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1.
Aquaculture ; 571: 739491, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-36968151

RESUMO

The global COVID-19 pandemic resulted in an unprecedented economic shock in current times. Previous literature on consumer shopping behaviors during economic downturns is limited, and studies specific to seafood focused primarily on supply-side shocks. A national survey was conducted using an online platform from February 22 to April 6, 2021 that targeted 100 seafood consumers in each of 20 market areas across the U.S. Following data cleaning, 1908 usable responses were obtained. Results documented significant changes in consumer shopping behaviors. Significantly greater percentages of meals (generally and of seafood) were consumed at home and fewer away from home, as expected. Demographic differences were found in shopping behaviors by age, education, income, and gender, but not by ethnic group. Frequency of shopping decreased in 2020, but the expenditure per shopping trip did not, resulting in less overall spending for groceries as compared to 2019. Respondents were less likely to purchase seafood for takeout or for home delivery of prepared meals as compared to general meals because of concerns over quality, freshness, and safety of seafood. Half of respondents consumed approximately the same amount of seafood as before the pandemic; with 31% reporting decreased seafood consumption, and only 19% increased seafood consumption. Thus, study results provide evidence of a pandemic-imposed shift to consuming greater proportions of seafood meals at-home than away-from-home, and not an overall increase in seafood consumption. The choice of species eaten most often did not differ pre- and post-pandemic. Those respondents who reported decreased seafood consumption in 2020 did so primarily because of: 1) its expense, given reduced incomes from working fewer hours or being laid off; 2) unwillingness to prepare fish at home for the smell and "mess", or being uncomfortable preparing it; or 3) simply not preferring or liking seafood well enough to eat it more frequently. Those who reported increasing seafood consumption did so primarily because it was considered to be a healthy food choice. Additional work is needed to further examine consumption and shopping behaviors throughout the recovery in 2021 and 2022.

2.
J Invertebr Pathol ; 186: 107397, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-32446865

RESUMO

Shrimp is not only one of the world's most valuable aquaculture species, but also a species that encounter high economic losses due to diseases. Diseases are sufficiently important to influence global supply and prices for longer periods. Profitability is the driving force behind shrimp farming and high profits associated with the absence of disease largely determines where shrimp production does take place; i.e. prevalence of disease leads to geographic relocation. In this paper, a basic economic model for the impact of the disease on a shrimp farm is provided and a Monte Carlo simulation is provided to illustrate the impact of disease on economic risk. Improved technologies, knowledge, and governance are important elements utilized in the mitigation of diseases in various shrimp producing countries. Economic aspects such as profitability in the absence and presence of diseases and cost of treatment determines the global production of shrimp along with shaping technologies and production systems.


Assuntos
Aquicultura/economia , Penaeidae/microbiologia , Penaeidae/parasitologia , Animais , Penaeidae/virologia
3.
Entropy (Basel) ; 23(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34681999

RESUMO

Feature selection is known to be an applicable solution to address the problem of high dimensionality in software defect prediction (SDP). However, choosing an appropriate filter feature selection (FFS) method that will generate and guarantee optimal features in SDP is an open research issue, known as the filter rank selection problem. As a solution, the combination of multiple filter methods can alleviate the filter rank selection problem. In this study, a novel adaptive rank aggregation-based ensemble multi-filter feature selection (AREMFFS) method is proposed to resolve high dimensionality and filter rank selection problems in SDP. Specifically, the proposed AREMFFS method is based on assessing and combining the strengths of individual FFS methods by aggregating multiple rank lists in the generation and subsequent selection of top-ranked features to be used in the SDP process. The efficacy of the proposed AREMFFS method is evaluated with decision tree (DT) and naïve Bayes (NB) models on defect datasets from different repositories with diverse defect granularities. Findings from the experimental results indicated the superiority of AREMFFS over other baseline FFS methods that were evaluated, existing rank aggregation based multi-filter FS methods, and variants of AREMFFS as developed in this study. That is, the proposed AREMFFS method not only had a superior effect on prediction performances of SDP models but also outperformed baseline FS methods and existing rank aggregation based multi-filter FS methods. Therefore, this study recommends the combination of multiple FFS methods to utilize the strength of respective FFS methods and take advantage of filter-filter relationships in selecting optimal features for SDP processes.

