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1.
EMBO Rep ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39160344

RESUMO

Zygotic genome activation (ZGA), the first transcription event following fertilization, kickstarts the embryonic program that takes over the control of early development from the maternal products. How ZGA occurs, especially in mammals, is poorly understood due to the limited amount of research materials. With the rapid development of single-cell and low-input technologies, remarkable progress made in the past decade has unveiled dramatic transitions of the epigenomes, transcriptomes, proteomes, and metabolomes associated with ZGA. Moreover, functional investigations are yielding insights into the key regulators of ZGA, among which two major classes of players are emerging: licensors and specifiers. Licensors would control the permission of transcription and its timing during ZGA. Accumulating evidence suggests that such licensors of ZGA include regulators of the transcription apparatus and nuclear gatekeepers. Specifiers would instruct the activation of specific genes during ZGA. These specifiers include key transcription factors present at this stage, often facilitated by epigenetic regulators. Based on data primarily from mammals but also results from other species, we discuss in this review how recent research sheds light on the molecular regulation of ZGA and its executors, including the licensors and specifiers.

2.
Nano Lett ; 24(20): 6061-6068, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38728017

RESUMO

van der Waals (vdW) superlattices, comprising different 2D materials aligned alternately by weak interlayer interactions, offer versatile structures for the fabrication of novel semiconductor devices. Despite their potential, the precise control of optoelectronic properties with interlayer interactions remains challenging. Here, we investigate the discrepancies between the SnS/TiS2 superlattice (SnTiS3) and its subsystems by comprehensive characterization and DFT calculations. The disappearance of certain Raman modes suggests that the interactions alter the SnS subsystem structure. Specifically, such structural changes transform the band structure from indirect to direct band gap, causing a strong PL emission (∼2.18 eV) in SnTiS3. In addition, the modulation of the optoelectronic properties ultimately leads to the unique phenomenon of thermally activated photoluminescence. This phenomenon is attributed to the inhibition of charge transfer induced by tunable intralayer strains. Our findings extend the understanding of the mechanism of interlayer interactions in van der Waals superlattices and provide insights into the design of high-temperature optoelectronic devices.

3.
J Transl Med ; 22(1): 900, 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39367493

RESUMO

BACKGROUND: Muscle invasive bladder cancer (MIBC) is a life-threatening malignant tumor characterized by high metastasis rates, poor prognosis, and limited treatment options. Immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 represent an emerging treatment for MIBC immunotherapy. However, the characteristics of patients likely to benefit from immunotherapy remain unclear. METHODS: We performed single-cell mass cytometry (CyTOF) analysis of 179,483 single cells to characterize potential immunotherapy-related cancer stem cells (CSCs)-like populations in the tumor microenvironment of 38 MIBC tissues. The upregulated expression of IGF2BP3 in CD274 + ALDH + CSC-like cells, which was associated with poor clinical prognosis, was analyzed by bulk RNA-sequencing data from an in-house cohort. The functional role of IGF2BP3 was determined through cell proliferation, colony formation, cell apoptosis and sphere formation assays. The regulation of SPHK1 expression by IGF2BP3 was  investigated using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and bulk RNA-sequencing (bulk RNA-seq). We further utilized single-nucleus RNA sequencing (snRNA-seq) data from 67,988 cells of 25 MIBC tissues and single-cell RNA sequencing (scRNA-seq) data from MIBC patient-derived organoids to characterize the molecular features of bladder cancer cells co-expressing IGF2BP3 and SPHK1. Spatial transcriptomics (ST) and co-detection by indexing (CODEX) analysis were used to describe the spatial distribution and interactions of IGF2BP3 + SPHK1 + bladder cancer cells and immune cells. RESULTS: A subset of CD274 + ALDH + CSC-like cells was identified, associating with immunosuppression and low survival rates in MIBC patients. IGF2BP3, an m6A reader gene, was found to be upregulated in the CD274 + ALDH + CSC-like cell population and linked to poor clinical prognosis in MIBC. Knockout of IGF2BP3 dramatically promoted cell apoptosis and reduced cell proliferation in T24 cells. By integrating MeRIP-seq and bulk RNA-seq analyses, we identified SPHK1 served as a substrate for IGF2BP3 in an m6A-dependent manner. Further snRNA-seq, scRNA-seq, ST, and CODEX analysis revealed a closer topographical distance between IGF2BP3 + SPHK1 + bladder cancer cells and exhausted CD8 + T cells, providing one explanation for the superior response to immunotherapy in IGF2BP3 + SPHK1 + bladder cancer cells-enriched patients. Finally, an ICI-associated signature was developed based on the enriched genes of IGF2BP3 + SPHK1 + bladder cancer cells, and its potential ability to predict the response to immunotherapy was validated in two independent immunotherapy cohort. CONCLUSIONS: Our study highlighted the critical involvement of the IGF2BP3/SPHK1 signaling in maintaining the stemness of CSCs and promoting MIBC progression. Additionally, these findings suggested that the IGF2BP3/SPHK1 signaling might serve as a biomarker for prognosis and immunotherapy response in MIBC.


