes, suggesting that gingipain inhibitors could be potential therapeutics for treating Pg-associated AD.
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Affiliation(s)
- M Xie
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - X Huang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Q Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - S Yu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - K Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - X Lu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Y Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - J Wang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - L Zhang
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - L Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
- Lead contact
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Eisenstein M. Do infections have a role in Alzheimer's disease? Nature 2025; 640:S8-S10. [PMID: 40240846 DOI: 10.1038/d41586-025-01104-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
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Retout M, Lepeintre V, Amer L, Yim W, Jokerst JV. Activatable Photoacoustic Probe for Imaging Infection: Gold Nanorod Dissociation In Vivo Reports Bacterial Protease Activity. ACS NANO 2025; 19:12041-12052. [PMID: 40116426 DOI: 10.1021/acsnano.4c17874] [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] [Indexed: 03/23/2025]
Abstract
We present a strategy for constructing activatable photoacoustic imaging (PAI) probes for in vivo enzyme activity measurements, based on a dissociation strategy previously applied to in vitro sensing. Unlike conventional nanoparticle aggregation strategies, dissociation minimizes false positives and functions effectively in complex biological environments. Overcoming the challenge of dissociating nanostructure aggregates, which arises from the strong van der Waals forces at short distances, we demonstrate the controlled assembly and dissociation of citrate-capped gold nanorods (AuNRs-citrate) using a diarginine peptide additive and a thiolated polyethylene glycol (HS-PEG-OMe), respectively. This assembly dissociation mechanism enables precise control of the optical and photoacoustic (PA) properties of AuNRs in both in vitro and in vivo settings. Building on these findings, we engineered an enzyme-sensitive PAI probe (AuNRs@RgpB) composed of AuNR assemblies and a PEG-peptide conjugate with a protease-specific cleavage sequence. The probe detects Arg-specific gingipain (RgpB), a protease expressed by Porphyromonas gingivalis associated with periodontal disease and Alzheimer's disease. Proteolytic cleavage of the peptide sequence triggers AuNR dissociation, resulting in enhanced PA signal output. The probe was designed to be injected intrathecally for preclinical trials to image gingipains and investigate the value of gingipain inhibitors developed for Alzheimer's disease. The probe's performance was characterized in vitro using UV-vis spectroscopy and PAI, achieving detection limits of 5 and 20 nM, respectively. In vivo studies involved intracranial injection of AuNRs@RgpB into RgpB-containing murine models, with PA monitoring over time. RgpB activity produced a four-fold PA signal increase within 2 h, while P. gingivalis-infected mice showed similar signal enhancement. Specificity was confirmed by negligible responses to Fusobacterium nucleatum, a non-RgpB-producing bacterium. Additionally, the system demonstrated utility in drug development by successfully monitoring the inhibition of RgpB activity using RgpB inhibitors (leupeptin and KYT-1) in vivo models. Beyond its immediate application to RgpB detection, this modular approach to plasmonic-based sensing holds significant potential for detecting other proteases, advancing both nanotechnology and protease-targeted diagnostics.
