Progression Of Systemic Diseases Research Articles

Periodontal disease: A systemic condition.

For decades, periodontitis has been considered to be a local inflammatory disease of the periodontal tissues in the oral cavity. Initially, associations of periodontitis with a multitude of noncommunicable diseases were each studied separately, and relationships were shown. The associations of periodontitis with morbidities, such as cardiovascular diseases, rheumatoid arthritis, diabetes mellitus, respiratory diseases, have been demonstrated. As most such studies were cross-sectional in nature, questions about causality cannot be univocally answered. And periodontitis as an independent risk factor for one systemic disease, becomes even more difficult to assess since recently periodontitis has also been associated with multimorbidity. Periodontitis and many systemic diseases share environmental, lifestyle and genetic risk factors, and share immunopathology. Moreover, suffering from one common noncommunicable disease may increase the susceptibility for another such chronic disease; the systemic effects of one condition may be one of various risk factors for another such disease. The overarching effect of any systemic disease is it causing a pro-inflammatory state in the individual; this has also been shown for periodontitis. Moreover, in periodontitis a prothrombotic state and elevated immunological activity have been shown. As such, when we consider periodontal disease as another systemic disease, it can affect the susceptibility and progression of other systemic diseases, and importantly, vice versa. And with this, it is not surprising that periodontitis is associated with a variety of other noncommunicable diseases. The medical definition of a systemic disease includes diseases that affect different organs and systems. Thus, the aim of this opinion paper is to propose that periodontitis should be considered a systemic disease in its own right and that it affects the individual's systemic condition and wellbeing. The dental and medical profession and researchers alike, should adapt this paradigm shift, advancing periodontal disease out of its isolated anatomical location into the total of chronic noncommunicable diseases, being for some conditions a comorbid disease and, vice versa, comorbidities can affect initiation and progression of periodontal disease.

Salivary Short-chain Fatty Acids (SCFAs) Are Viable Predictors of Early Changes in Systemic Health.

Short-chain fatty acids (SCFAs) are the metabolites identified in both the oral cavity and the gut. They play an important role in the triggering, development and progression of systemic diseases. SCFAs can alter the gut microbial components, intestinal epithelium and host immune system, and are also associated with cancer incidence. Salivary SCFAs, produced by the oral microbiome, are correlated with some oral diseases. The occurrence of systemic diseases associated with gut SCFAs is more clearly defined than oral SCFAs. Salivary SCFAs can enter the bloodstream directly via inflamed gingiva to cause continuous low-grade systemic inflammation. Hence, salivary SCFAs could be an indicator for the early diagnosis of systemic diseases. Furthermore, they provide a basis for understanding the oral-systemic axis driven through salivary SCFAs in the pathogenesis of several diseases.

Quantitative PET imaging and modeling of molecular blood-brain barrier permeability.

Blood-brain barrier (BBB) disruption is involved in the pathogenesis and progression of many neurological and systemic diseases. Non-invasive assessment of BBB permeability in humans has mainly been performed with dynamic contrast-enhanced magnetic resonance imaging, evaluating the BBB as a structural barrier. Here, we developed a novel non-invasive positron emission tomography (PET) method in humans to measure the BBB permeability of molecular radiotracers that cross the BBB through different transport mechanisms. Our method uses high-temporal resolution dynamic imaging and kinetic modeling to jointly estimate cerebral blood flow and tracer-specific BBB transport rate from a single dynamic PET scan and measure the molecular permeability-surface area (PS) product of the radiotracer. We show our method can resolve BBB PS across three PET radiotracers with greatly differing permeabilities, measure reductions in BBB PS of 18F-fluorodeoxyglucose (FDG) in healthy aging, and demonstrate a possible brain-body association between decreased FDG BBB PS in patients with metabolic dysfunction-associated steatotic liver inflammation. Our method opens new directions to efficiently study the molecular permeability of the human BBB in vivo using the large catalogue of available molecular PET tracers.

Unpaired fundus image enhancement based on constrained generative adversarial networks.

