In vitro evaluation of the selective cytotoxicity and genotoxicity of three synthetic ortho-nitrobenzyl derivatives in human cancer cell lines, with and without metabolic activation.

Although the presence of nitro groups in chemicals can be recognized as structural alerts for mutagenicity and carcinogenicity, nitroaromatic compounds have attracted considerable interest as a class of agents that can serve as source of potential new anticancer agents. In the present study, the in vitro cytotoxicity, genotoxicity, and mutagenicity of three synthetic ortho-nitrobenzyl derivatives (named ON-1, ON-2 and ON-3) were evaluated by employing human breast and ovarian cancer cell lines. A series of biological assays was carried out with and without metabolic activation. Complementarily, computational predictions of the pharmacokinetic properties and druglikeness of the compounds were performed in the Swiss ADME platform. The MTT assay showed that the compounds selectively affected selectively the cell viability of cancer cells in comparison with a nontumoral cell line. Additionally, the metabolic activation enhanced cytotoxicity, and the compounds affected cell survival, as demonstrated by the clonogenic assay. The comet assay, the cytokinesis-block micronucleus assay, and the immunofluorescence of the γ-H2AX foci formation assay have that the compounds caused chromosomal damage to the cancer cells, with and without metabolic activation. The results obtained in the present study showed that the compounds assessed were genotoxic and mutagenic, inducing double-strand breaks in the DNA structure. The high selectivity indices observed for the compounds ON-2 and ON-3, especially after metabolic activation with the S9 fraction, must be highlighted. These experimental biological results, as well as the theoretical properties predicted for the compounds have shown that they are promising anticancer candidates to be exploited in additional studies.

Override rate of drug-drug interaction alerts in clinical decision support systems: A brief systematic review and meta-analysis.

Primary studies have demonstrated that despite being useful, most of the drug-drug interaction (DDI) alerts generated by clinical decision support systems are overridden by prescribers. To provide more information about this issue, we conducted a systematic review and meta-analysis on the prevalence of DDI alerts generated by CDSS and alert overrides by physicians. The search strategy was implemented by applying the terms and MeSH headings and conducted in the MEDLINE/PubMed, EMBASE, Web of Science, Scopus, LILACS, and Google Scholar databases. Blinded reviewers screened 1873 records and 86 full studies, and 16 articles were included for analysis. The overall prevalence of alert generated by CDSS was 13% (CI95% 5-24%, p-value <0.0001, I^2 = 100%), and the overall prevalence of alert override by physicians was 90% (CI95% 85-95%, p-value <0.0001, I^2 = 100%). This systematic review and meta-analysis presents a high rate of alert overrides, even after CDSS adjustments that significantly reduced the number of alerts. After analyzing the articles included in this review, it was clear that the CDSS alerts physicians about potential DDI should be developed with a focus on the user experience, thus increasing their confidence and satisfaction, which may increase patient clinical safety.

Successful Pregnancy in Isolated 17,20-lyase Deficiency Without Glucocorticoid Use or Assisted Reproduction Techniques.

Isolated 17,20-lyase deficiency (ILD) is a partial form of 17α-hydroxylase/17,20-lyase deficiency that typically presents with infertility and lack of pubertal development. Successful live births have been achieved using assisted reproductive techniques. We present a case of spontaneous pregnancy in an 18-year-old female with ILD without reproduction treatments or glucocorticoid use. She presented to our clinic with absence of pubarche and oligomenorrhea and had typical external genitalia and complete breast development. Follicular phase progesterone and estradiol were within reference values, and androgen levels were undetectable. Corticosterone was increased, and cortisol responded partially to the ACTH-stimulation test. This profile raised a suspicion for ILD, which was confirmed by the finding of the homozygous p.R347H variant in the CYP17A1 gene. Sex steroid replacement and glucocorticoid use during stress were prescribed. She returned 2 years later 20 weeks pregnant. Her gestation was uneventful, and a full-term healthy male was born. This phenomenon could be partially explained by sufficient estrogen synthesis via residual 17,20-lyase enzymatic activity. Intermittent estradiol use may have favored uterine development and fine-tuned the pituitary-gonadal axis rhythm. Normal progesterone levels may have permitted an adequate endometrial "implantation window" without glucocorticoid use. Finally, elevated corticosterone may have compensated for the partial cortisol deficiency.

