New insights about the antidepressant-like effects of riparin A in a chronic murine model of depression.

Riparin A is a synthetic form of natural riparins. Acute scale studies that take into consideration the structure-activity relationship have shown preliminary evidence of antidepressant and anxiolytic effects of riparin A, similar to that already known for other riparins. However, for better pharmacological characterization of this new compound, further studies are required. The aim of this work was to evaluate the effect of chronic treatment with riparin A (10 mg/kg; intraperitoneally) on depressive-like behavior in the forced swimming test and tail suspension test, as well as the reduction of anhedonia in the sucrose preference test, and on anxiety-like behavior in the open field and elevated plus maze apparatus, triggered in rats previously subjected to unpredictable chronic mild stress by 4 weeks. In addition, a pentobarbital-induced sleep time test was also used. Riparin A reduced the duration of immobility in both the forced swimming test and tail suspension test, as well as attenuated the anhedonia in the sucrose preference test. Furthermore, riparin A appears to produce anxiolytic effects in rats exposed to an open field and elevated plus maze, while increasing the alertness/vigilance in rats submitted to pentobarbital-induced sleep time test, without altering their locomotor integrity. Our results suggest that chronic riparin A appears to be a potential pharmacological target for new studies on the control of depression- and anxiety-like behaviors in stressed rats.

Exploring CDKN1A Upregulation Mechanisms: Insights into Cell Cycle Arrest Induced by NC2603 Curcumin Analog in MCF-7 Breast Cancer Cells.

Breast cancer stands out as one of the most prevalent malignancies worldwide, necessitating a nuanced understanding of its molecular underpinnings for effective treatment. Hormone receptors in breast cancer cells substantially influence treatment strategies, dictating therapeutic approaches in clinical settings, serving as a guide for drug development, and aiming to enhance treatment specificity and efficacy. Natural compounds, such as curcumin, offer a diverse array of chemical structures with promising therapeutic potential. Despite curcumin's benefits, challenges like poor solubility and rapid metabolism have spurred the exploration of analogs. Here, we evaluated the efficacy of the curcumin analog NC2603 to induce cell cycle arrest in MCF-7 breast cancer cells and explored its molecular mechanisms. Our findings reveal potent inhibition of cell viability (IC50 = 5.6 µM) and greater specificity than doxorubicin toward MCF-7 vs. non-cancer HaCaT cells. Transcriptome analysis identified 12,055 modulated genes, most notably upregulation of GADD45A and downregulation of ESR1, implicating CDKN1A-mediated regulation of proliferation and cell cycle genes. We hypothesize that the curcumin analog by inducing GADD45A expression and repressing ESR1, triggers the expression of CDKN1A, which in turn downregulates the expression of many important genes of proliferation and the cell cycle. These insights advance our understanding of curcumin analogs' therapeutic potential, highlighting not just their role in treatment, but also the molecular pathways involved in their activity toward breast cancer cells.

Prevalence of errors causing events allegedly attributable to vaccination/immunization: systematic review and meta-analysis.

OBJECTIVE: To identify the prevalence of errors that caused events supposedly attributable to vaccination or immunization. METHOD: Systematic literature review with meta-analysis carried out on the Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; and Grey Lit databases; with studies that presented the prevalence of immunization errors that caused events or that provided data that allowed this indicator to be calculated. RESULTS: We evaluated 11 articles published between 2010 and 2021, indicating a prevalence of 0.044 errors per 10,000 doses administered (n=762; CI95%: 0.026 - 0.075; I2 = 99%, p < 0.01). The prevalence was higher in children under 5 (0.334 / 10,000 doses; n=14). The predominant events were fever, local pain, edema and redness. CONCLUSION: A low prevalence of errors causing events was identified. However, events supposedly attributable to vaccination or immunization can contribute to vaccine hesitancy and, consequently, have an impact on vaccination coverage.

The Transcriptome of BT-20 Breast Cancer Cells Exposed to Curcumin Analog NC2603 Reveals a Relationship between EGR3 Gene Modulation and Cell Migration Inhibition.

