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1.
Nat Immunol ; 20(7): 835-851, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31160797

RESUMEN

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.


Asunto(s)
Presentación de Antígeno/inmunología , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/inmunología , Oncogenes , ARN Largo no Codificante/genética , Escape del Tumor/genética , Escape del Tumor/inmunología , Adenoma/genética , Adenoma/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitinación , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Mol Cell ; 82(8): 1528-1542.e10, 2022 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-35245436

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Aminoácidos Esenciales/metabolismo , Aminoácidos Esenciales/farmacología , Aminoácidos Esenciales/uso terapéutico , Animales , Dieta Alta en Grasa/efectos adversos , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Ubiquitinación
3.
Proc Natl Acad Sci U S A ; 121(21): e2319519121, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38753508

RESUMEN

Transforming smallholder farms is critical to global food security and environmental sustainability. The science and technology backyard (STB) platform has proved to be a viable approach in China. However, STB has traditionally focused on empowering smallholder farmers by transferring knowledge, and wide-scale adoption of more sustainable practices and technologies remains a challenge. Here, we report on a long-term project focused on technology scale-up for smallholder farmers by expanding and upgrading the original STB platform (STB 2.0). We created a formalized and standardized process by which to engage and collaborate with farmers, including integrating their feedback via equal dialogues in the process of designing and promoting technologies. Based on 288 site-year of field trials in three regions in the North China Plain over 5 y, we find that technologies cocreated through this process were more easily accepted by farmers and increased their crop yields and nitrogen factor productivity by 7.2% and 28.1% in wheat production and by 11.4% and 27.0% in maize production, respectively. In promoting these technologies more broadly, we created a "one-stop" multistakeholder program involving local government agencies, enterprises, universities, and farmers. The program was shown to be much more effective than the traditional extension methods applied at the STB, yielding substantial environmental and economic benefits. Our study contributes an important case study for technology scale-up for smallholder agriculture. The STB 2.0 platform being explored emphasizes equal dialogue with farmers, multistakeholder collaboration, and long-term investment. These lessons may provide value for the global smallholder research and practitioners.


Asunto(s)
Agricultura , China , Agricultura/métodos , Agricultores , Humanos , Productos Agrícolas/crecimiento & desarrollo , Conducta Cooperativa , Zea mays/crecimiento & desarrollo , Desarrollo Sostenible , Conservación de los Recursos Naturales/métodos , Triticum/crecimiento & desarrollo , Producción de Cultivos/métodos
4.
Development ; 150(11)2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37260148

RESUMEN

Evolutionarily conserved Notch signaling is highly sensitive to changes in Notch receptor dose caused by intrinsic and environmental fluctuations. It is well known that epigenetic regulation responds dynamically to genetic, cellular and environmental stresses. However, it is unclear whether the Notch receptor dose is directly regulated at the epigenetic level. Here, by studying the role of the upstream epigenetic regulator Stuxnet (Stx) in Drosophila developmental signaling, we find that Stx promotes Notch receptor mRNA expression by counteracting the activity of Polycomb repressive complex 1 (PRC1). In addition, we provide evidence that Notch is a direct PRC1 target by identifying and validating in vivo the only bona fide Polycomb response element (PRE) among the seven Polycomb group (PcG)-binding sites revealed by DamID-seq and ChIP-seq analysis. Importantly, in situ deletion of this PRE results in increased Notch expression and phenotypes resembling Notch hyperactivation in cell fate specification. These results not only underscore the importance of epigenetic regulation in fine-tuning the Notch activity dose, but also the need to assess the physiological significance of omics-based PcG binding in development.


