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1.
Proc Natl Acad Sci U S A ; 120(50): e2302845120, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38055741

RESUMO

It has previously been reported that antioxidant vitamins can help reduce the risk of vision loss associated with progression to advanced age-related macular degeneration (AMD), a leading cause of visual impairment among the elderly. Nonetheless, how oxidative stress contributes to the development of choroidal neovascularization (CNV) in some AMD patients and geographic atrophy (GA) in others is poorly understood. Here, we provide evidence demonstrating that oxidative stress cooperates with hypoxia to synergistically stimulate the accumulation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE), resulting in increased expression of the HIF-1-dependent angiogenic mediators that promote CNV. HIF-1 inhibition blocked the expression of these angiogenic mediators and prevented CNV development in an animal model of ocular oxidative stress, demonstrating the pathological role of HIF-1 in response to oxidative stress stimulation in neovascular AMD. While human-induced pluripotent stem cell (hiPSC)-derived RPE monolayers exposed to chemical oxidants resulted in disorganization and disruption of their normal architecture, RPE cells proved remarkably resistant to oxidative stress. Conversely, equivalent doses of chemical oxidants resulted in apoptosis of hiPSC-derived retinal photoreceptors. Pharmacologic inhibition of HIF-1 in the mouse retina enhanced-while HIF-1 augmentation reduced-photoreceptor apoptosis in two mouse models for oxidative stress, consistent with a protective role for HIF-1 in photoreceptors in patients with advanced dry AMD. Collectively, these results suggest that in patients with AMD, increased expression of HIF-1α in RPE exposed to oxidative stress promotes the development of CNV, but inadequate HIF-1α expression in photoreceptors contributes to the development of GA.


Assuntos
Neovascularização de Coroide , Atrofia Geográfica , Degeneração Macular Exsudativa , Camundongos , Animais , Humanos , Idoso , Epitélio Pigmentado da Retina/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Inibidores da Angiogênese , Degeneração Macular Exsudativa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Acuidade Visual , Neovascularização de Coroide/genética , Neovascularização de Coroide/prevenção & controle , Neovascularização de Coroide/metabolismo , Oxidantes/metabolismo , Hipóxia/metabolismo
2.
Small ; : e2310664, 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38342707

RESUMO

Establishing effective charge transfer channels between two semiconductors is key to improving photocatalytic activity. However, controlling hetero-structures in situ and designing binding modes pose significant challenges. Herein, hydrolytic SnCl2 ·2H2 O is selected as the metal source and loaded in situ onto a layered carbon nitriden supramolecular precursor. A composite photocatalyst, S4 -Sn-N2 , with electron pathways of SnS2 and tubular carbon nitriden (TCN) is prepared through pyrolysis and vulcanization processes. The contact interface of SnS2 -TCN is increased significantly, promoting the formation of S4 -Sn-N2 micro-structure in a Z-scheme charge transfer channel. This structure accelerates the separation and transport of photogenerated carriers, maintains the stronger redox ability, and improves the stability of SnS2 in this series of heterojunctions. Therefore, the catalyst demonstrated exceptional photocatalytic hydrogen production efficiency, achieving a reaction rate of 86.4 µmol h-1 , which is 3.15 times greater than that of bare TCN.