Breast cancer represents a critical global health issue, accounting for a substantial portion of cancer-related deaths worldwide. Metastasis, the spread of cancer cells to distant organs, is the primary cause of approximately 90% of breast cancer-related fatalities. Despite advances in cancer treatment, conventional chemotherapeutic drugs often encounter resistance and demonstrate limited efficacy against metastasis. Natural products have emerged as promising sources for innovative cancer therapies, with curcumin being one such example. However, despite its therapeutic potential, curcumin exhibits several limitations. Analogous compounds possessing enhanced bioavailability, potency, or specificity offer a promising avenue for overcoming these challenges and demonstrate potent anti-tumor activities. Our study investigates the antimetastatic potential of the curcumin analog NC2603 in breast cancer cells, utilizing BT-20 cells known for their migratory properties. Cell viability assessments were performed using the MTT reduction method, while migration inhibition was evaluated through scratch and Transwell migration assays. Transcriptome analysis via next-generation sequencing was employed to elucidate gene modulation and compound mechanisms, with subsequent validation using RT-qPCR. The IC50 of NC2603 was determined to be 3.5 µM, indicating potent inhibition of cell viability, and it exhibited greater specificity for BT-20 cells compared with non-cancerous HaCaT cells, surpassing the efficacy of doxorubicin. Notably, NC2603 demonstrated superior inhibition of cell migration in both scratch and Transwell assays compared with curcumin. Transcriptome analysis identified 10,620 modulated genes. We validated the expression of six: EGR3, ATF3, EMP1, SOCS3, ZFP36, and GADD45B, due to their association with migration inhibition properties. We hypothesize that the curcumin analog induces EGR3 expression, which subsequently triggers the expression of ATF3, EMP1, SOCS3, ZFP36, and GADD45B. In summary, this study significantly advances our comprehension of the intricate molecular pathways involved in cancer metastasis, while also examining the mechanisms of analog NC2603 and underscoring its considerable potential as a promising candidate for adjuvant therapy.

Prevalence of errors causing events allegedly attributable to vaccination/immunization: systematic review and meta-analysis / Prevalencia de errores causantes de acontecimientos supuestamente atribuibles a la vacunación/inmunización: revisión sistemática y metanálisis / Prevalência de erros que causaram eventos supostamente atribuíveis à vacinação/imunização: revisão sistemática e metanálise

ABSTRACT Objective: To identify the prevalence of errors that caused events supposedly attributable to vaccination or immunization. Method: Systematic literature review with meta-analysis carried out on the Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; and Grey Lit databases; with studies that presented the prevalence of immunization errors that caused events or that provided data that allowed this indicator to be calculated. Results: We evaluated 11 articles published between 2010 and 2021, indicating a prevalence of 0.044 errors per 10,000 doses administered (n=762; CI95%: 0.026 - 0.075; I2 = 99%, p < 0.01). The prevalence was higher in children under 5 (0.334 / 10,000 doses; n=14). The predominant events were fever, local pain, edema and redness. Conclusion: A low prevalence of errors causing events was identified. However, events supposedly attributable to vaccination or immunization can contribute to vaccine hesitancy and, consequently, have an impact on vaccination coverage.

RESUMEN Objetivo: Identificar la prevalencia de errores que causaron eventos supuestamente atribuibles a la vacunación o inmunización. Método: Revisión sistemática de la literatura con metaanálisis realizada en las bases de datos Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; y Grey Lit; con estudios que presentaran la prevalencia de errores de inmunización que causaron eventos o que aportaran datos que permitieran calcular este indicador. Resultados: Se evaluaron 11 artículos publicados entre 2010 y 2021, indicando una prevalencia de 0,044 errores por cada 10.000 dosis administradas (n=762; IC95%: 0,026 - 0,075; I2 = 99%, p < 0,01). La prevalencia fue mayor en niños menores de 5 años (0,334 / 10.000 dosis; n=14). Los eventos predominantes fueron fiebre, dolor local, edema y enrojecimiento. Conclusión: Se identificó una baja prevalencia de eventos causantes de errores. Sin embargo, los eventos supuestamente atribuibles a la vacunación o inmunización pueden contribuir a la indecisión sobre la vacunación y, en consecuencia, repercutir en la cobertura vacunal.

