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BACKGROUND: Staphylococcus genus is widely spread in nature being part of the indigenous microbiota of skin and mucosa of animal and birds. Some Staphylococcus species are frequently recognized as etiological agents of many animal and human opportunistic infections This is the first report testing the antibiotic resistance-modifying activity of Turnera ulmifolia against methicillin-resistant Staphylococcus aureus--MRSA strain. METHODS: In this study an ethanol extract of Turnera ulmifolia L. and chlorpromazine were tested for their antimicrobial activity alone or in combination with aminoglycosides against an MRSA strain. RESULTS: The synergism of the ethanol extract and aminoglycosides were verified using microdillution method. A synergistic effect of this extract on gentamicin and kanamycin was demonstrated. Similarly, a potentiating effect of chlorpromazine on kanamycin, gentamicin and neomycin, indicating the involvement of an efflux system in the resistance to these aminoglycosides. CONCLUSION: It is therefore suggested that extracts from Turnera ulmifolia could be used as a source of plant-derived natural products with resistance-modifying activity, constituting a new weapon against the problem of bacterial resistance to antibiotics demonstrated in MRSA strains. [ABSTRACT FROM AUTHOR]

This work shows the synthesis of a series of Morita-Baylis-Hillman adducts from isatin derivatives via an efficient green approach involving the use of a new catalyst system, a mixture of copper-manganese iminodiacetate 1D coordination polymer (Cu/Mn-IDA) and choline chloride-urea deep eutectic solvent (ChCl/urea 1:2). The adducts 2a-2i were obtained in good to excellent yields (59-97%) with shorter reaction times. The results demonstrate for the first time the synergistic catalytic effect of the combination of deep eutectic solvent and coordination polymer on the Morita-Baylis-Hillman reactions. The catalyst recyclability was investigated, and it was found that Cu/Mn-IDA maintains consistent performance for at least four catalytic cycles. The synthesized compounds were evaluated for their in vitro antimicrobial activity against four bacteria and eight fungi species. Among all, 2a , 2b , 2d , 2e , and 2g showed antifungal and antibacterial activities in 70-83% of the strains tested. The adduct 2e exhibited significant antifungal activity with a minimum inhibitory concentration value of 128 μg mL -1 compared to the standard drug fluconazole (minimum inhibitory concentration, 256 μg mL -1 )., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Candida albicans is the primary species causing oral candidiasis. Its increasing drug resistance drives the search for more effective antifungal agents. Therefore, we assessed toxicological parameters and the antimicrobial activity and mechanisms of action of the monoterpene (-)-fenchone against oral C. albicans. We conducted an in silico study using PASS online and AdmetSAR, followed by evaluation of antifungal activity through Minimum Inhibitory Concentration (MIC), Minimum Fungicidal Concentration (MFC), association study with miconazole, and assays with sorbitol and ergosterol. Inhibition of biofilm formation and disruption of preformed biofilm were considered. Toxicity was also assessed through hemolysis assay. The in silico study revealed a higher likelihood of the compound being active for antifungal activity, as well as promising pharmacokinetic and toxicity characteristics. Subsequently, (-)-fenchone exhibited predominantly fungicidal activity (MIC90 = 8 μg/mL; MFC = 16 μg/mL), including against miconazole-resistant C. albicans isolates. The substance does not appear to act by damaging the fungal cell wall or plasma membrane, and exhibited synergy with miconazole. There was activity in inhibiting biofilm formation but not in disrupting preformed biofilm. Finally, the product exerted low hemolytic activity at more than MIC×10. Based on these results, (-)-fenchone may represent a promising therapeutic alternative for oral candidiasis.

The present study aimed to investigate the antifungal activity of citronellal (CIT) against clinical isolates of T. rubrum and to show the possible mechanism of action involved. The antifungal potential of CIT was evaluated from the Minimum Inhibitory Concentration (MIC), Minimum Fungicide Concentration (MFC) and assays with ergosterol and sorbitol, to elucidate the possible mechanisms of action, and molecular docking. MIC and MFC values ranged from 4 to 512 µg/mL. Regarding the mechanism of action, the monoterpene demonstrated interaction with fungal ergosterol. In addition, it is possible to observe that CIT acts on crucial enzymes for the biosynthesis and maintenance of the fungal cell membrane, due to the ability of the monoterpene to bind to CYP51. The results obtained in this research demonstrate that CIT has the potential to become, in the future, a product for the treatment of dermatophytosis.

Candida albicans is the main fungal species involved in oral candidiasis, and its increasing resistance to pharmacological treatment encourages the search for improved antifungal agents. Lavandula dentata L. essential oil (LD-EO) has been recognized for its antimicrobial activity, but little is known about its role against oral C. albicans. This study evaluated the antifungal and antibiofilm activities, mechanisms of action, and toxicity of LD-EO from Brazil against oral strains of C. albicans. Antifungal activity was assessed based on Minimum Inhibitory Concentration (MIC), Minimum Fungicidal Concentration (MFC), association study with miconazole (Checkerboard method), and sorbitol and ergosterol assays. Inhibition of biofilm formation and disruption of preformed biofilm were considered when studying the effects of the product. Additionally, the toxicity of LD-EO was evaluated by a hemolysis assay on human erythrocytes. Phytochemical analysis by gas chromatography-mass spectrometry identified eucalyptol (33.1%), camphor (18.3%), and fenchone (15.6%) as major constituents. The test substance showed mainly fungicidal activity (MIC100 = 8 μg/mL; MFC = 16 μg/mL), including against two miconazole-resistant isolates of C. albicans. The effects of LD-EO were synergistic with those of miconazole and appeared not to involve damage to the fungal cell wall or plasma membrane. Its effectiveness in inhibiting biofilm formation was higher than the effect of disrupting preformed biofilm. Finally, the product exhibited low hemolytic activity at MIC. Based on the favorable and novel results described here, LD-EO could constitute a promising therapeutic alternative for oral candidiasis, including miconazole-resistant cases.

Sesbania virgata (Cav.) Pers. seeds are protein sources with health and environmental benefits. In this research, proteins with lectin activity were identified in a protein fraction from S. virgata seeds (PFLA), as well its antioxidant and antimicrobial potentials, in addition to cytotoxic effects. To obtain PFLA, seed flour was homogenized in Glycine-NaOH (100 mM; pH 9.0; NaCl 150 mM) and precipitated in ammonium sulfate. PFLA concentrates bioactive lectins (32 HU/mL, 480 HU/gFa, 18.862 HU/mgP) and essential amino acids (13.36 g/100g protein). PFLA exerts antioxidant activity, acting as a promising metal chelating agent (~77% of activity). Analyzes of cell culture assay results suggest that antioxidant activity of PFLA may be associated with the recruitment of essential molecules to prevent the metabolic impairment of cells exposed to oxidative stress. PFLA (256 - 512 µg/mL) also exhibits antifungal activity, inhibiting the growth of Aspergillus flavus, Candida albicans, Candida tropicalis and Penicillium citrinum. Cytotoxic analysis indicates a tendency of low interference in the proliferation of 3T3 and HepG2 cells in the range of PFLA concentrations with biological activity. These findings support the notion that PFLA is a promising adjuvant to be applied in current policies on the management of metal ion chelation and fungal infections.

