Early Cardiac Mitochondrial Molecular and Functional Responses to Acute Anthracycline Treatment in Wistar Rats

Doxorubicin (DOX) is an anticancer drug widely used to treat human and nonhuman tumors but the late and persistent cardio-toxicity reduces the therapeutic utility of the drug. The full mechanism(s) of DOX-induced acute, subchronic and delayed toxicity, which has a preponderant mitochondrial component, remains unclear; therefore, it is clinically relevant to identify early markers to identify patients who are predisposed to DOX-related cardiovascular toxicity. To address this, Wistar rats (16 weeks old) were treated with a single DOX dose (20 mg/kg, i.p.); then, mRNA, protein levels and functional analysis of mitochondrial endpoints were assessed 24 h later in the heart, liver, and kidney. Using an exploratory data analysis, we observed cardiac-specific alterations after DOX treatment for mitochondrial complexes III, IV, and preferentially for complex I. Conversely, the same analysis revealed complex II alterations are associated with DOX response in the liver and kidney. Interestingly, H2O2 production by the mitochondrial respiratory chain as well as loss of calcium-loading capacity, markers of subchronic toxicity, were not reliable indicators of acute DOX cardiotoxicity in this animal model. By using sequential principal component analysis and feature correlation analysis, we demonstrated for the first time alterations in sets of transcripts and proteins, but not functional measurements, that might serve as potential early acute markers of cardiac-specific mitochondrial toxicity, contributing to explain the trajectory of DOX cardiac toxicity and to develop novel interventions to minimize DOX cardiac liabilities

Antiproliferative Activity Of Flavonoids From Croton Sphaerogynus Baill. (euphorbiaceae)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1-F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1-F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI(50) 0.54) higher than the hexane phase and EtOH extract (mean log GI(50) 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI(50) 1.2 mu g/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI(50) 1.05), while F5 showed weak activity (mean log GI(50) 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)FAPESP [FAPESP 2012/10079-0

Mitochondrionopathy Phenotype in Doxorubicin-Treated Wistar Rats Depends on Treatment Protocol and Is Cardiac-Specific

Although doxorubicin (DOX) is a very effective antineoplastic agent, its clinical use is limited by a dose-dependent, persistent and cumulative cardiotoxicity, whose mechanism remains to be elucidated. Previous works in animal models have failed to use a multi-organ approach to demonstrate that DOX-associated toxicity is selective to the cardiac tissue. In this context, the present work aims to investigate in vivo DOX cardiac, hepatic and renal toxicity in the same animal model, with special relevance on alterations of mitochondrial bioenergetics. To this end, male Wistar rats were sub-chronically (7 wks, 2 mg/Kg) or acutely (20 mg/Kg) treated with DOX and sacrificed one week or 24 hours after the last injection, respectively. Alterations of mitochondrial bioenergetics showed treatment-dependent differences between tissues. No alterations were observed for cardiac mitochondria in the acute model but decreased ADP-stimulated respiration was detected in the sub-chronic treatment. In the acute treatment model, ADP-stimulated respiration was increased in liver and decreased in kidney mitochondria. Aconitase activity, a marker of oxidative stress, was decreased in renal mitochondria in the acute and in heart in the sub-chronic model. Interestingly, alterations of cardiac mitochondrial bioenergetics co-existed with an absence of echocardiograph, histopathological or ultra-structural alterations. Besides, no plasma markers of cardiac injury were found in any of the time points studied. The results confirm that alterations of mitochondrial function, which are more evident in the heart, are an early marker of DOX-induced toxicity, existing even in the absence of cardiac functional alterations

Antimicrobial resistance of isolated Streptococcus pneumoniae in a hospital of the Brazilian public system