4.
Proc Natl Acad Sci U S A ; 114(6): 1413-1418, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28115703

RESUMO

Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (H2S) as the major effector molecule driving apneas. Genetic ablation of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2-/- mice. Pharmacologic inhibition of CSE with l-propargyl glycine prevented apneas in both HO-2-/- mice and SH rats. These observations demonstrate that dysregulated CO and H2S signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.


Assuntos
Monóxido de Carbono/metabolismo , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Síndromes da Apneia do Sono/metabolismo , Animais , Corpo Carotídeo/metabolismo , Corpo Carotídeo/fisiopatologia , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Feminino , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Respiração/genética , Síndromes da Apneia do Sono/genética , Síndromes da Apneia do Sono/fisiopatologia
5.
Org Biomol Chem ; 16(18): 3314-3327, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29645045

RESUMO

Reagents derived from hydroxylamines such as 2,4-dinitrophenylhydroxylamine (DPH), O-(diphenylphosphinyl)hydroxylamine (DPPH), hydroxylamine-O-sulfonic acid (HOSA) and other related reagents in which oxygen is substituted with good leaving groups recently showed remarkable potential as electrophilic aminating agents and as a source of the amino group. They facilitate stereo- and regioselective C-N, N-N, O-N, and S-N bond-formation reactions and intra-molecular cyclizations without the requirement of expensive metal catalysts. In this review we have discussed the important transformations achieved with these reagents.

6.
J Physiol ; 595(1): 63-77, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27506145

RESUMO

KEY POINTS: The effects of short-term (ST; 10 days) and long-term (LT; 30 days) intermittent hypoxia (IH) on blood pressure (BP), breathing and carotid body (CB) chemosensory reflex were examined in adult rats. ST- and LT-IH treated rats exhibited hypertension, irregular breathing with apnoea and augmented the CB chemosensory reflex, with all these responses becoming normalized during recovery from ST- but not from LT-IH. The persistent cardiorespiratory responses to LT-IH were associated with elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla, which were a result of DNA methylation-dependent suppression of genes encoding anti-oxidant enzymes (AOEs). Treating rats with decitabine either during LT-IH or during recovery from LT-IH prevented DNA methylation of AOE genes, normalized the expression of AOE genes and ROS levels, reversed the heightened CB chemosensory reflex and hypertension, and also stabilized breathing. ABSTRACT: Rodents exposed to chronic intermittent hypoxia (IH), simulating blood O2 saturation profiles during obstructive sleep apnoea (OSA), have been shown to exhibit a heightened carotid body (CB) chemosensory reflex and hypertension. CB chemosensory reflex activation also results in unstable breathing with apnoeas. However, the effect of chronic IH on breathing is not known. In the present study, we examined the effects of chronic IH on breathing along with blood pressure (BP) and assessed whether the autonomic responses are normalized after recovery from chronic IH. Studies were performed on adult, male, Sprague-Dawley rats exposed to either short-term (ST; 10 days) or long-term (LT, 30 days) IH. Rats exposed to either ST- or LT-IH exhibited hypertension, irregular breathing with apnoeas, an augmented CB chemosensory reflex as indicated by elevated CB neural activity and plasma catecholamine levels, and elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla (AM). All these effects were normalized after recovery from ST-IH but not from LT-IH. Analysis of the molecular mechanisms underlying the persistent effects of LT-IH revealed increased DNA methylation of genes encoding anti-oxidant enzymes (AOEs). Treatment with decitabine, a DNA methylation inhibitor, either during LT-IH or during recovery from LT-IH, prevented DNA methylation, normalized the expression of AOE genes, ROS levels, CB chemosensory reflex and BP, and also stabilized breathing. These results suggest that persistent cardiorespiratory abnormalities caused by LT-IH are mediated by epigenetic re-programming of the redox state in the CB chemosensory reflex pathway.


