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1.
Adv Biochem Eng Biotechnol ; 170: 107-119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30847536

RESUMO

Aptazymes are synthetic molecules composed of an aptamer domain and a catalytic active nucleic acid unit, which may be a ribozyme or a DNAzyme. In these constructs the aptamer domain serves as a molecular switch that can regulate the catalytic activity of the ribozyme or DNAzyme subunit. This regulation is triggered by binding of the aptamers target molecule, which causes significant structural changes in the aptamer and thus in the entire aptazyme. Therefore, aptazymes function similar to allosteric enzymes, whose catalytic activity is regulated by binding of ligands (effectors) to allosteric sites due to alteration of the three-dimensional structure of the active site of the enzyme. In case of aptazymes, the allosteric site is composed of an aptamer. Aptazymes can be designed for different applications and have already been used in analytical assays as well as for the regulation of gene expression.


Assuntos
Aptâmeros de Nucleotídeos , DNA Catalítico , RNA Catalítico , Aptâmeros de Nucleotídeos/química , Catálise , DNA Catalítico/química , DNA Catalítico/metabolismo , Ligantes , Ligação Proteica , RNA Catalítico/química , RNA Catalítico/metabolismo
2.
Rev Environ Contam Toxicol ; 251: 25-108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31011832

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are a class of hazardous organic contaminants that are widely distributed in nature, and many of them are potentially toxic to humans and other living organisms. Biodegradation is the major route of detoxification and removal of PAHs from the environment. Aerobic biodegradation of PAHs has been the subject of extensive research; however, reports on anaerobic biodegradation of PAHs are so far limited. Microbial degradation of PAHs under anaerobic conditions is difficult because of the slow growth rate of anaerobes and low energy yield in the metabolic processes. Despite the limitations, some anaerobic bacteria degrade PAHs under nitrate-reducing, sulfate-reducing, iron-reducing, and methanogenic conditions. Anaerobic biodegradation, though relatively slow, is a significant process of natural attenuation of PAHs from the impacted anoxic environments such as sediments, subsurface soils, and aquifers. This review is intended to provide comprehensive details on microbial degradation of PAHs under various reducing conditions, to describe the degradation mechanisms, and to identify the areas that should receive due attention in further investigations.


Assuntos
Bactérias Anaeróbias/metabolismo , Biodegradação Ambiental , Poluentes Ambientais/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Nitratos
3.
Rev Environ Contam Toxicol ; 252: 97-129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31346776

RESUMO

Human milk may sometimes contain chemical contaminants, which could have adverse effects on neonates or nursing infants. Lead (Pb) is of considerable interest due to its toxicity and occurrence. Furthermore, it has been suggested that human milk is a significant potential source of lead exposure to nursing infants. A systematic literature search in PubMed, Science Direct, and Google Scholar databases was performed to identify relevant studies, published in English until 2017, that investigated and explored common factors affecting the level of lead in human milk among lactating women around the world. Forty-nine papers were rated and explored the effect of one or several factors on the level of lead in human milk from 28 countries and carried out over a wide time frame from 1983 to 2017 and through Europe, Asia, America, and Africa, reviewing more than 5,000 subjects. Place of residence, maternal age, stage of lactation, smoking habits, maternal dietary intakes, and parity were the mostly assessed factors among the studies and considered as the main factors affecting Pb levels in BM. Other factors were not studied well enough and considered minor because few surveys evaluated their impacts. However, the literature findings are very controversial.


Assuntos
Poluentes Ambientais/metabolismo , Lactação , Chumbo/metabolismo , Leite Humano/metabolismo , Feminino , Humanos , Recém-Nascido , Gravidez
4.
Rev Environ Contam Toxicol ; 252: 1-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31451946

RESUMO

Microbe-assisted organopollutant removal, or in planta crop decontamination, is based on an interactive system between organopollutant-degrading endophytic bacteria (DEBOP) and crops in alleviating organic toxins in plants. This script focuses on the fast-growing body of literature that has recently bloomed in organopollutant control in agricultural plants. The various facets of DEBOP under study include their colonization, distribution, plant growth-promoting mechanisms, and modes of action in the detoxification process in plants. Also, an assessment of the biotechnological advances, advantages, and bottlenecks in accelerating the implementation of this decontamination strategy will be undertaken. The highlighted key research directions from this review will shape the future of agro-environmental sustainability and preservation of human health.