Asunto(s)
Proteínas de Drosophila , Epigénesis Genética , Animales , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Elementos de Respuesta/genética , Receptores Notch/genética , Receptores Notch/metabolismo
5.
Nat Methods ; 20(3): 448-458, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36797410

RESUMEN

Stimulated Raman scattering (SRS) offers the ability to image metabolic dynamics with high signal-to-noise ratio. However, its spatial resolution is limited by the numerical aperture of the imaging objective and the scattering cross-section of molecules. To achieve super-resolved SRS imaging, we developed a deconvolution algorithm, adaptive moment estimation (Adam) optimization-based pointillism deconvolution (A-PoD) and demonstrated a spatial resolution of lower than 59 nm on the membrane of a single lipid droplet (LD). We applied A-PoD to spatially correlated multiphoton fluorescence imaging and deuterium oxide (D2O)-probed SRS (DO-SRS) imaging from diverse samples to compare nanoscopic distributions of proteins and lipids in cells and subcellular organelles. We successfully differentiated newly synthesized lipids in LDs using A-PoD-coupled DO-SRS. The A-PoD-enhanced DO-SRS imaging method was also applied to reveal metabolic changes in brain samples from Drosophila on different diets. This new approach allows us to quantitatively measure the nanoscopic colocalization of biomolecules and metabolic dynamics in organelles.


Asunto(s)
Microscopía , Espectrometría Raman , Microscopía/métodos , Espectrometría Raman/métodos , Proteínas/metabolismo , Lípidos
6.
Planta ; 259(5): 106, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38554181

RESUMEN

MAIN CONCLUSION: The up-regulation of OsmiR5519 results in the decrease of grain size, weight and seed setting rate. OsmiR5519 plays important roles in the process of grain filling and down-regulates sucrose synthase gene RSUS2. MicroRNAs (miRNAs) are one class of small non-coding RNAs that act as crucial regulators of plant growth and development. In rice, the conserved miRNAs were revealed to regulate the yield components, but the function of rice-specific miRNAs has been rarely studied. The rice-specific OsmiR5519 was found to be abundantly expressed during reproductive development, but its biological roles remain unknown. In this study, the function of rice-specific OsmiR5519 was characterized with the miR5519-overexpressing line (miR5519-OE) and miR5519-silenced line (STTM5519). At seedling stage, the content of sucrose, glucose and fructose was obviously lower in the leaves of miR5519-OE lines than those of wild-type (WT) line. The grain size and weight were decreased significantly in miR5519-OE lines, compared to those of WT rice. The cell width of hull in miR5519-OE was smaller than that in WT. The seed setting rate was notably reduced in miR5519-OE lines, but not in STTM5519 lines. Cytological observation demonstrated that the inadequate grain filling was the main reason for the decline of seed setting rate in miR5519-OE lines. The percentage of the defects of grain amounted to 40% in miR5519-OE lines, which almost equaled to the decreased value of seed setting rate. Furthermore, the sucrose synthase gene RSUS2 was identified as a target of OsmiR5519 via RNA ligase-mediated 3'-amplification of cDNA ends (3'-RLM-RACE), dual luciferase assays and transient expression assays. In summary, our results suggest that OsmiR5519 regulates grain size and weight and down-regulates RSUS2 in rice.


Asunto(s)
Glucosiltransferasas , MicroARNs , Oryza , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Grano Comestible , Semillas , MicroARNs/genética , MicroARNs/metabolismo , Regulación de la Expresión Génica de las Plantas
7.
Microb Pathog ; 192: 106703, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38763315

RESUMEN

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.


Asunto(s)
Proteínas Bacterianas , Trampas Extracelulares , Neutrófilos , Infecciones Estreptocócicas , Streptococcus equi , Factores de Virulencia , Animales , Ratones , Neutrófilos/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Streptococcus equi/genética , Streptococcus equi/inmunología , Infecciones Estreptocócicas/inmunología , Infecciones Estreptocócicas/microbiología , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Ratones Noqueados , Proteínas Recombinantes/genética , Inmunidad Innata , Ratones Endogámicos C57BL , Gasderminas , Proteínas de Unión a Fosfato
8.
J Magn Reson Imaging ; 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38958118

RESUMEN

Intracardiac blood flow has long been proposed to play a significant role in cardiac morphology and function. However, absolute blood pressure within the heart has mainly been measured by invasive catheterization, which limits its application. Hemodynamic force (HDF) is the global force of intracavitary blood flow acquired by integrating the intraventricular pressure gradient over the entire ventricle and thus may be a promising tool for accurately characterizing cardiac function. Recent advances in magnetic resonance imaging technology allow for a noninvasive measurement of HDF through both 4D flow cardiac MRI and cine cardiac MRI. The HDF time curve provides comprehensive data for both qualitative and quantitative analysis. In this review, a series of HDF parameters is introduced and a summary of the current literature regarding HDF in clinical practice is presented. Additionally, the current dilemmas and future prospects are discussed in order to contribute to the future research. LEVEL OF EVIDENCE: 5. TECHNICAL EFFICACY: Stage 2.