Streptococcus pneumoniae is the predominant bacterial agent that affects the human population with pneumonia. This disease is an important cause of death in the elderly and the children under five years old. in this study, 29 strains of invasive S. pneumoniae were isolated from 29 patients of pneumonia, bacteremia and meningitis in the laboratory of the Municipal Hospital in Paulinia, Brazil, from May 2006 to October 2007. Patients' age ranged from 8 months old to 60 years old. These strains of S. pneumoniae were isolated from blood, pleural fluid and cerebrospinal fluid (CSF) of patients. After typing of encapsulated strains of S. pneumoniae through quellung reaction, their resistance to antimicrobial agents was gauged through Disc Diffusion Technique followed by determination of minimum inhibitory concentration (MIC). Among the 29 strains analyzed, 23 were methicillin-sensitive and six were methicillin-resistant and penicillin intermediate resistant. No strain presented full resistance to penicillin. Serotyping was performed only in two samples, which belonged to serotype 18. Our data may alert ambulatory regarding the incidence of pneumococcal strains resistant to the most common drugs due to inappropriate use of antimicrobials and also collaborate to the elaboration of pneumococcal conjugate vaccines specific to each region.NEPASHosp Municipal Paulinia, Setor Microbiol, Paulinia, SP, BrazilUniversidade Federal de São Paulo, Dept Farm Bioquim, Diadema, SP, BrazilFac Med ABC, Dept Morfol Fisiol, Lab Escrita Cientif, Santo Andre, BrazilUniv Estadual Paulista, Fac Filosofia & Ciencias, Dept Fonoaudiol, Marilia, SP, BrazilUniversidade Federal de São Paulo, Dept Farm Bioquim, Diadema, SP, BrazilWeb of Scienc

Antiproliferative activity of flavonoids from croton Sphaerogynus baill. (euphorbiaceae)

Croton sphaerogynus is a shrub from the Atlantic Rain Forest in southeastern Brazil. A lyophilized crude EtOH extract from leaves of C. sphaerogynus, obtained by maceration at room temperature (seven days), was suspended in methanol and partitioned with hexane. The purified MeOH phase was fractionated over Sephadex LH-20 yielding five fractions (F1-F5) containing flavonoids, as characterized by HPLC-DAD and HPLC-MS analyses. The antiproliferative activity of the crude EtOH extract, MeOH and hexane phases, and fractions F1-F5 was evaluated on in vitro cell lines NCI-H460 (nonsmall cell lung), MCF-7 (breast cancer), and U251 (glioma). The MeOH phase showed activity (mean log GI(50) 0.54) higher than the hexane phase and EtOH extract (mean log GI(50) 1.13 and 1.19, resp.). F1 exhibited activity against NCI-H460 (nonsmall cell lung) (GI(50) 1.2 mu g/mL), which could be accounted for the presence of flavonoids and/or diterpenes. F4 showed moderate activity (mean log GI(50) 1.05), while F5 showed weak activity (mean log GI(50) 1.36). It is suggested that the antiproliferative activity of the crude EtOH extract and MeOH phase is accounted for a synergistic combination of flavonoids and diterpenes2015COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2012/10079-

Borrelia valaisiana resist complement-mediated killing independently of the recruitment of immune regulators and inactivation of complement components

Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato complex differ in their resistance to complement-mediated killing, particularly in regard to human serum. In the present study, we elucidate the serum and complement susceptibility of B. valaisiana, a genospecies with the potential to cause Lyme disease in Europe as well as in Asia. Among the investigated isolates, growth of ZWU3 Ny3 was not affected while growth of VS116 and Bv9 was strongly inhibited in the presence of 50% human serum. Analyzing complement activation, complement components C3, C4 and C6 were deposited on the surface of isolates VS116 and Bv9, and similarly the membrane attack complex was formed on their surface. In contrast, no surface-deposited components and no aberrations in cell morphology were detected for serum-resistant ZWU3 Ny3. While further investigating the protective role of bound complement regulators in mediating complement resistance, we discovered that none of the B. valaisiana isolates analyzed bound complement regulators Factor H, Factor H-like protein 1, C4b binding protein or C1 esterase inhibitor. In addition, B. valaisiana also lacked intrinsic proteolytic activity to degrade complement components C3, C3b, C4, C4b, and C5. Taken together, these findings suggest that certain B. valaisiana isolates differ in their capability to resist complement-mediating killing by human serum. The molecular mechanism utilized by B. valaisiana to inhibit bacteriolysis appears not to involve binding of the key host complement regulators of the alternative, classical, and lectin pathways as already known for serum-resistant Lyme disease or relapsing fever borreliae

