Avaliação do perfil de mortalidade por síndrome cardiorrenal na última década do Município de São Paulo / Assessment of the mortality profile due to cardiorenal syndrome in the last decade in the city of São Paulo

INTRODUÇÃO: A síndrome cardiorrenal é uma condição complexa que afeta tanto o coração quanto os rins, representando um desafio significativo para a saúde pública devido à associação com complicações graves e alta taxa de mortalidade. A análise dos padrões de mortalidade decorrentes dessa síndrome em São Paulo, no período de 2013 a 2023, é crucial para aprimorar os cuidados clínicos e mitigar óbitos relacionados a essa condição. Compreender a extensão do problema e identificar padrões de mortalidade pode fornecer informações cruciais para melhorar a prestação de cuidados de saúde e direcionar recursos de forma mais eficaz. OBJETIVO: Fornecer um panorama epidemiológico da síndrome cardiorrenal de 2013 a 2023. MÉTODOS: O estudo em consideração empreende uma análise epidemiológica, descritiva e transversal, utilizando os dados provenientes do banco de saúde DATASUS (TABNET) referentes a 2013 até 2023 no município de São Paulo. Este se aprofunda na investigação das variáveis fundamentais: cor, sexo e faixa etária. RESULTADOS: Analisando os dados coletados entre 2013 e 2023, foram registrados 1.293 óbitos por síndrome cardiorrenal no município de São Paulo, sendo 2021 o ano de maior incidência de óbitos (180). No tangente à cor, os brancos representam o maior número (65,82%), seguidos por pardos (20,53%), negros (12,37%), amarelos (1,26%). Quanto ao sexo, há predominância no feminino (54,60%). Em relação à faixa etária, aqueles que possuem 75 anos ou mais são os mais afetados e representam 63,95% do total, sendo o grupo etário mais acometido em 2021 (65,55%). CONCLUSÕES: Analisando os dados coletados, podemos observar: O sexo feminino teve maior mortalidade, variando de 50% a 60%. A etnia branca, variando entre 60% e 70%. Também foi encontrada uma maior mortalidade na faixa etária de 75 anos ou mais, com uma variação entre 51% e 77%. Também podemos notar uma diminuição do número relativo de mortes da faixa etária de 55-64, com uma porcentagem de 17% no ano de 2013 que diminuiu para a metade a partir de 2019. Também é notável a influência da pandemia de COVID-19 em 2021 e sua influência para o aumento de mortes por síndrome cardiorrenal. A elevação na mortalidade nos últimos anos pode ser atribuído ao aumento na incidência populacional de agentes lesivos cardiorrenais (principalmente diabetes e hipertensão) e ao manejo insuficiente de tais fatores de risco. Estudos complementares e incrementos na saúde pública são necessários para melhorar tais parâmetros.

Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

5-Fluoroindole Reduces the Bacterial Burden in a Murine Model of Mycobacterium tuberculosis Infection.

Tuberculosis is a disease caused by a single pathogen that leads to a death toll estimated to be more than a million per year. Mycobacterium tuberculosis (Mtb), which affects mainly the lungs, spreads by airborne transmission when infectious respiratory particles from an infected human enter the respiratory tract of another person. Despite diagnosis and treatment being well established, the rise of cases of patients infected with Mtb strains with multidrug resistance to the antibiotics used in the regimen against the disease is alarming. Indole used as a core molecule has been described as a promising structure to treat several diseases. 5-Fluoroindole (5-FI) compound, evaluated in the free base and in the hydrochloride (5-FI.HCl) forms, inhibited the growth of pan-sensitive Mtb H37Rv strain in the same range (4.7-29.1 µM) of clinical isolates that have resistance to at least two first-line drugs. Although 5-FI showed no cytotoxicity in Vero and HepG2 cells, high permeability (2.4.10-6 cm/s) in the PAMPA assay, and high metabolic stability (Clint 9.0 mL/min/kg) in rat liver microsomes, limited solubility at plasmatic and intestinal pH values prompted formation and employment of its salt form (5-FI.HCl). Although the 5-FI.HCl compound showed increased solubility at pH values of 7.4 and 9.1 and increased stability in aqueous solutions, data for intrinsic clearance (Clint = 48 mL/min/kg) and a half-life (t 1/2 = 12 min) showed decreased metabolic stability. As 5-FI.HCl showed both good absorption and ability to reach the systemic circulation of animals without the need to use vehicles containing cosolvents or surfactants, it was chosen to evaluate its effectiveness in the model of tuberculosis in mice. The in vivo results showed the concentration of the compound in plasma increasing within 30 min in the systemic circulation and the capacity of reducing the Mtb burden in the lungs at the concentration of 200 µmol/kg after 21 days of infection, with no toxicity in mice.

