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1.
Nat Commun ; 11(1): 4928, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004791

RESUMO

High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.


Assuntos
Aclimatação/genética , Cromatina/metabolismo , Grupos Étnicos/genética , Redes Reguladoras de Genes , Modelos Genéticos , Altitude , Doença da Altitude/etnologia , Doença da Altitude/genética , Doença da Altitude/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular/genética , Células Cultivadas , Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , Resistência à Doença/genética , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Cultura Primária de Células , RNA-Seq , Elementos Reguladores de Transcrição/genética , Seleção Genética , Tibet/etnologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Genoma
2.
Nat Commun ; 11(1): 4627, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009389

RESUMO

Animals have evolved responses to low oxygen conditions to ensure their survival. Here, we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial sugar metabolism enzyme. PQM-1 promotes hypoxic fat metabolism by maintaining the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity positively regulates fat transport to developing oocytes through vitellogenins under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Hipóxia/metabolismo , Metabolismo dos Lipídeos , Transativadores/metabolismo , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Embrião de Mamíferos/metabolismo , Regulação da Expressão Gênica , Glicogênio/metabolismo , Insulina/metabolismo , Larva/metabolismo , Mutação/genética , Consumo de Oxigênio , Transdução de Sinais , Estresse Fisiológico , Análise de Sobrevida , Transativadores/genética , Transcrição Genética , Vitelogeninas/metabolismo
3.
BMC Pulm Med ; 20(1): 269, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066765

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. METHODS: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 non-COVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March-May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). RESULTS: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. CONCLUSIONS: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients.


Assuntos
Dióxido de Carbono/metabolismo , Infecções por Coronavirus/metabolismo , Eritrócitos/metabolismo , Hipóxia/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Pneumonia Viral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Betacoronavirus , Gasometria , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Feminino , Citometria de Fluxo , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pressão Parcial , Projetos Piloto , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/metabolismo , Vasodilatação , Adulto Jovem
4.
Nature ; 585(7826): 557-562, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32939093

RESUMO

Climate and physiology shape biogeography, yet the range limits of species can rarely be ascribed to the quantitative traits of organisms1-3. Here we evaluate whether the geographical range boundaries of species coincide with ecophysiological limits to acquisition of aerobic energy4 for a global cross-section of the biodiversity of marine animals. We observe a tight correlation between the metabolic rate and the efficacy of oxygen supply, and between the temperature sensitivities of these traits, which suggests that marine animals are under strong selection for the tolerance of low O2 (hypoxia)5. The breadth of the resulting physiological tolerances of marine animals predicts a variety of geographical niches-from the tropics to high latitudes and from shallow to deep water-which better align with species distributions than do models based on either temperature or oxygen alone. For all studied species, thermal and hypoxic limits are substantially reduced by the energetic demands of ecological activity, a trait that varies similarly among marine and terrestrial taxa. Active temperature-dependent hypoxia thus links the biogeography of diverse marine species to fundamental energetic requirements that are shared across the animal kingdom.


Assuntos
Organismos Aquáticos/classificação , Organismos Aquáticos/metabolismo , Ecossistema , Filogeografia , Aerobiose , Animais , Organismos Aquáticos/crescimento & desenvolvimento , Metabolismo Basal , Aves/metabolismo , Peso Corporal , Hipóxia/metabolismo , Hipóxia/veterinária , Mamíferos/metabolismo , Oxigênio/metabolismo , Répteis/metabolismo , Especificidade da Espécie , Temperatura
5.
Life Sci ; 259: 118389, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898522

RESUMO

AIMS: Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied. MATERIALS AND METHODS: We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted. RESULTS: CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels. CONCLUSION: Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Hipóxia/etiologia , Neoplasias Pulmonares/metabolismo , Adenosina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade
6.
Anticancer Res ; 40(9): 5071-5079, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878795

