Bacterial resistance to antimicrobial photodynamic therapy: A critical update.

Bacterial antibiotic resistance is one of the most significant challenges for public health. The increase in bacterial resistance, mainly due to microorganisms harmful to health, and the need to search for alternative treatments to contain infections that cannot be treated by conventional antibiotic therapy has been aroused. An alternative widely studied in recent decades is antimicrobial photodynamic therapy (aPDT), a treatment that can eliminate microorganisms through oxidative stress. Although this therapy has shown satisfactory results in infection control, it is still controversial in the scientific community whether bacteria manage to develop resistance after successive applications of aPDT. Thus, this work provides an overview of the articles that performed successive aPDT applications in models using bacteria published since 2010, focusing on sublethal dose cycles, highlighting the main PSs tested, and addressing the possible mechanisms for developing tolerance or resistance to aPDT, such as efflux pumps, biofilm formation, OxyR and SoxRS systems, catalase and superoxide dismutase enzymes and quorum sensing.

Candida species as potential risk factors for oral squamous cell carcinoma: Systematic review and meta-analysis.

Oral squamous cell carcinoma (OSCC) is considered a multifactorial disease and has been associated with microbial infections, although the association with Candida spp. is still controversial. This systematic review focused on clinical trials which evaluated the relation between oral Candida spp colonization and OSCC. PubMed; Scopus; Embase; Web of Science and Scientific Direct were assessed. Independent reviewers conducted the diagram steps. For data extraction the PRISMA protocol was followed. The quality analysis of case-control studies was performed based on the Newcastle-Ottawa scale. Meta-analysis was performed to evaluate the frequency of Candida spp and the levels of microbial acetaldehyde production (MAP) being odds ratio (OR) the effect-measure applied. Eight and six studies were included in the qualitative analysis and meta-analysis, respectively. It was noted that there was a significantly higher frequency of Candida species (p = 0.0003/OR = 9.50) in patients diagnosed with OSCC than healthy patients, especially Candida krusei (p = 0.0167/OR=4.62). Candida spp., from oral cancer patients demonstrated significantly greater biofilm, biofilm metabolic activity, phospholipase, proteinase activity and a higher production of MAP (p = 0.0111/OR = 2.67). Candida species may have a potential role in OSCC development. Further studies should be conducted to elucidate the mechanism of action of Candida spp and others risk factors in the development of OSCC.

Photodynamic Therapy Can Modulate the Nasopharyngeal Carcinoma Microenvironment Infected with the Epstein-Barr Virus: A Systematic Review and Meta-Analysis.

Nasopharyngeal carcinoma is a malignancy from epithelial cells predominantly associated with the Epstein-Barr virus (EBV) infection, and it is responsible for 140,000 deaths annually. There is a current need to develop new strategies to increase the efficacy of antineoplastic treatment and reduce side effects. Thus, the present study aimed to perform a systematic review and meta-analysis of the ability of photodynamic therapy (PDT) to modulate the tumor microenvironment and PDT efficacy in nasopharyngeal carcinoma treatment. The reviewers conducted all steps in the systematic review. PubMed, Science Direct, Scopus, Scielo, Lilacs, EMBASE, and the Cochrane library databases were searched. The OHAT was used to assess the risk of bias. Meta-analysis was performed with a random-effects model (α = 0.05). Nasopharyngeal carcinoma cells treated with PDT showed that IL-8, IL-1α, IL-1ß, LC3BI, LC3BII, MMP2, and MMP9 levels were significantly higher than in groups that did not receive PDT. NF-ĸB, miR BART 1-5p, BART 16, and BART 17-5p levels were significantly lower in the PDT group than in the control group. Apoptosis levels and the viability of nasopharyngeal carcinoma cells (>70%) infected with EBV were effective after PDT. This treatment also increased LMP1 levels (0.28-0.50/p < 0.05) compared to the control group. PDT showed promising results for efficacy in killing nasopharyngeal carcinoma cells infected with EBV and modulating the tumor microenvironment. Further preclinical studies should be performed to validate these results.

Evaluation of photodynamic therapy on nanoparticles and films loaded-nanoparticles based on chitosan/alginate for curcumin delivery in oral biofilms.

