Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 129
Filtrar
1.
Proc Natl Acad Sci U S A ; 121(8): e2314128121, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38359291

RESUMO

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.


Assuntos
Neoplasias Colorretais , Biossíntese de Proteínas , Humanos , Carcinogênese/genética , Transformação Celular Neoplásica , Neoplasias Colorretais/genética , Catálise , Microambiente Tumoral , Histona Acetiltransferases
2.
Nat Chem Biol ; 20(4): 484-492, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37945893

RESUMO

GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.


Assuntos
Receptores Acoplados a Proteínas G , Camundongos , Animais , Microscopia Crioeletrônica , Receptores Acoplados a Proteínas G/metabolismo , Ligantes
3.
Proc Natl Acad Sci U S A ; 119(29): e2117054119, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858343

RESUMO

The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for ß-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-ß-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Receptores Acoplados a Proteínas G , Fatores de Transcrição , Ácidos e Sais Biliares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Ácidos Cólicos/farmacologia , Microscopia Crioeletrônica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Transcrição/metabolismo , beta-Arrestina 1/metabolismo
4.
Proc Natl Acad Sci U S A ; 119(15): e2117004119, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35394864

RESUMO

GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.


Assuntos
Progesterona , Receptores Acoplados a Proteínas G , Receptores de Progesterona , Neoplasias de Mama Triplo Negativas , 17-alfa-Hidroxiprogesterona/metabolismo , Linhagem Celular Tumoral , Humanos , Progesterona/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
5.
Breast Cancer Res ; 26(1): 37, 2024 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-38454442

RESUMO

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.


Assuntos
Neoplasias da Mama , Proteínas de Ciclo Celular , Humanos , Feminino , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Prognóstico , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo
6.
Small ; : e2405107, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39300865

RESUMO

Palladium nanosheets (Pd NSs) are widely used as electrocatalysts due to their high atomic utilization efficiency, and long-term stability. Here, the electronic structure modulation of the Pd NSs is realized by a femtosecond laser irradiation strategy. Experimental results indicate that laser irradiation induces the variation in the atomic structures and the macrostrain effects in the Pd NSs. The electronic structure of Pd NSs is modulated by laser irradiation through the balancing between Au-Pd charge transfer and the macros-strain effects. Finite element analysis (FEA) indicates that the lattice of the nanostructures undergoes fast heating and cooling during laser irradiation. The structural evolution mechanism is disclosed by a combined FEA and molecule dynamics (MD) simulation. These results coincide well with the experimental results. The L-AuPd NSs exhibit excellent mass activity and specific activity of 7.44 A mg-1 Pd and 18.70 mA cm-2 toward ethanol oxidation reaction (EOR), 4.3 and 4.4 times higher than the commercial Pd/C. The 2500-cycle accelerated durability (ADT) test confirms the outstanding catalytic stability of the L-AuPd NSs. Density functional theory (DFT) calculations reveal the catalytic mechanism. This unique strategy provides a new pathway to design the ultrathin nanosheet-based materials with excellent performance.

7.
Microb Pathog ; 192: 106703, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38763315

RESUMO

Streptococcus equissp.zooepidemicus (SEZ) is a crucial pathogen and contributes to various infections in numerous animal species. Swine streptococcicosis outbreak caused by SEZ has been reported in several countries in recent years. SzM protein is a cell membrane-anchored protein, which exhibits as an important virulence factor of SEZ. Effects of SzM protein on host innate immune need further study. Here, recombinant SzM (rSzM) protein of the SEZ was obtained, and mice were intraperitoneally injected with rSzM protein. We discovered that rSzM protein can recruit neutrophils into the injected site. In further study, neutrophils were isolated and treated with rSzM protein, NETs release were triggered by rSzM protein independently, and GSDMD protein was promoted-expressed and activated. In order to investigate the role of GSDMD in NETs formation, neutrophils isolated from WT mice and GSDMD-/- mice were treated with rSzM protein. The results showed that GSDMD deficiency suppressed the NETs release. In conclusion, SzM protein of SEZ can trigger the NETs release in a GSDMD-depending manner.