Aspergillus niger causes infections such as otitis and pulmonary aspergillosis in immunocompromised individuals. Treatment involves voriconazole or amphotericin B, and due to the increase in fungal resistance, the search for new compounds with antifungal activity has intensified. In the development of new drugs, cytotoxicity and genotoxicity assays are important, as they allow predicting possible damage that a molecule can cause, and in silico studies predict the pharmacokinetic properties. The aim of this study was to verify the antifungal activity and the mechanism of action of the synthetic amide 2-chloro-N-phenylacetamide against Aspergillus niger strains and toxicity. 2-Chloro- N -phenylacetamide showed antifungal activity against different strains of Aspergillus niger with minimum inhibitory concentrations between 32 and 256 μg/mL and minimum fungicides between 64 and 1024 μg/mL. The minimum inhibitory concentration of 2-chloro-N-phenylacetamide also inhibited conidia germination. When associated with amphotericin B or voriconazole, 2-chloro- N- phenylacetamide had antagonistic effects. Interaction with ergosterol in the plasma membrane is the probable mechanism of action.2-Chloro- N -phenylacetamide has favorable physicochemical parameters, good oral bioavailability and absorption in the gastrointestinal tract, crosses the blood-brain barrier and inhibits CYP1A2. At concentrations of 50 to 500 µg/mL, it has little hemolytic effect and a protective effect for type A and O red blood cells, and in the cells of the oral mucosa it promotes little genotoxic change. It is concluded that 2-chloro- N -phenylacetamide has promising antifungal potential, favorable pharmacokinetic profile for oral administration and low cytotoxic and genotoxic potential, being a promising candidate for in vivo toxicity studies.

Loss of kidney function causes oral manifestations and multiple complications that have implications for dental treatment and patients' systemic conditions. We aimed to determine the clinical condition, epidemiological profile, and incidence of dental caries in patients with chronic kidney disease (CKD). This was an observational, cross-sectional, field study using a quantitative and epidemiological approach. The sample consisted of 45 randomly selected patients with CKD from a total of 114 patients. Data were collected through oral clinical examination, anamnesis, and medical records compiled in a clinical file specially developed for this research. Clinical evaluation was performed, including a Decayed, Missing, and Filled Teeth (DMFT) index examination. Data were analyzed using the Shapiro-Wilk test, Mann-Whitney test, and Spearman's rho coefficient. All analyses were performed using IBM SPSS Statistics software version 20.0, with a confidence interval of 95 % and significance level of 5 % (p < 0.05). The results indicated that CKD is more prevalent in the 5th decade of life, with a slight predilection for men. Oral cavity alterations were observed in 77.8 % of patients. The study population had a very high DMFT index, with a high number of missing teeth and a low number of decayed and filled teeth. Poor oral health in patients with CKD indicates a lack of care that supports the necessity of installing a preventive and therapeutic oral program and a regular follow-up aimed at this group of patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 THE AUTHORS.)

Glioblastoma is the most aggressive central nervous system primary tumor. Prognosis is poor, mainly due to the malignant characteristics of the tumor, such as high cell proliferation and invasiveness. CDH1 hypermethylation is linked to the invasive potential in various cancer types, but its importance is still unknown in glioblastoma. In this context, the methylation status of CDH1 was analyzed using MSP-PCR (Methylation-specific Polymerase Chain Reaction) in glioblastoma (n = 34) and normal glial tissue samples (n = 11). CDH1 hypermethylation was found in 39.4% (13/34) of the tumor samples and none of the normal glial tissue, suggesting a relation between CDH1 hypermethylation and glioblastoma ( P = 0.0195). Finally, this study showed unprecedented information that could contribute to clarifying the molecular pathways involved in the invasiveness and aggressiveness of this type of cancer., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study aimed to evaluate the effectiveness of transcranial direct current stimulation associated with brain-computer interface in stroke patients., Data Sources: The PubMed, Central, PEDro, Web of Science, SCOPUS, PsycINFO Ovid, CINAHL EBSCO, EMBASE, and ScienceDirect databases were searched from inception to April 2023 for randomized controlled studies reporting the effects of active transcranial direct current stimulation associated with brain-computer interface to a transcranial direct current stimulation sham associated with brain-computer interface condition on the outcome measure (motor performance and functional independence)., Review Methods: We searched for full-text articles which had investigated the effect of transcranial direct current stimulation associated with brain-computer interface on motor performance in the upper extremities in stroke patients. The standardized mean differences derived from the change in scores between pretreatment and post-treatment were adopted as the effect size measure, with a 95% confidence interval. Possible sources of heterogeneity were analyzed by performing subgroup analyses in order to examine the moderating effects for one variable: the level of injury severity., Results: Nine studies were included in the qualitative synthesis and the meta-analysis. The findings of the conducted analyses indicated there is not enough evidence to suggest that active transcranial direct current stimulation associated with brain-computer interface is more efficient in motor performance and functional independence when compared to sham transcranial direct current stimulation associated with brain-computer interface or brain-computer interface alone. In addition, the quality of evidence was rated very low. A subgroup analysis was performed for the motor performance outcome considering the injury severity level., Conclusion: We found evidence that transcranial direct current stimulation associated with brain-computer interface was not more beneficial than sham transcranial direct current stimulation associated with brain-computer interface or brain-computer interface alone., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chronic Hepatitis C (CHC) affects 71 million people globally and leads to liver issues such as fibrosis, cirrhosis, cancer, and death. A better understanding and prognosis of liver involvement are vital to reduce morbidity and mortality. The accurate identification of the fibrosis stage is crucial for making treatment decisions and predicting outcomes. Tests used to grade fibrosis include histological analysis and imaging but have limitations. Blood markers such as molecular biomarkers can offer valuable insights into fibrosis., Aim: To identify potential biomarkers that might stratify these lesions and add information about the molecular mechanisms involved in the disease., Methods: Plasma samples were collected from 46 patients with hepatitis C and classified into fibrosis grades F1 ( n = 13), F2 ( n = 12), F3 ( n = 6), and F4 ( n = 15). To ensure that the identified biomarkers were exclusive to liver lesions (CHC fibrosis), healthy volunteer participants ( n = 50) were also included. An untargeted metabolomic technique was used to analyze the plasma metabolites using mass spectrometry and database verification. Statistical analyses were performed to identify differential biomarkers among groups., Results: Six differential metabolites were identified in each grade of fibrosis. This six-metabolite profile was able to establish a clustering tendency in patients with the same grade of fibrosis; thus, they showed greater efficiency in discriminating grades., Conclusion: This study suggests that some of the observed biomarkers, once validated, have the potential to be applied as prognostic biomarkers. Furthermore, it suggests that liquid biopsy analyses of plasma metabolites are a good source of molecular biomarkers capable of stratifying patients with CHC according to fibrosis grade., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict-of-interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Pseudomonas aeruginosa is a non-lactose fermenting Gram-negative bacteria responsible for causing numerous nosocomial infections. The present research aimed to analyze the anti-Pseudomonas aeruginosa potential of 2-Chloro-N-(4-fluoro-3-nitrophenyl)acetamide (A8). The antibacterial potential of A8 was evaluated from the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and Association using the checkerboard method. MIC and MBC values were 512 µg/mL for all P. aeruginosa strains evaluated, demonstrating predominantly bactericidal activity. Furthermore, when A8 was associated with the drug ceftriaxone, pharmacological additivity and indifference were evidenced. In this sense, the synthetic amide was interesting, since it demonstrates the potential to become a possible candidate for an antimicrobial drug.