9.
Langmuir ; 40(26): 13412-13421, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38900137

RESUMEN

Solar steam generation (SSG) is regarded as an efficient approach for harnessing solar energy to purify polluted or saline water. Herein, we demonstrate a hydrogel composed of cellulose nanofibers (CNFs), polyethylenimine (PEI), and reduced graphene oxide (rGO) that functions as an independent solar steam generator, which shows enhanced solar water evaporation efficiency by incorporating silver nanoparticles (AgNPs). It presented that the presence of AgNPs increases the photothermal conversion efficiency and thermal conductivity of the evaporator and reduces the enthalpy of evaporation. As a result, an outstanding water evaporation rate of 3.62 kg m-2 h-1 and a photothermal conversion efficiency of 96.25% are successfully obtained under one sun illumination. Also, the resulting hydrogel exhibits exceptional mechanical properties, as well as outstanding desalination and salt-resistant abilities during prolonged seawater desalination. In oil/water mixtures, the evaporation of the hydrogel decreases to 2.94 kg m-2 h-1, owing to the oil layer barrier. This work paves a reference approach to produce easily addressed cellulose nanofiber (CNF)-based hydrogel evaporators with significantly enhanced evaporation rates.

10.
Inflamm Res ; 73(1): 35-46, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38147125

RESUMEN

OBJECTIVE: Here, we explored the phenotype and function of MAIT cells in the peripheral blood of patients with HSP. METHODS: Blood samples from HSP patients and HDs were assessed by flow cytometry and single-cell RNA sequencing to analyze the proportion, phenotype, and function of MAIT cells. Th-cytokines in the serum of HSP patients were analyzed by CBA. IgA in cocultured supernatant was detected by CBA to analyze antibody production by B cells. RESULTS: The percentage of MAIT cells in HSP patients was significantly reduced compared with that in HDs. Genes related to T cell activation and effector were up-regulated in HSP MAIT cells, indicating a more activated phenotype. In addition, HSP MAIT cells displayed a Th2-like profile with the capacity to produce more IL-4 and IL-5, and IL-4 was correlated with IgA levels in the serum of HSP patients. Furthermore, CD40L was up-regulated in HSP MAIT cells, and CD40L+ MAIT cells showed an increased ability to produce IL-4 and to enhance IgA production by B cells. CONCLUSION: Our data demonstrate that MAIT cells in HSP patients exhibit an activated phenotype. The enhanced IL-4 production and CD40L expression of MAIT cells in HSP patients could take part in the pathogenesis of HSP.


Asunto(s)
Vasculitis por IgA , Células T Invariantes Asociadas a Mucosa , Humanos , Formación de Anticuerpos , Ligando de CD40 , Inmunoglobulina A , Interleucina-4
11.
Int J Mol Sci ; 25(5)2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38474039

RESUMEN

Ascidian larvae undergo tail elongation and notochord lumenogenesis, making them an ideal model for investigating tissue morphogenesis in embryogenesis. The cellular and mechanical mechanisms of these processes have been studied; however, the underlying molecular regulatory mechanism remains to be elucidated. In this study, assays for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were applied to investigate potential regulators of the development of ascidian Ciona savignyi larvae. Our results revealed 351 and 138 differentially accessible region genes through comparisons of ATAC-seq data between stages 21 and 24 and between stages 24 and 25, respectively. A joint analysis of RNA-seq and ATAC-seq data revealed a correlation between chromatin accessibility and gene transcription. We further verified the tissue expression patterns of 12 different genes. Among them, Cs-matrix metalloproteinase 24 (MMP24) and Cs-krüppel-like factor 5 (KLF5) were highly expressed in notochord cells. Functional assay results demonstrated that both genes are necessary for notochord lumen formation and expansion. Finally, we performed motif enrichment analysis of the differentially accessible regions in different tailbud stages and summarized the potential roles of these motif-bearing transcription factors in larval development. Overall, our study found a correlation between gene expression and chromatin accessibility and provided a vital resource for understanding the mechanisms of the development of ascidian embryos.