Assuntos
Proteínas de Bactérias , Armadilhas Extracelulares , Neutrófilos , Infecções Estreptocócicas , Streptococcus equi , Fatores de Virulência , Animais , Camundongos , Neutrófilos/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Streptococcus equi/genética , Streptococcus equi/imunologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Fatores de Virulência/genética , Fatores de Virulência/metabolismo , Camundongos Knockout , Proteínas Recombinantes/genética , Imunidade Inata , Camundongos Endogâmicos C57BL , Gasderminas , Proteínas de Ligação a Fosfato
8.
Phys Rev Lett ; 132(8): 083201, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38457733

RESUMO

We introduce time-resolved multielectron coincidence spectroscopy and apply it to the double Auger-Meitner (AM) emission process following xenon 4d photoionization. The photoelectron and AM electron(s) are measured in coincidence by using a magnetic-bottle time-of-flight spectrometer, enabling an unambiguous assignment of the complete cascade pathways involving two AM electron emissions. In the presence of a near-infrared (NIR) laser pulse, the intermediate Xe^{2+*} state embedded in the Xe^{3+} continuum is probed through single NIR photon absorption and the lifetime of this intermediate Xe^{2+*} state is directly obtained as (109±22) fs.

9.
Sensors (Basel) ; 24(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38400411

RESUMO

In the process of silicon single-crystal preparation, the timely identification and adjustment of abnormal conditions are crucial. Failure to promptly detect and resolve issues may result in a substandard silicon crystal product quality or even crystal pulling failure. Therefore, the early identification of abnormal furnace conditions is essential for ensuring the preparation of perfect silicon single crystals. Additionally, since the thermal field is the fundamental driving force for stable crystal growth and the primary assurance of crystal quality, this paper proposes a silicon single-crystal growth temperature gradient trend classification algorithm based on multi-level feature fusion. The aim is to accurately identify temperature gradient changes during silicon crystal growth, in order to promptly react to early growth failures and ensure the stable growth of high-quality silicon single crystals to meet industrial production requirements. The algorithm first divides the temperature gradient trend into reasonable categories based on expert knowledge and qualitative analysis methods. Then, it fuses the original features of actual production data, shallow features extracted based on statistical information, and deep features extracted through deep learning. During the fusion process, the algorithm considers the impact of different features on the target variable and calculates mutual information based on the difference between information entropy and conditional entropy, ultimately using mutual information for feature weighting. Subsequently, the fused multi-level feature vectors and their corresponding trend labels are input into a Deep Belief Network (DBN) model to capture process dynamics and classify trend changes. Finally, the experimental results demonstrate that the proposed algorithm can effectively predict the changing trend of thermal field temperature gradients. The introduction of this algorithm will help improve the accuracy of fault trend prediction in silicon single-crystal preparation, thereby minimizing product quality issues and production interruptions caused by abnormal conditions.

10.
Phys Rev Lett ; 130(15): 153201, 2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37115860

RESUMO

We report a combined experimental and theoretical study on the effect of autoionizing resonances in time-resolved photoelectron spectroscopy. The coherent excitation of N_{2} by ∼14.15 eV extreme-ultraviolet photons prepares a superposition of three dominant adjacent vibrational levels (v^{'}=14-16) in the valence b^{'} ^{1}Σ_{u}^{+} state, which are probed by the absorption of two or three near-infrared photons (800 nm). The superposition manifests itself as coherent oscillations in the measured photoelectron spectra. A quantum-mechanical simulation confirms that two autoionizing Rydberg states converging to the excited A ^{2}Π_{u} and B ^{2}Σ_{u}^{+} N_{2}^{+} cores are accessed by the resonant absorption of near-infrared photons. We show that these resonances apply different filters to the observation of the vibrational wave packet, which results in different phases and amplitudes of the oscillating photoelectron signal depending on the nature of the autoionizing resonance. This work clarifies the importance of resonances in time-resolved photoelectron spectroscopy and particularly reveals the phase of vibrational quantum beats as a powerful observable for characterizing the properties of such resonances.