Fundus photography (FP) is a crucial technique for diagnosing the progression of ocular and systemic diseases in clinical studies, with wide applications in early clinical screening and diagnosis. However, due to the nonuniform illumination and imbalanced intensity caused by various reasons, the quality of fundus images is often severely weakened, brings challenges for automated screening, analysis, and diagnosis of diseases. To resolve this problem, we developed strongly constrained generative adversarial networks (SCGAN). The results demonstrate that the quality of various datasets were more significantly enhanced based on SCGAN, simultaneously more effectively retaining tissue and vascular information under various experimental conditions. Furthermore, the clinical effectiveness and robustness of this model were validated by showing its improved ability in vascular segmentation as well as disease diagnosis. Our study provides a new comprehensive approach for FP and also possesses the potential capacity to advance artificial intelligence-assisted ophthalmic examination.

Quercetin-Loaded Bioglass Injectable Hydrogel Promotes m6A Alteration of Per1 to Alleviate Oxidative Stress for Periodontal Bone Defects.

Periodontal disease ranks third among noncommunicable illnesses, behind cancer and cardiovascular disease, and is closely related to the occurrence and progression of various systemic diseases. However, elucidating the processes of periodontal disease and promoting periodontal bone regeneration remains a challenge. Here, quercetin is demonstrated to reduce the oxidative stress state of orofacial mesenchymal stem cells (OMSCs) in vitro and to affect the osteogenic growth of OMSCs through molecular mechanisms that mediate the m6A change in Per1. Nevertheless, the limited therapeutic efficacy of systemic medication and the limitations of local medication resulting from the small, moist, and highly dynamic periodontal environment make it challenging to treat periodontal tissues with medication. Herein, a biosafe injectable hydrogel drug-controlled delivery system is constructed as a bone-enhancing factory and loaded with quercetin to treat oxidative stress injury in periodontal tissues. This drug-carrying system made up of nanoscale bioglass microspheres and a light-cured injectable hydrogel, allows effective drug particle loading and cementation in the dynamic and moist periodontal environment. Furthermore, the system demonstrates the ability to stimulate OMSCs osteogenic differentiation in a Per1-dependent manner, which ultimately promotes periodontal bone repair, suggesting that this system has potential for clinical periodontal therapy.

GroEL triggers NLRP3 inflammasome activation through the TLR/NF-κB p-p65 axis in human periodontal ligament stem cells.

The interaction between bacteria and the host plays a vital role in the initiation and progression of systemic diseases, including gastrointestinal and oral diseases, due to the secretion of various virulence factors from these pathogens. GroEL, a potent virulence factor secreted by multiple oral pathogenic bacteria, is implicated in the damage of gingival epithelium, periodontal ligament, alveolar bone and other peripheral tissues. However, the underlying biomechanism is still largely unknown. In the present study, we verify that GroEL can trigger the activation of NLRP3 inflammasome and its downstream effector molecules, IL-1β and IL-18, in human periodontal ligament stem cells (hPDLSCs) and resultantly induce high activation of gelatinases (MMP-2 and MMP-9) to promote the degradation of extracellular matrix (ECM). GroEL-mediated activation of the NLRP3 inflammasome requires the participation of Toll-like receptors (TLR2 and TLR4). High upregulation of TLR2 and TLR4 induces the enhancement of NF-κB (p-p65) signaling and promotes its nuclear accumulation, thus activating the NLRP3 inflammasome. These results are verified in a rat model with direct injection of GroEL. Collectively, this study provides insight into the role of virulence factors in bacteria-induced host immune response and may also provide a new clue for the prevention of periodontitis.

Genetics causal analysis of oral microbiome on type 2 diabetes in East Asian populations: a bidirectional two-sample Mendelian randomized study.