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Affiliation(s)
- Maurice Retout
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, California 92093, United States
| | - Victor Lepeintre
- Laboratoire de Chimie Organique, Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, Brussels B-1050, Belgium
- Engineering of Molecular NanoSystems, Ecole Polytechnique de Bruxelles, Université libre de Bruxelles (ULB), Brussels B-1050, Belgium
| | - Lubna Amer
- Materials Science and Engineering Program, University of California, San Diego, La Jolla, California 92093, United States
| | - Wonjun Yim
- Materials Science and Engineering Program, University of California, San Diego, La Jolla, California 92093, United States
| | - Jesse V Jokerst
- Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, University of California, San Diego, La Jolla, California 92093, United States
- Materials Science and Engineering Program, University of California, San Diego, La Jolla, California 92093, United States
- Department of Radiology, University of California, San Diego, La Jolla, California 92093, United States
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Wu Z, Long W, Yin Y, Tan B, Liu C, Li H, Ge S. Outer membrane vesicles of Porphyromonas gingivalis: recent advances in pathogenicity and associated mechanisms. Front Microbiol 2025; 16:1555868. [PMID: 40256625 PMCID: PMC12007433 DOI: 10.3389/fmicb.2025.1555868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 02/20/2025] [Indexed: 04/22/2025] Open
Abstract
Periodontitis is a chronic infectious inflammatory disease primarily caused by periodontal pathogenic bacteria, which poses a significant threat to human health. The pathogenic mechanisms associated with Porphyromonas gingivalis (P. gingivalis), a principal causative agent of periodontitis, are particularly complex and warrant thorough investigation. The extensive array of virulence factors released by this bacterium during its growth and pathogenesis not only inflicts localized damage to periodontal tissues but is also intricately linked to the development of systemic diseases through various mechanisms. The outer membrane vesicles (OMVs) produced by P. gingivalis play a key role in this process. These OMVs serve as important mediators of communication between bacteria and host cells and other bacteria, carrying and delivering virulence factors to host cells and distant tissues, thereby damaging host cells and exacerbating inflammatory responses. The ability of these OMVs to disseminate and deliver bacterial virulence factors allows P. gingivalis to play a pathogenic role far beyond the confines of the periodontal tissue and has been closely associated with the development of a variety of systemic diseases such as cardiovascular disease, Alzheimer's disease, rheumatoid arthritis, diabetes mellitus, non-alcoholic hepatitis, and cancer. In view of this, it is of great pathophysiological and clinical significance to deeply investigate its pathogenic role and related mechanisms. This will not only help to better understand the pathogenesis of periodontitis and its related systemic diseases but also provide new ideas and more effective and precise strategies for the early diagnosis, prevention, and treatment of these diseases. However, the current research in this field is still insufficient and in-depth, and many key issues and mechanisms need to be further elucidated. This article summarizes the recent research progress on the role of P. gingivalis OMVs (P. g-OMVs) in related diseases, with the aim of providing a theoretical basis and direction for future research and revealing the pathogenic mechanism of P. g-OMVs more comprehensively.
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Affiliation(s)
| | | | | | | | | | | | - Song Ge
- School and Hospital of Stomatology, Zunyi Medical University, Zunyi, Guizhou, China
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Vujosevic S, Limoli C, Kozak I. Hallmarks of aging in age-related macular degeneration and age-related neurological disorders: novel insights into common mechanisms and clinical relevance. Eye (Lond) 2025; 39:845-859. [PMID: 39289517 PMCID: PMC11933422 DOI: 10.1038/s41433-024-03341-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/13/2024] [Accepted: 09/10/2024] [Indexed: 09/19/2024] Open
Abstract
Age-related macular degeneration (AMD) and age-related neurological diseases (ANDs), such as Alzheimer's and Parkinson's Diseases, are increasingly prevalent conditions that significantly contribute to global morbidity, disability, and mortality. The retina, as an accessible part of the central nervous system (CNS), provides a unique window to study brain aging and neurodegeneration. By examining the associations between AMD and ANDs, this review aims to highlight novel insights into fundamental mechanisms of aging and their role in neurodegenerative disease progression. This review integrates knowledge from the emerging field of aging research, which identifies common denominators of biological aging, specifically loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, and inflammation. Finally, we emphasize the clinical relevance of these pathways and the potential for cross-disease therapies that target common aging hallmarks. Identifying these shared pathways could open avenues to develop therapeutic strategies targeting mechanisms common to multiple degenerative diseases, potentially attenuating disease progression and promoting the healthspan.
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Affiliation(s)
- Stela Vujosevic
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
- Eye Clinic, IRCCS MultiMedica, Milan, Italy.
