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BackgroundCandidalysin is a cytolytic peptide toxin secreted by Candida albicans hyphae and has significantly advanced our understanding of fungal pathogenesis. Candidalysin is critical for mucosal C albicans infections and is known to activate epithelial cells to induce downstream innate immune responses that are associated with protection or immunopathology during oral or vaginal infections. Furthermore, candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. However, the role of candidalysin in driving systemic infections is unknown.MethodsIn this study, using candidalysin-producing and candidalysin-deficient C albicans strains, we show that candidalysin activates mitogen-activated protein kinase (MAPK) signaling and chemokine secretion in endothelial cells in vitro.ResultsCandidalysin induces immune activation and neutrophil recruitment in vivo, and it promotes mortality in zebrafish and murine models of systemic fungal infection.ConclusionsThe data demonstrate a key role for candidalysin in neutrophil recruitment and fungal virulence during disseminated systemic C albicans infections.

Aim: To investigate serum biomarkers of inflammation 2 years following non‐surgical root canal re‐treatment (Re‐RCT) and peri‐apical surgery (PS). The results were correlated with signs and symptoms, treatment outcome, metabolic syndrome factors, infection with severe acute respiratory syndrome coronavirus 2 SARS‐CoV‐2 (COVID‐19) infection and COVID‐19 vaccination. Methodology: Subjects from our previous study were recalled for 2 years post‐treatment follow‐up. Changes to the patient's history (medical, dental, social) were noted. Periapical health of the treated teeth was examined both clinically and radiographically. Blood pressure, fasting HbA1C and low‐density lipoprotein (LDL), high‐density lipoprotein (HDL), triglycerides and total cholesterol (TC) levels were measured. Serum inflammatory marker levels were assayed using a Bio‐Rad Bio‐Plex 200 analyser and values at different time points within the same group were compared using a Wilcoxon signed‐rank test and differences between groups with a Mann–Whitney test. Linear associations were tested using Pearson's correlations. Results: The recall percentage at 2 years was 56.9% (n = 37), with a 100% radiographic success rate using periapical radiographs. In total, 21 cases (56.8%) were completely healed, and 16 cases (43.2%) were healing. Higher matrix metalloprotease 2 (MMP2) levels were present in the healing group compared to the healed group. Serum levels of high‐sensitivity C‐reactive protein (hs‐CRP), asymmetric dimethylarginine (ADMA) and MMP‐2 were significantly reduced (p ≤.001) whereas other biomarkers showed significant increases at 2 year compared to pre‐operative levels, while FGF‐23 and ICAM‐1 were not significantly increased. HbA1C (p =.015), TC (p =.003), LDL (p =.003) and HDL (p =.003) reduced significantly at 2 years post‐treatment compared to their preoperative levels. COVID infection showed a significant association with MMP‐9 (p =.048). Conclusions: hs‐CRP, ADMA and MMP‐2 can be regarded as prognostic biomarkers of successful Re‐RCT and PS as they reduced at 2 year recall in cases which showed evidence of clinical and radiographic success. The successful treatment of chronic apical periodontitis is correlated with improvements in metabolic syndrome indicators, better glycemic control, and reduction at 2 year of some systemic inflammatory markers which are related to risks of cardiovascular disease events. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate metabolomics markers in the saliva of patients with periodontal health, gingivitis and periodontitis. Background: The use of metabolomics for diagnosing and monitoring periodontitis is promising. Although several metabolites have been reported to be altered by inflammation, few studies have examined metabolomics in saliva collected from patients with different periodontal phenotypes. Methods: Saliva samples collected from a total of 63 patients were analysed by nuclear magnetic resonance (NMR) followed by ELISA for interleukin (IL)‐1β. The patient sample, well‐characterised clinically, included periodontal health (n = 8), gingivitis (n = 19) and periodontitis (n = 36) cases, all non‐smokers and not diabetic. Results: Periodontal diagnosis (healthy/gingivitis/periodontitis) was not associated with any salivary metabolites in this exploratory study. Periodontal staging showed nominal associations with acetoin (p =.030) and citrulline (p =.047). Among other investigated variables, the use of systemic antibiotics in the previous 3 months was associated with higher values of the amino acids taurine, glycine and ornithine (p =.002, p =.05 and p =.005, respectively, at linear regression adjusted for age, gender, ethnicity, body mass index and staging). Conclusion: While periodontal staging was marginally associated with some salivary metabolites, other factors such as systemic antibiotic use may have a much more profound effect on the microbial metabolites in saliva. Metabolomics in periodontal disease is still an underresearched area that requires further observational studies on large cohorts of patients, aiming to obtain data to be used for clinical translation. [ABSTRACT FROM AUTHOR]