Renal ischemia/reperfusion induces prominent progressive kidney disease in diabetic mice.

Acute kidney injury (AKI) is a public health concern associated with high rates of mortality, even in milder cases. One of the reasons for the difficulty in managing AKI in patients is due to its association with pre-existing comorbidities, such as diabetes. In fact, diabetes increases the susceptibility to develop more severe AKI after renal ischemia. However, the long-term effects of this association are not known. Thus, an experimental model was designed to evaluate the chronic effects of renal ischemia/reperfusion (IR) in streptozotocin (STZ)-treated mice. We focused on the glomerular and tubulointerstitial damage, as well as kidney function and metabolic profile. It was found that pre-existing diabetes may potentiate progressive kidney disease after AKI, mainly by exacerbating proinflammatory and sustaining fibrotic responses and altering renal glucose metabolism. To our knowledge, this is the first report that highlights the long-term effects of renal IR on diabetes. The findings of this study can support the management of AKI in clinical practice.NEW & NOTEWORTHY This study demonstrated that early diabetes potentiates progressive kidney disease after ischemia/reperfusion (IR)-induced acute kidney injury, mainly by exacerbating pro-inflammatory and sustaining fibrotic responses and altering renal glucose metabolism. Thus, these findings will contribute to the therapeutic support of patients with type 1 diabetes with eventual renal IR intervention in clinical practice.

Exploring the BSA- and DNA-binding, cytotoxicity, and cell cycle evaluation of ternary copper(II)/diimine complexes with N,N-dibenzyl-N'-benzoylthiourea as promising metallodrug candidates.

Four new copper(II) complexes were synthesized and characterized with the general formula [Cu(N-N)(Th)(NO3)], where N-N corresponds to the N-heterocyclic ligands 1,10-phenanthroline (phen), 2,2'-bipyridine (bipy), 4,7-diphenyl-1,10-phenanthroline (dpp), and 4,4-dimethyl-2,2'-bipyridine (dmbp) and Th represents the N,N-dibenzyl-N'-benzoylthiourea. Cytotoxic activities of the complexes against HCT116 (human colon carcinoma), HepG2 (human hepatocellular carcinoma), and non-tumor MRC-5 (human lung fibroblast) cells were investigated. The copper(II) complexes 1-4 were characterized by spectroscopic techniques while complexes 1 and 2 were studied using single-crystal X-ray diffraction as well. The complexes possessed a five-coordinated structure with one nitrate ligand as a monodentate at the axial position and two bidentate ligands N-heterocyclic and N,N-dibenzyl-N'-benzoylthiourea. The complexes showed promising IC50 values, ranging from 0.3 to 9.0 µM. Furthermore, interaction studies with biomolecules such as calf thymus DNA (ct-DNA) and Bovine Serum Albumin (BSA), which can act as possible biological targets of the complexes, were carried out. The studies suggested that the compounds interact moderately with ct-DNA and BSA. Complexes 1, 2, and 4 did not lead to cell accumulation at any stage of the cell cycle but caused a significant increase in internucleosomal DNA fragmentation. Whereas, compound 3 caused cell cycle arrest in the S phase while doxorubicin caused cell cycle arrest in the G2/M phase. The effect of structural modifications on the metal compounds was correlated with their biological properties and it was concluded that an increase in biological activity occurred with increasing the extension of the diimine ligands. Thus, complex 3 was the most promising one.

Análise epidemiológica da mortalidade por cardiomiopatia periparto entre as pacientes do município de São Paulo na última década / Epidemiological analysis of mortality due to peripartum cardiomyopathy among patients in the city of São Paulo in the last decade