RESUMO

BACKGROUND/AIM: Liver cancer has extremely poor prognosis. The cancerous tissues contain hypoxic regions, and the available drugs are poorly effective in hypoxic environments. NADPH oxidase 4 (NOX4), producing reactive oxygen species (ROS), may contribute to cancer malignancy under hypoxic conditions. However, its role in liver cancer has not been examined in detail. Our aim was to explore the effects of setanaxib, a recently developed selective NOX4 inhibitor, in liver cancer cells under hypoxic conditions. MATERIALS AND METHODS: Liver cancer cell lines (HepG2, HLE and Alexander) were treated with hypoxia-mimetic agent cobalt chloride. Cytotoxicity assays, immunoblot analysis and ROS detection assay were performed to detect the effect of setanaxib under hypoxic conditions. RESULTS: Setanaxib exhibited hypoxia-selective cytotoxicity and triggered apoptosis in cancer cells. Moreover, setanaxib caused mitochondrial ROS accumulation under hypoxic conditions. Treatment with antioxidants markedly attenuated setanaxib-induced cytotoxicity and apoptosis under hypoxic conditions. CONCLUSION: Setanaxib caused mitochondrial ROS accumulation in a hypoxia-selective manner and evoked cancer cell cytotoxicity by inducing apoptosis. Thus, setanaxib has a great potential as a novel anticancer compound under hypoxic conditions.


Assuntos
Antineoplásicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Mitocôndrias/metabolismo , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
7.
Am J Physiol Heart Circ Physiol ; 319(3): H661-H681, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762557

RESUMO

Preeclampsia is a major complication of pregnancy manifested as hypertension and often intrauterine growth restriction, but the underlying pathophysiological mechanisms are unclear. Predisposing genetic and environmental factors cause placental maladaptations leading to defective placentation, apoptosis of invasive cytotrophoblasts, inadequate expansive remodeling of the spiral arteries, reduced uteroplacental perfusion pressure, and placental ischemia. Placental ischemia promotes the release of bioactive factors into the maternal circulation, causing an imbalance between antiangiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and proangiogenic vascular endothelial growth factor, placental growth factor, and transforming growth factor-ß. Placental ischemia also stimulates the release of proinflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin type 1 receptor agonistic autoantibodies. These circulating factors target the vascular endothelium, causing generalized endotheliosis in systemic, renal, cerebral, and hepatic vessels, leading to decreases in endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increases in vasoconstrictors such as endothelin-1 and thromboxane A2. The bioactive factors also target vascular smooth muscle and enhance the mechanisms of vascular contraction, including cytosolic Ca2+, protein kinase C, and Rho-kinase. The bioactive factors could also target matrix metalloproteinases and the extracellular matrix, causing inadequate vascular remodeling, increased arterial stiffening, and further increases in vascular resistance and hypertension. As therapeutic options are limited, understanding the underlying vascular mechanisms and molecular targets should help design new tools for the detection and management of hypertension in pregnancy and preeclampsia.


Assuntos
Pressão Arterial , Hipertensão Induzida pela Gravidez/metabolismo , Placenta/irrigação sanguínea , Pré-Eclâmpsia/metabolismo , Artéria Uterina/metabolismo , Animais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/etiologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Isquemia/metabolismo , Isquemia/fisiopatologia , Placentação , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Fatores de Risco , Transdução de Sinais , Artéria Uterina/fisiopatologia , Remodelação Vascular , Rigidez Vascular
8.
PLoS One ; 15(8): e0237933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822407