This systematic review aims to evaluate the impact of peri-implantitis on the components of metabolic syndrome, and to provide suggestions on the management of peri-implantitis patients with metabolic disorders. A search for relevant records was performed in MEDLINE, EMBASE, and Global Health on 1st September 2023. Clinical trials, cohort studies, cross-sectional studies, and case-control studies containing comparisons of metabolic factors between patients with and without peri-implantitis were considered eligible. Study quality was assessed using the Newcastle–Ottawa scale. Out of 1158 records identified, 5 cross-sectional studies were eligible for final inclusion. Two studies reported significant differences in the lipid profile of patients with peri-implantitis, one of which reported higher total cholesterol and LDL cholesterol levels, while the other reported higher triglyceride levels. Another study reported significantly higher HbA1c levels in patients with peri-implantitis. The remaining two studies containing comparisons of BMI between patients with and without peri-implantitis indicated no significant differences. Overall, there are suggestions that peri-implantitis is associated with altered metabolic factors, including lipid profile and HbA1c level. However, there is not enough evidence to support these clinical implications due to the paucity of related literature and the low evidence level of the included studies. More investigations with stronger evidence levels are needed to narrow this gap of knowledge. [ABSTRACT FROM AUTHOR]

Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name 'Candidalysin' for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans., The ability of mucosal surfaces to discriminate between commensal and pathogenic microbes is essential to human health. The fungus Candida albicans is normally a benign member of the human microbiota, [...]

Antimicrobial resistance (AMR) is one of the greatest challenges facing humanity, causing a substantial burden to the global healthcare system. AMR in Gram-negative organisms is particularly concerning due to a dramatic rise in infections caused by extended-spectrum beta-lactamase and carbapenemase-producing Enterobacterales (ESBL and CPE). These pathogens have limited treatment options and are associated with poor clinical outcomes, including high mortality rates. The microbiota of the gastrointestinal tract acts as a major reservoir of antibiotic resistance genes (the resistome), and the environment facilitates intra and inter-species transfer of mobile genetic elements carrying these resistance genes. As colonisation often precedes infection, strategies to manipulate the resistome to limit endogenous infections with AMR organisms, as well as prevent transmission to others, is a worthwhile pursuit. This narrative review presents existing evidence on how manipulation of the gut microbiota can be exploited to therapeutically restore colonisation resistance using a number of methods, including diet, probiotics, bacteriophages and faecal microbiota transplantation (FMT). [ABSTRACT FROM AUTHOR]