3.
J Neurosci ; 40(37): 7065-7079, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32817065

RESUMO

The crumbs (crb) apical polarity genes are essential for the development and functions of epithelia. Adult zebrafish retinal neuroepithelium expresses three crb genes (crb1, crb2a, and crb2b); however, it is unknown whether and how Crb1 differs from other Crb proteins in expression, localization, and functions. Here, we show that, unlike zebrafish Crb2a and Crb2b as well as mammalian Crb1 and Crb2, zebrafish Crb1 does not localize to the subapical regions of photoreceptors and Müller glial cells; rather, it localizes to a small region of cone outer segments: the cell membranes surrounding the axonemes. Moreover, zebrafish Crb1 is not required for retinal morphogenesis and photoreceptor patterning. Interestingly, Crb1 promotes rod survival under strong white light irradiation in a previously unreported non--cell-autonomous fashion; in addition, Crb1 delays UV and blue cones' chromatin condensation caused by UV light irradiation. Finally, Crb1 plays a role in cones' responsiveness to light through an arrestin-translocation-independent mechanism. The localization of Crb1 and its functions do not differ between male and female fish. We conclude that zebrafish Crb1 has diverged from other vertebrate Crb proteins, representing a neofunctionalization in Crb biology during evolution.SIGNIFICANCE STATEMENT Apicobasal polarity of epithelia is an important property that underlies the morphogenesis and functions of epithelial tissues. Epithelial apicobasal polarity is controlled by many polarity genes, including the crb genes. In vertebrates, multiple crb genes have been identified, but the differences in their expression patterns and functions are not fully understood. Here, we report a novel subcellular localization of zebrafish Crb1 in retinal cone photoreceptors and evidence for its new functions in photoreceptor maintenance and light responsiveness. This study expands our understanding of the biology of the crb genes in epithelia, including retinal neuroepithelium.


Assuntos
Axonema/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Visão Ocular , Proteínas de Peixe-Zebra/metabolismo , Animais , Membrana Celular/metabolismo , Membrana Celular/fisiologia , Cromatina/metabolismo , Feminino , Masculino , Proteínas do Tecido Nervoso/genética , Transporte Proteico , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Cones/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
4.
Mikrochim Acta ; 188(3): 74, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558967

RESUMO

The architecture of PO43- modified 2D TiO2 nanosheets was constructed by ionic liquids (ILs)-assisted hydrothermal method. The nanosheet structure can be regulated by the addition of different amount of ionic liquid. Using the composite nanosheets  a chemoresistive gas sensor was prepared for trimethylamine (TMA) detection. Most reported TMA sensors need to be operated at a relatively high operating temperature, but in this paper, the as-synthesized PO43--modified 2D TiO2/Ti2O(PO4)2 nanosheet sensor has high response (S = 87.46), short response time (14.6 s), and good reproducibility to 100 ppm TMA gas, when the temperature is 170 °C. In contrast to the single-phase TiO2 sensor, the gas-sensing property of the composite one is obviously enhanced. Moreover, its response shows excellent linear relationship with TMA concentration from 0.2 to 500 ppm, and a detection limit of 0.2 ppm. The TMA detection mechanism was investigated by analyzing the changes of the surface adsorption oxygen content by XPS and gaseous products using gas chromatography after the sensor was in contact with TMA.


Assuntos
Poluentes Atmosféricos/análise , Líquidos Iônicos/química , Metilaminas/análise , Nanoestruturas/química , Fosfatos/química , Titânio/química , Adsorção , Poluentes Atmosféricos/química , Gases/análise , Gases/química , Imidazóis/química , Limite de Detecção , Metilaminas/química , Oxirredução , Oxigênio/química , Fosfatos/síntese química , Espectroscopia Fotoeletrônica , Reprodutibilidade dos Testes , Compostos Orgânicos Voláteis/análise , Compostos Orgânicos Voláteis/química
5.
J Neurosci ; 37(11): 2834-2848, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28193687