Assuntos
Bactérias , Produtos Agrícolas/microbiologia , Endófitos , Poluentes do Solo/metabolismo , Agricultura , Produtos Agrícolas/metabolismo , Inativação Metabólica , Desenvolvimento Vegetal
5.
Rev Environ Contam Toxicol ; 249: 133-152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30879139

RESUMO

Mercury (Hg) is an environmental contaminant that has been reported in many wildlife species worldwide. The organic form of Hg bioaccumulates in higher trophic levels, and thus, long-lived predators are at risk for higher Hg exposure. Although ecological risk assessments for contaminants such as Hg include pertinent receptor species, snakes are rarely considered, despite their high trophic status and potential to accumulate high levels of Hg. Our current knowledge of these reptiles suggests that snakes may be useful novel biomarkers to monitor contaminated environments. The few available studies show that snakes can bioaccumulate significant amounts of Hg. However, little is known about the role of snakes in Hg transport in the environment or the individual-level effects of Hg exposure in this group of reptiles. This is a major concern, as snakes often serve as important prey for a variety of taxa within ecosystems (including humans). In this review, we compiled and analyzed the results of over 30 studies to discuss the impact of Hg on snakes, specifically sources of exposure, bioaccumulation, health consequences, and specific scientific knowledge gaps regarding these moderate to high trophic predators.


Assuntos
Monitoramento Ambiental , Mercúrio/metabolismo , Serpentes/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Biomarcadores/metabolismo , Ecossistema , Humanos
6.
Recent Results Cancer Res ; 215: 3-24, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605221

RESUMO

The traditional model of metastatic progression postulates that the ability to form distant metastases is driven by random mutations in cells of the primary tumor.


Assuntos
Metástase Neoplásica/genética , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Progressão da Doença , Humanos , Mutação
7.
Recent Results Cancer Res ; 215: 57-76, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605223

RESUMO

The classification of human cancers has traditionally relied on the tissue of origin, the histologic appearance and anatomical extent of disease, otherwise referred to as grade and stage. However, this system fails to explain the highly variable clinical behaviour seen for any one cancer. Molecular characterization through techniques such as next-generation sequencing (NGS) has led to an appreciation of the extreme genetic heterogeneity that underlies most human cancers. Because of the difficulties associated with fresh tissue biopsy, interest has increased in using circulating tumour material, such as circulating tumour cells (CTCs), as a non-invasive way to access tumour tissue. CTC enumeration has been demonstrated to have prognostic value in metastatic breast, colon and prostate cancers. Recent studies have also shown that CTCs are suitable material for molecular characterization, using techniques such as reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and NGS. Furthermore, genetic analysis of CTCs may be more suitable to study tumour heterogeneity and clonal evolution than fresh tissue biopsy. Whether blood-based biopsy techniques will be accepted as a replacement to fresh tissue biopsies remains to be seen, but there is reason for optimism. While significant barriers to this acceptance exist, blood-based biopsy techniques appear to be reliable and representative alternatives to fresh tissue biopsy.


Assuntos
Análise Mutacional de DNA , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes , Hibridização Genômica Comparativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , Prognóstico
8.
Recent Results Cancer Res ; 215: 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605224

RESUMO

Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.