Assuntos
Hipertensão/fisiopatologia , Hipóxia/fisiopatologia , Transtornos Respiratórios/fisiopatologia , Aconitato Hidratase/metabolismo , Medula Suprarrenal/metabolismo , Animais , Pressão Sanguínea , Corpo Carotídeo/metabolismo , Corpo Carotídeo/fisiologia , Catalase/genética , Metilação de DNA , Epigênese Genética , Expressão Gênica , Glutationa Peroxidase/genética , Hipertensão/sangue , Hipertensão/genética , Hipertensão/metabolismo , Hipóxia/sangue , Hipóxia/genética , Hipóxia/metabolismo , Masculino , Malondialdeído/metabolismo , Norepinefrina/sangue , Oxirredução , Peroxirredoxinas/genética , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transtornos Respiratórios/sangue , Transtornos Respiratórios/genética , Transtornos Respiratórios/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética
7.
BMC Genet ; 18(Suppl 1): 110, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29297395

RESUMO

BACKGROUND: The history of human populations occupying the plains and mountain ridges separating Europe from Asia has been eventful, as these natural obstacles were crossed westward by multiple waves of Turkic and Uralic-speaking migrants as well as eastward by Europeans. Unfortunately, the material records of history of this region are not dense enough to reconstruct details of population history. These considerations stimulate growing interest to obtain a genetic picture of the demographic history of migrations and admixture in Northern Eurasia. RESULTS: We genotyped and analyzed 1076 individuals from 30 populations with geographical coverage spanning from Baltic Sea to Baikal Lake. Our dense sampling allowed us to describe in detail the population structure, provide insight into genomic history of numerous European and Asian populations, and significantly increase quantity of genetic data available for modern populations in region of North Eurasia. Our study doubles the amount of genome-wide profiles available for this region. We detected unusually high amount of shared identical-by-descent (IBD) genomic segments between several Siberian populations, such as Khanty and Ket, providing evidence of genetic relatedness across vast geographic distances and between speakers of different language families. Additionally, we observed excessive IBD sharing between Khanty and Bashkir, a group of Turkic speakers from Southern Urals region. While adding some weight to the "Finno-Ugric" origin of Bashkir, our studies highlighted that the Bashkir genepool lacks the main "core", being a multi-layered amalgamation of Turkic, Ugric, Finnish and Indo-European contributions, which points at intricacy of genetic interface between Turkic and Uralic populations. Comparison of the genetic structure of Siberian ethnicities and the geography of the region they inhabit point at existence of the "Great Siberian Vortex" directing genetic exchanges in populations across the Siberian part of Asia. Slavic speakers of Eastern Europe are, in general, very similar in their genetic composition. Ukrainians, Belarusians and Russians have almost identical proportions of Caucasus and Northern European components and have virtually no Asian influence. We capitalized on wide geographic span of our sampling to address intriguing question about the place of origin of Russian Starovers, an enigmatic Eastern Orthodox Old Believers religious group relocated to Siberia in seventeenth century. A comparative reAdmix analysis, complemented by IBD sharing, placed their roots in the region of the Northern European Plain, occupied by North Russians and Finno-Ugric Komi and Karelian people. Russians from Novosibirsk and Russian Starover exhibit ancestral proportions close to that of European Eastern Slavs, however, they also include between five to 10 % of Central Siberian ancestry, not present at this level in their European counterparts. CONCLUSIONS: Our project has patched the hole in the genetic map of Eurasia: we demonstrated complexity of genetic structure of Northern Eurasians, existence of East-West and North-South genetic gradients, and assessed different inputs of ancient populations into modern populations.


Assuntos
Emigração e Imigração/história , Etnicidade/genética , Genética Populacional , Algoritmos , Ásia , DNA , Conjuntos de Dados como Assunto , Europa (Continente) , Feminino , Variação Genética , Técnicas de Genotipagem , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , História Medieval , Humanos , Masculino , Federação Russa
8.
Proc Natl Acad Sci U S A ; 111(3): 1174-9, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24395806

