Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

Inflammasomes are supramolecular platforms that organize in response to various damage-associated molecular patterns and pathogen-associated molecular patterns. Upon activation, inflammasome sensors (with or without the help of ASC) activate caspase-1 and other inflammatory caspases that cleave gasdermin D and pro-IL-1β/pro-IL-18, leading to pyroptosis and mature cytokine secretion. Pyroptosis enables intracellular pathogen niche disruption and intracellular content release at the cost of cell death, inducing pro-inflammatory responses in the neighboring cells. IL-1β is a potent pro-inflammatory regulator for neutrophil recruitment, macrophage activation, and T-cell expansion. Thus, pyroptosis and cytokine secretion are the two main mechanisms that occur downstream of inflammasome signaling; they maintain homeostasis, drive the innate immune response, and shape adaptive immunity. This review aims to discuss the possible mechanisms, timing, consequences, and significance of the two uncoupling preferences downstream of inflammasome signaling. While pyroptosis and cytokine secretion may be usually coupled, pyroptosis-predominant and cytokine-predominant uncoupling are also observed in a stimulus-, cell type-, or context-dependent manner, contributing to the pathogenesis and development of numerous pathological conditions such as cryopyrin-associated periodic syndromes, LPS-induced sepsis, and Salmonella enterica serovar Typhimurium infection. Hyperactive cells consistently release IL-1β without LDH leakage and pyroptotic death, thereby leading to prolonged inflammation, expanding the lifespans of pyroptosis-resistant neutrophils, and hyperactivating stimuli-challenged macrophages, dendritic cells, monocytes, and specific nonimmune cells. Death inflammasome activation also induces GSDMD-mediated pyroptosis with no IL-1β secretion, which may increase lethality in vivo. The sublytic GSDMD pore formation associated with lower expressions of pyroptotic components, GSDMD-mediated extracellular vesicles, or other GSDMD-independent pathways that involve unconventional secretion could contribute to the cytokine-predominant uncoupling; the regulation of caspase-1 dynamics, which may generate various active species with different activities in terms of GSDMD or pro-IL-1β, could lead to pyroptosis-predominant uncoupling. These uncoupling preferences enable precise reactions to different stimuli of different intensities under specific conditions at the single-cell level, promoting cooperative cell and host fate decisions and participating in the pathogen “game”. Appropriate decisions in terms of coupling and uncoupling are required to heal tissues and eliminate threats, and further studies exploring the inflammasome tilt toward pyroptosis or cytokine secretion may be helpful

Inflammasomes in Alveolar Bone Loss

Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense

Advances in the Role of Sodium Hypochlorite Irrigant in Chemical Preparation of Root Canal Treatment

Irrigation of root canal system is of great significance to the success of endodontic treatment, where sodium hypochlorite (NaOCl) is the most widely used irrigant in chemical preparation. NaOCl functions by eliminating bacterial biofilms and dissolving organic tissue, which may vary according to several factors such as the microbiology of root canal infection and the concentration of the irrigant. It has been proposed that the effectiveness of NaOCl could be enhanced via several methods, including heating the irrigant, applying in conjunction with certain reagents, or activating by agitation techniques. Despite its antibacterial and tissue-dissolving capacities, NaOCl should be used with caution to avoid detrimental effect due to its cytotoxicity and negative effect on dentin properties. In this narrative review, we discussed the factors that affect the properties of NaOCl, the methods to improve its efficacy, and the side effects that might occur in clinical practice

A novel method for periapical microsurgery with the aid of 3D technology: a case report

Abstract Background Three-dimensional (3D) technology has gained wide acceptance in dentistry. It has been used for treatment planning and surgical guidance. This case report presented a novel treatment approach to remove cortical bone and root-end during periapical surgery with the help of Cone-Beam Computed Tomography (CBCT), Computer Aided Design (CAD) and three-dimensional (3D) printing technology. Case presentation A 37-year-old female patient presented with a large periapical lesion of left maxillary lateral incisor and canine was referred for microsurgical endodontic surgery. The data acquired from a preoperative diagnostic CBCT scan and an intra-oral scan was uploaded into surgical planning software and matched. A template that could be used to locate root-ends and lesion areas was virtually designed based on the data and was fabricated using a 3D printer. With the guidance of the template, the overlying cortical bone and root-end were precisely removed by utilizing a trephine with an external diameter of 4.0 mm. The patient was clinically asymptomatic at a six-month follow-up review. One year after the surgery, the lesion was healing well and no periapical radiolucency was observed on radiographic examination. Conclusions The digitally designed directional template worked in all aspects to facilitate the periapical surgery as anticipated. The root-ends were accurately located and resected. The surgical procedure was simplified, and the treatment efficiency was improved. This technique minimized the damage and reduced iatrogenic injury

Direct resin composite restoration of maxillary central incisors using a 3D-printed template: two clinical cases