Background: Transcranial direct current stimulation (tDCS) is a promising treatment for Alzheimer's Disease (AD). However, identifying objective biomarkers that can predict brain stimulation efficacy, remains a challenge. The primary aim of this investigation is to delineate the cerebral regions implicated in AD, taking into account the existing lacuna in comprehension of these regions. In pursuit of this objective, we have employed a supervised machine learning algorithm to prognosticate the neurophysiological outcomes resultant from the confluence of tDCS therapy plus cognitive intervention within both the cohort of responders and non-responders to antecedent tDCS treatment, stratified on the basis of antecedent cognitive outcomes., Methods: The data were obtained through an interventional trial. The study recorded high-resolution electroencephalography (EEG) in 70 AD patients and analyzed spectral power density during a 6 min resting period with eyes open focusing on a fixed point. The cognitive response was assessed using the AD Assessment Scale-Cognitive Subscale. The training process was carried out through a Random Forest classifier, and the dataset was partitioned into K equally-partitioned subsamples. The model was iterated k times using K-1 subsamples as the training bench and the remaining subsample as validation data for testing the model., Results: A clinical discriminating EEG biomarkers (features) was found. The ML model identified four brain regions that best predict the response to tDCS associated with cognitive intervention in AD patients. These regions included the channels: FC1, F8, CP5, Oz, and F7., Conclusion: These findings suggest that resting-state EEG features can provide valuable information on the likelihood of cognitive response to tDCS plus cognitive intervention in AD patients. The identified brain regions may serve as potential biomarkers for predicting treatment response and maybe guide a patient-centered strategy., Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT02772185?term=NCT02772185&draw=2&rank=1, identifier ID: NCT02772185., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Andrade, da Silva-Sauer, de Carvalho, de Araújo, Lima, Fernandes, Moreira, Camilo, Andrade, Borges, da Silva Filho, Lindquist, Pegado, Morya, Yamauti, Alves, Fernández-Calvo and de Souza Neto.)

Cardiovascular disease is a leading cause of death worldwide. Heart failure is a cardiovascular disease with high prevalence, morbidity, and mortality. Several natural compounds have been studied for attenuating pathological cardiac remodeling. Orange juice has been associated with cardiovascular disease prevention by attenuating oxidative stress. However, most studies have evaluated isolated phytochemicals rather than whole orange juice and usually under pathological conditions. In this study, we evaluated plasma metabolomics in healthy rats receiving Pera or Moro orange juice to identify possible metabolic pathways and their effects on the heart., Methods: Sixty male Wistar rats were allocated into 3 groups: control (C), Pera orange juice (PO), and Moro orange juice (MO). PO and MO groups received Pera orange juice or Moro orange juice, respectively, and C received water with maltodextrin (100 g/L). Echocardiogram and euthanasia were performed after 4 weeks. Plasma metabolomic analysis was performed by high-resolution mass spectrometry. Type I collagen was evaluated in picrosirius red-stained slides and matrix metalloproteinase (MMP)-2 activity by zymography. MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-4, type I collagen, and TNF-α protein expression were evaluated by Western blotting., Results: We differentially identified three metabolites in PO (N-docosahexaenoyl-phenylalanine, diglyceride, and phosphatidylethanolamine) and six in MO (N-formylmaleamic acid, N2-acetyl-L-ornithine, casegravol isovalerate, abscisic alcohol 11-glucoside, cyclic phosphatidic acid, and torvoside C), compared to controls, which are recognized for their possible roles in cardiac remodeling, such as extracellular matrix regulation, inflammation, oxidative stress, and membrane integrity. Cardiac function, collagen level, MMP-2 activity, and MMP-9, TIMP-2, TIMP-4, type I collagen, and TNF-α protein expression did not differ between groups., Conclusion: Ingestion of Pera and Moro orange juice induces changes in plasma metabolites related to the regulation of extracellular matrix, inflammation, oxidative stress, and membrane integrity in healthy rats. Moro orange juice induces a larger number of differentially expressed metabolites than Pera orange juice. Alterations in plasma metabolomics induced by both orange juice are not associated with modifications in cardiac extracellular matrix components. Our results allow us to postulate that orange juice may have beneficial effects on pathological cardiac remodeling.

Zika virus (ZIKV) is a strongly neurotropic flavivirus whose infection has been associated with microcephaly in neonates. However, clinical and experimental evidence indicate that ZIKV also affects the adult nervous system. In this regard, in vitro and in vivo studies have shown the ability of ZIKV to infect glial cells. In the central nervous system (CNS), glial cells are represented by astrocytes, microglia, and oligodendrocytes. In contrast, the peripheral nervous system (PNS) constitutes a highly heterogeneous group of cells (Schwann cells, satellite glial cells, and enteric glial cells) spread through the body. These cells are critical in both physiological and pathological conditions; as such, ZIKV-induced glial dysfunctions can be associated with the development and progression of neurological complications, including those related to the adult and aging brain. This review will address the effects of ZIKV infection on CNS and PNS glial cells, focusing on cellular and molecular mechanisms, including changes in the inflammatory response, oxidative stress, mitochondrial dysfunction, Ca 2+ and glutamate homeostasis, neural metabolism, and neuron-glia communication. Of note, preventive and therapeutic strategies that focus on glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration and its consequences., (© 2023 Wiley Periodicals LLC.)