RESUMO

Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Humans and animals exhibit substantial interindividual variation in this chemosensory reflex response, with profound effects on cardiorespiratory functions. However, the underlying mechanisms are not known. Here, we report that inherent variations in carotid body O2 sensing by carbon monoxide (CO)-sensitive hydrogen sulfide (H2S) signaling contribute to reflex variation in three genetically distinct rat strains. Compared with Sprague-Dawley (SD) rats, Brown-Norway (BN) rats exhibit impaired carotid body O2 sensing and develop pulmonary edema as a consequence of poor ventilatory adaptation to hypobaric hypoxia. Spontaneous Hypertensive (SH) rat carotid bodies display inherent hypersensitivity to hypoxia and develop hypertension. BN rat carotid bodies have naturally higher CO and lower H2S levels than SD rat, whereas SH carotid bodies have reduced CO and greater H2S generation. Higher CO levels in BN rats were associated with higher substrate affinity of the enzyme heme oxygenase 2, whereas SH rats present lower substrate affinity and, thus, reduced CO generation. Reducing CO levels in BN rat carotid bodies increased H2S generation, restoring O2 sensing and preventing hypoxia-induced pulmonary edema. Increasing CO levels in SH carotid bodies reduced H2S generation, preventing hypersensitivity to hypoxia and controlling hypertension in SH rats.


Assuntos
Monóxido de Carbono/química , Corpo Carotídeo/fisiologia , Sulfeto de Hidrogênio/química , Hipertensão/metabolismo , Oxigênio/química , Edema Pulmonar/metabolismo , Animais , Peso Corporal , Catecolaminas/metabolismo , Cistationina gama-Liase/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hipóxia , Imuno-Histoquímica , Masculino , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Respiração , Transdução de Sinais , Especificidade da Espécie , Nervos Esplâncnicos/patologia
10.
J Neurophysiol ; 115(1): 345-54, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26561606

RESUMO

Chronic intermittent hypoxia (CIH) is a hallmark manifestation of sleep apnea. A heightened carotid body activity and the resulting chemosensory reflex mediate increased sympathetic nerve activity by CIH. However, the mechanisms underlying heightened carotid body activity by CIH are not known. An elevation of intracellular calcium ion concentration ([Ca(2+)]i) in glomus cells, the primary oxygen-sensing cells, is an essential step for carotid body activation by hypoxia. In the present study, we examined the effects of CIH on the glomus cell [Ca(2+)]i response to hypoxia and assessed the underlying mechanisms. Glomus cells were harvested from adult rats or wild-type mice treated with 10 days of either room air (control) or CIH (alternating cycles of 15 s of hypoxia and 5 min of room air; 9 episodes/h; 8 h/day). CIH-treated glomus cells exhibited an enhanced [Ca(2+)]i response to hypoxia, and this effect was absent in the presence of 2-(4-cyclopropylphenyl)-N-((1R)-1-[5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl]ethyl)acetamide (TTA-A2), a specific inhibitor of T-type Ca(2+) channels, and in voltage-gated calcium channel, type 3.2 (CaV3.2), null glomus cells. CaV3.2 knockout mice exhibited an absence of CIH-induced hypersensitivity of the carotid body. CIH increased reactive oxygen species (ROS) levels in glomus cells. A ROS scavenger prevented the exaggerated TTA-A2-sensitive [Ca(2+)]i response to hypoxia. CIH had no effect on CaV3.2 mRNA levels. CIH augmented Ca(2+) currents and increased CaV3.2 protein in plasma membrane fractions of human embryonic kidney-293 cells stably expressing CaV3.2, and either a ROS scavenger or brefeldin-A, an inhibitor of protein trafficking, prevented these effects. These findings suggest that CIH leads to an augmented Ca(2+) influx via ROS-dependent facilitation of CaV3.2 protein trafficking to the plasma membrane.


Assuntos
Canais de Cálcio Tipo T/metabolismo , Cálcio/metabolismo , Corpo Carotídeo/metabolismo , Hipóxia/metabolismo , Animais , Benzenoacetamidas/administração & dosagem , Canais de Cálcio Tipo T/fisiologia , Corpo Carotídeo/efeitos dos fármacos , Hipóxia Celular , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transporte Proteico , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
11.
Proc Natl Acad Sci U S A ; 110(19): E1788-96, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23610397