Nanoparticles and nanoparticle-loaded films based on chitosan/sodium alginate with curcumin (CUR) are promising strategies to improve the efficacy of antimicrobial photodynamic therapy (aPDT) for the treatment of oral biofilms. This work aimed to develop and evaluate the nanoparticles based on chitosan and sodium alginate encapsulated with CUR dispersed in polymeric films associated with aPDT in oral biofilms. The NPs were obtained by polyelectrolytic complexation, and the films were prepared by solvent evaporation. The photodynamic effect was evaluated by counting Colony Forming Units (CFU/mL). Both systems showed adequate characterization parameters for CUR release. Nanoparticles controlled the release of CUR for a longer period than the nanoparticle-loaded films in simulated saliva media. Control and CUR-loaded nanoparticles showed a significant reduction of 3 log10 CFU/mL against S. mutans biofilms, compared to treatment without light. However, biofilms of S. mutans showed no photoinactivation effect using films loaded with nanoparticles even in the presence of light. These results demonstrate the potential of chitosan/sodium alginate nanoparticles associated with aPDT as carriers for the oral delivery of CUR, offering new possibilities to improve the treatment of dental caries and infections. This work will contribute to advances in the search for innovative delivery systems in dentistry.

Potential Use of Brazilian Green Propolis Extracts as New Photosensitizers for Antimicrobial Photodynamic Therapy against Cariogenic Microorganisms.

The synergic effect of Streptococcus mutans and Candida albicans increases dental caries severity. Antimicrobial photodynamic therapy (aPDT) is a non-invasive treatment for antimicrobial aspects. However, the current photosensitizers (PS) have many downsides for dental applications. This study aimed to evaluate the efficiency of two different Brazilian green propolis (BGP-AF and BGP-AG) as PS for aPDT against these microorganisms. A single-species biofilm was irradiated with crude extracts and their fractions and controls. Such extracts showed the best results and were evaluated in dual-species biofilms. Photodegradation, reactive oxygen species (ROS), cytotoxicity, and color stability assays were also investigated. Reductions higher than 3 log10 CFU/mL (p < 0.0001) occurred for crude BGP in single- and dual-species biofilms. Singlet oxygen was produced in BGP (p < 0.0001). BGP-mediated aPDT delayed S. mutans and C. albicans regrowth after 24 h of treatment (p < 0.0001). Both BGP did not change the color of dental materials (p > 0.05). BGP-AF-mediated aPDT showed 72.41% of oral keratinocyte viability (p < 0.0001). BGP extracts may be used in aPDT against S. mutans and C. albicans. Specifically, BGP-AF may represent a promising PS for dental applications.

Efficacy of Antimicrobial Photodynamic Therapy Mediated by Photosensitizers Conjugated with Inorganic Nanoparticles: Systematic Review and Meta-Analysis.

Antimicrobial photodynamic therapy (aPDT) is a method that does not seem to promote antimicrobial resistance. Photosensitizers (PS) conjugated with inorganic nanoparticles for the drug-delivery system have the purpose of enhancing the efficacy of aPDT. The present study was to perform a systematic review and meta-analysis of the efficacy of aPDT mediated by PS conjugated with inorganic nanoparticles. The PubMed, Scopus, Web of Science, Science Direct, Cochrane Library, SciELO, and Lilacs databases were searched. OHAT Rob toll was used to assess the risk of bias. A random effect model with an odds ratio (OR) and effect measure was used. Fourteen articles were able to be included in the present review. The most frequent microorganisms evaluated were Staphylococcus aureus and Escherichia coli, and metallic and silica nanoparticles were the most common drug-delivery systems associated with PS. Articles showed biases related to blinding. Significant results were found in aPDT mediated by PS conjugated with inorganic nanoparticles for overall reduction of microorganism cultured in suspension (OR = 0.19 [0.07; 0.67]/p-value = 0.0019), E. coli (OR = 0.08 [0.01; 0.52]/p-value = 0.0081), and for Gram-negative bacteria (OR = 0.12 [0.02; 0.56/p-value = 0.0071). This association approach significantly improved the efficacy in the reduction of microbial cells. However, additional blinding studies evaluating the efficacy of this therapy over microorganisms cultured in biofilm are required.