Abstract Background Three-dimensional (3D) printing technology is used widely in dentistry for applications including implant surgery, oral and maxillofacial surgery, orthognathic surgery, endodontics and prosthodontics. Using a 3D-printed template makes performing the repair procedure faster and more convenient. The aesthetic restoration of anterior teeth can recover facial beauty, enhance speaking and chewing functions and improve the quality of life of the patient. Case presentation This article describes two kinds of clinical cases including fractured teeth and dental caries. In both, a 3D-printed template was used for direct resin composite restoration of maxillary central incisors. A 3D-printed template was built using the following 3-step process: data acquisition was conducted via intra-oral scanning, virtual modeling was performed using an imaging process, and manufacturing was performed using a 3D printer. Aesthetically restoring the maxillary incisors with the assistance of the 3D-printed template achieved the anticipated results, and the patients were very satisfied with the effect. Conclusions The direct resin composite restoration of maxillary central incisors using a 3D-printed template represents a rapid, convenient, aesthetic and functional option for treating maxillary central incisors. A 3D-printed template is therefore an acceptable and reliable alternative to traditional direct composite restoration of maxillary central incisors including fractured teeth and dental caries

Effectiveness of photon-initiated photoacoustic streaming in root canal models with different diameters or tapers

Background This study aimed to compare the use of photon-initiated photoacoustic streaming (PIPS) and conventional needle irrigation (CNI) in conjunction with different concentrations of sodium hypochlorite (NaOCl) to remove Enterococcus faecalis (E. faecalis) suspended bacteria and biofilms from root canal systems with different diameters or tapers. Methods Artificial root canal samples (n = 480) were randomly divided into three groups (n = 160/group). The canals were prepared to fit file sizes #10/.02, #25/.02, or #25/.06. The size #10/.02 group was incubated for seven days. The size #25/.02 or #25/.06 group was incubated for 2 days. A stable biological model of E. faecalis infection was established. The root canals were washed with distilled water or with 1%, 2%, or 5.25% NaOCl combined with CNI or PIPS. Bacterial suspensions and biofilms were assessed using an ATP assay kit and fluorescence microscopy. Image-Pro Plus was used to analyse the average fluorescence intensity to determine the most suitable root canal irrigation solution. Results In the CNI and PIPS groups, the ATP value of the 5.25% NaOCl subgroup was the lowest, followed by that of the 2% and 1% NaOCl subgroups. The ATP value of the distilled water subgroup was the highest (P < 0.05). When the root canal taper was 0.02, the ATP value of the #10/.02 + PIPS group was significantly lower than that of the #25/.02 + CNI group (P < 0.05). The average fluorescence intensity of the #10/.02 + PIPS group was lower than that of the #25/.02 + CNI group (P < 0.05). When the apical diameter was #25, the ATP value of the 0.02 taper in the PIPS group was lower than that of the 0.06 taper in the CNI group (P < 0.05), and the average fluorescence intensity of the 0.02 taper + PIPS group was lower than that of the 0.06 taper + CNI group (P < 0.05). PIPS combined with 2% and 5.25% NaOCl effectively improved the long-term antibacterial effect after irrigation and re-culture for 6 h. Conclusions Compared with CNI, PIPS has greater ability to remove bacteria in root canals with a small preparation diameter and a small taper. PIPS with 2% and 5.25% NaOCl exhibited superior antibacterial and bacteriostatic effects.Dentistry, Faculty ofNon UBCReviewedFacultyResearche

COVID-19 vaccination hesitancy and associated factors among solid organ transplant recipients in China

The mortality rate from COVID-19 appears to be higher in solid organ transplant (SOT) recipients when compared with other populations. Vaccination is a key strategy to prevent the COVID-19 pandemic. However, it is unclear how readily SOT recipients will get vaccinated against COVID-19. We conducted an internet-based survey to investigate the vaccination willingness among Chinese SOT recipients and further explore possible influencing factors. Eight hundred and thirteen respondents participated in the survey. Overall, 46 (5.7%) recipients were vaccinated against COVID-19, while 767 (94.3%) were not. Among those not vaccinated, 175 (22.8%) intended to be vaccinated, while 592 (77.2%) were categorized as vaccine-hesitant. The most common reason for vaccination hesitancy is fear of preexisting comorbidities, followed by fear of side effects and doctors’ negative advice. Factors associated with vaccination willingness were as follows: with liver transplantation, the main source of information on COVID-19 vaccines was from medical doctors, scientists, and scientific journals, with at least college-level education, positive intention toward influenza vaccination during the current season, perceived importance of vaccination for SOT recipients, and having been vaccinated against influenza during the last season. Our survey indicated the necessity for SOT recipients to receive more comprehensive and accessible health education about vaccination and emphasized the critical role of transplantation physicians in promoting vaccine acceptance among SOT recipients. We hope that our survey results will help governments to better target communication in the ongoing COVID-19 vaccination campaign