A potent and selective activator of large-conductance Ca2+-activated K+ channels induces preservation of mitochondrial function after hypoxia and reoxygenation by handling of calcium and transmembrane potential.

AIMS: Ischaemic heart disease remains a significant cause of mortality globally. A pharmacological agent that protects cardiac mitochondria against oxygen deprivation injuries is welcome in therapy against acute myocardial infarction. Here, we evaluate the effect of large-conductance Ca2+-activated K+ channels (BKCa) activator, Compound Z, in isolated mitochondria under hypoxia and reoxygenation. METHODS: Mitochondria from mice hearts were obtained by differential centrifugation. The isolated mitochondria were incubated with a BKCa channel activator, Compound Z, and subjected to normoxia or hypoxia/reoxygenation. Mitochondrial function was evaluated by measurement of O2 consumption in the complexes I, II, and IV in the respiratory states 1, 2, 3, and by maximal uncoupled O2 uptake, ATP production, ROS production, transmembrane potential, and calcium retention capacity. RESULTS: Incubation of isolated mitochondria with Compound Z under normoxia conditions reduced the mitochondrial functions and induced the production of a significant amount of ROS. However, under hypoxia/reoxygenation, the Compound Z prevented a profound reduction in mitochondrial functions, including reducing ROS production over the hypoxia/reoxygenation group. Furthermore, hypoxia/reoxygenation induced a large mitochondria depolarization, which Compound Z incubation prevented, but, even so, Compound Z created a small depolarization. The mitochondrial calcium uptake was prevented by the BKCa activator, extruding the mitochondrial calcium present before Compound Z incubation. CONCLUSION: The Compound Z acts as a mitochondrial BKCa channel activator and can protect mitochondria function against hypoxia/reoxygenation injury, by handling mitochondrial calcium and transmembrane potential.

Craniofrontonasal dysplasia: hypertelorism correction in late presenting patients.

BACKGROUND: Craniofrontonasal dysplasia (CFND) is a rare congenital craniofacial syndrome characterized by single suture synostosis, hypertelorism, other clinical facial features, and abnormalities in the upper extremities. There are only a few studies in the applicable literature that address hypertelorism management for CFND patients and outcomes and complication rates. METHODS: A retrospective study was performed on consecutive late presenting CFND patients referred to our hospital with substantially completed craniofacial skeleton growth, who underwent hypertelorism correction between 2007 and 2019 following intracranial pressure screening, and who received at least 1 year of follow-up care. None of the patients in this study underwent prior craniofacial surgery. Only those patients with a confirmed mutation of the EFNB1 gene were included in this study. All patients in this study underwent hypertelorism correction by facial bipartition or box osteotomy. RESULTS: A total of ten late presenting CFND patients (all female) were treated at our hospital during the study period. None of the patients presented signs of elevated intracranial pressure. The average patient age at hypertelorism correction was 13.4 ± 7.68 years of age. Major complications, defined as complications requiring a return to the operating room, were limited to infection of the frontal bone, which required partial bone removal, and cerebrospinal fluid (CSF) leak, which was completely resolved by insertion of a lumbar shunt for a 7-day period. CONCLUSION: The absence of elevated intracranial pressure enables hypertelorism correction in late presenting CFND patients via facial bipartition or box osteotomy without the need for additional operations that provide for cranial expansion.

BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats.

PURPOSE: In the present study, the therapeutic efficacy of a selective BKCa channel opener (compound X) in the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) was investigated. METHODS: PAH was induced in male Wistar rats by a single injection of MCT. After two weeks, the MCT-treated group was divided into two groups that were either treated with compound X or vehicle. Compound X was administered daily at 28 mg/kg. Electrocardiographic, echocardiographic, and haemodynamic analyses were performed; ex vivo evaluations of pulmonary artery reactivity, right ventricle (RV) and lung histology as well as expression levels of α and ß myosin heavy chain, brain natriuretic peptide, and cytokines (TNFα and IL10) in heart tissue were performed. RESULTS: Pulmonary artery rings of the PAH group showed a lower vasodilatation response to acetylcholine, suggesting endothelial dysfunction. Compound X promoted strong vasodilation in pulmonary artery rings of both control and MCT-induced PAH rats. The untreated hypertensive rats presented remodelling of pulmonary arterioles associated with increased resistance to pulmonary flow; increased systolic pressure, hypertrophy and fibrosis of the RV; prolongation of the QT and Tpeak-Tend intervals (evaluated during electrocardiogram); increased lung and liver weights; and autonomic imbalance with predominance of sympathetic activity. On the other hand, treatment with compound X reduced pulmonary vascular remodelling, pulmonary flow resistance and RV hypertrophy and afterload. CONCLUSION: The use of a selective and potent opener to activate the BKCa channels promoted improvement of haemodynamic parameters and consequent prevention of RV maladaptive remodelling in rats with MCT-induced PAH.