RESUMO

Breathing and blood pressure are under constant homeostatic regulation to maintain optimal oxygen delivery to the tissues. Chemosensory reflexes initiated by the carotid body and catecholamine secretion from the adrenal medulla are the principal mechanisms for maintaining respiratory and cardiovascular homeostasis; however, the underlying molecular mechanisms are not known. Here, we report that balanced activity of hypoxia-inducible factor-1 (HIF-1) and HIF-2 is critical for oxygen sensing by the carotid body and adrenal medulla, and for their control of cardio-respiratory function. In Hif2α(+/-) mice, partial HIF-2α deficiency increased levels of HIF-1α and NADPH oxidase 2, leading to an oxidized intracellular redox state, exaggerated hypoxic sensitivity, and cardio-respiratory abnormalities, which were reversed by treatment with a HIF-1α inhibitor or a superoxide anion scavenger. Conversely, in Hif1α(+/-) mice, partial HIF-1α deficiency increased levels of HIF-2α and superoxide dismutase 2, leading to a reduced intracellular redox state, blunted oxygen sensing, and impaired carotid body and ventilatory responses to chronic hypoxia, which were corrected by treatment with a HIF-2α inhibitor. None of the abnormalities observed in Hif1α(+/-) mice or Hif2α(+/-) mice were observed in Hif1α(+/-);Hif2α(+/-) mice. These observations demonstrate that redox balance, which is determined by mutual antagonism between HIF-α isoforms, establishes the set point for hypoxic sensing by the carotid body and adrenal medulla, and is required for maintenance of cardio-respiratory homeostasis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Corpo Carotídeo/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/metabolismo , Medula Suprarrenal/fisiologia , Animais , Pressão Sanguínea , Sistema Cardiovascular , Corpo Carotídeo/metabolismo , Catecolaminas/metabolismo , Heterozigoto , Homeostase , Hipóxia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Oxirredução , Células PC12 , Ratos , Superóxido Dismutase/metabolismo
12.
Am J Physiol Cell Physiol ; 308(2): C146-54, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25377087

RESUMO

Arterial blood O2 levels are detected by specialized sensory organs called carotid bodies. Voltage-gated Ca(2+) channels (VGCCs) are important for carotid body O2 sensing. Given that T-type VGCCs contribute to nociceptive sensation, we hypothesized that they participate in carotid body O2 sensing. The rat carotid body expresses high levels of mRNA encoding the α1H-subunit, and α1H protein is localized to glomus cells, the primary O2-sensing cells in the chemoreceptor tissue, suggesting that CaV3.2 is the major T-type VGCC isoform expressed in the carotid body. Mibefradil and TTA-A2, selective blockers of the T-type VGCC, markedly attenuated elevation of hypoxia-evoked intracellular Ca(2+) concentration, secretion of catecholamines from glomus cells, and sensory excitation of the rat carotid body. Similar results were obtained in the carotid body and glomus cells from CaV3.2 knockout (Cacna1h(-/-)) mice. Since cystathionine-γ-lyase (CSE)-derived H2S is a critical mediator of the carotid body response to hypoxia, the role of T-type VGCCs in H2S-mediated O2 sensing was examined. Like hypoxia, NaHS, a H2S donor, increased intracellular Ca(2+) concentration and augmented carotid body sensory nerve activity in wild-type mice, and these effects were markedly attenuated in Cacna1h(-/-) mice. In wild-type mice, TTA-A2 markedly attenuated glomus cell and carotid body sensory nerve responses to hypoxia, and these effects were absent in CSE knockout mice. These results demonstrate that CaV3.2 T-type VGCCs contribute to the H2S-mediated carotid body response to hypoxia.


Assuntos
Canais de Cálcio Tipo T/metabolismo , Canais de Cálcio/metabolismo , Corpo Carotídeo/metabolismo , Sulfeto de Hidrogênio/farmacologia , Hipóxia/metabolismo , Animais , Cálcio/metabolismo , Corpo Carotídeo/efeitos dos fármacos , Catecolaminas/metabolismo , Células Cultivadas , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/metabolismo , Cistationina gama-Liase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfetos
13.
Cancer Cell ; 11(5): 407-20, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17482131

RESUMO

Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.