Asunto(s)
Ciona , Urocordados , Animales , Cromatina , Urocordados/genética , Secuenciación de Inmunoprecipitación de Cromatina , Morfogénesis , Factores de Transcripción/genética
12.
Molecules ; 29(3)2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38338486

RESUMEN

Egg white proteins pose notable limitations in emulsion applications due to their inadequate wettability and interfacial instability. Polyphenol-driven alterations in proteins serve as an effective strategy for optimizing their properties. Herein, covalent and non-covalent complexes of egg white proteins-proanthocyanins were synthesized. The analysis of structural alterations, amino acid side chains and wettability was performed. The superior wettability (80.00° ± 2.23°) and rigid structure (2.95 GPa) of covalent complexes established favorable conditions for their utilization in emulsions. Furthermore, stability evaluation, digestion kinetics, free fatty acid (FFA) release kinetics, and correlation analysis were explored to unravel the impact of covalent and non-covalent modification on emulsion stability, dynamic digestion process, and interlinkages. Emulsion stabilized by covalent complex exhibited exceptional stabilization properties, and FFA release kinetics followed both first-order and Korsmeyer-Peppas models. This study offers valuable insights into the application of complexes of proteins-polyphenols in emulsion systems and introduces an innovative approach for analyzing the dynamics of the emulsion digestion process.


Asunto(s)
Digestión , Ácidos Grasos no Esterificados , Emulsiones/química , Ácidos Grasos no Esterificados/metabolismo , Proteínas del Huevo , Tamaño de la Partícula
13.
J Am Chem Soc ; 145(47): 25664-25672, 2023 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-37921495

RESUMEN

Polymeric spherulites are typically formed by melt crystallization: spherulitic growth in solution is rare and requires complex polymers and dilute solutions. Here, we report the mild and unique formation of luminescent spherulites at room temperature via the simple molecule benzene-1,4-dithiol (BDT). Specifically, BDT polymerized into oligomers (PBDT) via disulfide bonds and assembled into uniform supramolecular nanoparticles in aqueous buffer; these nanoparticles were then dissolved back into PBDT in a good solvent (i.e., dimethylformamide) and underwent chain elongation to form spherulites (rPBDT) in 10 min. The spherulite geometry was modulated by changing the PBDT concentration and reaction time. Due to the step-growth polymerization and reorganization of PBDT, these spherulites not only exhibited robust structure but also showed broad clusterization-triggered emission. The biocompatibility and efficient cellular uptake of the spherulites further underscore their value as traceable drug carriers. This system provides a new pathway for designing versatile superstructures with value for hierarchical assembly of small molecules into a complicated biological system.


Asunto(s)
Nanopartículas , Polímeros , Cristalización , Polímeros/química , Congelación
14.
Small ; : e2305875, 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-38054799

RESUMEN

Synthetic hydrogel strain sensors rarely exhibit a comprehensive combination of mechanical properties such as ultra-stretchability, ultrafast self-healing, and high sensitivity. Herein, seven small molecule enhanced mechanical behaviors of polymer-cluster based hydrogels are demonstrated. The oxidized polyethyleneimine/polymeric acrylic acid (ohPEI/PAA) hydrogels with aromatic formic acids as supramolecular cross-linkers are prepared by simultaneous formation of ohPEI polymer clusters and PAA upon the addition of ammonium persulfate. The optimized hydrogel adhesive exhibits comprehensive excellent properties, such as high extensibility (up to 12 298%), real-time mechanical self-healing capability (<1 s, 93% efficiency), high uniformity, underwater adhesivity, and water-sealing ability. The proper binding strength of hydrogel and skin (47 kPa) allows the hydrogel to be utilized as highly sensitive (gauge factor:16.08), highly conductive (2.58 mS cm-1 ), and underwater strain sensors. Specially, the adhesive strength of the adhesive to wood after dehydration is extremely high, reaching up to 29.59 MPa. Additionally, when glycerol is introduced, the obtained gel maintains the physical properties even at harsh-temperature conditions (-40 to 80 °C). It presents that multiple and hierarchical non-covalent interactions including multiple hydrogen bonding interactions, π-π stacking, electrostatic interactions, and dipole-dipole interactions of polymer clusters, allow for the energy dissipation and contribute to the excellent performance of the hydrogel.