Effectiveness of a two-component nutritional strategy for blood pressure control in individuals with hypertension users of a public health system: a randomized controlled clinical trial.

OBJECTIVE: To evaluate the effectiveness of a nutritional strategy based on two components and adapted for the public health system on blood pressure, cardiometabolic features, self-care, qualify of life and diet quality in individuals with hypertension. METHODS: NUPRESS was an open-label, parallel-group, superiority randomized controlled clinical trial in which participants at least 21 years with hypertension and poorly controlled blood pressure were randomly assigned (1 : 1 allocation ratio) to either an individualized dietary prescription according to nutritional guidelines (control group, n  = 205); or a two-component nutrition strategy, including a goal-directed nutritional counseling and mindfulness techniques (NUPRESS [intervention] group, n  = 205). Primary outcomes were SBP (mmHg) after 24 weeks of follow up and blood pressure control, defined as either having SBP more than 140 mmHg at baseline and achieving 140 mmHg or less after follow-up or having SBP 140 mmHg or less at baseline and reducing the frequency of antihypertensive drugs in use after follow-up. RESULTS: In total, 410 participants were randomized and submitted to an intention-to-treat analysis regarding primary outcomes. Both groups decreased blood pressure, but after adjusting for baseline values, there was no significant difference between them on SBP [intervention-control difference: -0.03 (-3.01; 2.94); P  = 0.98] nor blood pressure control [odds ratio 1.27 (0.82; 1.97); P  = 0.28]. No differences between groups were also detected regarding secondary and tertiary outcomes. CONCLUSION: There was no difference between a two-component nutritional strategy and an established dietary intervention on blood pressure in participants with hypertension.

Clear aligner's adverse effects: A systematic review protocol.

With the growing popularity of clear aligners, more patients have chosen to use them instead of traditional orthodontic braces to correct their malocclusions. Clear aligners offer distinct advantages over conventional fixed braces, such as limited aesthetic impact, the convenience of easily removing them for meals, improved accessibility for brushing and flossing, and a treatment approach that avoids the use of metal, minimizing potential irritation to the cheeks and gums. Manufacturers point out a disadvantage that can be administered in this type of treatment. Still, to our knowledge, a comprehensive review of the published literature assessing the adverse/negative effects of clear aligners has not yet been conducted. A systematic review, with or without meta-analysis, will be performed. The inclusion criteria will be studies involving individuals using clear aligners and reporting potential adverse/negative effects during or after treatment. No restrictions about time or language will be applied. The studies screening will be conducted in two stages. Two independent reviewers will initially evaluate the title and abstract under the eligibility criteria. Subsequently, the same two reviewers will examine the articles' full text in-depth. The results will be synthesized in the form of a narrative description and incorporate a meta-analysis if justified. Furthermore, we will present details regarding the sample characteristics, intervention, study objectives, methodologies employed, and primary findings. This study aims to investigate the potential adverse effects and their frequency among orthodontic patients wearing clear aligners. Moreover, the outcomes of this review have the potential to illuminate specific inherent limitations of aligner therapy as a comprehensive orthodontic approach.

Tuning the Chemical and Electrochemical Properties of Paper-Based Carbon Electrodes by Pyrolysis of Polydopamine.