RESUMO

Defining the relationship between maternal care, sensory development and brain gene expression in neonates is important to understand the impact of environmental challenges during sensitive periods in early life. In this study, we used a selection approach to test the hypothesis that variation in maternal licking and grooming (LG) during the first week of life influences sensory development in Wistar rat pups. We tracked the onset of the auditory brainstem response (ABR), the timing of eye opening (EO), middle ear development with micro-CT X-ray tomography, and used qRT-PCR to monitor changes in gene expression of the hypoxia-sensitive pathway and neurotrophin signaling in pups reared by low-LG or high-LG dams. The results show the first evidence that the transcription of genes involved in the hypoxia-sensitive pathway and neurotrophin signaling is regulated during separate sensitive periods that occur before and after hearing onset, respectively. Although the timing of ABR onset, EO, and the relative mRNA levels of genes involved in the hypoxia-sensitive pathway did not differ between pups from different LG groups, we found statistically significant increases in the relative mRNA levels of four genes involved in neurotrophin signaling in auditory brain regions from pups of different LG backgrounds. These results suggest that sensitivity to hypoxic challenge might be widespread in the auditory system of neonate rats before hearing onset, and that maternal LG may affect the transcription of genes involved in experience-dependent neuroplasticity.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Asseio Animal/fisiologia , Comportamento Materno/fisiologia , Fatores de Crescimento Neural/metabolismo , Animais , Animais Recém-Nascidos , Olho/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Audição , Hipóxia/genética , Hipóxia/metabolismo , Fatores de Crescimento Neural/genética , Plasticidade Neuronal/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Microtomografia por Raio-X
9.
PLoS One ; 15(8): e0237010, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780739

RESUMO

This study analyzed the physiological adjustments caused by the use of the Elevation training mask® (2.0), an airflow restriction mask (ARM) during continuous exercise. Eighteen physically active participants (12 men and 6 women) were randomized to two protocols: continuous exercise with mask (CE-ARM) and continuous exercise without mask (CE). Exercise consisted of cycling for 20 minutes at 60% of maximum power. Metabolic variables, lactate, and gas concentration were obtained from arterialized blood samples at pre and post exercise. Continuous expired gases and myoelectric activity of the quadriceps were performed at rest and during the test. We observed no reduction in oxygen saturation in CE-ARM, leading to lower pH, higher carbon dioxide, and greater hematocrit (all p <0.05). The expired gas analysis shows that the CE-ARM condition presented higher oxygen uptake and expired carbon dioxide concentrations (p <0.05). The CE-ARM condition also presented lower ventilatory volume, ventilatory frequency, and expired oxygen pressure (p <0.05). No changes in electromyography activity and lactate concentrations were identified. We conclude that using ARM does not induce hypoxia and represents an additional challenge for the control of acid-base balance, and we suggest the use of ARM as being suitable for respiratory muscle training.


Assuntos
Exercício Físico/fisiologia , Consumo de Oxigênio/fisiologia , Ventilação Pulmonar/fisiologia , Adulto , Exercícios Respiratórios/métodos , Dióxido de Carbono/sangue , Teste de Esforço/métodos , Feminino , Voluntários Saudáveis , Humanos , Hipóxia/metabolismo , Pulmão/metabolismo , Masculino , Máscaras , Oxigênio/sangue , Respiração , Testes de Função Respiratória
10.
Gene ; 761: 145039, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32777527

RESUMO

The wood frog (Rana sylvatica) can tolerate full body freezing in winter. As a protective response, wood frogs dehydrate their cells and accumulate large quantities of glucose as an intracellular cryoprotectant. Freezing causes ischemia since blood delivery to organs is interrupted. Fascinatingly, wood frogs can tolerate dehydration, extreme hyperglycemia, and anoxia independently of freezing. In response to low oxygen levels, wood frogs strategically reduce their metabolic rates and allocate the finite amount of intracellular fuel available to pro-survival processes while reducing or interrupting all others. In this study, the involvement of advanced glycation end products (AGEs) and the high mobility group box 1 (HMGB1) protein in activating RAGE (AGE receptor) were investigated. The results show that freezing, anoxia and dehydration induced the expression of total HMGB1 and its acetylation in the heart. RAGE levels were induced in response to all stress conditions, which resulted in differential regulation of the ETS1 transcription factor. While the nuclear localization of total ETS1 was not affected, the DNA binding activity of total and its active form increased in response to freezing and dehydration but not in response to anoxia. Current results indicate that ETS1 acts as a transcriptional activator for peroxiredoxin 1 in response to freezing but acts as a transcriptional repressor of several nuclear-encoded mitochondrial genes in response to all stresses. Altogether, current results show that the HMGB1/RAGE axis may activate ETS1 and that this activation could result in both transcriptional activation and/or repression in a stress-dependent manner.