Photodynamic therapy for treating infected skin wounds: A systematic review and meta-analysis from randomized clinical trials.

BACKGROUND: Infected skin wounds represent a public health problem that effects 20 million people worldwide. Photodynamic therapy (PDT) is a treatment option with excellent results against several infections. OBJECTIVE: This study aimed to perform a systematic review and meta-analysis on PDT efficacy for treating infected wounds based on randomized clinical trials (RCTs). METHODS: PubMed, Scopus, Web of Science, SciELO, and the Cochrane library were searched. The Delphi List criteria and the Revised Cochrane risk-of-bias (Rob 2) were used for evaluating the quality of clinical trials. Meta-analyses were performed with the random-effect model. The odds ratio was the effect measure for binary outcomes, while the standard mean difference was used for continuous outcomes. The trim-and-fill method was used to detect small-study effects. The quality of evidence was verified for each outcome. RESULTS: Only four out of 573 articles were selected for the qualitative and quantitative analyses. The most frequent cause of infected wounds was impaired venous circulation (75%). All studies used red LED light. PDT reduced healing time and improved the healing process and wound oxygenation. Patients treated with PDT showed 15% to 17% (p = 0.0003/ I2=0%) lower microbial cell viability in the wound and a significantly smaller wound size (0.72 cm2/p = 0.0187/I2=0%) than patients treated with placebo or red-light exposure. There was a high level of evidence for each meta-analysis outcome. CONCLUSION: PDT can be an excellent alternative treatment for infected skin wounds, though larger trials are needed.

A systematic review and meta-analysis of the effect of thymol as an anti-inflammatory and wound healing agent: A review of thymol effect on inflammation and wound healing: A review of thymol effect on inflammation and wound healing.

Thymol (THY) exhibits antibacterial and antioxidant properties. Recent studies have also shown that THY presents anti-inflammatory and healing properties. This review focused on in vitro and in vivo investigations related to THY utilization, as an anti-inflammatory and/or wound healing agent. PubMed, WebOfScience, and Scopus were examined. Independent reviewers conducted all diagram steps. PRISMA was followed for data extraction. RoB 2 and SYRCLE were utilized to assess the risk of bias for in vitro and animal studies. Meta-analysis was performed for in vitro and in vivo articles that investigated THY as an anti-inflammatory agent. Thirty-six and 15 articles were included in the qualitative analysis and meta-analysis, respectively. Studies showed high risk of bias related to sampling, allocation procedures, randomization, and blinding. Even so, for in vitro studies, significant result was observed for IL-2. For in vivo studies, significant results were found for IL-1, IL-17, TNF-α, AST, MPO, and CRP, with higher levels noticed in control groups. THY presents significant properties as anti-inflammatory, ameliorating affections of the digestive system, cardiovascular problems, respiratory system and dermal damages, and burns. Researches are needed to clarify THY dose-response relationship and its mechanism of action, especially in the application of THY as a healing agent.

Efficacy of curcumin-mediated antibacterial photodynamic therapy for oral antisepsis: A systematic review and network meta-analysis of randomized clinical trials.

BACKGROUND: The presence of oral microorganisms resistant to traditional treatment is increasing, thus a search for new therapies is needed. In this context, antimicrobial photodynamic therapy (aPDT) is an approach for the treatment of antibiotic resistant andnon resistant microorganisms. Therefore, the aim of the present study was to conduct a systematic review and meta-analysis of randomized clinical trials of aPDT for oral antisepsis against oral polymicrobial biofilms. METHODS: PubMed, Science Direct, Scopus, SciELO, Lilacs, Cochrane Library and Embase databases were searched. In total, five articles were included for qualitative analysis and four articles were used for quantitative analyses. Bias assessment of the eligible articles was made using the RoB 2 criteria. Network meta-analysis was performed using the random-effect model. Subgroup's analysis was also conducted. The groups evaluated were aPDT, exposure to light only and no treatment at all (control group). The quality of evidence was assessed by CINeMA approach. RESULTS: aPDT mediated by curcumin had significant results in the reducing bacterial load (0.31-0.49 log10 UFC/ I2=0%) when compared with the control group. The included articles were classified as low risk of bias, despite biases detected by allocation and blinding. Moreover, quantitative analysis between aPDT and control group and between light and control group were classified with low risk of confidence rating, while the results from aPDT versus light were classified as moderate risk of confidence rating. CONCLUSION: aPDT has significant efficacy for oral antisepsis, however more randomized clinical trials will be needed to validate the present results.