Electrochemical paper-based analytical devices represent an important platform for portable, low-cost, affordable, and decentralized diagnostics. For this kind of application, chemical functionalization plays a pivotal role to ensure high clinical performance by tuning surface properties and the area of electrodes. However, controlling different surface properties of electrodes by using a single functionalization route is still challenging. In this work, we attempted to tune the wettability, chemical composition, and electroactive area of carbon-paper-based devices by thermally treating polydopamine (PDA) at different temperatures. PDA films were deposited onto pyrolyzed paper (PP) electrodes and thermally treated in the range of 300-1000 °C. After deposition of PDA, the surface is rich in nitrogen and oxygen, it is superhydrophilic, and it has a high electroactive area. As the temperature increases, the surface becomes hydrophobic, and the electroactive area decreases. The surface modifications were followed by Raman, X-ray photoelectron microscopy (XPS), laser scanning confocal microscopy (LSCM), contact angle, scanning electron microscopy (SEM-EDS), electrical measurements, transmission electron microscopy (TEM), and electrochemical experiments. In addition, the chemical composition of nitrogen species can be tuned on the surface. As a proof of concept, we employed PDA-treated surfaces to anchor [AuCl4]- ions. After electrochemical reduction, we observed that it is possible to control the size of the nanoparticles on the surface. Our route opens a new avenue to add versatility to electrochemical interfaces in the field of paper-based electrochemical biosensors.

BENEFITS OF A CLINICAL PATHWAY IN TOTAL KNEE ARTHROPLASTY.

Objective: Demonstrate whether a multiprofessional Clinical Pathway Program in Total Knee Arthroplasty (CPPA) contributesto optimizing hospital care. Method: Retrospective study of medical data of care indicators in 310 patients divided into two groups: A- who underwent arthroplasty in the last biennium before the introduction of the CPPA (n=144) and group B- who underwent TKA in the biennium after the introduction of the CPPA (n=166). Results: Postoperative showed a significant difference in favor of group B over group A for hospitalization time in days 4.33 ± 2.79 and 5.4 ± 1.67 (p<0.001), time of prophylactic antibiotic in hours 28.13 ± 33.77 and 81.49 ± 40.91 (p<0.001), referral to the intensive care unit 40.9% and 73.4% (p<0.001), initiation of thromboprophylaxis within 24 hours 97.9% and 82.5% (p<0.001), use of elastic stockings and/or intermittent compression prescribed for thromboprophylaxis 89.5% and 31.2% (p<0.001), initiation of rehabilitation within 24 hours 90.1% and 66.1% (p<0.001), readmissions within 30 days 4.1% and 3% (p = 0.76), readmissions 90 days 2.7% and 6.6% (p = 0.183), transfusions 5.5% and 15.2% (p = 0.033). Conclusion: The implementation of a multiprofessional CPPA contributed to the implementation of care protocols, favoring greater patient safety. Level of Evidence III; Retrospective Comparative Study.

Objetivo: Demonstrar se um Programa de Cuidados Clínicos multiprofissional em Artroplastia Total de Joelho (PCCA) contribui para a otimização assistencial hospitalar. Método: Estudo retrospectivo em prontuários de indicadores assistenciais em 310 pacientes divididos em dois grupos: A- submetidos a artroplastia no último biênio antecessor a introdução do PCCA (n=144) e grupo B- submetidos a ATJ no biênio após a introdução do PCCA (n=166). Resultados: Indicadores pós-operatórios mostraram diferença significativa a favor do grupo B sobre o grupo A para tempo de hospitalização em dias 4,33 ± 2,79 e 5,4 ± 1,67 (p<0,001), tempo de antibiótico profilático em horas 28,13 ± 33,77 e 81,49 ± 40,91 (p<0,001), encaminhamento para unidade de terapia intensiva 40,9% e 73,4% (p<0,001), início da tromboprofilaxia dentro de 24h 97,9% e 82,5% (p<0,001), uso de meias elásticas e/ou compressão intermitente prescritos para tromboprofilaxia 89,5% e 31,2% (p<0,001), tempo para iniciação da reabilitação em 24h 90,1% e 66,1% (p<0,001), readmissões em 30 dias 4,1% e 3% (p = 0,76), readmissões 90 dias 2,7% e 6,6% (p = 0,183), transfusões 5,5% e 15,2% (p = 0,033). Conclusão: A implementação de um PCCA multiprofissional contribuiu para o cumprimento dos protocolos assistenciais favorecendo maior segurança para os pacientes. Nível de Evidência III; Estudo Retrospectivo Comparativo.

Primary results of the brazilian registry of atherothrombotic disease (NEAT).