Assuntos
Mitocôndrias/metabolismo , Miocárdio/metabolismo , Ranidae/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Desidratação/metabolismo , Congelamento , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/fisiologia , Proteína HMGB1/metabolismo , Proteína HMGB1/fisiologia , Coração/fisiologia , Hipóxia/metabolismo , Oxigênio/metabolismo , Ranidae/genética , Receptor para Produtos Finais de Glicação Avançada/fisiologia , Estresse Fisiológico/fisiologia
11.
Life Sci ; 259: 118171, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738362

RESUMO

Hypoxia, an important feature of the tumor microenvironment, is responsible for the chemo-resistance and metastasis of malignant solid tumors. Recent studies indicated that mitochondria undergo morphological transitions as an adaptive response to maintain self-stability and connectivity under hypoxic conditions. NAD+ may not only provide reducing equivalents for biosynthetic reactions and in determining energy production, but also functions as a signaling molecule in mitochondrial dynamics regulation. In this review, we describe the upregulated KDAC deacetylase expression in the mitochondria and cytoplasm of tumor cells that results from sensing the changes in NAD+ to control mitochondrial dynamics and distribution, which is responsible for survival and metastasis in hypoxia.


Assuntos
Hipóxia/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , NAD/metabolismo , Metástase Neoplásica , Neoplasias/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Microambiente Tumoral
12.
PLoS One ; 15(7): e0236928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735610

RESUMO

The rabbit retinal vein occlusion (RVO) model is an experimental system that mimics retinal ischemic diseases in humans. The rabbit RVO model is widely used to assess the therapeutic efficacy of various experimental surgical procedures. In the present study, we measured temporal retinal expression of Vegfa, which is known as an ischemic response gene, in rabbit RVO. This analysis revealed that the retinal Vegfa transcriptional response began 7 days after generation of RVO, rather than immediately after induction of ischemia. Next, in order to analyze ischemia-induced changes in gene expression profiles, we performed microarray analysis of day 7 RVO retina versus control retina. The angiogenic regulators Dcn and Mmp1 and pro-inflammatory factors Mmp12 and Cxcl13 were significantly upregulated in RVO retinas. Further, we suggest that epigenetic regulation via the REST/cofactor-complex could contribute to RVO pathology. Among human homologous genes in rabbits, genes associated with hypoxia, angiogenesis, and inflammation were significantly upregulated in RVO retinas. Components of the Tumor necrosis factor-alpha (TNFα) and Nuclear factor-kappa B (NF-κB) pathways, which play regulatory roles in angiogenesis and inflammation, were significantly upregulated in RVO, and the expression levels of downstream factors, such as the transcription factor AP-1 and chemokines, were increased. Further, connectivity map analyses suggested that inhibitors of the NF-κB pathway are potential therapeutic agents for retinal ischemic disease. The present study revealed new insights into the pathology of retinal ischemia using the rabbit RVO model, which accurately recapitulates human disease.


Assuntos
Isquemia/metabolismo , Retina/patologia , Oclusão da Veia Retiniana , Indutores da Angiogênese/metabolismo , Animais , Quimiocinas/metabolismo , Conectoma , Modelos Animais de Doenças , Epigênese Genética , Angiofluoresceinografia , Regulação da Expressão Gênica , Hipóxia/metabolismo , Inflamação/metabolismo , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Análise em Microsséries , NF-kappa B/genética , NF-kappa B/metabolismo , Coelhos , Oclusão da Veia Retiniana/genética , Oclusão da Veia Retiniana/metabolismo , Transcriptoma , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
13.
Am J Physiol Regul Integr Comp Physiol ; 319(3): R329-R342, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697653

