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Gender is an important determinant of health. Its relationship with inequality and violence allows us to consider being a woman as a risk factor for health. Girls and teenager girls are not exempt from this circumstance, which conditions their lives from before birth and can determine their health status throughout life. It can vary according to social contexts, as various factors intersect with gender, adding risk and vulnerability to being a woman. Gender-based violence is often identified as a problem for adult women; however, the experience of discriminatory gender-based violence is constructed throughout women's lives, producing serious individual and social consequences from childhood. Accepting this violence as a «private or domestic matter¼ often prevents seeing the true dimension of the problem, its consequences, and the need to address it as a global issue.
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BACKGROUND AND OBJECTIVES: There is a concern about a possible deleterious effect of pathogen reduction (PR) with methylene blue (MB) on the function of immunoglobulins of COVID-19 convalescent plasma (CCP). We have evaluated whether MB-treated CCP is associated with a poorer clinical response compared to other inactivation systems at the ConPlas-19 clinical trial. MATERIALS AND METHODS: This was an ad hoc sub-study of the ConPlas-19 clinical trial comparing the proportion of patients transfused with MB-treated CCP who had a worsening of respiration versus those treated with amotosalen (AM) or riboflavin (RB). RESULTS: One-hundred and seventy-five inpatients with SARS-CoV-2 pneumonia were transfused with a single CCP unit. The inactivation system of the CCP units transfused was MB in 90 patients (51.4%), RB in 60 (34.3%) and AM in 25 (14.3%). Five out of 90 patients (5.6%) transfused with MB-treated CCP had worsening respiration compared to 9 out of 85 patients (10.6%) treated with alternative PR methods (p = 0.220). Of note, MB showed a trend towards a lower rate of respiratory progressions at 28 days (risk ratio, 0.52; 95% confidence interval, 0.18-1.50). CONCLUSION: Our data suggest that MB-treated CCP does not provide a worse clinical outcome compared to the other PR methods for the treatment of COVID-19.
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COVID-19 , Humanos , COVID-19/terapia , Soroterapia para COVID-19 , Imunização Passiva/métodos , Azul de Metileno/farmacologia , Azul de Metileno/uso terapêutico , SARS-CoV-2 , Resultado do TratamentoRESUMO
Microbial communities occurring in reference materials for artificial barriers (e.g., bentonites) in future deep geological repositories of radioactive waste can influence the migration behavior of radionuclides such as curium (CmIII). This study investigates the molecular interactions between CmIII and its inactive analogue europium (EuIII) with the indigenous bentonite bacterium Stenotrophomonas bentonitica at environmentally relevant concentrations. Potentiometric studies showed a remarkably high concentration of phosphates at the bacterial cell wall compared to other bacteria, revealing the great potential of S. bentonitica for metal binding. Infrared spectroscopy (ATR-FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed the role of phosphates and carboxylate groups from the cell envelope in the bioassociation of EuIII. Additionally, time-resolved laser-induced fluorescence spectroscopy (TRLFS) identified phosphoryl and carboxyl groups from bacterial envelopes, among other released complexing agents, to be involved in the EuIII and CmIII coordination. The ability of this bacterium to form a biofilm at the surface of bentonites allows them to immobilize trivalent lanthanide and actinides in the environment.
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Resíduos Radioativos , Cúrio , Európio , StenotrophomonasRESUMO
The Arava Valley in is a rock desert within the Great African Rift valley. Soil from this area is covered with a salt crust. Here, we report microbial diversity from arid, naturally saline samples collected near Ein Yahav from the Arava Valley by culture-independent as well as culture-dependent analysis. High-throughput sequencing of the hypervariable region V4 of the 16S rRNA gene revealed that the microbial community consists of halophiles from the domain Bacteria as well as Archaea. Bacterial diversity was mainly represented by the genus Salinimicrobium of the order Flavobacteriales within the phylum Bacteroidetes, from the gammaproteobacterial orders Alteromonadales and Oceanospirillales as well as representatives from the order Bacillales of the phylum Firmicutes. Archaeal diversity was dominated by euryarchaeal Halobacteria from the orders Halobacteriales, Haloferacales, and Natrialbales. But more than 40% of the sequences affiliated with Archaea were assigned to unknown or unclassified archaea. Even if taxonomic resolution of the 16S rRNA gene V4 region for Archaea is limited, this study indicates the need of further and more detailed studies of Archaea. By using culture-dependent analysis, bacteria of the order Bacillales as well as archaea from all three halobacterial orders Halobacteriales, Haloferacales, and Natrialbales including potentially novel species from the genera Halorubrum and Haloparvum were isolated.