Brain metastases (BM) from lung cancer are among the most common intracranial tumors. Several studies have published scales to estimate the survival of patients with BM. Routine access to molecular diagnostics and modern oncologic treatments, including targeted therapy and immunotherapy, is limited in low- and middle-income countries (LMICs); therefore, incorporating them into recent prognostic scales may diminish the reliability of the scales in LMICs. This retrospective study aimed to determine the survival of 55 patients who were surgically treated for BM from lung cancer at a Brazilian public tertiary teaching hospital between 2012 and 2022. We determined clinical factors associated with survival, and compared observed survival rates with the estimated survival on prognostic scales. The mean overall survival (OS) was 9.3 months (range:0.2-76.5). At univariate analysis, female sex and improved postoperative Karnofsky performance status (KPS) score were associated with longer survival. The median survival did not differ between groups when classified using the Graded Prognostic Assessment (GPA)-2008, Lung-molecular GPA-2017, and Lung-GPA-2021 scales. According to the Diagnosis-Specific (DS)-GPA-2012 scale, there was a significant difference between the groups. In the multivariate Cox regression survival analysis, a higher DS-GPA-2012 and improved postoperative KPS score remained significantly associated with longer survival. In conclusion, this cohort showed a mean OS of < 1 year. Improved KPS score after surgery was associated with increased survival. This cohort DS-GPA scale demonstrated the highest concordance with observed survival, indicating its potential as a valuable tool for patient stratification in surgical treatment decision-making in LMICs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Onychomycosis is the most common disease affecting the nail unit and accounts for at least 50% of all nail diseases. In addition, Candida albicans is responsible for approximately 70% of onychomycoses caused by yeasts. This study investigated the antifungal effect of (R) and (S)-citronellal enantiomers, as well as its predictive mechanism of action on C. albicans from voriconazole-resistant onychomycoses. For this purpose, in vitro broth microdilution and molecular docking techniques were applied in a predictive and complementary manner to the mechanisms of action. The main results of this study indicate that C. albicans was resistant to voriconazole and sensitive to the enantiomers (R) and (S)-citronellal at a dose of 256 and 32 µg/mL respectively. In addition, there was an increase in the minimum inhibitory concentration (MIC) of the enantiomers in the presence of sorbitol and ergosterol, indicating that these molecules possibly affect the integrity of the cell wall and cell membrane of C. albicans. Molecular docking with key biosynthesis proteins and maintenance of the fungal cell wall and plasma membrane demonstrated the possibility of (R) and (S)-citronellal interacting with two important enzymes: 1,3-β-glucan synthase and lanosterol 14α-demethylase. Therefore, the findings of this study indicate that the (R) and (S)-citronellal enantiomers are fungicidal on C. albicans from onychomycoses and probably these substances cause damage to the cell wall and cell membrane of these micro-organisms possibly by interacting with enzymes in the biosynthesis of these fungal structures.

Glioblastoma (GB) is the most aggressive and frequent primary malignant tumor of the central nervous system and is associated with poor overall survival even after treatment. To better understand tumor biochemical alterations and broaden the potential targets of GB, this study aimed to evaluate differential plasma biomarkers between GB patients and healthy individuals using metabolomics analysis. Plasma samples from both groups were analyzed via untargeted metabolomics using direct injection with an electrospray ionization source and an LTQ mass spectrometer. GB biomarkers were selected via Partial Least Squares Discriminant and Fold-Change analyses and were identified using tandem mass spectrometry with in silico fragmentation, consultation of metabolomics databases, and a literature search. Seven GB biomarkers were identified, some of which were unprecedented biomarkers for GB, including arginylproline ( m / z 294), 5-hydroxymethyluracil ( m / z 143), and N-acylphosphatidylethanolamine ( m / z 982). Notably, four other metabolites were identified. The roles of all seven metabolites in epigenetic modulation, energy metabolism, protein catabolism or folding processes, and signaling pathways that activate cell proliferation and invasion were elucidated. Overall, the findings of this study highlight new molecular targets to guide future investigations on GB. These molecular targets can also be further evaluated to derive their potential as biomedical analytical tools for peripheral blood samples.

Klebsiella pneumoniae is a species of Gram-negative bacteria related to a wide range of infections and high rates of drug resistance. The combined use of antibacterial agents is one of the strategies that has been analyzed in recent years as part of the alternatives in the treatment of drug-resistant infections. Recently, the antibacterial activity of of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide has been demonstrated against K. pneumoniae, also indicating that this acetamide did not show significant cytotoxic potential in preliminary tests. Thus, it becomes an interesting substance for future studies that explore its antimicrobial capacity, including investigating its association with antibacterial drugs. Based on this, this research aimed to analyze the effects of the association of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide (CFA) with ciprofloxacin, cefepime, ceftazidime, meropenem and imipenem against K. pneumoniae strains. The results showed additivity when the substance was combined with ciprofloxacin and cefepime, indifference when associated with ceftazidime and synergistic effect when combined with meropenem and imipenem. Thus, the acetamide was able to optimize the effects of antibacterial drugs, reducing the concentrations necessary to cause bacterial death. These data indicate a potential future clinical use of these combinations, and further studies are needed to analyze this viability.

The ability of dermatophytes to develop biofilms is possibly involved in therapeutic failure because biofilms impair drug effectiveness in the infected tissues. Research to find new drugs with antibiofilm activity against dermatophytes is crucial. In this way, riparins, a class of alkaloids that contain an amide group, are promising antifungal compounds. In this study, we evaluated the antifungal and antibiofilm activity of riparin III (RIP3) against Trichophyton rubrum, Microsporum canis , and Nannizzia gypsea strains. We used ciclopirox (CPX) as a positive control. The effects of RIP3 on fungal growth were evaluated by the microdilution technique. The quantification of the biofilm biomass in vitro was assessed by crystal violet, and the biofilm viability was assessed by quantifying the CFU number. The ex vivo model was performed on human nail fragments, which were evaluated by visualization under light microscopy and by quantifying the CFU number (viability). Finally, we evaluated whether RIP3 inhibits sulfite production in T. rubrum . RIP3 inhibited the growth of T. rubrum and M. canis from 128 mg/L and N. gypsea from 256 mg/L. The results showed that RIP3 is a fungicide. Regarding antibiofilm activity, RIP3 inhibited biofilm formation and viability in vitro and ex vivo. Moreover, RIP3 inhibited the secretion of sulfite significantly and was more potent than CPX. In conclusion, the results indicate that RIP3 is a promising antifungal agent against biofilms of dermatophytes and might inhibit sulfite secretion, one relevant virulence factor.