RESUMO

Peripheral chemosensitivity in fishes is thought to be mediated by serotonin-enriched neuroepithelial cells (NECs) that are localized to the gills of adults and the integument of larvae. In adult zebrafish (Danio rerio), branchial NECs are presumed to mediate the cardiorespiratory reflexes associated with hypoxia or hypercapnia, whereas in larvae, there is indirect evidence linking cutaneous NECs to hypoxic hyperventilation and hypercapnic tachycardia. No study yet has examined the ventilatory response of larval zebrafish to hypercapnia, and regardless of developmental stage, the signaling pathways involved in CO2 sensing remain unclear. In the mouse, a background potassium channel (TASK-2) contributes to the sensitivity of chemoreceptor cells to CO2. Zebrafish possess two TASK-2 channel paralogs, TASK-2 and TASK-2b, encoded by kcnk5a and kcnk5b, respectively. The present study aimed to determine whether TASK-2 channels are expressed in NECs of larval zebrafish and whether they are involved in CO2 sensing. Using immunohistochemical approaches, TASK-2 protein was observed on the surface of NECs in larvae. Exposure of larvae to hypercapnia caused cardiac and breathing frequencies to increase, and these responses were blunted in fish experiencing TASK-2 and/or TASK-2b knockdown. The results of these experiments suggest that TASK-2 channels are involved in CO2 sensing by NECs and contribute to the initiation of reflex cardiorespiratory responses during exposure of larvae to hypercapnia.


Assuntos
Dióxido de Carbono/metabolismo , Hipercapnia/metabolismo , Hipóxia/metabolismo , Células Neuroepiteliais/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Células Quimiorreceptoras/metabolismo , Brânquias/metabolismo , Hiperventilação/metabolismo , Células Neuroepiteliais/citologia , Oxigênio/metabolismo , Peixe-Zebra/fisiologia
14.
Am J Physiol Cell Physiol ; 319(3): C533-C540, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726159

RESUMO

Humans have internal circadian clocks that ensure that important physiological functions occur at specific times of the day. These molecular clocks are regulated at the genomic level and exist in most cells of the body. Multiple circadian resetting cues have been identified, including light, temperature, and food. Recently, oxygen has been identified as a resetting cue, and emerging science indicates that this occurs through interactions at the cellular level between the circadian transcription-translation feedback loop and the hypoxia-inducible pathway (hypoxia-inducible factor; subject of the 2019 Nobel Prize in Physiology or Medicine). This review will cover recently identified relationships between HIF and proteins of the circadian clock. Interactions between the circadian clock and hypoxia could have wide-reaching implications for human diseases, and understanding the molecular mechanisms regulating these overlapping pathways may open up new strategies for drug discovery.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Fator 1 Induzível por Hipóxia/metabolismo , Fatores de Tempo , Animais , Descoberta de Drogas , Humanos , Hipóxia/metabolismo
15.
Nature ; 585(7825): 397-403, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610343

RESUMO

Mutations in PLP1, the gene that encodes proteolipid protein (PLP), result in failure of myelination and neurological dysfunction in the X-chromosome-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. Patients who lack PLP1 expression, and Plp1-null mice, can display comparatively mild phenotypes, suggesting that PLP1 suppression might provide a general therapeutic strategy for PMD1,3-5. Here we show, using CRISPR-Cas9 to suppress Plp1 expression in the jimpy (Plp1jp) point-mutation mouse model of severe PMD, increased myelination and restored nerve conduction velocity, motor function and lifespan of the mice to wild-type levels. To evaluate the translational potential of this strategy, we identified antisense oligonucleotides that stably decrease the levels of Plp1 mRNA and PLP protein throughout the neuraxis in vivo. Administration of a single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point. These results suggest that PLP1 suppression could be developed as a treatment for PMD in humans. More broadly, we demonstrate that oligonucleotide-based therapeutic agents can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, establishing a new pharmaceutical modality for myelin disorders.


Assuntos
Modelos Animais de Doenças , Proteína Proteolipídica de Mielina/deficiência , Doença de Pelizaeus-Merzbacher/genética , Doença de Pelizaeus-Merzbacher/terapia , Animais , Sistemas CRISPR-Cas , Feminino , Edição de Genes , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Atividade Motora/genética , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Doença de Pelizaeus-Merzbacher/metabolismo , Mutação Puntual , Testes de Função Respiratória , Análise de Sobrevida
16.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L360-L368, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32692577

RESUMO

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.