INTRODUÇÃO: A Cardiomiopatia Periparto (CMPP) é uma insuficiência cardíaca (IC), idiopática, que acomete gestantes e puérperas, desde o 9° mês de gravidez até o 5° mês pósparto. Os sintomas são semelhantes às alterações fisiológicas gestacionais, o que dificulta o diagnóstico. No entanto, a diminuição da função sistólica ventricular esquerda, associada à ausência de doença cardíaca prévia e outra etiologia determinável para IC, falam a favor da CMPP. O prognóstico varia, sendo possível haver recuperação completa do ventrículo esquerdo, disfunção cardíaca persistente, necessidade de transplante e óbito. Não há dados consistentes quanto à prevalência da CMPP, mas estima-se que 1 a cada 4000 gestações tenha esse desfecho. OBJETIVO: Analisar a mortalidade por cardiomiopatia periparto entre as pacientes do município de São Paulo na última década. MÉTODOS: O estudo elaborado trata-se de uma análise epidemiológica, descritiva e transversal. Os dados expostos foram obtidos através do banco informativo de saúde DATASUS (TABNET) entre 2013 a 2023, do município de São Paulo. A análise utiliza as variáveis: cor, faixa etária e escolaridade. RESULTADOS: Durante a última década, apenas 31 mortes por CMPP foram registradas no município de São Paulo. A taxa de mortalidade não seguiu padrões de aumento ou redução ao longo do tempo. A média de registros foi de 3 por ano. O parâmetro cor apresentou uma diferença pouco significativa, pois 55% das padecedoras eram brancas, e 45% pretas ou pardas. Quanto à faixa etária, a maioria das mulheres tinham entre 25 e 34 anos (44%), já as faixas entre 15 a 24 e 35 a 44 anos representaram a mesma porcentagem de 26%. Acerca da escolaridade, padeceram mais mulheres com 8 a 11 anos de estudo (48%), seguido por 26% que frequentaram a escola por 4 a 7 anos. Os grupos que tiveram 1 a 3 e 12 ou mais anos de escolaridade, representaram 6,5% cada, e outras 13% não informaram esse parâmetro. Conclusões: Os resultados sugerem que faleceram mais mulheres por cardiomiopatia periparto com idade entre 25 e 35 anos e com escolaridade de 8 a 11 anos. Apesar dessas conclusões, o estudo demonstrou, sobretudo, uma preocupante subnotificação da prevalência e dos óbitos pela CMPP. Diante de possíveis prognósticos desfavoráveis, aprimorar o diagnóstico e registro dessa patologia é substancial para torná-la evidente, incentivando o aumento de pesquisas que contribuirão para melhores desfechos no futuro.

Avaliação do perfil de mortalidade por cardiomegalia na última década do município de São Paulo / Assessment of the mortality profile due to cardiomegaly in the last decade in the city of São Paulo

INTRODUÇÃO: A cardiomegalia é uma condição, na qual o coração assume um tamanho maior e desproporcional diante de um estímulo estressor. Nesse contexto, para aumentar a performance cardíaca ocorre hipertrofia dos cardiomiócitos. No entanto, esse mecanismo torna-se patológico quando o crescimento celular excede a angiogênese, deprimindo assim a função contrátil. O aumento cardíaco pode ser transitório, como em atletas e gestantes, ou secundário a condições sustentadas, como hipertensão arterial, etilismo, doenças infecciosas e mutações genéticas. Apesar de frequentemente ser assintomática, a cardiomegalia é um fator de risco importante para arritmias, insuficiência cardíaca, eventos tromboembólicos e morte súbita. OBJETIVO: Analisar a mortalidade por cardiomegalia no município de São Paulo entre 2013 e 2023. MÉTODOS: Este estudo é uma análise epidemiológica, descritiva e transversal. Os dados expostos foram obtidos através do banco informativo de saúde DATASUS (TABNET) entre os anos de 2013 e 2023, do município de São Paulo. A análise utiliza as variáveis: cor, sexo e faixa etária. Resultados: Em 10 anos, foram registrados 2244 óbitos por cardiomegalia no município de São Paulo. Nesse período, a taxa de mortalidade teve um aumento progressivo de 248%, e 2023 foi o ano de maior incidência (374). Quanto à cor, brancos representaram o maior número de padecedores (60%), seguidos por pardos (27,6%), pretos (11%) e amarelos (1,2%). Quanto ao sexo prevalente, mais da metade dos afetados eram homens (65,86%). Por último, foram registradas mortes em todas as faixas etárias, desde indivíduos menores de 1 ano (8) até maiores de 75 anos (529). Sendo que, 2% eram crianças de até 14 anos, 4% adolescentes e jovens adultos, 53% adultos até 64 anos e 42% idosos acima de 65 anos. CONCLUSÕES: Segundo a análise dos resultados, a taxa de mortalidade por cardiomegalia no município de São Paulo aumentou progressivamente na última década. A incidência de óbitos foi maior em indivíduos brancos (60%), do sexo masculino (66%) e com mais de 35 anos (95%). Por fim, a ampliação de prognósticos fatais pode estar relacionada ao crescimento da prevalência dos fatores de risco. Ademais, é provável que os resultados sejam subnotificados, pois os óbitos de indivíduos que tiveram cardiomegalia, mas faleceram pelas patologias decorrentes dessa condição, podem não estar registrados nos dados obtidos neste estudo.