RESUMO Objetivo: Identificar a prevalência de erros que causaram eventos supostamente atribuíveis à vacinação ou imunização. Método: Revisão sistemática da literatura com metanálise realizada nas bases Medline, Cochrane Library, Cinahl, Web of Science, Lilacs, Scopus; Embase; Open Grey; Google Scholar; e Grey Lit; com estudos que apresentassem prevalência de erros de imunização que causaram eventos ou que disponibilizassem dados que permitissem o cálculo deste indicador. Resultados: Avaliou-se 11 artigos publicados entre 2010 e 2021, apontando prevalência de 0,044 erros por 10.000 doses administradas (n=762; IC95%: 0,026 - 0,075; I2= 99%, p < 0,01). A prevalência foi maior em crianças menores de 5 anos (0,334 / 10.000 doses; n=14). Quanto aos eventos, predominou-se: febre, dor local, edema, rubor. Conclusão: Identificou-se uma prevalência baixa de erros que causaram eventos. Entretanto, os eventos supostamente atribuíveis à vacinação ou imunização podem contribuir para a hesitação vacinal e, consequentemente, impactar nas coberturas vacinais.

The Potential of Films as Transmucosal Drug Delivery Systems.

Pharmaceutical films are polymeric formulations used as a delivery platform for administration of small and macromolecular drugs for local or systemic action. They can be produced by using synthetic, semi-synthetic, or natural polymers through solvent casting, electrospinning, hot-melt extrusion, and 3D printing methods, and depending on the components and the manufacturing methods used, the films allow the modulation of drug release. Moreover, they have advantages that have drawn interest in the development and evaluation of film application on the buccal, nasal, vaginal, and ocular mucosa. This review aims to provide an overview of and critically discuss the use of films as transmucosal drug delivery systems. For this, aspects such as the composition of these formulations, the theories of mucoadhesion, and the methods of production were deeply considered, and an analysis of the main transmucosal pathways for which there are examples of developed films was conducted. All of this allowed us to point out the most relevant characteristics and opportunities that deserve to be taken into account in the use of films as transmucosal drug delivery systems.

Transcriptome Analysis of Co-Cultures of THP-1 Human Macrophages with Inactivated Germinated Trichophyton rubrum Conidia.

Although most mycoses are superficial, the dermatophyte Trichophyton rubrum can cause systemic infections in patients with a weakened immune system, resulting in serious and deep lesions. The aim of this study was to analyze the transcriptome of a human monocyte/macrophage cell line (THP-1) co-cultured with inactivated germinated T. rubrum conidia (IGC) in order to characterize deep infection. Analysis of macrophage viability by lactate dehydrogenase quantification showed the activation of the immune system after 24 h of contact with live germinated T. rubrum conidia (LGC). After standardization of the co-culture conditions, the release of the interleukins TNF-α, IL-8, and IL-12 was quantified. The greater release of IL-12 was observed during co-culturing of THP-1 with IGC, while there was no change in the other cytokines. Next-generation sequencing of the response to T. rubrum IGC identified the modulation of 83 genes; of these, 65 were induced and 18 were repressed. The categorization of the modulated genes showed their involvement in signal transduction, cell communication, and immune response pathways. In total, 16 genes were selected for validation and Pearson's correlation coefficient was 0.98, indicating a high correlation between RNA-seq and qPCR. Modulation of the expression of all genes was similar for LGC and IGC co-culture; however, the fold-change values were higher for LGC. Due to the high expression of the IL-32 gene in RNA-seq, we quantified this interleukin and observed an increased release in co-culture with T. rubrum. In conclusion, the macrophages-T. rubrum co-culture model revealed the ability of these cells to modulate the immune response, as demonstrated by the release of proinflammatory cytokines and the RNA-seq gene expression profile. The results obtained permit to identify possible molecular targets that are modulated in macrophages and that could be explored in antifungal therapies involving the activation of the immune system.

Silencing of the GluN1-NMDA Glutamate Receptor Subunit by Intranasal siRNA Increases the Latency Time for Seizures in the Pilocarpine Rodent Model of Epilepsy.