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Archaea/isolamento & purificação , Bactérias/isolamento & purificação , Biodiversidade , Solo/química , Archaea/classificação , Archaea/genética , Archaea/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/metabolismo , DNA Arqueal/genética , DNA Bacteriano/genética , Clima Desértico , Ecossistema , Sequenciamento de Nucleotídeos em Larga Escala , Microbiota , Filogenia , RNA Ribossômico 16S/genética , Salinidade , Cloreto de Sódio/análise , Cloreto de Sódio/metabolismo , Microbiologia do SoloRESUMO
BACKGROUND & AIMS: Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. METHODS: WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. RESULTS: Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. CONCLUSIONS: We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases.
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Ductos Biliares/lesões , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fator 2 de Diferenciação de Crescimento/metabolismo , Regeneração Hepática , Células-Tronco/citologia , Animais , Apoptose , Proliferação de Células , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fator 2 de Diferenciação de Crescimento/genética , Fígado/citologia , Fígado/lesões , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piridinas , Transdução de SinaisRESUMO
The methods to obtain chitooligosaccharides are tightly related to the physicochemical properties of the end products. Knowledge of these physicochemical characteristics is crucial to describing the biological functions of chitooligosaccharides. Chitooligosaccharides were prepared either in a single-step enzymatic hydrolysis using chitosanase, or in a two-step chemical-enzymatic hydrolysis. The hydrolyzed products obtained in the single-step preparation were composed mainly of 42% fully deacetylated oligomers plus 54% monoacetylated oligomers, and they attenuated the inflammation in lipopolysaccharide-induced mice and in RAW264.7 macrophages. However, chitooligosaccharides from the two-step preparation were composed of 50% fully deacetylated oligomers plus 27% monoacetylated oligomers and, conversely, they promoted the inflammatory response in both in vivo and in vitro models. Similar proportions of monoacetylated and deacetylated oligomers is necessary for the mixtures of chitooligosaccharides to achieve anti-inflammatory effects, and it directly depends on the preparation method to which chitosan was submitted.
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Anti-Inflamatórios/farmacologia , Quitina/análogos & derivados , Inflamação/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Quitina/biossíntese , Quitina/química , Quitina/farmacologia , Quitina/uso terapêutico , Quitosana , Modelos Animais de Doenças , Glicosídeo Hidrolases/metabolismo , Humanos , Hidrólise , Inflamação/imunologia , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oligossacarídeos , Células RAW 264.7 , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
UNLABELLED: Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte-specific truncated form of human EGFR, which acts as negative dominant mutant (ΔEGFR) and allows definition of its tyrosine kinase-dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two-thirds partial hepatectomy, ΔEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor-ß pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor-ß through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in ΔEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, ΔEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c-Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because ΔEGFR mice showed a delay in the appearance of diethyl-nitrosamine-induced tumors, which correlated with decreased proliferation and delay in the diethyl-nitrosamine-induced inflammatory process. CONCLUSION: These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology. (Hepatology 2016;63:604-619).
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Carcinogênese , Receptores ErbB/fisiologia , Neoplasias Hepáticas/etiologia , Regeneração Hepática/fisiologia , Animais , Catálise , Humanos , Masculino , CamundongosRESUMO
A Gram-stain negative, rod-shaped, aerobic bacterial strain, BII-R7T, was isolated during a study targeting the culture-dependent microbial diversity occurring in bentonite formations from southern Spain. Comparative 16S rRNA gene sequence analysis showed that BII-R7T represented a member of the genus Stenotrophomonas (class Gammaproteobacteria), and was related most closely to Stenotrophomonas rhizophila e-p10T (99.2â% sequence similarity), followed by Stenotrophomonas pavanii ICB 89T (98.5â%), Stenotrophomonas maltophilia IAM 12423T, Stenotrophomonas chelatiphaga LPM-5T and Stenotrophomonas tumulicola T5916-2-1bT (all 98.3â%). Pairwise sequence similarities to all other type strains of species of the genus Stenotrophomonas were below 98â%. Genome-based calculations (orthologous average nucleotide identity, original average nucleotide identity, genome-to-genome distance and DNA G+C percentage) indicated clearly that the isolate represents a novel species within this genus. Different phenotypic analyses, such as the detection of a quinone system composed of the major compound ubiquinone Q-8 and a fatty acid profile with iso-C15â:â0 and anteiso-C15â:â0 as major components, supported this finding at the same time as contributing to a comprehensive characterization of BII-R7T. Based on this polyphasic approach comprising phenotypic and genotypic/molecular characterization, BII-R7T can be differentiated clearly from its phylogenetic neighbours, establishing a novel species for which the name Stenotrophomonas bentonitica sp. nov. is proposed with BII-R7T as the type strain (=LMG 29893T=CECT 9180T=DSM 103927T).