RESUMO

Photoreceptor-specific transcription of individual genes collectively constitutes the transcriptional profile that orchestrates the structural and functional characteristics of each photoreceptor type. It is challenging, however, to study the transcriptional specificity of individual photoreceptor genes because each gene's distinct spatiotemporal transcription patterns are determined by the unique interactions between a specific set of transcription factors and the gene's own cis-regulatory elements (CREs), which remain unknown for most of the genes. For example, it is unknown what CREs underlie the zebrafish mpp5bponli (ponli) and crumbs2b (crb2b) apical polarity genes' restrictive transcription in the red, green, and blue (RGB) cones in the retina, but not in other retinal cell types. Here we show that the intronic enhancers of both the ponli and crb2b genes are conserved among teleost species and that they share sequence motifs that are critical for RGB cone-specific transcription. Given their similarities in sequences and functions, we name the ponli and crb2b enhancers collectively rainbow enhancers. Rainbow enhancers may represent a cis-regulatory mechanism to turn on a group of genes that are commonly and restrictively expressed in RGB cones, which largely define the beginning of the color vision pathway.SIGNIFICANCE STATEMENT Dim-light achromatic vision and bright-light color vision are initiated in rod and several types of cone photoreceptors, respectively; these photoreceptors are structurally distinct from each other. In zebrafish, although quite different from rods and UV cones, RGB cones (red, green, and blue cones) are structurally similar and unite into mirror-symmetric pentamers (G-R-B-R-G) by adhesion. This structural commonality and unity suggest that a set of genes is commonly expressed only in RGB cones but not in other cells. Here, we report that the rainbow enhancers activate RGB cone-specific transcription of the ponli and crb2b genes. This study provides a starting point to study how RGB cone-specific transcription defines RGB cones' distinct functions for color vision.


Assuntos
Opsinas dos Cones/genética , Peixes/genética , Proteínas de Membrana/genética , Células Fotorreceptoras Retinianas Cones/fisiologia , Ativação Transcricional/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Peixes/classificação , Regulação da Expressão Gênica/genética , Proteínas de Membrana/metabolismo , Elementos Reguladores de Transcrição/genética , Especificidade da Espécie , Proteínas de Peixe-Zebra/metabolismo
6.
BMC Genet ; 17: 24, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26785614

RESUMO

BACKGROUND: Groupers (Epinephelus spp.) have been widely cultivated in China and South-East Asian countries. As a novel hybrid offspring crossed between E. fuscogutatus♀ and E. lanceolatus♂, Hulong grouper exhibits significant growth superiority over its female parent, which made it a promising farmed species in grouper aquaculture industry in China. Hulong grouper present a good combination of beneficial traits from both parent species, but the molecular mechanisms of its heterosis still remain poorly understood. RESULTS: Based on RNA sequencing and gene expression profiling, we conducted comparative transcriptome analyses between Hulong grouper and its parents E. fuscoguttatus & E. lanceolatus. Six hundred sixty-two and 5239 differentially expressed genes (DEGs) were identified in the brains and livers, respectively. GO enrichment analysis of these DEGs revealed that metabolic process and catalytic activity were the most enriched GO terms. Further analysis showed the expressions of GnRH1 and GnRH3 in the brain, and GH/IGF axis related genes such as IGF-1, IGF-2b, IGFBP-1, IGFBP-2, IGFBP-4 and IGFBP-5a in the liver of the hybrid F1 were significantly up-regulated, which is in accordance with the growth superiority of hybrid grouper. Meanwhile, expressions of genes related to the protein and glycogen synthesis pathway, such as PI3KC, PI3KR, Raptor, EIF4E3, and PP1 were up-regulated, while PYG expression was down-regulated. These changes might contribute to increased protein and glycogen synthesis in the hybrid grouper. CONCLUSIONS: We identified a number of differentially expressed genes such as GnRH1 and GnRH3, and genes involved in GH/IGF axis and its downstream signaling pathways for protein and glycogen synthesis in Hulong Grouper. These findings provided molecular basis underlying growth superiority of hybrid grouper, and comprehensive insights into better understanding the molecular mechanisms and regulative pathways regulating heterosis in fish.


Assuntos
Bass/crescimento & desenvolvimento , Bass/genética , Vigor Híbrido , Animais , Encéfalo/fisiologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Ontologia Genética , Genoma , Fígado/fisiologia , Masculino , Reação em Cadeia da Polimerase em Tempo Real
7.
J Gen Virol ; 95(Pt 5): 1144-1155, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24535211