There is limited contemporary prospective real-world evidence of patients with chronic arterial disease in Latin America. The Network to control atherothrombosis (NEAT) registry is a national prospective observational study of patients with known coronary (CAD) and/or peripheral arterial disease (PAD) in Brazil. A total of 2,005 patients were enrolled among 25 sites from September 2020 to March 2022. Patient characteristics, medications and laboratorial data were collected. Primary objective was to assess the proportion of patients who, at the initial visit, were in accordance with good medical practices (domains) for reducing cardiovascular risk in atherothrombotic disease. From the total of patients enrolled, 2 were excluded since they did not meet eligibility criteria. Among the 2,003 subjects included in the analysis, 55.6% had isolated CAD, 28.7% exclusive PAD and 15.7% had both diagnoses. Overall mean age was 66.3 (± 10.5) years and 65.7% were male patients. Regarding evidence-based therapies (EBTs), 4% were not using any antithrombotic drug and only 1.5% were using vascular dose of rivaroxaban (2.5 mg bid). Only 0.3% of the patients satisfied all the domains of secondary prevention, including prescription of EBTs and targets of body-mass index, blood pressure, LDL-cholesterol, and adherence of lifestyle recommendations. The main barrier for prescription of EBTs was medical judgement. Our findings highlight that the contemporary practice does not reflect a comprehensive approach for secondary prevention and had very low incorporation of new therapies in Brazil. Large-scale populational interventions addressing these gaps are warranted to improve the use of evidence-based therapies and reduce the burden of atherothrombotic disease.ClinicalTrials.gov NCT04677725.

Main Pathogens Causing Infections and Antibiotic Resistance Profile in Major Burns in Brazil Comparing Two Periods: 2015/2016 and 2019/2020.

Sepsis is the main cause of death in major burns. In this retrospective study conducted in a reference hospital in Brazil, the main agents causing infection and the resistance profile to antibiotics were identified. In addition, the epidemiological profile, length of hospital stay, type of burn, and total body surface area (TBSA) in major burns were collected from medical records, comparing the years 2015/2016 and 2019/2020. In both time periods, there was a predominance of males with a mean age of 43 years. Burns with less than 30% of TBSA predominated. There was a significant increase in positive cultures (P = .00026), from 58.7% to 80%, and an increase in skin punch culture collection from 25.6% to 43.9% in the years 2019/2020. The predominant etiological agent was Pseudomonas aeruginosa, followed by Acinetobacter baumannii resistant to carbapenems, and Staphylococcus aureus in both evaluated periods. The percentage of deaths was higher in 2019/2020 (26.2% vs. 14.6%; P = .026). The length of hospital stay was shorter in the latter period (P = .0081). Sepsis was the cause of death in 81.2% of cases in 2015/2020 and 78.3% in 2019/2020. Among the deaths, P. aeruginosa was the main agent identified. There was no change in the main pathogens and bacterial antibiotic resistance between the 2 time periods.

Prediction of acute fish toxicity (AFT) and fish embryo toxicity (FET) tests by cytotoxicity assays using liver and embryo zebrafish cell lines (ZFL and ZEM2S).

Fish cell-based assays represent potential alternative methods to vertebrates' use in ecotoxicology. In this study, we evaluated the cytotoxicity of thirteen chemicals, chosen from OECD guidelines 236 and 249, in two zebrafish cell lines (ZEM2S and ZFL). We aimed to investigate whether the IC50 values obtained by viability assays (alamar blue, MTT, CFDA-AM, and neutral red) can predict the LC50 values of Acute Fish Toxicity (AFT) test and Fish Embryo Toxicity (FET) test. There was no significant difference between the values obtained by the different viability assays. ZFL strongly correlated with AFT and FET tests (R2AFT = 0.73-0.90; R2FET48h = 0.79-0.90; R2FET96h = 0.76-0.87), while ZEM2S correlated better with the FET test (48h) (R2 = 0.70-0.86) and weakly with AFT and FET tests (96h) (R2AFT = 0.68-0.74 and R2FET96h = 0.62-0.64). The predicted LC50 values allowed the correct categorization of the chemicals in 76.9% (AFT test) - 90.9% (FET test) using ZFL and in 30.7% (AFT test) - 63.6% (FET test) using ZEM2S considering the US EPA criterion for classifying acute aquatic toxicity. ZFL is a promising cell line to be used in alternative methods to adult fish and fish embryos in ecotoxicity assessments, and the method performed in 96-well plates is advantageous in promoting high-throughput cytotoxicity assessment.