An increase in the incidence of arboviral, microbial and parasitic infections, and to disorders related to oxidative stress has encouraged the development of adjuvant therapies based on natural formulations, such as those involving plant extracts. Thus, to expand the repertoire of the available therapeutic options, this study aimed to describe the versatility of Tephrosia toxicaria (Sw.) (Pers., 1807) extracts for the control of arbovirus vectors, as well as their antioxidant, antileishmanial, and antimicrobial potential. Among the aqueous and hydroethanolic extracts obtained, the hydroethanolic extract from roots (RHA) was identified as the most active larvicide extract demonstrating, respectively, the lowest lethal concentration (mg/mL) for 50%, 90% and 99% of Aedes aegypti (L., 1762) and Aedes albopictus (S., 1894) larvae, observed at 24 h (0.33, 0.84 and 1.80; 0.32, 0.70 and 1.32) and 48 h (0.17, 0.51 and 1.22; 0.26, 0.47 and 0.78) post-exposure. Field assays revealed that RHA (0.84 mg/mL) is a potential oviposition deterrent, reducing egg-laying by approximately 90%. RHA (0.1 mg/mL) also exhibited antioxidant activity for the following tests: total antioxidant capacity (286.86 mg AAE/g), iron (87.16%) and copper (25.64%) chelation, and superoxide scavenging (10%). In the cell culture assays, RHA (0.1 mg/mL) promoted regeneration of metabolic activity (92% cell viability) in cells exposed to oxidative stress. Furthermore, RHA displayed weak antileishmanial activity (IC50 = 3.53 mg/mL) against Leishmania amazonensis and not exhibit antimicrobial activity. The extraction favored the concentration of carbohydrates in RHA, in addition to lectins and protease inhibitors, with molecular masses estimated between 10 and 24 kDa. Cytotoxicity and phytotoxicity analyses of RHA suggested its biosecurity. Thus, RHA is a multivalent extract with insecticide and antioxidant properties at low and safe concentrations. However, others studies on its indirect toxic effects are ongoing to ensure the complete safety of RHA., Competing Interests: The authors have declared no competing interests exist., (Copyright: © 2023 Sá et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Meningiomas (MGMs) are currently classified into grades I, II, and III. High-grade tumors are correlated with decreased survival rates and increased recurrence rates. The current grading classification is based on histological criteria and determined only after surgical tumor sampling. This study aimed to identify plasma metabolic alterations in meningiomas of different grades, which would aid surgeons in predefining the ideal surgical strategy. Plasma samples were collected from 51 patients with meningioma and classified into low-grade (LG) (grade I; n = 43), and high-grade (HG) samples (grade II, n = 5; grade III, n = 3). An untargeted metabolomic approach was used to analyze plasma metabolites. Statistical analyses were performed to select differential biomarkers among HG and LG groups. Metabolites were identified using tandem mass spectrometry along with database verification. Five and four differential biomarkers were identified for HG and LG meningiomas, respectively. To evaluate the potential of HG MGM metabolites to differentiate between HG and LG tumors, a receiving operating characteristic curve was constructed, which revealed an area under the curve of 95.7%. This indicates that the five HG MGM metabolites represent metabolic alterations that can differentiate between LG and HG meningiomas. These metabolites may indicate tumor grade even before the appearance of histological features.

Using Brownian dynamics simulations we investigate the melting processes of a square crystalline lattice of colloidal particles interacting via an isotropic potential, which comprises both a hard-core repulsion and an additional softened square-well potential. For temperatures slightly lower than the transition one, we found a proliferation of small liquid clusters surrounded by the square lattice. These clusters are not static, quite the opposite, they have an intense dynamics and are continuously formed and destroyed over time. However, no unbound topological defects are observed. At the transition temperature, one of these liquid clusters starts to grow, until the entire system becomes in the liquid phase, then, characterizing a first-order phase transition. The tetratic intermediate phase, as given by the KTHNY theory, was not observed. Moreover, the liquid phase exhibits a considerable number of crystalline clusters having square and triangular orderings, which remain present even when increasing temperature by an order of magnitude. As the temperature increases, structural changes within the liquid phase are analyzed by evaluating the number and sizes of the square and triangular clusters. A transition of the dominant clusters is observed.

This study aimed to investigate biocompatibility, integration, and tissue host response of the Poly (Lactic-co-Glycolic acid) (PLGA)/Poly (isoprene) (PI) epoxidized (PLGA/PIepox) innovative scaffold combined with adipose derived mesenchymal stem cells (ADSC). We implanted the scaffold subcutaneously on the back of 18 female rats and monitored them for up to 14 days. When compared to controls, PLGA/PIepox + ADSC demonstrated an earlier vascularization, a tendency of inflammation reduction, an adequate tissue integration, higher cell proliferation, and a tendency of expression of collagen decreasing. However, 14 days post-implantation we found similar levels of CD31, Ki67 and AE1/AE3 in PLGA/PIepox when compared to control groups. The interesting results, lead us to the assumption that PLGA/PIepox is able to provide an effective delivery system for ADSC on tissue host. This animal study assesses PLGA/PIepox + ADSC in in vivo tissue functionality and validation of use, serving as a proof of concept for future clinical translation as it presents an innovative and promising tissue engineering opportunity for the use in tissue reconstruction.

Candida albicans is the most frequently isolated opportunistic pathogen in the female genital tract, with 92.3% of cases in Brazil associated with vulvovaginal candidiasis (VVC). Linalool is a monoterpene compound from plants of the genera Cinnamomum, Coriandrum, Lavandula, and Citrus that has demonstrated a fungicidal effect on strains of Candida spp., but its mechanism of action is still unknown. For this purpose, broth microdilution techniques were applied, as well as molecular docking in a predictive manner for this mechanism. The main results of this study indicated that the C. albicans strains analyzed were resistant to fluconazole and sensitive to linalool at a dose of 256 µg/mL. Furthermore, the increase in the minimum inhibitory concentration (MIC) of linalool in the presence of sorbitol and ergosterol indicated that this molecule possibly affects the cell wall and plasma membrane integrity of C. albicans. Molecular docking of linalool with proteins that are key in the biosynthesis and maintenance of the cell wall and the fungal plasma membrane integrity demonstrated the possibility of linalool interacting with three important enzymes: 1,3-β-glucan synthase, lanosterol 14α-demethylase, and Δ 14-sterol reductase. In silico analysis showed that this monoterpene has theoretical but significant oral bioavailability, low toxic potential, and high similarity to pharmaceuticals. Therefore, the findings of this study indicated that linalool probably causes damage to the cell wall and plasma membrane of C. albicans, possibly by interaction with important enzymes involved in the biosynthesis of these fungal structures, in addition to presenting low in silico toxic potential.

In the current context of emerging drug-resistant fungal pathogens such as Candida albicans and Candida parapsilosis, discovery of new antifungal agents is an urgent matter. This research aimed to evaluate the antifungal potential of 2-chloro-N-phenylacetamide against fluconazole-resistant clinical strains of C. albicans and C. parapsilosis. The antifungal activity of 2-chloro-N-phenylacetamide was evaluated in vitro by the determination of the minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), inhibition of biofilm formation and its rupture, sorbitol and ergosterol assays, and association between this molecule and common antifungal drugs, amphotericin B and fluconazole. The test product inhibited all strains of C. albicans and C. parapsilosis, with a MIC ranging from 128 to 256 µg.mL-1, and a MFC of 512-1,024 µg.mL-1. It also inhibited up to 92% of biofilm formation and rupture of up to 87% of preformed biofilm. 2-chloro-N-phenylacetamide did not promote antifungal activity through binding to cellular membrane ergosterol nor it damages the fungal cell wall. Antagonism was observed when combining this substance with amphotericin B and fluconazole. The substance exhibited significant antifungal activity by inhibiting both planktonic cells and biofilm of fluconazole-resistant strains. Its combination with other antifungals should be avoided and its mechanism of action remains to be established.