Estudo comparativo entre as mortalidades por doença renal hipertensiva e doença cardíaca hipertensiva no município de São Paulo na última década / Comparative study between mortality from hypertensive kidney disease and hypertensive heart disease in the city of São Paulo in the last decade

INTRODUÇÃO: O aumento crônico da pressão arterial interfere na hemodinâmica do paciente à medida que, com os níveis elevados de pressão, as artérias são prejudicadas e suas paredes danificadas. Ao longo do tempo, o paciente manifesta doença hipertensiva, que pode ter diferentes etiologias; como doença cardíaca hipertensiva ou doença renal hipertensiva. A doença cardíaca hipertensiva, é uma condição clínica multifatorial caracterizada por elevação sustentada dos níveis pressóricos de pressão arterial sistólica - maior ou igual a 140 mmHg, e aumento da pressão arterial diastólica - maior ou igual a 90 mmHg; que se não tratada, a longo prazo provoca danos irreversíveis ao corpo, aumentando riscos cardiovasculares fatais. Enquanto isso, a doença renal hipertensiva pode se manifestar por doença parenquimatosa renal ou por estenose da artéria renal - caracterizada pela doença aterosclerotica degenerativa ou doença inflamatória, que caso progressão, danifica o parênquima renal. MÉTODOS: O estudo elaborado trata-se de uma análise epidemiológica, descritiva e transversal. Os dados expostos foram obtidos através do banco informativo de saúde DATASUS (TABNET) correspondente aos óbitos por doença renal hipertensiva e doença cardíaca hipertensiva entre os anos de 2013 a 2023, do município de São Paulo. A análise utiliza as variáveis: cor, sexo e faixa etária. RESULTADOS: Analisando os dados coletados, é notável a prevalência da incidência de óbitos por doença hipertensiva cardíaca em comparação com a doença hipertensiva renal. Contudo, é perceptivel uma semelhança entre as predominâncias de óbitos entre ambas enfermidades nas variáveis cor e faixa etária, com certa discrepância na variavel sexo. No quesito cor, a predominância foi da cor branca em ambas; representando 61,43% na doença renal hipertensiva e 66,96% na doença cardíaca hipertensiva. Acerca da variável etária os grupos mais afetados foram aqueles com 75 anos ou mais, representando 48,34% na doença renal hipertensiva e 50,61% na doença cardíaca hipertensiva. Quanto ao sexo, a predominancia foi do sexo masculino na doença renal hipertensiva (52,69%) e feminino na doença cardíaca hipertensiva (55,6%). CONCLUSÕES: Diante deste estudo comparativo, com enfoque na etiologia hipertensiva resultando em mortalidade cardiovascular, nota-se a prevalência da enfermidade na população que, embora seja subdiagnosticada, resulte em uma alta taxa de mortalidade à medida em que há progressão de doença sem o tratamento adequado.

Avaliação da mortalidade hospitalar de pacientes submetidos a revascularização miocárdica na última década em São Paulo / Assessment of hospital mortality of patients undergoing myocardial revascularization in the last decade in São Paulo

INTRODUÇÃO: A doença cardiovascular continua estabelecida como a principal causa de óbito no Brasil e também em São Paulo, tendo como fator de risco cardinal o crescimento de depósitos gordurosos nas artérias coronárias, as chamadas placas de aterosclerose. O tratamento para doença aterosclerótica coronária (DAC) inclui intervenções bem consolidadas na prática, sendo a cirurgia de revascularização miocárdica (CRM) uma das mais importantes medidas terapêuticas no contexto hospitalar, principalmente em pacientes portadores de lesões triarteriais ou com diabetes associada. Nesse sentido, a CRM vem apresentando importantes avanços em relação à redução da mortalidade e morbidade inerentes ao procedimento cirúrgico, principalmente através das inovações tecnológicas dos últimos anos. Sendo assim, o seguinte trabalho se objetiva a analisar a mortalidade da revascularização miocárdica em pacientes com DAC supracitadas, para uma melhoria da assistência hospitalar e das políticas públicas de saúde, pleiteando uma mortalidade hospitalar cada vez menor. MÉTODOS: Estudo de caráter epidemiológico, descritivo e transversal. Foi realizada coleta de dados através do banco informativo de saúde DATASUS (TABNET), correspondente aos óbitos de pacientes submetidos a revascularização miocárdica entre os anos de 2013 a 2023 no município de São Paulo. As variáveis utilizadas são: raça/cor, sexo e faixa etária. RESULTADOS: Analisando os dados coletados, é notável que o ano de maior incidência de óbitos foi 2014 com 123 óbitos, representando aproximadamente 13,91% do total do período estudado. A raça mais afetada foi a branca, com 65% dos óbitos. Já a faixa etária mais acometida foi entre 65 e 69 anos, totalizando 22,05% dos óbitos. Em relação ao sexo, a prevalência é masculina, caracterizando 58,37% dos óbitos. CONCLUSÕES: Em relação à abordagem terapêutica analisada nos últimos 10 anos no município de São Paulo, foi verificada uma maior mortalidade no sexo masculino, em idades avançadas e na raça branca. Além disso, é importante destacar que houve uma redução significativa nas taxas de desfecho cardiovascular primário nos pacientes submetidos ao procedimento. Esse cenário reforça a projeção da CRM como um tratamento cada vez mais seguro e eficiente no contexto das doenças coronarianas.