15.
Acc Chem Res ; 55(19): 2833-2847, 2022 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-36121350

RESUMEN

Magnetic resonance imaging (MRI) is a clinical imaging modality that provides high-resolution images of soft tissues, including cancerous lesions. Stable gadolinium(III) chelates have been used as contrast agents (CA) in MRI to enhance the contrast between the tissues of interest and surrounding tissues for accurate diagnostic imaging. Magnetic resonance molecular imaging (MRMI) of cancer requires targeted CA to specifically elucidate cancer-associated molecular processes and can provide high-resolution delineation and characterization of cancer for precision medicine. The main challenge for MRMI is the lack of sufficient sensitivity to detect the low concentration of the cellular oncogenic markers. In addition, targeted CA must satisfy regulatory safety requirements prior to clinical development. Up to now, there is no FDA-approved targeted CA for MRMI of cancer.In this Account, we discuss the latest developments in the design and development of clinically translatable targeted CA for MRMI of cancer, with an emphasis on our own research. The primary limitation of MRMI can be overcome by designing small molecular targeted CA to target abundant cancer-specific targets found in the tumor microenvironment (TME). For example, aggressive tumors have a unique extracellular matrix (ECM) composed of oncoproteins, which can be used as targetable markers for MRMI. We have designed and prepared small peptide conjugates of clinical contrast agents, including Gd-DTPA and Gd-DOTA, to target fibrin-fibronectin clots in tumors. These small molecular CA have been effective in enhancing MRMI detection of solid tumors and have demonstrated the ability to detect submillimeter cancer micrometastases in mouse tumor models, exceeding the detection limit of current clinical imaging modalities. We have also identified extradomain B fibronectin (EDB-FN), an oncofetal subtype of fibronectin, as a promising TME target to leverage in the design and development of small peptide targeted CA for clinical translation. The expression level of EDB-FN is correlated with invasiveness of cancer cells and poor patient survival of multiple cancer types. ZD2 peptide with a sequence of seven amino acids (TVRTSAD) was identified to specifically bind to the EDB protein fragment. Several ZD2 conjugates of macrocyclic GBCA, including Gd-DOTA and Gd(HP-DO3A), have been synthesized and tested in mouse tumor models. ZD2-N3-Gd(HP-DO3A) (MT218) with a high r1 relaxivity was selected as the lead agent for clinical translation. The physicochemical properties and preclinical assessments of MT218 are summarized in this Account. MRMI of EDB-FN with MT218 can effectively detect invasive tumors of multiple cancers with risk-stratification and monitor tumor response to anticancer therapies in mouse models. Currently, MT218 is in clinical trials for precision cancer MRMI. Herein, we will show that using targeted MRI contrast agents specific to abundant TME biomarkers is a pragmatic solution for effective precision cancer imaging in high spatial resolution. And thus, we illustrate a replicable approach for CA development that is vital for cancer MRMI.


Asunto(s)
Gadolinio , Neoplasias , Aminoácidos , Animales , Medios de Contraste/química , Fibrina , Fibronectinas/metabolismo , Gadolinio/química , Gadolinio DTPA , Compuestos Heterocíclicos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética , Ratones , Imagen Molecular/métodos , Neoplasias/diagnóstico por imagen , Proteínas Oncogénicas , Compuestos Organometálicos , Péptidos , Microambiente Tumoral
16.
Cardiovasc Diabetol ; 22(1): 216, 2023 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-37592255