Effect of the technique of photodynamic therapy against the main microorganisms responsible for periodontitis: A systematic review of in-vitro studies.

OBJECTIVE: The present study aimed to conduct a systematic review of the literature, to evaluate, in vitro, the effectiveness of the technique of photodynamic therapy against microorganisms associated with periodontal disease. DESIGN: This systematic review was carried out in accordance with the items on the PRISMA checklist and Cochrane guidelines. Only in vitro studies that evaluated the effect of the technique of antimicrobial photodynamic therapy on periodontopathogenic microorganisms were included. RESULTS: A total of 32 articles published between 2000 and 2021 were included for qualitative analysis. For microorganisms in suspension, 25 studies (78.12%) showed a reduction greater than or equal to 3 logs CFU/mL of species associated with periodontal disease. In biofilms, three studies (42.7%) showed a reduction greater than or equal to 3 logs CFU/mL. CONCLUSIONS: The results showed that the technique of photodynamic therapy may be a promising alternative to conventional antimicrobial approaches for reducing bacteria closely associated with periodontal disease. Some parameters (pre-irradiation time, type of photosensitizer, standardization of light parameters) need to be better established before conducting clinical studies.

Photodynamic therapy associated with nanomedicine strategies for treatment of human squamous cell carcinoma: A systematic review and meta-analysis.

A systematic review and meta-analysis were conducted about photodynamic therapy (PDT) associated with nanomedicine approaches in the treatment of human squamous cell carcinoma (HSSC). Independent reviewers conducted all steps in the systematic review. For evaluating the risk of bias, RoB 2, OHAT and SYRCLE tools were used. Meta-analysis was performed using a random-effect model (α = 0.05). For PDT against HSSC, Protoporphyrin IX was the photosensitizer, and liposomes were the nanomaterial more frequently used. Photosensitizers conjugated with nanoparticles exhibited positive results against HSSC. Tumors treated with PDT in combination with a nanotechnology drug-delivery system had an increased capacity for inhibiting the tumor growth rate (51.93%/P < 0.0001) when compared with PDT only. Thus, the PDT associated with nanomedicine approaches against HSCC could be a significant option for use in future clinical studies, particularly due to improved results in tumor growth inhibition.

Photobiomodulation in the treatment of xerostomia associated with hyposalivation in a pediatric patient with systemic scleroderma.

Scleroderma is a rare autoimmune disease characterized by excessive collagen production. The oral manifestations of the patient with scleroderma can include microstomia, xerostomia, and changes in the resorption teeth. We report the case of a 7-year-old female patient diagnosed with systemic scleroderma where photobiomodulation therapy was used to treat xerostomia associated with hyposalivation. She attended a pediatric clinic and presented with dry and rigid facial skin, trismus, xerostomia, malocclusion, and difficulty swallowing. Stimulated salivary flow was assessed before, during, and after treatment. Photobiomodulation therapy was conducted at four points at the sublingual glands with 660 nm, 100 mW, and 0.8 J/cm2 to each point; eight points at the parotid glands; and six points at the submandibular glands with 808 nm, 100 mW, and 0.8 J/cm2 for 8 seconds at each point. After this therapy, an increase in salivary flow, remission of the xerostomia, and an improvement in mastication and swallowing were observed. Photobiomodulation therapy was effective in controlling xerostomia in this pediatric patient, resulting in increased salivary flow and an improvement in her quality of life.

A systematic review and meta-analysis of the effect of photodynamic therapy for the treatment of oral mucositis.

