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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Salivary IL-34 is increased in AD patients and is associated with MMSE scores.

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.

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.

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.

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.

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.

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.

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).

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.

This study was to investigate associations of periodontitis, tooth loss and self-rated oral health with circadian syndrome.

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.

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.

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.

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.

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.

To determine bacterial blood translocation signatures and their association with the subgingival microbiota in individuals with and without periodontitis.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

The purpose of this review is to determine the association between Porphyromonas gingivalis and Alzheimer's disease in older adults.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.