Strongyloidiasis, a parasitosis caused by Strongyloides stercoralis in humans, is a very prevalent infection in tropical or subtropical areas. Gaps on public health strategies corroborates to the high global incidence of strongyloidiasis especially due to challenges involved on its diagnosis. Based on the lack of a gold-standard diagnostic tool, we aimed to present a metabolomic study for the assessment of stool metabolic alterations. Stool samples were collected from 25 patients segregated into positive for strongyloidiasis (n = 10) and negative control (n = 15) and prepared for direct injection high-resolution mass spectrometry analysis. Using metabolomics workflow, 18 metabolites were annotated increased or decreased in strongyloidiasis condition, from which a group of 5 biomarkers comprising caprylic acid, mannitol, glucose, lysophosphatidylinositol and hydroxy-dodecanoic acid demonstrated accuracy over 89% to be explored as potential markers. The observed metabolic alteration in stool samples indicates involvement of microbiota remodeling, parasite constitution, and host response during S. stercoralis infection., (Copyright © 2021. Published by Elsevier B.V.)

Aberrant inflammatory signaling has been shown to be a key pathogenic driver in myelodysplastic syndromes (MDS). Abnormal IL-33 expression has been implicated in inflammatory, immune-related disorders and, some tumors. However, its role in MDS remains widely unknown. This study aimed to evaluate the relationship between plasma levels of IL-33, clinical and prognostic data and, IL-6 levels in 101 patients with MDS. A comparative group of 59 healthy individuals was also evaluated. Plasma levels of cytokines were determined by enzyme-linked immunosorbent assay. Lower levels of IL-33 were found in patients with MDS when compared to the control group (p = 0.001), mainly in patients with more advanced stages of the disease and worse prognosis. No significant correlation between the levels of IL-33 and IL-6 was observed (r = 0.175; p = 0.081). These results reinforce the close association between immunological disorders and the pathogenesis of MDS. A greater understanding of the role of inflammatory cytokines in the disease can potentially provide new diagnosis and prognosis markers and new therapeutic targets., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The genus Candida is one of the main causes of otomycosis. The growing index of fungal strains resistant to antifungals makes necessary the search for new agents and α-pinene is a phytoconstituent present in plants with remarkable antimicrobial activity, which becomes an interesting object of study. Thus, the objective of this research was to evaluate the antifungal activity of α-pinene against Candida species isolated from otomycosis, determining the Minimum Inhibitory and Fungicide Concentrations, micromorphological analysis and verifying the effects of the association with boric acid. α-pinene showed significant antifungal activity, with greater inhibitory activity against C. parapsilosis , fungicidal action and proved to be effective in inhibiting fungal structures, such as pseudo-hyphae and promoting a marked decrease in blastoconidia. The combination of α-pinene with boric acid produced additive effects that may be interesting for use in clinical practice.

Infections associated with biofilms developed by Candida spp. are becoming a great problem due to its resistance against the immune response of the host and the action of antifungal agents. Hence, finding substances that can inhibit the development of biofilms increases the likelihood that these compounds one day can become good antifungals applied in the clinic. The aim of this study was to evaluate the effect of β-citronellol enantiomers on the biofilm formation by Candida albicans and Candida tropicalis isolated from bloodstream infections. Inhibition was evaluated by reading microplates treated with different concentrations of R-(+)-β-citronellol, S-(-)-β-citronellol and amphotericin B, compared to negative control, in spectrophotometer at 590 nm. All tested concentrations of β-citronellol enantiomers inhibited the biofilm formation of Candida . However, it is still necessary to evaluate the behavior of these isomers on mature biofilms, so that they can become more viable as antifungal therapeutical agents.

Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood-brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

Aspergillus genus causes many diseases, and the species Aspergillus flavus is highly virulent. Treatment of aspergillosis involves azole derivatives such as voriconazole and polyenes such as amphotericin B. Due to an increase in fungal resistance, treatments are now less effective; the search for new compounds with promising antifungal activity has gained importance. The aims of this study were to evaluate the effects of the synthetic amide 2-chloro-N-phenylacetamide (A1Cl) against strains of Aspergillus flavus and to elucidate its mechanism of action. Thus, the minimum inhibitory concentration, minimum fungicidal concentration, conidial germination, associations with antifungal agents, cell wall activities, membrane activities and molecular docking were evaluated. A1Cl presented antifungal activity against Aspergillus flavus strains with a minimum inhibitory concentration of between 16 and 256 μg/mL and a minimum fungicidal concentration between 32 and 512 μg/mL. The minimum inhibitory concentration of A1Cl also inhibited conidial germination, but when associated with amphotericin B and voriconazole, it promoted antagonistic effects. Binding to ergosterol on the fungal plasma membrane is the likely mechanism of action, along with possible inhibition of DNA synthesis through the inhibition of thymidylate synthase. It is concluded that the amide 2-chloro-N-phenylacetamide has promising antifungal potential.

Tissue engineering has provided new treatment alternatives for tissue reconstruction. Advances in the tissue engineering field have resulted in mechanical support and biological substitutes to restore, maintain or improve tissue/organs structures and functions. The application of tissue engineering technology in the vaginal reconstruction treatment can not only provide mechanical requirements, but also offer tissue repairing as an alternative to traditional approaches. In this review, we discuss recent advances in cell-based therapy in combination with scaffolds strategies that can potentially be adopted for gynaecological transplantation., (© 2021. The Author(s).)

Objectives: to understand how the therapeutic itineraries of people affected by leprosy are processed., Methods: this is a descriptive, qualitative study, conducted in April 2018 in Barão de Grajaú in Maranhão, with interviews in the form of narratives of seven patients who had a late leprosy diagnosis., Results: the search for diagnosis is a major difficulty in accessing health services, resulting in a late diagnosis and, consequently, with the presence of visible deformities. It was noticed that the health units do not have a flow, nor protocols for comprehensive treatment, and these people are referred to a referral unit in another state to perform sputum smear microscopy., Final Considerations: leprosy control actions need reformulations that seek the relationship between operational activities, epidemiological indicators and risk factors, in accordance with the real needs of each region, thus highlighting the gaps evidenced in the therapeutic itineraries.