Temporal lobe epilepsy (TLE) is the most prevalent and treatment-refractory type of epilepsy. Among the different mechanisms associated with epileptogenesis, overstimulation of glutamatergic neurotransmission has been associated with the onset and progression of seizures in TLE. Experimental evidence indicates that blocking the N-methyl-D-aspartate (NMDA) receptor or suppressing the expression of its subunit, mainly GluN1, may be effective in preventing epileptic seizures. Small interfering RNA (siRNA) has received attention as a potential therapeutic tool due to the inhibition of gene expression in some diseases. The present work evaluated the potential silencing effect of intranasal administration of an siRNA conjugate against the GluN1 subunit in animals submitted to the pilocarpine model of epilepsy. The results showed that the siRNA conjugate transfection system silences the GluN1 subunit in the hippocampus of rats when administered intranasally. As demonstrated by the RT-qPCR and Western blotting approaches, the silencing of GluN1 was specific for this subunit without affecting the amount of mRNA for other subunits. Silencing increased the latency time for the first tonic-clonic seizure when compared to controls. The overlapping of findings and the validation of the intranasal route as a pharmacological route of siRNA targeting the GluN1 subunit give the work a significant biotechnological interest.

Targeting C5aR1 signaling reduced neutrophil extracellular traps and ameliorates COVID-19 pathology

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions, and plays immunopathological roles in inflammatory diseases, we investigated whether C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill COVID-19 patients compared to patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular trap (NET)s-dependent immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonist of C5aR1 could be useful for COVID-19 treatment.

CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19

Infection with SARS-CoV-2 induces COVID-19, an inflammatory disease that is usually self-limited, but depending on patient conditions may culminate with critical illness and patient death. The virus triggers activation of intracellular sensors, such as the NLRP3 inflammasome, which promotes inflammation and aggravates the disease. Thus, identification of host components associated with NLRP3 inflammasome is key for understanding the physiopathology of the disease. Here, we reported that SARS-CoV-2 induces upregulation and activation of human Caspase-4/CASP4 (mouse Caspase-11/CASP11) and this process contributes to inflammasome activation in response to SARS-CoV-2. CASP4 was expressed in lung autopsy of lethal cases of COVID-19 and CASP4 expression correlates with expression of inflammasome components and inflammatory mediators such as CASP1, IL1B, IL18 and IL6. In vivo infections performed in transgenic hACE2 humanized mouse, deficient or sufficient for Casp11, indicate that hACE2 Casp11-/- mice were protected from disease development, with reduced body weight loss, reduced temperature variation, increased pulmonary parenchymal area, reduced clinical score of the disease and reduced mortality. Collectively, our data establishes that CASP4/11 contributes to disease pathology and contributes for future immunomodulatory therapeutic interventions to COVID-19.

Redox Profiling of Selected Apulian Red Wines in a Single Minute.

Wine is a complex bioproduct whose chemical composition is highly variable across production regions. In order to shed light on affordable ways to promote the characterization of wines and explore the physicochemical basis of their antioxidant capacity, this work reported on the quick and easy redox profiling of selected red wines from Apulia, Italy. Therefore, an affordable and quickly performed semiempirical quantum chemistry approach, i.e., the extended Hückel method, was used to compute the bandgaps of the main phytochemical markers attributed to red wines. The findings of these calculations were then compared to an electroanalytical investigation in the form of cyclic and square-wave voltammetry, and the electric current of the redox profiles was used as the input dataset for principal component analysis. Results showcased that the semiempirical quantum chemistry calculations allowed the correlation of the bandgaps to the observed faradaic signals upon voltammetry; thereby, also providing insights on their antioxidant appeal by highlighting the feasibility of charge-transfer processes at low electric potentials. Furthermore, the principal component analysis showed that the electric current dataset gathered in a time span of 55 s allowed the appropriate separation of the samples, which hints at the possible use of quick voltammetric assays as fingerprinting tools.

Spray-drying of casein/pectin bioconjugate microcapsules containing grape (Vitis labrusca) by-product extract.