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Bentonita , Stenotrophomonas/classificação , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/química , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Espanha , Stenotrophomonas/genética , Stenotrophomonas/isolamento & purificação , Ubiquinona/químicaRESUMO
Wastewaters generated during mining and processing of metal sulfide ores are often acidic (pH < 3) and can contain significant concentrations of nitrate, nitrite, and ammonium from nitrogen based explosives. In addition, wastewaters from sulfide ore treatment plants and tailings ponds typically contain large amounts of inorganic sulfur compounds, such as thiosulfate and tetrathionate. Release of these wastewaters can lead to environmental acidification as well as an increase in nutrients (eutrophication) and compounds that are potentially toxic to humans and animals. Waters from cyanidation plants for gold extraction will often conjointly include toxic, sulfur containing thiocyanate. More stringent regulatory limits on the release of mining wastes containing compounds such as inorganic sulfur compounds, nitrate, and thiocyanate, along the need to increase production from sulfide mineral mining calls for low cost techniques to remove these pollutants under ambient temperatures (approximately 8 °C). In this study, we used both aerobic and anaerobic continuous cultures to successfully couple inorganic sulfur compound (i.e. thiosulfate and thiocyanate) oxidation for the removal of nitrogenous compounds under neutral to acidic pH at the low temperatures typical for boreal climates. Furthermore, the development of the respective microbial communities was identified over time by DNA sequencing, and found to contain a consortium including populations aligning within Flavobacterium, Thiobacillus, and Comamonadaceae lineages. This is the first study to remediate mining waste waters by coupling autotrophic thiocyanate oxidation to nitrate reduction at low temperatures and acidic pH by means of an identified microbial community.
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Processos Autotróficos , Temperatura Baixa , Desnitrificação , Elétrons , Tiocianatos/farmacologia , Tiossulfatos/farmacologia , Aerobiose , Anaerobiose , Processos Autotróficos/efeitos dos fármacos , Biodegradação Ambiental/efeitos dos fármacos , Reatores Biológicos/microbiologia , Desnitrificação/efeitos dos fármacos , Concentração de Íons de Hidrogênio , FilogeniaRESUMO
BACKGROUND: Pivotal phase studies of telaprevir (TLV) and boceprevir (BOV) showed 10-56% rates of early treatment interruption. However, there have been no reports on the sustained virological response (SVR) rates of these patients. AIM: To assess the SVR rate in a large cohort of patients who discontinued triple therapy with TLV or BOV for reasons other than stopping rules and to identify variables predicting SVR. MATERIAL AND METHOD: A survey was sent to 15 hospitals in Catalonia asking them to report all TLV/BOV treatments finished by 31 May 2014. Demographic, clinical, laboratory, liver fibrosis and therapeutic data were recorded for treatments with early discontinuation. Logistic regression analysis, ROC curves and prognostic assessment of the variables identified were calculated. RESULTS: Twelve hospitals responded to the survey, representing 467 treatments and 121 (21.2%) early discontinuations, 76 (62.8%) due to stopping rules and 45 (37.2%) for other reasons. Early discontinuation was more frequent with BOV [38.2% (50/131) versus 21.1% (71/336) p<0.005], mainly due to stopping rules [78% (39/50) versus 52.1% (37/71); p=0.004]. SVR was achieved in 21/121 patients (17.4%), 19/71 (26.8%) treated with TLV and 2/50 (4.0%) treated with BOV. In patients discontinuing treatment for reasons other than stopping rules, SVR was achieved in 19/37 (55.9%) treated with TLV and in 2/11 (18.2%) treated with BOV. The SVR rate in patients treated with TLV who discontinued due to a severe adverse event was 61.5% (16/26). A logistic regression analysis was performed only with triple therapy with TLV and early discontinuation. The predictive variables of SVR were undetectable HCV-RNA at treatment week 4 and treatment length longer than 11 weeks. Treatment duration longer than 11 weeks showed the best accuracy (0.794), with a positive predictive value of 0.928. CONCLUSIONS: Early discontinuation of TLV-based triple therapy due to reasons other than stopping rules still have a significant SVR rate (55.9%). Undetectable HVC-RNA at week 4 of treatment and treatment duration longer than 11 weeks are predictive of SVR in this subset of patients.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Resposta Viral Sustentada , Viremia/tratamento farmacológico , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Quimioterapia Combinada , Feminino , Genótipo , Pesquisas sobre Atenção à Saúde , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Prognóstico , Prolina/administração & dosagem , Prolina/análogos & derivados , Prolina/uso terapêutico , RNA Viral/sangue , Estudos Retrospectivos , Adulto JovemAssuntos