Contamination of goat milk with aflatoxin M 1 (AFM 1 ) is a public health concern. This study investigated filamentous fungi in goat feed and quantified AFM 1 in milk samples (n = 108) from goat fed forage and concentrate. Based on the detected AFM 1 concentration, risk assessment analyses were performed concerning the Estimated Daily Intake (EDI) for one-year-old children and adults. Filamentous fungi were found in goat feed samples in a range of 3.1 ± 1.9 to 4.2 ± 0.2 log CFU/g. Five genera were identified, to cite Aspergillus, Penicillium, Fusarium, Rhizopus and Acremonium. Aspergillus species comprised A. flavus, A. niger, and A. ochraceus . All goat milk samples were contaminated with AFM 1 (5.60-48.20 ng/L; mean 21.90 ± 10.28 ng/L) in amounts below the limits imposed by regulatory agencies. However, EDI values for AFM 1 through goat milk estimated for one-year-old children were above the Tolerable Daily Intake. The calculated Hazard Index for one-year-old children indicated potential risk of liver cancer due to goat milk consumption. The Margin of Exposure values to AFM 1 in one-year-old children and adults consuming goat milk as the unique milk source indicated increased health risk. Therefore, contamination of goat milk with AFM 1 should be considered a high priority for Brazil's risk management actions.

Background: (-)-Fenchone is a bicyclic monoterpene present in essential oils of plant species, such as Foeniculum vulgare and Peumus boldus , used to treatment of gastrointestinal diseases. Pharmacological studies report its anti-inflammatory, antioxidant, and antinociceptive activity., Aim: To investigate antidiarrheal activity related to gastrointestinal motility, intestinal secretion and antimicrobial activity., Methods: A castor oil-induced diarrhea model was used to evaluate antidiarrheal activity. Intestinal transit and gastric emptying protocols were used to assess a possible antimotility effect. Muscarinic receptors, presynaptic α 2 -adrenergic and tissue adrenergic receptors, K ATP channels, nitric oxide were investigated to uncover antimotility mechanisms of action and castor oil-induced enteropooling to elucidate antisecretory mechanisms. The antimicrobial activity was evaluated in the minimum inhibitory concentration model, the fractional inhibitory concentration index using the (-)-fenchone association method with standard antifungal agents., Results: (-)-Fenchone (75, 150 and 300 mg/kg) showed antidiarrheal activity, with a significant decrease in the evacuation index. This activity is possibly related to a percentage of reduced intestinal transit (75, 150 and 300 mg/kg). The antimotility effect of (-)-fenchone decreased in the presence of pilocarpine, yohimbine, propranolol, L-NG-nitroarginine methyl ester or glibenclamide. In the enteropooling model, no reduction in intestinal fluid weight was observed. (-)- Fenchone did not show antibacterial activity; on the other hand, inhibits the growth of strains of fungi with a minimum fungicide concentration of 32 μg/mL. However, when it was associated with amphotericin B, no synergism was observed., Conclusion: The antidiarrheal effect of (-)-fenchone in this study involves antimotility effect and not involve antisecretory mechanisms. (-)-Fenchone presents antifungal activity; however, it did not show antibacterial activity., Competing Interests: Conflict-of-interest statement: Authors declare that no conflict of interest exists., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background/aim: Magnetic stimulation is used in the treatment of a diversity of diseases, but a complete understanding of the underlying mechanisms of action requires further investigation. We examined the effect of static magnetic stimulation (SMS) in different cell lines., Materials and Methods: A culture plate holder with attached NeFeB magnets was developed. Different magnetic field intensities and periods were tested in tumoral and non-tumoral cell lines. To verify the cellular responses to SMS, cell viability, cell death, cell cycle and BDNF expression were evaluated., Results: Exposure of SH-SY5Y cells to SMS for 24 hours led to a decrease in cell viability. Analysis 24 h after stimulation revealed a decrease in apoptotic and double-positive cells, associated with an increase in the number of necrotic cells., Conclusion: The effects of SMS on cell viability are cell type-specific, inducing a decrease in cell viability in SH-SY5Y cells. This suggests that SMS may be a potential tool in the treatment of neuronal tumors., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cryptococcus neoformans is a yeast fungus, which causes cryptococcosis, triggered by basidiospore inhalation and consequent dissemination to the central nervous system. In this study, we analyzed the antifungal action of thymol against 10 clinical strains of C. neoformans and analyzed the interaction of this monoterpene with sterols. The MICs of thymol ranged from 20 to 51 μg/ml, while the MFC values varied between 40 and 101 μg/ml. For the strains ICB-2601 and LM-39, in the presence of ergosterol, the MIC of thymol was 64 μg/ml, and in the presence of cholesterol, its MIC was 32 μg/ml. Based on the results, thymol presents antifungal action and seems to interact with ergosterol, but not with cholesterol. Complementary studies are needed to analyze its full effects.

Brazil and many other Latin American countries are areas of endemicity for different neglected diseases, and the fungal infection paracoccidioidomycosis (PCM) is one of them. Among the clinical manifestations, pneumopathy associated with skin and mucosal lesions is the most frequent. PCM definitive diagnosis depends on yeast microscopic visualization and immunological tests, but both present ambiguous results and difficulty in differentiating PCM from other fungal infections. This research has employed metabolomics analysis through high-resolution mass spectrometry to identify PCM biomarkers in serum samples in order to improve diagnosis for this debilitating disease. To upgrade the biomarker selection, machine learning approaches, using Random Forest classifiers, were combined with metabolomics data analysis. The proposed combination of these two analytical methods resulted in the identification of a set of 19 PCM biomarkers that show accuracy of 97.1%, specificity of 100%, and sensitivity of 94.1%. The obtained results are promising and present great potential to improve PCM definitive diagnosis and adequate pharmacological treatment, reducing the incidence of PCM sequelae and resulting in a better quality of life. IMPORTANCE Paracoccidioidomycosis (PCM) is a fungal infection typically found in Latin American countries, especially in Brazil. The identification of this disease is based on techniques that may fail sometimes. Intending to improve PCM detection in patient samples, this study used the combination of two of the newest technologies, artificial intelligence and metabolomics. This combination allowed PCM detection, independently of disease form, through identification of a set of molecules present in patients' blood. The great difference in this research was the ability to detect disease with better confidence than the routine methods employed today. Another important point is that among the molecules, it was possible to identify some indicators of contamination and other infection that might worsen patients' condition. Thus, the present work shows a great potential to improve PCM diagnosis and even disease management, considering the possibility to identify concomitant harmful factors., (Copyright © 2020 Lima et al.)