Microwave Assisted Synthesis of 4-Phenylquinazolin-2(1H)-one Derivatives that Inhibit Vasopressor Tonus in Rat Thoracic Aorta.

Quinazolinones have pharmacological effects on vascular reactivity through different mechanisms. We synthesized 4-phenylquinazolin-2(1H)-one derivatives under microwave irradiation and tested them on the rat thoracic aorta. The prepared compounds 2a-2f were obtained in about 1 h with suitable yields (31-92%). All derivatives produced vasorelaxant effects with IC50 values ranging from 3.41 ± 0.65 µM to 39.72 ± 6.77 µM. Compounds 2c, 2e and 2f demonstrated the highest potency in endothelium-intact aorta rings (IC50 4.31 ± 0.90 µM, 4.94 ± 1.21 µM and 3.41 ± 0.65 µM respectively), and they achieved around 90% relaxation (30 µM). In aorta rings without an endothelium, the effect of compound 2f was abolished. Using the MTT assay to test for cell viability, only compound 2b induced cytotoxicity at the maximum concentration employed (30 µM). The results show that vasorelaxation by 4-phenylquinazolin-2(1H)-one derivatives might depend on the activation of a signalling pathway triggered by endothelium-derived factors.

Efficient Synthesis and Antibacterial Profile of Bis(2-hydroxynaphthalene- 1,4-dione).

BACKGROUND: Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains. OBJECTIVE: In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains. METHODS: The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays. RESULTS: L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics. CONCLUSION: Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria.

In vitro effects of the asymmetric peptidomimetic 157, containing l-tartaric acid core and valine/leucine substituents, on Leishmania amazonensis promastigotes and amastigotes.

The current treatments for leishmaniasis bump into several obstacles, including low efficacy, high costs, long monitoring, and several/severe side effects. Consequently, the search for promising compounds is a tangible need. Recently, we reported the anti-Leishmania amazonensis action of asymmetric peptidomimetic compounds containing tartaric acid as core, especially the 157 derivative that contains valine/leucine substituents in its structure. Herein, we decipher the multiple effects of 157 on the L. amazonensis physiology and on the interaction process with macrophages. The peptidomimetic 157 induced significant changes on the morphometric (internal granularity reduction as judged by flow cytometer) and on the ultrastructural (round-shaped parasites, presence of plasma membrane blebs and flagellum loss as visualized by scanning electron microscopy) aspects of treated promastigotes compared to untreated ones. The alteration on the plasma membrane permeability was confirmed by the passive incorporation of propidium iodide in 157-treated promastigotes. In parallel, the low viability of promastigotes was also associated to the perturbation of mitochondrial transmembrane electric potential. These combined results demonstrated that 157 induced irreversible metabolic damages that led to L. amazonensis death. The pre-treatment of promastigotes with 157 inhibited the association index with macrophages in a typically dose-dependent manner. Additionally, 157 significantly reduced the number of intramacrophage amastigotes after 72 h of drug contact, presenting an IC50 value of 30.2 µM. Under our experimental conditions, 157 showed higher toxicity to promastigotes and amastigotes when compared to RAW cells, resulting in good selective indexes. Therefore, 157 can be considered as an interesting candidate for further optimization, since its synthesis is simple and cheap.

Asymmetric peptidomimetics containing L-tartaric acid core inhibit the aspartyl peptidase activity and growth of Leishmania amazonensis promastigotes.

Aspartyl-type peptidases are promising chemotherapeutic targets in protozoan parasites. In the present work, we identified an aspartyl peptidase activity from the soluble extract of Leishmania amazonensis promastigotes, which cleaved the fluorogenic peptide 7-methoxycoumarin-4-acetyl-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-amide (cathepsin D substrate) under acidic pH conditions at 37°C, showing a KM of 0.58 µM and Vmax of 129.87 fluorescence arbitrary units/s mg protein. The leishmanial aspartyl peptidase activity was blocked by pepstatin A (IC50 = 6.8 µM) and diazo-acetyl-norleucinemetilester (IC50 = 10.2 µM), two classical aspartyl peptidase inhibitors. Subsequently, the effects of 6 asymmetric peptidomimetics, containing L-tartaric acid core, were tested on both aspartyl peptidase and growth of L. amazonensis promastigotes. The peptidomimetics named 88, 154 and 158 promoted a reduction of 50% on the leishmanial aspartyl peptidase activity at concentrations ranging from 40 to 85 µM, whereas the peptidomimetic 157 was by far the most effective, presenting IC50 of 0.04 µM. Furthermore, the peptidomimetics 157 and 154 reduced the parasite proliferation in a dose-dependent manner, displaying IC50 values of 33.7 and 44.5 µM, respectively. Collectively, the peptidomimetic 157 was the most efficient compound able to arrest both aspartyl peptidase activity and leishmanial proliferation, which raises excellent perspectives regarding its use against this human pathogenic protozoan.