BACKGROUND: Oral mucositis is a significant reaction to antineoplastic treatment characterized with pain, nutritional compromise, impact on the quality of life, interruption in cancer therapy and risk for infection. There is no effective standard protocol for the treatment of oral mucositis. This study aims to synthesize the scientific evidence available about the effects of photodynamic therapy on treatment of oral mucositis. METHODS: PubMed, Scopus, Web of Science, Science Direct, Scielo, Embase and Cochrane libraries were searched. Two independent and calibrated researchers (kappa = 0.92) performed all systematic steps according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). To access the risk of bias, RoB 2 and Delphi list criteria for clinical trials were used. Meta-analysis was conducted using the R software with "META" package. RESULTS: Clinical and randomized clinical trials were included with a total of five articles. Meta-analysis, level of evidence, and risk of bias assessment were performed showing that photodynamic therapy was effective in reducing healing time in association with low-power laser therapy when compared to low-power laser therapy alone (p = 0.0005). CONCLUSION: Photodynamic therapy presents promising results for the treatment of oral mucositis. It may be an effective therapeutic option, contributing to the healing of injured tissues especially in the time needed for repair.

The role of CD68+ and CD163+ macrophages in immunopathogenesis of oral lichen planus and oral lichenoid lesions.

Macrophages are phagocytic cells with essential participation in immunological events of the oral cavity. However, the role of these cells in oral lichen planus (OLP) and oral lichenoid lesions (OLL) remains unclear. The present study aimed to evaluate the density of macrophages in OLP and OLL, and to compare it with that of oral inflammatory fibrous hyperplasia (OIFH) (control group). 14 cases of OLP, 14 cases of OLL and 14 cases of OIFH were selected for immunohistochemical analysis of CD68+ (M1) and CD163+ (M2) macrophage expression. CD68+ and CD163+ macrophages densities were measured in the intraepithelial and subepithelial areas. The statistical tests used were multivariate analysis of variance, as well as a correlation and linear regression. OLP has more CD68+ macrophages when comparing with OLL (p = 0.001) and OIFH (p = 0.045). There is a very strong relationship between the macrophages types (p < 0.0001) in OLP and OLL. The linear regression showed that to OLL development (p < 0.0001/R2' = 0.9584), the presence of different types of macrophages are more essential than to OLP (p < 0.0001/R2' = 0.8983). However, in the OLP these dependencies are also largely. CD68+ macrophages may be associated with immunopathogenesis of OLP, indicating a pro-inflammatory activity and regulatory role in the type of T-cell response. Besides, CD68+ macrophages can cooperate in the diagnosis of OLP. These results are essential to future studies that seek a therapeutic target for OLP and OLL.

COVID-19 (SARS-CoV-2) infection and thrombotic conditions: A systematic review and meta-analysis.

BACKGROUND: COVID-19 is an infectious disease caused by SARS-CoV-2 associated with haematological manifestations (thrombolytic events). AIMS: Considering the high prevalence of the thrombotic scenarios associated with COVID-19, the aim of this study was to perform a systematic review of the available literature, concerning the relation of COVID-19 and the thrombotic events, and identify prognostic factors for these events. MATERIALS & METHODS: PubMed, Web of Science and Scopus databases were searched. Independent reviewers conducted all flow diagram steps. For qualitative analysis, Oxford level of evidence and Newcastle-Ottawa scale were used in the eligible articles. For the prognostic factors, a meta-analysis was conducted to age, number of neutrophils and platelets, and levels of ferritin, C-reactive protein, lactate dehydrogenase and D-dimer. Publication bias was accessed by funnel plot and by trim-and-fill test. Trim-and-fill test was also applied to evaluate meta-analysis bias. RESULTS: Twenty articles were included in the qualitative analysis, and 6 articles were included in the meta-analysis. Case-control studies showed bias related to exposure, and the main bias in cohort studies were related to selection and outcome. All articles received score 4 for the level of evidence. Hypertension and diabetes were the comorbidities more frequently associated with thrombolytic events. Significant results were found regarding D-dimer (P < .0001) and age (P = .0202) for thrombotic events in patients diagnosed with COVID-19. CONCLUSION: Patients older than 60 years, with hypertension, diabetes and D-Dimer values above 3.17 µg/mL, can be considered prognostic factors for developing thrombotic events due to COVID-19.

Immunohistochemical evaluation of Langerhans cells in oral lichen planus and oral lichenoid lesions.