Assuntos
Separação Celular/métodos , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes , RNA Neoplásico/análise , Progressão da Doença , Humanos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/metabolismo , RNA Neoplásico/genética
9.
Recent Results Cancer Res ; 215: 89-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605225

RESUMO

Circulating tumor cells (CTCs) represent novel biomarkers, since they are obtainable through a simple and noninvasive blood draw or liquid biopsy. Here, we review the high-definition single-cell analysis (HD-SCA) workflow, which brings together modern methods of immunofluorescence with more sophisticated image processing to rapidly and accurately detect rare tumor cells among the milieu of platelets, erythrocytes, and leukocytes in the peripheral blood. In particular, we discuss progress in methods to measure CTC morphology and subcellular protein expression, and we highlight some initial applications that lead to fundamental new insights about the hematogenous phase of cancer, as well as its performance in early-stage diagnosis and treatment monitoring. We end with an outlook on how to further probe CTCs and the unique advantages of the HD-SCA workflow for improving the precision of cancer care.


Assuntos
Biologia Computacional , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Células Neoplásicas Circulantes/patologia , Análise de Célula Única
10.
Recent Results Cancer Res ; 215: 105-125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605226

RESUMO

Circulating tumour cells (CTCs) constitute a potential tumour surrogate that could serve as "liquid biopsy" with the advantage to be a minimally invasive approach compared to traditional tissue biopsies. As CTCs are thought to be the source of metastatic lesions, their analysis represents a potential means of tracking cancer cells from the primary tumour en route to distant sites, thus providing valuable insights into the metastatic process. However, several problems, such as their rarity in the peripheral blood, the technical limitations of single-cell downstream analysis and their phenotypic variability, make CTC detection and molecular characterisation very challenging. Nevertheless, in the last decade, there has been an exponential increase of interest in the development of powerful cellular and molecular methodologies applied to CTCs. In this chapter, we focus on the recent advances of functional studies and molecular profiling of CTCs. We will also highlight the clinical relevance of CTC detection and enumeration, and discuss their potential as tumour biomarkers with special focus on lung cancer.


Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Tumorais/análise , Humanos , Células Neoplásicas Circulantes/patologia
11.
Recent Results Cancer Res ; 215: 127-145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605227

RESUMO

With active screening for early detection and advancements in treatment, there has been a significant decrease in mortality from breast cancer. However, a significant proportion of patients with non-metastatic breast cancer at time of diagnosis will relapse. Therefore, it is suggested that the dissemination of bloodstream tumor cells (circulating tumor cells, CTCs) undetectable by currently available diagnostic tools occurs during the early stages of breast cancer progression, and may be the potential source of micrometastases responsible for treatment failures. Here, we review the clinical significance of CTCs, as detected by the FDA-approved CellSearch® System, in both metastatic and non-metastatic breast cancer patients. Studies so far suggest that CTCs are prognostic of poorer outcomes in breast cancer patients; however, there is currently insufficient data to support use of CTC data to guide treatment. Therefore, there are ongoing studies to evaluate the utility of assessing CTC phenotypes to develop personalized breast cancer treatment, which will be reviewed in this chapter.


Assuntos
Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/metabolismo , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Progressão da Doença , Humanos , Células Neoplásicas Circulantes/patologia , Medicina de Precisão , Prognóstico
12.
Recent Results Cancer Res ; 215: 163-180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605229

RESUMO

The clinical implications of being able to accurately detect tumor-derived DNA in the circulation, termed circulating tumor DNA (ctDNA), could be enormous. Already, a plethora of clinical applications is under validation that include detection of minimal residual disease and predicting recurrence, monitoring response and resistance to treatment, identifying targets for therapies, and early detection. ctDNA is only a fraction of the total cell-free DNA (cfDNA) which confounds its detection and sometimes conceals its properties. To use ctDNA as a cancer biomarker with confidence, we need to understand its nature. Its characteristics, including size, half-life, and amount, are critical for the development of tests for its detection and discrimination from the rest of the cfDNA. Technological advances have enabled the detection and quantification of individual fragments of cfDNA, which is pivotal for clinical applications. Understanding the causes, the source of and the mechanisms of release of ctDNA are important for the interpretation of test results. Despite the many advances in understanding the nature and biology of ctDNA, we do not yet have a clear appreciation of the processes that govern its presence and levels in the circulation. ctDNA is not detectable in the blood of every cancer patient, and there is not a directly proportional relationship to tumor type, size, or stage. It is not clear if the lack of correlation with these specific clinical parameters is strictly due to technical or biological challenges. Better understanding of the pathophysiology of ctDNA is therefore important for the improvement of clinical applications and interpretation of their results.