The dysbiosis of the oral microbiome is associated with the progression of various systemic diseases, including diabetes. However, the precise causal relationships remain elusive. This study aims to investigate the potential causal associations between oral microbiome and type 2 diabetes (T2D) using Mendelian randomization (MR) analyses. We conducted bidirectional two-sample MR analyses to investigate the impact of oral microbiome from saliva and the tongue T2D. This analysis was based on metagenome-genome-wide association studies (mgGWAS) summary statistics of the oral microbiome and a large meta-analysis of GWAS of T2D in East Asian populations. Additionally, we utilized the T2D GWAS summary statistics from the Biobank Japan (BBJ) project for replication. The MR methods employed included Wald ratio, inverse variance weighting (IVW), weighted median, MR-Egger, contamination mixture (ConMix), and robust adjusted profile score (RAPS). Our MR analyses revealed genetic associations between specific bacterial species in the oral microbiome of saliva and tongue with T2D in East Asian populations. The MR results indicated that nine genera were shared by both saliva and tongue. Among these, the genera Aggregatibacter, Pauljensenia, and Prevotella were identified as risk factors for T2D. Conversely, the genera Granulicatella and Haemophilus D were found to be protective elements against T2D. However, different species within the genera Catonella, Lachnoanaerobaculum, Streptococcus, and Saccharimonadaceae TM7x exhibited multifaceted influences; some species were positively correlated with the risk of developing T2D, while others were negatively correlated. This study utilized genetic variation tools to confirm the causal effect of specific oral microbiomes on T2D in East Asian populations. These findings provide valuable insights for the treatment and early screening of T2D, potentially informing more targeted and effective therapeutic strategies.

The Prevalence of Systemic Diseases and Its Association with Periodontal Disease among Patients Referred to a Government Periodontal Specialist Clinic in Melaka, Malaysia

Abstract Aim: The aim of the study was to identify the prevalence of systemic diseases among patients referred to a newly established government periodontal specialist clinic and to analyze the association between the severity (staging) and the rate of progression (grading) of periodontitis with the presence of these systemic diseases. Materials and Methods: Records of all new patients within the first 5 years of the clinic’s operation were reviewed, and their periodontitis status was classified according to the 2017 World Workshop Classification system. The association between the severity of periodontitis and the presence of systemic diseases was analyzed using the Chi-square test, whereas Fisher’s exact test was used to determine the association between the rate of progression and the presence of systemic diseases. Results: A total of 489 dental records were reviewed. We found that 40.1% of our patients suffered from systemic diseases. The two most common systemic diseases were cardiovascular disease (CVD) (11.4%) and diabetes mellitus (9.4%). No significant association was found between the severity of periodontitis and the presence of systemic diseases (P = 0.376). However, we found a significant association between the rate of progression of periodontitis and systemic diseases (P = 0.004). There was also a significant association between the rate of progression of periodontitis and CVDs (P = 0.001). Conclusion: The rate of progression of periodontitis is significantly associated with the presence of systemic diseases and CVDs. This highlights that periodontitis is not a stand-alone disease. Instead, it reaches across a spectrum of other noncommunicable diseases. The collaboration between medical and dental practitioners can further improve the management of this group of patients.

Receptor modulators associated with the hypothalamus -pituitary-thyroid axis.

The hypothalamus-pituitary-thyroid (HPT) axis maintains normal metabolic balance and homeostasis in the human body through positive and negative feedback regulation. Its main regulatory mode is the secretion of thyrotropin (TSH), thyroid hormones (TH), and thyrotropin-releasing hormone (TRH). By binding to their corresponding receptors, they are involved in the development and progression of several systemic diseases, including digestive, cardiovascular, and central nervous system diseases. The HPT axis-related receptors include thyrotropin receptor (TSHR), thyroid hormone receptor (TR), and thyrotropin-releasing hormone receptor (TRHR). Recently, research on regulators has become popular in the field of biology. Several HPT axis-related receptor modulators have been used for clinical treatment. This study reviews the developments and recent findings on HPT axis-related receptor modulators. This will provide a theoretical basis for the development and utilisation of new modulators of the HPT axis receptors.

Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review.

The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.