This study aimed to assess the effect of apical periodontitis and its treatment on the profile of salivary inflammatory markers and to investigate its correlation with serum inflammatory markers. Saliva samples were collected from 115 recruited participants. Patients were reviewed after 1 and 2 years following treatment. Saliva samples were analysed using Multiplex microbead immunoassay for identifying the inflammatory biomarkers' profile. Biomarker levels were compared against healthy controls at baseline. Longitudinal comparison of those markers was further analysed for the review appointments and correlated with the size of the periapical radiolucency, treatment outcome and serum inflammatory biomarker levels. The salivary cytokines, matrix metalloproteinases (MMPs) and vascular adhesion molecules were higher at the review appointments. Pre-operative salivary levels of high-sensitivity C-reactive protein (hs-CRP) were significantly higher in the treatment group than in the control group (p < 0.001). At 1 year, hs-CRP was decreased than baseline. While, in 2 years, fibroblast growth factor (FGF)-23 was significantly lower compared to baseline levels (p = 0.005). Furthermore, the post-operative size of radiolucency was significantly correlated with the levels of several markers. When correlating the salivary levels of biomarkers with the serum levels, a significant correlation was seen in FGF-23 (p = 0.04) at baseline; in intercellular adhesion molecule (ICAM)-1 (p = 0.02) at 1 year post-treatment; and in TNF-α, ICAM-1 and E-Selectin at 2 years post-treatment (p = 0.046; p = 0.033; p = 0.019, respectively). Therefore, his study suggests that higher salivary cytokines, MMPs and vascular adhesion molecules at the post-treatment reviews are related to periapical bone healing and remodelling, whereas salivary FGF-23 and hs-CRP could be prognostic biomarkers. Correlation of some salivary with serum biomarkers suggests that saliva sampling could be a feasible non-invasive option for the measurement of inflammatory marker levels; however, further longitudinal studies are required. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to measure serum levels of molecular markers of inflammation in patients undergoing non‐surgical root canal retreatment (Re‐RCT) and periapical surgery (PS) for the treatment of apical periodontitis and to establish if such levels are influenced by the size of apical radiolucencies at baseline and by the treatment outcome. Methodology: A total of 115 participants were recruited (n = 50 Controls, n = 35 Re‐RCT, n = 30 PS). Preoperative periapical radiographs and cone beam CT (CBCT) scans of teeth were taken. Blood was collected from treatment groups at baseline, 3‐, 6‐, and 12‐month post‐treatment and from controls at baseline and 12 months. Serum levels of IL‐1β, IL‐6, IL‐8, TNF‐α, Pentraxin 3, ICAM‐1, VCAM‐1, hs‐CRP, FGF‐23, MMP‐2, MMP‐8, MMP‐9, C3 and ADMA were analysed using multiplex immunoassay and enzyme‐linked immunosorbent assay. Different time points within the same group were compared using Wilcoxon signed‐rank test, and differences between groups were analysed using the Mann–Whitney test. Non‐linear association between different factors was assessed using Spearman's correlation. Results: Preoperative serum levels of FGF‐23, IL‐1β, hs‐CRP and ADMA were significantly higher in the diseased groups compared with controls (p <.001; p =.008; p <.001; p =.013, respectively). The preoperative size of the radiolucency was associated with increased levels of FGF‐23, IL‐1β and IL‐6. At 3‐months following treatment, IL‐1β, IL‐8, hs‐CRP, C3, MMP‐2 and MMP‐9 levels increased compared with baseline in treatment groups. IL‐1β and IL‐8 further increased at 6 months, whereas FGF‐23, hs‐CRP, C3, MMP2 and MMP‐9 decreased. One‐year post‐treatment, FGF‐23, pentraxin‐3 and ADMA were significantly reduced below baseline levels. At the 1‐year review, CBCT revealed that 25.9% of treated cases completely healed, while 63% were healing, and 11.1% failed. Treatment outcome was found to be influenced by preoperative levels of ADMA and IL‐8 levels at 6 months. Conclusions: Both symptomatic and asymptomatic apical periodontitis (AP) can contribute to increased levels of molecular markers of inflammation. A further transient inflammatory markers rise after root canal retreatment and apical surgery were demonstrated. Successful endodontic treatment and periapical surgery result in a long‐term reduction in inflammatory marker levels. [ABSTRACT FROM AUTHOR]

A quantitative real-time RT-PCR system was established to identify which secreted aspartyl proteinase (SAP) genes are most highly expressed and potentially contribute to Candida albicans infection of human epithelium in vitro and in vivo. C. albicans SC5314 SAP1-10 gene expression was monitored in organotypic reconstituted human epithelium (RHE) models, monolayers of oral epithelial cells, and patients with oral (n = 17) or vaginal (n= 17) candidiasis. SAP gene expression was also analysed in [DELTA]sap1-3, [DELTA]sap4-6, [DELTA]efg1 and [DELTA]efg1/cph1 mutants to determine whether compensatory SAP gene regulation occurs in the absence of distinct proteinase gene subfamilies. In monolayers, RHE models and patient samples SAP9 was consistently the most highly expressed gene in wild-type cells. SAP5 was the only gene significantly upregulated as infection progressed in both RHE models and was also highly expressed in patient samples. Interestingly, the SAP4-6 subfamily was generally more highly expressed in oral monolayers than in RHE models. SAP1 and SAP2 expression was largely unchanged in all model systems, and SAP3, SAP7 and SAP8 were expressed at low levels throughout. In [DELTA]sap1-3, expression was compensated for by increased expression of SAP5, and in [DELTA]sap4-6, expression was compensated for by SAP2: both were observed only in the oral RHE. Both [DELTA]sap1-3 and [DELTA]sap4-6 mutants caused RHE tissue damage comparable to the wild-type. However, addition of pepstatin A reduced tissue damage, indicating a role for the Sap family as a whole in inducing epithelial damage. With the hypha-deficient mutants, RHE tissue damage was significantly reduced in both [DELTA]efg1/cph1 and [DELTA]efg1, but SAP5 expression was only dramatically reduced in [DELTA]efg1/cph1 despite the absence of hyphal growth in both mutants. This indicates that hypha formation is the predominant cause of tissue damage, and that SAP5 expression can be hypha-independent and is not solely controlled by the Efg1 pathway but also by the Cph1 pathway. This is believed to be the first study to fully quantify SAP gene expression levels during human mucosal infections; the results suggest that SAP5 and SAP9 are the most highly expressed proteinase genes in vivo. However, the overall contribution of the Sap1-3 and Sap4-6 subfamilies individually in inducing epithelial damage in the RHE models appears to be low.