11.
Phys Rev Lett ; 128(13): 133001, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35426704

RESUMO

We report the first observation of intermolecular Coulombic decay (ICD) in liquid water following inner-valence ionization. By combining a monochromatized tabletop high-harmonic source with a liquid microjet, we record electron-electron coincidence spectra at two photon energies that identify the ICD electrons, together with the photoelectrons originating from the 2a_{1} inner-valence band of liquid water. Our results confirm the importance of ICD as a source of low-energy electrons in bulk liquid water and provide quantitative results for modeling the velocity distribution of the slow electrons that are thought to dominate radiation damage in aqueous environments.

12.
Nutr J ; 21(1): 63, 2022 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-36242082

RESUMO

BACKGROUND: Diet is a modifiable risk factor for cardiovascular diseases (CVD), but there is still a lack of tools to assess dietary intakes of this high-risk population in Ningxia, China. OBJECTIVE: We aim to evaluate the validity and reliability of the semi-quantitative food frequency questionnaire (SFFQ) in the groups in Ningxia using a 24-hour dietary recall method. METHOD: Two hundred five participants were included in the analysis. The two FFQs were 6 months apart, and during this time two 24-hour dietary recalls (24HDRs) were completed. Statistical methods were compared using inter-class correlation coefficient, unadjusted, energy-adjusted, de-attenuated correlation coefficient, quartile classification, weighted K values, and 95% limits of agreement (LOA). RESULTS: The inter-class correlation coefficients between FFQ1 and FFQ2 ranged from 0.25 to 0.73. The number of subjects classified as identical or adjacent was 72.2 to 85.9%. The crude correlation coefficient between FFQs and 24HDRs was 0.30 ~ 0.81, the energy-adjusted correlation coefficient was 0.16 ~ 0.83, and the de-attenuated correlation coefficient was 0.19 ~ 0.98. Weighted k statistics and Bland-Altman plots showed acceptable agreement between FFQs and 24HDRs. CONCLUSION: The FFQ developed for the population at high risk of cardiovascular and cerebrovascular diseases in areas of Ningxia can be used to measure the dietary intake of nutrients and food groups reliably and validly.


Assuntos
Doenças Cardiovasculares , Ingestão de Energia , Doenças Cardiovasculares/epidemiologia , Dieta , Inquéritos sobre Dietas , Humanos , Reprodutibilidade dos Testes , Inquéritos e Questionários
13.
Appl Opt ; 61(13): 3533-3541, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36256390

RESUMO

In a static wind imaging Michelson interferometer we developed, one of the Michelson mirrors is divided into four quadrants, with coatings on the quadrants that provide small phase steps from one quadrant to another, realizing the four simultaneous sampling of the interferogram. Restricted by the coating process and interferometer adjustment, the instrument visibility and phase steps of the four quadrants will deviate from the design value. In the actual passive detection of the atmospheric wind field, quasi-real-time calibration is required, and the calibration will also be affected by the instrument noise. In this paper, we propose a deep-learning-based denoising algorithm that can quickly denoise the wind interferogram with no need to adjust parameters, combined with conventional least-squares fitting cosine curves to obtain the visibility and phase steps of four quadrants from a series of interferograms with varying phase differences. The proposed algorithm framework is verified by experiment, and the measurement of visibility and phase steps of the wind field interferogram is efficiently realized. It can provide a reference for the visibility and phase steps measurement of the wind imaging interferometer and may have applications in wind imaging interferometer calibration.