Enhancing RECK Expression Through miR-21 Inhibition: A Promising Strategy for Bladder Carcinoma Control.

Bladder carcinoma (BC) is the tenth most frequent malignancy worldwide, with high morbidity and mortality rates. Despite recent treatment advances, high-grade BC and muscle-invasive BC present with significant progression and recurrence rates, urging the need for alternative treatments. The microRNA-21 (miR-21) has superexpression in many malignancies and is associated with cellular invasion and progression. One of its mechanisms of action is the regulation of RECK, a tumor suppressor gene responsible for inhibiting metalloproteinases, including MMP9. In a high-grade urothelial cancer cell line, we aimed to assess if miR-21 downregulation would promote RECK expression and decrease MMP9 expression. We also evaluated cellular migration and proliferation potential by inhibition of this pathway. In a T24 cell line, we inhibited miR-21 expression by transfection of a specific microRNA inhibitor (anti-miR-21). There were also control and scramble groups, the last with a negative microRNA transfected. After the procedure, we performed a genetic expression analysis of miR-21, RECK, and MMP9 through qPCR. Migration, proliferation, and protein expression were evaluated via wound healing assay, colony formation assay, flow cytometry, and immunofluorescence.After anti-miR-21 transfection, miR-21 expression decreased with RECK upregulation and MMP9 downregulation. The immunofluorescence assay showed a significant increase in RECK protein expression (p < 0.0001) and a decrease in MMP9 protein expression (p = 0.0101). The anti-miR-21 transfection significantly reduced cellular migration in the wound healing assay (p < 0.0001). Furthermore, in the colony formation assay, the anti-miR-21 group demonstrated reduced cellular proliferation (p = 0.0008), also revealed in the cell cycle analysis by flow cytometry (p = 0.0038). Our results corroborate the hypothesis that miR-21 is associated with BC cellular migration and proliferation, revealing its potential as a new effective treatment for this pathology.

Evaluation of glomerular sirtuin-1 and claudin-1 in the pathophysiology of nondiabetic focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.

Development of a Melting-Curve-Based Multiplex Real-Time PCR Assay for the Simultaneous Detection of Viruses Causing Respiratory Infection.

The prompt and accurate identification of the etiological agents of viral respiratory infections is a critical measure in mitigating outbreaks. In this study, we developed and clinically evaluated a novel melting-curve-based multiplex real-time PCR (M-m-qPCR) assay targeting the RNA-dependent RNA polymerase (RdRp) and nucleocapsid phosphoprotein N of SARS-CoV-2, the Matrix protein 2 of the Influenza A virus, the RdRp domain of the L protein from the Human Respiratory Syncytial Virus, and the polyprotein from Rhinovirus B genes. The analytical performance of the M-m-qPCR underwent assessment using in silico analysis and a panel of reference and clinical strains, encompassing viral, bacterial, and fungal pathogens, exhibiting 100% specificity. Moreover, the assay showed a detection limit of 10 copies per reaction for all targeted pathogens using the positive controls. To validate its applicability, the assay was further tested in simulated nasal fluid spiked with the viruses mentioned above, followed by validation on nasopharyngeal swabs collected from 811 individuals. Among them, 13.4% (109/811) tested positive for SARS-CoV-2, and 1.1% (9/811) tested positive for Influenza A. Notably, these results showed 100% concordance with those obtained using a commercial kit. Therefore, the M-m-qPCR exhibits great potential for the routine screening of these respiratory viral pathogens.

Overexpression of miR-17-5p may negatively impact p300/CBP factor-associated inflammation in a hypercholesterolemic advanced prostate cancer model.