Assuntos
Imunoterapia , Invasividade Neoplásica , Células-Tronco Neoplásicas , Proteínas de Ligação a RNA , Transdução de Sinais , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/imunologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Pessoa de Meia-Idade , Proliferação de Células , Músculos/patologia , Músculos/metabolismo , Idoso , Multiômica
4.
Respir Res ; 25(1): 186, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38678295

RESUMO

BACKGROUND: Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. METHODS: COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. RESULTS: The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1ß attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1ß/STAT1 signaling via MTs. CONCLUSIONS: These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1ß/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD.


Assuntos
Apoptose , Vírus da Influenza A Subtipo H3N2 , Melatonina , Doença Pulmonar Obstrutiva Crônica , Animais , Melatonina/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/virologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Camundongos , Apoptose/efeitos dos fármacos , Células RAW 264.7 , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/imunologia , Camundongos Endogâmicos C57BL , Masculino , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Progressão da Doença , Polaridade Celular/efeitos dos fármacos , Modelos Animais de Doenças , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virologia
5.
Ann Hematol ; 103(3): 999-1005, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38285081

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is highly aggressive with a poor prognosis. There is no standard treatment for BPDCN. Although conventional chemotherapies are usually sensitive in the initial therapy, relapse and drug resistance are inevitable within a short duration. Targeted therapies have enlightened new prospects for the treatment of BPDCN, especially for those in a frail state and intolerable to standard chemotherapies or hematopoietic stem cell transplantation. Here, we report an 82-year-old man diagnosed with cutaneous-limited BPDCN. Considering the old age and limited involvement of the tumor, we reduced the dosage of venetoclax. His skin lesions subsided significantly after 1 cycle of azacytidine (100 mg d1-7) combined with reduced doses of venetoclax (200 mg d1-14). The reduction in the dose of venetoclax avoided severe myelosuppression while achieving satisfactory outcomes. The patient received 2 cycles of therapy with no skin lesions re-occurred for 7 months before relapsing.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Sulfonamidas , Masculino , Humanos , Idoso de 80 Anos ou mais , Azacitidina/uso terapêutico , Células Dendríticas/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Hematológicas/terapia , Transtornos Mieloproliferativos/patologia
6.
Opt Lett ; 48(11): 3011-3014, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37262268

RESUMO

A more practical model for plasmonic core@shell-satellite antenna-reactor photocatalysts is promoted. In contrast to the mainstream view, total light absorption in the Pt nanoparticle (NP) reactors can be further improved by 70% after coating a 10-nm-thick high refractive index TiO2 shell on the large Ag antenna as a result of more Pt NPs undergoing high absorption enhancement. The enhancement effect is maximized at the electric quadrupole (EQ) resonance. Considering the high refractive index of the TiO2 coating and the embedding of the Pt NPs, the underlying physics is addressed within classical electrodynamics, making a necessary supplement to the conventional plasmonic near-field enhancement mechanism. These findings provide a general strategy for developing novel, to the best of our knowledge, visible light photocatalysts made of transition metals directly.