14.
Anim Biotechnol ; : 1-8, 2022 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-36542538

RESUMO

Dermal papilla cells (DPCs) are the key dermal component of the hair follicle that directly regulates hair follicle development, growth and regeneration. Successfully isolated and cultured DPCs from Small-tail Han sheep could provide a good model for the study of hair follicle development mechanism in vitro. DPCs were isolated using enzyme digestion and dissecting microscope from Small-tail Han sheep. Adherent cells were identified by cell characteristics, particular gene expression, differentiation capability to adipocyte and osteoblast using specific differentiation mediums. Additionally, flow cytometry was used to detect the cell cycle of DPCs. Cells originating from the dermal papilla showed the morphological appearance of mesenchymal cells (fibroblast-like cells). Purified DPCs were positive for α-SMA (α smooth muscle actin) and vimentin; in addition to their strong proliferation abilities in vitro, these DPCs can be differentiated into adipocyte and osteoblasts lineage under appropriate culture condition. DPCs were successfully isolated and subcultured from Small-tail Han sheep, which exhibited progenitor cell features and multiple differentiation potency. It provides a material for studying the molecular mechanism of hair follicle development and hair cycle, which will promote wool production in the future.

15.
J Acoust Soc Am ; 152(5): 2840, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36456288

RESUMO

Remote acoustic sensing can be used to estimate the error signals in human ears without placing any physical microphones there. In this paper, the coherence between the signals picked up by physical microphones over a sphere surface and the signal obtained at the sphere center is investigated. Based on the multiple channel coherence formulas in the time domain and frequency domain, the relationship between the coherence and the placement of physical microphones is analyzed by numerical simulations first, then the experimental results obtained in a reverberation chamber and a car cabin are presented to verify the simulation results. Finally, a placement of physical microphones for active control of road noise in car cabins is discussed. Both the numerical and experimental results show that an upper limit frequency exists for accurate sound pressure estimation at the center of a sphere with the sound pressure on the sphere surface. For a sufficiently complex sound field such as that in a reverberation room or in a car, half the wavelength of the upper limit frequency is about the average distance among the physical microphones.


Assuntos
Acústica , Som , Humanos , Simulação por Computador
16.
Environ Toxicol ; 37(5): 1136-1151, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35099110

RESUMO

The pesticide 2,4-dichlorophenoxyacetic acid (2,4-D) exerts neurotoxic effects; however, its action mechanism remains unclear. Here, we used BV2 cells as a model and divided them into six groups: control group (serum-free medium), lipopolysaccharide (LPS) (1 µg/mL), 2,4-D (1.2 µmol/mL), Lycium barbarum polysaccharide (LBP; 300 µg/mL LBP), LPS (1 µg/mL) + LBP (300 µg/mL), and 2,4-D (1.2 µmol/mL) + LBP (300 µg/mL) with dimethyl sulfoxide as the solvent. Our results showed that 2,4-D treatment decreased superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde content. The percentage of microglial activation (co-expression of ionized calcium-binding adaptor protein-1 + CD68) in the LPS and 2,4-D groups and the levels of tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, and IL-18 in the cell supernatant were increased. The protein and mRNA levels of Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein, caspase-1, IL-1ß, IL-18, and p62 increased, whereas those of LC3II/I and Beclin-1 decreased in the 2,4-D group. The protein expression and mRNA levels of NLRP3, cleaved caspase-1, IL-1ß, IL-18, and p62 decreased significantly, whereas the protein expression and mRNA levels of LC3II/I and Beclin-1 increased in small interfering RNA of NLRP3-treated BV2 cells stimulated with 2,4-D and LPS. In conclusion, 2,4-D enhanced cell migration, promoted oxidative stress, induced excessive release of mitochondrial reactive oxygen species, promoted microglial cell activation, released inflammatory factors, activated NLRP3 inflammasomes, and inhibited autophagy. Meanwhile, LBP reduced inflammation and the release of mitochondrial reactive oxygen species, inhibited NLRP3 inflammasome activation, and regulated autophagy, thereby playing a neuroprotective role.