Assuntos
Doença da Altitude/sangue , Doença da Altitude/metabolismo , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/metabolismo , Hipóxia/sangue , Hipóxia/metabolismo , MicroRNAs/sangue , Edema Pulmonar/sangue , Edema Pulmonar/metabolismo , Adaptação Fisiológica/fisiologia , Adulto , Altitude , Apelina/metabolismo , Linhagem Celular , Feminino , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Adulto Jovem
17.
Free Radic Biol Med ; 156: 190-199, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32653511

RESUMO

Studies have shown that infection, excessive coagulation, cytokine storm, leukopenia, lymphopenia, hypoxemia and oxidative stress have also been observed in critically ill Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) patients in addition to the onset symptoms. There are still no approved drugs or vaccines. Dietary supplements could possibly improve the patient's recovery. Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present an anti-inflammatory effect that could ameliorate some patients need for intensive care unit (ICU) admission. EPA and DHA replace arachidonic acid (ARA) in the phospholipid membranes. When oxidized by enzymes, EPA and DHA contribute to the synthesis of less inflammatory eicosanoids and specialized pro-resolving lipid mediators (SPMs), such as resolvins, maresins and protectins. This reduces inflammation. In contrast, some studies have reported that EPA and DHA can make cell membranes more susceptible to non-enzymatic oxidation mediated by reactive oxygen species, leading to the formation of potentially toxic oxidation products and increasing the oxidative stress. Although the inflammatory resolution improved by EPA and DHA could contribute to the recovery of patients infected with SARS-CoV-2, Omega-3 fatty acids supplementation cannot be recommended before randomized and controlled trials are carried out.


Assuntos
Infecções por Coronavirus/dietoterapia , Síndrome da Liberação de Citocina/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Leucopenia/dietoterapia , Pandemias , Pneumonia Viral/dietoterapia , Anti-Inflamatórios não Esteroides/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/dietoterapia , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/virologia , Humanos , Hipóxia/dietoterapia , Hipóxia/epidemiologia , Hipóxia/metabolismo , Hipóxia/virologia , Leucopenia/epidemiologia , Leucopenia/metabolismo , Leucopenia/virologia , Estresse Oxidativo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
18.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R211-R222, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609532

RESUMO

Although severe intermittent hypoxia (IH) is well known to induce deleterious cardiometabolic consequences, moderate IH may induce positive effects in obese individuals. The present study aimed to evaluate the effect of two hypoxic conditioning programs on cardiovascular and metabolic health status of overweight or obese individuals. In this randomized single-blind controlled study, 35 subjects (54 ± 9.3 yr, 31.7 ± 3.5 kg/m2) were randomized into three 8-wk interventions (three 1-h sessions per week): sustained hypoxia (SH), arterial oxygen saturation ([Formula: see text]) = 75%; IH, 5 min [Formula: see text] = 75% - 3 min normoxia; normoxia. Ventilation, heart rate, blood pressure, and tissue oxygenation were measured during the first and last hypoxic conditioning sessions. Vascular function, blood glucose and insulin, lipid profile, nitric oxide metabolites, and oxidative stress were evaluated before and after the interventions. Both SH and IH increased ventilation in hypoxia (+1.8 ± 2.1 and +2.3 ± 3.6 L/min, respectively; P < 0.05) and reduced normoxic diastolic blood pressure (-12 ± 15 and -13 ± 10 mmHg, respectively; P < 0.05), whereas changes in normoxic systolic blood pressure were not significant (+3 ± 9 and -6 ± 13 mmHg, respectively; P > 0.05). IH only reduced heart rate variability (e.g., root-mean-square difference of successive normal R-R intervals in normoxia -21 ± 35%; P < 0.05). Both SH and IH induced no significant change in body mass index, vascular function, blood glucose, insulin and lipid profile, nitric oxide metabolites, or oxidative stress, except for an increase in superoxide dismutase activity following SH. This study indicates that passive hypoxic conditioning in obese individuals induces some positive cardiovascular and respiratory improvements despite no change in anthropometric data and even a reduction in heart rate variability during IH exposure.