RESUMO

Semaphorins are a large, phylogenetically conserved family of proteins that are involved in a wide range of biological processes including axonal steering, organogenesis, neoplastic transformation, as well as immune responses. In this study, a novel semaphorin homologue gene belonging to the Singapore grouper iridovirus (SGIV), ORF155R (termed SGIV-sema), was cloned and characterized. The coding region of SGIV-sema is 1728 bp in length, encoding a predicted protein with 575 aa. SGIV-sema contains a ~370 aa N-terminal Sema domain, a conserved plexin-semaphorin-integrin (PSI) domain, and an immunoglobulin (Ig)-like domain near the C terminus. SGIV-sema is an early gene product during viral infection and predominantly distributed in the cytoplasm with a speckled and clubbed pattern of appearance. Functionally, SGIV-sema could promote viral replication during SGIV infection in vitro, with no effect on the proliferation of host cells. Intriguingly, ectopically expressed SGIV-sema could alter the cytoskeletal structure of fish cells, characterized by a circumferential ring of microtubules near the nucleus and a disrupted microfilament organization. Furthermore, SGIV-sema was able to attenuate the cellular immune response, as demonstrated by decreased expression of inflammation/immune-related genes such as IL-8, IL-15, TNF-α and mediator of IRF3 activation (MITA), in SGIV-sema-expressing cells before and after SGIV infection. Ultimately, our study identified a novel, functional SGIV gene that could regulate cytoskeletal structure, immune responses and facilitate viral replication.


Assuntos
Citoesqueleto/metabolismo , Imunidade Celular , Ranavirus/imunologia , Ranavirus/fisiologia , Semaforinas/imunologia , Semaforinas/metabolismo , Animais , Células Cultivadas , Clonagem Molecular , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Citoplasma/química , DNA Viral/química , DNA Viral/genética , Regulação para Baixo , Peixes , Expressão Gênica , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Ranavirus/genética , Semaforinas/genética , Análise de Sequência de DNA , Replicação Viral
8.
Fish Shellfish Immunol ; 36(1): 194-205, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24239598

RESUMO

The lysosomal cysteine protease cathepsin B of papain family is a key regulator and signaling molecule that involves in various biological processes, such as the regulation of apoptosis and activation of virus. In the present study, cathepsin B gene (Ec-CB) was cloned and characterized from orange-spotted grouper, Epinephelus coioides. The full-length Ec-CB cDNA was composed of 1918 bp and encoded a polypeptide of 330 amino acids with higher identities to cathepsin B of teleosts and mammalians. Ec-CB possessed typical cathepsin B structural features including an N-terminal signal peptide, the propeptide region and the cysteine protease domain which were conserved in other cathepsin B sequences. Phylogenetic analysis revealed that Ec-CB was most closely related to Lutjanus argentimaculatus. RT-PCR analysis showed that Ec-CB transcript was expressed in all the examined tissues which abundant in spleen, kidney and gill. After challenged with Singapore grouper iridovirus (SGIV) stimulation, the mRNA expression of cathepsin B in E. coioides was up-regulated at 24 h post-infection. Subcellular localization analysis revealed that Ec-CB was distributed predominantly in the cytoplasm. When the fish cells (GS or FHM) were treated with the cathepsin B specific inhibitor CA-074Me, the occurrence of CPE induced by SGIV was delayed, and the viral gene transcription was significantly inhibited. Additionally, SGIV-induced typical apoptosis was also inhibited by CA-074Me in FHM cells. Taken together, our results demonstrated that the Ec-CB might play a functional role in SGIV infection.


Assuntos
Catepsina B/imunologia , Infecções por Vírus de DNA/veterinária , Doenças dos Peixes/virologia , Iridovirus/imunologia , Perciformes , Filogenia , Sequência de Aminoácidos , Animais , Sequência de Bases , Catepsina B/antagonistas & inibidores , Catepsina B/genética , Clonagem Molecular , Efeito Citopatogênico Viral/imunologia , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/virologia , Dipeptídeos/farmacologia , Doenças dos Peixes/imunologia , Dados de Sequência Molecular , RNA/química , RNA/genética , Técnica de Amplificação ao Acaso de DNA Polimórfico/veterinária , Alinhamento de Sequência , Análise de Sequência de DNA , Transcrição Gênica/imunologia
9.
Foods ; 13(7)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38611339