The fungal pathogen Candida albicans secretes the peptide toxin candidalysin, which damages epithelial cells and drives an innate inflammatory response mediated by the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathways and the transcription factor c-Fos. In cultured oral epithelial cells, candidalysin activated the MAPK p38, which resulted in heat shock protein 27 (Hsp27) activation, IL-6 release, and EGFR phosphorylation without affecting the induction of c-Fos. p38 activation was not triggered by EGFR but by two nonredundant pathways involving MAPK kinases (MKKs) and the kinase Src, which differentially controlled p38 signaling outputs. Whereas MKKs mainly promoted p38-dependent release of IL-6, Src promoted p38-mediated phosphorylation of EGFR in a ligand-independent fashion. In parallel, candidalysin also activated the EGFR-ERK pathway in a ligand-dependent manner, resulting in c-Fos activation and release of the neutrophil-activating chemokines G-CSF and GM-CSF. In mice, early clearance events of oral C. albicans infection required p38 but not c-Fos. These findings delineate how candidalysin activates the pathways downstream of the MAPKs p38 and ERK that differentially contribute to immune activation during C. albicans infection. MAPK pathways in Candida infection: Candidalysin, a toxin secreted by the opportunistic fungal pathogen Candida albicans, induces inflammation by stimulating EGFR signaling and several MAPK pathways in host cells. Nikou et al. found that stimulation of human oral epithelial cells with candidalysin induced distinct host cell responses mediated by pathways downstream of the MAPKs ERK and p38. Depending on the activating stimulus, p38 promoted the release of the inflammatory cytokine IL-6 or the phosphorylation of EGFR in a ligand-independent manner. Ligand-dependent EGFR signaling promoted the release of neutrophil-stimulating cytokines through ERK and the transcription factor c-Fos. In mice, p38, but not c-Fos, was required for early clearance of the pathogen. Thus, different MAPK pathways mediate discrete host cell responses to candidalysin and Candida infection. [ABSTRACT FROM AUTHOR]

Candida albicans is a common opportunistic fungal pathogen that causes a wide range of infections from superficial mucosal to hematogenously disseminated candidiasis. The hyphal form plays an important role in the pathogenic process by invading epithelial cells and causing tissue damage. Notably, the secretion of the hyphal toxin candidalysin is essential for both epithelial cell damage and activation of mucosal immune responses. However, the mechanism of candidalysin‐induced cell death remains unclear. Here, we examined the induction of cell death by candidalysin in oral epithelial cells. Fluorescent imaging using healthy/apoptotic/necrotic cell markers revealed that candidalysin causes a rapid and marked increase in the population of necrotic rather than apoptotic cells in a concentration dependent manner. Activation of a necrosis‐like pathway was confirmed since C. albicans and candidalysin failed to activate caspase‐8 and ‐3, or the cleavage of poly (ADP‐ribose) polymerase. Furthermore, oral epithelial cells treated with candidalysin showed rapid production of reactive oxygen species, disruption of mitochondria activity and mitochondrial membrane potential, ATP depletion and cytochrome c release. Collectively, these data demonstrate that oral epithelial cells respond to the secreted fungal toxin candidalysin by triggering numerous cellular stress responses that induce necrotic death. Take aways: Candidalysin secreted from Candida albicans causes epithelial cell stress.Candidalysin induces calcium influx and oxidative stress in host cells.Candidalysin induces mitochondrial dysfunction, ATP depletion and epithelial necrosis.The toxicity of candidalysin is mediated from the epithelial cell surface. [ABSTRACT FROM AUTHOR]

This Basic Science Workshop addressed the oral microbiome. At the 7th World Workshop on Oral Health & Disease in HIV/AIDS in India in 2014, some aspects of the human microbiome were discussed, and research questions formulated. Since that time, there have been major advances in technology, which have stimulated a number of publications on many aspects of the human microbiome, including the oral cavity. This workshop aimed to summarize current understanding of the "normal" microbiome of the oral cavity compared to that during HIV infection, and how oral immune factors and other clinical variables alter or control the oral microbiome. An important question is whether successful treatment with anti‐retroviral therapy, which leads to a significant drop in viral loads and immune reconstitution, is associated with any change or recovery of the oral microbiome. Additionally, the workshop addressed the issue of which parameters are most appropriate/correct to evaluate the oral microbiome and how clinically relevant are shifts/changes in the oral microbiome. The workshop evaluated current knowledge in five research areas related to five basic questions and identified further topics where further research is required. [ABSTRACT FROM AUTHOR]