Assuntos
Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ácido 2,4-Diclorofenoxiacético/metabolismo , Ácido 2,4-Diclorofenoxiacético/toxicidade , Animais , Autofagia , Medicamentos de Ervas Chinesas , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
Environ Toxicol ; 37(11): 2764-2779, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36214342

RESUMO

The herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D) is widely used to control broadleaved weeds and has been associated with male infertility. We studied the molecular mechanisms of 2,4-D induced male reproductive system damage and the protective effects of Lycium barbarum polysaccharides (LBP) using Sprague Dawley rats and TM4 cells. Treatment with 2,4-D caused architectural and functional changes in the testis, including collapsed and atrophied seminiferous tubules with reduced number of spermatozoa, scarce sperm in the epididymal duct, low levels of serum testosterone, decreased superoxide dismutase and glutathione peroxidase activity, high malondialdehyde content, and increased apoptosis in the testis and epididymis. The expression of Fas, FasL, FADD, Pro-caspase-8, Cleaved-Caspase-8, Pro-Caspase-3, and Cleaved-Caspase-3 were significantly increased in the testicular tissue of 2,4-D-treated rats. The proliferative activity of TM4 cells decreased with an increase in dose and time of 2,4-D exposure, along with enhanced Fas/Fas ligand expression and a decreased concentration of inhibin B in TM4 cell culture medium. Depletion of Fas by specific shRNA transfection reversed the effects of 2,4-D in TM4 cells, further confirming the involvement of death receptor pathway in 2,4-D-mediated apoptosis of sertoli cells. Treatment with LBP also reversed the effects of 2,4-D in testicular cells, resulting in improved cell architecture along with enhanced proliferative capacity. Moreover, in response to LBP treatment of Sertoli cells, the content of inhibin B increased, the level of reactive oxygen species and malondialdehyde decreased, the activities of superoxide dismutase and glutathione peroxidase increased, and the rate of apoptosis as well as the expression of Fas/Fas ligand signaling pathway proteins decreased.


Assuntos
Herbicidas , Lycium , Ácido 2,4-Diclorofenoxiacético/metabolismo , Ácido 2,4-Diclorofenoxiacético/toxicidade , Animais , Apoptose , Caspase 3/metabolismo , Caspase 8/metabolismo , Proteína Ligante Fas/metabolismo , Glutationa Peroxidase/metabolismo , Herbicidas/toxicidade , Lycium/metabolismo , Masculino , Malondialdeído/metabolismo , Polissacarídeos/farmacologia , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptores de Morte Celular/metabolismo , Sementes/metabolismo , Superóxido Dismutase/metabolismo , Testículo , Testosterona
18.
Biochem Biophys Res Commun ; 561: 106-112, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34022710

RESUMO

Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. The ability to switch between yeast and hyphal growth forms is critical for its pathogenesis. Hyphal development in C. albicans requires two temporally linked regulations for initiation and maintenance. Here, we performed transcriptome sequencing (RNA-Seq) to analyze the transcriptional consequences for the two different phases of hyphal development. Genome-wide transcription profiling reveals that the sets associated with hyphal initiation were significantly enriched in genes for hyphal cell wall, biofilm matrix and actin polarization. In addition to hypha-specific genes, numerous genes involved in iron acquisition, such as FTR1 and SEF1, are highly induced specifically during sustained hyphal development even when additional free iron is supplied in the medium. Therefore, iron uptake genes are induced by signals that can support prolonged hyphal development in an iron-independent manner. The induction of iron acquisition genes during hyphal elongation was further confirmed by quantitative reverse transcription-PCR under various hypha-inducing conditions. Remarkably, preventing C. albicans from acquiring iron blocks BRG1 activation, leading to impaired hyphal maintenance, and ectopically expressed BRG1 can sustain hyphal development bypassing the requirement of iron. Our study elucidates an underlying mechanism of how multiple virulence factors are interconnected and are induced simultaneously during infection.