Benefits of a clinical pathway in total knee arthroplasty / Beneficios de um programa de cuidados clínicos em artroplastia total de joelho

ABSTRACT Objective: Demonstrate whether a multiprofessional Clinical Pathway Program in Total Knee Arthroplasty (CPPA) contributesto optimizing hospital care. Method: Retrospective study of medical data of care indicators in 310 patients divided into two groups: A- who underwent arthroplasty in the last biennium before the introduction of the CPPA (n=144) and group B- who underwent TKA in the biennium after the introduction of the CPPA (n=166). Results: Postoperative showed a significant difference in favor of group B over group A for hospitalization time in days 4.33 ± 2.79 and 5.4 ± 1.67 (p<0.001), time of prophylactic antibiotic in hours 28.13 ± 33.77 and 81.49 ± 40.91 (p<0.001), referral to the intensive care unit 40.9% and 73.4% (p<0.001), initiation of thromboprophylaxis within 24 hours 97.9% and 82.5% (p<0.001), use of elastic stockings and/or intermittent compression prescribed for thromboprophylaxis 89.5% and 31.2% (p<0.001), initiation of rehabilitation within 24 hours 90.1% and 66.1% (p<0.001), readmissions within 30 days 4.1% and 3% (p = 0.76), readmissions 90 days 2.7% and 6.6% (p = 0.183), transfusions 5.5% and 15.2% (p = 0.033). Conclusion: The implementation of a multiprofessional CPPA contributed to the implementation of care protocols, favoring greater patient safety. Level of Evidence III; Retrospective Comparative Study.

RESUMO Objetivo: Demonstrar se um Programa de Cuidados Clínicos multiprofissional em Artroplastia Total de Joelho (PCCA) contribui para a otimização assistencial hospitalar. Método: Estudo retrospectivo em prontuários de indicadores assistenciais em 310 pacientes divididos em dois grupos: A- submetidos a artroplastia no último biênio antecessor a introdução do PCCA (n=144) e grupo B- submetidos a ATJ no biênio após a introdução do PCCA (n=166). Resultados: Indicadores pós-operatórios mostraram diferença significativa a favor do grupo B sobre o grupo A para tempo de hospitalização em dias 4,33 ± 2,79 e 5,4 ± 1,67 (p<0,001), tempo de antibiótico profilático em horas 28,13 ± 33,77 e 81,49 ± 40,91 (p<0,001), encaminhamento para unidade de terapia intensiva 40,9% e 73,4% (p<0,001), início da tromboprofilaxia dentro de 24h 97,9% e 82,5% (p<0,001), uso de meias elásticas e/ou compressão intermitente prescritos para tromboprofilaxia 89,5% e 31,2% (p<0,001), tempo para iniciação da reabilitação em 24h 90,1% e 66,1% (p<0,001), readmissões em 30 dias 4,1% e 3% (p = 0,76), readmissões 90 dias 2,7% e 6,6% (p = 0,183), transfusões 5,5% e 15,2% (p = 0,033). Conclusão: A implementação de um PCCA multiprofissional contribuiu para o cumprimento dos protocolos assistenciais favorecendo maior segurança para os pacientes. Nível de Evidência III; Estudo Retrospectivo Comparativo.

Prolactin does not seem to mediate the improvement on insulin resistance markers and blood glucose levels related to breastfeeding.