BACKGROUND: Previously, we demonstrated that cholesterol triggers the increase in p300/CBP-associated factor (PCAF), targeted by miR-17-5p. The p300, IL-6, PCAF, and miR-17-5p genes have important and contradictory roles in inflammation and prostate cancer (PCa). This study aimed to demonstrate the potential anti-inflammatory effect of miR-17-5 in an advanced PCa model with diet-induced hypercholesterolemia. METHODS AND RESULTS: In vitro, using the PC-3 cell line, we show that induction of miR-17-5p reduces p300 and PCAF expression, increases apoptosis, and decreases cell migration. Furthermore, we demonstrate that supplementing this same cell with cholesterol (2 µg/mL) triggers increased p300, IL-6, and PCAF. In vivo, after establishing the hypercholesterolemic (HCOL) model, xenografts were treated with miR-17-5p. Increased expression of this miR after intratumoral injections attenuated tumor growth in the control and HCOL animals and reduced cell proliferation. CONCLUSION: Our results demonstrate that inducing miR-17-5p expression suppresses tumor growth and inflammatory mediator expression. Further studies should be conducted to fully explore the role of miR-17-5p and the involvement of inflammatory mediators p300, PCAF, and IL-6.

Intratumoral Restoration of miR-137 Plus Cholesterol Favors Homeostasis of the miR-137/Coactivator p160/AR Axis and Negatively Modulates Tumor Progression in Advanced Prostate Cancer.

MicroRNAs (miRNAs) have gained a prominent role as biomarkers in prostate cancer (PCa). Our study aimed to evaluate the potential suppressive effect of miR-137 in a model of advanced PCa with and without diet-induced hypercholesterolemia. In vitro, PC-3 cells were treated with 50 pmol of mimic miR-137 for 24 h, and gene and protein expression levels of SRC-1, SRC-2, SRC-3, and AR were evaluated by qPCR and immunofluorescence. We also assessed migration rate, invasion, colony-forming ability, and flow cytometry assays (apoptosis and cell cycle) after 24 h of miRNA treatment. For in vivo experiments, 16 male NOD/SCID mice were used to evaluate the effect of restoring miR-137 expression together with cholesterol. The animals were fed a standard (SD) or hypercholesterolemic (HCOL) diet for 21 days. After this, we xenografted PC-3 LUC-MC6 cells into their subcutaneous tissue. Tumor volume and bioluminescence intensity were measured weekly. After the tumors reached 50 mm3, we started intratumor treatments with a miR-137 mimic, at a dose of 6 µg weekly for four weeks. Ultimately, the animals were killed, and the xenografts were resected and analyzed for gene and protein expression. The animals' serum was collected to evaluate the lipid profile. The in vitro results showed that miR-137 could inhibit the transcription and translation of the p160 family, SRC-1, SRC-2, and SRC-3, and indirectly reduce the expression of AR. After these analyses, it was determined that increased miR-137 inhibits cell migration and invasion and impacts reduced proliferation and increased apoptosis rates. The in vivo results demonstrated that tumor growth was arrested after the intratumoral restoration of miR-137, and proliferation levels were reduced in the SD and HCOL groups. Interestingly, the tumor growth retention response was more significant in the HCOL group. We conclude that miR-137 is a potential therapeutic miRNA that, in association with androgen precursors, can restore and reinstate the AR-mediated axis of transcription and transactivation of androgenic pathway homeostasis. Further studies involving the miR-137/coregulator/AR/cholesterol axis should be conducted to evaluate this miR in a clinical context.

The Antibacterial and Wound Healing Properties of Natural Products: A Review on Plant Species with Therapeutic Potential against Staphylococcus aureus Wound Infections.

Wounds of an acute or chronic etiology affect millions of people worldwide, with increasing prevalence every year. Microbial infections are one of the main causes that impair the wound healing process, and Staphylococcus aureus, a commensal member of the skin microbiota, is one of the main causative agents of wound infections. Crucially, a high proportion of these infections are caused by methicillin-resistant Staphylococcus aureus, which, in addition to ß-lactams, has acquired resistance to almost all the antibacterial agents used to treat it, limiting therapeutic options. Studies on the antimicrobial and healing activities of extracts, essential oils, or metabolites obtained from native plants have been reported in many countries that have a diverse flora and traditions with the use of medicinal plants for the treatment of wound infections. Due to their great chemical diversity, plants have proven to be promising sources of bioactive molecules for the discovery and development of new drugs or strategies for the treatment of wounds. This review highlights the main herbal preparations that have antimicrobial and healing activities with potential for the treatment of wound infections caused by Staphylococcus aureus.

Detection of Cutibacterium acnes in Tissue Samples from Clean Primary Shoulder Surgeries - Part II.