Assuntos
Carcinoma de Células Renais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neoplasias Renais/metabolismo , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Mensageiro/genética , Proteínas de Ligação a RNA , Transcrição Gênica/fisiologia
14.
Biochem J ; 458(2): 203-11, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24328859

RESUMO

Increased catalytic activity of CBS (cystathionine ß-synthase) was recently shown to mediate vasodilation of the cerebral microcirculation, which is initiated within minutes of the onset of acute hypoxia. To test whether chronic hypoxia was a stimulus for increased CBS expression, U87-MG human glioblastoma and PC12 rat phaeochromocytoma cells were exposed to 1% or 20% O2 for 24-72 h. CBS mRNA and protein expression were increased in hypoxic cells. Hypoxic induction of CBS expression was abrogated in cells transfected with vector encoding shRNA targeting HIF (hypoxia-inducible factor) 1α or 2α. Exposure of rats to hypobaric hypoxia (0.35 atm; 1 atm=101.325 kPa) for 3 days induced increased CBS mRNA, protein and catalytic activity in the cerebral cortex and cerebellum, which was blocked by administration of the HIF inhibitor digoxin. HIF-binding sites, located 0.8 and 1.2 kb 5' to the transcription start site of the human CBS and rat Cbs genes respectively, were identified by ChIP assays. A 49-bp human sequence, which encompassed an inverted repeat of the core HIF-binding site, functioned as a hypoxia-response element in luciferase reporter transcription assays. Thus HIFs mediate tissue-specific CBS expression, which may augment cerebral vasodilation as an adaptive response to chronic hypoxia.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Cistationina beta-Sintase/biossíntese , Regulação Enzimológica da Expressão Gênica , Hipóxia Encefálica/enzimologia , Animais , Encéfalo/irrigação sanguínea , Células Cultivadas , Cistationina beta-Sintase/genética , Células HEK293 , Humanos , Hipóxia Encefálica/genética , Hipóxia Encefálica/patologia , Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Células PC12 , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Distribuição Tecidual/genética , Vasodilatação/genética
15.
Adv Exp Med Biol ; 860: 195-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26303481

RESUMO

Intermittent hypoxia (IH) increases reactive oxygen species generation resulting in oxidative stress in the adrenal medulla (AM), a major end-organ of the sympathetic nervous system which facilitates catecholamine secretion by hypoxia. Here, we show that carotid body chemoreflex contributes to IH-induced oxidative stress in the AM. Carotid bodies were ablated by cryocoagulation of glomus cells, the putative O(2) sensing cells. Carotid body ablated (CBA) and control rats were exposed to IH and the redox state of the AM was assessed biochemically. We found that IH raised reactive oxygen species levels along with an increase in NADPH oxidase (Nox), a pro-oxidant enzyme and a decrease in superoxide dismutase-2 (SOD2), an anti-oxidant enzyme. Further, IH increased hypoxia-inducible factor (HIF)-1α, whereas decreased HIF-2α, the transcriptional regulator of Nox and SOD-2, respectively. These IH-induced changes in the AM were absent in CBA rats. Moreover, IH increased splanchnic nerve activity and facilitated hypoxia-evoked catecholamine efflux from the AM and CBA prevented these effects. These findings suggest that IH-induced oxidative stress and catecholamine efflux in the AM occurs via carotid body chemoreflex involving HIF α isoform mediated imbalance in pro-, and anti-oxidant enzymes.


Assuntos
Medula Suprarrenal/metabolismo , Corpo Carotídeo/fisiologia , Hipóxia/metabolismo , Estresse Oxidativo , Reflexo/fisiologia , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Masculino , Ratos , Ratos Sprague-Dawley
16.
Proc Natl Acad Sci U S A ; 109(7): 2515-20, 2012 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-22232674

RESUMO

Recurrent apnea with intermittent hypoxia is a major clinical problem in preterm infants. Recent studies, although limited, showed that adults who were born preterm exhibit increased incidence of sleep-disordered breathing and hypertension, suggesting that apnea of prematurity predisposes to autonomic dysfunction in adulthood. Here, we demonstrate that adult rats that were exposed to intermittent hypoxia as neonates exhibit exaggerated responses to hypoxia by the carotid body and adrenal chromaffin cells, which regulate cardio-respiratory function, resulting in irregular breathing with apneas and hypertension. The enhanced hypoxic sensitivity was associated with elevated oxidative stress, decreased expression of genes encoding antioxidant enzymes, and increased expression of pro-oxidant enzymes. Decreased expression of the Sod2 gene, which encodes the antioxidant enzyme superoxide dismutase 2, was associated with DNA hypermethylation of a single CpG dinucleotide close to the transcription start site. Treating neonatal rats with decitabine, an inhibitor of DNA methylation, during intermittent hypoxia exposure prevented oxidative stress, enhanced hypoxic sensitivity, and autonomic dysfunction. These findings implicate a hitherto uncharacterized role for DNA methylation in mediating neonatal programming of hypoxic sensitivity and the ensuing autonomic dysfunction in adulthood.