Introduction: The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Strategies to decrease this risk should be strongly encouraged. Lactation has been associated, for the mother, with reduction in future T2DM risk in several studies. The mechanisms behind this phenomenon, however, are poorly understood. The aims of this study were, first, to compare blood glucose levels and markers of insulin resistance (MIR) in early postpartum women with overweight/obesity according to their breastfeeding status and, second, to evaluate whether prolactin (PRL) levels could mediate improvements in these parameters. Methods: The prospective study followed 95 women older than 18 years from early pregnancy for up to 60 to 180 days postpartum. All participants had a BMI > 25 kg/m2 and a singleton pregnancy. At each visit, questionnaires and clinical and biochemical evaluations were performed. Participants were divided into two groups according to the breastfeeding status as "yes" for exclusive or predominant breastfeeding, and "no" for not breastfeeding. Results: Breastfeeding women (n = 44) had significantly higher PRL levels [47.8 (29.6-88.2) vs. 20.0 (12.0-33.8), p< 0.001]. They also had significantly lower fasting blood glucose levels [89.0 (8.0) vs. 93.9 (12.6) mg/dl, p = 0.04], triglycerides (TG) [92.2 (37.9) vs. 122.4 (64.4) mg/dl, p = 0.01], TG/HDL ratio [1.8 (0.8) vs. 2.4 (1.6) mg/dl, p = 0.02], TyG index [8.24 (0.4) vs. 8.52 (0.53), p = 0.005], fasting serum insulin [8.9 (6.3-11.6) vs. 11.4 (7.7-17.0), p = 0.048], and HOMA-IR [2.0 (1.3-2.7) vs. 2.6 (1.6-3.9), p = 0.025] in the postpartum period compared to the non-breastfeeding group. Groups were homogeneous in relation to prevalence of GDM, pre-gestational BMI, as well as daily caloric intake, physical activity, and weight loss at postpartum. Linear regression analysis with adjustments for confounders showed a statistically significant association of breastfeeding with fasting blood glucose [-6.37 (-10.91 to -1.83), p = 0.006], HOMA-IR [-0.27 (-0.51 to -0.04), p = 0.024], TyG index [-0.04 (-0.06 to -0.02), p = 0.001], and TG/HDL ratio [-0.25 (-0.48 to -0.01), p = 0.038]. Mediation analysis showed that PRL did not mediate these effects. Sensitivity analyses considering different cutoffs for PRL levels also did not show modification effect in the mediation analyses. Conclusion: Breastfeeding was associated with improvement in glucose metabolism and MIR 60 to 180 days after birth in overweight and obese women, even when adjusted for confounders. PRL levels were not found to mediate the association between breastfeeding and improvement in MIR.

Responses of patients with cancer to mRNA vaccines depend on the time interval between vaccination and last treatment.

BACKGROUND: Personalized mRNA vaccines are promising new therapeutic options for patients with cancer. Because mRNA vaccines are not yet approved for first-line therapy, the vaccines are presently applied to individuals that received prior therapies that can have immunocompromising effects. There is a need to address how prior treatments impact mRNA vaccine outcomes. METHOD: Therefore, we analyzed the response to BioNTech/Pfizer's anti-SARS-CoV-2 mRNA vaccine in 237 oncology outpatients, which cover a broad spectrum of hematologic malignancies and solid tumors and a variety of treatments. Patients were stratified by the time interval between the last treatment and first vaccination and by the presence or absence of florid tumors and IgG titers and T cell responses were analyzed 14 days after the second vaccination. RESULTS: Regardless of the last treatment time point, our data indicate that vaccination responses in patients with checkpoint inhibition were comparable to healthy controls. In contrast, patients after chemotherapy or cortisone therapy did not develop an immune response until 6 months after the last systemic therapy and patients after Cht-immune checkpoint inhibitor and tyrosine kinase inhibitor therapy only after 12 months. CONCLUSION: Accordingly, our data support that timing of mRNA-based therapy is critical and we suggest that at least a 6-months or 12-months waiting interval should be observed before mRNA vaccination in systemically treated patients.

Perturbation-based balance training leads to improved reactive postural responses in individuals with Parkinson's disease and freezing of gait.