Assuntos
DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/metabolismo , Neoplasias/genética , Neoplasias/patologia , Humanos , Neoplasia Residual/sangue , Neoplasia Residual/genética
13.
Einstein (Sao Paulo) ; 18: eAO4876, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31576909

RESUMO

OBJECTIVE: To investigate the effects of sericin extracted from silkworm Bombyx mori cocoon on morphophysiological parameters in mice with obesity induced by high-fat diet. METHODS: Male C57Bl6 mice aged 9 weeks were allocated to one of two groups - Control and Obese, and fed a standard or high-fat diet for 10 weeks, respectively. Mice were then further subdivided into four groups with seven mice each, as follows: Control, Control-Sericin, Obese, and Obese-Sericin. The standard or high fat diet was given for 4 more weeks; sericin (1,000mg/kg body weight) was given orally to mice in the Control-Sericin and Obese-Sericin Groups during this period. Weight gain, food intake, fecal weight, fecal lipid content, gut motility and glucose tolerance were monitored. At the end of experimental period, plasma was collected for biochemical analysis. Samples of white adipose tissue, liver and jejunum were collected and processed for light microscopy analysis; liver fragments were used for lipid content determination. RESULTS: Obese mice experienced significantly greater weight gain and fat accumulation and had higher total cholesterol and glucose levels compared to controls. Retroperitoneal and periepididymal adipocyte hypertrophy, development of hepatic steatosis, increased cholesterol and triglyceride levels and morphometric changes in the jejunal wall were observed. CONCLUSION: Physiological changes induced by obesity were not fully reverted by sericin; however, sericin treatment restored jejunal morphometry and increased lipid excretion in feces in obese mice, suggesting potential anti-obesity effects.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Dieta Hiperlipídica , Obesidade/tratamento farmacológico , Sericinas/uso terapêutico , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Colesterol/análise , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/patologia , Trânsito Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/fisiopatologia , Reprodutibilidade dos Testes , Sericinas/farmacologia , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/análise , Ganho de Peso/efeitos dos fármacos
14.
Acta Neurochir Suppl ; 127: 43-46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407061

RESUMO

Early brain injury is now considered as an important cause of delayed neurological deterioration after aneurysmal subarachnoid hemorrhage (SAH), and neuronal apoptosis is one of the constituents of early brain injury. Caspase family is popular proteases in apoptotic pathways, but there also exist caspase-independent cell death pathways in many pathologic states. In this study, we investigated the ratio of caspase-related and caspase-unrelated neuronal deaths in a mice endovascular perforation SAH model. At 24 h after SAH, about half of neurons in the perforation-side cortex showed increased cleaved caspase-3 immunoreactivity. On the other hand, about half of cleaved caspase-3-immunonegative neurons showed abnormal morphology, suggesting that they were in the process of some sort of cell death in the absence of caspase-3 activity. These findings suggest that both caspase-dependent and caspase-independent signaling pathways may cause neuronal death after SAH.