RESUMO

The aim of this study was to assess the effectiveness of different biomarkers to identify the levels of protein oxidation in pork patties induced by assorted cooking methods. To achieve this purpose, pork patties prepared from longissimus dorsi were cooked using three methods (frying, steaming, and roasting) at different internal temperatures (60, 70, 80, and 90 °C). Traditional biomarkers including total carbonyl and total thiol and novel biomarkers including α-aminoadipic semialdehyde (AAS) and lysinonorleucine (LNL) were determined. Results demonstrated that total thiol and AAS were the most successful biomarkers in distinguishing the three cooking methods in relation to protein oxidation, with AAS being the most sensitive. Moreover, as indicated by the biomarkers of total thiol and AAS, frying caused the highest level of protein oxidation, while steaming resulted in the lowest level when pork patties were cooked to the internal temperatures of 70 or 80 °C.

10.
J Gen Virol ; 94(Pt 12): 2759-2770, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24062533

RESUMO

Insulin-like growth factors (IGFs) play crucial roles in regulating cell differentiation, proliferation and apoptosis. In this study, a novel IGF homologue gene (IGF-like) encoded by Singapore grouper iridovirus (SGIV) ORF062R (termed SGIV-IGF), was cloned and characterized. The coding region of SGIV-IGF is 771 bp in length, with a variable number of tandem repeats (VNTR) locus at the 3'-end. We cloned one isoform of this novel gene, 582 bp in length, containing the predicted IGF domain and 3.6 copy numbers of the 27 bp repeat unit. SGIV-IGF was an early transcribed gene during viral infection, and SGIV-IGF was distributed predominantly in the cytoplasm with a diffused granular appearance. Intriguingly, overexpression of SGIV-IGF was able to promote the growth of grouper embryonic cells (GP cells) by promoting G1/S phase transition, which was at least partially dependent on its 3'-end VNTR locus. Furthermore, viral titre assay and real-time quantitative PCR (RT-qPCR) analysis proved that SGIV-IGF could promote SGIV replication in grouper cells. In addition, overexpression of SGIV-IGF mildly facilitated apoptosis in SGIV-infected non-host fathead minnow (FHM) cells. Together, our study demonstrated a novel functional gene of SGIV which may regulate viral replication and cellular processes through multiple mechanisms that appear to be cell type-dependent.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Perciformes/virologia , Ranavirus/fisiologia , Somatomedinas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Células Cultivadas , Perfilação da Expressão Gênica , Iridovirus/classificação , Iridovirus/genética , Iridovirus/metabolismo , Iridovirus/fisiologia , Perciformes/embriologia , Ranavirus/genética , Ranavirus/metabolismo , Singapura , Somatomedinas/genética , Somatomedinas/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais/farmacologia
11.
Plant Cell Rep ; 32(5): 687-702, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23462936

RESUMO

KEY MESSAGE: A gene encoding a coproporphyrinogen III oxidase mediates disease resistance in plants by the salicylic acid pathway. A number of genes that regulate powdery mildew resistance have been identified in Arabidopsis, such as ENHANCED DISEASE RESISTANCE 1 to 3 (EDR1 to 3). To further study the molecular interactions between the powdery mildew pathogen and Arabidopsis, we isolated and characterized a mutant that exhibited enhanced resistance to powdery mildew. The mutant also showed dramatic powdery mildew-induced cell death as well as growth defects and early senescence in the absence of pathogens. We identified the affected gene by map-based cloning and found that the gene encodes a coproporphyrinogen III oxidase, a key enzyme in the tetrapyrrole biosynthesis pathway, previously known as LESION INITIATION 2 (LIN2). Therefore, we designated the mutant lin2-2. Further studies revealed that the lin2-2 mutant also displayed enhanced resistance to Hyaloperonospora arabidopsidis (H.a.) Noco2. Genetic analysis showed that the lin2-2-mediated disease resistance and spontaneous cell death were dependent on PHYTOALEXIN DEFICIENT 4 (PAD4), SALICYLIC ACID INDUCTION-DEFICIENT 2 (SID2), and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1), which are all involved in salicylic acid signaling. Furthermore, the relative expression levels of defense-related genes were induced after powdery mildew infection in the lin2-2 mutant. These data indicated that LIN2 plays an important role in cell death control and defense responses in plants.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Arabidopsis/microbiologia , Coproporfirinogênio Oxidase/genética , Resistência à Doença/genética , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/metabolismo , Ascomicetos/patogenicidade , Sequência de Bases , Morte Celular/genética , Coproporfirinogênio Oxidase/metabolismo , Ciclopentanos/metabolismo , Etilenos/metabolismo , Etilenos/farmacologia , Regulação da Expressão Gênica de Plantas , Dados de Sequência Molecular , Mutação , Oomicetos/patogenicidade , Oxilipinas/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Plantas Geneticamente Modificadas , Ácido Salicílico/metabolismo
12.
Food Res Int ; 173(Pt 2): 113420, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37803758