Salivary Biomarkers in the Diagnosis of Sjogren’s Syndrome: A Review of Current Research Progress

Saliva contains a variety of biomarkers, which are closely related to the occurrence, progression, diagnosis and treatment of oral and systemic diseases. Currently, the diagnosis of Sjögren’s syndrome (SS) still relies on invasive salivary gland biopsy procedures and serum Ro-52/SSA and La/SSB testing, which often makes early diagnosis extremely difficult, so screening for specific saliva biomarkers is extremely beneficial in the diagnosis and individualized treatment of Sjögren’s syndrome. This article elaborates the research progress of Sjogren’s syndrome-related biomarkers in saliva, in order to provide new methods and ideas for the early diagnosis of Sjogren’s syndrome.

COVID-19 associated oral and oropharyngeal microbiome: Systematic review and meta-analysis.

Three years into the coronavirus disease 2019 (COVID-19) pandemic, there are still growing concerns with the emergence of different variants, unknown long- and short-term effects of the virus, and potential biological mechanisms underlying etiopathogenesis and increased risk for morbidity and mortality. The role of the microbiome in human physiology and the initiation and progression of several oral and systemic diseases have been actively studied in the past decade. With the proof of viral transmission, carriage, and a potential role in etiopathogenesis, saliva and the oral environment have been a focus of COVID-19 research beyond diagnostic purposes. The oral environment hosts diverse microbial communities and contributes to human oral and systemic health. Several investigations have identified disruptions in the oral microbiome in COVID-19 patients. However, all these studies are cross-sectional in nature and present heterogeneity in study design, techniques, and analysis. Therefore, in this undertaking, we (a) systematically reviewed the current literature associating COVID-19 with changes in the microbiome; (b) performed a re-analysis of publicly available data as a means to standardize the analysis, and (c) reported alterations in the microbial characteristics in COVID-19 patients compared to negative controls. Overall, we identified that COVID-19 is associated with oral microbial dysbiosis with significant reduction in diversity. However, alterations in specific bacterial members differed across the study. Re-analysis from our pipeline shed light on Neisseria as the potential key microbial member associated with COVID-19.

Interactions between systemic diseases and oral microbiota shifts in the aging community: A narrative review.

As a gateway to general health and a diverse microbial habitat, the oral cavity is colonized by numerous microorganisms such as bacteria, fungi, viruses, and archaea. Oral microbiota plays an essential role in preserving oral health. Besides, the oral cavity also significantly contributes to systemic health. Physiological aging influences all body systems, including the oral microbial inhabitants. The cited effect can cause diseases by forming dysbiotic communities. Since it has been demonstrated that microbial dysbiosis could disturb the symbiosis state between the host and the resident microorganism, shifting the condition toward a more pathogenic one, this study investigated how the oral microbial shifts in aging could associate with the development or progression of systemic diseases in older adults. The current study focused on the interactions between variations in the oral microbiome and prevalent diseases in older adults, including diabetes mellitus, Sjögren's syndrome, rheumatoid arthritis, pulmonary diseases, cardiovascular diseases, oral candidiasis, Parkinson's disease, Alzheimer's disease, and glaucoma. Underlying diseases can dynamically modify the oral ecology and the composition of its resident oral microbiome. Clinical, experimental, and epidemiological research suggests the associations of systemic disorders with bacteremia and inflammation after oral microbial changes in older adults.

Multi-omics insights reveal the remodeling of gut mycobiome with P. gingivalis.

As a keystone periodontal pathogen, Porphyromonas gingivalis (P. gingivalis) was suggested to be involved in the progression of systemic diseases by altering the intestinal microecology. However, studies concerning gut microbiome have focused entirely on the bacterial component, while the fungal community (gut mycobiome) has been overlooked. In this study, we aimed to characterize the alteration of gut mycobiome profile with P. gingivalis administration using mice fecal samples. Metagenomic analysis showed a distinct composition pattern of mycobiome and significant difference of beta diversity between control and the P. gingivalis group. Some fungal species were differentially characterized with P. gingivalis administration, among which Pyricularia pennisetigena and Alternaria alternata showed positive correlation with P. gingivalis. KEGG functional analyses revealed that three pathways, namely, “pentose and glucuronate interconversions”, “metabolic pathways”, and “two-component system”, were statistically enriched with P. gingivalis administration. Moreover, the alteration of gut mycobiome was also closely related with serum metabolites, especially lipid and tryptophan metabolic pathways. Taken together, this study demonstrated the alteration of fungal composition and function with P. gingivalis administration for the first time, and investigated the fungi–bacterial interaction and fungi–metabolite interaction preliminarily, providing a whole insight into gut mycobiome remodeling with oral pathobiont through multi-omics analyses.

The combination of experimental periodontitis and oral microbiota from periodontitis patients aggravates liver fibrosis in mice.

Periodontitis (PD) is the sixth most prevalent disease around the world and is involved in the development and progression of multiple systemic diseases. Previous studies have reported that PD may aggravate liver injuries. The objective of this study was to investigate whether and how PD affects liver fibrosis. Ligature-induced PD (LIP) was induced in male C57/B6J mice, and sub-gingival plaques (PL) from patients with PD were applied to mouse teeth. Liver fibrosis was induced by carbon tetrachloride (CCl4 ) injection. The mice were randomly divided into six groups: Oil, Oil+LIP, Oil+LIP+PL, CCl4 , CCl4 +LIP, and CCl4 +LIP+PL. Alveolar bone resorption was evaluated by methylene blue staining. Hepatic function was analysed by serum alanine aminotransferase and hepatic hydroxyproline. Picrosirius red and α-smooth muscle actin (SMA) staining were used to evaluate the fibrotic area. RNA sequencing and quantitative RT-PCR were used to measure gene expression. Western blotting was used to measure protein levels. Flow cytometry was used to analyse the accumulation of immune cells. Mouse microbiota were analysed using 16S rRNA gene sequencing. Mice in the CCl4 +LIP+PL group displayed higher serum alanine aminotransferase and hepatic hydroxyproline as well as more Picrosirius red-positive and α-SMA-positive areas in liver samples than those of the CCl4 group, suggesting that PD (LIP+PL) aggravated CCl4 -induced hepatic dysfunction and liver fibrosis. Consistently, the expression of fibro-genic genes and the protein levels of transforming growth factor β were much higher in the CCl4 +LIP+PL group than in the CCl4 group. Flow cytometry revealed that PD increased the accumulation of immune cells, including Kupffer cells, B cells, and Th17 cells, in the liver of mice with CCl4 treatment. PD also increased the expression of inflammatory genes and activated pro-inflammatory nuclear factor-kappa B pathway in the livers of CCl4 -injected mice. Moreover, PD altered both oral and liver microbiota in CCl4 -injected mice. PD aggravates CCl4 -induced hepatic dysfunction and fibrosis in mice, likely through the increase of inflammation and alteration of microbiota in the liver.

Inflammatory response of gut, spleen, and liver in mice induced by orally administered Porphyromonas gingivalis

ABSTRACT Background Periodontitis is a chronic multifactorial inflammatory disease. Porphyromonas gingivalis is a primary periopathogen in the initiation and development of periodontal disease. Evidence has shown that P. gingivalis is associated with systemic diseases, including IBD and fatty liver disease. Inflammatory response is a key feature of diseases related to this species. Methods C57BL/6 mice were administered either PBS, or P. gingivalis. After 9 weeks, the inflammatory response in gut, spleen, and liver was analyzed. Results The findings revealed significant disturbance of the intestinal microbiota and increased inflammatory factors in the gut of P. gingivalis-administered mice. Administrated P. gingivalis remarkably promoted the secretion of IRF-1 and activated the inflammatory pathway IFN-γ/STAT1 in the spleen. Histologically, mice treated with P. gingivalis exhibited hepatocyte damage and lipid deposition. The inflammatory factors IL-17a, IL-6, and ROR-γt were also upregulated in the liver of mice fed with P. gingivalis. Lee’s index, spleen index, and liver index were also increased. Conclusion These results suggest that administrated P. gingivalis evokes inflammation in gut, spleen, and liver, which might promote the progression of various systemic diseases.