Assuntos
Caspases , Hemorragia Subaracnóidea , Animais , Apoptose , Caspases/metabolismo , Camundongos , Neurônios , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/enzimologia
15.
Acta Neurochir Suppl ; 127: 47-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407062

RESUMO

BACKGROUND: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats. METHODS: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats. RESULTS: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage. CONCLUSION: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , NADPH Oxidase 2 , NADPH Oxidase 4 , Traumatismo por Reperfusão , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , NADPH Oxidase 2/antagonistas & inibidores , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , NADPH Oxidase 4/metabolismo , NADPH Oxidases , Ratos , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão/metabolismo
16.
Acta Neurochir Suppl ; 127: 65-68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407065

RESUMO

Despite advances in diagnosis and treatment of subarachnoid hemorrhage (SAH), combined morbidity and mortality rate in SAH patients accounted for greater than 50%. Many prognostic factors have been reported including delayed cerebral ischemia, cerebral vasospasm-induced infarction, and shunt-dependent hydrocephalus as potentially preventable or treatable causes. Recent experimental studies emphasize that early brain injury, a concept to explain acute pathophysiological events that occur in brain before onset of cerebral vasospasm within the first 72 h of SAH, may be more important than cerebral vasospasm, a classically important determinant of poor outcome, in post-SAH outcome. Galectin-3 is known for one of matricellular proteins and a mediator of inflammation in the central nervous system. Galectin-3 was also reported to contribute to poor outcomes in SAH patients, but the role of galectin-3 after SAH has not been determined. We produced experimental SAH mice, of which the top of the internal carotid artery was perforated by 4-0 monofilament, and evaluated effects of a galectin-3 inhibitor. We assessed neurological scores and brain water content at 24 h. The administration of a galectin-3 inhibitor significantly ameliorated brain edema and neuronal score in experimental SAH mice.


Assuntos
Lesões Encefálicas , Infarto Cerebral , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Animais , Galectina 3/fisiologia , Humanos , Camundongos , Hemorragia Subaracnóidea/metabolismo
17.
Acta Neurochir Suppl ; 127: 69-75, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407066

RESUMO

BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe and emergent cerebrovascular disease, the prognosis of which usually very poor. Microthrombi formation highlighted with inflammation occurs early after SAH. As the main cause of DCI, microthrombosis associated with the prognosis of SAH. The aim of this study was to show HSP90 inhibitor 17-AAG effect on microthrombosis after SAH in rats. METHODS: Ninety-five SD rats were used for the experiment. For time course study, the rats were randomly divided into five groups: sham group and SAH group with different time point (1d, 2d, 3d, 5d). Endovascular perforation method was conducted for SAH model. Neurological score, SAH grade, and mortality were measured after SAH. The samples of the left hemisphere brain were collected. The expression of HSP90 was detected by Western blot. The microthrombosis after SAH in rats' brain was detected by immunohistochemistry. For mechanism study, rats were randomly divided into three groups: sham, SAH + vehicle, and SAH +17-AAG (n = 6/group). 17-AAG was given by intraperitoneal injection (80 mg/kg) 1 h after SAH. Neurological function were measured at 24 h after SAH. The expression of RIP3, NLRP3, ASC, and IL-1ß was measured by Western blot. Microthrombosis was detected by immunohistochemistry. RESULTS: Our results showed that the HSP90 protein level increased and peaked at 2 days after SAH. Microthrombosis caused by SAH was increased in 1 day and peaked at 2 days after SAH. Administration HSP90 specific inhibitor 17-AAG reduced expression of RIP3, NLRP3, ASC, and IL-1ß, reduced microthrombosis after SAH, and improved neurobehavior when compared to vehicle group. CONCLUSIONS: 17-AAG can ameliorate microthrombosis via HSP90/RIP3/NLRP3 pathway and improve neurobehavior after SAH.