| | - Celeste Limoli
- Eye Clinic, IRCCS MultiMedica, Milan, Italy
- University of Milan, Milan, Italy
| | - Igor Kozak
- Moorfields Eye Hospital Centre, Abu Dhabi, UAE
- Ophthalmology and Vision Science, University of Arizona, Tucson, USA
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Zhang D, Qu J, Ke C, Kong X, Liu M, Nawaz Khan I, Huang S, Tian H, Xie T, Qiu K, Li J, Wang M, Li H, Yuan F, Guo W, Cao M, Zhang J, Zhu K, Luo J, Zhang F, Cui X, Mu H, Hu Y. Macrophage-Hosted Porphyromonas gingivalis Is a Risk Factor for Cataract Development. Invest Ophthalmol Vis Sci 2025; 66:68. [PMID: 40266593 PMCID: PMC12025317 DOI: 10.1167/iovs.66.4.68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 03/27/2025] [Indexed: 04/24/2025] Open
Abstract
Purpose We studied the regulatory association of Porphyromonas gingivalis (PG) and cataracts. Methods PCR and FISH assays were used for detecting PG 16s ribosomal RNA genome, Immunofluorescence was for expression of RpgA in anterior capsular epithelium and fibrosis markers in anterior subcapsular cataract (ASC) model. Flow cytometry was for reactive oxygen species and apoptosis. RNA deep sequencing is for differential gene expression analysis. Results PG's 16s ribosomal RNA gene is positively in 43.3% (101/233 cases) of aqueous humor (AH) samples of patients with cataracts, which differs from 4.7% (6/127) of PG-positive AH in patients with glaucoma. Diabetic and high myopia cataracts increase PG-positive AH compared with age-related cataracts. No PG is observed in AH of congenital cataracts. PG is positive in 82% to 94% of the cataractous anterior capsule tissues from high myopia and age-related, congenital, and diabetic cataracts. The PG-positive cells in the cataractous anterior capsular epithelium are CD68+/CD14+ macrophages, but not anterior epithelial cells. In rat ASC models, PG injected via the tail vein or PG-carried bone marrow monocytes can migrate into the equatorial lens epithelium in form of PG-positive macrophages, which promote ASC progression with upregulation of collagen, fibronectin and α smooth muscle actin (α-SMA) expression, and increase 8-OHdG levels and α-SMA expression in the surrounding lens epithelial cells. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis of the RNA sequencing dataset of ASC tissues shows that signaling pathways related to epithelial-mesenchymal transition, oxidative stress, and cell death are up-regulated in PG + ASC compared with that in ASC alone. Co-culture of supernatants of Raw264.7/PG+ cells with rat primary lens epithelial cells increases the 8-OHdG levels, mitochondrial fission, apoptosis, and expression of α-SMA. Conclusions Chronic infection with PG can access the lens epithelium via macrophages during stress conditions, which promotes cataract development by possibly elevating oxidative stress, apoptosis, and epithelial-mesenchymal transition in lens tissues. PG infection is a novel a risk factor for cataract development.
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Affiliation(s)
- Dongzhe Zhang
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Junwei Qu
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Cuncun Ke
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Xiumei Kong
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Mengyun Liu
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Iqbal Nawaz Khan
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Shuxin Huang
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Haijiao Tian
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Tong Xie
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Ke Qiu
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Jing Li
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Mingli Wang
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Hui Li
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Fengling Yuan
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Weikai Guo
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Mingya Cao
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Jing Zhang
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Keke Zhu
- Kaifeng Key Lab for Cataract and Myopia, Institute of Eye Disease, Kaifeng Central Hospital, Kaifeng, China
| | - Jin Luo
- Department of Pathology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China
| | - Fengyan Zhang
- Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiukun Cui
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
| | - Hongmei Mu
- Kaifeng Key Lab for Cataract and Myopia, Institute of Eye Disease, Kaifeng Central Hospital, Kaifeng, China
| | - Yanzhong Hu
- Division of Vision Science, Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China
- Kaifeng Key Lab for Cataract and Myopia, Institute of Eye Disease, Kaifeng Central Hospital, Kaifeng, China
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Han J, Liu Y, Guo X, Gao G, Wu Q. Research Trends in the Comorbidity Between Periodontitis and Neurodegenerative Diseases. Int Dent J 2025; 75:564-574. [PMID: 39138099 PMCID: PMC11976591 DOI: 10.1016/j.identj.2024.07.1212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/01/2024] [Accepted: 07/23/2024] [Indexed: 08/15/2024] Open
Abstract