Novel microcapsules containing grape peel by-product extract were obtained. In this pursuit, complex coacervation of casein/pectin bioconjugate and spray-drying were combined. We have investigated the role of the dispersion feed rate (FR), drying air inlet temperature (IT) and drying air flow rate (AR) in the drying yield, microencapsulation efficiency, total polyphenols and anthocyanins contents, antioxidant activity, and morphology of the products. Also, the first-order degradation kinetics of the phytochemicals for both the extract and dried microcapsules was assessed and compared. The loss on the phytochemicals during spray-drying was attenuated in up to 88%, and the IT was the main factor affecting the particle properties. The polyphenols on the extract interacted with the polymers, influencing the assemble of the bioconjugate and the particle's features. Such microencapsulation strategy enhanced the thermal stability of the phytochemicals and rendered biocompatible and biodegradable products of which the nutraceutical and cosmeceutical application may have potential.

Needle-free anesthesia: clinical efficacy of a mucoadhesive patch for atraumatic anesthesia in dental procedures.

This study showcases the clinical efficacy of mucoadhesive patches designed for the buccal delivery of lidocaine and prilocaine hydrochlorides (1:1, 30 mg/patch). Such patches were developed for needle-free pre-operative local anesthesia in dentistry, aiming at mitigating the use of infiltrative anesthesia for medium-complexity clinical procedures. The patches were manufactured encompassing drug-release, mucoadhesive and backing layers, all prepared through film casting using biocompatible materials. Fifty-eight (n = 58) adult patients (65% women and 35% men) were randomly selected and included in a one-arm open clinical prospective cohort study. The average age of the subjects was of 50 years. The majority (59%) of the subjects, mostly women (82%), reported needle-phobia or anxiety due to dental procedures, which was assessed through a questionnaire approved by the ethical council for human use in research. The patches were positioned in the gingival region of the teeth involved in the procedure (86% on the maxillary and 14% on the mandibular bone). Two anesthetic patches were applied on each patient: one in the vestibular region and another in the palate/lingual portion, and these patches remained attached to the placement sites throughout the procedures. Concerning the dental procedures performed, 40% were cavity preparations and dental restorations of medium cavities; 29% staple facilities; 10% gingival retractions; 9% subgingival scrapings; 3% gingivalplasties; 3% supragingival preparations; 3% occlusal adjustments; and 2% subgingival preparations. In 90% of the cases, it was not necessary to complement with conventional infiltrative local anesthesia during the procedures. Patients did not report any discomfort or side effect during or after the administration of the patches. Among the cases in which there was the need for complementation, 50% were cavity preparations and dental restorations; 33% supragingival preparations; and 17% gingivoplasties. The complementary anesthesia volume was of 0.63 ± 0.23 mL and women corresponded to 83% of the participants who needed such intervention. Furthermore, in most cases, the patch was capable of initiating the anesthesia within a short time frame (5 minutes) and reaching the maximum anesthetic effect within 15 and 25 min, lasting at least 50 min. Undesirable side effects were not reported either 2 h after the administration or within the 6-month follow-up. Therefore, the anesthetic patches developed provide needle-free, painless, safe, and patient/dentist-friendly advances in performing routine medium-complexity dental procedures.

Antidepressant activity of Riparin A in murine model.

Depression and anxiety are common neuropsychiatric disorders that usually appear as comorbidities. The development of new drugs is crucial for safer and more effective clinical management of both disorders. Riparin A is a synthetic chemical analog of riparins that naturally occur in several medicinal plants. Marked pharmacological effects such as anxiolytic and antidepressant properties characterize this class of compounds. However, little is known about the potential anxiolytic and antidepressant effects of Riparin A. In this work, we showed that, unlike other riparins, Riparin A exerts only a very mild anxiolytic-like effect as demonstrated by the results of classical behavioral tests such as the elevated plus-maze, light-dark box and open-field tests in rats. However, all doses of Riparin A (2.5; 5.0 and 10 mg/kg; intraperitoneal) have shown significant antidepressant activity in rats submitted to forced swimming test. In addition to this interesting pharmacological property, Riparin A did not promote any important alterations in the locomotor performance of the animals as specifically demonstrated by the rotarod test. Furthermore, Riparin A did not induce sedation in treated animals; instead, this compound appears to increase the animal's state of alertness as measured by the latency time to loss of reflexes and time to recovery from sleep in rats submitted to the pentobarbital-induced sleep time test. The present results point to an antidepressant effect of Riparin A and reinforce the pharmaceutical interest in the group of riparins, particularly their high potential for use in new studies investigating the structure-activity relationships between member compounds.