Objective Research and identification of Cutibacterium acnes ( C. acnes ) and other microorganisms in deep tissue samples collected in clean shoulder surgeries of patients who did not undergo any previous invasive joint procedure and who had no clinical history of infection. Methods We analyzed the results of cultures of intraoperative deep tissue samples from 84 patients submitted to primary clean shoulder surgery. Tubes containing culture medium were used for storage and transport of anaerobic agents, prolonged incubation time, and mass spectrometer for diagnosis of bacterial agents. Results Bacteria growth was evidenced in 34 patients (40.4%) of the 84 included in the study. Of these, 23 had growth of C. acnes in at least one sample of deep tissue collected, corresponding to 27.3% of the total patients. The second most common agent was Staphylococcus epidermidis , present in 7.2% of the total individuals included. We showed a higher relationship between sample positivity and males, a lower mean age, absence of diabetes mellitus, ASA I score, and antibiotic prophylaxis in anesthetic induction with cefuroxime. Conclusions A high percentage of isolates of different bacteria was found in shoulder tissue samples of patients undergoing clean and primary surgeries, who had no history of previous infection. Identification of C. acnes was high (27.6%), and Staphylococcus epidermidis was the second most frequent agent (7.2%).

Synergistic Antifungal Interaction between Pseudomonas aeruginosa LV Strain Metabolites and Biogenic Silver Nanoparticles against Candida auris.

Candida auris has been found to be a persistent colonizer of human skin and a successful pathogen capable of causing potentially fatal infection, especially in immunocompromised individuals. This fungal species is usually resistant to most antifungal agents and has the ability to form biofilms on different surfaces, representing a significant therapeutic challenge. Herein, the effect of metabolites of Pseudomonas aeruginosa LV strain, alone and combined with biologically synthesized silver nanoparticles (bioAgNP), was evaluated in planktonic and sessile (biofilm) cells of C. auris. First, the minimal inhibitory and fungicidal concentration values of 3.12 and 6.25 µg/mL, respectively, were determined for F4a, a semi-purified bacterial fraction. Fluopsin C and indolin-3-one seem to be the active components of F4a. Like the semi-purified fraction, they showed a time- and dose-dependent fungicidal activity. F4a and bioAgNP caused severe changes in the morphology and ultrastructure of fungal cells. F4a and indolin-3-one combined with bioAgNP exhibited synergistic fungicidal activity against planktonic cells. F4a, alone or combined with bioAgNP, also caused a significant decrease in the number of viable cells within the biofilms. No cytotoxicity to mammalian cells was detected for bacterial metabolites combined with bioAgNP at synergistic concentrations that presented antifungal activity. These results indicate the potential of F4a combined with bioAgNP as a new strategy for controlling C. auris infections.

Detection of Cutibacterium acnes in Tissue Samples from Clean Primary Shoulder Surgeries - Part II / Detecção de Cutibacterium acnes em amostras de tecidos de cirurgias limpas primárias do ombro - Parte II

Abstract Objective Research and identification of Cutibacterium acnes (C. acnes) and other microorganisms in deeptissue samples collected in clean shoulder surgeries of patients who did not undergo any previous invasive joint procedure and who had no clinical history of infection. Methods We analyzed the results of cultures of intraoperative deep tissue samples from 84 patients submitted to primary clean shoulder surgery. Tubes containing culture medium were used for storage and transport of anaerobic agents, prolonged incubation time, and mass spectrometer for diagnosis of bacterial agents. Results Bacteria growth was evidenced in 34 patients (40.4%) of the 84 included in the study. Of these, 23 had growth of C. acnes in at least one sample of deep tissue collected, corresponding to 27.3% of the total patients. The second most common agent was Staphylococcus epidermidis, present in 7.2% of the total individuals included. We showed a higher relationship between sample positivity and males, a lower mean age, absence of diabetes mellitus, ASA I score, and antibiotic prophylaxis in anesthetic induction with cefuroxime. Conclusions A high percentage of isolates of different bacteria was found in shoulder tissue samples of patients undergoing clean and primary surgeries, who had no history of previous infection. Identification of C. acnes was high (27.6%), and Staphylococcus epidermidis was the second most frequent agent (7.2%).

Resumo Objetivo Pesquisa e identificação de Cutibacterium acnes (C. acnes) e de outros microrganismos em amostras de tecidos profundos coletados em cirurgias limpas de ombro em pacientes que não foram submetidos a nenhum procedimento invasivo articular prévio e que não possuíam antecedentes clínicos de infecção. Métodos Foram analisados os resultados das culturas de amostras de tecidos profundos intraoperatórias de 84 pacientes submetidos à cirurgia limpa primária do ombro. Foram utilizados tubos contendo meio de cultivo para armazenamento e transporte de agentes anaeróbicos, tempo prolongado de incubação e espectrômetro de massa para diagnósticos de agentes bacterianos. Resultados Foi evidenciado o crescimento de bactérias em 34 pacientes (40,4%) dos 84 incluídos no estudo. Desses, 23 apresentavam crescimento de C. acnes em pelo menos uma amostra de tecido profundo coletada, correspondendo a 27,3% do total de pacientes. O segundo agente mais encontrado foi o Staphylococcus epidermidis, presente em 7,2% do total de indivíduos incluídos. Evidenciamos maior relação da positividade de amostras com o gênero masculino, uma média de idade inferior, a ausência de diabetes mellitus, o escore ASA I e a profilaxia antibiótica na indução anestésica com cefuroxima. Conclusões Verificou-se um elevado percentual de isolados de diferentes bactérias em amostras de tecidos de ombros de pacientes submetidos a cirurgias limpas e primárias e sem histórico de infecção anterior. A identificação de C. acnes foi elevada (27,6%) e o Staphylococcus epidermidis foi o segundo agente mais frequente (7,2%).