Perturbation-based balance training (PBT) exposes individuals to a series of sudden upright balance perturbations to improve their reactive postural responses. In this study, we aimed to evaluate the effect of a short PBT program on body balance recovery following a perturbation in individuals with freezing of gait due to Parkinson's disease. Volunteers (mean age = 64 years, SD = 10.6) were pseudorandomly assigned either to a PBT (n = 9) or to a resistance training (RT, n = 10) group. PBT was implemented through balance perturbations varying in the kind, direction, side and magnitude of support base displacements. Both groups exercised with progressive difficulty/load activities twice a week for 4 weeks. Specific gains and generalization to dual-tasking and faster-than-trained support base displacements were evaluated 24 h after the end of the training, and retention was evaluated after 30 days of no training. Results showed that, compared with RT, PBT led to more stable postural responses in the 30-day retention evaluation, as indicated by decreased CoP displacement, velocity and time to direction reversal and reduced numbers of near-falls. We found no transfer either to a dual task or to a higher perturbation velocity. In conclusion, a training program based on diverse unpredictable balance perturbations improved the stability of reactive postural responses to those perturbations suffered during the training, without generalization to more challenging tasks.

Genotoxicity and Anticancer Effects of the Aminothiophene Derivatives SB-44, SB- 83, and SB-200 in Cancer Cells.

INTRODUCTION: Thiophene derivatives have been widely studied as promising options for the treatment of solid tumors. Previous studies have shown that thiophene derivatives have antileishmanial activity and cytotoxic activity against breast, colon, and ovarian cancer cells. METHODS: In our study, we evaluated the anticancer activities of three aminothiophene derivatives: SB-44, SB-83, and SB-200, in prostate and cervical adenocarcinoma cells. Several in vitro methods were performed, including cytotoxicity, clonogenic migration, mutagenic, and cleaved Poly (ADP-ribose) polymerase (PARP) assays and annexin V staining. RESULTS: Significant cytotoxicity was observed in cell lines with IC50 values less than 35 µM (15.38-34.04 µM). All aminothiophene derivatives significantly reduced clone formation but had no effect on cell motility. SB-83 and SB-44 induced a significant increase in the percentage of cells in the sub-G1 phase, while SB-200 derivatives significantly decreased the percentage of S/G2/M as well as induced apoptosis, with an increase of cleaved PARP. SBs compounds also showed significant mutagenic potential. Beyond that, in silico analyses revealed that all three thiophene derivatives fulfilled the criteria for oral druggability, which underscores the potential of using them in anticancer therapies. CONCLUSION: Our findings show that the thiophene nucleus may be used to treat solid tumors, including prostate cancer and cervical adenocarcinoma.

Leptospira spp. in Free-Ranging Capybaras (Hydrochoerus hydrochaeris) from Midwestern Brazil.

Background: Leptospirosis is a contagious disease that affects domestic and wild animals as well as humans. It is caused by infection with some pathogenic species of the genus Leptospira. In Brazil, studies on leptospirosis in capybaras are scarce or nonexistent in some regions, such as the Federal District. The objective of this study was to analyze the presence of DNA of the agent and/or anti-Leptospira spp. antibodies in capybaras. Materials and Methods: Blood samples were collected from 56 free-living capybaras captured in two different sites in the study region. The samples were submitted to hematology and clinical chemistry tests. To identify Leptospira positive samples, a conventional PCR (cPCR) and analysis of anti-Leptospira spp. antibodies by microscopic agglutination test (MAT) were used. Results: No animal showed cPCR amplification of the Lip32 gene, but 41.1% (23/56) of the animals had anti-Leptospira spp. antibodies on MAT. The serovars present were icterohaemorrhagiae (82.61%), copenhageni (65.22%), grippotyphosa (4.35%), and hardjo (4.35%). In the laboratorial tests, differences (p < 0.05) were observed in the biochemical assays of alkaline phosphatase, creatinine, albumin, and globulin. Although these values differed significantly between groups, they all remained within reference range (excluding albumin), and thus there is not enough to infer that this alteration could be caused by Leptospira infection. Conclusions: cPCR using whole blood samples to evaluate Leptospira spp. infection of free-living capybaras was not an efficient tool. The presence of Leptospira seroreactive capybaras shows that the bacteria are circulating in the urban environment of the Federal District.

Alkaloids (emetine and cephalin) production - affected by full sunlight stress in Carapichea ipecacuanha.