RESUMO

The present study aimed to compare two oxidizing systems commonly present in meat for their influence on protein oxidation patterns, with emphasis on the specific lysine-derived markers for protein carbonylation (α-aminoadipic semialdehyde, AAS; lysinonorlucine, LNL) and their relationships with the common markers for protein oxidation. For this purpose, pork myofibrillar proteins (MFP, 5 mg/mL) were suspended in 0.6 M NaCl (pH 7.5) and incubated at 4 ℃ for 24 h with two oxidizing systems: (1) a metal-catalyzed oxidizing system (MOS: 10 µM FeCl3, 100 µM ascorbic acid, and 0-10 mmol/L H2O2), (2) a linoleic acid - lipoxidase oxidizing system (LOS: 7500 units of lipoxidase/mL, and 0-10 mM linoleic acid). Results showed that the amounts of AAS and LNL in both MOS- and LOS-oxidized MFP was proportional to the oxidant concentrations (H2O2 or linoleic acid), while the formation of total carbonyl and total thiol also exhibited similar oxidant-dose-dependent patterns. Meanwhile, the α-helix contents of MFP declined with oxidant concentrations irrespective of the oxidizing systems. The reducing SDS-PAGE revealed that the myosin heavy chain band started to diminish at high H2O2 concentration (5 and 10 mM) in MOS whereas at low level of linoleic acid (0.5 mM) in LOS. Overall, these results demonstrated both oxidizing systems could be involved in the formation of AAS and LNL, and that the generation of AAS and LNL can be used as reliable markers for protein oxidation, but also might be directly involved in protein structural changes and then contribute to the alternations of protein functionality.


Assuntos
Peróxido de Hidrogênio , Lipoxigenase , Suínos , Animais , Ácido Linoleico , Carbonilação Proteica , Oxirredução , Ácido Ascórbico , Metais , Oxidantes
13.
J Clin Invest ; 133(2)2023 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-36413411

RESUMO

BACKGROUNDStudies assessing the efficacy of therapies for neovascular age-related macular degeneration (nvAMD) have demonstrated that aflibercept may have a longer treatment interval than its less-expensive alternative, bevacizumab. However, whether this benefit justifies the additional cost of aflibercept remains under debate. We have recently reported that a treat-and-extend-pause/monitor approach can be used to successfully wean 31% of patients with nvAMD off anti-VEGF therapy. Here, we examined whether the choice of therapy influences the outcomes of this approach.METHODSIn this retrospective analysis, 122 eyes of 106 patients with nvAMD underwent 3 consecutive monthly injections with either aflibercept (n = 70) or bevacizumab (n = 52), followed by a treat-and-extend protocol, in which the decision to extend the interval between treatments was based on visual acuity, clinical exam, and the presence or absence of fluid on optical coherence tomography. Eyes that remained stable 12 weeks from their prior treatment were given a 6-week trial of holding further treatment, followed by quarterly monitoring. Treatment was resumed for worsening vision, clinical exam, or optical coherence tomography findings.RESULTSAt the end of 1 year, eyes receiving bevacizumab had similar vision but required more injections (8.7 ± 0.3 treatments vs. 7.2 ± 0.3 treatments) compared with eyes receiving aflibercept. However, eyes treated with aflibercept were almost 3 times more likely to be weaned off treatment (43% vs. 15%) compared with eyes treated with bevacizumab at the end of 1 year.CONCLUSIONThese observations expose an advantage of aflibercept over bevacizumab and have important clinical implications for the selection of therapy for patients with nvAMD.FUNDINGThis work was supported by the National Eye Institute, NIH grants R01EY029750 and R01EY025705, Research to Prevent Blindness, the Alcon Young Investigator Award from the Alcon Research Institute, and the Branna and Irving Sisenwein Professorship in Ophthalmology.