Assuntos
Inibidores Enzimáticos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Hemorragia Subaracnóidea , Trombose , Animais , Córtex Cerebral , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90 , Inflamação , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Trombose/tratamento farmacológico
18.
Acta Neurochir Suppl ; 127: 91-96, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407069

RESUMO

Toll-like receptor 4 (TLR4) is expressed in various cell types in the central nervous system and exerts maximal inflammatory responses among the TLR family members. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of a cerebral aneurysm, and therefore its activation is reasonable as an initial step of cascades to brain injuries after aneurysmal subarachnoid hemorrhage (SAH). TLR4 activation induces tenascin-C (TNC), a representative of matricellular proteins that are a class of inducible, nonstructural, secreted, and multifunctional extracellular matrix glycoproteins. TNC is also an endogenous activator and inducer of TLR4, forming positive feedback mechanisms leading to more activation of the signaling transduction. Our studies have demonstrated that TLR4 as well as TNC are involved in inflammatory reactions, blood-brain barrier disruption, neuronal apoptosis, and cerebral vasospasm after experimental SAH. This article reviews recent understanding of TLR4 and TNC in SAH to suggest that the TLR4-TNC signaling may be an important therapeutic target for post-SAH brain injuries.


Assuntos
Lesões Encefálicas , Hemorragia Subaracnóidea , Tenascina , Receptor 4 Toll-Like , Vasoespasmo Intracraniano , Lesões Encefálicas/metabolismo , Matriz Extracelular , Humanos , Hemorragia Subaracnóidea/metabolismo , Tenascina/metabolismo , Receptor 4 Toll-Like/metabolismo , Vasoespasmo Intracraniano/metabolismo
19.
Acta Neurochir Suppl ; 127: 105-119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31407071

RESUMO

The protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, which is a branch of the unfolded protein response, participates in a range of pathophysiological processes of neurological diseases. However, few studies have investigated the role of the PERK in intracerebral hemorrhage (ICH). The present study evaluated the role of the PERK pathway during the early phase of ICH-induced secondary brain injury (SBI) and its potential mechanisms. An autologous whole blood ICH model was established in rats, and cultured primary cortical neurons were treated with oxyhemoglobin to mimic ICH in vitro. We found that levels of phosphorylated alpha subunit of eukaryotic translation initiation factor 2 (p-eIF2α) and activating transcription factor 4 (ATF4) increased significantly and peaked at 12 h during the early phase of the ICH. To further elucidate the role of the PERK pathway, we assessed the effects of the PERK inhibitor, GSK2606414, and the eIF2α dephosphorylation antagonist, salubrinal, at 12 h after ICH both in vivo and in vitro. Inhibition of PERK with GSK2606414 suppressed the protein levels of p-eIF2α and ATF4, resulting in increase of transcriptional activator CCAAT/enhancer-binding protein homologous protein (CHOP) and caspase-12, which promoted apoptosis and reduced neuronal survival. Treatment with salubrinal yielded opposite results, which suggested that activation of the PERK pathway could promote neuronal survival and reduce apoptosis. In conclusion, the present study has demonstrated the neuroprotective effects of the PERK pathway during the early phase of ICH-induced SBI. These findings highlight the potential value of PERK pathway as a therapeutic target for ICH.


Assuntos
Lesões Encefálicas , Hemorragia Cerebral , RNA , eIF-2 Quinase , Animais , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/metabolismo , Fator de Iniciação 2 em Eucariotos , Ratos , eIF-2 Quinase/metabolismo
20.
Adv Exp Med Biol ; 1131: 7-26, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646505

RESUMO

Measuring free Ca2+ concentration ([Ca2+]) in the cytosol or organelles is routine in many fields of research. The availability of membrane permeant forms of indicators coupled with the relative ease of transfecting cell lines with biological Ca2+ sensors have led to the situation where cellular and subcellular [Ca2+] is examined by many non-specialists. In this chapter, we evaluate the most used Ca2+ indicators and highlight what their major advantages and disadvantages are. We stress the potential pitfalls of non-ratiometric techniques for measuring Ca2+ and the clear advantages of ratiometric methods. Likely improvements and new directions for Ca2+ measurement are discussed.


Assuntos
Cálcio , Citosol , Organelas , Animais , Cálcio/metabolismo , Técnicas Citológicas , Citosol/química , Citosol/metabolismo , Humanos , Organelas/química , Organelas/metabolismo
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