RESUMEN

BACKGROUND: Myocardial microvascular injury is the key event in early diabetic heart disease. The injury of myocardial microvascular endothelial cells (CMECs) is the main cause and trigger of myocardial microvascular disease. Mitochondrial calcium homeostasis plays an important role in maintaining the normal function, survival and death of endothelial cells. Considering that mitochondrial calcium uptake 1 (MICU1) is a key molecule in mitochondrial calcium regulation, this study aimed to investigate the role of MICU1 in CMECs and explore its underlying mechanisms. METHODS: To examine the role of endothelial MICU1 in diabetic cardiomyopathy (DCM), we used endothelial-specific MICU1ecKO mice to establish a diabetic mouse model and evaluate the cardiac function. In addition, MICU1 overexpression was conducted by injecting adeno-associated virus 9 carrying MICU1 (AAV9-MICU1). Transcriptome sequencing technology was used to explore underlying molecular mechanisms. RESULTS: Here, we found that MICU1 expression is decreased in CMECs of diabetic mice. Moreover, we demonstrated that endothelial cell MICU1 knockout exacerbated the levels of cardiac hypertrophy and interstitial myocardial fibrosis and led to a further reduction in left ventricular function in diabetic mice. Notably, we found that AAV9-MICU1 specifically upregulated the expression of MICU1 in CMECs of diabetic mice, which inhibited nitrification stress, inflammatory reaction, and apoptosis of the CMECs, ameliorated myocardial hypertrophy and fibrosis, and promoted cardiac function. Further mechanistic analysis suggested that MICU1 deficiency result in excessive mitochondrial calcium uptake and homeostasis imbalance which caused nitrification stress-induced endothelial damage and inflammation that disrupted myocardial microvascular endothelial barrier function and ultimately promoted DCM progression. CONCLUSIONS: Our findings demonstrate that MICU1 expression was downregulated in the CMECs of diabetic mice. Overexpression of endothelial MICU1 reduced nitrification stress induced apoptosis and inflammation by inhibiting mitochondrial calcium uptake, which improved myocardial microvascular function and inhibited DCM progression. Our findings suggest that endothelial MICU1 is a molecular intervention target for the potential treatment of DCM.


Asunto(s)
Proteínas de Unión al Calcio , Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Proteínas de Transporte de Membrana Mitocondrial , Animales , Ratones , Calcio , Dependovirus , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/prevención & control , Células Endoteliales , Inflamación
17.
J Vasc Res ; 60(4): 234-244, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37643584

RESUMEN

INTRODUCTION: Culturing cerebrovascular smooth muscle cells (CVSMCs) in vitro can provide a model for studying many cerebrovascular diseases. This study describes a convenient and efficient method to obtain mouse CVSMCs by enzyme digestion. METHODS: Mouse circle of Willis was isolated, digested, and cultured with platelet-derived growth factor-BB (PDGF-BB) to promote CVSMC growth, and CVSMCs were identified by morphology, immunofluorescence analysis, and flow cytometry. The effect of PDGF-BB on vascular smooth muscle cell (VSMC) proliferation was evaluated by cell counting kit (CCK)-8 assay, morphological observations, Western blotting, and flow cytometry. RESULTS: CVSMCs cultured in a PDGF-BB-free culture medium had a typical peak-to-valley growth pattern after approximately 14 days. Immunofluorescence staining and flow cytometry detected strong positive expression of the cell type-specific markers alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain 11 (SMMHC), smooth muscle protein 22 (SM22), calponin, and desmin. In the CCK-8 assay and Western blotting, cells incubated with PDGF-BB had significantly enhanced proliferation compared to those without PDGF-BB. CONCLUSION: We obtained highly purified VSMCs from the mouse circle of Willis using simple methods, providing experimental materials for studying the pathogenesis and treatment of neurovascular diseases in vitro. Moreover, the experimental efficiency improved with PDGF-BB, shortening the cell cultivation period.


Asunto(s)
Círculo Arterial Cerebral , Músculo Liso Vascular , Animales , Ratones , Becaplermina/farmacología , Becaplermina/metabolismo , Proteínas Proto-Oncogénicas c-sis/farmacología , Proteínas Proto-Oncogénicas c-sis/metabolismo , Músculo Liso Vascular/metabolismo , Células Cultivadas , Proliferación Celular , Miocitos del Músculo Liso/metabolismo , Movimiento Celular
18.
Microb Pathog ; 184: 106336, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37683832