Kallikrein-kinin system (KKS) is involved in vascular reactivity and inflammatory response to cytotoxic drugs. Since cisplatin is a widely used chemotherapy and its cytotoxic mechanism can trigger inflammation and oxidative damage, in this work we evaluated the role of KKS in an animal model of cisplatin-induced ovarian toxicity. Biomarkers of ovarian stem cells, activity of KKS, inflammation and oxidative damage were measured in ovarian tissue of C57BL/6 female mice treated with vehicle or cisplatin (2.5 mg/kg). Cisplatin group presented greater number of atretic follicles, and lower numbers of antral and total viable follicles. Ki67, DDX4 and OCT-4 markers were similar between groups. Cisplatin triggered plasma and ovarian tissue kallikrein generation; and increased expression of bradykinin receptors B1 and B2. Neutrophil and macrophage infiltration markers increased. Superoxide anion generation also increased, while reduced glutathione levels decreased. These results suggest that KKS is activated and contributes to ovarian injury during cisplatin treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study investigated the monoterpene linalool and its resistance modulating activity involving ergosterol biosynthesis inhibitors (ketoconazole, fluconazole, and itraconazole) in strains of Microsporum spp. and Trichophyton spp. The minimum inhibitory concentration (MIC) of test-drugs were determined by microdilution. The modulating effect of linalool was evaluated by determining the MIC of the antifungals in the presence of subinhibitory concentrations of linalool. We also investigated the association effect (checkerboard) of linalool together with ketoconazole and itraconazole. The fungi became more sensitive to ketoconazole and itraconazole in the presence of linalool. The linalool and azole drug associations presented synergism., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

The recent outbreak of Zika virus (ZIKV) infection associated with microcephaly cases has elicited much research on the mechanisms involved in ZIKV-host cell interactions. It has been described that Zika virus impairs cell growth, raising a hypothesis about its oncolytic potential against cancer cells. ZIKV tumor cell growth inhibition was later confirmed for glioblastoma. It was also demonstrated that an inactivated ZIKV prototype (ZVp) based on bacterial outer membrane vesicles has antiproliferative activity upon other cancer cell lines, such as PC-3 prostate cancer cell. This study aims at understanding the pathways that might be involved with the antiproliferative effect of Zika virus against prostate cancer cells. A metabolomic approach based on high-resolution mass spectrometry analysis led to the identification of 21 statistically relevant markers of PC-3 cells treated with ZVp. The markers were associated with metabolic alterations that trigger lipid remodeling, endoplasmic reticulum stress, inflammatory mediators, as well as disrupted porphyrin and folate metabolism. These findings highlight molecular signatures of ZVp-induced response that may be involved on cellular pathways triggered by its antiproliferative effect. To our knowledge, this is the first reported metabolomic assessment of ZIKV effect on prostate cancer cells, a promising topic for further research.

Zika virus (ZIKV) has emerged as one of the most medically relevant viral infections of the past decades; the devastating effects of this virus over the developing brain are a major matter of concern during pregnancy. Although the connection with congenital malformations are well documented, the mechanisms by which ZIKV reach the central nervous system (CNS) and the causes of impaired cortical growth in affected fetuses need to be better addressed. We performed a non-invasive, metabolomics-based screening of saliva from infants with congenital Zika syndrome (CZS), born from mothers that were infected with ZIKV during pregnancy. We were able to identify three biomarkers that suggest that this population suffered from an important inflammatory process; with the detection of mediators associated with glial activation, we propose that microcephaly is a product of immune response to the virus, as well as excitotoxicity mechanisms, which remain ongoing even after birth.

The recent microcephaly outbreak in Brazil has been associated with Zika virus (ZIKV) infection. The current understanding of damage caused by ZIKV infection is still unclear, since it has been implicated in other neurodegenerative and developmental complications. Here, the differential proteome analysis of human mesenchymal stem cells (hMSC) infected with a Brazilian strain of ZIKV was identified by shotgun proteomics (MudPIT). Our results indicate that ZIKV induces a potential reprogramming of the metabolic machinery in nucleotide metabolism, changes in the energy production via glycolysis and other metabolic pathways, and potentially inhibits autophagy, neurogenesis, and immune response by downregulation of signaling pathways. In addition, proteins previously described in several brain pathologies, such as Alzheimer's disease, autism spectrum disorder, amyotrophic lateral sclerosis, and Parkinson's disease, were found with altered expression due to ZIKV infection in hMSC. This potential link between ZIKV and several neuropathologies beyond microcephaly is being described here for the first time and can be used to guide specific follow-up studies concerning these specific diseases and ZIKV infection.

Some biomaterial scaffolds can positively interfere with tissue regeneration and are being developed to successfully repair the tissue function. The possibility of using epithelial cells combined with biomaterials appears to be a new option as therapeutic application. This combination emerges as a possibility for patients with Mayer-Rokitansky-Kuster-Hauser syndrome which requires vaginal repair and can be performed with tissue-engineered solution containing cells and biomaterials. It is expected that tissue-engineered solution containing cells and biomaterials would promote tissue repair in a more efficient, modern, and safe way. This study tested the efficiency of tissue-engineered solution containing human malignant melanoma cell line (HMV-II) and different biomaterials, including Cellprene ® , Membracel ® , and poly lactic-co-glycolic acid/epoxidized polyisoprene. The cells adhered better on poly lactic-co-glycolic acid/epoxidized polyisoprene, and it was found that tissue-engineered solution may also contain mesenchymal stem cells cultivated on poly lactic-co-glycolic acid/epoxidized polyisoprene. Histological, immunofluorescence, and scanning electron microscopy analyses were performed. These initial in vitro results suggest that tissue-engineered solution containing cells and poly lactic-co-glycolic acid/epoxidized polyisoprene is a potential for tissue reconstruction.

Background: Lonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capacities. In the present study, we aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairment., Methodology/principal Findings: Addition of L. obliqua venom to purified prekallikrein and human plasma in vitro or to vascular smooth muscle cells (VSMC) in culture, was able to generate kallikrein in a dose-dependent manner. Injected in rats, the venom induced AKI and increased kallikrein levels in plasma and kidney. Kallikrein inhibition by aprotinin prevented glomerular injury and the decrease in glomerular filtration rate, restoring fluid and electrolyte homeostasis. The mechanism underlying these effects was associated to lowering renal inflammation, with decrease in pro-inflammatory cytokines and matrix metalloproteinase expression, reduced tubular degeneration, and protection against oxidative stress. Supporting the key role of kallikrein, we demonstrated that aprotinin inhibited effects directly associated with vascular injury, such as the generation of intracellular reactive oxygen species (ROS) and migration of VSMC induced by L. obliqua venom or by diluted plasma obtained from envenomed rats. In addition, kallikrein inhibition also ameliorated venom-induced blood incoagulability and decreased kidney tissue factor expression., Conclusions/significance: These data indicated that kallikrein and consequently kinin release have a key role in kidney injury and vascular remodeling. Thus, blocking kallikrein may be a therapeutic alternative to control the progression of venom-induced AKI and vascular disturbances., Competing Interests: The authors have declared that no competing interests exist.