Artrite Reumatoide , Artrite , Artrite/diagnóstico , Artrite/etiologia , Humanos , Doenças RarasRESUMO
Hedgehog (Hh) signaling is involved in patterning and morphogenesis of most organs in the developing mammalian embryo. Despite many advances in understanding core components of the pathway, little is known about how the activity of the Hh pathway is adjusted in organ- and tissue-specific developmental processes. Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. Using mouse models, we show here that Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. Consistent with Evc and Evc2 functioning as a complex, the skeletal phenotypes in either single or double homozygous mutant mice are virtually indistinguishable. Smo translocation to the cilium was normal in Evc2-deficient chondrocytes following Hh activation with the Smo-agonist SAG. However, Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. Interestingly, we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. Expression of a dominantly acting Evc2 mutation previously identified in Weyer's acrodental dysostosis (Evc2Δ43) caused mislocalization of Evc/Evc2Δ43 within the cilium and also reproduced the Gli3-related molecular defects observed in Evc2(-/-) chondrocytes. Moreover, Evc silencing in Sufu(-/-) cells attenuated the output of the Hh pathway, suggesting that Evc/Evc2 also promote Hh signaling in the absence of Sufu. Together our data reveal that the Hh pathway involves Evc/Evc2-dependent modulations that are necessary for normal endochondral bone formation.
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Condrócitos/metabolismo , Cílios/metabolismo , Proteínas Hedgehog/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Repressoras/metabolismo , Animais , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Transporte Proteico , Receptor Smoothened , Proteína Gli3 com Dedos de ZincoRESUMO
The long-term disposal of radioactive wastes in a deep geological repository is the accepted international solution for the treatment and management of these special residues. The microbial community of the selected host rocks and engineered barriers for the deep geological repository may affect the performance and the safety of the radioactive waste disposal. In this work, the bacterial population of bentonite formations of Almeria (Spain), selected as a reference material for bentonite-engineered barriers in the disposal of radioactive wastes, was studied. 16S ribosomal RNA (rRNA) gene-based approaches were used to study the bacterial community of the bentonite samples by traditional clone libraries and Illumina sequencing. Using both techniques, the bacterial diversity analysis revealed similar results, with phylotypes belonging to 14 different bacterial phyla: Acidobacteria, Actinobacteria, Armatimonadetes, Bacteroidetes, Chloroflexi, Cyanobacteria, Deinococcus-Thermus, Firmicutes, Gemmatimonadetes, Planctomycetes, Proteobacteria, Nitrospirae, Verrucomicrobia and an unknown phylum. The dominant groups of the community were represented by Proteobacteria and Bacteroidetes. A high diversity was found in three of the studied samples. However, two samples were less diverse and dominated by Betaproteobacteria.
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Bactérias/classificação , Bentonita/análise , Resíduos Radioativos , Acessibilidade Arquitetônica , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bactérias/isolamento & purificação , Biodiversidade , DNA Bacteriano/genética , DNA Ribossômico/genética , Dados de Sequência Molecular , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Microbiologia do Solo , Poluentes Radioativos do Solo/análise , EspanhaRESUMO
The study of bone morphogenetic proteins (BMPs) role in tumorigenic processes, and specifically in the liver, has gathered importance in the last few years. Previous studies have shown that BMP9 is overexpressed in about 40% of hepatocellular carcinoma (HCC) patients. In vitro data have also shown evidence that BMP9 has a pro-tumorigenic action, not only by inducing epithelial to mesenchymal transition (EMT) and migration, but also by promoting proliferation and survival in liver cancer cells. However, the precise mechanisms driving these effects have not yet been established. In the present work, we deepened our studies into the intracellular mechanisms implicated in the BMP9 proliferative and pro-survival effect on liver tumor cells. In HepG2 cells, BMP9 induces both Smad and non-Smad signaling cascades, specifically PI3K/AKT and p38MAPK. However, only the p38MAPK pathway contributes to the BMP9 growth-promoting effect on these cells. Using genetic and pharmacological approaches, we demonstrate that p38MAPK activation, although dispensable for the BMP9 proliferative activity, is required for the BMP9 protective effect on serum withdrawal-induced apoptosis. These findings contribute to a better understanding of the signaling pathways involved in the BMP9 pro-tumorigenic role in liver tumor cells.