Assuntos
Candida albicans/crescimento & desenvolvimento , Candida albicans/metabolismo , Proteínas Fúngicas/metabolismo , Hifas/crescimento & desenvolvimento , Ferro/metabolismo , Candida albicans/genética , Proteínas Fúngicas/genética , Hifas/genética , Hifas/metabolismo , Virulência
19.
Microb Pathog ; 157: 104885, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33991641

RESUMO

To prevent and control H3N8 subtype equine influenza, we prepared virus-like particles (VLPs) comprising the HA, NA and M1 proteins of H3N8 equine influenza virus (EIV) through the insect cell-baculovirus expression system. The results of Western blot and hemagglutination analyses demonstrated that the constructed VLPs comprising HA, NA and M1 proteins have good hemagglutination activity. Immunoelectron microscope revealed that the VLPs share similar morphology and structure with natural virus particles. The hyperimmune serum from horses immunized with the VLPs were injected into mice by means of artificial passive immunization and then challenge, or challenge following by injecting hyperimmune serum. The results showed that the equine hyperimmune serum has good preventive and therapeutic efficacy against the infection of H3N8 EIV. The study provides a technical foundation for the development of H3N8 EIV VLP vaccine.


Assuntos
Doenças dos Cavalos , Vírus da Influenza A Subtipo H3N8 , Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Vacinas de Partículas Semelhantes a Vírus , Animais , Anticorpos Antivirais , Doenças dos Cavalos/prevenção & controle , Cavalos , Vírus da Influenza A Subtipo H3N8/genética , Camundongos , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/veterinária
20.
BMC Cancer ; 21(1): 1124, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34666705

RESUMO

BACKGROUND: Different pathological subtypes of invasive pulmonary adenocarcinoma (IPA) have different surgical methods and heterogeneous prognosis. It is essential to clarify IPA subtypes before operation and high-resolution computed tomography (HRCT) plays a very important role in this regard. We aimed to investigate the HRCT features of lepidic-predominant type and other pathological subtypes of early-stage (T1N0M0) IPA appearing as a ground-glass nodule (GGN). METHODS: We performed a retrospective analysis on clinical data and HRCT features of 630 lesions in 589 patients with pathologically confirmed IPA (invasive foci > 5 mm) appearing as pure GGN (pGGN) and mixed GGN (mGGN) with consolidation-to-tumor ratio (CTR) ≤0.5 from January to December 2019. All GGNs were classified as lepidic-predominant adenocarcinoma (LPA) and nonlepidic-predominant adenocarcinoma (n-LPA) groups. Univariate analysis was performed to analyze the differences of clinical data and HRCT features between the LPA and n-LPA groups. Multivariate analysis was conducted to determine the variables to distinguish the LPA from n-LPA group independently. The diagnostic performance of different parameters was compared using receiver operating characteristic curves. RESULTS: In total, 367 GGNs in the LPA group and 263 GGNs in the n-LPA group were identified. In the univariate analysis, the CTR, mean CT values, and mean diameters as well as mixed GGN, deep lobulation, spiculation, vascular change, bronchial change, and tumor-lung interface were smaller in the LPA group than in the n-LPA group (P <  0.05). Logistic regression model was reconstructed including the mean CT value, CTR, deep lobulation, spiculation, vascular change, and bronchial change (P <  0.05). Area under the curve of the logistic regression model for differentiating LPA and n-LPA was 0.840 (76.4% sensitivity, 78.7% specificity), which was significantly higher than that of the mean CT value or CTR. CONCLUSIONS: Deep lobulation, spiculation, vascular change, and bronchial change, CT value > - 472.5 HU and CTR > 27.4% may indicate nonlepidic predominant invasive pulmonary adenocarcinoma in GGNs.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada Espiral/métodos , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Análise de Variância , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Estudos Retrospectivos , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA