Safe and Durable Treatment of Dentin Hypersensitivity via Nourishing and Remineralizing Dentin Based on ß-Chitooligosaccharide Graft Derivative.

Dentin hypersensitivity (DH) is a common symptom of various dental diseases that usually produces abnormal pain with external stimuli. Various desensitizers are developed to treat DH by occluding dentine tubules (DTs) or blocking intersynaptic connections of dental sensory nerve cells. However, the main limitations of currently available techniques are the chronic toxic effects of chemically active ingredients and their insufficiently durable efficacy. Herein, a novel DH therapy with remarkable biosafety and durable therapeutic value based on ß-chitooligosaccharide graft derivative (CAD) is presented. Particularly, CAD indicates the most energetic results, restoring the amino polysaccharide protective membrane in DTs, significantly promoting calcium and phosphorus ion deposition and bone anabolism, and regulating the levels of immunoglobulin in saliva and cellular inflammatory factors in plasma. Exposed DTs are occluded by remineralized hydroxyapatite with a depth of over 70 µm, as shown in in vitro tests. The bone mineral density of Sprague-Dawley rats' molar dentin increases by 10.96%, and the trabecular thickness of bone improves to about 0.03 µm in 2 weeks in the CAD group compared to the blank group. Overall, the ingenious concept that modified marine biomaterial can be a safe and durable therapy for DH is demonstrated by nourishing and remineralizing dentin.

Single-cell transcriptome dissecting the microenvironment remodeled by PD1 blockade combined with photodynamic therapy in a mouse model of oral carcinogenesis.

Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4-nitroquinoline 1-oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single-cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor-promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor-promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment-associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis.

Amyloid-ß but not tau accumulation is strongly associated with longitudinal cognitive decline.

OBJECTIVE: Alzheimer's disease (AD) pathology is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles in the brain. We studied whether Aß and tau accumulation are independently associated with future cognitive decline in the AD continuum. METHODS: Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) public database. A total of 1272 participants were selected based on the availability of Aß-PET and CSF tau at baseline and of those 777 participants with follow-up visits. RESULTS: We found that Aß-PET and CSF tau pathology were related to cognitive decline across the AD clinical spectrum, both as potential predictors for dementia progression. Among them, Aß-PET (A + T- subjects) is an independent reliable predictor of longitudinal cognitive decline in terms of ADAS-13, ADNI-MEM, and MMSE scores rather than tau pathology (A - T+ subjects), indicating tau accumulation is not closely correlated with future cognitive impairment without being driven by Aß deposition. Of note, a high percentage of APOE ε4 carriers with Aß pathology (A+) develop poor memory and learning capacity. Interestingly, this condition is not recurrence in terms of the ADNI-MEM domain when adding APOE ε4 status. Finally, the levels of Aß-PET SUVR related to glucose hypometabolism more strongly in subjects with A + T- than A - T+ both happen at baseline and longitudinal changes. CONCLUSIONS: In conclusion, Aß-PET alone without tau pathology (A + T-) measure is an independent reliable predictor of longitudinal cognitive decline but may nonetheless forecast different status of dementia progression. However, tau accumulation alone without Aß pathology background (A - T+) was not enough to be an independent predictor of cognitive worsening.

Identification of mitophagy-associated proteins profile as potential plasma biomarkers of idiopathic Parkinson's disease.

BACKGROUND: Despite extensive work to identify diagnostic plasma markers for Parkinson's disease (PD), there are still no accepted and validated surrogate biomarkers. Mitophagy-associated proteins (MAPs), including PTEN-induced putative kinase 1 (PINK1), Parkin, phosphoglycerate mutase 5 (PGAM5), BCL2 interacting protein 3 (BNIP3), and phosphorylated-TBK1 (p-TBK1), are, to our best knowledge, not well studied as a panel of biomarkers of neurodegeneration in PD. METHODS: The study population comprised 116 age-matched controls (HC), 179 PD patients, alongside and 90 PD syndromes (PDs) divided between two cohorts: (i) the modeling cohort (cohort 1), including 150 PD, 97 HC, and 80 PDs; and (ii) the validated cohort (cohort 2), including 29 PD, 19 HC, and 10 PDs. RESULTS: MAPs are elevated in the plasma of PD patients. PINK1, Parkin, and PGAM5 displayed the top three measurable increase trends in amplitude compared to BNIP3 and p-TBK1. Moreover, the area under the curve (AUC) values of PINK1, PGAM5, and Parkin were ranked the top three MAP candidates in diagnosis accuracy for PD from HC, but the MAPs make it hard to differentiate PD from PDs. In addition, there are higher plasma PINK1-Parkin levels and prominent diagnostic accuracy in A-synuclein (+) subjects than in A-synuclein (-) subjects. CONCLUSIONS: These results uncover that plasma MAPs (PINK1, Parkin, and PGAM5) may be potentially useful diagnostic biomarkers for PD diagnosis. Studies on larger cohorts would be required to test whether elevated plasma MAP levels are related to PD risk or prognosis.

A synergized machine learning plus cross-species wet-lab validation approach identifies neuronal mitophagy inducers inhibiting Alzheimer disease.

Failed recognition and clearance of damaged mitochondria contributes to memory loss as well as Aß and MAPT/Tau pathologies in Alzheimer disease (AD), for which there is an unmet therapeutic need. Restoring mitophagy to eliminate damaged mitochondria could abrogate metabolic dysfunction, neurodegeneration and may subsequently inhibit or slow down cognitive decline in AD models. We have developed a high-throughput machine-learning approach combined with a cross-species screening platform to discover novel mitophagy-inducing compounds from a natural product library and further experimentally validated the potential candidates. Two lead compounds, kaempferol and rhapontigenin, induce neuronal mitophagy and reduce Aß and MAPT/Tau pathologies in a PINK1-dependent manner in both C. elegans and mouse models of AD. Our combinational approach provides a fast, cost-effective, and highly accurate method for identification of potent mitophagy inducers to maintain brain health.

C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration.

Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.

Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-ß and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

Effects of Antibiotics Versus Repeated Applications of Photodynamic Therapy as an Adjunctive Treatment for Periodontitis: A Systematic Review and Meta-Analysis.

Objective: Although multiple applications of antimicrobial photodynamic therapy (aPDT) and antibiotics (AB) have been proved to have a biomodulatory effect, no systematic review has exclusively compared the effectiveness as an adjunct to scaling and root planning (SRP). This study sought to systematically compare the clinical efficacy of repeated antimicrobial photodynamic therapy (RaPDT) with that of the systemic administered AB as an alternative approach to SRP in treating periodontitis. Methods: In this systematic review, two independent reviewers searched PubMed, Embase, and CENTRAL databases. The primary outcomes assessed were bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL). Results: Five randomized clinical trials were included after screening 457 records. Results revealed that when patients from all studies were categorized based on their baseline CAL, AB demonstrated significant benefits over RaPDT in the improvement of PPD [weighted mean differences (WMD) = -0.36, 95% confidence interval (CI) = -0.71 to -0.02, p < 0.05] in the patients with severe periodontitis (CAL baseline ≥5 mm) 3-month postoperatively, and CAL (WMD = -0.57, 95% CI = -1.11 to -0.04, p < 0.05) at 6-month observation. Nevertheless, AB failed to show significant benefits over RaPDT, when CAL baseline <5 mm in terms of clinical parameters. Conclusions: RaPDT may represent an alternative approach to SRP in treating slight-to-moderate periodontitis cases (CAL <5 mm), whereas AB remain a main therapy for treating severe periodontitis (CAL ≥5 mm).

Role of miR-155 in immune regulation and its relevance in oral lichen planus.

Oral lichen planus (OLP) is a chronic mucosal inflammatory disease. The World Health Organization has described it as a potentially malignant condition. The pathogenesis of OLP remains to be fully elucidated, but extensive evidence suggests that immunologic and inflammatory factors have important roles. MicroRNAs (miRs), which are small non-coding RNAs, have been reported to be involved in OLP. In particular, miR-155 is significantly upregulated in patients with OLP. miR-155 has numerous functions and is closely linked to inflammation and immune system regulation. However, in-depth studies of the mechanisms via which miR-155 is involved in OLP are currently insufficient. Considering the close association between miR-155 and immune regulation as well as the importance of immune factors in OLP, the role of miR-155 in the immune system was herein summarized with a focus on OLP. The present review provides a basis for further study of the molecular mechanisms underlying the development and progression of OLP.

A meta-analysis of randomized trials assessing the effects of probiotic preparations on oral candidiasis in the elderly.

OBJECTIVE: Oral candidiasis is the most common fungal infection and can be attributed in part to dysbiosis, an imbalance in the resident oral microflora. Therefore, probiotics, which counter pathogenic microorganisms through competitive, antagonistic, and immunological effects, have been used by some clinicians. To date, the effect of probiotics in preventing oral candidiasis in the elderly is controversial. A systematic review that summarizes and critically appraises the available clinical trials is therefore necessary. DESIGN: Electronic searches were performed using the Pubmed, Embase, and Cochrane databases. Only randomized controlled trials were included. The Mantel-Haenszel test was used to appraise the odds ratio for single studies and an overall combined odds ratio for all studies combined. RESULTS: Three studies matched the inclusion criteria and were homogeneous. The data from one study that estimated candida growth from plaque and saliva were subdivided, thus a total of four studies with 595 people were included. The overall combined odds ratio was 0.54 (95% CI: 0.38-0.77). Three studies provided that active treatment reduced the risk of oral candidiasis more than placebo: Hatakka et al. (OR 0.51, 95% CI 0.26 to 0.97; 192 participants, plaque); Kraft-Bodi et al. (OR 0.46, 95% CI 0.24 to 0.86; 174 participants, palatal); Kraft-Bodi et al. (OR 0.50, 95% CI 0.26 to 0.98; 174 participants, plaque), while one study provided reverse result: Ishikawa et al. (OR 1.24, 95% CI 0.48 to 3.58; 55 participants, saliva). CONCLUSION: Probiotics have a preventative effect on oral candidiasis in the elderly.

Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy.

Oral potentially malignant disorders (OPMD) develop in a complex tissue microenvironment where they grow sustainably, acquiring oral squamous cell carcinoma (OSCC) characteristics. The malignant tumor depends on interactions with the surrounding microenvironment to achieve loco-regional invasion and distant metastases. Unlike abnormal cells, the multiple cell types in the tissue microenvironment are relatively stable at the genomic level and, thus, become therapeutic targets with lower risk of resistance, decreasing the risk of OPMD acquiring cancer characteristics and carcinoma recurrence. However, deciding how to disrupt the OPMD and OSCC microenvironments is itself a daunting challenge, since their microenvironments present opposite capacities, resulting in diverse consequences. Furthermore, recent studies revealed that tumor-associated immune cells also participate in the process of differentiation from OPMD to OSCC, suggesting that reeducating stromal cells may be a new strategy to prevent OPMD from acquiring OSCC characteristics and to treat OSCC. In this review, we discuss the characteristics of the microenvironment of OPMD and OSCC as well as new therapeutic strategies.