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Fatores de Diferenciação de Crescimento/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Cromonas/farmacologia , Ativação Enzimática , Fator 2 de Diferenciação de Crescimento , Fatores de Diferenciação de Crescimento/farmacologia , Células Hep G2 , Humanos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais/efeitos dos fármacosRESUMO
Cot/tpl2 (MAP3K8) activates MKK1/2-Erk1/2 following stimulation of the Toll-like/IL-1 receptor superfamily. Here, we investigated the role of Cot/tpl2 in sterile inflammation and drug-induced liver toxicity. Cot/tpl2 KO mice exhibited reduced hepatic injury after acetaminophen challenge, as evidenced by decreased serum levels of both alanine and aspartate aminotransferases, decreased hepatic necrosis, and increased survival relative to Wt mice. Serum levels of both alanine and aspartate aminotransferases were also lower after intraperitoneal injection of acetaminophen in mice expressing an inactive form of Cot/tpl2 compared with Wt mice, suggesting that Cot/tpl2 activity contributes to acetaminophen-induced liver injury. Furthermore, Cot/tpl2 deficiency reduced neutrophil and macrophage infiltration in the liver of mice treated with acetaminophen, as well as their hepatic and systemic levels of IL-1α. Intraperitoneal injection of damage-associated molecular patterns from necrotic hepatocytes also impaired the recruitment of leukocytes and decreased the levels of several cytokines in the peritoneal cavity in Cot/tpl2 KO mice compared with Wt counterparts. Moreover, similar activation profiles of intracellular pathways were observed in Wt macrophages stimulated with Wt or Cot/tpl2 KO damage-associated molecular patterns. However, upon stimulation with damage-associated molecular patterns, the activation of Erk1/2 and JNK was deficient in Cot/tpl2 KO macrophages compared with their Wt counterparts; an effect accompanied by weaker release of several cytokines, including IL-1α, an important component in the development of sterile inflammation. Taken together, these findings indicate that Cot/tpl2 contributes to acetaminophen-induced liver injury, providing some insight into the underlying molecular mechanisms.
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Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Fígado/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Acetaminofen/farmacologia , Alanina Transaminase/sangue , Alanina Transaminase/genética , Analgésicos não Narcóticos/farmacologia , Animais , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/genética , Linhagem Celular Transformada , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Fígado/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/genética , Macrófagos/enzimologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/genética , Neutrófilos/enzimologia , Neutrófilos/patologia , Proteínas Proto-Oncogênicas/genéticaRESUMO
It has been known for a long time that mitochondria isolated from hepatocytes treated with glucagon or Ca(2+)-mobilizing agents such as phenylephrine show an increase in their adenine nucleotide (AdN) content, respiratory activity, and calcium retention capacity (CRC). Here, we have studied the role of SCaMC-3/slc25a23, the mitochondrial ATP-Mg/Pi carrier present in adult mouse liver, in the control of mitochondrial AdN levels and respiration in response to Ca(2+) signals as a candidate target of glucagon actions. With the use of SCaMC-3 knock-out (KO) mice, we have found that the carrier is responsible for the accumulation of AdNs in liver mitochondria in a strictly Ca(2+)-dependent way with an S0.5 for Ca(2+) activation of 3.3 ± 0.9 µm. Accumulation of matrix AdNs allows a SCaMC-3-dependent increase in CRC. In addition, SCaMC-3-dependent accumulation of AdNs is required to acquire a fully active state 3 respiration in AdN-depleted liver mitochondria, although further accumulation of AdNs is not followed by increases in respiration. Moreover, glucagon addition to isolated hepatocytes increases oligomycin-sensitive oxygen consumption and maximal respiratory rates in cells derived from wild type, but not SCaMC-3-KO mice and glucagon administration in vivo results in an increase in AdN content, state 3 respiration and CRC in liver mitochondria in wild type but not in SCaMC-3-KO mice. These results show that SCaMC-3 is required for the increase in oxidative phosphorylation observed in liver mitochondria in response to glucagon and Ca(2+)-mobilizing agents, possibly by allowing a Ca(2+)-dependent accumulation of mitochondrial AdNs and matrix Ca(2+), events permissive for other glucagon actions.