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans.

Introduction: Cryptococcus neoformans is one of the leading causes of invasive fungal infections worldwide. Cryptococcal meningoencephalitis is the main challenge of antifungal therapy due to high morbidity and mortality rates, especially in low- and middle-income countries. This can be partly attributed to the lack of specific diagnosis difficulty accessing treatment, antifungal resistance and antifungal toxicity. Methods: In the present study, the effect of the synthetic thiourea derivative N-(butylcarbamothioyl) benzamide (BTU-01), alone and combined with amphotericin B (AmB), was evaluated in planktonic and sessile (biofilm) cells of C. neoformans. Results: BTU-01 alone exhibited a fungistatic activity with minimal inhibitory concentrations (MICs) ranging from 31.25 to 62.5 µg/mL for planktonic cells; and sessile MICs ranging from 125.0 to 1000.0 µg/mL. BTU-01 caused a concentration-dependent inhibitory activity on cryptococcal urease and did not interfere with plasma membrane fluidity. Molecular docking was performed on Canavalia ensiformis urease, and BTU-01 showed relevant interactions with the enzyme. The combination of BTU-01 and AmB exhibited synergistic fungicidal activity against planktonic and sessile cells of C. neoformans. Microscopic analysis of C. neoformans treated with BTU-01, alone or combined with AmB, revealed a reduction in cell and capsule sizes, changes in the morphology of planktonic cells; a significant decrease in the number of cells within the biofilm; and absence of exopolymeric matrix surrounding the sessile cells. Neither hemolytic activity nor cytotoxicity to mammalian cells was detected for BTU-01, alone or combined with AmB, at concentrations that exhibited antifungal activity. BTU-01 also displayed drug-likeness properties. Conclusion: These results indicate the potential of BTU-01, for the development of new strategies for controlling C. neoformans infections.

High Prevalence of Panton-valentine Leukocidin-encoding Genes in Methicillin-resistant Staphylococcus aureus Isolated from Inpatients with Invasive Infections at a University Hospital in Southern Brazil.

BACKGROUND: Staphylococcus aureus is a major cause of a wide diversity of infections in humans, and the expression of Panton-Valentine Leukocidin (PVL) has been associated with severe clinical syndromes. OBJECTIVES: The present study aimed to investigate the prevalence of PVL-encoding genes in S. aureus isolated from clinical samples of inpatients with invasive infections in a teaching hospital in Southern Brazil. Furthermore, phenotypic and genotypic characteristics of bacterial isolates were analyzed. METHODS: A total of 98 S. aureus isolates recovered from different body sites were characterized according to their antimicrobial susceptibility profile, methicillin-resistance and SCCmec typing, genetic relatedness and occurrence of virulence-encoding genes, such as icaA, lukS-PV/lukF-PV, and tst. RESULTS: Sixty-eight (69.4%) isolates were classified as methicillin-resistant, and among them, four (5.9%) did not harbor the mecA gene. The mecA-harboring methicillin-resistant S. aureus (MRSA) isolates were grouped into SCCmec types I (6.3%), II (64.1%), III (6.3%), IV (15.6%), V (4.7%), and VI (1.6%). One isolate (1.6%) was classified as non-typeable (NT). Seventy isolates (71.4%) were classified as multidrug-resistant. The overall prevalence of virulence-encoding genes was as follows: icaA, 99.0%; tst, 27.5%; and lukS-PV/lukF-PV, 50.0%. The presence of tst gene was significantly higher (p < 0.001) in methicillin-susceptible S. aureus (MSSA) compared to MRSA isolates. CONCLUSION: The present study reports a high prevalence of multidrug-resistant S. aureus harboring lukS-PV/lukF-PV and tst genes in invasive infections. The continuous monitoring of the antimicrobial susceptibility profile and virulence of S. aureus is an important measure for the control of infections caused by this bacterium.