This study evaluated the responses of Carapichea ipecacuanha to sunlight stress-induced changes in the electron transport chain and its extended effects on alkaloid production (emetine and cephalin). The treatments consisted of: (i). 50, 70, and 90% shading (controls) and their respective exposure to full sunlight; besides, full sunlight (55 days of direct sun exposure). Photosynthetic pigments, chlorophyll a fluorescence transient, antioxidant enzymatic system, and quantification of cephalin and emetine were analyzed. Several changes in the Chl a fluorescence induction were observed, such as a decline in the quantum yield of the conversion of photochemical energy and photosynthetic performance and; an increase in emetine production of plants exposed to full sunlight. These results demonstrated that ipecac plants are extremely sensitive to full exposure to solar radiation, especially in periods with high temperatures, such as in summer, however with increment in emetine production.

Synthesis by Microwave Irradiation, Molecular Structural Analysis and Trypanocidal Activity of Novel Pyrazole-tetrahydropyrimidine Derivatives.

BACKGROUND: A series of new eight 2-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1,4,5,6-tetrahydropyrimidines 1(a-h) were synthesized by microwave irradiation technique. In vitro phenotypic screening was performed to evaluate the effect of these compounds on intracellular amastigotes forms of Trypanosoma cruzi, the etiological agent of Chagas disease. METHODS: Compounds 1(a-h) were synthesized from pyrazole-carbonitriles 2(a-h) employing microwave irradiation (50W) for 10-20 minutes. Physicochemical properties were calculated using OSIRIS DataWarrior. The toxic effect on mammalian cells (Vero Cells) and the trypanocidal activity against Trypanosoma cruzi (Dm28c-Luc) were also evaluated. RESULTS: Compounds 1(a-h) were obtained in 24-94% yields. They were completely characterized by Fourier Transform Infrared (FT-IR), Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS) analyses. The derivatives showed low trypanocidal activity, with IC50 ranging from 47.16 to > 100 µM, with lower activity than benznidazole (1.93 µM) used as reference drug. CONCLUSION: The attractive features of this synthetic methodology are mild conditions, short reaction time, and low power. All derivatives showed low toxicity in mammalian cells, good oral bioavailability, and did not violate Lipinski´s rule of 5.

Evaluation of oxidative damage to biomolecules and inflammation in patients with urea cycle disorders.

Urea cycle disorders (UCD) are inborn errors of metabolism that occur due to a loss of function in enzymes and transporters involved in the urea cycle, causing an intoxication by hyperammonemia and accumulation of metabolites. Patients can develop hepatic encephalopathy (HE), severe neurological and motor disabilities, and often death. The mechanisms involved in the pathophysiology of UCD are many and complex, but there are strong indications that oxidative stress and inflammation are present, being responsible for at least part of the cellular damage that occurs in these diseases. The aim of this study was to evaluate oxidative and nitrosative damage and inflammation in UCD, to better understand the pathophysiology mechanisms of these diseases. We evaluated the nitrite and nitrate content, thiobarbituric acid-reactive substances (TBARS), carbonyl protein content and a panel of cytokines in plasma sample of 14 patients. The UCD patients group consisted of individuals affected with ornithine transcarbamylase deficiency (n = 8), carbamoyl phosphate synthetase deficiency (n = 2), argininosuccinate synthetase deficiency (n = 2); arginase 1 deficiency (n = 1) and argininosuccinate lyase deficiency (n = 1). Patients mean age at diagnosis was 5.25 ± 9.86 years-old and mean concentrations were compared with healthy individuals of matched age and gender. We found a significant reduction in nitrogen reactive species in patients when compared to controls. TBARS was increased in patients, indicating lipid peroxidation. To evaluate protein oxidative damage in UCD, the carbonyl content was measured, and the results also demonstrated an increase in this biomarker. Finally, we found that UCD patients have enhanced concentrations of cytokines, with pro-inflammatory interleukins IL-6, IL-8, interferon-γ and TNF-α, and anti-inflammatory IL-10 being increased when compared to the control group. In conclusion, our results demonstrate that oxidative stress and inflammation occurs in UCD and probably contribute to the severe brain damage present in patients.