7.
Langmuir ; 39(37): 13028-13037, 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37671509

RESUMO

Water scarcity presents a pressing global challenge, necessitating innovative solutions, such as the collection of water from the air using conical structures. However, current research primarily focuses on mist collection rather than on nanoscale clusters of water molecules. Under standard atmospheric conditions, water vapor predominantly exists as imperceptible clusters. Therefore, it is crucial to investigate the interactions between these water molecule clusters and conical structures, particularly regarding whether the conical shape induces Laplace pressure difference on the adhering cluster formations. To gain deeper insights and determine optimal droplet collection structures, we conducted molecular dynamics simulations to investigate interactions between water molecule clusters and conical structures. Our investigations focused on studying the interactions between conical structures and water molecule clusters with varying densities, as well as the impact of surface energies on the collection of water by these conical structures. Notably, our simulations unveiled the significant roles played by van der Waals forces and Laplace pressure in the process of collecting water molecule clusters. Furthermore, our simulations revealed that Janus conical structures, featuring two distinct surface energy regions, played a crucial role in promoting the aggregation of water molecules, resulting in the formation of larger droplets. This aggregation was driven by surface tension gradients, which arise from the contrasting wetting properties in different regions of the Janus structure. As a consequence, under the influence of gravitational forces, these larger droplets could eventually detach from the structure. Through the combined effects of surface tension gradients and gravitational forces, Janus conical structures offer a promising avenue for enhancing the collection efficiency of water from the air. Our research sheds light on the fundamental mechanisms governing water molecule cluster-based water collection and provides valuable insights for the design of more efficient and effective water collection systems.

8.
Exp Lung Res ; 49(1): 220-230, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38047519

RESUMO

Background: Sepsis has become one of the main factors inducing the development of acute lung injury (ALI) in clinical practice. Currently, inhibiting the activation of NLRP3 mediated pyroptosis is the target of multiple drugs in the treatment of sepsis induced ALI. This study aimed to explore the effects of METTL14 on the pyroptosis in the sepsis induced ALI progression.Methods: LPS-stimulated A549 cells and cecal ligation and puncture (CLP)-treated mice were used to establish the ALI model in vitro and in vivo. Then, the cell viability was measured by CCK-8 assay. ELISA kits were used to determine the IL-18 and IL-1ß contents. Pyroptosis rate was tested by flow cytometry. M6A dot blot was conducted to analyze the global m6A levels and MeRIP assay was performed to detect the m6A levels of NLRP3. The relationship between METTL14 and NLRP3 was confirmed by RIP and dual-luciferase report assays.Results: The global m6A levels were significantly increased in the LPS-stimulated A549 cells and CLP-treated mice. METTL14 knockdown decreased the cell viability, IL-18 and IL-1ß contents, and pyroptosis rate of the LPS-stimulated A549 cells. Furthermore, the increase of pyroptosis-related proteins in LPS-stimulated A549 cells was significantly decreased after METTL14 knockdown. Additionally, METTL14 knockdown decreased the m6A and mRNA levels of NLRP3, and NLRP3 overexpression reversed the effects of METTL14 knockdown on the pyroptosis in the LPS-stimulated A549 cells. In CLP-treated mice, METTL14 knockdown relieved the injury and decreased the IL-18 and IL-1ß contents in the lung tissues, serum and bronchoalveolar lavage fluid.Conclusion: This study demonstrated that METTL14 knockdown inhibited the pyroptosis in the sepsis-induced ALI progression through decreasing the NLRP3 levels dependent on m6A methylation modification.


Assuntos
Lesão Pulmonar Aguda , Sepse , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Interleucina-18/efeitos adversos , Lipopolissacarídeos/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Sepse/complicações
9.
Bioorg Chem ; 134: 106468, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36933338

RESUMO

A chemoenzymatic strategy has been implemented to synthesize nitriles from benzyl amines under mild conditions. Aldoxime dehydratase (Oxd) plays a decisive role to convert aldoximes into corresponding nitriles. However, natural Oxds commonly exhibit extremely low catalytic capacity toward benzaldehyde oximes. Here, we engineered the OxdF1 from Pseudomonas putida F1 to enhance its catalytic efficiency toward benzaldehyde oximes by a semi-rational design strategy. The protein structure-based CAVER analysis indicates that M29, A147, F306, and L318 are located adjacent to the substrate tunnel entrance of OxdF1, which were responsible for the transportation of substrate into the active site. After two rounds of mutagenesis, the maximum activities of the mutants L318F and L318F/F306Y were 2.6 and 2.8 U/mg respectively, which were significantly higher than the wild OxdF1 of 0.7 U/mg. Meanwhile, the lipase type B from Candida antarctica was functionally expressed in Escherichia coli cells to selectively oxidize benzyl amines to aldoximes using urea-hydrogen peroxide adduct (UHP) as an oxidant in ethyl acetate. To merge the oxidation and dehydration reactions, a reductive extraction solution was added to remove the residue UHP, which is critical to eliminate its inhibition on the Oxd activity. Consequently, nine benzyl amines were efficiently converted into corresponding nitriles by the chemoenzymatic sequence.