Assuntos
Inibidores da Angiogênese , Degeneração Macular , Humanos , Bevacizumab/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Ranibizumab/efeitos adversos , Estudos Retrospectivos , Proteínas Recombinantes de Fusão/uso terapêutico , Degeneração Macular/tratamento farmacológico , Resultado do Tratamento , Seguimentos
14.
J Hazard Mater ; 442: 130041, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36166911

RESUMO

In recent years, carbon monoxide (CO) intoxication incidents occur frequently, and the sensitive detection of CO is particularly significant. At present, most reported carbon monoxide (CO) sensors meet the disadvantage of high working temperature. It is always a challenge to realize the sensitive detection of carbon monoxide at room temperature. In this study, CuO nanosheets exposed more (111) active crystal facets and oxygen vacancy defects were synthesized by a simple and environmentally friendly one-step hydrothermal method. The sensor has good comprehensive gas sensing performance, compared with other sensors that can detect CO at room temperature. The response value to 100 ppm CO at room temperature is as high as 39.6. In addition, it also has excellent selectivity, low detection limit (100 ppb), good reproducibility, moisture resistance and long-term stability (60 days). This excellent gas sensing performance is attributed to the special structural characteristics of 2D materials and the synergistic effect of more active crystal facets exposed on the crystal surface and oxygen vacancy defects. Therefore, it is expected to become a promising sensitive material for rapid and accurate detection of trace CO gas under low energy consumption, reduce the risk of poisoning, and then effectively protect human life safety.


Assuntos
Monóxido de Carbono , Oxigênio , Humanos , Temperatura , Reprodutibilidade dos Testes , Oxigênio/química
15.
Cell Rep ; 42(1): 111976, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36640318

RESUMO

Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Hipoglicemia , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Retinopatia Diabética/metabolismo , Glucose/metabolismo , Hipoglicemia/complicações , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia
16.
J Clin Invest ; 133(13)2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37227777

RESUMO

Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Neovascularização Retiniana , Humanos , Camundongos , Animais , Acriflavina/metabolismo , Acriflavina/farmacologia , Acriflavina/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Retina/metabolismo , Neovascularização Retiniana/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
17.
J Hazard Mater ; 435: 129005, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35500342

RESUMO

Micro-nano heterogeneous oxides have received extensive attention due to their distinctive physicochemical properties. However, it is a challenge to prepare the hierarchical multicomponent metal oxide nanomaterials with abundant heterogeneous interfaces in a controllable way. In this work, the effective construction of the heterogeneous structure of the material is achieved by regulating the ratio of metal salts under thermal solvent condition. Three-dimensional spheres (ZnFe2O4) constructed by zero-dimensional ultra-small nanoparticles, in particular three-dimensional hollow sea urchin spheres (ZnO/ZnFe2O4) constructed by one-dimensional nanorods and three-dimensional hydrangeas (α-Fe2O3/ZnFe2O4) assembled by two-dimensional nanosheets were obtained. The two composite materials contain a large number of heterojunctions, which enhances the sensitivity of material to volatile organic compounds gas. Among them, the α-Fe2O3/ZnFe2O4 composite shows the best sensing performance for VOCs. For example, its response to 100 ppm acetone reaches 142 at 170 °C with the response time shortened to 3 s and the detection limit falling to 10 ppb. Meanwhile, the composite material presents a degradation rate of more than 90% for VOCs at a flow rate of 20 mL/min at 170 °C. In addition, the sensing and sensitivity mechanism of the composite material are studied in detail by combining GC-MS, XPS with UV diffuse reflectance tests.