COVID-19 Bimodal Clinical and Pathological Phenotypes

BackgroundPatients with coronavirus disease-2019 (COVID-19) present varying clinical complications. Different viral load and host response related to genetic and immune background are probably the reasons for these differences. We aimed to sought clinical and pathological correlation that justifies the different clinical outcomes among COVID-19 autopsies cases. MethodsMinimally invasive autopsy was performed on forty-seven confirmed COVID-19 patients from May-July, 2020. Electronic medical record of all patients was collected and a comprehensive histopathological evaluation was performed. Immunohistochemistry, immunofluorescence, special stain, western blotting and post-mortem real-time reverse transcriptase polymerase chain reaction on fresh lung tissue were performed. ResultsWe show that 5/47 (10,6%) patients present a progressive decline in oxygenation index for acute respiratory distress syndrome (PaO2/FiO2 ratio), low compliance levels, interstitial fibrosis, high -SMA+ cells/protein expression, high collagens I/III deposition and NETs(P<0.05), named as fibrotic phenotype (N=5). Conversely, 10/47 (21,2%) patients demonstrated progressive increase in PaO2/FiO2 ratio, high pulmonary compliance levels, preserved elastic framework, increase thrombus formation and high platelets and D-dimer levels at admission (P<0.05), named as thrombotic phenotype. While 32/47 (68,1%) had a mixed phenotypes between both ones. ConclusionsWe believe that categorization of patients based on these two phenotypes can be used to develop prognostic tools and potential therapies since the PaO2/FiO2 ratio variation and D-dimer levels correlate with the underlying fibrotic or thrombotic pathologic process, respectively; which may indicate possible clinical outcome of the patient.

Towards the advance of a novel iontophoretic patch for needle-free buccal anesthesia.

The aim of this work was to develop a mucoadhesive iontophoretic patch for anesthetic delivery in the buccal epithelium. The patch was comprised of three different layers, namely i) drug release (0.64 cm2); ii) mucoadhesive (1.13 cm2); and iii) backing (1.13 cm2). Prilocaine and lidocaine hydrochlorides were used as model drugs (1:1 ratio, 12.5 mg per unit). An anode electrode (0.5 cm2 spiral silver wire) was placed in between the drug release and mucoadhesive/backing layers to enable iontophoresis. Surface microscopy; mechanical and in vitro mucoadhesive properties; drug release kinetics and mechanism; and drug permeation through the porcine esophageal epithelium were assessed. Topographic analysis evidenced differences in the physical structures for the several layers. All layers presented suitable handling properties i.e., flexibility, elasticity and resistance. Both the release and mucoadhesive layers presented features of a soft and tough material, while the backing layer matched the characteristics of a hard and brittle material. A synergy between the drug release and mucoadhesive layers on the mucoadhesive force and work of adhesion of the tri-layered patch was observed. Passive drug release of both drugs fitted to First-order, Hixson-Crowell and Weibull kinetic models; and the release mechanism was attributed to anomalous transport. Iontophoresis remarkably enhanced the permeation of both drugs, but mainly prilocaine through the mucosa as evidenced by the permeability coefficient parameter (3.0-fold). The amount of these amino amide salts retained in the mucosa were also equally enhanced (4.7-fold), while the application of a tiny constant electric current (1 mA·cm-2·h-1) significantly decreased the lag time for lidocaine permeation by about 45%. In view of possible in vitro / in vivo correlations, the buccal iontophoretic patch displays a promising strategy for needle-free and patient-friendly local anesthesia in dentistry.