Assuntos
Benzaldeídos , Nitrilas , Nitrilas/metabolismo , Oximas/química
10.
Appl Microbiol Biotechnol ; 107(23): 7089-7104, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37733049

RESUMO

Nitriles are of significant interest in the flavor and fragrance industries with potential application in cosmetics due to their higher stability than analogous aldehydes. However, the traditional methods to prepare nitriles need toxic reagents and hash conditions. This work aimed to develop a chemoenzymatic strategy to synthesize nitriles from natural aldehydes with aldoxime as the intermediate. A non-classical aldoxime dehydratase (Oxd) was discovered from the fungus Aspergillus ibericus (OxdAsp) to catalyze the dehydration of aldoximes to corresponding nitriles under mild conditions. The amino acid sequence of OxdAsp exhibits an approximately 20% identity with bacterial Oxds. OxdAsp contains a heme prosthetic group bound with the axial H287 in the catalytic pocket. The structure models of OxdAsp with substrates suggest that its catalytic triad is Y138-R141-E192, which is different from the classically bacterial Oxds of His-Arg-Ser/Thr. The catalytic mechanism of OxdAsp was proposed based on the mutagenesis of key residues. The hydroxyl group of the substrate is fixed by E192 to increase its basicity. Y138 acts as a general acid-based catalyst, and its phenolic proton is polarized by the adjacent R141. The protonated Y138 would donate a proton to the hydroxyl group of the substrate and eliminate a water molecule from aldoxime to produce nitrile. The recombinant OxdAsp can efficiently dehydrate citronellal oxime and cinnamaldoxime to citronellyl nitrile and cinnamonitrile in aqueous media, which are applied as fragrance ingredients in the food and cosmetic fields. KEY POINTS: • A novel aldoxime dehydratase from the Aspergillus genus was first characterized as a heme-binding protein. • The catalytic mechanism was predicted based on the molecular interactions of the catalytic pocket with the substrate. • A chemoenzymatic strategy was developed to synthesize nitriles from natural aldehydes with aldoxime as the intermediate.


Assuntos
Bactérias , Prótons , Bactérias/metabolismo , Hidroliases/metabolismo , Nitrilas/metabolismo , Aldeídos
11.
Int Wound J ; 20(3): 861-870, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36065789

RESUMO

The advance in nursing care for stoma patients is a challenging issue, which will influence the life quality. The quality of life is a major issue in the recovery of stoma patients. The evidence of experimental nursing has not been explored enough. A systematic search and a meta-analysis were performed for the studies of experimental nursing interventions versus routine warming interventions on patients with a stoma. The comparisons between nursing interventions were performed to find which kind of intervention will be superior in improving life quality. After a restricted selection, 10 studies, 460 subjects with experimental nursing intervention, and 478 controls with the routine nursing intervention were enrolled in a variety of causes of the stoma. The focused outcome was the quality of life. The meta-analysis was performed by Review Manager 5.4. Among the stoma patients, the meta-analysis favours the experimental nursing intervention group with higher scores of life quality when compared to the routine nursing intervention group. The meta-analysis results were with positive mean differences, significant tests for overall effect, and significant heterogeneities in the random-effects model. The experimental nursing intervention showed higher positive effects on the quality of life when compared to routine nursing intervention for stoma patients. Experimental nursing intervention might be an option for stoma nursing practitioners to improve stoma care.


Assuntos
Qualidade de Vida , Estomas Cirúrgicos , Humanos
12.
Opt Lett ; 47(23): 6113-6116, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37219185

RESUMO

By rational design and parameter engineering of the TiO2-Pt core-satellite construction, visible light absorption in small Pt nanoparticles (NPs) can be enhanced by nearly 100 times. The TiO2 microsphere support works as the optical antenna, giving rise to superior performance compared to conventional plasmonic nanoantennas. A crucial step is to bury the Pt NPs completely in the high refractive index TiO2 microsphere, because light absorption in the Pt NP approximately scales with the fourth power of the refractive index of its surrounding media. The proposed evaluation factor for light absorption enhancement in the Pt NPs at different positions is proved to be valid and useful. The physics modeling of the buried Pt NPs corresponds to the general case in practice where the surface of the TiO2 microsphere is naturally rough or a thin TiO2 coating is subsequently added. These results offer new avenues for directly transforming dielectric supported nonplasmonic catalytic transition metals into visible light photocatalysts.