Assuntos
Epigênese Genética , Coração/fisiologia , Homeostase , Hipóxia/fisiopatologia , Pulmão/fisiologia , Animais , Animais Recém-Nascidos , Ilhas de CpG , Metilação de DNA , Ratos
17.
Am J Physiol Cell Physiol ; 306(8): C745-52, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24477234

RESUMO

The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Oxigênio/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células Cultivadas , Citoesqueleto/fisiologia , Impedância Elétrica , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Humanos , Hipóxia/metabolismo , Junções Intercelulares/metabolismo , Pulmão/irrigação sanguínea , Estresse Oxidativo , Oxigênio/metabolismo , Fosforilação , Fatores de Tempo
18.
J Physiol ; 592(17): 3841-58, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24973414

RESUMO

Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia-inducible factor-α (HIF-α) isoforms and oxidative stress in rodents, which may be due either to the direct effect of CIH or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a potent regulator of gene transcription, we hypothesized that carotid body (CB) neural activity contributes to CIH-induced HIF-α isoform expression and oxidative stress in the chemoreflex pathway. Experiments were performed on adult rats exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1α and decreased HIF-2α expression; increased NADPH oxidase 2 and decreased superoxide dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major end organ of the sympathetic nervous system. Selective ablation of the CB abolished these effects. In the AM, sympathetic activation by the CB chemoreflex mediates CIH-induced HIF-α isoform imbalance via muscarinic acetylcholine receptor-mediated Ca(2+) influx, and the resultant activation of mammalian target of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with hypertension, elevated sympathetic activity and increased circulating catecholamines. Selective ablation of either the CB (afferent pathway) or sympathetic innervation to the AM (efferent pathway) abolished these effects. These observations uncover CB neural activity-dependent regulation of HIF-α isoforms and the redox state by CIH in the central and peripheral nervous systems associated with the chemoreflex.


Assuntos
Corpo Carotídeo/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Estresse Oxidativo , Medula Suprarrenal/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cálcio/metabolismo , Calpaína/metabolismo , Hipóxia/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Reflexo , Núcleo Solitário/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
19.
FASEB J ; 27(8): 2946-56, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23603837

RESUMO

Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-ß-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40-80% along with a 50-70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50-90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Cisplatino/toxicidade , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Ácido 8,11,14-Eicosatrienoico/administração & dosagem , Ácido 8,11,14-Eicosatrienoico/farmacologia , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Creatinina/sangue , Reagentes de Ligações Cruzadas/toxicidade , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia
20.
J Org Chem ; 79(21): 10323-33, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25321319

RESUMO

Methyltrioxorhenium (MTO) complexed with pyridine was shown to be a highly effective catalyst for the regioselective monoepoxidation of conjugated di- and trienes using 30% H2O2 at or below room temperature. The resultant allylic epoxides, and the triols derived from them, are versatile synthetic intermediates as well as substructures present in many bioactive natural products. The site of epoxidation was dependent upon olefin substitution, olefin geometry (Z vs E), and the presence of electron-withdrawing substituents on adjacent carbons. For 1-acyl(silyl)oxypenta-2,4-dienes, epoxidation of the distal olefin was generally favored in contrast to the adjacent regioselectivity characteristic of Sharpless, peracid, and other directed epoxidations of hydroxylated dienes.


Assuntos
Alcenos/química , Compostos de Epóxi/síntese química , Peróxido de Hidrogênio/química , Compostos Organometálicos/química , Catálise , Compostos de Epóxi/química , Estrutura Molecular , Estereoisomerismo
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