O poder de normalização e a produção do indivíduo perigoso / The power of normalization and the production of the dangerous individual

Resumo Partindo da análise de prontuários de internação de crianças e adolescentes no Hospital Psiquiátrico São Pedro, em Porto Alegre, observa-se, nos motivos de internação, componentes essencialmente morais, sem uma relação específica com os diagnósticos. Tomando essa discrepância em análise, resgata-se, na obra de Michel Foucault, elementos que permitem a construção do conceito de "poder de normalização". Utilizando tal ferramenta conceitual, opera-se uma genealogia dos saberes e técnicas que fazem da internação psiquiátrica uma operação repleta de componentes morais, atentando para as forças que constituem esse campo no Hospital Psiquiátrico São Pedro.(AU)

Abstract Examining the hospitalization records of children and juveniles in the São Pedro Psychiatric Hospital, in Porto Alegre, one notices, in the hospitalization causes, essentialy moral aspects, with no specific relation to the diagnostics. Taking such discrepancy into analysis, we rescue, in the work of Michel Foucault, aspects which allow us to forge the notion of "power of normalization". Using such concept, we conduct a genealogic research of the knowledges and techniques that turn the psychiatric hospitalization into an operation full of moral components, paying attention to the forces that constitute such a field in the São Pedro Psychiatric Hospital.(AU)

Avaliação do tratamento definitivo do hipertireoidismo com radioiodo na Faculdade de Medicina do Triângulo Mineiro / Evaluation of radioiodine therapy as a definitive treatment for hyperthyroidism in the Triângulo Mineiro School of Medicine

O hipertireoidismo de origem auto-imune ou devido a doença autonômica da tireóide pode ser eficientemente controlado seja pela inibição temporária da hormoniogênese com as tiouréias, seja pela redução definitiva da massa folicular funcionante pela tireoidectomia ou administração de radioiodo. Com a intenção de conhecer os efeitos da radioiodoterapia na Faculdade de Medicina de Triângulo Mineiro, foram revisados 255 prontuários de pacientes com hipertireoidismo atendidos no ambulatório de tireóide entre janeiro de 1991 e 2001. O 1¹³¹ foi administrado a 61 pacientes portadores de doença de Basedow-Graves (DBG) (n=143), a seis com bócio multinodular tóxico (BMT) (n=17), e a 3 com bócio uninodular tóxico (BUI) (n=7). Apenas 1 caso de Hashitoxicese (n=40) de mais longa duração recebeu o mesmo tratamento. A maioria dos pacientes com DBG recebeu de 185 a 370MBq (5-10mCi) de 1¹³¹ e em dez pacientes com bócios volumosos foi necessário repetir a dose. Os pacientes com BMT e BUT receberam de 185 a 925MBg (5-25mCi) e uma segunda dose foi dada a três deles.Todos os pacientes foram curados do hipertireoidismo, não foram observadas complicações agudas, entretanto, o seguimento pós-dose até o momento detectou hipotireoidismo em 63% dos pacientes.

Hyperthyroidism either auto-immune or due to autonomic thyroid disease can be efficiently controlled by hormoniogenesis inhibition with antithyroid drugs or definitive reduction of functioning thyroid follicles number by either subtotal thyroidectomy or radioiodine administration. The effects of radioiodine therapy in the Triângulo Mineiro Medical School was investigated in 255 hyperthyroid patients treated between 1991 and 2001. 1¹³¹ was administered to 61 patients with Basedow-Graves disease (BGD), to six patients with multinodular toxic goiter (MTG), and to three patients with solitary toxic goiter (STG). Only one patient with Hashitoxicose ot unusual and longer duration received the same treatment. Patients with BGD were treated with 185 to 370MBq (5-10mCi) of 1¹³¹ but in ten of them with larger goiters it was necessary a second dose. Patients with MTG and STG received 185 to 925MBq (5-25mCi) and a second dose was given to three of them. All patients were considered cured from hyperthyroidism without acute complications, however follow up so far detected hypothyroidism in 63%.