Assuntos
Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Sistema Cardiovascular/fisiopatologia , Frequência Cardíaca/fisiologia , Hipóxia/fisiopatologia , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Adulto , Sistema Cardiovascular/metabolismo , Colesterol/sangue , Feminino , Humanos , Hipóxia/metabolismo , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Sobrepeso/metabolismo , Método Simples-Cego , Triglicerídeos/sangue
19.
Am J Physiol Regul Integr Comp Physiol ; 319(2): R148-R155, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32663032

RESUMO

Naked mole-rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to suppress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers). A recent goldfish study demonstrated that remodeling of membrane lipids may mediate these responses, but it is unknown if NMR employs the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals 1) downregulate the activity of key enzymes of glycolysis, tricarboxylic acid (TCA) cycle, and ß-oxidation, 2) inhibit sodium-potassium-ATPase, and 3) alter membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 wk had a lower metabolic rate by 34%. This suppression occurs concurrently with tissue-specific 25-99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium-ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and ß-oxidation fluxes, NMRs decrease the supply of acetyl-CoA to the TCA cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between changes in membrane composition and enzyme activities could not be established. Nevertheless, this is the first demonstration that hypometabolic NMRs alter the lipid composition of their membranes in response to chronic in vivo exposure to hypoxia.


Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Metabolismo Energético/fisiologia , Hipóxia/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Encéfalo/metabolismo , Ratos-Toupeira , Oxigênio/metabolismo
20.
ACS Chem Neurosci ; 11(16): 2416-2421, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32600045

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been established as a cause of severe alveolar damage and pneumonia in patients with advanced Coronavirus disease (COVID-19). The consolidation of lung parenchyma precipitates the alterations in blood gases in COVID-19 patients that are known to complicate and cause hypoxemic respiratory failure. With SARS-CoV-2 damaging multiple organs in COVID-19, including the central nervous system that regulates the breathing process, it is a daunting task to compute the extent to which the failure of the central regulation of the breathing process contributes to the mortality of COVID-19 affected patients. Emerging data on COVID-19 cases from hospitals and autopsies in the last few months have helped in the understanding of the pathogenesis of respiratory failures in COVID-19. Recent reports have provided overwhelming evidence of the occurrence of acute respiratory failures in COVID-19 due to neurotropism of the brainstem by SARS-CoV-2. In this review, a cascade of events that may follow the alterations in blood gases and possible neurological damage to the respiratory regulation centers in the central nervous system (CNS) in COVID-19 are related to the basic mechanism of respiratory regulation in order to understand the acute respiratory failure reported in this disease. Though a complex metabolic and respiratory dysregulation also occurs with infections caused by SARS-CoV-1 and MERS that are known to contribute toward deaths of the patients in the past, we highlight here the role of systemic dysregulation and the CNS respiratory regulation mechanisms in the causation of mortalities seen in COVID-19. The invasion of the CNS by SARS-CoV-2, as shown recently in areas like the brainstem that control the normal breathing process with nuclei like the pre-Bötzinger complex (pre-BÖTC), may explain why some of the patients with COVID-19, who have been reported to have recovered from pneumonia, could not be weaned from invasive mechanical ventilation and the occurrences of acute respiratory arrests seen in COVID-19. This debate is important for many reasons, one of which is the fact that permanent damage to the medullary respiratory centers by SARS-CoV-2 would not benefit from mechanical ventilators, as is possibly occurring during the management of COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipóxia/fisiopatologia , Pneumonia Viral/fisiopatologia , Centro Respiratório/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Betacoronavirus , Gasometria , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/mortalidade , Humanos , Hipóxia/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/mortalidade , Centro Respiratório/metabolismo , Centro Respiratório/virologia , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/mortalidade , Tropismo Viral
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