Assuntos
Nucleotídeos de Adenina/metabolismo , Antiporters/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Glucagon/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Oxigênio/metabolismo , Difosfato de Adenosina/química , Trifosfato de Adenosina/química , Animais , Glucose/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Hepáticas/metabolismo , Modelos Biológicos , Fosforilação Oxidativa , Consumo de OxigênioRESUMO
Mitochondrial DNA (mtDNA) has largely been used for species delimitation. However, mtDNA introgression across species boundaries can lead to inconsistent phylogenies. Partial sequences of the mitochondrial genome in the chamois, genus Rupicapra, show the presence of three well differentiated clades, West (mtW), Central (mtC) and East (mtE), each with a geographically restricted distribution. The complete mtDNAs of the clades mtW and mtE (main representatives of the two currently considered species R. pyrenaica and R. rupicapra respectively) have been reported. In the present study, we sequenced the clade mtC present in populations from both species inhabiting the central area of Europe: the Apennines (R. pyrenaica ornata) and the Chartreuse Mountains (R. rupicapra cartusiana). The phylogenetic comparison with the genomes of Caprini highlights the ancient presence of chamois in Europe relative to the fossil record, and the old age of the chamois clade mtC that was split from the clade mtW in the early Pleistocene. The separation of R. pyrenaica ornata and R. rupicapra cartusiana female lineages was recent, dating of the late Pleistocene. Our data represent an example of mtDNA introgression of resident females of Chartreuse Mountains into immigrant males of R. rupicapra due to male-biased migration and female phylopatry.
Assuntos
Evolução Molecular , Genoma Mitocondrial , Filogenia , Rupicapra/classificação , Animais , Teorema de Bayes , DNA Mitocondrial/genética , Europa (Continente) , Feminino , Funções Verossimilhança , Masculino , Rupicapra/genética , Análise de Sequência de DNAAssuntos
Periostite , Radiografia Torácica/métodos , Cintilografia/métodos , Tomografia Computadorizada por Raios X/métodos , Voriconazol/efeitos adversos , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Feminino , Humanos , Hospedeiro Imunocomprometido , Periostite/induzido quimicamente , Periostite/diagnóstico por imagem , Periostite/fisiopatologia , Resultado do Tratamento , Voriconazol/administração & dosagem , Imagem Corporal Total/métodos , Suspensão de TratamentoRESUMO
Electronic cigarettes (or e-cigarettes) and vape products have multisystemic adverse effects despite being advertised as a safer smoking alternative and cessation device. We present a 22-year-old Filipino male with sudden chest pain. He had no known comorbidities but had a two-year history of daily vape use. Work-up revealed elevated cardiac markers, anteroseptal ST-elevation myocardial infarction, hypokinesia of the anterior wall and interventricular septum, and an ejection fraction of 30%. Chest radiography showed consolidation pneumonia but culture studies and Biofire Pneumonia Panel were negative for microbial detection. Coronary angiography revealed chronic total obstruction of the mid-left anterior descending (LAD) and right coronary arteries (RCA). Percutaneous coronary angioplasty of the LAD was done. The patient eventually required mechanical ventilation for progressive respiratory distress but expired after three hospital days despite medical management. This case highlights a possible association between vape use and the development of both acute lung injury and myocardial infarction.
RESUMO
Characterizing uranium (U) mine water is necessary to understand and design an effective bioremediation strategy. In this study, water samples from two former U-mines in East Germany were analysed. The U and sulphate (SO42-) concentrations of Schlema-Alberoda mine water (U: 1 mg/L; SO42-: 335 mg/L) were 2 and 3 order of magnitude higher than those of the Pöhla sample (U: 0.01 mg/L; SO42-: 0.5 mg/L). U and SO42- seemed to influence the microbial diversity of the two water samples. Microbial diversity analysis identified U(VI)-reducing bacteria (e.g. Desulfurivibrio) and wood-degrading fungi (e.g. Cadophora) providing as electron donors for the growth of U-reducers. U-bioreduction experiments were performed to screen electron donors (glycerol, vanillic acid, and gluconic acid) for Schlema-Alberoda U-mine water bioremediation purpose. Thermodynamic speciation calculations show that under experimental conditions, U(VI) is not coordinated to the amended electron donors. Glycerol was the best-studied electron donor as it effectively removed 99% of soluble U, 95% of Fe, and 58% of SO42- from the mine water, probably by biostimulation of indigenous microbes. Vanillic acid removed 90% of U, and no U removal occurred using gluconic acid.