The mucosal surfaces of the human body are challenged by millions of microbes on a daily basis. Co-evolution with these microbes has led to the development of plastic mechanisms in both host and microorganisms that regulate the balance between preserving beneficial microbes and clearing pathogens. Candida albicans is a fungal pathobiont present in most healthy individuals that, under certain circumstances, can become pathogenic and cause everything from mild mucosal infections to life-threatening systemic diseases. As an essential part of the innate immunity in mucosae, epithelial cells elaborate complex immune responses that discriminate between commensal and pathogenic microbes, including C. albicans. Recently, several significant advances have been made identifying new pieces in the puzzle of host-microbe interactions. This review will summarize these advances in the context of our current knowledge of anti- Candida mucosal immunity, and their impact on epithelial immune responses to this fungal pathogen. [ABSTRACT FROM AUTHOR]

Mycoses, innate immunity, leukocytes, lymphocytes, cytokines Risk factors for invasive mycosis represent medical advances, including the use of intravenous catheters, cancer chemotherapy and immunosupressive therapies which have created a growing population of vulnerable patients. Keywords: mycoses; innate immunity; leukocytes; lymphocytes; cytokines EN mycoses innate immunity leukocytes lymphocytes cytokines 1 3 3 07/19/21 20210715 NES 210715 Fungal infections represent a major health concern which, according estimations, account for nearly 1.6 million deaths annually (Brown et al., [2]). Thus, comprehension of the immunity to fungal pathogens offers new possibilities for the treatment of invasive mycoses. [Extracted from the article]

Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swim-bladder model of infection. Investigation into the mechanism of EGFR activation revealed the requirement of matrix metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis. [ABSTRACT FROM AUTHOR]

This study arose from a knowledge exchange project whereby business support and knowledge exchange opportunities were provided to rural small businesses as an academic outreach programme. We review how academic support to small businesses in rural Southwest Scotland was delivered. Academic support for micro-business in Southwest Scotland is an under-researched topic. The owners volunteered to share their experiences of this support with the wider business community and university staff acted as consultants and researchers, mentoring the businesses and developing insights into rural business support. The article describes the processes and outcomes of the project, and the factors which affected the ability of the businesses to take advantage of academic business support. We utilised a case-study approach, in-depth interviews and follow-ups over a one-year period, later adding a longitudinal perspective. Our findings indicate that rural factors, business life cycle stage, sectoral skills availability along with the specific market and organisational context combine to create challenges for small business owners and impact on their ability to access and benefit from business support services. The results are significant for business engagement strategies of universities and for business support policy for small and micro-businesses in geographically isolated regions. The participant-consultant roles of the researchers facilitated the development of rich, ‘insider’ insights into this neglected topic. [ABSTRACT FROM AUTHOR]

Purpose – Building on previous work (Cano and Moyes, 2013; Moyes, 2012) this study further develops the proposition that word-of-mouth (WOM) and customer retention are enhanced through the “three Rs” of service quality; namely, reliability, responsiveness and recovery. Work to date in this field has developed and tested the model in two different rural locations. However, there may be underlying factors in rural areas which cause the correlation between customer satisfaction and loyalty behaviour to be overstated. Therefore, to control for the possibly distorting effects of rurality, the purpose of this paper is to examine the loyalty responses of urban service-users. Design/methodology/approach – Using the critical incident technique a study of young, relatively affluent women was carried out in a city-centre in Scotland. The study was carried out in spring 2014 over a one-week period. Results were analysed using qualitative analysis software. Findings – Results confirmed the validity of the three Rs model. Findings demonstrate that the model is valid for different population densities. Research limitations/implications – The qualitative method yields rich, insightful data, but the results cannot be generalised to a wider population. The findings provide service providers with a clear set of quality dimensions used by respondents to evaluate their service experiences. Loyalty behaviours were found to be highly responsive to quality evaluations; both repeat purchase intentions and WOM behaviours are highly quality-elastic. Practical implications – The results confirm that a business which provides the quality of service which customers expected to receive, which demonstrates responsiveness to customer needs and which remedies failings in service delivery appropriately, will benefit from increased loyalty and WOM recommendations. Those which fail to provide these three essential elements will suffer loss of loyalty and incur negative WOM. Originality/value – A clear set of dimensions is presented which reflect service priorities of consumers. [ABSTRACT FROM AUTHOR]