INTRODUCTION AND AIMS Evidence suggests an association between periodontitis and neurodegenerative diseases, but a comprehensive analysis of research trends remains absent. Therefore, we aim to identify research trends and hotspots on the comorbidity between periodontitis and neurodegenerative diseases, understand mechanisms, provide guidance for subsequent studies and show its clinical translational possibility. METHODS A bibliometric analysis covering 1982 to 2023 was conducted using the Web of Science Core Collection. English-language articles range from January 1, 1982 to November 30, 2023 were analyzed. Data were downloaded on November 30, 2023 and analyzed on December, 2023. Data visualization and statistical analysis were performed to identify trends of annual publications, countries, sources, institutions, authors, most cited articles, and keywords by using Microsoft Excel, VOSviewer, Citespace, R-bibliometrix and Origin Pro. RESULTS A total of 1,238 articles from 1982 to 2023 on the comorbidity between periodontitis and neurodegenerative diseases were identified. Annual publications showed an upward trend. The United States, University College of London, BRAIN and Shy, Michael E. were the leading nation, affiliation, source and author, respectively. The United States, NEUROLOGY, and Curtis Maurice A. were the most cited nation, source, and author. Keywords network analysis highlighted 'Charcot-Marie-Tooth Disease', 'Alzheimer's Disease' and 'Periodontitis' as focal points. Detection of keywords citation bursts demonstrated 'Porphyromonas gingivalis' and 'Cognitive Dysfunction' as hot topics in recent research. CONCLUSIONS In recent years, emerging interests of the comorbidity between periodontitis and neurodegenerative diseases (NDs) are growing. Our study enhances the understanding of recent research trends of periodontitis and NDs and provides valuable perspectives within this expanding field, offering new insights into research trends regarding the interplay between 'Porphyromonas gingivalis' and 'Cognitive Dysfunction'. Further research of the molecular mechanisms between P. gingivalis-induced periodontitis, neuroinflammation, that leads neurodegeneration are clearly warranted.
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Affiliation(s)
- Jiale Han
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China; Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yihan Liu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaoyang Guo
- Tongji University School of Medicine, Shanghai, China
| | - Ge Gao
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.
| | - Qihui Wu
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
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50
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Luan X, Jin Z, Xia S, Li J, An Y, Gao J, Wang S, Xia H, Pan S, Zhang Y, Song W, Wu Y. Smoking impairs cognitive function through the mediating effect of periodontitis in older adults. BMC Psychiatry 2025; 25:292. [PMID: 40148790 PMCID: PMC11948936 DOI: 10.1186/s12888-025-06699-2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
OBJECTIVES Evidence has shown that both smoking and periodontitis were linked to cognitive impairment. This study examines whether periodontitis mediates the effects of smoking status on cognitive function in older adults. METHODS Using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, the study included 1728 older participants who have data on smoking, serum cotinine, periodontal examination, and cognitive function. Mediation analysis was performed to test whether extent of periodontitis mediated associations between smoking status and cognitive function, adjusted for sociodemographic and basic health factors. RESULTS Compared to never-smokers, daily smokers exhibited significantly worse global cognitive function, with periodontitis mediating this effect (effect= -0.16; 95% CI= -0.29, -0.05). Similarly, periodontitis mediated the association between serum cotinine levels and cognitive function in the total sample (effect= -0.02; 95% CI= -0.03, -0.00). CONCLUSIONS Periodontitis significantly mediates the impact of smoking on cognitive function. The findings highlight the potential roles of maintaining oral health and smoking cessation in mitigating cognitive decline.
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Affiliation(s)
- Xiaoqian Luan
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Zhou Jin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
- Wenzhou Key Laboratory of Basic and Translational Research for Mental Disorders, Zhejiang Provincial Clinical Research Center for Mental Health, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Shenhang Xia
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Jin Li
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Yao An
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Jiaqi Gao
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Shengya Wang
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Huwei Xia
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Sipei Pan
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
| | - Yao Zhang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China
- Department of Prosthodontics, Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
| | - Weihong Song
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, The Center for Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), 999 Jinshi Road, Yongzhong Street, Longwan District, Wenzhou, 325035, Zhejiang Province, China.
| | - Yili Wu
- Wenzhou Key Laboratory of Basic and Translational Research for Mental Disorders, Zhejiang Provincial Clinical Research Center for Mental Health, School of Mental Health and The Affiliated Wenzhou Kangning Hospital, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
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