Can parabens be added to cosmetics without posing a risk to human health? A systematic review of its toxic effects Pode adicionar parabenos a cosméticos sem risco para a saúde humana? Uma revisão sistemática de seus efeitos tóxicos

Objective: To summarize evidence regarding the toxic potential of administering parabenscontaining cosmetics in humans. Methods: The systematic review followed the methodology proposed in Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA). Electronic searches of the PubMed, Virtual Health Library (BVS), and Science Direct databases were performed between October 1st and 31st, 2018. No language restriction was determined. Original articles reporting observational, in vitro and in silico studies of toxicity caused by parabens in human or human cells were considered for eligibility. Two independent reviewers performed data extraction and assessed the methodological quality and risk of bias of articles by using the Downs & Black Scale. Score levels greater than 70% were assumed to reflect good methodological quality. The Kappa coefficient was calculated. Results: A total of 254 studies were found. Following the eligibility evaluation, 22 studies were included for the qualitative synthesis. The concordance between the reviewers was substantial (Kappa coefficient = 0.650). The meaningful reported outcomes were: high concentrations of parabens in the body; apoptosis damage to sperm DNA; oxidative stress; DNA damage; irritative potential; interference in the control of adipogenesis; estrogenic activity; genotoxicity; necrosis; role in carcinogenesis of breast cancer; harmful effects on human skin when exposed to the sun; stimulation of oncogenes expression; and interference with DNA transcription. Despite most included articles presenting appreciable methodological quality, remarkable limitations were observed and the mechanisms by which parabens exert toxicity on humans remained unclear. Conclusions: The accumulation of parabens in the human organism following repeated cosmetics administration on the skin is noteworthy. However overall, the evidence so far does not make it possible to determine whether, and in what extent, the use of paraben-containing cosmetics can disturb human health. Further investigations are still required for clarifying these issues.

Antifungal efficacy of atorvastatin-containing emulgel in the treatment of oral and vulvovaginal candidiasis.

Drug repositioning has been an important ally in the search for new antifungal drugs. Statins are drugs that act to prevent sterol synthesis in both humans and fungi and for this reason they are promissory candidates to be repositioned to treat mycoses. In this study we evaluated the antifungal activity of atorvastatin by in vitro tests to determine the minimum inhibitory concentration against azole resistant Candida albicans and its mechanisms of action. Moreover, the efficacy of both atorvastatin-loaded oral and vaginal emulgels (0.75%, 1.5% and 3% w/w) was evaluated by means of in vivo experimental models of oral and vulvovaginal candidiasis, respectively. The results showed that atorvastatin minimal inhibitory concentration against C. albicans was 31.25 µg/ml. In oral candidiasis experiments, the group treated with oral emulgel containing 3.0% atorvastatin showcased total reduction in fungal load after nine days of treatment. Intravaginal delivery atorvastatin emulgel showed considerable effectiveness at the concentration of 3% (65% of fungal burden reduction) after nine days of treatment. From these findings, it is possible to assert that atorvastatin may be promising for drug repositioning towards the treatment of these opportunistic mycoses.

Atorvastatin is a statin drug that presents antifungal activity. This study showed that atorvastatin-containing oral and vaginal emulgels were able to treat vulvovaginal and oral candidiasis of infected animal model. Therefore, we showcased that atorvastatin may be a possible therapeutic agent in order to be a used to control opportunistic mucosal fungal infections caused by Candida albicans.

Cellular and Molecular Response of Macrophages THP-1 during Co-Culture with Inactive Trichophyton rubrum Conidia.

Trichophyton rubrum is causing an increasing number of invasive infections, especially in immunocompromised and diabetic patients. The fungal invasive infectious process is complex and has not yet been fully elucidated. Therefore, this study aimed to understand the cellular and molecular mechanisms during the interaction of macrophages and T. rubrum. For this purpose, we used a co-culture of previously germinated and heat-inactivated T. rubrum conidia placed in contact with human macrophages cell line THP-1 for 24 h. This interaction led to a higher level of release of interleukins IL-6, IL-2, nuclear factor kappa beta (NF-κB) and an increase in reactive oxygen species (ROS) production, demonstrating the cellular defense by macrophages against dead fungal elements. Cell viability assays showed that 70% of macrophages remained viable during co-culture. Human microRNA expression is involved in fungal infection and may modulate the immune response. Thus, the macrophage expression profile of microRNAs during co-culture revealed the modulation of 83 microRNAs, with repression of 33 microRNAs and induction of 50 microRNAs. These data were analyzed using bioinformatics analysis programs and the modulation of the expression of some microRNAs was validated by qRT-PCR. In silico analysis showed that the target genes of these microRNAs are related to the inflammatory response, oxidative stress, apoptosis, drug resistance, and cell proliferation.