RESUMEN

Pasteurella multocida.(PM) infection is a major cause of avian cholera, but the pathogenesis of the disease is unknown. The purpose of this study was to further understand the host response to infection by using a duck model of PM, 20 female ducks were divided into two groups (n = 10). One group was infected with PM, while the other served as an uninfected control group. The ducks were observed after infection and samples were collected for testing. In this study, we report the mechanism of PM-induced inflammation to further mediate apoptosis and autophagic signaling pathways in liver cells. Our results demonstrated that PM infection initially induces hemorrhagic and necrotic lesions in the liver tissue of duck, promoting inflammasome assembly and release, triggering inflammation. The TLR4/NF-κB axis activated and interacted with multiple inflammation-related proteins, including TNF-α and IL-1ß, which affected apoptosis and autophagy. Tumor necrosis factor induced hepatocyte apoptosis was implicated in a wide range of liver diseases; the release of TNF-α and activation with NF-κB further incite apoptotic pathways,such as Bax/BCL2/caspase to promote apoptotic genes APAF1, Bax, Caspase3, BCL-2, p53, and Cytc expression. Finally, PM-induced autophagy suppressed liver injury by promoting the Beclin-1, LC3B, p62, and mTOR. Thus, liver injury caused by PM via promoting autophagy was induced. In conclusion, we analyzed the liver injury of ducks infected with PM, and confirmed that inflammation appeared in the liver; this was followed by the intricate interplay between inflammation, apoptosis, and autophagy signaling pathways. The observed results provided a reference basis for studying pathogenic mechanisms of PM-host interactions.


Asunto(s)
Pasteurella multocida , Animales , Femenino , Pasteurella multocida/metabolismo , Patos , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa , Proteína X Asociada a bcl-2 , Hígado/patología , Inflamación/patología , Autofagia , Apoptosis
19.
Chemistry ; 29(10): e202203108, 2023 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-36401597

RESUMEN

Due to the limited resources and high cost of noble metals, boosting their catalytic activities is highly desired in the current catalysis industry. Here, we report a synergetic catalyst, combining Pd2+ and Pd0 species in a nitrogen-doped porous carbons (NPC), which shows boosted catalytic activities in hydrogenation reactions of organic nitro compounds (nitrobenzene, 4-nitrophenol, 1-nitronaphthalene and 1-nitropropane) under near ambient conditions. This synergetic catalyst NPC-[Pd] was synthesized by partial reduction of a palladium-loaded NPC. The catalytic activities and selectivity of NPC-[Pd] for hydrogenation were enhanced significantly compared with those of NPC-Pd2+ or NPC-Pd0 nanoparticles. Theoretical calculations show that H2 preferentially dissociates on Pd nanoparticles, and then organic molecules (nitrobenzene) can be captured and react with the dissociated H atom on Pd2+ sites. Similar reaction procedure also occur on Pt or Rh. Hydrogenation of different aromatic compounds with different functional groups (naphthalene, 4-nitrochlorobenzene, benzaldehyde and acetophenone) confirmed the broad excellent catalytic activity of this synergistic catalyst.

20.
Inorg Chem ; 62(5): 2105-2115, 2023 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-36705439

RESUMEN

A huge amount of data inundated in our daily life; there is an ever-increasing need to develop a new strategy of information encryption-decryption-erasing. Herein, a polymeric DCTpy/PAM hydrogel has been fabricated to store information via controllable Eu3+/Zn2+ ionoprinting for hierarchical and multidimensional information decryption. Eu3+ and Zn2+ have a competition and dynamic interaction toward DCTpy under NH3 stimuli in the polymeric DCTpy/PAM hydrogel network. The Eu(III)/Zn(II)@DCTpy/PAM hydrogel exhibits light red fluorescence of Eu3+ due to the antenna effect. Upon the addition of NH3, dissociation of the Eu3+-DCTpy complex takes place, and the Zn(II)/DCTpy/NH3 complex is formed with both ICT (intramolecular charge-transfer) and PET (photo-induced electron-transfer) process characteristics that exhibits yellow emission color. Subsequently, HCl can quench the fluorescence of the resulting hydrogel. By integrating transparency, adhesiveness, and programmable stimuli responsiveness of the hydrogel blocks in to one system, complex, multistage, and time-controlled information storage-encryption-decryption-erasing in sequence with multidimensions is illustrated via the molecule diffusion method. This work provides a novel and representative strategy in fabricating information encryption-decryption-erasing materials with high capacity and complexity by a simple terpyridine-based hydrogel.

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