13.
Liver Int ; 42(10): 2283-2298, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35810457

RESUMO

BACKGROUND & AIMS: The multiplicity of hepatocellular carcinoma (HCC) recurrence patterns is the most important determinant of patients' postsurgical survival. A systematic HCC recurrence classification is needed to help prevent and treat postoperative HCC recurrence in the era of precision medicine. METHODS: A total of 1319 patients with recurrent HCC from four hospitals were enrolled and divided into a development cohort (n = 916), internal validation cohort (n = 225) and external validation cohort (n = 178). A comprehensive study of patients' clinicopathological factors and biological features was conducted. RESULTS: Four subtypes of recurrence were identified, which integrated recurrence features, survival, effects on systemic and liver function and potential therapeutics after recurrence: type I (solitary-intrahepatic oligorecurrence); type II (multi-intrahepatic oligorecurrence); type III (progression recurrence) and type IV (hyper-progression recurrence). Type III~IV recurrence indicated exceptionally poor prognosis. Subsequently, two nomogram models were established for type III~IV recurrence prediction, and both demonstrated excellent predictive performance and applicability of pre and postoperative strategy formulation. Multiple biological analyses revealed that HCC cases with type III~IV recurrence were characterized by enrichment in p53 mutations, CCND1 amplification, high proliferation/metastasis potential, inactive metabolism and immune exhaustion features. Over-expression of high mobility group protein 2 (HMGA2) enhanced the highly malignant behaviour of HCC through multiple molecular pathways, making it a potential prognostic predictor and therapeutic target. CONCLUSIONS: This 'recurrent HCC classification' has important potential value in identifying patients with surgical benefit, predicting postsurgical survival and guiding treatment strategies. Multidimensional biological insights also increased knowledge of factors associated with HCC recurrence.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Hepatectomia/métodos , Humanos , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Nomogramas , Prognóstico
14.
Cell Biol Toxicol ; 38(5): 741-763, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-33950334

RESUMO

Adipogenesis is a multi-step process orchestrated by activation of numerous TFs, whose cooperation and regulatory network remain elusive. Activating transcription factor 4 (ATF4) is critical for adipogenesis, yet its regulatory network is unclarified. Here, we mapped genome-wide ATF4 binding landscape and its regulatory network by Chip-seq and RNA-seq and found ATF4 directly modulated transcription of genes enriching in fat cell differentiation. Motifs of TFs especially CTCF were found from ATF4 binding sites, suggesting a direct role of ATF4 in regulating adipogenesis associated with CTCF and other TFs. Deletion of CTCF attenuated adipogenesis while overexpression enhanced adipocyte differentiation, indicating CTCF is indispensable for adipogenesis. Intriguingly, combined analysis of Chip-seq data of these two TFs showed that ATF4 co-localized with CTCF in the promoters of key adipogenic genes including Cebpd and PPARg and co-regulated their transactivation. Moreover, ATF4 directly regulated CTCF expression and interacted with CTCF in differentiated 3T3-L1 cells. In vivo, downregulation of ATF4 suppressed the expression of CTCF, Cebpd, and PPARg, leading to reduced adipose tissue expansion in refeeding mice. Consistently, mRNA expression of ATF4 and CTCF was positively correlated with each other in human subcutaneous adipose tissue and inversely associated with BMI, indicating a possible involvement of these two TFs in adipose development. Taken together, our data propose for the first time that ATF4 and CTCF work cooperatively to control adipogenesis and adipose development via orchestrating transcription of adipogenic genes. Our findings reveal novel therapeutic targets in obesity treatment.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Adipogenia , Fator de Ligação a CCCTC/metabolismo , Fator 4 Ativador da Transcrição/genética , Adipócitos/metabolismo , Adipogenia/genética , Animais , Diferenciação Celular/genética , Humanos , Camundongos , PPAR gama/genética , RNA Mensageiro/genética
15.
J Clin Lab Anal ; 35(5): e23754, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33813769