Genome analysis of Desulfotomaculum gibsoniae strain GrollT a highly versatile Gram-positive sulfate-reducing bacterium

Desulfotomaculum gibsoniae is a mesophilic member of the polyphyletic spore-forming genus Desulfotomaculum within the family Peptococcaceae. This bacterium was isolated from a freshwater ditch and is of interest because it can grow with a large variety of organic substrates, in particular several aromatic compounds, short-chain and medium-chain fatty acids, which are degraded completely to carbon dioxide coupled to the reduction of sulfate. It can grow autotrophically with H2 + CO2 and sulfate and slowly acetogenically with H2 + CO2, formate or methoxylated aromatic compounds in the absence of sulfate. For growth it does not require any vitamins. Here, we describe the features of D. gibsoniae strain GrollT together with the genome sequence and annotation. The chromosome has 4,855,529 bp organized in one circular contig and is the largest genome of all sequenced Desulfotomaculum spp., so far. A total of 4666 candidate protein-encoding genes and 96 RNA genes were identified. Genes of the acetyl-CoA pathway possibly involved in heterotrophic growth, and in CO2 fixation during autotrophic growth are present. The genome contains a large set of genes for the anaerobic transformation and degradation of aromatic compounds, which are lacking in the other sequenced Desulfotomaculum genomes.DOE -U.S. Department of EnergyThe work conducted by the U.S. Department of Energy Joint Genome Institute was supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231, and was also supported by grants CW-TOP 700.55.343, ALW 819.02.014 of the Netherlands Science Foundation (NWO), ERC (project 323009), and BE-Basic (project F07.002.03)

It Takes Two to Tango, Part II : Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/seleniumcontaining triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of paranaphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango

Health System Support for Childbirth care in Southern Tanzania: Results from a Health Facility Census.

Progress towards reaching Millennium Development Goals four (child health) and five (maternal health) is lagging behind, particularly in sub-Saharan Africa, despite increasing efforts to scale up high impact interventions. Increasing the proportion of birth attended by a skilled attendant is a main indicator of progress, but not much is known about the quality of childbirth care delivered by these skilled attendants. With a view to reducing maternal mortality through health systems improvement we describe the care routinely offered in childbirth offered at dispensaries, health centres and hospitals in five districts in rural Southern Tanzania. We use data from a health facility census assessing 159 facilities in five districts in early 2009. A structural and operational assessment was undertaken based on staff reports using a modular questionnaire assessing staffing, work load, equipment and supplies as well as interventions routinely implemented during childbirth. Health centres and dispensaries attended a median of eight and four deliveries every month respectively. Dispensaries had a median of 2.5 (IQR 2--3) health workers including auxiliary staff instead of the recommended four clinical officer and certified nurses. Only 28% of first-line facilities (dispensaries and health centres) reported offering active management in the third stage of labour (AMTSL). Essential childbirth care comprising eight interventions including AMTSL, infection prevention, partograph use including foetal monitoring and newborn care including early breastfeeding, thermal care at birth and prevention of ophthalmia neonatorum was offered by 5% of dispensaries, 38% of health centres and 50% of hospitals consistently. No first-line facility had provided all signal functions for emergency obstetric complications in the previous six months. Essential interventions for childbirth care are not routinely implemented in first-line facilities or hospitals. Dispensaries have both low staffing and low caseload which constraints the ability to provide high-quality childbirth care. Improvements in quality of care are essential so that women delivering in facility receive "skilled attendance" and adequate care for common obstetric complications such as post-partum haemorrhage