The role of thrombin in the pathogenesis of atherosclerosis and its complications

Thrombin is a key regulator of the homeostasis system. Also, it actively participates in progression of various systemic diseases, including atherosclerosis. There is a large amount of experimental and clinical data on the involvement of thrombin in the pathogenesis of ischemic heart disease (IHD). Thus, studying thrombin activity regulation is promising. Also, the question whether it is possible to use biomarkers of thrombin activity as predictors of cardiovascular complications in IHD patients is relevant. The present review focuses on major mechanisms of thrombin functioning, its role in development and progression of atherosclerosis, and available tests for evaluation of thrombin functional activity. Major clinical studies are discussed that evaluated the efficacy of thrombin inhibitors and protease-activated receptor antagonists.

Development and Influencing Factors of Oral Microbiota in Early Life

Oral cavity, an important component of and the gateway to the digestive system, is also the colonization site and the microecological environment of trillions of microorganisms. The establishment and succession of oral microbiota are of great importance for the development of human immune system, and function as a major determinant of oral and systemic health. Within a few hours after birth, early colonizers such as Streptococcus and Lactobacillus can be detected in an infant's mouth. The oral microbiota communities mature gradually along with the growth of the host, expanding in their species abundance and diversity. In addition to genetic factors, a number of cross-sectional studies have revealed that the development of oral microecosystems in early life is influenced and tuned by multiple external factors, including maternal health status, mode of delivery, feeding habits, antibiotics use, etc. The dysbiosis of oral microecology in early life is closely related to the pathogenesis and progression of oral and systemic diseases. Therefore, good oral hygiene habits are of vital importance to the early management of oral microbial diseases and their effective prevention and control. Herein, we summarized the colonization and succession of oral microbiota in early life and further discussed the key external factors that affect early life oral microecosystem, as well as the impact of early life oral microbiota on the host's health at a later stage, intending to help providing new insights into and new strategies for the management of the whole lifecycle oral and systemic health.

A Mouse Periodontitis Model With Humanized Oral Bacterial Community.

Increasing evidence suggests that periodontitis, characterized by oral dysbiosis, is a critical player in the progression of multiple systemic diseases in humans. However, there is still a lack of a proper mouse model of periodontitis with the colonization of human periodontitis-associated bacteria. We here established a new mouse periodontitis model by combining ligation of the second molars with application of subgingival plaques from periodontitis patients. Using 16S rRNA gene sequencing and Taxonomic classification, we found that human periodontitis-associated bacteria efficiently colonized in the mouse model and were enriched in both ligature silk and mouse saliva. Furthermore, the well-recognized periodontal pathogens including Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, and Tannerella forsythia were enriched in the new model, but not in ligature-induced periodontitis model or Sham mice. The human periodontitis-associated bacteria potently aggravated mouse periodontitis, as demonstrated by more severe bone resorption and higher expression of inflammatory and osteoclastogenesis genes. In summary, the new mouse periodontitis model paves the way for studying human periodontitis-associated bacteria in oral diseases and systemic diseases.

TNF-α in Uveitis: From Bench to Clinic.

Uveitis is an inflammation of the iris, ciliary body, vitreous, retina, or choroid, which has been shown to be the first manifestation of numerous systemic diseases. Studies about the immunopathogenesis and treatment of uveitis are helpful to comprehend systemic autoimmune diseases, and delay the progression of systemic autoimmune diseases, respectively. Tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, plays a pivotal role in intraocular inflammation based on experimental and clinical data. Evidence of the feasibility of using anti-TNF-α agents for uveitis management has increased. Although there are numerous studies on TNF-α in various autoimmune diseases, the pathological mechanism and research progress of TNF-α in uveitis have not been reviewed. Therefore, the objective of this review is to provide a background on the role of TNF-α in the immunopathogenesis of uveitis, as well as from bench to clinical research progress, to better guide TNF-α-based therapeutics for uveitis.