RESUMO

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease with varying clinical courses and responses to treatment. To improve the prognosis of patients, it is necessary to understand such heterogeneity. METHODS: We used single-sample gene set enrichment analysis to classify 35 MIBC cases into immunity-high and immunity-low groups. Bioinformatics analyses were conducted to compare the differences between these groups. Eventually, single-cell mass cytometry (CyTOF) was used to compare the characteristics of the immune microenvironment between the patients in the two groups. RESULTS: Compared with patients in the immunity-low group, patients in the immunity-high group had a higher number of tumor-infiltrating immune cells and greater enrichment of gene sets associated with antitumor immune activity. Furthermore, positive immune response-related pathways were more enriched in the immunity-high group. We identified 26 immune cell subsets, including cytotoxic T cells (Tcs), helper T cells (Ths), regulatory T cells (Tregs), B cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs) using CyTOF. Furthermore, there was a higher proportion of CD45+ lymphocytes and enrichment of one Tc subset in the immunity-high group. Additionally, M2 macrophages were highly enriched in the immunity-low group. Finally, there was higher expression of PD-1 and Tim-3 on Tregs as well as a higher proportion of PD-1+ Tregs in the immunity-low group than in the immunity-high group. CONCLUSION: In summary, the immune microenvironments of the immunity-high and immunity-low groups of patients with MIBC are heterogeneous. Specifically, immune suppression was observed in the immune microenvironment of the patients in the immunity-low group.


Assuntos
Citometria de Fluxo , Músculos/patologia , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem , Terapia de Imunossupressão , Invasividade Neoplásica , Microambiente Tumoral/genética
16.
Electrophoresis ; 41(1-2): 123-130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674686

RESUMO

A novel micro matrix solid phase dispersion method was successfully used for the extraction of quaternary alkaloids in Phellodendri chinensis cortex. The elution of target compounds was accomplished with sodium hexanesulfonate as the eluent solvent. A neutral ion pair was formed between ion-pairing reagent and positively charged alkaloids in this process, which was beneficial for selectively extraction of polar alkaloids. Several parameters were optimized and the optimal conditions were listed as follows: silica gel as the sorbent, silica to sample mass ratio of 1:1, the grinding time of 1 min. The exhaustive elution of targets was achieved by 200 µL methanol/water (9:1) containing 150 mM sodium hexane sulfonate at pH 4.5. The method validation covered linearity, recovery, precision of intraday and interday, limits of detection, limits of quantitation, and repeatability. This established method was rapid, simple, environmentally friendly, and highly sensitive.


Assuntos
Berberina , Medicamentos de Ervas Chinesas/química , Quinolizinas , Extração em Fase Sólida/métodos , Berberina/análise , Berberina/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Limite de Detecção , Modelos Lineares , Phellodendron/química , Plantas Medicinais/química , Quinolizinas/análise , Quinolizinas/isolamento & purificação , Reprodutibilidade dos Testes
17.
Theor Appl Genet ; 133(7): 2259-2269, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32347319

RESUMO

KEY MESSAGE: An InDel marker closely linked with a major and stable quantitative trait locus (QTL) on chromosome 4BS, QSnpa.cau-4B, controlling spike number per unit area will benefit wheat yield improvement. Spike number per unit area (SNPA) is an essential yield-related trait, and analyzing its genetic basis is important for cultivar improvement in wheat (Triticum aestivum L.). In this study, we used the F2 population derived from a cross between two wheat accessions displaying significant differences in SNPA to perform quantitative trait locus (QTL) analysis. Through bulked segregant analysis, a major and stable QTL that explained 18.11-82.11% of the phenotypic variation was identified on chromosome 4BS. The QTL interval was validated using F4:5 and F6:7 families and narrowed it to a 24.91-38.36 Mb region of chromosome 4BS according to the 'Chinese Spring' reference genome sequence. In this region, variations in 16 genes caused amino acid changes and three genes were present in only one parent. Among these, we annotated a gene orthologous to TB1 in maize (Zea mays), namely TraesCS4B01G042700, which carried a 44-bp deletion in its promoter in the higher-SNPA parent. An InDel marker based on the insertion/deletion polymorphism was designed and used to diagnose the allelic distribution within a natural population. The frequency of the 44-bp deletion allele associated with higher SNPA was relatively low (13.24%), implying that this favorable allele has not been widely utilized and could be valuable for wheat yield improvement. In summary, we identified a major and stable QTL for SNPA and developed a diagnostic marker for the more-spiked trait, which will be beneficial for molecular-assisted breeding in wheat.