OBJECTIVE: the aim of this study was to evaluate the density of Langerhans cells in oral lichen planus (OLP) and oral lichenoid lesions (OLL). DESIGN: 14 cases of OLP, 15 cases of OLL and 14 cases of oral inflammatory fibrous hyperplasia (OIFH), were selected for immunohistochemical analysis of CD1a, CD207 and S100 expression. The OIFH group was subdivided according to the presence (OIFHL n = 14) or absence (OIFHNL n = 14) of lichenoid inflammatory infiltrate. Positive cells were counted in intraepithelial and subepithelial areas. Results were analyzed by multivariate comparative analysis, correlation analysis, linear regression models and Student's T-test. RESULTS: A significantly higher amount of CD207+ cells in OLL vs OLP was observed (p = 0.015). The prevailing reticular pattern observed was CD207high for OLP (p = 0.0329). A statistically significant difference in the expression of CD1a and CD207 was observed for intraepithelial vs subepithelial areas (p = 0.024 and p=0.015, for CD1a and CD207, respectively). Significant correlations were also observed between the expression of CD1a + and CD207+ cells in the pathogenesis of OLP and OLL. CONCLUSION: High levels of CD207+cells in OLP compared with OLL may help explain the differences in the immunopathogenesis of both diseases. Additionally, CD1a + and CD207+ cells appear to be more essential to immunopathogenesis of OLL than to the pathogenesis of OLP.

Effect of arginine on microorganisms involved in dental caries: a systematic literature review of in vitro studies.

This systematic review aimed to discuss the effects of arginine on caries-related microorganisms in different in vitro biofilm models. The eligibility criteria were in vitro studies that evaluated the effect of arginine at different concentrations on caries-related microorganisms using biofilm models. Eighteen studies published between 2012 and 2019 were included. Different bacterial species were studied. Seventeen studies (94.4%) achieved a low risk of bias and only one showed a medium risk of bias. The studies showed that arginine is a promising approach for the ecological management of dental caries. The focus of this review was to evaluate the effects of arginine on microorganisms involved in the mechanism of dental caries.

Effect of Photodynamic Therapy on Microorganisms Responsible for Dental Caries: A Systematic Review and Meta-Analysis.

The aim of this study was to perform a systematic review of the literature followed by a meta-analysis about the efficacy of photodynamic therapy (PDT) on the microorganisms responsible for dental caries. The research question and the keywords were constructed according to the PICO strategy. The article search was done in Embase, Lilacs, Scielo, Medline, Scopus, Cochrane Library, Web of Science, Science Direct, and Pubmed databases. Randomized clinical trials and in vitro studies were selected in the review. The study was conducted according the PRISMA guideline for systematic review. A total of 34 articles were included in the qualitative analysis and four articles were divided into two subgroups to perform the meta-analysis. Few studies have achieved an effective microbial reduction in microorganisms associated with the pathogenesis of dental caries. The results highlight that there is no consensus about the study protocols for PDT against cariogenic microorganisms, although the results showed the PDT could be a good alternative for the treatment of dental caries.

Screening of plants with antimicrobial activity against enterobacteria, Pseudomonas spp. and Staphylococcus spp.

AIM: This study screened plants for antibacterial properties against bacteria of medical importance. MATERIALS & METHODS: 60 extracts were obtained from the leaves of ten plants (Jatropha weddelliana, Attalea phalerata, Buchenavia tomentosa, Croton doctoris, Mouriri elliptica, Mascagnia benthamiana, Senna aculeata, Unonopis guatterioides, Allagoptera leucocalyx and Bactris glaucescens) using different extraction methods: A) Ethanol 70°C/72 h; B) Water/5 min/100°C; C) Water/1 h/55°C; D) Water/72 h; E) Hexane/72 h and F) Ethanol 99°C/72 h. Enterobacteria/Pseudomonas and staphylococci reference strains and 201 clinical isolates were used. Primary screening was done using agar well-diffusion assay. MIC/minimum bactericidal concentration and chemical characterization were determined. RESULTS: Extracts 5F and 3A showed the best MIC/minimum bactericidal concentration against clinical isolates and showed the presence of phenols. CONCLUSION: The present study demonstrated that Mouriri elliptica and Buchenavia tomentosa were the most active plants against the studied bacteria.