18.
Adv Mater ; 34(27): e2200612, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35543386

RESUMO

Selective oxidation of CH bonds is one of the most important reactions in organic synthesis. However, activation of the α-CH bond of ethylbenzene by use of photocatalysis-generated superoxide anions (O2 •- ) remains a challenge. Herein, the formation of individual Fe atoms on polymeric carbon nitride (CN), that activates O2  to create O2 •- for facilitating the reaction of ethylbenzene to form acetophenone, is demonstrated. By utilizing density functional theory and materials characterization techniques, it is shown that individual Fe atoms are coordinated to four N atoms of CN and the resultant low-spin Fe-N4  system (t2g 6 eg 0 ) is not only a great adsorption site for oxygen molecules, but also allows for fast transfer of electrons generated in the CN framework to adsorbed O2 , producing O2 •- . The oxidation reaction of ethylbenzene triggered by O2 •- ions turns out to have a high conversion rate of 99% as well as an acetophenone selectivity of 99%, which can be ascribed to a novel reaction pathway that is different from the conventional route involving hydroxyl radicals and the production of phenethyl alcohol. Furthermore, it possesses great potential for other CH activation reactions besides ethylbenzene oxidation.

19.
Nat Commun ; 13(1): 3910, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35798744

RESUMO

Core fucosylation of N-linked glycoproteins has been linked to the functions of glycoproteins in physiological and pathological processes. However, quantitative characterization of core fucosylation remains challenging due to the complexity and heterogeneity of N-linked glycosylation. Here we report a mass spectrometry-based method that employs sequential treatment of intact glycopeptides with enzymes (STAGE) to analyze site-specific core fucosylation of glycoproteins. The STAGE method utilizes Endo F3 followed by PNGase F treatment to generate mass signatures for glycosites that are formerly modified by core fucosylated N-linked glycans. We benchmark the STAGE method and use it to characterize site specific core fucosylation of glycoproteins from human hepatocellular carcinoma and pancreatic ductal adenocarcinoma, resulting in the identification of 1130 and 782 core fucosylated glycosites, respectively. These results indicate that our STAGE method enables quantitative characterization of core fucosylation events from complex protein mixtures, which may benefit our understanding of core fucosylation functions in various diseases.


Assuntos
Glicopeptídeos , Neoplasias Hepáticas , Fucose/metabolismo , Glicopeptídeos/química , Glicoproteínas/metabolismo , Glicosilação , Humanos , Espectrometria de Massas/métodos
20.
Artigo em Inglês | MEDLINE | ID: mdl-35822804

RESUMO

Lithium (Li) metal is one of the most promising anode materials for the next-generation batteries, which owns superior specific capacity and energy density. Unfortunately, lithium dendrites that is formed during the charging/discharging process tends to induce capacity degradation and thus short lifespan. In this study, the vanadium oxide (V2O5) and nitrogen-doped vanadium oxide (N-V2O3, N-VO0.9)-modified three-dimensional (3D) reduced graphene oxide ((N)-VOx@rGO) with tunable electronic properties are demonstrated to enable the dendrite-free Li deposition. The soft lithiophilic rGO as the scaffold can provide sufficient void space for Li storage. Meanwhile, the rigid (N)-VOx uniformly anchored on rGO can perfectly maintain the 3D structure, which is crucial for Li to enter the inner space of the 3D framework. Consequently, the (N)-VOx@rGO electrodes achieve dendrite-free electrodeposition under the multifarious deposition capacity and current densities. Compared with the bare lithium electrodes, the asymmetrical cells of (N)-VOx@rGO anode can cycle stably up to 400 h at 2 mA cm-2 current density, together with a low nucleation overpotential of ∼20 mV.

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