Assuntos
Cromossomos de Plantas , Genes de Plantas , Locos de Características Quantitativas , Triticum/genética , Alelos , Mapeamento Cromossômico , Cruzamentos Genéticos , Ligação Genética , Marcadores Genéticos , Fenótipo , Melhoramento Vegetal
18.
J Clin Lab Anal ; 34(5): e23155, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31855296

RESUMO

BACKGROUND: Renal tumors are highly heterogeneous, and identification of tumor heterogeneity is an urgent clinical need for effective treatment. Mass cytometry (MC) can be used to perform high-dimensional single-cell proteomics analysis of heterogeneous samples via cytometry by time-of-flight (CyTOF), in order to achieve more accurate observation and classification of phenotypes within a cell population. This study aimed to develop a high-dimensional MC method for the detection and analysis of heterogeneity in renal tumors. MATERIALS AND METHODS: We collected tissue samples from 8 patients with different types of renal tumors. Single-cell suspensions were prepared and stained using a panel of 28 immune cell-centric antibodies and a panel of 21 stem-like cell-centric antibodies. The stained cells were detected using CyTOF. RESULT: Renal tumors were divided into 25 immune cell subsets (4 CD4+ T cells, 7 CD8+ T cells, 1 B cells, 8 macrophages, 1 dendritic cells, 2 natural killer (NK) cells, 1 granulocyte, and 1 other subset) and 7 stem-like cells subsets (based on positivity of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47). Different types of renal tumors have different cell subsets with significantly different characteristics. CONCLUSION: High-dimensional single-cell proteomics analysis using MC aids in the discovery and analysis of renal tumors heterogeneity. Additionally, it can be used to accurately classify the immune cell population and analyze the expression of stem cell-related markers in renal tumors. Our findings provide a valuable resource for deciphering tumor heterogeneity and might improve the clinical management of patients with renal tumors.


Assuntos
Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Análise de Célula Única/métodos , Antígenos CD/análise , Antígenos CD/metabolismo , Linfócitos B/imunologia , Linfócitos B/patologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Granulócitos/imunologia , Granulócitos/patologia , Humanos , Imunofenotipagem/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células-Tronco Neoplásicas/patologia , Proteômica/métodos
19.
J Asian Nat Prod Res ; 22(9): 879-885, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31535572

RESUMO

A new bile acid tauro-16ß-hydroxy-12α-sulfate-5ß-cholenoic acid (1), along with six known ones (2-7), was isolated from the snake bile. Its planar structure and relative configuration were elucidated based on extensive spectroscopic analyses. Moreover, compound 2 showed inhibitory effect on NO production in RAW 264.7 macrophages at non-cytotoxic concentration (20 µM) with inhibitory rate of 69.7%. [Formula: see text].


Assuntos
Bile , Medicina Tradicional Chinesa , Ácidos e Sais Biliares , Estrutura Molecular
20.
Mol Cell ; 42(6): 758-70, 2011 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-21636303

RESUMO

Endoplasmic reticulum-associated degradation (ERAD) employs membrane-bound ubiquitin ligases and the translocation-driving ATPase p97 to retrotranslocate misfolded proteins for proteasomal degradation. How retrotranslocated polypeptides bearing exposed hydrophobic motifs or transmembrane domains (TMDs) avoid aggregation before reaching the proteasome is unclear. Here we identify a ubiquitin ligase-associated multiprotein complex comprising Bag6, Ubl4A, and Trc35, which chaperones retrotranslocated polypeptides en route to the proteasome to improve ERAD efficiency. In vitro, Bag6, the central component of the complex, contains a chaperone-like activity capable of maintaining an aggregation-prone substrate in an unfolded yet soluble state. The physiological importance of this holdase activity is underscored by observations that ERAD substrates accumulate in detergent-insoluble aggregates in cells depleted of Bag6, or of Trc35, a cofactor that keeps Bag6 outside the nucleus for engagement in ERAD. Our results reveal a ubiquitin ligase-associated holdase that maintains polypeptide solubility to enhance protein quality control in mammalian cells.


Assuntos
Retículo Endoplasmático/metabolismo , Chaperonas Moleculares/metabolismo , Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células HEK293 , Humanos , Chaperonas Moleculares/genética , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Solubilidade , Proteínas Virais/metabolismo
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